Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1097/HS9.0000000000000899

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Publishing type：Research paper (scientific journal)   Publisher：Informa UK Limited  

DOI： 10.1080/16078454.2022.2052601

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Smoking is associated with a high risk for different diseases including respiratory tract infections in immunocompetent patients. However, data about the effects of cigarette smoking on the outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) are limited. Therefore, we retrospectively investigated 608 patients aged ≥20 years with hematological disorders who received their first allo-HSCT at our group of hospitals between 2000 and 2015, and evaluated the impact of cigarette smoking before allo-HSCT on clinical outcomes by dividing patients into two groups according to the Brinkman index (BI) (nonsmokers or light smokers [BI: 0-500] and heavy smokers [BI: ≥ 500]). Multivariate analyses showed that heavy smoking was associated with a high 5-year cumulative incidence of chronic graft-versus-host disease (cGVHD) (hazard ratio [HR]: 1.73, 95% confidence interval [CI]: 1.15-2.61, p < 0.01). The 5-year overall survival (HR: 1.16, 95% CI: 0.86-1.58, p = 0.33) and disease-free survival (HR: 1.12, 95% CI: 0.83-1.52, p = 0.45) were similar between the two groups. Hence, cigarette smoking is correlated with cGVHD, although prospective studies must be conducted to further verify this result.

DOI： 10.1038/s41409-022-01678-7

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The efficacy and clinical significance of pre-conditioning intervention (PCI) before allogeneic hematopoietic cell transplantation (HCT) in patients with acute lymphoblastic leukemia (ALL) not in remission remain inconclusive. The purpose of this multicenter retrospective study was to clarify the clinical significance of PCI before HCT in patients with non-remission ALL. Patients with non-remission ALL who received HCT between 2005 and 2015 at 16 institutions were included. PCI was objectively defined and classified to three groups according to the intensity of PCI (no, intensive, or moderate). The study cohort consisted of 104 patients with a median age of 38 (range 17-68). A significant decrease of blast percentage in the peripheral blood (PB) was confirmed in both PCI groups, suggesting that PCIs were effective to stabilize the disease activity. The group with moderate PCI had higher nucleated cell count in the BM compared to the group with intensive PCI or the group without PCI. The overall survival (OS) rates of groups with intensive and no PCI showed comparable and significantly better compared to the group with moderate PCI (P = 0.009). Multivariate analysis demonstrated that the OS of moderate PCI group was significantly worse compared to that of intensive PCI group (HR = 2.43, 95% CI: 1.32-4.14, P = 0.004), while the OS of intensive PCI group was comparable to that of the group without PCI. These results suggest that the intensity of PCI rather than the response to PCI may contribute to improve the transplant outcome in patients with ALL not in remission.

DOI： 10.1007/s00277-021-04607-8

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Chronic myeloid leukemia (CML) is a form of myeloproliferative neoplasm caused by the oncogenic tyrosine kinase BCR-ABL. Although tyrosine kinase inhibitors have dramatically improved the prognosis of patients with CML, several problems such as resistance and recurrence still exist. Immunological control may contribute to solving these problems, and it is important to understand why CML patients fail to spontaneously develop anti-tumor immunity. Here, we show that differentiation of conventional dendritic cells (cDCs), which are vital for anti-tumor immunity, is restricted from an early stage of hematopoiesis in CML. In addition, we found that monocytes and basophils, which are increased in CML patients, express high levels of PD-L1, an immune checkpoint molecule that inhibits T cell responses. Moreover, RNA-sequencing analysis revealed that basophils express genes related to poor prognosis in CML. Our data suggest that BCR-ABL not only disrupts the "accelerator" (i.e., cDCs) but also applies the "brake" (i.e., monocytes and basophils) of anti-tumor immunity, compromising the defense against CML cells.

DOI： 10.1038/s41598-021-97371-8

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Molecular relapse after allogeneic hematopoietic cell transplantation (allo-HCT) has been thought to predict clinical relapse in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (PhALL). Tyrosine kinase inhibitor (TKI) administration after allo-HCT may dynamically change the status from molecular relapse to molecular remission, but these state changes cannot be accurately represented by conventional survival indicators such as relapse-free survival, where events are usually considered irreversible. We aimed to develop novel indicators of transplant outcomes for allo-HCT recipients with PhALL and to visualize current molecular-relapse-free survival (CMRFS) and current on-TKI status (CTKI), treating molecular relapse or TKI administration after allo-HCT as a reversible event. We retrospectively analyzed 286 patients with PhALL who received allo-HCT between 2000 and 2016 in order to develop the indicators. CMRFS was defined as the probability of molecular remission without clinical relapse or death at any time after allo-HCT. Similarly, CTKI was defined as the probability of TKI administration without clinical relapse or death at any time after allo-HCT. The 1- and 5-year CMRFS rates were 67% and 59%, respectively, whereas the 1- and 5-year conventional molecular relapse-free survival rates were 42% and 37%. The 1- and 5-year CTKI rates were 14% and 8%, respectively. In a post hoc analysis focusing on patients who had achieved a molecular complete remission within 6 weeks (n = 201), the 5-year CMRFS rate (71%) was similar to the 5-year conventional molecular relapse-free survival (molRFS) rate (70%) in the non-TKI group. On the other hand, the 5-year CMRFS rate in the TKI group was 61%, whereas the 5-year conventional molRFS rate was only 38%. CMRFS and CTKI might become useful indicators of transplant success in terms of survival, leukemia-free status, and treatment-free status at any time point. Future extension of these survival models to other clinical situations is warranted.

DOI： 10.1016/j.jtct.2021.06.020

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Minimal residual disease (MRD) monitoring by quantitative real-time reverse transcription PCR (qRT-PCR) is the standard of care in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL). We evaluated the impact of MRD status at hematopoietic cell transplantation (HCT) on relapse, as measured by a unified protocol at a central laboratory. Only patients with Ph-positive ALL who had minor transcripts (e1a2) and who underwent allogeneic HCT in first complete remission between 2008 and 2017 were included. First, patients with negative-MRD (n = 196) and positive-MRD (n = 61) at HCT were analyzed. As expected, MRD positivity at HCT was significantly associated with an increased risk of hematological relapse (hazard ratio [HR], 2.91; 95% CI 1.67-5.08; P < 0.001) in the multivariate analysis. Next, patients with positive-MRD were divided into low-MRD (n = 39) and high-MRD (n = 22) groups. In the multivariate analysis, high-MRD at HCT was not significantly associated with an increased risk of hematological relapse compared to the low-MRD group (HR 1.10; 95% CI 0.54-2.83; P = 0.620). These results indicate that the therapeutic decisions should be made based on MRD positivity, rather than on the MRD level, at HCT.

DOI： 10.1007/s12185-021-03094-x

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For patients with Philadelphia chromosome (Ph)-positive leukemia, there is no consensus regarding how long tyrosine kinase inhibitors (TKI) should be given or whether TKI could be stopped if TKI is administrated after allogeneic hematopoietic cell transplantation (allo-HCT). We analyzed relapse-free survival (RFS) in 92 allo-HCT patients who received TKI for >3 months after allo-HCT, and aimed to develop a novel indicator, called as current TKI- & relapse-free (cTRFree) achievement. TKI after allo-HCT was started as planned in 39 patients, based on measurable residual disease (MRD) in 53 at a median of 152 days after allo-HCT. There was no difference in post-TKI RFS between the planned and MRD-based starting groups (P = 0.69). Second-generation TKIs were associated with superior RFS in Ph-positive acute leukemia (HR 2.71, P = 0.031). TKI was stopped before relapse in 48 patients. Stopping TKI as a time-dependent covariate was not associated with subsequent hematological relapse (HR 1.18, P = 0.72). In the TKI-stop group, TKI administration for >6 months tended to be associated with superior RFS (HR = 0.30, P = 0.08). As an indicator of transplant success, cTRFree was 35% 5 years after starting TKI. TKI could be stopped for recipients with sustained undetectable MRD. However, further prospective studies will be required to establish clinical recommendations.

DOI： 10.1038/s41409-020-01206-5

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A multicenter retrospective study was conducted to evaluate the clinical significance of preconditioning intervention (PCI) before allogeneic hematopoietic cell transplantation (HCT) in patients with acute myelogenous leukemia (AML) not in remission. The study cohort consisted of 519 patients classified according to the intensity (intensive/moderate) of PCI and their response to PCI. The group treated with PCI had higher blast counts in the peripheral blood (PB) and had a lower overall survival (OS) rate (P < .001) and higher nonrelapse mortality (NRM) rate (P = .035) compared with those without PCI (no PCI group). Approximately 40% of the patients (68 of 236) achieved a good response to PCI (good PCI group), and those patients had lower blast counts in the PB compared with the group with poor response to PCI (poor PCI group). OS in the good PCI group was comparable to that in the no PCI group and significantly better than that in the poor PCI group (hazard ratio, .54; 95% confidence interval, .39 to .77; P < .001). However, OS was significantly lower in patients with intensive/moderate PCI compared with the no PCI group. These results suggest that PCI increases NRM without decreasing the post-transplantation relapse rate, but may be beneficial for patients with lower blast counts in PB irrespective of its intensity.

DOI： 10.1016/j.bbmt.2020.09.025

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We analyzed clinical cutoffs for defining computed tomography (CT) methods for sarcopenia and examined the prognostic value of CT for allogeneic hematopoietic stem cell transplantation (allo-HCST) outcomes of patients with myeloid malignancy. One hundred twenty-five adult patients with acute myeloid leukemia and myelodysplastic syndrome who underwent first allo-HSCT between 2000 and 2017 were included. Sarcopenia was assessed using CT-based skeletal muscle index (SMI) and mean muscle attenuation at L3. A statistical difference in SMI was confirmed between sarcopenia (n = 52) and nonsarcopenia (n = 73) patients. There were no significant correlations of muscularity with age, performance status, or other characteristics of HSCT. After 2 years, overall survival (OS) was 43.5% and 70.1%, disease-free survival was 52.9% and 68.6%, nonrelapse mortality (NRM) was 20.8% and 8.4%, incidence of acute GVHD (≥ grade 2) was 38.8% and 39.1%, that of chronic GVHD was 53.2% and 37.3%, and median duration of hospitalization was 88 days and 74 days (P = 0.026), respectively, in the sarcopenia and nonsarcopenia groups. Multivariate analysis showed that presence of sarcopenia is a novel adverse factor for high NRM and poor OS. Pretransplant CT-defined sarcopenia is correlated with decreased OS, increased NRM, and prolonged hospitalization.

DOI： 10.1007/s12185-020-02870-5

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A multicenter retrospective study was performed to evaluate the prognostic factors in 104 patients with relapsed or refractory acute lymphoblastic leukemia (ALL), who underwent allogeneic hematopoietic cell transplantation (HCT) between 2005 and 2015. The median age was 38 (range, 17 to 68), and the median blast fraction in peripheral blood and bone marrow was 1% (range, 0 to 99%) and 52% (range, 0 to 100%), respectively. With a median follow-up of 47 months (range, 8.3 to 105 months), overall survival (OS), nonrelapse mortality, and relapse mortality at 1 year were 25%, 44%, and 31%, respectively. Multivariate analysis demonstrated independent predictors for poor OS, including nuclear cell count in the bone marrow ≥10 × 104/μL (hazard ratio [HR], 2.14; 95% confidence interval [CI], 1.33 to 3.43; P = .002), elevated lactate dehydrogenase level (HR, 1.66; 95% CI, 1.05 to 2.62; P = .031), and no primary induction failure (HR, 2.05; 95% CI, 1.11 to 3.78; P = .022). A prognostic scoring index was designed based on these survival predictors. At 2 years, OS was 28%, 14%, and 0% for good (score 0 or 1; n = 47), intermediate (score 2; n = 40), and poor (score 3; n = 17), respectively (P < .001). This scoring system may be useful in identifying the patient population for which allogeneic HCT is least beneficial in advanced stages of ALL.

DOI： 10.1016/j.bbmt.2020.01.007

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DOI： 10.1177/0963689720976567

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Language：English   Publishing type：Research paper (scientific journal)  

To prospectively validate the incidence, manifestations, and outcomes of graft-versus-host disease (GVHD) by National Institutes of Health criteria, we recruited 406 hematopoietic stem cell transplantation recipients at 16 transplant centers in Japan from May 2012 to June 2014. The 2-year cumulative incidence of late acute and chronic GVHD was 3.2% (n = 13) and 35.4% (n = 145), with a median onset of 3.6 and 4.7 months after transplant, respectively. The global severity at onset was mild in 30.3%, moderate in 43.5%, and severe in 26.2%. Eighty-two patients were followed up for 2 years, with 79.3% still manifesting GVHD symptoms, and 80.6% (n = 117) of the patients received systemic immunosuppressive treatment (IST), with a 2-year cumulative incidence of IST termination of 33.1%. Severe patients showed a significantly lower rate of IST termination than those with mild and moderate severities (mild, 38.5%; moderate, 40.9%; and severe, 17.2%). The 2-year incidence of nonrelapse mortality (NRM) and relapse was not significantly different according to the severity at onset (NRM: mild [16.6%] versus moderate [8.7%] versus severe [16.1%]; relapse: mild [14.9%] versus moderate [14.7%] versus severe [5.3%]). As a result, 2-year overall survival (OS) and GVHD-specific survival (GSS) were equivalent according to the severity at onset (mild: OS = 81.0%, GSS = 85.7%; moderate: OS = 84.2%, GSS = 92.5%; severe: OS = 83.9%, GSS = 89.2%). Our study helped identify the characteristics of late acute and chronic GVHD in Japanese patients. Further investigation is needed to identify an optimal endpoint for survival prediction.

DOI： 10.1016/j.bbmt.2019.09.016

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Although cytogenetic abnormalities at diagnosis are recognized as an important prognostic factor in patients with Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL), the prognostic impact has not been evaluated in allogeneic stem cell transplant (allo-SCT) recipients. Thus, we assessed 373 Ph-negative ALL patients who underwent allo-SCT. The high-risk (HR) group included those with t(4;11), t(8;14), low hypodiploidy, and complex karyotype, and the standard risk (SR) group included all other karyotypes. Among the 204 patients who underwent a transplant during the first remission (167 in the SR group and 37 in the HR group), the overall survival (OS) rates were similar between these groups (64.1% vs. 80.0% at 5 years, respectively; p = 0.12). Conversely, among the 106 patients who underwent a transplant while not in remission (84 in the SR group and 22 in the HR group), patients in the SR group showed a significantly superior OS rate compared to the HR group (15.4% vs. 4.5% at 5 years, respectively; p = 0.022). These results suggested that treatment outcomes of Ph-negative ALL patients with HR cytogenetic abnormalities may improve following allo-SCT, especially in the first remission. Innovative transplant approaches are warranted in patients who are not in remission.

DOI： 10.1038/s41409-019-0585-2

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DOI： 10.1038/s41409-019-0689-8

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Publishing type：Research paper (scientific journal)   Publisher：Galenos Yayinevi  

DOI： 10.4274/tjh.galenos.2019.2019.0139

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DOI： 10.1007/s00277-019-03717-8

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We hypothesized that treatment-related weight loss is associated with worse outcomes following HSCT. Overall, 184 patients with AML who underwent induction therapy were classified according to d-BMI (BMI at transplant minus BMI at diagnosis) (kg/m2) as < -2, - 2 to + 2, and > + 2. At 1 year, OS was 67.9% (95% CI, 60.7-74.2), DFS was 64.1% (95% CI, 56.7-70.6), and GRFS was 40.2% (95% CI, 33.1-47.2). For d-BMI groups < - 2, - 2 to + 2, and > + 2, GRFS at 1 year was 16.1% (95% CI, 5.1-31.4), 45.4% (95% CI, 36.4-53.7), and 41.7% (95% CI, 22.2-60.1), respectively (P = 0.0067). Multivariate analysis showed that both worse OS (HR, 1.78; 95% CI, 1.02-3.14; P = 0.007) and GRFS (HR, 2.34; 95% CI, 1.26-4.35; P = 0.007) were associated with reduced BMI (d-BMI < - 2). Treatment-related weight reduction in AML was associated with poor outcome after HSCT.

DOI： 10.1007/s12185-019-02647-5

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A multicenter retrospective study was performed to explore a prognostic scoring index in order to identify a population who are least likely to benefit from allogeneic hematopoietic cell transplantation (HCT) in patients with relapsed or refractory acute myeloid leukemia (AML). The cohort included 519 patients with AML, who received HCT between 2005 and 2015 at a status of relapse or primary induction failure. Multivariate analysis demonstrated five independent predictors for OS, including C-reactive protein ≥ 1 mg/dL, peripheral blood blast fraction ≥ 20%, poor-risk karyotype, performance status ≥ 2, and bone marrow unrelated donor as a stem cell source. A prognostic scoring index was explored based on these predictors, and successfully separated the cohort into four groups. At 2 years, OS was 47%, 24%, 8%, and 0% for Good (Score 0, 1: n = 118), Intermediate-1 (Score 2: n = 75), Intermediate-2 (Score 3: n = 39), and Poor (Score 4: n = 24), respectively (P < 0.001). The predicting value of the index was confirmed in a validation cohort. Although a further validation study is warranted, the scoring index may be useful to predict survival and to identify the population with the lowest survival prior to HCT in patients with relapsed or refractory AML.

DOI： 10.1038/s41375-019-0494-9

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DOI： 10.1038/s41409-018-0343-x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

Background Treatment-free remission (TFR), the ability to maintain a molecular response (MR), occurs in approximately 50% of patients with chronic myelogenous leukemia (CML) treated with tyrosine kinase inhibitors (TKIs).Methods A multicenter phase 2 trial (Delightedly Overcome CML Expert Stop TKI Trial: DOMEST Trial) was conducted to test the safety and efficacy of discontinuing imatinib. Patients with CML with a sustained MR of 4.0 or MR4.0-equivalent for at least 2 years and confirmed MR4.0 at the beginning of the study were enrolled. In the TFR phase, the international scale (IS) was regularly monitored by IS-PCR testing. Molecular recurrence was defined as the loss of MR4.0. Recurrent patients were immediately treated with dasatinib or other TKIs including imatinib.Results Of 110 enrolled patients, 99 were evaluable. The median time from diagnosis to discontinuation of imatinib was 103 months, and the median duration of imatinib therapy was 100 months. Molecular recurrence-free survival rates were 69.6%, 68.6% and 64.3% at 6, 12, and 24 months, respectively. After discontinuation of imatinib therapy, 26 patients showed molecular recurrence, and 25 re-achieved deep MR after dasatinib treatment. Molecular response MR4.0 was achieved in 23 patients within 6 months and 25 patients within 12 months. Multivariate analysis revealed that a longer time from diagnosis to discontinuation of imatinib therapy (p=0.0002) and long duration of imatinib therapy (p=0.0029) predicted a favorable prognosis.Conclusions This DOMEST Trial showed the feasibility of TKI discontinuation in a Japanese clinical setting.

DOI： 10.1007/s10147-018-1368-2

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AIM: Primary malignant lymphomas arising from the female genital tract are very rare, with an incidence rate of 0.5%. Because of its rarity, its clinical characteristics, prognosis and optimal treatment are still unclear. Here, we retrospectively evaluated female patients with uterine lymphoma. METHODS: Between January 2000 and October 2016, 4362 patients were newly diagnosed with malignant lymphoma by the participating institutions of YACHT. Among these 4362 patients, we retrospectively evaluated 14 adult patients with primary uterine lymphoma. RESULTS: The median follow up time was 41 months. The median age at diagnosis was 68 years. Of 14 patients, 10 (72%) were diagnosed with diffuse large B-cell lymphoma. Seven patients presented with vaginal bleeding and three with abdominal pain. Eleven patients (79%) had advanced stages at diagnosis. Three patients (21%) had ovarian involvement and 2 (14%) had vaginal involvement. Induction chemotherapy regimens were R-CHOP in seven patients (50%), CHOP in three (21%) and other regimens in four (29%). Among 14 patients, 12 patients (86%) achieved a complete response and 2 (14%) experienced disease progression. Three patients (21%) showed relapse. Five patients (36%) died because of malignant lymphoma. The 3-year overall survival rate was 57.9%. Soluble interleukin-2 receptor levels > 5000 U/mL, anemia, a bulky mass and the presence of > 1 extranodal sites, B symptom at diagnosis were associated with a poor prognosis. CONCLUSION: Female genital lymphoma is very rare, and further study of more cases is warranted.

DOI： 10.1111/ajco.13049

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Language：English   Publisher：(一社)日本血液学会-東京事務局  

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Language：English   Publisher：(一社)日本血液学会-東京事務局  

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Language：English   Publisher：(一社)日本血液学会-東京事務局  

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Objective: Useful prognostic biomarkers for diffuse large B-cell lymphoma (DLBCL) patients have been reported. To determine the prognostic value of hemoglobin (Hb) level in DLBCL patients, we performed a retrospective study. Materials and Methods: We evaluated disease outcome, progression-free survival (PFS), overall survival as the endpoint, and clinical and laboratory factors affecting the outcome of 185 DLBCL patients who had received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone therapy during 2004-2014. Results: The study group included 121 men and 64 women with a median age of 66 years minimum-maximum: 21-83 years. In univariate analysis, factors independently associated with worse PFS were Eastern Cooperative Oncology Group performance status ≥2, Ann Arbor stage III or IV, anemia with Hb levels of <10 g/dL, and serum albumin of <3.5 g/dL. In multivariate analysis, anemia with Hb levels of <10 g/dL and Ann Arbor stage III or IV were found to be international index-independent prognostic factors (hazard ratio: 2.4; p=0.04). Conclusion: Anemia is an independent prognostic marker of poor outcome in DLBCL patients. Hb can be an easily available prognostic marker for risk stratification in these patients.

DOI： 10.4274/tjh.2017.0437

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PURPOSE: A multicenter retrospective analysis was performed to evaluate the clinical significance of serum ferritin at diagnosis in patients with acute myeloid leukemia (AML). METHODS: The study cohort included 305 patients who were newly diagnosed with AML from 2000 to 2015 and received standard induction chemotherapy. Transplantation was performed in 168 patients. RESULTS: The median ferritin value was 512 ng/mL (range, 8-9475 ng/mL). Ferritin correlated with lactate dehydrogenase, C-reactive protein, white blood cell count, and blast count, and elevation of ferritin was associated with poor performance status. The median follow-up period was 58 months (range, 4-187 months) among survivors. The high ferritin group (≥ 400 ng/mL) demonstrated inferior event-free survival (EFS) at the 5-year interval (30% vs. 40%; P = .033) compared to the low ferritin group. Multivariate analysis in the high-risk karyotype revealed that high ferritin levels predicted worse EFS (hazard ratio = 2.07; 95% confidence interval, 1.28-3.33; P = .003). CONCLUSION: Elevated ferritin at diagnosis may indicate tumor burden in patients with AML and predict worse EFS in the high-risk group.

DOI： 10.1016/j.clml.2018.03.009

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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment for chronic myelomonocytic leukemia (CMML); however, factors predicting allo-HSCT outcomes for CMML have not been well defined. This study assessed whether the existing five scoring systems for CMML prognosis could be applied for predicting allo-HSCT outcomes. We retrospectively evaluated 38 patients who underwent allo-HSCT for CMML from 2000 to 2014. At 3 years, overall survival (OS) and disease-free survival were 34.6 and 24.7%, respectively. According to the risk stratification at the time of transplantation, only the CMML-specific cytogenetic risk scoring system could successfully predict transplantation outcomes. At 3 years, OS was 56.7, 12.5, and 0% (p = .01) in the low, intermediate, and high-risk groups. Our data suggest that the CMML-specific cytogenetic risk stratification at transplant may be useful for identifying patients with CMML who may benefit from HSCT. However, further studies are warranted to confirm this observation.

DOI： 10.1080/10428194.2017.1387913

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DOI： 10.1007/s12288-017-0848-2

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We evaluated the effects of regulatory T cell (Treg) inhibition during dasatinib treatment on the anticancer immune response, particularly on natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). Fifty-two newly diagnosed Japanese patients with chronic myeloid leukemia (CML) in the chronic phase were enrolled in the D-first study; all received 100 mg of dasatinib once daily and were followed for at least 36 months. The cumulative deep molecular response (DMR, MR4) rate was 65% by 36 months; the 3-year overall survival was 96%. CD4+ T cell counts were stable, whereas the proportion of CD4+CD25+CD127low (Treg) cells decreased in a time-dependent manner. The DMR rate by18 months was significantly better in low Treg patients (<5.7% at 12 months) compared to the remaining patients (odds ratio 4.07). NK cell and CTL counts at several time points were inversely correlated with Treg counts. Furthermore, the degree of NK cell differentiation (CD3-CD57+/CD3-CD56+) was closely and inversely correlated with the proportion of Treg cells throughout the observation period, and showed a gradually increasing trend. In conclusion, our results demonstrate that Treg inhibition by dasatinib contributes to better treatment response through enhancement of the immune system, particularly via NK cell differentiation.

DOI： 10.1016/j.leukres.2018.01.010

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

The prognosis for disease relapse after first hematopoietic cell transplantation (HCT1) is poor. Here, we present a retrospective multicenter study to evaluate the clinical outcome and the prognostic factors for second hematopoietic cell transplantation (HCT2). The cohort in this study comprised 60 patients diagnosed with acute leukemia, who underwent HCT2 due to hematological relapse after HCT1. The overall survival (OS) at two years, non-relapse mortality (NRM), and relapse mortality (RM) were 30.3%, 40.9%, and 28.8%, respectively. Multivariate analysis for OS identified the use of a donor other than matched-related (MR) donor (hazard ratios [HR]=4.10, 95% confidence intervals [CI]: 1.72-9.74, p=.001) and high disease status (HR=2.90, 95% CI: 1.28-6.56, p=.011) as the adverse risk factors for HCT2. On analyzing the combination of factors during HCT1 and HCT2, MR donor, reduced intensity conditioning regimen, and standard status were found to be significant as favorable prognostic factors for OS. Therefore, evaluating these prognostic factors would be helpful in taking decisions regarding post-relapse management.

DOI： 10.1080/10428194.2016.1243678

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

The international phase III DASISION trial demonstrated improved efficacy of dasatinib versus imatinib in treatment-naive patients with chronic myeloid leukemia in the chronic phase (CML-CP). We report efficacy and safety outcomes in a Japanese population from the final, 5-year follow-up of DASISION. At the end of the study, 77% (20/26) of dasatinib-treated and 61% (14/23) of imatinib-treated patients remained on initial therapy. Improved responses were observed in Japanese patients who received dasatinib versus imatinib (complete cytogenetic response: 96 vs 87%; major molecular response: 88 vs 74%; BCR-ABL1 ae&lt;currency&gt;0.0032% International Scale [MR4.5]: 58 vs 52%). In patients who achieved BCR-ABL1 ae&lt;currency&gt;10% at 3 months, 5-year progression-free survival and overall survival rates were high with dasatinib (96 and 96%) and imatinib (88 and 100%). The majority of adverse events were grade 1/2 in Japanese patients. Pleural effusion occurred more frequently in dasatinib-treated Japanese patients versus all patients (42 vs 28%), with no treatment discontinuations. Overall, in Japanese patients, dasatinib maintained its safety profile and had higher or comparable response and survival outcomes compared with imatinib or with all patients in DASISION. These findings demonstrate the long-term efficacy and tolerability of dasatinib and support frontline treatment of Japanese patients with CML-CP with dasatinib.

DOI： 10.1007/s12185-017-2208-2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

Body mass index (BMI), which represents the proportion of weight to height, is a controversial prognostic factor for acute myeloid leukemia (AML). We evaluated prognostic value of BMI in Japanese AML. The study included 369 adult patients with newly diagnosed AML who were administered either daunorubicin or idarubicin with cytarabine as induction chemotherapy. The patients were categorized into two groups according to their BMI: the NW group (BMI &lt; 25.0 kg/m(2); normal and underweight) and OW group (BMI &gt;= 25.0 kg/m(2); overweight and obese). We analyzed treatment efficacy and toxicity of induction chemotherapy, and survival outcomes in each group. Patients in the OW group showed a better complete remission rate than the NW group (86.1 versus 76.5%, P = 0.045), no early death (0.0 versus 4.1%, P = 0.042), and better overall survival (OS) at 3 years (62.2 versus 50.1%, P = 0.012). Multivariate analysis showed BMI is an independent prognostic factor for OS (hazard ratio 0.62, 95% confidence interval 0.42-0.92, P = 0.017). These results indicate the prognostic value of BMI in adult AML patients.

DOI： 10.1007/s12185-017-2183-7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

This study investigated the efficacy of imatinib based therapy with intensified consolidation therapy in patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) to prevent early relapse. We conducted a phase II trial of imatinib-combined chemotherapy for newly diagnosed BCR-ABL-positive ALL in adults. Sixty-eight patients were included in the trial between October 2008 and December 2010. The median age was 49years, with 28patients &gt;55years of age. Sixty-five patients achieved CR (95.6%). The estimated 2-year event-free survival (EFS) and overall survival (OS) were 62.3% and 67.4%, respectively. Allogeneic stem cell transplantation (allo-SCT) at initial CR was performed in 43 patients. Thirty-five of 39 patients &lt;55years and 8 of 26 patients &gt;55years underwent allo-SCT at first CR. The 3-year OS in patients &lt;55years receiving allo-SCT at first CR, patients &gt;55years receiving allo-SCT at first CR, patients &lt;55years not receiving allo-SCT at first CR, and patients &gt;55years not receiving allo-SCT at first CR were 80.4%, 41.1%, 32.5%, and 52.0%, respectively (P=0.058). The three-year EFS in each group was 76.7%, 53.6%, not reached, and 26.4%, respectively (P=0.150). A high CR rate was observed with imatinib-based chemotherapy allowing allo-SCT in a high proportion of patients, particularly those &lt;55years. Moreover, intensified consolidation therapy reduced early relapse rates following induction therapy and resulted in improved OS and EFS rates following allo-SCT. This trial was registered with the UMIN (000001226).

DOI： 10.1002/ajh.24653

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Language：Japanese   Publisher：The Japanese Society of Hematology  

<p>The survival outcomes for children with acute lymphoblastic leukemia (ALL) have dramatically improved over recent years, and improved outcomes in adolescents and young adults patients have been achieved by applying regimens based on pediatric protocols. The treatment strategies for adult ALL are similar to those for pediatric ALL. T-cell ALL is less common than B-cell ALL. Therefore, there are only few reports of investigations in a large group of adult T-ALL patients. In Japan, nelarabine-combined chemotherapy has been tested in a phase II study in patients with newly diagnosed T-ALL. Patients with Philadelphia chromosome-positive ALL had a poor prognosis. However, the introduction of a tyrosine kinase inhibitor (TKI) has dramatically altered treatment strategies, resulting in complete remission in virtually all patients and an increased proportion of patients who undergo allogeneic stem cell transplantation. The prognosis of adults with relapsed and refractory ALL is extremely poor, and some novel agents are currently under development for relapsed and refractory ALL. This article describes the current treatment strategy and future perspectives for adult ALL.</p>

DOI： 10.11406/rinketsu.58.1983

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

We verified the association between standard clinical and laboratory variables and the risk of relapse in acute myeloid leukemia (AML), which led us to retrospectively examine the effect of regeneration of hematopoiesis in patients with newly diagnosed AML. We used data from 230 patients who obtained remission after cytarabine-based induction chemotherapy. Platelet counts &gt;= 500 x 10(9)/L and hemoglobin levels &gt;= 9 g/dL on day 28 after treatment initiation were significantly associated with relapse-free survival (RFS) rate, conferring respective multivariate risk ratios of 0.38 (95% CI: 0.18-0.79) and 0.60 (95% CI: 0.40-0.89) for the occurrence of relapse or death. No disease relapse occurred in core binding factor leukemia patients whose platelet counts recovered &gt;= 500 x 10(9)/L at 28 days after therapy initiation. We conclude that regeneration of hematopoiesis, especially platelet hyper-recovery, after induction chemotherapy is a significant predictor of RFS in patients with AML.

DOI： 10.1080/10428194.2016.1190969

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

We previously developed a prognostic index, SIL, which includes advanced stage (5), soluble interleukin-2 receptor level (I), and elevated lactate dehydrogenase level (L) in diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab, cyclophosphamide, hydroxydaunomycin, oncovin, and prednisone (R-CHOP). This time we evaluated the index in a larger cohort and its utility in the risk stratification. The above three factors were independent risk of progression-free survival (PFS). Five-year PFS rates in the standard-risk (SIL index: 0 or 1, n = 367) and high-risk groups (SIL index: 2 or 3, n = 205) were 79% and 53%, respectively (p &lt; 0.0001). When the patients were divided by age (&lt;= 60 years and &gt;60 years), the SIL index was a good prognostic indicator for PFS in both groups as well as divided by the number of extranodal involvement site (0-1 and &gt;1). The SIL index is a simple and objective prognostic indicator in DLBCL.

DOI： 10.1080/10428194.2016.1195498

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Language：English   Publisher：AMER SOC HEMATOLOGY  

DOI： 10.1182/blood.V128.22.2795.2795

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Language：English   Publisher：AMER SOC HEMATOLOGY  

DOI： 10.1182/blood.V128.22.1616.1616

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DOI： 10.1111/ctr.12702

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

Objective Fludarabine plus melphalan (FM) and fludarabine plus busulfan (FB) are two major conditioning regimens for allogeneic hematopoietic stem cell transplantation (allo-HSCT).
Methods We retrospectively analyzed patients who underwent allo-HSCT after a conditioning regimen consisting of FM or FB with/without total body irradiation for hematological malignancies between 2005 and 2014.
Results There were 41 patients who met the criteria. The median follow-up time for the survivors was 3 years. Thirty-two patients received allo-HSCT after the FM regimen and nine patients received allo-HSCT after the FB regimen. Patients who received FB were older than those who received FM (p=0.041). There was no significant difference in the 3-year overall survival between patients who had received FB and those who had received FM (29.6% vs. 56.5%, p=0.267). The 3-year cumulative incidence of relapse was significantly higher in patients who had received FB than that in patients who had received FM (66.7% vs. 17.8%, p=0.004), and FB was an independent prognostic factor for relapse by a multivariate analysis (hazard ratio, 9.8; 95% confidential interval, 2.5-39.3; p=0.001). When we restricted the evaluation to patients with acute myeloid leukemia and myelodysplastic syndrome, the 3-year cumulative incidence of relapse was also significantly higher in patients who had received FB than that in patients who had received FM (75.0% vs. 16.1%, p=0.004).
Conclusion The results suggest that FM may provide better disease control than FB.

DOI： 10.2169/internalmedicine.55.6094

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive T-cell lymphoma. A 63-year-old man was diagnosed with AITL. He received 6 cycles of CHOP therapy, but showed progressive disease. Subsequently, he received ESHAP chemotherapy; however, it was not effective. He received mogamulizumab (an anti-CCR4 monoclonal antibody). After 4 cycles, his respiratory condition worsened and he was diagnosed with cytomegalovirus (CMV) pneumonia. Despite antiviral and antibiotic therapy, he died. We speculate that the combination of progressive lymphoma with mogamulizumab and chemotherapy likely caused CMV pneumonia. Because mogamulizumab therapy causes immunosuppression, if CMV pneumonia is suspected, then rapid treatment should be initiated.

DOI： 10.2169/internalmedicine.55.5644

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Language：English   Publisher：AMER SOC HEMATOLOGY  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

A multicenter retrospective study was performed to determine the significance of adding cytarabine (CA) or thiotepa (TT) in the context of total body irradiation (TBI) and cyclophosphamide (CY). A total of 322 patients who underwent allogeneic hematopoietic cell transplantation (HCT) were distributed to the following three groups: TBI/CY (n = 75), TBI/CY/CA (n = 77), and TBI/CY/TT (n = 170). In the TBI/CY/TT group, 164 of patients (96 %) received HCT during the previous year (2000-2005). Multivariate analysis revealed that the TBI/CY/TT group demonstrated a trend of poorer survival rate than the TBI/CY group, [hazard ratio (HR) = 1.49, 95 % confidence interval (CI) 0.99-2.24, P = 0.055] with a higher non-relapse mortality (NRM) (HR = 2.34, 95 % CI 1.35-4.06, P = 0.002) rates, while TBI/CY/CA group demonstrated similar outcomes. Even in the subgroup analyses of disease type or disease risk, the outcomes with intensified conditioning regimens were not superior to those with TBI/CY. In conclusion, although the significant bias has to be carefully considered, the clinical benefit of adding CA or TT to the TBI/CY regimen was not demonstrated.

DOI： 10.1007/s12185-015-1836-7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

When discussing treatment options for patients with acute leukemia, it is important to acknowledge the impact of allogeneic hematopoietic cell transplantation (allo-HCT) or chemotherapy on quality of life (QOL). We performed a cross-sectional questionnaire study that administered SF-36, FACT-Leukemia and EuroQOL5D to 524 acute leukemia survivors, to compare patient-reported QOL between chemotherapy and allo-HCT, and to elucidate predictors of QOL. Patients who received chemotherapy alone had a better physical QOL than those who received allo-HCT. On the other hand, the allo-HCT group reported a better mental QOL. In the comparison of QOL in the allo-HCT patients according to the presence of GVHD at survey, patients who had GVHD symptoms experienced statistically and clinically significantly worse QOL than those who did not. In the allo-HCT patients without GVHD, the physical QOL was comparable to that in the chemotherapy patients, and they experienced significantly better mental and general QOL than the chemotherapy patients. GVHD and immunosuppressive drugs at survey were strongly associated with worse QOL after allo-HCT. In the chemotherapy group, a shorter time between treatment completion and survey was significantly associated with worse QOL. Further evaluation of QOL by a longitudinal assessment with quantitative and qualitative analyses are warranted.

DOI： 10.1038/bmt.2015.137

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© 2015 Macmillan Publishers Limited. This prospective study aimed to investigate the influence of pretransplant serum ferritin levels on the outcomes of allogeneic hematopoietic SCT (HSCT). In total, 190 patients with acute leukemia or myelodysplastic syndrome were consecutively enrolled. The patients were divided into two groups: low-ferritin group (<1000 ng/mL) and high-ferritin group (≥1000 ng/mL). The primary end point was the cumulative incidence of infection within 100 days after HSCT, which was similar between the two groups: bloodstream infection, 35 vs 38%, P=0.65; bacterial infection, 44 vs 41%, P=0.68; and fungal infection, 6 vs 8%, P=0.71. The 1-year adjusted probability of OS of the high-ferritin group was significantly lower than that of the low-ferritin group (76 vs 63%, P=0.017). Using receiver operating characteristic curve, the threshold of pretransplant serum ferritin levels for bloodstream infection was 1400 ng/mL; the threshold for OS, EFS and non-relapse mortality was 1349 ng/mL. In conclusion, pretransplant serum ferritin levels of ≥1000 ng/mL did not influence the incidence of infection but adversely affected OS after HSCT. A higher threshold of pretransplant serum ferritin levels may predict HSCT outcomes.

DOI： 10.1038/bmt.2015.17

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

自家末梢血幹細胞移植(SCT)目的にbortezomib+dexamethasone療法にて寛解導入療法を受けた65歳以下未治療多発性骨髄腫35例の治療成績,予後因子を後方視的に検討した。治療効果:Complete response(CR) 4例(11%),Very good partial response(VGPR) 13例(37%),奏効例27例(77%),SCT遂行18例(51%)。SCT群,非SCT群3年Progression free survival(PFS)は41%,0%でSCT群が優れた(P=0.0037)。非SCT群で有害事象が重症化した。SCTの脱落理由に不可逆性のしびれや痛みの末梢神経障害を29%認めた。診断時染色体予後良好群がPFSの予後因子だった(P値;単変量解析0.0004,多変量解析0.0405)。有害事象の軽減と予後不良染色体克服が治療成績向上に必要と思われた。(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2015&ichushi_jid=J01540&link_issn=&doc_id=20150501380006&doc_link_id=1390282680011524352&url=https%3A%2F%2Fcir.nii.ac.jp%2Fcrid%2F1390282680011524352&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_3.gif

Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

DOI： 10.1002/ajh.23923

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DOI： 10.11406/rinketsu.56.392

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UNLABELLED: Prognosis for adult patients with acute lymphoblastic leukemia (ALL) has been reported to be approximately 35% to 50%, even after allogeneic stem cell transplantation (allo-SCT). We previously reported retrospective analyses of a conditioning regimen of medium-dose etoposide, cyclophosphamide (CY), and total body irradiation (TBI) before allo-SCT for ALL. To prospectively analyze the efficacy of this conditioning regimen, we conducted a trial prospectively. METHODS: The eligibility criteria of this study were as follows: diagnosis of ALL, aged between 15 and 50 years, in complete remission, and first SCT from HLA serologically matched donor. The primary endpoint of this study was event-free survival at 1 year after SCT, and the events were defined as death and relapse. RESULTS: Fifty eligible patients were treated, and the median age of the patients was 33.5 years. Nineteen patients were Philadelphia chromosome-positive, and 47 were in first complete remission at SCT. All patients achieved neutrophil engraftment. Grade 3 to 4 acute graft-versus-host disease and extensive chronic graft-versus-host disease developed in 4 patients and 18 patients, respectively. No patient died within 100 days after SCT. One-year event-free survival was 76.0%, and 1-year overall survival was 80.0%. The cumulative incidences of relapse and non-relapse mortality at 1-year after SCT were 10.0% and 14.0%, respectively. CONCLUSIONS: Medium-dose etoposide + CY + TBI is an effective conditioning before allo-SCT for adult patients with ALL, enabling good disease control without an increase in nonrelapse mortality. A phase 3 trial comparing this regimen with the standard CY + TBI regimen for adult patients with ALL is warranted.

DOI： 10.1097/TXD.0000000000000514

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The International Harmonization Project on Lymphoma recommends (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) for the routine assessment of treatment efficacy in patients with FDG-avid lymphomas such as Hodgkin's and diffuse large B cell lymphomas. The utility of FDG-PET in predicting outcomes in patients with peripheral T cell lymphomas (PTCL) has not been fully elucidated. We retrospectively determined the predictive value of FDG-PET after first-line treatment (post-PET) for outcome in PTCL. Of the 36 patients enrolled, 16 were histologically diagnosed with PTCL not otherwise specified and 20 were diagnosed with angioimmunoblastic T cell lymphoma. All patients received curative-intent anthracycline-containing chemotherapy regimens. Post-PET images were visually evaluated by local nuclear medicine physicians. The median observation period for the surviving patients was 44 months. Positive and negative post-PET results were obtained in 31 % (11/36) and 69 % (25/36) of patients, respectively. The 3-year progression-free survival rates in the positive and negative post-PET result groups were 18 % and 62 %, respectively (P < 0.001). Nine of the 11 patients in the positive post-PET result group experienced progressive disease (PD) (positive predictive value, 82 %), whereas 16 of the 25 patients in the negative post-PET result group did not experience PD (negative predictive value, 64 %). The 3-year overall survival rates in the positive and negative post-PET result groups were 44 % and 84 %, respectively (P = 0.03). Our findings indicate that post-PET is predictive of outcome in patients with PTCL.

DOI： 10.1007/s00277-014-2227-5

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

The prognostic implications of infra-diaphragmatic (InD) versus supra-diaphragmatic (SpD) primary lesions in limited-stage diffuse large B-cell lymphoma (DLBCL) remains unknown. This retrospective study aimed to assess the prognostic impact of spD and InD lesions as well as presence of gastrointestinal (GI) involvements in adults with limited-stage DLBCL. We analyzed data from 178 patients with limited-stage DLBCL who were treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone therapy at 7 institutions of the Yokohama City University Hematology Group between 2003 and 2009. The median age was 63 years (range, 18-80 years). The primary sites were SpD in 109 patients, and InD in 69. No statistical differences in progression-free survival (PFS) or overall survival (OS) were observed between patients with SpD lesions and those with InD lesions. However, when patients with SpD lesions, InD lesions with (n = 35), and without (n = 34) GI involvement were compared, the presence of GI lesions was associated with favorable PFS. The multivariate analysis revealed that SpD or InD localization had no independent effect on PFS or OS, whereas the presence of GI lesions was correlated with favorable PFS (P = 0.024, HR 0.09). (C) 2014 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.leukres.2014.11.030

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© 2014 American Society for Blood and Marrow Transplantation. Recent advances in allogeneic hematopoietic stem cell transplantation have led to increasing use of this modality in older patients who tend to have been more heavily pretreated and have more comorbidities. Thus, the evaluation of comorbidity is of increasing importance to more precisely assess the benefits and risks of the transplantation procedure. Researchers from Seattle developed the hematopoietic cell transplantation-specific comorbidity index (HCT-CI), which was associated with the risk of mortality in several retrospective studies. However, its clinical utility has not been extensively documented in prospective studies. The aim of the present study was to evaluate the utility of the HCT-CI prospectively in a multicenter setting. Overall survival (OS) and nonrelapse mortality (NRM) at 2years were 59% and 20%, respectively (n=243). We found that the HCT-CI in its original scale failed to predict OS and NRM in this set of patients. Thus, we applied a flexible HCT-CI risk scoring system (restratifying scores from 0 to 3 to indicate low risk, and scores of 4 or higher as high-risk). The flexible HCT-CI was found to predict 2-year NRM and OS better than the original HCT-CI (NRM: P=01, OS: P=003). In subgroup analysis, we evaluated the usefulness of the original HCT-CI for patients excluding those who received cord blood transplantation (n=186). Both 2-year OS and 2-year NRM were not significantly different according to the original HCT-CI (P=304, P=996), but with the flexible HCT-CI, there were significant differences in 2-year OS and 2-year NRM (P=005 and P=005, respectively). Multivariate analysis identified age >50, performance status (PS) <90, donor type (HLA-mismatched/unrelated donor), and the flexible HCT-CI ≥4 as significant predictors for worse OS at 2years. However, the flexible HCT-CI did not remain a significant predictor for NRM at 2years in multivariate analysis, whereas age, PS, and donor type did. The HCT-CI did not consistently predict both NRM and OS, but it still can be a useful tool in combination with other factors, such as PS and age. Furthermore, the HCT-CI, although potentially useful for capturing pretransplantation comorbidity and risk assessment, may need further validation before its adoption for routine clinical use.

DOI： 10.1016/j.bbmt.2014.06.005

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Humana Press Inc.  

The objective of the current study was to assess the prognostic factors in patients with extranodal natural killer (NK)/T cell lymphoma, nasal type (ENKL). We retrospectively analyzed 35 patients who were diagnosed with ENKL between 1998 and 2011. The median patient age was 63 years, and the male/female ratio was 22:13
twenty patients had localized ENKL, and 26 had a good Eastern Cooperative Oncology Group performance status (score 0 or 1). B symptoms were present in 17 patients. Twenty-five patients presented with nasal or paranasal lesions, or both. With a median follow-up duration among patients still alive at their last follow-up of 47 months (range 8–93 months), the 3-year overall survival (OS) rate was 44.5 %. Multivariate analysis revealed that advanced disease stage (P = 0.002), the presence of extranasal disease (P = 0.013), and serum ferritin levels greater than 300 ng/ml (P &lt
 0.001) were significant and independent (negative) prognostic factors. High serum ferritin levels were associated with the presence of B symptoms, elevated lactate dehydrogenase levels, and high soluble interleukin-2 receptor levels, but not with clinical stage. Patients with high ferritin levels had a remarkably low remission rate (23 %) and a short OS time (median: 4 months). Serum ferritin level at the time of diagnosis of ENKL was a useful prognostic factor.

DOI： 10.1007/s12032-014-0149-7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

Dasatinib is a highly potent BCR-ABL kinase inhibitor with established efficacy and safety in imatinib-resistant or -intolerant patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia. In the global phase III DASISION trial in patients with newly diagnosed chronic phase CML (CML-CP), dasatinib was found to have an acceptable safety profile and demonstrated significantly faster and higher rates of complete cytogenetic response (CCyR) and major molecular response (MMR) compared with imatinib. Here, we report the results of a subset analysis of Japanese patients enrolled in the DASISION trial, showing safety and efficacy profiles generally consistent with patients enrolled worldwide, including higher response rates (CCyR, MMR) with dasatinib compared with imatinib and similar high rates of progression-free and overall survival with both therapies. However, the small sample size of the present study limits the strength of these conclusions, and further exploration is needed to confirm any differences observed in Japanese patients compared with the total treated population. These findings support the use of dasatinib 100 mg QD as a first-line treatment in Japanese patients with newly diagnosed CML-CP.

DOI： 10.1007/s12185-013-1470-1

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Lymphocytosis in response to dasatinib for chronic myelogenous leukemia (CML) may be associated with favorable response. However, it occurs at varying times and in a limited subset of patients. To identify early clinical markers for favorable responses applicable to all patients with or without lymphocytosis, we prospectively analyzed lymphocyte profiles of 50 Japanese CML patients treated with dasatinib after intolerance/resistance to imatinib. Although absolute lymphocyte counts did not differ significantly until 3 months between patients with complete molecular response (CMR) at 12 months and those without it, relative increases in lymphocyte compared with baselines differed significantly from 1 month. Patients with relative lymphocyte counts >150 % at 1 month or >200 % at 3 months had higher CMR rates at 12 months than others (57.9 vs. 23.3 %, P = 0.015, and 76.5 vs. 16.1 %, P < 0.0001, respectively). A relative increase in lymphocyte subset of CD57(+)CD14(-), CD8(+)T, or NK cells >200 % at 1 month was also significantly associated with a higher CMR rate. There were significant negative correlations between relative lymphocyte increases and BCR/ABL transcript levels. CD57(+)CD14(-) cells were a highly specific focus of proliferation. Relative increases in lymphocyte count and its subsets from 1 month are reliable early markers of favorable responses to dasatinib.

DOI： 10.1007/s12185-013-1483-9

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The Sokal and Hasford scores were developed in the chemotherapy and interferon era and are widely used as prognostic indicators in patients with chronic myeloid leukemia (CML). Recently, a new European Treatment and Outcome Study (EUTOS) scoring system was developed. We performed a multicenter retrospective study to validate the effectiveness of each of the three scoring systems. The study cohort included 145 patients diagnosed with CML in chronic phase who were treated with imatinib. In the EUTOS low- and high-risk groups, the cumulative incidence of complete cytogenetic response (CCyR) at 18 months was 86.9% and 87.5% (P = 0.797) and the 5-year overall survival rate was 92.6% and 93.3% (P = 0.871), respectively. The cumulative incidence of CCyR at 12 months, 5-year event-free survival and 5-year progression-free survival were not predicted using the EUTOS scoring system. However, there were significant differences in both the Sokal score and Hasford score risk groups. In our retrospective validation study, the EUTOS score did not predict the prognosis of patients with CML in chronic phase treated with imatinib.

DOI： 10.1111/cas.12321

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Language：Japanese   Publisher：(公社)神奈川県医師会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Blackwell Publishing Ltd  

We validated the European Group for Blood and Marrow Transplantation (EBMT) risk score in 273 consecutive adult patients receiving allogeneic hematopoietic stem cell transplantation between 2000 and 2010 at our center. The patients were divided into four groups according to the EBMT risk score: low risk (LR, score 0-2), intermediate risk-1 (IR-1, score 3), intermediate risk-2 (IR-2, score 4), and high risk (HR, score 5-7). The five-yr overall survival of the LR (n = 65), IR-1 (n = 67), IR-2 (n = 70), and HR (n = 71) groups was 72%, 57%, 41%, and 25%, respectively (p &lt
0.001). The five-yr transplant-related mortality rates were 16%, 30%, 25%, and 36%, respectively (p = 0.07). The five-yr cumulative incidence of relapse was 20%, 18%, 37%, and 41%, respectively (p &lt
0.001). In the subgroup analysis, the prognostic value of the EBMT risk score was confirmed in patients undergoing myeloablative conditioning (MAC), but not in those undergoing reduced-intensity conditioning (RIC). The results suggest that the EBMT risk score is a useful tool to predict transplant outcome for patients undergoing MAC, but not for those undergoing RIC and may be beneficial for stratifying patients in clinical studies. © 2014 John Wiley &amp
Sons A/S.

DOI： 10.1111/ctr.12324

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Dasatinib is a BCR-ABL kinase inhibitor with improved potency compared with imatinib, for which efficacy and safety in imatinib-resistant and imatinib-intolerant patients with chronic myelogenous leukemia (CML) have been established. Here, an open-label phase II study evaluated the efficacy and safety of dasatinib in 50 Japanese patients with imatinib-resistant or imatinib-intolerant CML during the chronic phase (CML-CP). Dasatinib was effective in imatinib-resistant and imatinib-intolerant patients. After 12 months of dasatinib therapy, 35 patients (70%) had achieved a major molecular response (MMR) and 16 patients (32%) had achieved a complete molecular response (CMR). Among the imatinib-resistant CML-CP cohort, 21 and 8 patients had achieved an MMR and a CMR after 12 months of dasatinib therapy, respectively. Among the imatinib-intolerant CML-CP cohort, 14 and 8 patients had achieved an MMR and a CMR after 12 months of dasatinib therapy, respectively. After 18 months of dasatinib therapy, 38 out of 50 patients (76.0%) had achieved an MMR and 19 patients (38.0%) had achieved a CMR. A lower level of BCR-ABL transcript at 1 or 3 months after the initiation of dasatinib treatment was more strongly correlated with the BCR-ABL transcript level at 12 and 18 months (p ＜ 0.001) than a higher level of BCR-ABL. The T315I mutation was identified in two patients receiving dasatinib therapy. Dasatinib was generally well tolerated, with only 3 patients (5%) having treatment discontinuation as a result of adverse hematologic events (thrombocytopenia, anemia, neutropenia) and/or non-hematologic events at a 12-month follow-up evaluation. Dasatinib was a safe and effective treatment for Japanese patients with imatinib-resistant or imatinib-intolerant CML. In addition, the molecular response at 1 or 3 months predicted a response to dasatinib at 12 or 18 months.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Informa Healthcare  

To clarify the significance of post-transplant serum ferritin (SF), we retrospectively assessed pre- and post-transplant SF. Among 256 patients undergoing allogeneic stem cell transplant (SCT) for hematologic malignancies between 2000 and 2011, those who had relapsed within 1 year were excluded, and 110 patients surviving for more than 1 year were included in the analysis. The cut-off value of SF was 1000 ng/mL, and four pre- and post-SF groups were defined: low-low (n = 62), low-high (n = 12), high-low (n = 13) and high-high (n = 23). Outcomes at 5 years for each group were as follows: overall survival (OS) 88.2, 38.1, 92.3 and 76.7%, respectively, p = 0.004, and non-relapse mortality (NRM) 11.3, 53.6, 7.7 and 18.9%, respectively, p = 0.037. Patients receiving larger transfusion volumes or developing chronic graft-versus-host disease (GVHD) demonstrated higher 1-year SF values. In multivariate analysis for OS and NRM, low-high SF remained a significant predictor of OS (hazard ratio [HR] = 3.49, 95% confidence interval [CI]: 1.10-11.0, p = 0.032) and NRM (HR = 2.95, 95%CI: 1.04-8.36, p = 0.041). These results suggest that the elevation of SF at 1 year after SCT, which may reflect transfusion and the development of chronic GVHD, may have an aggravating influence on outcomes after SCT. This study provides a clue to clarifying the clinical significance of SF in a transplant setting. © 2014 Informa UK, Ltd.

DOI： 10.3109/10428194.2013.842981

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

BCR-ABL tyrosine kinase inhibitors (TKI) have dramatically improved therapy for chronic myelogenous leukemia (CML). However, several problems leading to TKI resistance still impede a complete cure of this disease. IFN regulatory factor-8 (IRF8) is a transcription factor essential for the development and functions of immune cells, including dendritic cells. Irf8(-/-) mice develop a CML-like disease and IRF8 expression is downregulated in patients with CML, suggesting that IRF8 is involved in the pathogenesis of CML. In this study, by using a murine CML model, we show that BCR-ABL strongly inhibits a generation of dendritic cells from an early stage of their differentiation in vivo, concomitant with suppression of Irf8 expression. Forced expression of IRF8 overrode BCR-ABL (both wild-type and T315I-mutated) to rescue dendritic cell development in vitro, indicating that the suppression of Irf8 causes dendritic cell deficiency. Gene expression profiling revealed that IRF8 restored the expression of a significant portion of BCR-ABL-dysregulated genes and predicted that BCR-ABL has immune-stimulatory potential. Indeed, IRF8-rescued BCR-ABL-expressing dendritic cells were capable of inducing CTLs more efficiently than control dendritic cells. Altogether, our findings suggest that IRF8 is an attractive target in next-generation therapies for CML. (C) 2013 AACR.

DOI： 10.1158/0008-5472.CAN-13-0802

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Sinusoidal obstruction syndrome (SOS) is one of the severe complications of hematopoietic stem cell transplantation (HSCT). Systemic management including respiratory and circulatory support is necessary. In addition, abdominal paracentesis is often needed for pain relief and to reduce the pressure of tense ascites. Concentrated ascites reinfusion therapy (CART) involves the filtration, concentration, and reinfusion of drained ascites, which contributes to reuse of autologous proteins. CART has been reported as supportive therapy for patients with liver cirrhosis and cancer. We retrospectively reviewed the efficacy and safety of CART in three patients (two with acute myelogenous leukemia and one with chronic myeloid leukemia) who developed SOS after allo-HSCT. They all had symptomatic, tense, and diuretic-refractory ascites with right costal pain and marked weight gain. Two patients showed immediate improvement after CART. However, one patient experienced four CARTs with slow recovery. All patients are now alive and are being monitored as outpatients over 2 years with remission. No severe adverse event was observed related to CART, and 25.2-98.0 (median 30.2) grams of albumin was collected and reinfused. CART after paracentesis reduces protein loss in ascites by reinfusion of autologous protein instead of exogenous albumin preparations. Although transient fever is reported as a frequent adverse event, no events like severe bleeding or infection were observed. While its safety has not been fully established in patients with hematological disease after HSCT, CART may be a considerable supportive therapy for SOS with tense ascites.

DOI： 10.1111/aor.12080

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Elevated absolute monocyte counts (AMCs) have been reported to indicate poor prognosis for patients with lymphoproliferative disease, including those with follicular lymphoma (FL) receiving various treatments. We evaluated the prognostic impact of AMC in 150 consecutive FL patients who received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. Progression-free survival (PFS) did not differ significantly according to the AMC level. Univariate and multivariate analyses did not indicate a prognostic significance of AMC for PFS. Thus, the AMC is not a prognostic factor for FL patients treated with R-CHOP. However, immunochemotherapy might influence the prognostic impact of AMC. (C) 2013 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.leukres.2013.07.015

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Core binding factor acute myeloid leukemia is known to have a favorable prognosis, however, there have been no detailed analyses on prognostic factors after first relapse. Using a nationwide database, we retrospectively analyzed core binding factor acute myeloid leukemia patients who relapsed after being treated with chemotherapy alone during their first complete remission. Of a total of 397 patients who were diagnosed with core binding factor acute myeloid leukemia, 208 experienced a first relapse, and analyses were performed in 139 patients for whom additional data were available. In the entire cohort, the overall survival rate after relapse was 48% at 3 years. By multivariate analysis, younger age at diagnosis, a longer interval before relapse, and inv(16) were shown to be independently associated with better survival after relapse. Although there was no significant difference in survival after relapse between patients who underwent allogeneic hematopoietic cell transplantation and those who did not in the overall series of relapsed patients, we found that transplantation significantly improved survival among patients who had t(8;21) (54% versus 26% at 3 years, P=0.002). In addition, among patients with t(8;21), those who had different cytogenetics at relapse had a significantly improved survival after transplantation, while those who had same cytogenetics did not. We showed that the prognosis differs significantly and optimal treatment strategies may vary between groups of patients with core binding factor acute myeloid leukemia with different cytogenetic profiles at relapse. These findings may help to guide therapeutic decisions after first relapse.

DOI： 10.3324/haematol.2012.078030

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

A 23-year-old woman developed acute severe hepatitis and jaundice on day 183 after bone marrow transplantation from HLA-B antigen mismatched-related donor. The administration of prednisolone and cessation of the prescribed drugs resolved the liver injury. Drug lymphocyte stimulation test was positive for acyclovir, and liver biopsy indicated the characteristics of drug-induced liver injury (DILI) rather than graft-versus-host disease. Physicians should keep DILI in mind when considering differential diagnosis for liver complications after allogeneic cell transplantation.

DOI： 10.1007/s12185-013-1434-5

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Language：English   Publisher：The Japanese Society for Lymphoreticular Tissue Research  

The introduction of rituximab (R) has measurably improved the outcome of patients with follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). To evaluate the outcome of patients with FL and DLBCL under R plus CHOP therapy, we performed a retrospective analysis in Yokohama City University Hematology Group in Japan. Five hundred and twenty-six patients (158, FL ; 368, DLBCL) were scheduled to undergo primary therapy with 6 cycles of full-dose R-CHOP therapy with curative intent. The median observation periods in livingpatients with FL and DLBCL were 45 months and 43 months, respectively. The complete response, 5-year progression-free survival (PFS), and 5-year overall survival (OS) rates were 86%, 50%, and 92% in the FL group, and 89%, 72%, and 80% in the DLBCL group, respectively. Although PFS was significantly better in the DLBCL group than in the FL group, OS was significantly better in FL patients. We also found that the OS and PFS of grade 3 FL patients were not statistically different from those with grade 1-2. These findings indicate that all grades of FL should be categorized simply as "FL" with regard to R-CHOP therapy. Our results also demonstrate the incurability of FL (grade 1-3B), even with R-CHOP therapy. [<I>J Clin Exp Hematop 53(2) : 121-125, 2013</I>]

DOI： 10.3960/jslrt.53.121

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Other Link： http://search.jamas.or.jp/link/ui/2014164063

Language：English   Publishing type：Research paper (scientific journal)   Publisher：CIG MEDIA GROUP, LP  

We retrospectively investigated high-dose chemotherapy (HDT) plus rituximab followed by autologous stem cell transplantation (ASCT) for patients with poor-prognosis untreated diffuse large B-cell lymphoma (DLBCL). The 5-year overall survival rate using this therapy was 81.0% and the progression-free survival rate was 73.0%. Adding rituximab to upfront HDT/ASCT can improve the outcome of poor-prognosis untreated DLBCL.
Background: Although rituximab added to CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) is the standard chemotherapy for untreated DLBCL, its therapeutic effect is limited in younger patients with high-intermediate risk or high-risk disease according to the age-adjusted international prognostic index. In fact, the efficacy and safety of HDT plus rituximab followed by ASCT for such patients remain unclear. Patients and Methods: We retrospectively investigated the safety and effectiveness of HDT/ASCT in patients with untreated DLBCL. Twenty-two patients, aged 60 years and younger, with untreated DLBCL (classified as high-intermediate [n = 14 (64%)] or high [n = 8 (32%)] risk) underwent upfront HDT/ASCT between January 2004 and December 2008, achieving either a complete response (CR; n = 15 (68%)) or a partial response (PR; n = 7 (32%)). Results: The 5-year overall survival rate was 81.0% and the progression-free survival rate was 73.0%, with no significant difference between risk groups based on the international prognostic index. The most common nonhematologic toxicity was febrile neutropenia [n = 9 (41%)]. The cause of all 3 fatalities was exacerbation of the underlying disease, and no treatment-related mortality was observed. No variables with a significant influence on overall survival were identified, but a correlation of the treatment response before transplanation with progression-free survival was suggested (CR vs. PR: 92% vs. 30%, P = .002). Conclusion: These results suggest that adding rituximab to upfront HDT/ASCT is feasible and can improve the outcome in untreated patients with poor-prognosis DLBCL. In the future, upfront HDT/ASCT should be more extensively evaluated in clinical trials. (C) 2013 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.clml.2013.03.003

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Language：Japanese   Publisher：(公社)神奈川県医師会  

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Long-term observation has identified a pattern of continuing relapse in limited stage diffuse large B-cell lymphoma (DLBCL) treated by three cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) plus involved-field irradiation. We retrospectively analysed 190 untreated patients with limited stage DLBCL treated by R-CHOP alone. All the patients were scheduled to undergo primary therapy with six cycles of full-dose R-CHOP. Cases with a dose reduction of more than 20% were excluded from the study. Additional local irradiation was allowed in patients with partial response (PR). Five patients received additional local irradiation after PR at the end of the R-CHOP therapy. The median observation period was 52 months. Median age at diagnosis was 63 years. The responses to therapy were 180 complete responses, eight PR, and two progression of disease (PD). The 5-year progression-free survival and 5-year overall survival rates were 84% and 90%, respectively, both in plateau. During the observation period, 29 patients experienced PD. The progression sites were the primary sites in 15 patients, outside the primary sites in 10, and undetermined in four patients. These results suggest that the 'standard' strategy of three cycles of R-CHOP followed by involved-field radiotherapy for limited stage DLBCL could be effectively replaced by six cycles of R-CHOP alone.

DOI： 10.1111/bjh.12281

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The optimal treatments for relapsed acute promyelocytic leukemia (APL) remain equivocal. We conducted a phase 2 study to evaluate the efficacy and feasibility of a sequential treatment consisting of induction and consolidation with arsenic trioxide (ATO), peripheral blood stem cell (PBSC) harvest after high-dose cytarabine chemotherapy, and autologous hematopoietic cell transplantation (HCT). Between 2005 and 2009, 35 patients (26 with hematologic and 9 with molecular relapse) were enrolled. Induction therapy resulted in complete remission in 81% of those with hematologic relapse, and most patients became negative for PML-RARα after the first ATO consolidation course, but 4 remained positive. Administration of the second ATO consolidation course further decreased the transcript levels in 3 patients. In total, 25 patients proceeded to PBSC harvest, all of whom successfully achieved the target CD34+ cell doses, and 23 underwent autologous HCT with PML-RARα-negative PBSC graft. Posttransplant relapse occurred in 3 patients, and there was no transplant-related mortality. With a median follow-up of 4.9 years, the 5-year event-free and overall survival rates were 65% and 77%, respectively. These findings demonstrate the outstanding efficacy and feasibility of the sequential treatment featuring ATO and autologous HCT for relapsed APL. This study was registered at http://www.umin.ac.jp/ctr/ as #C000000302.

DOI： 10.1182/blood-2012-11-466862

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Although the use of cord blood transplantation (CBT) is increasing, the optimal methods for conditioning and graft-versus-host disease (GVHD) prophylaxis remain to be established. Among previous reports, the Institute of Medical Science, University of Tokyo (IMSUT) has reported remarkably favorable results of CBT for hematologic malignancies as a single-institute experience. The aim of the present multicenter prospective study was to assess the safety and efficacy of CBT performed precisely according to IMSUT transplantation procedures. Thirty-three adult patients with hematologic malignancies, such as acute leukemia, chronic myelogenous leukemia, or myelodysplastic syndrome, either lacking an HLA-identical sibling/HLA-matched unrelated donor or requiring urgent transplantation were enrolled. Conditioning consisted of total body irradiation (12 Gy), cytarabine, and cyclophosphamide. Cyclosporine A and methotrexate were used for GVHD prophylaxis. Diagnoses were acute leukemia in 26 patients, chronic myelogenous leukemia in 4, and myelodysplastic syndrome in 3; 12 patients were in first complete remission, and the others were in advanced stages at the time of CBT. Thirty-one patients achieved engraftment, and the cumulative incidence of grade II-IV acute GVHD was 45% (95% confidence interval, 28%-62%). With a median follow-up of 46.2 months in 16 surviving patients, the 1-year cumulative incidence of nonrelapse mortality was 15% (95% confidence interval, 5%-30%). Causes of nonrelapse mortality were infection (n = 4) and graft failure (n = 1). The overall and disease-free survival rates were 51% (95% CI, 34%-68%) and 42% (95% CI, 26%-59%), respectively. These results suggest that the IMSUT CBT procedures can safely provide a high disease-free survival rate in patients with high-risk hematologic malignancies.

DOI： 10.1016/j.bbmt.2012.12.007

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DOI： 10.3109/10428194.2012.720374

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While renal comorbidity is generally defined by the serum creatinine level, the creatinine clearance rate (Ccr) is a more accurate indicator of renal function. Therefore, we retrospectively assessed how mildly reduced renal function as defined based on Ccr affects the outcome after allogeneic hematopoietic stem cell transplantation (HSCT). Patients who underwent allogeneic HSCT at the eight institutes of the Kanto Study Group for Cell Therapy were included in this study. Based on the corrected Ccr, patients were classified into group 0 (n = 440,  ≥ 90 mL/min/1.73 m(2)), group 1 (n = 56, 60-89 mL/min/1.73 m(2)), or group 2 (n = 11, 30-59 mL/min/1.73 m(2)). Therefore, 67 patients were considered to have mild renal impairment, whereas only 2 had a serum creatinine level higher than 1.2 mg/dL. Twenty-eight patients required hemodialysis after HSCT, with 5.5, 5.4, and 9.1 % in groups 0, 1, and 2, respectively (p = 0.65). The incidence of non-relapse mortality (NRM) was higher in group 2, although these differences were not statistically significant probably due to the small sample size (23.7, 28.2, and 47.2 % at 3 years, p = 0.20). In conclusion, NRM may be associated with mildly reduced renal function before allogeneic HSCT, which cannot be detected by measurement of the serum creatinine level alone.

DOI： 10.1007/s00277-012-1584-1

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Medical Association of Yokohama City University  

Lenalidomide (Len) in combination with dexamethasone (DEX) shows superior treatment outcome in patients with relapsed/refractory multiple myeloma (MM). We retrospectively analyzed 28 patients with MM who were administered Len from July 2010 to March 2011. The median follow-up period was 120 days (range, 4-181). The median number of treatment cycles was3 (range, 1-6). Two patients were administered a high dose DEX (40mg/day on daysl-4, 9-12, 17-20). Twenty-three patients started with a lower dose of DEX and 3 patients did not receive DEX. The most common grade2 or higher adverse events were neutropenia, thrombocytopenia,renal toxicity, and exanthema. No patients experienced thrombosis. Overall survival on day 100 (after initiation of Len) was 81.2%. The rate of more than partial response was 41. 2%. Reasons for treatment discontinuation of Len were adverse events in 3 patients and progressive disease in 7 patients. Dose reduction or temporary cessation of Len was required in five patients. The dose of DEX was reduced in 7 patients. Although Len is effective for relapsed/refractory MM, further studies are needed to determine the optimal dose of Len and DEX.

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Language：Japanese   Publisher：The Japanese Society of Hematology  

A 60-year-old male with POEMS syndrome received lenalidomide and high-dose dexamethasone combination therapy as an initial treatment, with no severe adverse events occurring during the treatment. Two cycles of the therapy led to significantly decreased serum VEGF level, and IgA-λ type M-protein was not detected by immunofixation electrophoresis. We next performed autologous stem cell transplantation, without severe complications such as engraftment syndrome. He improved enough to walk independently and now is being followed up without treatment. This case suggests that lenalidomide-dexamethasone therapy is highly effective and can be a good option for pre-transplant treatment for POEMS syndrome.

DOI： 10.11406/rinketsu.53.2025

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Other Link： https://jlc.jst.go.jp/DN/JALC/10013528958?from=CiNii

Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

We recently reported that adult acute myeloid leukemia (AML) patients with granulocytic sarcoma (GS) possessed unique clinical features and poor prognosis. However, the optimal therapeutic strategy for this entity has not been established. Therefore, the aim of this study was to assess the efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for the management of AML with GS. We retrospectively analyzed 503 consecutive adult AML patients (median age, 44 years; range, 15-73 years) who received allo-HSCT. A total of 44 patients (8.7%) had GS before transplantation. Patients with GS achieved comparable survival to those without GS (5-year overall survival (OS), 47% vs 44%, respectively, P = 0.621). In patients with GS, excellent outcomes were seen in those that underwent allo-HSCT while in complete remission, whereas nine out of ten patients with GS at the time of transplant experienced a relapse within 6 months after allo-HSCT. Local irradiation for GS prior to allo-HSCT and acute and chronic graft-versus-host disease did not affect survival significantly. Multivariate analysis identified age, disease status and the use of myeloablative conditioning as independent prognostic factors for OS. These data suggest that better control of GS prior to allo-HSCT is crucial to improve the outcome of transplantation for those with GS. Leukemia (2012) 26, 2469-2473; doi: 10.1038/leu.2012.156

DOI： 10.1038/leu.2012.156

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Rituximab (R) plus doxorubicin, cyclophosphamide, vincristine, and prednisolone (CHOP) chemotherapy (R-CHOP) is widely accepted as standard care for diffuse large B-cell lymphoma (DLBCL) patients. The revised International Prognostic Index (R-IPI) was established in 2007 after the addition of rituximab to standard DLBCL treatment. To reassess the utility of R-IPI, we carried out a retrospective analysis of patients with DLBCL uniformly treated with standard R-CHOP. Progression-free survival (PFS) curves in very good and good risk groups as defined by the R-IPI showed no statistical difference. We added soluble interleukin-2 receptor (sIL-2R) level to the factors comprising the R-IPI. Five levels of sIL-2R were weighed with respect to their impact on PFS. sIL-2R of &gt;2500 U/mL was determined as the most appropriate threshold. We developed a new prognostic SIL index, which includes three independent prognostic risk factors: clinical stage (S); sIL-2R level over 2500 U/mL (I); and elevated lactate dehydrogenase level (L). This index indicates standard risk (0 or 1 risk factors, 4-year PFS 83%, 4-year overall survival 91%) and high risk (2 or 3 risk factors, 4-year PFS 52%, 4-year overall survival 67%) outcomes. The SIL index is a simple and objective prognostic index for DLBCL patients to identify candidates for experimental therapy other than R-CHOP. (Cancer Sci 2012; 103: 15181523)

DOI： 10.1111/j.1349-7006.2012.02331.x

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Language：Japanese   Publishing type：Research paper (scientific journal)  

We conducted a retrospective study to evaluate outcomes and prognostic factors of newly diagnosed patients with t(8;21) acute myeloid leukemia (AML). There were 70 patients (43 men and 27 women) with a median age of 48 years old (range, 17∼76 years old). Sixty-five patients achieved complete remission (CR) after induction chemotherapy. Fifty-seven patients received consolidation chemotherapy based on the policy of not performing allogeneic hematopoietic stem cell transplantation (allo-HSCT) at the time of first CR. Twenty-seven of the 57 patients relapsed (relapse rate, 47%). The median time from the achievement of the first CR to relapse was 307 days (96∼1,256 days). A white blood cell count of more than 25,400/μl at diagnosis was associated with a higher relapse rate than a white blood cell count of less than or equal to 25,400/μl (75% vs. 43%, P=0.04). Nineteen of the 25 relapsed patients who received re-induction therapy experienced a second CR (second CR rate, 76%). Twenty-six patients (5 with first CR, 12 with second CR, and 9 without remission) received allo-HSCT. The five-year overall survival and disease-free survival rates were 61% and 45%, respectively. Patients with t(8;21) AML had a high CR rate, but about half of them relapsed. However, this report could not show prognostic factors for the identification of patients who should receive allo-HSCT at the time of their first CR.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

A prospective multicenter Phase II study was performed to examine the efficacy and safety of imatinib therapy in newly diagnosed Japanese patients with chronic-phase CML. Patients were scheduled to receive imatinib 400 mg daily. Plasma imatinib concentrations were measured by liquid chromatographytandem mass spectrometry. In 481 evaluable patients, estimated 7-year overall survival (OS) and event-free survival (EFS) at a median follow-up of 65 months were 93% and 87%, respectively. Because imatinib dosage was reduced in many patients due mainly to adverse events, subgroup analysis was performed according to the mean daily dose during the first 24 months of treatment: =360 mg (400-mg group; n = 294), 270359 mg (300-mg group; n = 90) and &lt;270 mg (200-mg group; n = 67). There were no significant differences in OS and EFS between the 300- and 400-mg groups; however, cumulative rates of complete cytogenetic and major molecular responses differed significantly between the two groups. There were no significant differences in mean imatinib trough levels between these two groups for the patients in whom trough levels had been measured. Survival and efficacy in the 200-mg group were markedly inferior to the former two groups. These results suggest that, although a daily dose of 400 mg imatinib is associated with better outcomes, 300 mg imatinib may be adequate for a considerable number of Japanese patients who are intolerant to 400 mg imatinib. Blood level monitoring would be useful to determine the optimal dose of imatinib. (Cancer Sci 2012; 103: 10711078)

DOI： 10.1111/j.1349-7006.2012.02253.x

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A multicenter retrospective analysis of the influence of pretransplant serum ferritin (SF) was performed in 261 adult recipients of allogeneic hematopoietic stem cell transplant (allo-HSCT), including 159 patients with acute myeloid leukemia (AML), 66 with acute lymphoid leukemia (ALL) and 36 with myelodysplastic syndrome (MDS). Patients were divided into subgroups according to the pretransplant SF level [< 1000 ng/mL (low) vs. ≥ 1000 ng/mL (high)] and disease status at transplant. A high SF level was significantly associated with high disease risk (p = 0.041), but pretransplant SF and disease risk were independent significant prognostic factors for overall survival (OS), disease-free survival (DFS) and non-relapse mortality rate (NRM) on multivariate analysis. The high-SF group showed a worse outcome than the low-SF group among both standard-risk patients (OS: 54% vs. 64%, p = 0.043; DFS: 46% vs. 57%, p = 0.031) and high-risk patients (OS: 16% vs. 35%, p = 0.001; DFS: 15% vs. 34%, p = 0.001). In conclusion, a high SF at transplant adversely influences the outcome of allo-HSCT regardless of disease risk in patients with acute leukemia and MDS.

DOI： 10.3109/10428194.2011.619607

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER TOKYO  

Hospital-acquired pneumonia (HAP) is the second most common cause of hospital-acquired infection and is the leading cause of death. In 2002, the Japanese Respiratory Society (JRS) published guidelines for the diagnosis and treatment of HAP (JRS GL 2002). In these guidelines, treatment with carbapenems is recommended for all disease types of HAP, excluding cases of mild or moderate pneumonia with no risk factors, and cases with early-onset ventilation-acquired pneumonia. To evaluate the efficacy of carbapenems on HAP in accordance with JRS GL 2002, we conducted a prospective study of HAP patients treated with carbapenems based on JRS GL 2002. The results of this study were also analyzed based on the revised guidelines published in June 2008 (JRS GL 2008), and the validity of the new guidelines was examined. Of the 33 subjects, 19 were judged as responders to the treatment, corresponding to a response rate of 57.6%. There were 3 deaths, corresponding to a mortality rate of 9.1%. The efficacy of carbapenems for the treatment of HAP based on JRS GL 2002 was confirmed. The severity rating system in JRS GL 2002 has a tendency to overestimate the severity of the cases and may lead to overtreatment in some cases. On the other hand, the severity rating system by JRS GL 2008 seemed to be more accurate and closely correlated with the efficacy of the treatment. It is suggested that JRS GL 2008 is more useful in clinical practice for accurately judging the severity of the disease and initiating appropriate subsequent antibiotic therapy.

DOI： 10.1007/s10156-011-0253-y

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Human herpesvirus-6 (HHV-6) encephalitis is recognized as a relatively rare, but sometimes lethal, complication of allogeneic hematopoietic stem cell transplantation (HSCT). Although the development of new diagnostic techniques and antiviral therapy has improved, the prognosis of encephalitis is still unclear. We surveyed 197 patients who underwent allogeneic HSCT between January 2004 and March 2008 at our institution, and 8 (4.0%) were diagnosed as having HHV-6 encephalitis. Five were male and 3 were female, with a median age of 40.5 years. The median onset of HHV-6 encephalitis was 18 days after HSCT, and the median duration of antiviral therapy was 41 days. The median survival time from the onset of encephalitis was 23.1 months (range: 2.7-66.7), and 3 patients died of unrelated causes (sepsis in 2 and gastrointestinal tract bleeding in 1). Cord blood transplantation was identified as the only independent risk factor (relative risk [RR] = 4.98; P = .049) by multivariate analysis. There was no statistical significance of survival after HSCT between the patients with HHV-6 encephalitis and those without HHV-6 encephalitis (the 2-year survival rate was 60% and 52.6%, respectively; P = .617). Four of the 5 surviving patients were unable to return to society because of neuropsychological disorders, including anterograde amnesia and seizures with prominent hippocampal atrophy. Although HHV-6 encephalitis occurring after HSCT is now becoming a curable complication, its sequelae, such as neuropsychological disorders, have a marked influence on the quality of life of long-term survivors. Accordingly, it is necessary to identify risk factors for HHV-6 encephalitis and establish methods for prevention of this complication.

DOI： 10.1016/j.bbmt.2011.01.014

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER TOKYO  

The aim of this retrospective study was to evaluate the toxicity profiles of dasatinib in patients with Philadelphia chromosome positive chronic myeloid leukemia (CML) or acute lymphatic leukemia (ALL) who were intolerant to imatinib, and who had been enrolled in our previous clinical trials to evaluate efficacy of dasatinib in patients resistant or tolerant to imatinib therapy. Twenty-four patients with CML and four with ALL were enrolled in the clinical studies to evaluate the efficacy according to the eligibility criteria related to intolerance to imatinib therapy. The toxicities reported during imatinib therapy were non-hematological toxicities in 23 patients and hematological toxicities in six patients. Patients were administered dasatinib 50-70 mg BID or 100 mg QD. Cross intolerance was observed in four patients who showed hematological toxicity after dasatinib treatment. However, it was possible to successfully continue therapy with only temporary interruption. No cross intolerance in non-hematological toxicity was found with the exception of one patient who showed cross intolerance, which did not result in treatment interruption. Dasatinib can be safely administered to imatinib-intolerant CML or Ph-positive ALL patients.

DOI： 10.1007/s12185-011-0864-1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER TOKYO  

A multi-institutional study was conducted to assess efficacy and safety of biapenem (BIPM), a carbapenem antibiotic, as an initial-stage therapeutic agent for febrile neutropenia (FN) in patients with hematopoietic diseases. A total of 216 patients from 25 medical institutions were enrolled in this study; of these, 204 were included in the safety analysis and 178 in the efficacy analysis. The combined (excellent and good) response rate was 67.9%, and antipyretic effect (subsidence + tendency to subsidence) was achieved within 3 and 5 days of treatment in 67.3 and 75.9% of patients, respectively. Thus, the clinical responses were gratifying. A response rate of 61.7% (37/60) was observed even in high-risk FN patients in whom neutrophil counts prior to and at 72 h after the start of BIPM were a parts per thousand currency sign100/mu l. BIPM is considered to be a highly promising drug, with prompt onset of clinical benefit, as an initial-stage therapeutic agent for the treatment of FN in patients with hematopoietic diseases.

DOI： 10.1007/s10156-010-0075-3

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Imatinib is a drug for patients with chronic myeloid leukemia in its chronic phase. Poor drug adherence decreases response to therapy, because the therapeutic effect is related to the imatinib dose. Although the association between adherence and response to therapy has been assessed by various methods, the precise evaluation of adherence is difficult. We investigated the relationship between adherence and response to imatinib by an anonymous survey. Questionnaires were sent to 58 outpatients who had been treated with imatinib for more than one year. The return rate of the questionnaires was 82%. A lack of complete adherence was observed in 26% of all patients, but this lack of adherence was less than 90% in only 4 patients. When adherence was good, there was no relationship between adherence and response to imatinib in most patients, such as that reported in previous papers. We suggest that a better understanding of imatinib therapy by patients may contribute to the improvement of adherence.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society for Cancer Chemotherapy  

DOI： 10.1007/s10156-010-0185-y

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JOHN WILEY & SONS LTD  

The prognosis of diffuse large B-cell lymphoma (DLBCL) has improved markedly in recent years of rituximab era. The prognosis of de novo CD5-positive DLBCL is reported to be poor, but the effect of rituximab on this type of lymphoma remains unclear. To investigate the effect of rituximab on CD5-positive DLBCL, we collected DLBCL, patients and analysed prognostic factors. A total of 157 patients with DLBCL who were immunophenotyped with flow-cytometry (FCM) and treated with chemotherapy were subjected to analysis. Those treated with radiotherapy alone or with supportive therapy only were not included. Patients diagnosed in 2003 or later were treated with rituximab combined chemotherapy. There were 95 males and 62 females. Their age ranged from 20 to 91 years old, and the median was 65 years. Nineteen patients were diagnosed as having de novo CD5-positive DLBCL. Rituximab was given alongside chemotherapy in 85 patients. Of these, 11 were positive for CD5 and 74 were negative. The addition of rituximab improved the overall survival (OS) of DLBCL patients (2-year OS: 82% vs. 70%, p = 0.01). For CD5-negative DLBCL, patients treated with rituximab showed 2-year OS of 84%, which was significantly better than those treated without rituximab (70%, p = 0.008). However, for CD5-positive DLBCL, the prognosis was not statistically different between the patients treated with and without rituximab (59% vs. 50%, p = 0.72). Although rituximab improved the prognosis of DLBCL, such improvement was restricted to the CD5-negative group. Further investigation is required to improve the prognosis of patients with CD5-positive DLBCL. Copyright (C) 2009 John Wiley & Sons, Ltd.

DOI： 10.1002/hon.896

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Language：Japanese   Publisher：(公社)神奈川県医師会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-LISS  

The combination of cyclophosphamide and granulocyte-colony stimulating factor (G-CSF) has widely been used to mobilize hematopoietic stem cells (HSCs) for autologous stem cell transplantation (ASCT) for multiple myeloma (MM). Recently, however, alternative approaches such as G-CSF alone or etoposide followed by G-CSF have been investigated. We, therefore, retrospectively analyzed the effects of these mobilization methods on collection yield and disease outcome in ASCT for MM. We reviewed 146 MM patients from whom we intended to collect stem cells. For mobilization, 67, 58, and 21 patients received cyclophosphamide and G-CSF, etoposide and G-CSF, and G-CSF alone (including nonmyelosuppressive chemotherapy followed by G-CSF), respectively. Among them, 136 achieved the target number of HSCs (at least 2 x 10(6)/kg). Lower creatinine and higher albumin levels at diagnosis were significantly associated with successful yield. A lower number of infused HSCs, use of the etoposide for mobilization and high ISS were associated with delayed hematopoietic recovery. The mobilization methods did not significantly affect either the successful collection of more than 2 x 10(6) CD34-positive cells/kg or PFS after ASCT. G-CSF alone was sufficient for stem cell mobilization for a single ASCT. The optimal approach to collect HSCs in MM remains to be elucidated. Am. J. Hematol. 84:809-814, 2009. (C) 2009 Wiley-Liss, Inc.

DOI： 10.1002/ajh.21552

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

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We sought to determine the frequency of primary extranodal lymphoma (ENL) and its characteristics in Kanagawa, a human T-cell leukemia virus type 1 (HTLV-1) nonendemic area in Japan. Subjects were 847 newly diagnosed patients with malignant lymphoma at the Yokohama City University Hospital and 8 affiliated hospitals mainly located in Kanagawa prefecture from 1999 to 2005. We compared the clinicopathological characteristics of primary ENL with primary nodal lymphoma (NL). Histological specimens were evaluated according to the World Health Organization classifications. A total of 395 (46.6%) and 452 (53.4%) patients had primary ENL and primary NL, respectively. The frequency of primary ENL increased with age. Primary extranodal sites included the gastrointestinal tract (30.4%), Waldeyer's ring (17.8%), orbits (7.0%), soft tissue and subcutaneous tissue (5.2%), bone (4.6%), skin (4.3%), thyroid gland (4.3%), testis and prostate (3.3%), bone marrow (3.3%), nasal and paranasal cavities (2.6%), salivary glands (2.3%), lung and pleura (2.0%), breast (1.8%), central nervous system (1.0%), uterus and ovary (0.5%), and others (9.8%). Among the 395 cases of primary ENL, diffuse large B-cell lymphoma (61.2%) was most frequently diagnosed, followed by extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (13.3%) and follicular lymphoma (5.6%). The frequency of primary ENL is approximately 50% of the total lymphoma cases in Kanagawa, an HTLV-1 nonendemic area in Japan. This frequency appears to be higher than that in Western countries. © 2008 Humana Press Inc.

DOI： 10.1007/s12032-008-9080-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：KARGER  

Background: The existence of immunoglobulin light chain restriction (LCR) strongly indicates B cell monoclonality. Although LCR-deficient B cell malignancies are often observed, their details are barely known. Methods: We retrospectively analyzed LCR-negative diffuse large B cell lymphoma (DLBCL) to elucidate their clinical features. Consecutive DLBCL patients (n = 119), whose histological diagnostic specimens were analyzed by flow cytometry (FCM), were divided into 2 groups: LCR-positive and LCR-negative DLBCL. Cases wherein FCM did not capture tumor cells were excluded. Results: There were 91 LCR-positive (76%) and 28 LCR-negative (24%) DLBCL. The 2 groups did not differ with regard to background, including the International Prognostic Index (IPI), each factor of IPI, gender, bulky mass and B-symptoms. FCM analysis showed that CD10-positive cases were less frequent in the LCR-negative DLBCL group than in the LCR-positive DLBCL group. CD5-positive cases were absent in the LCR-negative DLBCL group. Chromosomal analysis showed that the frequency of BCL2, BCL6 and MYC translocations did not differ between the groups. There was no survival difference in the groups. Conclusion: LCR-negative DLBCL accounts for about one fourth of all DLBCL and their prognosis is similar to that of LCR-positive DLBCL. CD10-negative status might characterize LCR-negative DLBCL. Copyright (C) 2009 S. Karger AG, Basel

DOI： 10.1159/000220332

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Language：English   Publisher：AMER SOC HEMATOLOGY  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Little information is available regarding central nervous system (CNS) relapse of adult leukemia after allogeneic hematopoietic stem cell transplantation (HSCT). Therefore, we reviewed the data of 1226 patients with acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myelogenous leukemia (CML) who received first allogeneic HSCT between 1994 and 2004, using the database of the Kanto Study Group for Cell Therapy (KSGCT), and analyzed the incidence, risk factors, and outcome of patients with CNS relapse. Twenty-nine patients developed CNS relapse at a median of 296 (9-1677) days after HSCT with a cumulative incidence of 2.3%. Independent significant factors associated with CNS relapse included ALL as the underlying diagnosis (relative risk [RR] = 9.55, 95% confidence interval [CI] = 1.26-72.2, P =.029), nonremission at HSCT (RR = 2.30, 95% CI = 1.03-5.15, P =.042), the history of CNS invasion before HSCT (RR 5.62,95% CI = 2.62-12.0, P = 9.2 x 10(-6)), and the prophylactic intrathecal chemotherapy after HSCT (RR 2.57, 95% CI = 1.21-5.46, P = .014). The 3-year overall survival (OS) after CNS relapse was 18%. In 7 of 29 patients with CNS relapse, leukemia was observed only in CNS. Three of 7 patients were alive without systemic relapse, resulting in 3-year survival after CNS relapse of 46%. Although the outcome of patients with CNS relapse was generally poor, long-term disease-free survival could be achieved in some patients.

DOI： 10.1016/j.bbmt.2008.07.002

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

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Language：Japanese   Publisher：The Japanese Society of Hematology  

A 42-year-old woman was admitted to our hospital with acute myelogenous leukemia. We conducted blood-type examination, and her serum showed strong agglutination with all B cells but questionable agglutination with A₁ cells, which became stronger with incubation. We considered her blood type as O, but her previously assessed blood type was A. After receiving one cycle of induction therapy, she achieved complete remission and blood group A antigen was proven on her red blood cells. Anti-A₁ in her serum disappeared after induction therapy. We should be aware that blood group antigens are not entirely independent of the environment and are occasionally modified by disease.

DOI： 10.11406/rinketsu.49.51

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Language：Japanese   Publishing type：Research paper (scientific journal)  

We retrospectively investigated the hematopoietic cell transplantation-specific comorbidity index(HCT-CI)to predict non relapse mortality. Of 127 patients who underwent transplantation between January 2000 and December 2003 with conditioning consisting of total body irradiation, cyclophosphamide and thiotepa, HCT-CI scores were obtained for 83 patients. Median age was 42 years. The sources of stem cells included HLA-identical bone marrow or peripheral blood from sibling(30), HLA-matched bone marrow from unrelated donors(45), and HLA-mismatched bone marrow or peripheral blood from family donors(8). Hematological disease was divided into two groups, standard risk(47)and high risk(36). Standard risk indicates acute leukemia in first or second remission and chronic myelocytic leukemia in first chronic phase, while high risk indicates all other diagnoses. There were 45 patients with moderate or severe pulmonary comorbidities. 55 patients with HCT-CI scores of 2 or less had higher 2-year overall survival than 28 patients with HCT-CI scores of 3 or more(65% vs. 36%, p=0.0009). Although the non relapse mortality rate was not different, HCT-CI scores were a more useful indicator to predict survival in high risk patients than in standard risk patients. Prospective evaluation is warranted to clarify the usefulness of HCT-CI.

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Language：English   Publisher：The Japanese Society of Internal Medicine  

<b>Objective</b> To reduce the relapse rate for hematological malignancies after allogeneic hematopoietic stem cell transplantation, we employed a myeloablative regimen comprising thiotepa 400 mg/m², cyclophosphamide 3,600 mg/m² and total body irradiation 10 Gy.<br> <b>Materials and Methods</b> Subjects comprised 17 patients (median age, 53 years; range, 50-56 years) with hematological malignancies who received allogeneic hematopoietic stem cell transplantation from HLA-identical related (n=6), HLA-mismatched family (n=2) or unrelated donors (n=9). Prophylaxis of acute graft-versus-host disease (GVHD) consisted of short-term methotrexate and cyclosporine (n=4) or short-term methotrexate and tacrolimus (n=13).<br> <b>Results</b> No grade IV regimen-related toxicities as determined by Bearman's criteria were encountered. Acute grade II-IV GVHD developed in 7 patients, with chronic GVHD in 11 patients. With a median follow-up of 39 months, 3 years survival rate after transplantation was 59%. Two patients died due to infection by 100 days after transplantation. Only 1 patient with Philadelphia-positive acute lymphoblastic leukemia experienced relapse. Eight patients died of non-leukemic causes (sepsis, n=2; liver dysfunction, n=2; idiopathic interstitial pneumonia, n=1; bacterial pneumonia, n=1; bronchiolitis obliterans resulting from chronic GVHD, n=1; and disseminated infection with varicella zoster virus, n=1).<br> <b>Conclusions</b> This regimen was tolerable, but a large trial is warranted to confirm the efficacy of this conditioning.<br>

DOI： 10.2169/internalmedicine.47.0598

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Other Link： http://search.jamas.or.jp/link/ui/2008245502

Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

We analysed the long-term outcome of the L86 protocol using L-asparaginase (L-asp), vincristine (VCR) and prednisolone (PSL), collectively known as LVP or L97 protocol using LVP along with pirarubicin hydrochloride (THP-ADR) for 97 patients with acute lymphoblastic leukemia (ALL) diagnosed between 1986 and 2002. No significant differences were seen in the two protocols regarding the complete remission (CR) rate or survival. Seventy-five of the 97 patients (77%) achieved a CR. The overall survival (OS) and disease-free survival (DFS) rates were 32.1% and 30.4% at 10 years, respectively. By univariate analysis, we identified seven adverse factors for DFS which included the L2 subtype by French-American-British classification, hepatosplenomegaly, a white blood cell count of more than 30 x 10(9)/L, a blast cell count of more than 10 x 10(9)/L in the peripheral blood, hemoglobin concentration greater than 10 g/dL, a serum lactate dehydrogenase value greater than twice the upper limit of normal and the presence of the Philadelphia chromosome (Ph). According to multivariate analysis, only the presence of Ph was a significant unfavourable factor for DFS and OS. In the 30 patients under 35 years of age without Ph, the OS in the 20 patients treated with L86 and in the 10 patients treated with L97 were 48 and 86%, respectively (P = 0.011). These results indicate that intensified chemotherapy, such as the L97 protocol that includes an anthracycline, might be beneficial for younger patients who are Ph-negative.

DOI： 10.1080/10428190802464711

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JOHN WILEY & SONS INC  

BACKGROUND. Peripheral T-cell lymphomas (PTCLs) are a biologically heterogeneous subgroup of lymphomas with poor prognosis. In this study, the authors analyzed the clinical behaviors of PTCLs and diffuse large B-cell lymphoma (DLBCL).
METHODS. The authors compared the characteristics and outcomes of 59 patients with PTCLs, including 33 angioimmunoblastic T-cell lymphomas and 26 unspecified peripheral T-cell lymphomas, with the characteristics and outcomes of 193 patients with DLBCLs who were treated in the era before rituximab.
RESULTS. Based on the clinical characteristics, elevated lactate dehydrogenase (LDH), poor PS, advanced stage, higher International Prognostic Index score, and B symptoms were more common in patients with PTCLs, and bulky mass was more common in patients with DLBCL. The rates of complete response (CR) or an unconfirmed CR (CRu) were higher in patients with DLBCL (72%) than in patients with PTCLs (56%; P =.03). The 5-year overall survival (OS), progression free survival (PFS), and disease-free survival (DFS) rates were 31%, 26%, and 47%, respectively, in patients with PTCLs and 59%, 55%, and 73%, respectively, in patients with DLBCL (P =.001, P &lt;.001, and P =.003, respectively). Although multivariate analysis identified several risk factors that were significant in PTCLs, but not in DLBCLs, for the CR/CRu, OS, PFS, and DFS rates, the immunophenotype was not identified as a risk factor.
CONCLUSIONS. The poor response and survival of patients who had PTCLs, compared with patients who had DLBCL, was caused by numerous initial risk factors. T-cell phenotype itself did not appear to have a significant impact on either response or survival. Cancer 2007;109:1146-:31. (c) 2007 American Cancer Society.

DOI： 10.1002/cncr.22507

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Language：English   Publisher：AMER SOC HEMATOLOGY  

DOI： 10.1182/blood.V108.11.2005.2005

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

Recently, the cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) regimen plus rituximab (R-CHOP) have been used widely to treat patients with follicular lymphoma. We investigated a fixed scheme of combination chemotherapy protocol including CHOP, granulocyte colony stimulating factor (G-CSF) and rituximab (CHOP-GR) for patients with advanced-stage grade 1 or grade 2 follicular lymphoma in a phase II clinical trial, assessing enhancement of antibody-dependent cellular cytotoxicity of rituximab by G-CSF. Twenty-one untreated patients received two courses of CHOP chemotherapy followed by four courses of CHOP-GR, including G-CSF (s.c.) on days 11-14 and rituximab on day 15. Overall response rate was 76% (16 of 21 patients). Two patients, one with no response and subsequent allogeneic hematopoietic stem cell transplantation and one with progressive disease, died of lymphoma. One patient refused to continue therapy, whereas two were rediagnosed and no longer met histologic criteria; these three patients were classified as nonresponders. After a median observation time of 23 months, the 19 histologically assessable patients showed a 2-year progression-free survival rate of 82%, whereas 2-year overall survival was 95%. Fifteen patients (79%) continued in remission during this median follow-up period. Of seven patients with initial bulky mass, five responded to therapy. The most frequent adverse events were leukocytopenia (100%) and neutropenia (100%), followed in turn by alopetia (94%) and nausea/vomiting (79%). Of 11 patients examined for bcl-2 translocation in peripheral blood or marrow by polymerase chain reaction (PCR), four were positive, whereas three of the four had complete remissions and converted to PCR negativity after therapy. According to short-term observation, CHOP-GR is a safe and effective therapy for patients with advanced-stage follicular lymphoma.

DOI： 10.1080/10428190500472784

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Language：Japanese   Publisher：(一社)日本リンパ網内系学会  

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Language：Japanese   Publisher：The Japanese Society of Hematology  

We retrospectively evaluated the diagnosis and clinical courses of 8 patients with intravascular large B-cell lymphoma (IVL) diagnosed while they were alive. The median age was 67 years old (range 54 to 82). Most complaints at diagnosis were fever or dyspnea. All patients were in clinical stage IV with B symptoms and 4 patients showed performance status 4. The diagnosis of IVL was confirmed by biopsy specimens from the bone marrow in 4, lung in 2, muscle, adrenal gland, and lymph node in 1 case, respectively. Initial bone marrow involvement was found in 6 patients. Chemotherapy was performed in 7 patients. Rituximab was added to chemotherapy in 5 patients. Though 5 patients are alive at the median follow up of 12.3 months, only 1 patient is in remission. Four of 5 patients treated with Rituximab relapsed. In suspicious cases, it is important to bear IVL in mind and examine bone marrow biopsies for an early diagnosis. In addition, it is suggested that Rituximab may play only a temporary role in the treatment of IVL.

DOI： 10.11406/rinketsu.46.453

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Other Link： http://search.jamas.or.jp/link/ui/2005290296

Language：Japanese   Publisher：The Japanese Society of Hematology  

High-intermediate (HI)- and high (H)-risk non-Hodgkin lymphoma was treated with front-line intensive chemotherapy followed by autologous peripheral blood stem cell transplantation (auto-PBSCT). Twenty-eight cases were enrolled after obtaining informed consent, from November, 1998 to October, 2003. Initial treatment was 2 or 3 cycles of CHOP-V regimen, followed by three high-dose therapy, one each of cyclophosphamide, methotrexate and etoposide. The final high-dose therapy was a combination of ranimustine, ifosphamide and etoposide, which was followed by auto-PBSCT. Patients with a bulky mass received involved-field radiation therapy (IF-RT) after auto-PBSCT. Complete remission (CR) was achieved in 16 cases (57%) and partial remission (PR) in 9 cases (32%), after auto-PBSCT. The final responses after IF-RT were CR in 20 cases (71%) and PR in 5 cases (18%). Overall survival of cases with 2 cycles of CHOP-V regimen was 56% after a median observation time of 30 months, compared with 82% in cases with 3 cycles (p=0.0732). The results suggested that the reduction of tumor size with the initial CHOP-V treatment was most important. In all cases, progression-free survival was 64% and the overall survival was 74% after a median observation time of 30 months, which showed a good outcome compared with that of HI- and H-risk group defined by the age-adjusted international prognostic index reported by Shipp et al.

DOI： 10.11406/rinketsu.46.350

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Language：English   Publishing type：Research paper (scientific journal)  

We describe a 73-year-old woman who developed fever and inflammation with ulceration at the site of mosquito bites in the lower thigh. Soon she developed disseminated skin lesions characterized by redness, induration, and local heat. Some lesions showed necrosis and ulceration, including those located in the nasal cavity. She had no history of hypersensitivity to mosquito bites, and the serum IgE concentration was within the reference range. A skin biopsy specimen from the lower thigh adjoining the mosquito bites was diagnosed pathologically as showing extranodal NK/T cell lymphoma, nasal type. Southern analysis of the biopsy specimen showed an oligoclonal band representing Epstein-Barr virus (EBV) DNA. Bone marrow examination revealed infiltration by lymphoma cells and marked hemophagocytosis. The patient underwent three cycles of chemotherapy with carboplatin, etoposide, ifosfamide, and dexamethasone (DeVIC), but died of lymphoma progression during treatment. We speculate that, rather than an allergic reaction, this late-life occurrence of hypersensitivity to mosquito bites might represent lymphoproliferative disease induced by a direct action of mosquito salivary gland secretions on EBV- infected NK cells. © 2004 Taylor &amp
Francis Ltd.

DOI： 10.1080/10428190410001697403

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We describe a patient with acute promyelocytic leukemia (APL) who developed pulmonary embolism (PE) and thrombotic thrombocytopenic purpura (TTP) during remission induction all-trans retinoic acid (ATRA) therapy. A 44-year-old man was diagnosed with APL and was treated with ATRA. On day 14, he developed PE, and on day 24, he developed TTP. Both PE and TTP occurred in association with leukocytosis due to ATRA administration. The PE responded to dexamethasone and TTP responded to plasma infusion. The PE and TTP remitted, and he achieved complete remission of APL. To our knowledge, there have been no reports of TTP occurring as a complication of ATRA therapy.

DOI： 10.1080/1042819031000097401

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Language：Japanese   Publisher：The Japanese Society of Hematology  

A solitary cutaneous or subcutaneous mass in lymphoblastic lymphoma (LBL) is a rare manifestation. A 15-year-old girl presented with a subcutaneous LBL on her left back. There were no other lesions. Complete remission (CR) was achieved after 2 courses of ACOMP-B (doxorubicin, cyclophosphamide, vincristine, methotrexate, prednisolone, and bleomycin) therapy. Two courses of the chemotherapy and 4 sessions of prophylactic intrathecal methotrexate (15 mg/body) and hydrocortisone (25 mg/body) were added after CR. However, the patient relapsed with bone marrow involvement after 14 months remission. It is necessary to accumulate more experience with this kind of case to find the appropriate treatment strategy for solitary cutaneous or subcutaneous LBL.

DOI： 10.11406/rinketsu.44.25

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Other Link： http://search.jamas.or.jp/link/ui/2003168393

Language：Japanese   Publisher：The Japanese Society of Hematology  

A 35-year-old man with chronic myeloid leukemia (CML) in blastic crisis (BC) received an allogeneic bone marrow transplant from an unrelated donor in October 1998 after three cycles of chemotherapy. BC relapse developed on day 349 after transplantation. After one cycle of chemotherapy and treatment with interferon, the patient received donor lymphocyte infusion (DLI), and this resulted in a complete cytogenetic response 21 days later. Grade III acute graft-versus-host disease developed on day 25 after DLI, but this was resolved after administration of prednisolone. Disease relapse occurred at extramedullary sites on day 162 after DLI, and the patient died of sepsis after receiving chemotherapy. This case illustrates that unrelated DLI can induce remission successfully in patients with relapse of CML in BC through a graft-versus-leukemia effect.

DOI： 10.11406/rinketsu.42.204

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Language：English   Publishing type：Research paper (scientific journal)  

We describe the case of a 73-year-old woman with secondary myelofibrosis who developed subcutaneous extramedullar hematopoiesis. Although extramedullary hematopoiesis has been generally observed in primary myelofibrosis, in this case it was seen in myelofibrosis secondary to polycythemia vera. Histological examination of the subcutaneous nodule revealed that the lesion included cells from the myeloid and megakaryocytc series. The skin lesion almost disappeared after treatment with hydroxyurea. We report here this rare manifestation in secondary myelofibrosis including a review of literature. © 2001, Informa UK Ltd All rights reserved: reproduction in whole or part not permitted. All rights reserved.

DOI： 10.3109/10428190109057946

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A 22-year-old woman was admitted with purpura. Acute promyelocytic leukemia (APL) with disseminated intravascular coagulation (DIC) was diagnosed. On the 17th day after treatment with all-<i>trans</i> retinoic acid (ATRA), left subdural hematoma developed. Although coagulation abnormalities were still observed, emergency surgery was perfomed. Acute epidural hematoma was confirmed by computed tomographic scan after the operation. A second operation for drainage was successful. Post-operative intracranial hematoma may be caused by rapid decompression induced by surgery, but DIC could also be involved. This case underscored the need for careful consideration of the indications for surgical treatment of such DIC patients, with close follow-up monitoring for the postoperative development of neurological symptoms.

DOI： 10.11406/rinketsu.40.606

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Other Link： http://search.jamas.or.jp/link/ui/2000020558

Language：English   Publisher：The Japanese Society of Internal Medicine  

We describe a rare case of de novo acute myelogenous leukemia with trilineage myelodysplasia (AML/TMDS) associated with t(8;21)(q22;q22). The patient was admitted to our hospital with leukocytopenia. AML/TMDS was diagnosed by excess myeloblasts and morphological findings of bone marrow. The karyotype revealed 45, X, -Y, t(8;21)(q22;q22) in 17 of 20 analyzed mitoses, and also AML1/MTG8 transcripts were detected by the reverse transcription polymerase chain reaction (RT-PCR) method. The patient achieved a complete remission with a combination chemotherapy of daunorubicin, cytarabine, and prednisolone. This case suggests that t(8;21)(q22;q22) may participate in the pathogenesis of AML/TMDS, although this type is usually found as one of the chromosomal abnormalities in de novo acute myelogenous leukemia (AML) with maturation.<br>(Internal Medicine 38: 607-611, 1999)

DOI： 10.2169/internalmedicine.38.607

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Harwood Academic Publishers GmbH  

A 34-year-old woman of HTLV-I carrier with T-PLL, whose quality of life improved and survival was prolonged after splenectomy, is described. The patient had marked splenomegaly, generalized lymphadenopathy and marked proliferation of abnormal lymphocytes in the peripheral blood with an irregular nucleus, deeply basophilic cytoplasm and a single prominent nucleolus, which were positive for CD2, CD3, CD5, CD7, CD4 and CD8. Although the patient had serum antibody against HTLV-I, HTLV-I proviral DNA integration was not detected. She was diagnosed as an HTLV-I carrier with T-PLL and received combination chemotherapy and 15.1 Gy splenic irradiation. However, the generalized lymphadenopathy and splenomegaly did not improve. The patient underwent splenectomy to palliate abdominal distension and hypersplenism. After the operation, her symptoms improved dramatically and within a week her hemoglobin concentration and platelet count normalized. She was discharged from hospital two weeks after the splenectomy, however 11 months later, she relapsed and despite treatment with chemotherapy and alpha-interferon, she died two months after the second admission. Autopsy findings revealed that PLL cells had invaded the bone marrow, lymph nodes, liver, lungs, kidneys, uterus, ovaries and adrenal glands.

DOI： 10.1080/10428199909169626

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A 48-year-old woman was admitted with chronic myelogenous leukemia in November, 1996 and was treated with hydroxyurea (HU), because of marked leukocytosis; WBC 404,000/&mu;<i>l</i>. On January 29, 1997, administration of HU was stopped, and treatment of &alpha;-interferon (IFN&alpha;) was started with 6x10⁶U, every day. However, the WBC count rose from 19,600/&mu;<i>l</i> to 56,800/&mu;<i>l</i>, and the combination of IFN and 2,000 mg of HU was started on February 4. The dose of HU was reduced to 500 mg on February 27, and the IFN administration was reduced to 3 times a week from April 4, because the WBC count was less than 10,000/&mu;<i>l</i>. Pancytopenia was revealed in May. The bone marrow biopsy specimen demonstrated marked hypoplastic changes, and chromosome analysis of bone marrow cells showed Philadelphia chromosome in all 20 metaphases. Treatment was interrupted for 7 months, but hematologic parameters did not recover. There were 9 cases reported in detail with bone marrow hypoplasia induced by IFN. One patient received IFN alone and 8 patients received anti-cancer drugs before treatment of IFN. We concluded that great care must be taken for IFN treatment of CML.

DOI： 10.11406/rinketsu.39.302

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Eleven therapy related leukemias (TRL) who were hospitalized in the Department of Hematology and Chemotherapy, Kanagawa Cancer Center between October 1983 and December 1993 were identified. Six of the patients were males and five were females. Their median age was 62 years (range from 14 to 75). Three patients had previously received treatment for breast cancer and two patients for malignant lymphoma. The other patients had received treatment for lung cancer, urinary bladder cancer, gastric cancer, brain tumor, maxillary sinus cancer and macroglobulinemia, respectively. Seven patients had been treated with chemotherapy and four patients had been treated with chemotherapy and irradiation for the primary tumor. The TRL cases consisted of 8 acute non-lymphoid leukemias, two acute lymphoid leukemias and one hypoplastic leukemia, respectively. The status of primary tumors at the developement of TRL was complete remission in ten patients and partial remission in one patient. Three of the 10 patients who received anti-leukemic therapy entered complete remission and the median survival time was 36 days (from 7 days to 489 days). One patient expired of pneumonia before he received anti-leukemic therapy. TRL patients showed poor response to chemotherapy and had poor prognosis. These data suggest that the use of reduced doses of carcinogenic drugs for primary tumors might be required to prevent the development of TRL.

DOI： 10.11406/rinketsu.36.1163

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Language：Japanese   Publisher：The Japanese Society of Hematology  

We investigated the relevance of cytomegalovirus (CMV) to interstitial pneumonitis (IP) using formalin-fixed and paraffin-embedded lung tissues obtained from 12 autopsy cases who died following bone marrow transplantation (BMT) from May 1985 to March in 1992. The lung tissues were examined by hematoxylin and eosin (H.E.) staining, immunohistochemistry with monoclonal antibodies (DDG9, CCH2) and polymerase chain reaction (PCR) for amplifying human CMV DNA. Eight of 12 cases were clinically diagnosed as IP. The 4 cases showed no signs of IP, and their tissues were used as controls. H.E. staining revealed inclusion bodies in two of the eight and only severe fibrosis in the other six. In 4 of the 6 cases, however, CMV was identified by immunohistochemistry or PCR. We concluded that the relevance of CMV in the genesis of IP is often overlooked by H.E. staining alone. Immunohistochemistry and PCR are useful in examining tissues which are suspected of CMV-IP.

DOI： 10.11406/rinketsu.36.735

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Other Link： http://search.jamas.or.jp/link/ui/1996038504

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A 50-year-old female was admitted with acute promyelocytic leukemia (APL) in August, 1988. She was treated with behenoyl-ara-C, daunomycin, 6-mercaptopurine and prednisolone (BH-AC&middot;DMP), which led to a complete remission. Thereafter, she was treated with 2 courses of BH-AC&middot;DM and discharged from hospital. Intensification therapy was performed twice a year, with 1 course of BH-AC&middot;DM and 5 courses of intermittent-dose ara-C/mitoxantrone which ended in March, 1992. She had a relapse in September, 1993 and was treated with all-trans retinoic acid, which led to a second remission. A second relapse occured in May, 1994, and intermittent-dose ara-C/mitoxantrone, combinated with granulocyte colony-stimulating factor (G-CSF), led to a third remission. However, she had a third relapse in September, 1994. She was treated with a trial of G-CSF (300 &mu;g/body, day 1-7), to stimulate dormant leukemic cells to enter the cell cycle, and cyclosporin-A (78 mg/kg, day 2-5), in order to overcome daunomycin resistance in refractory leukemia, combinated with daunomycin (45 mg/m², day 3-5) and ara-C (1.4 g/m², day 3-7), after obtaining informed consent. The fourth remission needed 46 days after combination chemotherapy because of severe myelosuppression. It was suggested that intermittent-dose ara-C/daunomycin therapy combinated with G-CSF and cyclosporin-A may be useful for relapsed and refractory leukemia.

DOI： 10.11406/rinketsu.36.762

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DOI： 10.3109/10428194.2015.1064531

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DOI： 10.3109/10428194.2015.1037763

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DOI： 10.1038/bmt.2015.142

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DOI： 10.1007/s00277-015-2448-2

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Allogeneic stem cell transplantation (allo-SCT) is a curative option for patients with relapsed follicular lymphoma (FL). Prospective studies of reduced-intensity conditioning (RIC) have revealed that chemosensitivity at allo-SCT is the most reliable predictor of outcome; however, limited data are available for progressive/refractory disease. We report here a retrospective analysis of RIC allo-SCT for patients with FL. The purpose of this study was to elucidate the role of allo-SCT for patients with relapsed/refractory FL. We analyzed 46 patients-11 (24%) transplanted in CR, 6 (13%) transplanted in PR and 29 (63%) with progressive/refractory disease. The estimated 5-year overall survival rate was 71.6% (95% confidence interval (CI), 51.5-84.5%). According to the disease status at transplantation, the 5-year survival rate was 80.7% (95% CI, 37.7-95.4%) in the patients with CR or PR and 66.1% (95% CI, 41.5-82.3%) in those with progressive/refractory disease (P=0.29). There were no differences in relapse/progression and non-relapse mortality between the patients with chemosensitive disease and progressive/refractory disease. Allo-SCT may be a valuable treatment option, even for patients with progressive/refractory FL.

DOI： 10.1038/bmt.2015.158

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Language：English   Publisher：WILEY-BLACKWELL  

Dasatinib is one of the key treatment options for chronic myeloid leukemia (CML) patients. Increase in lymphocyte counts has been known to be predictive of a good treatment response under dasatinib treatment as a second line therapy. However, clinical significance of lymphocyte dynamics in the upfront setting has yet to be clarified. To investigate the significance of lymphocyte dynamics in newly diagnosed chronic phase (CP)-CML, patient data of D-First study ( NCT01464411) were analyzed. Fifty-two CML-CP patients enrolled to this study were treated with dasatinib (100 mgday(-1)) and all were followed-up for 18 months. The incidence of lymphocyosis was observed in 14 (27%), but it was not associated with deep molecular response achievement. However, natural killer (NK) cell or cytotoxic T lymphocyte (CTL) counts at 1 month were significantly higher in patients with deep molecular response (DMR) by 18 months compared to those without DMR. When the patients were divided into two groups according to those calculated thresholds by receiver operating characteristic curve (407/L for NK cells and 347/L for CTLs), the cumulative DMR rates by 18 months were significantly better in higher value group compared to lower value group. In contrast, regulatory T cell counts were significantly lower at 12 and 15 months in patients achieved DMR. These results suggest the presence of dual effects of dasatinib on immune system through the cytotoxic lymphocytes activation and Treg deregulation in different periods in newly diagnosed CML-CP. Am. J. Hematol. 90:819-824, 2015. (c) 2015 Wiley Periodicals, Inc.

DOI： 10.1002/ajh.24096

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Irradiation therapy alone is a standard strategy for limited-stage FL, leading to a 10-year progression-free survival (PFS) rate of 30-50%. However, we have been administering R-CHOP therapy alone to patients with limited-stage FL. A total of 35 patients with newly diagnosed FL received R-CHOP therapy with curative intent between 2002 and 2009. The median age of the 35 patients was 61 years; 7 patients had in CS 1 FL, and 28 patients, CS 2 FL. The median number of R-CHOP cycles was 6. On completion of the R-CHOP therapy, 33 patients achieved complete response and 1 showed partial response (PR). The patient showing PR after the completion of R-CHOP was administered additional irradiation. The remaining 1 patient was not evaluated because of discontinuation of hospital visit. In all the 35 patients, the 5-year PFS rate was 70%, and the 5-year overall survival rate was 92%. In the 15 patients with a PFS &gt; 5 years, only 1 patient showed disease progression. The outcome of R-CHOP therapy alone in patients with limited-stage FL was at least equivalent to the reported outcome of irradiation therapy alone. R-CHOP therapy could be an alternative to irradiation therapy in limited-stage FL patients. (C) 2015 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.leukres.2015.03.008

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As the number of young long-term survivors of hematopoietic stem cell transplantation (HSCT) for acute leukemia continues to increase, post-transplant infertility is becoming a significant concern. HSCT, particularly with cyclophosphamide and total body irradiation conditioning, is known to cause secondary premature ovarian failure, resulting in infertility. To preserve post-transplant fertility, several methods have been proposed, including in vitro fertilization (IVF) with embryo cryopreservation. Due to the aggressiveness of acute leukemia, however, patients have little chance to undergo egg harvesting and IVF before they must begin receiving chemotherapy. To the best of our knowledge, there have been no detailed reports of successful pregnancy after HSCT using IVF with embryo cryopreservation and transfer in a patient with acute myeloid leukemia. Here, we report the case of a 42-year-old woman with acute myeloid leukemia who became pregnant 2 years and 2 months after allogeneic bone marrow transplantation via IVF-embryo transfer with an egg collected after induction therapy and delivered a full-term healthy infant.

DOI： 10.1007/s12185-014-1709-5

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Pirarubicin tetrahydropyranyl adriamycin (THP-ADR) is an analogue of doxorubicin. This agent exhibits activity against some doxorubicin-resistant cell lines. We performed a phase II study of biweekly THP-COP [50mg/m(2) pirarubicin, 750mg/m(2) cyclophosphamide, 1.4mg/m(2) vincristine (2.0mg maximum) on day 1, and 100mg/body predonisolone on days 1-5] in patients with peripheral T-cell lymphoma (PTCL). Seventeen patients with newly diagnosed PTCL were enrolled. Histological diagnoses were of PTCL, not otherwise specified (n=5), or angioimmunoblastic T-cell lymphoma (n=12). All diagnostic specimens including those of the historical control group were centrally reviewed by hematological pathologists. All patients received six cycles of biweekly THP-COP. The patient group included 13 male and 4 female patients, with a median age of 62years. The median follow-up time in surviving patients was 30months. Overall response rate was 94% with 15 cases of complete remission (88%). The 3-year progression-free survival and overall survival rates were 57% and 75%, respectively. The most frequent adverse events associated with biweekly THP-COP were leukocytopenia (100%), neutropenia (100%), and lymphopenia (100%), followed by alopecia (92%) and anaemia (88%). All of these occurred only transiently, and the patients subsequently recovered. Biweekly THP-COP is a safe and promising therapy for patients with newly diagnosed PTCL. This study is registered in a public database (UMIN000010485). Copyright (c) 2014 John Wiley & Sons, Ltd.

DOI： 10.1002/hon.2136

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Primary graft failure occurred after cord blood transplantation for a patient with acute lymphoblastic leukemia. The second transplantation was performed using haploidentical peripheral blood. The conditioning regimen consisted of fludarabine (day -1; 30 mg/m(2)), cyclophosphamide (day -1; 2,000 mg/m(2)), and total body irradiation (day - 1; 2 Gy). The immunosuppressants contained tacrolimus, prednisolone, and rabbit antithymocyte globulin (day - 3 to - 2; total dose: 3.75 mg/kg). The engraftment was confirmed on day 9. Both acute and chronic graft-versus-host disease were controllable. The present regimen appears to be suitable for immediate management, fast engraftment, and the durable control of complications.

DOI： 10.2169/internalmedicine.54.4809

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DOI： 10.3109/10428194.2015.1010161

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ObjectivesThe tumor microenvironment, including tumor-infiltrating lymphocytes and myeloid-derived cells, is an important factor in the pathogenesis and clinical behavior of malignant lymphoma. However, the prognostic significance of peripheral lymphocytes and monocytes in lymphoma remains unclear.
MethodsWe evaluated the prognostic impact of the absolute lymphocyte count (ALC), absolute monocyte count (AMC), and lymphocyte/monocyte ratio (LMR) in 359 diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).
ResultsThe median follow-up time of the surviving patients was 58months. Low ALC and an elevated AMC were both associated with poor survival rates. Receiver operating characteristic curve analysis showed that LMR was the best predictor of survival, with 4.0 as the cutoff point. Patients with LMR 4.0 were more likely to have an aggressive tumor, and this was associated with poor treatment responses. Patients with LMR 4.0 at diagnosis had significantly poorer overall survival (OS) and progression-free survival (PFS) than those with LMR &gt;4.0. Multivariate analysis, which included prognostic factors of the International Prognostic Index, showed LMR 4.0 to be an independent predictor for the OS (hazard ratio [HR], 2.507; 95% confidence interval [CI], 1.255-5.007; P=0.009) and PFS (HR, 2.063; 95% CI, 1.249-3.408; P=0.005).
ConclusionsThe LMR at diagnosis, as a simple index which reflects host systemic immunity, predicts clinical outcomes in DLBCL patients treated with R-CHOP.

DOI： 10.1111/ejh.12221

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DOI： 10.3109/10428194.2012.730613

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We analyzed minimal residual disease (MRD) by multidimensional flow cytometry (MFC) after allogeneic stem cell transplantation in 41 patients with acute myeloid leukemia (AML) (n = 31) or acute lymphoblastic leukemia (ALL) (n = 10). Aberrant antigen expression was compared with the results of quantitative PCR for WT1 mRNA (n = 41) and leukemia-specific fusion transcripts (n = 12; AML in seven, ALL in five). There was a significant correlation between detection of MRD by MFC and WT1 mRNA, as well as between MFC and fusion transcripts. Serial monitoring of MRD by the three techniques correlated in parallel to the clinical course in most of the patients, but three patients were only positive for WT1 during hematological remission. The overall survival time of patients with complete remission was significantly associated with the appearance of aberrant expression after transplantation. In conclusion, MFC is valuable for clinical management decisions after transplantation. (C) 2012 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.leukres.2012.04.005

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DOI： 10.3109/10428194.2011.566395

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We conducted a prospective randomized study to assess the optimal postremission therapy for adult acute myeloid leukemia in patients younger than 65 years in the first complete remission. A total of 781 patients in complete remission were randomly assigned to receive consolidation chemotherapy of either 3 courses of high-dose cytarabine (HiDAC, 2 g/m(2) twice daily for 5 days) alone or 4 courses of conventional standard-dose multiagent chemotherapy (CT) established in the previous JALSG AML97 study. Five-year disease-free survival was 43% for the HiDAC group and 39% for the multiagent CT group (P = .724), and 5-year overall survival was 58% and 56%, respectively (P = .954). Among the favorable cytogenetic risk group (n = 218), 5-year diseasefree survival was 57% for HiDAC and 39% for multiagent CT (P = .050), and 5-year overall survival was 75% and 66%, respectively (P = .174). In the HiDAC group, the nadir of leukocyte counts was lower, and the duration of leukocyte less than 1.0 x 10(9)/L longer, and the frequency of documented infections higher. The present study demonstrated that the multiagent CT regimen is as effective as our HiDAC regimen for consolidation. Our HiDAC regimen resulted in a beneficial effect on disease-free survival only in the favorable cytogenetic leukemia group. This trial was registered at www.umin.ac.jp/ctr/as #C000000157. (Blood. 2011;117(8):2366-2372)

DOI： 10.1182/blood-2010-07-295279

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We retrospectively surveyed patients who received a second transplantation for graft failure (GF) after allogeneic hematopoietic stem cell transplantation (SCT) in hospitals participating in the Kanto Study Group for Cell Therapy. A second SCT was performed in 21 of 45 patients with primary GF and in 13 of 15 with secondary GF. The median time between the first and second SCT was 49 days (range, 18-1204 days). The diagnosis included 28 patients with hematologic malignancies and 6 with aplastic anemia. Non-myeloablative or reduced-intensity conditioning was performed in 30 patients. Cord blood was frequently used as the source of stem cells followed by related donor peripheral blood, and unrelated bone marrow. Engraftment was achieved in 23 patients (68%). Conditioning regimen including total body or total lymphoid irradiation, was significantly associated with a higher engraftment rate. Overall survival at 5 years in all patients who underwent second SCT was 34%. Prognostic factors for better survival after second SCT were a time to second SCT longer than 90 days, the performance status at second SCT with 0 or 1, and the administration of tacrolimus for GVHD prophylaxis. The major cause of death after second SCT was infection. Although the outcome of a second SCT for graft failure remains poor, these findings suggest that the selection of patients as well as transplant methods, such as conditioning and GVHD prophylaxis, may contribute to survival.

DOI： 10.11406/rinketsu.51.390

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A phase 1/2 study was conducted to assess the safety and efficacy of dasatinib in Japanese patients with chronic myelogenous leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) resistant or intolerant to imatinib. In phase 1, 18 patients with chronic phase (CP) CML were treated with dasatinib 50, 70, or 90 mg twice daily to evaluate safety. Dasatinib a parts per thousand currency sign 90 mg twice daily was well tolerated. In phase 2, dasatinib 70 mg was given twice daily to CP-CML patients for 24 weeks and to CML patients in accelerated phase (AP)/blast crisis (BC) or Ph(+) ALL for 12 weeks. In the CP-CML group (n = 30) complete hematologic response was 90% and major cytogenetic response (MCyR) 53%. In the AP/BC-CML group (n = 11) major hematologic response (MaHR) was 64% and MCyR 27%, whereas in the Ph(+) ALL group (n = 13) MaHR was 38% and MCyR 54%. Dasatinib was well tolerated and most of the nonhematologic toxicities were mild or moderate. Dasatinib therapy resulted in high rates of hematologic and cytogenetic response, suggesting that dasatinib is promising as a new treatment for Japanese CML and Ph(+) ALL patients resistant or intolerant to imatinib.

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The reciprocal translocation t(1
3)(p36
q21) is associated with myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML) characterized by trilineage dysplasia, in particular dysmegakaryocytopoiesis, and a poor prognosis. As yet no molecular genetic analyses of the t(1
3) have been reported. In four patients with t(1
3), all of whom had AML-M4, which evolved from MDS, the breakpoints at 3q21 clustered within a 60-kb region centromeric to the breakpoint of the inv(3)(q21q26), whereas the breakpoints at 1p36 clustered within a 90-kb region at 1p36.3. The presence of novel clusters in both the 3q21 and 1p36 breakpoints (BCRs) suggests a common, underlying molecular mechanism for the development of t(1
3)-positive MDS/AML. The Ribophorin 1 (RPN1) gene close to the BCR at 3q21 was highly expressed without gross structural changes, whereas the GR6 gene located within the BCR at 3q21 was not expressed. No other highly expressed genes were isolated in a 150-kb region at 3q21. Thus, it is likely that a gene at 1p36,3 is activated by the translocation of the 3q21 region or a gene important for transformation lies on 3q21, outside the 150-kb region. Further characterization of the BCRs at 1p36.3 and 3q21 should provide important insights into the molecular genetic mechanisms involved in the genesis of t(1
3)-positive MDS/AML.

DOI： 10.1002/(SICI)1098-2264(200003)27:3<229::AID-GCC2>3.0.CO;2-0

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