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Background and aims Immunoglobulin 4 (IgG4)-related disease (IgG4-RD) is a lymphoproliferative disorder characterized by elevated serum IgG4 levels and tissue infiltration of IgG4-positive plasma cells. We analyzed the serum proteins, whose levels varied based on the disease state and treatment. Materials and methods Serum proteins from patients with IgG4-related disease and healthy subjects were resolved using two-dimensional electrophoresis, silver-stained, and scanned. Alternatively, the proteins were labeled with Cy2, Cy3, and Cy5 before electrophoresis. The proteins, whose expression differed significantly between patients and healthy individuals, and between before and after steroid treatment, were identified and validated using enzyme-linked immunosorbent assays. Results Pre-treatment sera from patients with IgG4-related disease was characterized by increased levels of immunoglobulins such as IgG1, IgG4; inflammatory factors such as α-1 antitrypsin (A1AT); and proteins associated with immune system regulation such as clusterin and leucine-rich α-2-glycoprotein (LRG-1). The serum levels of A1AT, LRG-1 and clusterin, during treatment with prednisolone for up to 12 months revealed that LRG-1 levels were halved after 1 month of treatment, comparable to those in healthy subjects; LRG-1 levels remained normal until the end of treatment. Conclusion LRG-1 could serve as a novel biomarker of IgG4-related diseases.

Tyrosine kinase inhibitor (TKI) administration after allogeneic hematopoietic stem cell transplantation (HSCT) may carry a survival benefit in Philadelphia chromosome‐positive acute lymphoblastic leukemia (Ph+ ALL). Therefore, we investigated whether TKI prophylaxis for negative‐minimal residual disease (MRD) after HSCT would improve patient outcomes in this nationwide retrospective cohort study. We included patients with Ph+ ALL who underwent their first allogeneic HSCT between 2001 and 2016, received TKI before HSCT, and achieved negative‐MRD status within 180 days after HSCT. Of 850 patients for inclusion, 50 patients received TKI prophylaxis, mostly imatinib or dasatinib (median dose: 400 mg with imatinib and 40 mg with dasatinib). In a multivariate analysis, disease status at HSCT was the sole risk factor for relapse (hazard ratio, 3.58; P

A 73-year-old man was referred to our hospital with a persistent fever, anemia, and a mass in the left pubic region. The findings of biopsy evaluations of the mass and a left inguinal lymph node were consistent with Castleman disease (CD) of plasma cell type. His serum interleukin 6 (IL-6) level was remarkably elevated, supporting the diagnosis of CD. However, imaging analyses revealed destruction of the pubic bone by the mass, which was atypical for CD. Therefore, another deeper biopsy was performed, which finally led to the diagnosis of IL-6-producing osteosarcoma. We conclude that clinicians should carefully exclude malignancies prior to making a CD diagnosis.

The optimal treatment for Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) in first complete remission (CR1) has not been established in the high-intensity chemotherapy era. The outcomes of patients with Ph-negative ALL who underwent allogeneic hematopoietic stem cell transplantation (HSCT) from a human leukocyte antigen-matched related or unrelated donor in CR1 (HSCT-MRD group and HSCT-MUD group) were obtained from a Japanese registry database. Patients aged 16–24 years and 25–65 years were analyzed separately, and their outcomes were compared to those of patients who continued high-intensity chemotherapy in CR1 in studies (202U group and 202O group) by the Japan Adult Leukemia Study Group (JALSG). In the HSCT-MRD group, patients younger than 25 years had lower overall survival (OS) than the 202U group, presumably due to the higher non-relapse mortality (NRM) in the HSCT-MRD group. Patients 25 years and older had similar OS to the 202O group. The lower relapse rate was counterbalanced by higher NRM in the HSCT-MRD group. In the HSCT-MUD group, patients in both age groups had similar OS to their corresponding groups in the JALSG studies. In conclusion, high-intensity chemotherapy may change the role of HSCT for Ph-negative ALL.

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

High-dose chemotherapy with autologous stem cell transplantation (HDC-ASCT) is an option for patients with peripheral T-cell lymphoma (PTCL); however, neither prospective nor retrospective studies support proceeding with ASCT upfront, and the timing of HDC-ASCT remains controversial. We retrospectively analyzed the risk factors for outcomes of 570 patients with PTCL, including PTCL not otherwise specified (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL), who received ASCT for frontline consolidation (n = 98 and 75, respectively) or alternative therapies after either relapse (n = 112 and 75) or primary induction failure (PIF; n = 127 and 83) between 2000 and 2015. Significant risk factors for overall survival (OS) after upfront ASCT were a ≥ 2 prognostic index for T-cell lymphoma (P 0.001) and partial response (PR) at ASCT (P = 0.041) in PTCL-NOS patients, and 60 years of age (P = 0.0028) and PR at ASCT (P = 0.0013) in AITL patients. Performance status of ≥ 2 at ASCT (P 0.001), receiving ≥ 3 regimens before ASCT (P = 0.018), and PR at ASCT (P = 0.018) in PTCL-NOS patients and 60 years of age at ASCT (P = 0.0077) in AITL patients were risk factors for OS after ASCT with a chemosensitive PIF status. Strategies that carefully select PTCL patients may allow identification of individuals suitable for ASCT.

Background Dasatinib has shown promising anti-leukemic activity against chronic myeloid leukemia (CML). However, patients receiving dasatinib frequently require dose reductions and treatment interruptions (treatment alteration). Methods We prospectively analyzed the frequency and significance of treatment alteration during dasatinib therapy in patients with CML. In all patients, trough plasma concentrations of dasatinib (Cmin) at steady state were assessed on day 28 of therapy. Results 28% of patients had their doses reduced at a median of 42 days, and 25% of patients had temporarily interrupted at a median of 54 days after treatment initiation. The overall dasatinib treatment alteration-free rate at 1 year was 66%. Age was significantly correlated with Cmin on day 28 (p = 0.014), and the correlation remained significant after adjusting dasatinib dose (g), body weight (kg) (Cmin/D/W) (p = 0.026). In the univariate analysis, deep molecular response, advanced PS, higher Cmin/D/W were associated with a significantly higher risk of treatment alteration (HR 4.19, 95% CI: 1.06–16.60, p = 0.041; HR 5.26, 95% CI: 1.33–20.80, p = 0.018; and HR 10.15, 95% CI: 2.55–40.48, p = 0.001, respectively). In the multivariate analysis, advanced PS and higher Cmin/D/W were correlated with the incidence of treatment alteration (HR 4.78, 95% CI: 1.01–22.70, p = 0.049; HR 6.17, 95% CI: 1.17–32.50, respectively). Conclusion Current data demonstrate that patients treated with dasatinib who displayed a high Cmin/D/W value and/or advanced PS were at a high risk for altered treatment.

Allogeneic hematopoietic stem cell transplantation (HSCT) with the conventional cyclophosphamide and total body irradiation (CY/TBI) regimen is an essential therapeutic strategy for acute lymphoblastic leukemia (ALL) in adults. Medium-dose etoposide (VP16, 30-40 mg/kg) can be added to intensify this CY/TBI regimen and reduce relapse; however, differences in prognosis between the VP16/CY/TBI and CY/TBI regimens have not yet been fully analyzed. We conducted a retrospective cohort study using a Japanese transplant registry database to compare the prognosis between the VP16/CY/TBI (VP16, total 30-40 mg/kg) (N = 376) and CY/TBI (N = 1178) regimens in adult patients with ALL transplanted at complete remission (CR) between January 1, 2000 and December 31, 2014. Our analyses indicated that VP16/CY/TBI significantly reduced relapse compared with CY/TBI (risk ratio, 0.75; 95% confidence interval [CI], 0.56-1.00; P = .05) with a corresponding improvement in leukemia-free survival (hazard ratio [HR], 0.76; 95%CI, 0.62-0.93; P = .01), particularly in patients transplanted at CR1 with advanced-risk (positive minimal residual disease, presence of poor-risk cytogenetics, or an initial elevated leukocyte count) (HR, 0.75; 95%CI, 0.56-1.00; P = .05) or those transplanted beyond CR2 (HR, 0.58; 95%CI, 0.39-0.88; P = .01). The addition of VP16 did not increase post-transplant complications or nonrelapse mortality (HR, 0.88; 95%CI, 0.65-1.18; P = .38). This study is the first to reveal the efficacy of the addition of medium-dose VP16 to CY/TBI in high-risk ALL. To establish new myeloablative conditioning regimens including VP16, a large-scale prospective study is necessary.

To investigate better GVHD prophylaxis in reduced intensity conditioning umbilical cord blood transplantation (RIC-UCBT), we compared transplant outcomes after UCBT among GvHD prophylaxes using the registry data. We selected patients transplanted for AML or ALL with a calcineurin inhibitor and methotrexate (MTX)/mycophenolate mofetil (MMF) combination. A total of 748 first RIC-UCBT between 2000 and 2012 (MTX+ group, 446, MMF+ group, 302) were included. The cumulative incidence of neutrophil and platelet counts higher than 50 000/μL was significantly better in the MMF+ group (relative risk (RR), 1.55; P

Summary The efficacy of high-dose cytarabine (HDCA) plus cyclophosphamide/total-body irradiation (CY/TBI) has been proved in cord blood transplantation (CBT) for acute lymphoblastic leukaemia (ALL), but not in bone marrow or peripheral blood stem cell transplantation (BMT/PBSCT). In this cohort study, we compared the prognosis of CY/TBI (N = 1244) and HDCA/CY/TBI (N = 316) regimens in BMT/PBSCT for ALL. The addition of HDCA decreased post-transplant relapse, while significantly increasing non-relapse mortality (risk ratio, 1·33), and overall survival was not improved. The positive effects of HDCA reported in CBT cannot be extrapolated to BMT/PBSCT, and HDCA may not be recommended in these procedures.

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 49 years, with 28 patients55 years 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 patients55 years and 8 of 26 patients55 years underwent allo-SCT at first CR. The 3-year OS in patients55 years receiving allo-SCT at first CR, patients55 years receiving allo-SCT at first CR, patients55 years not receiving allo-SCT at first CR, and patients55 years 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 those55 years. 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).

Castleman disease (CD) is a rare lymphoproliferative disorder that can be unicentric or multicentric. Multicentric CD (MCD) is further subdivided into human herpesvirus type-8-associated, POEMS syndrome-associated, and idiopathic (iMCD). TAFRO syndrome is a newly identified disorder of unknown etiology characterized by thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal dysfunction, and organomegaly. The TAFRO syndrome is sometimes regarded as a subtype of iMCD (TAFRO-iMCD), whereas iMCD without TAFRO syndrome is considered "not otherwise specified" (iMCD-NOS). However, a proportion of patients with TAFRO syndrome have been diagnosed without lymph node biopsies (TAFRO syndrome without proven iMCD; TAFRO-w/op-iMCD). To clarify the clinical features of iMCD-NOS, TAFRO-iMCD, and TAFRO-w/op-iMCD, we retrospectively analyzed 220 patients extracted from the database of the Multicenter Collaborative Retrospective Study for Establishing the Concept of TAFRO Syndrome. The patients included 87 with iMCD-NOS, 63 with TAFRO-iMCD, and 19 with TAFRO-w/op-iMCD. Patients in all three groups exhibited anemia, hypoalbuminemia, and elevated serum C-reactive protein and interleukin-6 levels. No significant differences in clinical, laboratory, and prognostic features were noted between the TAFRO-iMCD, and TAFRO-w/op-iMCD groups. However, the iMCD-NOS group exhibited polyclonal hyper-γ-globulinemia. The five-year survival rates of patients in the iMCD-NOS and TAFRO-involved groups were 100% and 66.5%, respectively (dropping markedly during the first few months in the latter). The iMCD-NOS and the TAFRO-iMCD samples typically showed plasma cell and mixed-type histologies, respectively. Thus, iMCD can be classified into two distinct subtypes, iMCD-NOS and TAFRO-iMCD. As such, TAFRO-iMCD and TAFRO-w/op-iMCD may be considered the same entity, requiring prompt diagnosis and intensive care.

We conducted a retrospective analysis to compare outcomes in adult patients with acute lymphoblastic leukemia (ALL) who underwent allogeneic hematopoietic cell transplantation (allo-HCT) with conditioning regimens containing cyclophosphamide (CY) in combination with total body irradiation (TBI), oral busulfan (p.o. BU), or intravenous busulfan (i.v. BU). We used data for January 2000 to December 2012 from the Transplant Registry Unified Management Program of the Japan Society of Hematopoietic Cell Transplantation. We identified 2130 patients treated with TBI/CY (n = 2028), p.o. BU/CY (n = 60), or i.v. BU/CY (n = 42). Two-year overall survival (OS) and 2-year relapse-free survival rates were 69.0% and 62.1%, respectively, in the TBI/CY group, 55.9% and 54.2% in the p.o. BU/CY group, and 71.0% and 46.8% in the i.v. BU/CY group. In multivariate analysis, compared with TBI/CY, p.o. BU/CY, but not i.v. BU/CY, was associated with lower OS (hazard ratio [HR], 1.46; P = .047) and a higher incidence of sinusoidal obstruction syndrome (HR, 3.36; P = .030). No between-group differences were seen in the incidence of nonrelapse mortality, relapse, acute graft-versus-host disease (GVHD), or chronic GVHD. We suggest that i.v. BU/CY might be a possible alternative allo-HCT conditioning regimen for adults with ALL who are not suitable for TBI.

Cytogenetic abnormalities are well known and powerful independent prognostic factors for various hematologic disorders. Although the combination of chemotherapy with tyrosine kinase inhibitor (TKI) is now considered the standard of care in patients with Philadelphia chromosome–positive acute lymphoblastic leukemia, little is known about the impact of additional cytogenetic abnormalities (ACAs). Therefore, we retrospectively evaluated 1375 adult patients who underwent their first allogeneic hematopoietic stem cell transplantation in the TKI era. In this study, 224 patients had ACAs (16.3%). The ACAs that were seen in more than 20 cases (1.5%) were as follows: -7, der(22), der(9), +8, and +X. Overall survival at 4 years was 56.9% (95% confidence interval [CI], 49.4% to 63.7%) in the group with ACAs and 60.5% (95% CI, 57.3% to 63.5%) in the group without ACAs (P = .266). The cumulative incidence of relapse at 4 years was 28.9% (95% CI, 22.6% to 35.6%) in the group with ACAs and 21.9% (95% CI, 19.4% to 24.6%) in the group with Ph alone (P = .051). In multivariate analyses there were no statistically significant differences in the risk of overall mortality or risk of relapse between the groups with and without ACAs. In the subgroup analyses of specific ACAs, although the presence of +8 was associated with a higher relapse rate in univariate and multivariate analyses, no specific ACA was associated with poor overall survival. Further studies will be needed to verify the impact of specific ACAs on transplantation outcomes.

Introduction The addition of tyrosine-kinase inhibitor (TKI) to conventional chemotherapy followed by allogenic hematopoietic stem cell transplantation (HSCT) is a standard treatment for transplant-eligible patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Although TKI administration after HSCT may carry a survival benefit, available data are scarce. Objectives We conducted a nationwide retrospective study to evaluate whether TKI prophylaxis after allogenic HSCT in patients with negative-MRD would reduce relapse and improve overall survival. Methods In this nationwide retrospective cohort study, we included patients with Ph+ ALL who underwent their first allogenic HSCT between 2001 and 2016, received TKI before HSCT, and achieved negative-MRD status within 180 days after HSCT. Administration of TKI within 180 days after HSCT in a patient who maintained negative-MRD was defined as prophylactic TKI. Cox proportional hazards regression models were used to evaluate the impact of post-transplant TKI prophylaxis as a time-dependent covariate. Results We identified 850 patients for inclusion in this study. Fifty patients received TKI prophylaxis, mostly imatinib or dasatinib. TKI was more frequently administered in late time periods of HSCT or in cases of positive-MRD at HSCT. In a multivariate analysis, disease status at HSCT was the sole risk factor for relapse (hazard ratio, 3.58; P Conclusions Routine post-transplant TKI prophylaxis especially with imatinib is not recommended because this strategy yielded no clinical benefits. Since the risk of relapse in patients who did not achieve negative-MRD at HSCT was higher, even though they did achieve negative-MRD after HSCT, close monitoring and different post-transplant strategies using new-generation TKIs might be preferable in such patients.

It is still a matter of debate whether detection of Epstein–Barr virus (EBV) DNA in pretreatment serum has clinical implications for diffuse large B‐cell lymphoma. For this study, we measured EBV DNA load in pretreatment serum from 127 diffuse large B‐cell lymphoma patients without any underlying immunodeficiency to evaluate its effects on clinical manifestations and prognosis. Anthracycline‐based chemotherapy in combination with rituximab was given as initial therapy for 119 patients (94%). Epstein–Barr virus DNA was detected in 15 patients (12%), who were older (P = 0.005) and tended to be at a more advanced disease stage (P = 0.053). They showed significantly worse progression‐free survival (PFS) and overall survival (OS) than other patients (P < 0.001 each). This effect remained significant (P = 0.004 and P = 0.027, respectively) after adjustment for age, lactate dehydrogenase, performance status, stage, and extranodal sites. The status of EBV‐encoded small RNA in situ hybridization was known for 123 patients; 6 of 8 positive patients (75%) and 9 of 115 negative patients (8%) had detectable EBV DNA in pretreatment serum. While patients positive for EBV‐encoded small RNA had significantly worse PFS and OS than negative patients (P = 0.001 and P = 0.029, respectively), EBV DNA detection in pretreatment serum was associated with poorer PFS and OS even for the 115 patients negative for EBV‐encoded small RNA (P < 0.001 each). These findings suggest that EBV DNA detection in pretreatment serum may have an adverse prognostic impact for patients with diffuse large B‐cell lymphoma.

Epstein-Barr virus (EBV)-encoded small RNA in situ hybridization (EBER-ISH) is a widely accepted method to evaluate EBV involvement in diffuse large B-cell lymphoma (DLBCL), although little is known regarding associations between EBV DNA load and the EBER status and whether EBV DNA load data provide additional clinical information. In this study, we quantified EBV DNA load in diagnostic specimens from DLBCL patients diagnosed at our hospital to evaluate clinical implications of EBV DNA load in diagnostic specimens as contrasted with EBER-ISH. Among 140 DLBCL patients without underlying immunodeficiency, 51 were evaluable for both EBER and EBV DNA load, 83 for EBER only and one for EBV DNA load only. The median EBV DNA load was 708 copies/µg. Although EBV DNA load was significantly higher for EBER-positive patients than for EBER-negative patients (p

BACKGROUND: Transfusion of group O blood to non-O recipients, or transfusion of D- blood to D+ recipients, can result in shortages of group O or D- blood, respectively. This study investigated RBC utilization patterns at hospitals around the world and explored the context and policies that guide ABO blood group and D type selection practices.STUDY DESIGN AND METHODS: This was a retrospective study on transfusion data from the 2013 calendar year. This study included a survey component that asked about hospital RBC selection and transfusion practices and a data collection component where participants submitted information on RBC unit disposition including blood group and D type of unit and recipient. Units administered to recipients of unknown ABO or D group were excluded.RESULTS: Thirty-eight hospitals in 11 countries responded to the survey, 30 of which provided specific RBC unit disposition data. Overall, 11.1% (21,235/191,397) of group O units were transfused to non-O recipients; 22.6% (8777/38,911) of group O D- RBC units were transfused to O D+ recipients, and 43.2% (16,800/38,911) of group O D- RBC units were transfused to recipients that were not group O D-. Disposition of units and hospital transfusion policy varied within and across hospitals of different sizes, with transfusion of group O D- units to non-group O D- patients ranging from 0% to 33%.CONCLUSION: A significant proportion of group O and D- RBC units were transfused to compatible, nonidentical recipients, although the frequency of this practice varied across sites.

The optimal conditioning regimen for elderly patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT) remains unclear. We retrospectively analyzed 1607 patients aged 50 years or older with acute myeloid leukemia (AML), acute lymphoblastic leukemia, or myelodysplastic syndrome (MDS) who underwent allo-HCT using fludarabine/busulfan (FB) or fludarabine/melphalan (FM) between 2007 and 2014. We compared the clinical outcomes among FB2 (busulfan at 6.4 mg/kg iv, n = 463), FB4 (busulfan at 12.8 mg/kg iv, n = 721), and FM140 (melphalan at 140 mg/m2, n = 423). The nonrelapse mortality (NRM) rates in the FB4 and FM140 groups were higher than that in the FB2 group (hazard ratio [HR], 1.63 [P

Varicella, characterized by a vesicular rash, occurs primarily in young children. Although older individuals can also be affected or vaccinated, outbreaks among adults are rare. We investigated a small outbreak of varicella in B-cell lymphoma patients for elucidation of risk factor of the disease. We experienced four cases of varicella after an index herpes zoster case. All varicella cases were confirmed varicella zoster virus (VZV) infection by PCR. All varicella cases occurred in diffuse large B-cell lymphoma patients receiving rituximab-containing chemotherapy. On the other hand, only three of the 18 non-varicella patients in the same room were receiving rituximab-containing chemotherapy (P = 0.005). All varicella patients had detectable serum anti-varicella zoster virus IgG antibodies before chemotherapy. Even in the presence of neutralizing antibodies to the virus, lymphoma patients treated with rituximab-containing chemotherapy can possibly become re-infected with varicella. These findings suggest that zoster patients should be strictly isolated in hematology and oncology ward, and prophylactic acyclovir should be considered for such patients when exposed to zoster/varicella.

We aimed to evaluate the impact of pretransplant imatinib administration on the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in adults with Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL). We retrospectively analyzed 738 patients with Ph(+) ALL that underwent allo-HSCT between 1990 and 2010 using data from the Transplant Registry Unified Management Program of the Japan Society of Hematopoietic Cell Transplantation. We compared the allo-HSCT outcomes between 542 patients who received imatinib before allo-HSCT during the initial complete remission period (imatinib cohort) and 196 patients who did not receive imatinib (non-imatinib cohort). The 5-year overall survival after allo-HSCT was significantly higher in the imatinib cohort than in the non-imatinib cohort (59% vs 38%; 95% confidence interval [CI], 31-45%; P < .001). Multivariate analysis indicated that pretransplant imatinib administration had beneficial effects on overall survival (hazard ratio [HR], 0.57; 95% CI, 0.42-0.77; P < .001), relapse (HR, 0.66; 95% CI, 0.43-0.99; P = .048), and nonrelapse mortality (HR, 0.55; 95% CI, 0.37-0.83; P = .005). In conclusion, our study showed that imatinib administration before allo-HSCT had advantageous effects on the clinical outcomes of allo-HSCT in patients with Ph(+) ALL.

[Background] We previously demonstrated that allogeneic hematopoietic stem cell transplantation (HSCT) in the first complete remission (CR1) was recommended for adult patients wih Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) who have a human leukocyte antigen (HLA)-matched related (Leukemia 2011;25:259-265) or unrelated donor (Bone Marrow Transplant 2013;48:1077-1083). However, pediatric-inspired high-intensity chemotherapy dramatically improved the prognosis of adult patients with Ph-negative ALL. Therefore, the optimal treatment strategy for Ph-negative ALL in CR1 has not been established in the era of high-intensity chemotherapy. [Methods] Outcomes of patients with Ph-negative ALL who underwent HSCT from HLA-matched related or unrelated donor in CR1 performed between 2002 and 2011 (HSCT-MRD group and HSCT-MUD group, respectively) were obtained from the Transplant Registry Unified Management Program (TRUMP), which is the registry database of the Japanese Society for Hematopoietic Cell Transplantation (JSHCT). Patients aged between 16 and 24 and between 25 and 65 were analyzed separately, and their outcomes were compared with those of patients who did not receive HSCT in CR1 in clinical studies by Japan Adult Leukemia Study Group (JALSG), ALL-202U study in which patients received chemotherapy designed for pediatric patients (Blood Cancer J 2014;4:e252)(202U group) and ALL-202O study in which patients were randomly assigned to receive adult-type chemotherapy with high-dose or intermediate-dose methotrexate (MTX) therapy (Leukemia 2018;32:626-632)(202O group), respectively. Median durations between diagnosis to HSCT were obtained from the TRUMP data, and only patients who were disease-free more than each median duration were included from the JALSG studies. Risk stratifications were performed based on the white blood cell (WBC) count and cytogenetics. [Results] In patients aged less than 25 who underwent HSCT from related donor, the median duration between diagnosis to HSCT was 188 days. Overall survival (OS) in 202U group (N = 93) was significantly superior compared with OS in HSCT-MRD group (N = 102) (OS at 5 years: 81.8% vs 67.8%, P = 0.016) (Figure 1(A)), and which was attributed to the higher non-relapse mortality in HSCT-MRD group (NRM at 5 years: 1.4% vs 9.5%, P = 0.015). Disease-free survival (DFS) and relapse rate (RR) were similar between two groups (DFS at 5 years: 70.2% vs 62.5%, P = 0.115, and RR at 5 years: 28.4% vs 28.4%, P = 0.689). Higher OS was preserved in younger ( In patients aged more than 24 who underwent HSCT from related donor, the median duration between diagnosis to HSCT was 158 days. OS rate was not different between 202O group (N = 147) and HSCT-MRD group (N = 152) (OS at 5 years: 57.0% vs 60.2%, P = 0.114) (Figure 1(B)). The lower RR was counterbalanced by the higher NRM in HSCT-MRD group (RR at 5 years: 51.6% vs 30.0%, P < 0.001, and NRM at 5 years: 4.1% vs 15.2%, P = 0.015). No difference in OS was demonstrated among any subgroups. Superior DFS in HSCT-MRD group was observed only in high-risk patients (DFS at 5 years: 26.5% vs 57.2%, P = 0.003), but it diminished when only patients who actually received high-dose MTX were included in 202O group (DFS at 5 years: 36.4% vs 57.2%, P = 0.092). In patients aged more than 24 who underwent HSCT from unrelated donor, the median duration between diagnosis to HSCT was 214 days. OS rate was not different between 202O group (N = 138) and HSCT-MUD group (N = 104) (OS at 5 years: 60.0% vs 65.8%, P = 0.563). Superior DFS in HSCT-MUD group was observed even in all patients (DFS at 5 years: 47.2% vs 64.2%, P = 0.029). RR in HSCT-MUD group was lower (RR at 5 years: 14.3%) than that in HSCT-MRD group. [Discussions & Conclusions] High-intensity chemotherapy may change the role of HSCT for Ph-nagative ALL. Improved outcomes in HSCT-MUD group were observed, and it was partially because patients who had long CR before HSCT could underwent HSCT from MUD in CR1. Disclosures Kako: Bristol-Myers Squibb: Honoraria; Pfizer Japan Inc.: Honoraria. Tanaka:Bristol-Myers Squibb: Research Funding. Ichinohe:JCR Pharmaceuticals: Honoraria; Celgene: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Astellas Pharma: Research Funding; Chugai Pharmaceutical Co.: Research Funding; CSL Behring: Research Funding; Eisai Co.: Research Funding; Kyowa Hakko Kirin Co.: Research Funding; Ono Pharmaceutical Co.: Research Funding; Pfizer: Research Funding; Nippon Shinyaku Co.: Research Funding; MSD: Research Funding; Otsuka Pharmaceutical Co.: Research Funding; Repertoire Genesis Inc.: Research Funding; Sumitomo Dainippon Pharma Co.: Research Funding; Taiho Pharmaceutical Co.: Research Funding; Takeda Pharmaceutical Co.: Research Funding; Zenyaku Kogyo Co.: Research Funding; Alexion Pharmaceuticals: Honoraria; Bristol-Myers Squibb: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria. Kurahashi:Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Novartis Pharma Co., Ltd.: Honoraria; Takeda Pharmaceutical Co., Ltd: Honoraria; Bristol-Myers Squibb, Ltd.: Honoraria. Usui:Alexion Pharmaceuticals: Other: Personal Fees; Bristol-Myers Squibb: Other: Personal Fees, Research Funding; Kyowa-Hakko-Kirin Co.Ltd.: Other: Personal Fees; Astellas Pharma Inc.: Other: Personal Fees; Huya Bioscience International: Other: Personal Fees; Nippon Shinyaku Co.: Other: Personal Fees; SymBio Pharmaceuticals: Other: Personal Fees; Celgene Corporation: Other: Personal Fees; Pfizer: Other: Personal Fees, Research Funding; Takeda Pharmaceutical Co. Ltd: Other: Personal Fees; Cmic Co: Other: Personal Fees; Otsuka Pharmaceutical Co.Ltd.: Other: Personal Fees; AbbVie Inc: Other: Personal Fees. Kiyoi:Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Astellas Pharma Inc.: Honoraria, Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Pfizer Japan Inc.: Honoraria; Perseus Proteomics Inc.: Research Funding; Otsuka Pharmaceutical Co.,Ltd.: Research Funding; Bristol-Myers Squibb: Research Funding; Daiichi Sankyo Co., Ltd: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; FUJIFILM Corporation: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding. Matsumura:Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau; Otsuka Pharmaceutical: Consultancy, Research Funding; Pfizer: Research Funding, Speakers Bureau. Miyazaki:Chugai: Research Funding; Otsuka: Honoraria; Novartis: Honoraria; Nippon-Shinyaku: Honoraria; Dainippon-Sumitomo: Honoraria; Kyowa-Kirin: Honoraria. Atsuta:CHUGAI PHARMACEUTICAL CO., LTD.: Honoraria; Kyowa Kirin Co., Ltd: Honoraria.

The beneficial effect of rituximab for first-line treatment of diffuse large B-cell lymphoma (DLBCL) has been demonstrated by several randomized controlled trials. To clarify whether results for selected patient populations also apply to unselected patients, we analyzed long-term outcomes for all the 277 consecutive adults diagnosed with de novo DLBCL in a single center between 1998 and 2008. The study population included 147 and 130 patients diagnosed before (Cohort A) and after the advent of rituximab (Cohort B). Progression-free survival (PFS) was significantly better for Cohort B than for Cohort A (P = 0.005). For patients age 60 or younger, PFS did not differ significantly between Cohort A and Cohort B (P = 0.329), but for patients over 60, Cohort B showed superior PFS (P = 0.002). Patients with high or high-intermediate risk according to the International Prognostic Index score showed less improvement in PFS than did those with low or low-intermediate risk primarily because of still unfavorable outcomes of patients with poor performance status. These results indicate that the advent of rituximab has significantly improved outcome for unselected patients with DLBCL, and that improvement was greater for older patients. Further investigations are warranted in the hope of improving outcomes for younger patients with DLBCL.

The prognosis for adult acute lymphoblastic leukemia (ALL) patients with central nervous system (CNS) involvement (CNS+) who received allogeneic hematopoietic stem cell transplantation (allo-SCT) remains unclear. We retrospectively compared the outcomes of allo-SCT for patients with CNS involvement and for patients without CNS involvement (CNS−) using a database in Japan. The eligibility criteria for this study were as follows: diagnosis of ALL, aged more than 16 years, allo-SCT between 2005 and 2012, and first SCT. Data for 2582 patients including 136 CNS+ patients and 2446 CNS− patients were used for analyses. As compared with CNS− patients, CNS+ patients were younger, had worse disease status at SCT and had poorer performance status (PS) at SCT (P < 0.01). Incidence of relapse was higher in CNS+ patients (P = 0.02), and incidence of CNS relapse was also higher (P < 0.01). The probability of 3-year overall survival (OS) was better in CNS− patients (P < 0.01) by univariate analysis. However, in patients who received SCT in CR, there was no difference in the probability of OS between CNS+ and CNS− patients (P = 0.38) and CNS involvement did not have an unfavorable effect on OS by multivariate analysis. CNS+ patients who achieved CR showed OS comparable to that of CNS− patients.

High dose chemotherapy followed by autologous stem cell transplantation (SCT) has been shown to be effective therapy for patients with relapsed lymphoma responsive to standard-dose salvage chemotherapy. Here we report a patient in second complete remission (CR) from relapsed follicular lymphoma (grade 3) who was successfully treated with peripheral blood stem cells (PBSC) that had been harvested in first CR 10 years before. One of six frozen bags was thawed and submitted for progenitor cell assays. Because the number of progenitors was considered to be sufficient for engraftment, autologous SCT was performed without further stem cell harvest. At infusion, the viability of all nucleated cells (ANC) of the 5 remaining bags was 61.4%. She was expected to receive 2.87

既に治療法として確立している造血幹細胞移植に用いる細胞処理のガイドラインを，日本輸血・細胞治療学会と日本造血細胞移植学会との共同指針として今回初めて策定した．欧米のFACT-JACIE基準を参考にする一方で，移植施設が小規模で分散し移植に係るコメディカルの少ないわが国の状況を踏まえて，多くの施設が受容し得る内容とした．ただし，必ずしも現在の大半の施設が満たす基準ではなく「目指すべき基準（理想的な基準）」の内容も含めた．構成は，1目的，2対象，3細胞の採取，4責任者と作業者，5設備・機器，6細胞処理（プロセシング），7払い出し，8保存と解凍，9検体保存，10投与，11廃棄，12雑則からなり，教育的観点から「付」として代表的な細胞処理法に関して，解説，標準作業手順書（SOP）サンプル，記録シートサンプル，結果シートサンプルなどを設けた．今後この指針が多くの場面で運用されるように努めるとともに，現場に即した指針となるように改訂を重ねていく必要がある．また，将来的に欧米の最新の指針と同等の基準となり，また輸血・細胞処理部門認定や有害事象の監視体制を構築するのに活用されることが期待される．

The optimal treatment for adult Philadelphia chromosome-negative acute lymphoblastic leukemia [Ph(−)ALL] during first complete remission (CR1) remains a matter of debate. One treatment option for Ph(−)ALL is autologous hematopoietic stem cell transplantation (auto-SCT).[1][1],[2][2] Previous

Acute promyelocytic leukemia (APL) is the most curable subtype of acute myeloid leukemia. Second complete remission (CR2) can be easily achieved with several therapeutic options even after relapse. However, the optimal strategy to treat APL in CR2 is still controversial. We retrospectively compared the outcome of autologous (auto) and allogeneic (allo) hematopoietic stem cell transplantation (HSCT) for patients with APL in CR2 or CR3. Fifteen patients received auto and 13 received allo HSCT between 1999 and 2004 at eight hospitals belonging to the Nagoya Blood and Marrow Transplantation Group. Four-year disease-free survival (DFS) and overall survival (OS) for autografted patients were 68.9 and 75.8%, whereas those for allografted patients were 46.2 (P = 0.350) and 46.2% (P = 0.185), respectively. Three autografted patients and one allografted patient relapsed, and one autografted patient and five allografted patients died without leukemia relapse. Among 14 autografted patients who were evaluated for MRD with molecular analysis, relapse occurred in one with positive MRD (n = 2) and two with negative MRD (n = 12). These data suggest that auto HSCT is very effective for APL in CR2 or CR3, and may be preferable to allo HSCT for a portion of patients. Prospective studies are required to define the role of auto HSCT in the treatment of relapsed APL.

We describe the clinical outcome of autologous bone marrow transplantation (ABMT) for patients with Philadelphia chromosome —positive acute lymphoblastic leukemia (Ph-ALL). Between 1985 and 2000, 14 patients in first complete remission underwent transplantation. In all cases, harvested marrow was purged with a cocktail of complement and monoclonal antibodies to common acute lymphoblastic leukemia antigen (CALLA). Eight patients died following BMT: 2 patients from interstitial pneumonia and 6 from disease recurrence. For the 6 surviving patients in continuous remission, the median follow-up period was 96 months. The probability of disease-free survival and the rate of relapse at 5 years were 41.7% and 51.4%, respectively. Minimal residual disease (MRD) was assayed quantitatively with patient-specific D-JH probes in 6 of 14 cases. A higher residual tumor burden at marrow harvest was associated with subsequent relapse. Efforts to reduce the MRD burden before harvesting stem cells should improve the clinical outcome of ABMT.

The net benefits of induction therapy for older adults with acute myeloid leukemia (AML) remain controversial. Because AML in older adults is a heterogeneous disease, it is important to identify those who are unlikely to benefit from induction therapy based on information available at the initial assessment. We used next-generation sequencing to analyze TP53 mutation status in AML patients aged 60 years or older, and evaluated its effects on outcomes. TP53 mutations were detected in 12 of 77 patients (16 %), and there was a significant association between TP53 mutations and monosomal karyotype. Patients with TP53 mutations had significantly worse survival than those without (P = 0.009), and multivariate analysis identified TP53 mutation status as the most significant prognostic factor for survival. Neverthelsess, TP53-mutated patients had a 42 % chance of complete remission and a median survival of 8.0 months, which compares favorably with those who did not undergo induction therapy, even in the short term. These results suggest that screening for TP53 mutations at diagnosis is useful for identifying older adults with AML who are least likely to respond to chemotherapy, although the presence of this mutation alone does not seem to justify rejecting induction therapy.

Advances in chemotherapy for acute myeloid leukemia (AML) have resulted in the exclusion of patients not undergoing induction chemotherapy from research studies. To examine in detail the clinical experience of such patients, we retrospectively analyzed the outcomes of consecutive patients diagnosed with AML at our hospital from 2004 to 2012. Of 158 AML patients, 43 (27 %) did not undergo induction chemotherapy. Their median survival duration was 1.5 months, with 11, six, and four patients surviving more than 3, 6, and 12 months, respectively. As expected, their survival was worse than that of those treated with intensive or less-intensive induction therapy (14, 74, and 47 % at 1 year, and 0, 40, and 10 % at 4 years, respectively). Low white blood cell count at AML diagnosis and prior history of myelodysplastic syndrome were significantly associated with longer survival. Our findings suggest that modern supportive care measures do not prolong survival for AML patients not undergoing induction chemotherapy, although certain patients show relatively long survival. These data should prove helpful in discussing treatment pathways with patients for cases in which palliative or supportive therapy alone may be a viable treatment option.

The number of elderly patients with diffuse large B cell lymphoma (DLBCL) continues to increase but the data regarding autologous stem cell transplantation (ASCT) for elderly patients are limited. We analyzed 484 patients, ages 60 years or over, diagnosed with relapsed/refractory DLBCL who received ASCT from 1993 to 2010 in the Japan Society for Hematopoietic Cell Transplantation database. Median age was 64 years (range, 60 to 78). To evaluate the impact of age at ASCT, patients were classified into 3 groups: those between the ages of 60 to 64, 65 to 69, and 70 years or over. Overall nonrelapse mortality (NRM) at day 100, 1 year, and 2 years was 4.1%, 5.9% and 7.7%, respectively. NRM did not significantly differ among age groups (P = .60). Two-year progression-free survival (PFS) and overall survival (OS) were 48% and 58%, respectively. PFS and OS were significantly longer in patients 60 to 64 years old; however, the survival rate was acceptable even in those 70 or over, with a 2-year OS of 46%. ASCT is feasible in selected elderly patients and age alone should not be a contraindication for ASCT. Eligibility should be individualized and identification of a subset of elderly patients at high risk of treatment-related morbidity or mortality warrants investigation.

Introduction: Reduced-intensity conditioning (RIC) regimens have been increasingly used in allogeneic hematopoietic stem cell transplantation (allo-HCT), because they can reduce non-relapse mortality in comparison with standard myeloablative conditioning regimens and allow previously ineligible patients such as older patients and patients with comorbidities to receive allo-HCT. However, the optimal RIC regimen in allo-HCT remains unclear. Therefore, we conducted a nationwide retrospective study to compare the transplant outcomes between fludarabine/busulfan (FB) and fludarabine/melphalan (FM) regimens which are two most widely used RIC regimens for allo-HCT. Methods: We retrospectively analyzed 2008 patients aged 50 years or older with acute myeloid leukemia (AML) (n=1219), acute lymphoblastic leukemia (ALL) (n=209), or myelodysplastic syndrome (MDS) (n=580) who underwent allo-HCT using fludarabine/busulfan (FB) or fludarabine/melphalan (FM) between 2001 and 2014. The patients who underwent cord blood transplantation were excluded in this study, but those who received low dose of total body irradiation in addition to the FB or FM regimen were included. Acute leukemia in the first or second remission and MDS excluding refractory anemia with excess blasts or leukemic transformation were defined as standard-risk diseases. Clinical data for these patients were obtained from the Transplant Registry Unified Management Program (TRUMP), which includes clinical data of HCT performed in Japan. We compared the outcomes between FB2 (busulfan at 8 mg/kg po or 6.4 mg/kg iv, n=738), FB4 (busulfan at 16 mg/kg po or 12.8 mg/kg iv, n=749), and FM140 (melphalan at 140 mg/m2, n=521). Results: The median ages were 60 (50-74), 60 (50-75), 59 (50-71) years in the FB2, FB4, and FM140 groups, respectively. The cumulative incidences of grade II-IV and III-IV acute GVHD were 30.7% (95% confidence interval (CI), 27.3-34.1%) and 10.1% (95% CI, 8.0-12.4%), 36.8% (95% CI, 33.3-40.2%) and 12.5% (95% CI 10.2-15.0%), and 39.3% (95% CI, 35.0-43.5%) and 15.2% (95% CI, 12.2-18.4%) in the FB2 group, the FB4 group, and FM140 group, respectively (p=0.0061 and p=0.050). The incidence of relapse at 3 years was higher in the FB2 group (38.2%; 95% confidence interval (CI), 34.5- 41.9%) than the FB4 group (31.5%; 95% CI, 28.0- 35.0%) or the FM140 groups (28.3%; 95% CI, 24.2- 32.4%, p Conclusion: FM140 was associated with better OS in patients with high-risk AML and MDS than FB2 because of lower relapse rate and FB4 was not superior to FB2 in OS, although OS in patients with standard-risk disease did not differ among the 3 groups. A large prospective study is warranted to confirm these findings. Disclosures Kako: Otsuka Pharmaceutical: Honoraria. Kanda:Otsuka Pharmaceutical: Honoraria, Research Funding.

Severe disseminated varicella zoster virus (VZV) infection rarely occurs in patients who are not recipients of hematopoietic stem cell transplantation. This report concerns severe disseminated VZV infection in a diffuse large B cell lymphoma (DLBCL) patient treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP). The patient was an 82-year-old male with DLBCL who had a history of type II diabetes mellitus. He incurred VZV infection with severe hepatitis and disseminated intravascular coagulopathy after three courses of R-CHOP. When the VZV infection occurred, anti-VZV IgG was not detected and lymphopenia was observed. We initiated treatment with acyclovir, immunoglobulin, and thrombomodulin alpha, and rescued this patient. We suggest that the use of chemotherapy for immune-suppressed elderly lymphoma patients may involve the risk of severe VZV infection.

Introduction: The outcome of BCR–ABL positive acute lymphoblastic leukemia (ALL) has drastically improved since the introduction of imatinib. We recently reported the clinical results of the Japan Adult Leukemia Study Group (JALSG) ALL-202 study at the 51th ASH Annual Meeting. Most patients (97.1%) achieved complete remission (CR) and 9% of them relapsed within 100 days after CR. In addition, 60% of patients received allogeneic stem cell transplantation during their first CR, and the 3-year overall survival (OS) rate was 57%. We now present the data of the subsequent JALSG Ph+ALL208 study, where we have modified a part of consolidation therapy to prevent early relapse after achieving CR. Methods: The JALSG Ph+ALL208 study was a phase 2 trial for patients newly diagnosed with BCR–ABL positive ALL. Imatinib at a dose of 600 mg/day was administered from day 8 to day 42 combined with daunorubicine (DNR), cyclophosphamide (CPM), vincristine (VCR) and prednisolone (PSL) for induction therapy. Consolidation therapy comprised course 1 (C1: high-dose methotrexate and high-dose cytarabine with imatinib for 18 days) and course 2 (C2: DNR, CPM, VCR, and PSL with imatinib for 20 days). C1 and C2 were repeated alternately for 4 cycles. After consolidation therapy, allogeneic stem cell transplantation (allo-SCT) was recommended if a suitable stem cell donor was identified. Those ineligible for allo-SCT, due to the lack of a suitable donor and/or comorbidity, received maintenance therapy comprising VCR, PSL and imatinib for 2 years from the date they achieved CR. Seventy patients were enrolled between October 2008 and December 2010. Of these, two patients were excluded because they were diagnosed with chronic myeloid leukemia blast phase. Therefore, 68 patients newly diagnosed with BCR–ABL positive ALL were included in this study. The median age was 49 years (18–64 years) and 41% were >54 years. Results: With this treatment regimen, 65 patients achieved CR (95.6%) and only 1% of them relapsed within 100 days after CR. Finally, 35/40 patients (81%) 54 years-old were able to receive allo-SCT in their first CR (13 from a sibling donor, 23 from an unrelated bone marrow donor, and 7 from unrelated cord blood). The 3-year OS and disease-free survival (DFS) rates were estimated at 62% and 52%, respectively. Three early deaths occurred during the induction course. One patient (51 years) died of pulmonary bleeding on day 9, another patient (59 years) died of sepsis on day 15, and the third patient (62 years) died of cerebral hemorrhage on day 15. Grade 3 or 4 non-hematologic adverse events including febrile neutropenia and liver dysfunction was reported in 60.3% and 11.8% of the patients, respectively. Twelve patients relapsed after achieving CR with a median time of 307 (64–1053) days. Moreover, 6/43 patients who received allo-SCT relapsed with a median time of 346 (149–602) days. The probability of DFS at 3 years was 72% for patients who underwent allo-SCT in CR compared to only 21% for patients without allo-SCT (p = 0.0004)(Figure.1). Conclusion: We conclude that imatinib-based chemotherapy produced a very high CR rate, thus allowing a high proportion of patients to prepare for allo-SCT, particularly patients 55 years. Moreover, the intensified consolidation therapy reduced the rate of early relapse after induction therapy and resulted in a higher rate of DFS after allo-SCT. Figure 1 Figure 1. Disclosures Hatta: Bristol Myers Squibb: Honoraria. Miyazaki:Novartis: Honoraria. Ohnishi:Novartis: Honoraria.

Abstract Background: Dasatinib is a novel kinase inhibitor of BCR-ABL and SRC family kinases that has shown promising anti-leukemic activity against chronic myeloid leukemia (CML). However, some patients experience treatment-related toxicity shortly after initiating dasatinib administration and are managed by drug interruption and/or dose reduction (altered treatment) which can limit the potential benefits of treatment. Methods: To determine the factors that influence compliance and the efficacy of dasatinib therapy, we conducted a phase 2 study of mid-term compliance and the effectiveness of dasatinib therapy in patients with chronic phase CML (CML-CP) (DARIA-01 Study). Treatment was administered until disease progression or intolerable toxicity, as determined by the treating physician. Dasatinib at 100 mg once daily was initially administrated. Dose interruption or reduction to 50 mg once daily was allowed after grade 2 or worse nonhematologic toxicity or grade 3 or worse hematologic toxicity. Trough plasma concentrations of dasatinib (Cmin) at steady state were assessed at 28 days of therapy. Results: In April 2014, 32 CML-CP patients were enrolled in the study, which included at least 6 months of follow-up. The median age was 53 years (range, 20–86). Twenty-four (75.0%) were previously untreated patients with CML-CP, and the remaining eight (25.0%) were switched from other tyrosine kinase inhibitors (imatinib, five patients; nilotinib, three patients) because of intolerance or resistance to these drugs. During the initial 28 days, 28 patients continued with 100 mg/day treatment, and four received doses of 50 mg/day. The incidence of altered treatment was 25% during the initial 3 months and 34% during the initial 6 months from dasatinib administration. Four patients who experienced dose reduction during the initial 3 months continued with 50 mg/day treatment thereafter at their request. Except one who experienced gastro-intestinal bleeding, all patients could continue dasatinib therapy. Age (>60 years) and Cmin divided by the given dasatinib dose (Cmin/D) were significantly correlated with a higher incidence of altered treatment during the initial 3 months (p = 0.0095) (p = 0.0083). Twenty-five (78%) patients achieved complete cytogenetic response (CCyR), and 13 (40%) achieved major molecular response at 6 months. The incidence of pleural effusion during the initial 28 days was significantly correlated with Cmin/D (p = 0.032) but was not related to the molecular response rate at 6 months (40% vs. 41%, p = 0.98). Conclusion: Current data demonstrate that patients treated with dasatinib who displayed a high Cmin/D (>1.0) value at day 28 and/or who were aged 60 and over were at a high risk for altered treatment during the early periods of therapy. Patients who experienced pleural effusion could be well managed by dose reduction and/or temporal interruption of dasatinib and could still achieve the preferable molecular response rate. Individualizing therapy by incorporating a pharmacokinetic assay would improve compliance and the efficacy of dasatinib therapy, particularly for elderly patients. Disclosures Morita: Bristol: Honoraria.

Background: Varicella, characterized by a vesicular rash, occurs primarily in young children. Although older individuals can also be affected or vaccinated, outbreaks among adults are rare. We experienced sequential four cases of varicella after an index herpes zoster case in hematological wards. Methods: All varicella cases were confirmed varicella zoster virus (VZV) infection by PCR. We analyzed presence of anti-VZV IgG and IgM antibodies at the first hospital admission (cryopreserved serum) and the onset of VZV infection by enzyme immunoassay. To identify VZV-positive specimens and to differentiate these strains from the Oka vaccine virus, PCR designed to target the initial part of VZV open reading frame (ORF) 62 was performed on PBMCs or vesicular swabs. Furthermore, we investigated the incidence of localized zoster and generalized zoster/ varicella in rituximab administered patients. Between January 2010 and December 2013 (48 months), we collected data including the number ofrituximab administered patients, rituximab administration, localized zoster patients, and generalized zoster/varicella patients. Findings: All varicella cases occured in diffuse large B-cell lymphoma patients receiving rituximab-containing chemotherapy (Table 1). On the other hand, only three of the 18 non-varicella patients in the same room were receiving rituximab-containing chemotherapy ( P = 0.005, Table 2). Furthermore, all varicella patients had anti-VZV IgG antibody at the first hospital admission (Table 1). Sequencing the first part of ORF 62 in these cases showed the identical sequences and could be distinguished from the Oka vaccine virus, Oka parental virus and Dumas strain. During the 48 months, there were 340 patients who received rituximab. The total number of rituximab administrations was 2086. There were 29 patients with localized zoster (8.5%), and 5 patients with generalized zoster/varicella (1.4%). Four of these patients constituted the cluster reported here. The incidence of generalized zoster/ varicella for 2 months in this case was significantly higher than another 46 months (p

In order to improve the disappointing prognosis of adult patients with acute lymphoblastic leukemia (ALL), we applied similar induction therapy as that used for acute myeloid leukemia (AML), ie frequent administration of doxorubicin (DOX). DOX 30 mg/m(2) was administered from days 1 to 3 and from days 8 to 10 together with vincristine, prednisolone, cyclophosphamide and L-asparaginase, followed by three courses of consolidation and four courses of intensification. From December 1993 to February 1997, 285 untreated adult patients with de novo ALL were entered. Of 263 evaluable patients (age 15 to 59; median 31), 205 (78%) obtained complete remission (CR). At a median follow-up period of 63 months, the predicted 6-year overall survival (OS) rate of all patients was 33%, and disease-free survival (DFS) rate of CR patients was 30%, respectively. By multivariate analysis, favorable prognostic factors for the achievement of CR were age

Abstract 2021 Background: Postremission treatment for adult Philadelphia chromosome-negative acute lymphoblastic leukemia [Ph(-)ALL] in first remission remains elucidated and the role of autologous stem cell transplantation (auto-SCT) is still controversial in the application for Ph(-)ALL patients. We retrospectively analyzed the consolidative role of auto-SCT as a postremission therapy for adult Ph(-)ALL in first remission. Patients and Methods: Among 1962 adult Ph(-)ALL patients registered in the JSHCT database, we selected cases receiving auto-SCT with myeloablative preparative regimens in first complete remission from 1983 to 2009. Results: A total of 155 patients with 86 male patients were analyzed. The median age was 25 years (range: 16 to 74) and 79% of patients were less than 45 years of age at transplant. The number of patients having white blood cell (WBC) count We next performed comparison of auto-SCT with allogeneic stem cell transplantation (allo-SCT) in adult Ph(-)ALL patients. Patients undergoing allo-SCT were selected from the same JSHCT database. A total of 921 patients were identified as cases receiving allo-SCT with myeloablative preparative regimens in first complete remission. With a median follow-up of 4.95 years, the 4-year overall survival rate was 63% (95%CI: 51 to 59). Allo-SCT yielded better overall survival rate than that of auto-SCT (63% vs. 48% at 4 year, p=0.0004). In subset analyses, we limited analyses to the groups of patients younger than 45 years and receiving TBI regimens followed by auto-SCT (n=31) or allo-SCT (n=685). There were no differences in baseline patients' characteristics between the two groups except age [auto-SCT: 20 years (range: 16 to 40) vs. allo-SCT: 28 years (range: 16 to 44), p Conclusions: Our analyses demonstrated that auto-SCT produced excellent results showing a plateau in long-term survival and that clinical outcome of auto-SCT was comparable to that of allo-SCT in some part of patients. Candidates who obtained most benefit from auto-SCT was those younger than 45 years and well tolerated with TBI combined myeloablative conditioning regimens. Since optimal timing of postremission therapy is critical for adult Ph(-)ALL patients, auto-SCT in first complete remission could be one of promising treatment strategies for the patients. Disclosures: No relevant conflicts of interest to declare.

We investigated prognostic factors for the clinical outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) following imatinib-based therapy. Among 100 adult patients who were prospectively enrolled in the JALSG Ph+ALL202 study, 97 patients obtained complete remission (CR) by imatinib-combined chemotherapy, among whom 60 underwent allo-HSCT in their first CR. The probabilities of overall survival (OS) and disease-free survival (DFS) at 3 years after HSCT were 64% (95% CI, 49–76) and 58% (95% CI, 43–70), respectively. Prognostic factor analysis revealed that the major BCR–ABL transcript was the only unfavorable predictor for OS and DFS after HSCT by both univariate (HR, 3.67 (95% CI 1.49–9.08); P=0.005 and HR, 6.25 (95% CI, 1.88–20.8); P=0.003, respectively) and multivariate analyses (HR, 3.20 (95% CI, 1.21–8.50); P=0.019 and HR, 6.92 (95% CI, 2.09–22.9); P=0.002, respectively). Minimal residual disease status at the time of HSCT had a significant influence on relapse rate (P=0.015). Further study of the BCR–ABL subtype for the clinical impact on outcome of allo-HSCT in Ph+ALL is warranted., Blood Cancer Journal, 2(5), e72; 2012

Abstract 3090 Poster Board III-27 The outcome of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) has dramatically improved since the start of treatment with imatinib. The Japan Adult Leukemia Study Group (JALSG) has reported a high complete remission (CR) rate for Ph+ALL treated with imatinib-combined chemotherapy (Yanada et al, J Clin Oncol 2006). Here we report a follow-up analysis of the results of the JALSG imatinib-combined chemotherapy. In the study, remission was induced by administering imatinib from day 8 to day 62 in combination with cyclophosphamide, daunorubicin, vincristine (VCR), and prednisolone (PSL). Consolidation regimen consisted of an odd course comprising high-dose methotrexate and high-dose cytarabine and an even course with 28 days administration of single-agent imatinib. The consolidation regimens were alternated for four courses each. Maintenance consisting of VCR, PSL, and imatinib was continued for two years after a CR. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) was recommended if HLA identical sibling donor was available and was allowed from an alternative donor. A total of 103 newly diagnosed Ph+ALL patients were enrolled in the study between August 2002 and August 2004. Median age of the patients was 45 years (range, 15-64 years), and there were 57 males and 46 females. Median follow-up period was 2.6 years (range, 0.1-5.1 years). A CR was achieved in 100 (97.1%) of the 103 patients and not achieved in a patient in whom imatinib was discontinued because of ileus. There were two early deaths during induction. The probability of overall survival (OS) rate for the entire group at three years was 56.8%. No severe adverse effects were observed. Allo-HSCT was performed in the 1st CR (CR1) in 54 of the 74 CR patients under 55 years of age. Relapse occurred in 18 of 20 patients (90.0%) in whom allo-HSCT was not performed in CR1, but in only seven of the 54 patients (13.0%) who underwent allo-HSCT. At three years, the probability of OS rate for patients under 55 years of age was 75.0% in the transplanted group and 36.4% in the non-transplanted group. Allo-HSCT was performed in CR1 in eight of the 25 patients over 55 years of age. Two were myeloablative and six reduced intensity conditionings. Seven of eight patients who underwent HSCT are still alive in a CR. However, the probability of OS rate at three years in the non-transplanted group was 43.2%. In the group that did not receive allo-HSCT in CR1, age (55< years or 55> years), WBC count, bcr/abl transcript level, bcr/abl transcript type (major or minor), co-expression of myeloid antigens (CD13 and/or CD33), and additional chromosomal abnormalities at diagnosis were not associated with OS. The results demonstrated that the imatinib-combined chemotherapy regimen was effective and feasible. The regimen provided a better chance to receive allo-HSCT which resulted in an excellent outcome. However, relapse still remains a problem, especially in patients who are not candidates for allo-HSCT. Disclosures No relevant conflicts of interest to declare.

The treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) has been changed dramatically since the introduction of imatinib. We previously reported a 96% complete remission (CR) rate in newly diagnosed patients treated with imatinib-combined chemotherapy (Yanada et al. J Clin Oncol2006;24:460–466), and showed that the combination therapy is useful in terms of providing patients with a better chance for receiving allogeneic hematopoietic stem cell transplantation (HSCT) in first CR. However, little is known about the outcome after allogeneic HSCT in such patients. To address this issue, we analyzed detailed data from 60 patients who underwent allogeneic HSCT in first CR following a uniform treatment protocol consisting of imatinib and chemotherapy. The median age of the studied patients was 37 years (range, 15–64 years), with 32 males and 28 females. Donors were HLA-matched related (n=24), matched unrelated (n=21), mismatched cord blood (n=9), and mismatched related (n=6). All 52 patients aged less than 55 years received a myeloablative conditioning regimen, whereas 6 of 8 patients aged 55 years or older received a reduced intensity conditioning (RIC) regimen. Grade 2–4 acute graft-versus-host disease (GVHD) was recorded in 20 patients, and chronic GVHD was recorded in 32 patients, 17 of whom had the extensive form. During a median follow-up of 2.6 years (maximum, 4.6 years) after transplantation, relapse and death in first CR occurred in 9 and 15 patients. The probabilities for overall survival (OS) and relapse-free survival (RFS) were 64% and 53%, respectively, at 3 years. Patients younger than 40 years had a trend toward better RFS than those at 40 to 54 years (60% vs. 38% at 3 years, p=0.16). Unexpectedly, all of the 8 patients aged 55 years or older remained alive in first CR. In relation to the donor type, RFS did not differ among patients allografted from a matched related donor, a matched unrelated donor, and mismatched cord blood (52% vs. 59% vs. 56% at 3 years, p=0.92). For risk factor analysis, the following variables were examined: donor type (sibling vs. unrelated vs. cord blood), age group ( Conclusion: In patients with Ph+ ALL who were initially treated with imatinibcombined chemotherapy, the outcome after allogeneic HSCT in first CR was favorable irrespective of the donor type. Cord blood transplantation and RIC transplantation might be attractive options for those without a suitable donor and for those unfit for conventional myeloablative conditioning, respectively. Prospective studies are warranted to confirm the roles of these forms of transplantation, especially RIC for patients between 40 and 54 years of age.