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Background In a Phase 3 international clinical trial (VIALE-C), venetoclax plus low-dose cytarabine improved the response rate and overall survival versus placebo plus low-dose cytarabine in patients with newly diagnosed acute myeloid leukemia who were ineligible for intensive chemotherapy. After the enrollment period of VIALE-C ended, we conducted an expanded access study to provide preapproval access to venetoclax in combination with low-dose cytarabine in Japan. Methods Previously, untreated patients with acute myeloid leukemia who were ineligible for intensive chemotherapy were enrolled according to the VIALE-C criteria. Patients received venetoclax (600 mg, Days 1–28, 4-day ramp-up in Cycle 1) in 28-day cycles and low-dose cytarabine (20 mg/m2, Days 1–10). All patients took tumor lysis syndrome prophylactic agents and hydration. Safety endpoints were assessed. Results Fourteen patients were enrolled in this study. The median age was 77.5 years (range = 61–84), with 78.6% over 75 years old. The most common grade ≥ 3 treatment-emergent adverse event was neutropenia (57.1%). Febrile neutropenia was the most frequent serious adverse event (21.4%). One patient developed treatment-related acute kidney injury, leading to discontinuation of treatment. Two patients died because of cardiac failure and disease progression that were judged not related to study treatment. No patients developed tumor lysis syndrome. Conclusions The safety outcomes were similar to those in VIALE-C without new safety signals and were well managed with standard medical care. In clinical practice, more patients with severe background disease are expected, in comparison with in VIALE-C, suggesting that it is important to carefully manage and prevent adverse events.

Introduction: The safety and efficacy of blinatumomab, a CD19/CD3 bispecific T-cell engager (BiTE®) molecule, was evaluated in an expansion cohort of the phase 1b/2 study (NCT02412306) in Japanese adult (n = 14) and pediatric (n = 17) patients with relapsed/refractory Philadelphia-negative B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). Materials and methods: Globally recommended blinatumomab doses were administered to adult (9–28 μg/day) and pediatric (5–15 μg/m2/day) patients. Primary endpoint was the incidence of treatment-emergent adverse events (TEAEs) and treatment-related AEs. Results: All adult and pediatric patients experienced ≥1 TEAE. Grade ≥3 TEAEs were observed in 11 (79%) adult and 15 (88%) pediatric patients. Blinatumomab was discontinued in 1 (6%) pediatric patient due to treatment-related grade 4 cytokine release syndrome. Fatal AEs such as disease progression and multiple-organ dysfunction syndrome, which were not treatment-related, were reported in 2 (12%) pediatric patients. Eleven (79%) adults achieved complete remission (CR)/CR with partial hematological recovery (CRh) within the first two blinatumomab cycles. Nine of 10 adult patients with CR/CRh and evaluable minimal residual disease (MRD) achieved MRD response. CR/CRh was achieved by 5 (29%) pediatric patients, of which two had MRD response. Conclusion: In conclusion, blinatumomab was safe and efficacious in Japanese patients with relapsed/refractory BCP ALL.

Background Until recently, no effective targeted therapies for FLT3-mutated (FLT3mut+) relapsed/refractory (R/R) acute myeloid leukemia (AML) were available in Japan. The FLT3 inhibitor, gilteritinib, was approved in Japan for patients with FLT3mut+ R/R AML based on the phase 3 ADMIRAL trial, which demonstrated the superiority of gilteritinib over salvage chemotherapy (SC) with respect to overall survival (OS; median OS, 9.3 vs 5.6 months, respectively; hazard ratio, 0.64 [95% confidence interval 0.49, 0.83]; P Methods We evaluated the Japanese subgroup (n = 48) of the ADMIRAL trial, which included 33 patients randomized to 120-mg/day gilteritinib and 15 randomized to SC. Results Median OS was 14.3 months in the gilteritinib arm and 9.6 months in the SC arm. The complete remission/complete remission with partial hematologic recovery rate was higher in the gilteritinib arm (48.5%) than in the SC arm (13.3%). After adjustment for drug exposure, fewer adverse events (AEs) occurred in the gilteritinib arm than in the SC arm. Common grade ≥ 3 AEs related to gilteritinib were febrile neutropenia (36%), decreased platelet count (27%), and anemia (24%). Conclusion Findings in Japanese patients are consistent with those of the overall ADMIRAL study population.

Background In a multinational phase 3 trial (VIALE-C), venetoclax plus low-dose cytarabine prolonged overall survival vs placebo plus low-dose cytarabine in patients with newly diagnosed acute myeloid leukaemia ineligible for intensive chemotherapy, although it was not statistically significant. Herein, we assess the benefit of venetoclax plus low-dose cytarabine in the Japanese subgroup of VIALE-C patients (n = 27). Methods VIALE-C, a randomized (2:1), double-blind study (NCT03069352), enrolled untreated patients (≥18 years) with acute myeloid leukaemia. Patients received venetoclax (600 mg days 1–28, 4-day ramp-up in cycle 1) or placebo in 28-day cycles with low-dose cytarabine (20 mg/m2 days 1–10). The primary endpoint was median overall survival. Results In the Japanese subgroup, at a 6-month follow-up from the primary analysis, median overall survival for venetoclax (n = 18) and placebo (n = 9), plus low-dose cytarabine, was 4.7 and 8.1 months, respectively (hazard ratio, 0.928, 95% confidence intervals : 0.399, 2.156). The rate of complete remission plus complete remission with incomplete blood count recovery was higher with venetoclax plus low-dose cytarabine (44.4%) vs placebo plus low-dose cytarabine (11.1%). All patients experienced at least 1 adverse event. The most common grade ≥3 adverse events with venetoclax or placebo, plus low-dose cytarabine, were febrile neutropenia (50.0% vs 44.4%, respectively) and thrombocytopenia (27.8% vs 44.4%, respectively). Serious adverse events were reported in 50.0 and 33.3% of patients in the venetoclax and placebo, plus low-dose cytarabine arms, respectively; pneumonia was the most common (22.2% each). Conclusions Limited survival benefit in the Japanese subgroup can be attributed to small patient numbers and to baseline imbalances observed between treatment arms, with more patients in the venetoclax plus low-dose cytarabine arm presenting poor prognostic factors. Venetoclax plus low-dose cytarabine was well tolerated in Japanese patients with acute myeloid leukaemia ineligible for intensive chemotherapy., In the Japanese subgroup of VIALE-C patients (n = 27), venetoclax plus low-dose cytarabine (LDAC) was well tolerated and showed high response vs placebo plus low-dose cytarabine in patients with acute myeloid leukaemia ineligible for intensive chemotherapy.

Background Global studies have demonstrated the efficacy and safety of blinatumomab-a BiTE® (bispecific T-cell engager) targeted immuno-oncology therapy that mediates the lysis of cells expressing CD19 in patients with relapsed/refractory acute lymphoblastic leukemia (R/R ALL). Because limited data are available in Asian patients, we conducted a post hoc pooled analysis in 45 Asian adult patients with R/R ALL-19 from the blinatumomab arm of TOWER (NCT02013167) and 26 from Study 265, a phase 1b/2 study in Japanese adults (NCT02412306). Methods Patients received a maximum of two cycles of induction blinatumomab for 4 weeks by continuous intravenous infusion (cycle 1/week 1: 9 μg/day; cycle 1/weeks 2-4: 28 μg/day) followed by 2 weeks of no blinatumomab (each 6-week cycle); patients received 28 μg/day blinatumomab in subsequent cycles. Results Twenty of 45 patients enrolled (44%) achieved complete remission with full or partial hematologic recovery compared with 44% in TOWER and 80% and 38% in phase 1b and phase 2, respectively, of Study 265. The Kaplan-Meier (KM) median overall survival was 11.9 months (95% confidence interval [CI], 9.9-17.1) and the KM median duration of relapse-free survival was 8.9 months (95% CI, 3.8-10.7). Ninety-three percent of patients had grade ≥ 3 treatment-emergent adverse events (AEs) compared with 87% in TOWER and 80% and 100% in phase 1b and phase 2, respectively, of Study 265. Five patients (11.4%) had fatal AEs. Conclusions The safety and efficacy of blinatumomab in Asian patients were comparable with those reported in previous global studies with no new safety signals.

Objective In Japan, immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG), and cyclosporine A (CsA) is the standard of care in patients with aplastic anemia (AA) who are not indicated for stem-cell transplantation, although some patients may experience relapse. This study assessed the efficacy and safety of eltrombopag in combination with rabbit-ATG/CsA in IST-naive patients with non-severe or severe AA in Japan. Methods In this non-randomized, open-label, single-arm, phase II study, rabbit-ATG/CsA and eltrombopag were initiated on Days 1 and 15 (±3 days), respectively, and continued for ≥26 weeks; rabbit-ATG was given for 5 days (Days 1 to 5). The primary endpoint was the overall response rate (ORR) at Week 26. Patients Patients with AA who were IST-naive and ≤70 years old or between 71 and 75 years old based on the recommendation of the investigator were enrolled in Japan. Results Of the 11 enrolled patients, 10 started treatment with eltrombopag. The ORRs at Weeks 26 and 52 were 70.0% and 60.0%, respectively. The ORR at Week 26 was 100% (all 3 patients) in patients with non-severe AA and 57.1% (4/7) in patients with severe AA. Among transfusion-dependent patients, 66.7% (4/6) and 62.5% (5/8) became red blood cell- and platelet-transfusion independent, respectively. The most common adverse events were nausea and headache. No deaths or hematologic malignancies were reported. A cytogenetic abnormality was reported in one patient. Conclusion This study confirmed the clinical benefit of eltrombopag plus rabbit-ATG/CsA in IST-naive patients with non-severe or severe AA in Japan.

The impact of calcineurin inhibitor types and anti-thymocyte globulin (ATG) in conditioning on overall survival (OS) and GVHD-free, relapse-free survival (GRFS) has not yet been analyzed in detail for aplastic anemia. We herein examined 517 adult patients with aplastic anemia who underwent BMT from HLA-matched sibling donors (MSD, n = 255) and unrelated donors (UD, n = 262) and were treated with cyclosporine A (CSA) + methotrexate (MTX) (n = 258) and tacrolimus (TAC) + MTX (n = 259). In total, 330 patients received ATG in conditioning. CSA + MTX versus TAC + MTX did not have a significant impact on acute and chronic GVHD, OS, or GRFS in each donor type. The use of ATG in conditioning reduced the risk of grade II–IV acute GVHD in the MSD and UD cohorts (HR 0.42, P = 0.014, and HR 0.3, P

Recently, progression of disease within 24 months (POD24) has been demonstrated as a strong prognostic indicator in various types of malignant lymphoma. Peripheral T-cell lymphoma (PTCL) has an aggressive course and poor clinical outcomes. In this multicenter retrospective study, 111 consecutively registered patients with newly diagnosed PTCL were analyzed. Of these patients, 72 (64.9%) experienced POD24 (POD24 group), and the other 39 patients (35.1%) were analyzed as the no POD24 group. In the POD24 group, overall survival (OS) was significantly inferior to all patients, and in the no POD24 group, subsequent OS was significantly superior to the POD24 group, although the clinical characteristics between the POD24 group and no POD24 group were not significantly different. Twenty-three patients (20.7%) showed primary refractory disease to first-line therapy, and the prognosis was poor. The International Prognostic Index score and POD24 were identified as independent predictors in multivariate analysis for OS in all patients, and only performance status was an independent prognostic factor for OS in the POD24 group in multivariate analysis. In conclusion, the clinical significance of assessing POD24 in PTCL and the poor prognosis in patients with early disease progression were demonstrated.

We conducted a multicenter study on anti-programmed cell death-1 monoclonal antibodies (anti-PD-1 mAbs) before/after allogeneic hematopoietic cell transplantation (allo-HCT) for Hodgkin lymphoma. Anti-PD-1 mAbs were administered to 25 patients before allo-HCT and to 20 after allo-HCT. In pre-allo-HCT setting, the median interval from the last administration to allo-HCT was 59 days. After allo-HCT, 12 patients developed non-infectious febrile syndrome requiring high-dose corticosteroid. The cumulative incidences of grade II-IV acute graft-versus-host disease (aGvHD) were 47.1%. Eight patients who had GvHD prophylaxis with post-transplant cyclophosphamide (PTCy) had less frequent aGvHD (grade II-IV, 14.6% versus 58.8%; P = 0.086). The 1 year overall survival (OS), relapse/progression, and non-relapse mortality rates were 81.3%, 27.9%, and 8.4%. In post-allo-HCT setting, the median interval from allo-HCT to the first administration was 589 days. The overall and complete response rates were 75% and 40%. At 100 days after anti-PD-1 therapy, the cumulative incidences of grade II-IV aGvHD, moderate-to-severe chronic GvHD, and grade 3-4 immune-related toxicity were 15.0%, 30.0%, and 30.0%. While the 1 year relapse/progression rate was 47.4%, the 1 year OS probability was 89.7%. In conclusion, immune-related complications were frequent despite modifications of GvHD prophylaxis or anti-PD-1 mAb dosing. In anti-PD-1-mAb-pretreated patients, PTCy-based GvHD prophylaxis may be effective.

A prospectively registered observational study was conducted to assess the significance of allogeneic hematopoietic stem cell transplantation from highly HLA-matched unrelated donors (UD) and cord blood (CB) on outcomes in adult acute leukemia (AL) and myelodysplastic syndrome (MDS). Between 2007 and 2015, 231 transplant-eligible patients were registered for a phase 2 study of alternative donor transplantation. After registration, a sufficient time period was given to find appropriate UD. Patients received CB transplantation (CBT) if an appropriate UD was unavailable. In total, 119 patients received CBT (106 AL and 13 MDS) and 91 patients received UD transplantation (UDT) (86 AL and 5 MDS). The median age was 39 years in both groups. The primary objective was overall survival (OS); secondary objectives included cumulative incidences of non-relapse mortality (NRM) and relapse, and disease-free survival. Diagnosis, disease status at transplantation, refined disease risk index, and hematopoietic cell transplant-specific comorbidity index did not differ between UDT and CBT. In multivariate analyses, graft source was not a significant risk factor for all objectives. In adjusted analyses, UDT and CBT showed similar OS, NRM, and relapse in this prospective study. CB can be a comparable alternative stem cell source to UD by achieving a timely transplant.

Mixed chimerism (MC) and/or secondary graft failure (SGF) with recipient- or donor-type chimerism is a major obstacle in allogeneic transplantation for aplastic anemia (AA). From a registry database in Japan, patients with AA age >15 years who underwent a first allogeneic bone marrow or peripheral blood stem cell transplantation between 2000 and 2014 and achieved engraftment were included in this study. MC that did not require either granulocyte-colony stimulating factor (G-CSF) or transfusion support (group 1), MC (not SGF) that required G-CSF and/or transfusion support (group 2), SGF with MC or complete recipient-type chimerism (group 3), and SGF with complete donor-type chimerism (group 4) developed in 26, 16, 19, and 17 patients, respectively. The overall median duration of follow-up for survivors was 1727 days. The overall survival (OS) was 90.4% at 1 year and 83.5% at 5 years in patients without MC or SGF (n = 340), which was not different from the OS in groups 1 and 2. However, inferior OS was observed in group 3 (1 year, 52.1%; 5 years, 52.1%) and group 4 (1 year, 82.4%; 5 years, 56.3%). In multivariate analyses, the use of fludarabine (Flu) and the absence of irradiation in conditioning were associated with the development of SGF with MC or complete recipient-type chimerism, and the use of Flu in conditioning was associated with SGF with complete donor-type chimerism. In conclusion, the use of Flu may affect the occurrence of SGF with both recipient-type and donor-type chimerism.

Adult patients with relapsed/refractory (R/R) B‐precursor acute lymphoblastic leukemia (ALL) have a poor prognosis. Blinatumomab is a bispecific T‐cell engager (BiTE) immuno‐oncology therapy with dual specificity for CD19 and CD3 that redirects patients’ CD3‐positive cytotoxic T cells to lyse malignant and normal B cells. We conducted an open‐label, phase 1b/2 study to determine the safety, pharmacokinetics, efficacy and recommended dose of blinatumomab in Japanese adults with R/R B‐precursor ALL. Patients received 9 μg/day blinatumomab during week 1 and 28 μg/day during weeks 2‐4, with a 2‐week treatment‐free interval (6‐week cycle); patients received 28 μg/day blinatumomab in subsequent cycles. Primary endpoints were the incidence of dose‐limiting toxicities (DLT) in phase 1b and complete remission (CR)/CR with partial hematologic recovery (CRh) within the first two cycles in phase 2. A total of 26 patients enrolled and 25 (96%) reported grade ≥3 adverse events (mostly cytopenias). There were no DLT. CR/CRh within two cycles was achieved by 4 of 5 patients (80%) in phase 1b and 8 of 21 patients (38%) in phase 2. Among patients with evaluable minimal residual disease, 4 (100%) in phase 1b and 3 (38%) in phase 2 had a complete MRD response. Median RFS for 8 patients who achieved CR/CRh in phase 2 was 5 (95% CI: 3.5‐6.4) months; median OS was not estimable. There were no significant associations between maximum cytokine levels or percentage of specific cell types during cycle 1 and response. Consistent with global studies, blinatumomab appeared to be safe and efficacious in Japanese adults with R/R ALL., Flow of patients through the study. (A) Phase 1b part. (B) Phase 2 part.

There is a controversy which short term high dose dexamethasone therapy (HDD) or standard dose prednisolone therapy as the initial treatment leads to long term efficacy in idiopathic thrombocytopenic purpura (ITP) patients. We conducted a multicenter, prospective trial to determine the efficacy and safety of short-term HDD in ITP patients aged 18–80 years with platelet counts of

Almost comparable transplantation outcomes have been reported with HLA-matched unrelated donor transplantation (UDT) and cord blood transplantation (CBT). We conducted a prospective phase 2 study to assess the efficacy and safety of single-unit myeloablative CBT in adult leukemia and myelodysplastic syndrome. Because the day 180 survival of UDT was approximately 80%, we determined the alternative hypothesis of expected day 180 survival with a successful engraftment rate of 80% and set the null hypothesis of threshold rate at 65%. Sixty-two patients (median age, 37 years) were registered, including 28 with acute myelogenous leukemia, 25 with acute lymphoblastic leukemia, and 9 with myelodysplastic syndrome. Of 61 eligible patients, 52 were successfully engrafted and survived at day 180 (85%; 95% confidence interval, 74% to 93%). Single-unit CBT was judged to be effective because the null hypothesis was rejected (P.001). Furthermore, neutrophil engraftment was observed in 57 patients (92%); the incidences of grade II-IV acute and chronic graft-versus-host disease were 30% and 32%, respectively; and the cumulative incidences of nonrelapse mortality and relapse at 2 years were 18% and 13%, respectively. The present study showed favorable survival outcomes with single-unit CBT. Therefore, this method may be considered if a well-HLA-matched UDT cannot be obtained.

Objectives Eltrombopag, a thrombopoietin-receptor agonist, stimulates hematopoiesis in patients with acquired aplastic anemia (AA). Cytomorphologic changes in bone marrow after eltrombopag administration are still unclear. This study examined the effect of eltrombopag on cytomorphologic findings using data from prior phase 2 studies (E1201 and E1202). Methods Microscopic examinations were performed in 31 patients with AA (E1201 [n = 21], E1202 [n = 10]). The relationship between hematologic improvement and morphologic findings was also investigated. Results In 5 patients (E1201 [n = 3], E1202 [n = 2]), the bone marrow blast count increased after initiation of eltrombopag treatment compared with screening values. The blast count was less than 5%, and the increase in bone marrow blasts was transient in all 4 patients who had bone marrow examinations at follow-up. In 8 patients (E1201 [n = 5], E1202 [n = 3]), dysplastic forms of megakaryocytes were found in the bone marrow following treatment initiation. Dysmegakaryopoiesis of 10% or more was found in 3 patients. None of the patients revealed micromegakaryocytes. Ten patients showed an increase in bone marrow blasts and/or dysmegakaryopoiesis following treatment initiation. Nine of 10 patients showed hematologic improvement in 1 or more lineages. Conclusions Dysmegakaryopoiesis without micromegakaryocytes and a transient increase of less than 5% in bone marrow blast count may be signs of hematologic improvement with eltrombopag for patients with AA.

A multicenter phase II study was conducted in 44 elderly (≥ 65 years) Japanese patients with newly diagnosed acute myeloid leukemia (AML) to evaluate whether azacitidine is also effective and feasible in Japanese AML patients. The 28 patients with AML with poor-risk cytogenetics and/or myelodysplasia-related changes (unfavorable AML) were randomly assigned to receive either azacitidine or conventional care regimens (CCR), and the other 16 patients without unfavorable AML received azacitidine alone. The primary endpoint was overall survival. At the median follow-up of 29 months, among the 26 evaluable patients with unfavorable AML, the median survival time (MST) of patients who received azacitidine (N = 14) was 9.6 months and that of patients who received CCR (N = 12) was 5.3 months (HR 0.73; 95% CI 0.31-1.69; log-rank P = 0.459). The MST of all 29 patients who received azacytidine, including the 15 evaluable patients without unfavorable AML, was 12.4 months. Adverse events of azacitidine were manageable and consistent with its established safety profile. Azacitidine tended to prolong survival in newly diagnosed elderly Japanese patients with AML, and was feasible as a front-line therapy for elderly AML patients.

The BLd regimen, which is a triplet regimen of bortezomib (Bor), lenalidomide (Len), and dexamethasone (Dex), is effective against newly diagnosed multiple myeloma (NDMM). However, non-hematological toxicities, such as peripheral neuropathy (PN), often hamper long-term continuation of the regimen, particularly in older adult patients. In this study, we examined the efficacy and safety of the modified BLd regimen with reduced-intensity Bor and standard-dose Len. The chemotherapy regimen consisted of 1.3 mg/m

Expanded therapeutic options are warranted for patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) who have FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations. The present phase 1, multicenter, open-label, dose-escalation and dose-expansion study was conducted to assess the safety, pharmacokinetics, and efficacy of multiple-dose monotherapy of the FLT3 inhibitor, quizartinib, in Japanese patients with R/R AML. Patients received oral quizartinib, once daily, under fasting conditions in 28-day cycles. Sixteen patients (median age, 68.0 years; male, 56.3%; FLT3-ITD positive, 43.8%) received quizartinib (9, 3, and 4 patients at 20, 30, and 60 mg/day, respectively; median treatment duration, 95.0 days; median relative dose intensity, 100.0%). No dose-limiting toxicities were observed. The most common treatment-emergent adverse events were electrocardiogram QT prolonged (43.8%, grade 1 or 2) followed by nausea and pyrexia (37.5% each). No quizartinib-related deaths were reported. A dose-dependent increase of quizartinib and its active metabolite AC886 levels was observed at the steady state. The composite complete remission rate was 37.5%. Quizartinib was well tolerated in Japanese R/R AML patients at doses up to 60 mg/day; quizartinib 60 mg/day was considered as the recommended dose for the Japanese patient population in a subsequent study. Trial registration ClinicalTrials.gov identifier NCT02675478.

3080 Background: CTX-712 is a first in class, orally available, highly potent and selective small-molecular inhibitor of CDC2-like kinase (CLK), a key regulator of the RNA splicing process that plays a critical role in driving cell growth. CTX-712 demonstrated potent inhibition of proliferation in a variety of human tumor cell lines in vitro and elicited robust antitumor activity in vivo in multiple xenograft models. The objectives of this study are to determine the recommended dose (RD) by evaluating maximum tolerated dose (MTD) and dose limiting toxicity (DLT), safety, pharmacokinetics (PK) and pharmacodynamics (PD) profiles, and preliminary efficacy of CTX-712 in patients with solid tumors (ST) and hematologic malignancies (HM). Methods: This study consists of ST and HM dose escalation cohorts to identify MTD and ST dose expansion cohort to identify RD. The ST dose escalation cohort was initiated with accelerated titration and then switched to a 3+3 design (10, 20, 40, 70, 105, 140 and 175 mg/body twice a week in 28-day cycles). The initial dose of HM dose escalation cohort was decided from the safety information of ST dose escalation cohort. A 3+3 design was used in HM dose escalation cohort. Results: As of Dec. 31, 2021, 30 patients were enrolled (16 in the ST dose escalation cohort (10/20/40/70 mg [1], 105/175 mg [3], 140 mg [6]), 10 in the ST expansion cohort, and 4 in the HM dose escalation cohort). In the ST dose escalation cohorts, DLTs were observed in 2 patients (140 mg [platelet count decreased, hypokalemia], 175 mg [dehydration]) and MTD was determined to be 140 mg. Based on this safety information, the ST dose expansion cohort and the HM dose escalation cohort were initiated with the dose of 105 mg twice a week. Among all enrolled patients, the common any-grade Adverse Events (AEs) (≥30%) were nausea (97%), vomiting (63%), diarrhoea (63%), decreased appetite (57%), blood creatinine increased (40%), dysgeusia (37%), constipation (33%), pyrexia (33%) and white blood cell count decreased (30%). The most common Grade 3 or higher AEs were hypokalemia (10%), amylase increased and platelet count decreased (7%). In PK analysis, a dose-dependent increase in systemic exposure of CTX-712 was observed. PD response was assessed in RNA extracted from peripheral blood cells. Dose dependent increases of exon skipping in two marker RNAs were detected. Two Partial Responses and two Complete Responses were observed in ST and HM, respectively. Conclusions: CTX-712 demonstrated an acceptable safety profile with early signs of clinical antitumor activity, establishing the initial proof of concept of the CLK inhibitor. Observed DLTs included dehydration, platelet count decreased, and hypokalemia. Investigation is ongoing to determine RD. Clinical trial information: JapicCTI-184188.

The genetic basis of leukemogenesis in adults with B-cell acute lymphoblastic leukemia (B-ALL) is largely unclear, and its clinical outcome remains unsatisfactory. This study aimed to advance the understanding of biological characteristics, improve disease stratification, and identify molecular targets of adult B-ALL. Adolescents and young adults (AYA) (15 to 39 years old, n = 193) and adults (40 to 64 years old, n = 161) with Philadelphia chromosome-negative (Ph−) B-ALL were included in this study. Integrated transcriptomic and genetic analyses were used to classify the cohort into defined subtypes. Of the 323 cases included in the RNA sequencing analysis, 278 (86.1%) were classified into 18 subtypes. The ZNF384 subtype (22.6%) was the most prevalent, with 2 novel subtypes (CDX2-high and IDH1/2-mut) identified among cases not assigned to the established subtypes. The CDX2-high subtype (3.4%) was characterized by high expression of CDX2 and recurrent gain of chromosome 1q. The IDH1/2-mut subtype (1.9%) was defined by IDH1 R132C or IDH2 R140Q mutations with specific transcriptional and high-methylation profiles. Both subtypes showed poor prognosis and were considered inferior prognostic factors independent of clinical parameters. Comparison with a previously reported pediatric B-ALL cohort (n = 1003) showed that the frequencies of these subtypes were significantly higher in AYA/adults than in children. We delineated the genetic and transcriptomic landscape of adult B-ALL and identified 2 novel subtypes that predict poor disease outcomes. Our findings highlight the age-dependent distribution of subtypes, which partially accounts for the prognostic differences between adult and pediatric B-ALL.

More than 40% of Japanese patients with multiple myeloma (MM) are over 75 years of age at diagnosis. Regardless of the treatment benefits, complications and relapses obstruct long-term survival. We conducted a phase II, open-label, single-arm, multicenter clinical trial to assess the efficacy and safety of alternating bortezomib-dexamethasone (Bd) and lenalidomide-dexamethasone (Ld) (Bd/Ld) treatment in MM patients aged over 75 years (MARBLE trial). Patients received Bd therapy from days 1 to 35 and Ld therapy from days 36 to 63. For Bd therapy, patients were administered bortezomib 1.3 mg/m

We retrospectively analyzed the risk factors for outcomes among patients with peripheral T-cell lymphoma not otherwise specified (PTCL-NOS, n = 100) and angioimmunoblastic T-cell lymphoma (AITL, n ...

High-dose chemotherapy and autologous stem cell transplantation (ASCT) are too toxic for elderly patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Therefore, effective and tolerable regimens for elderly patients are urgently needed. The present phase II study assessed the efficacy and safety of dose-adjusted therapy with gemcitabine, dexamethasone, cisplatin, and rituximab (GDP-R) in this population. ASCT-ineligible elderly patients with relapsed or refractory DLBCL received dose-adjusted GDP-R in each 28-day cycle for up to six cycles. The primary endpoint was overall response rate (ORR), and secondary endpoints were complete response (CR) rate, progression-free survival (PFS), and safety. Thirty-three patients were enrolled and received dose-adjusted GDP-R. The median age was 75 years (range: 68-87 years). The ORR was 82.8% (90% confidence interval [CI], 67.1-93.0%), with a CR rate of 58.6% (90% CI, 41.7-74.1%). At a median follow-up of 20.9 months, the 2-year PFS rate was 46.8% (90% CI, 30.7-61.5%) and the 2-year overall survival rate was 63.2% (90% CI, 45.8-76.3%). The most frequently observed grade 4 adverse events were neutropenia (63.6%), thrombocytopenia (57.6%), and lymphocytopenia (39.4%). Dose-adjusted GDP-R is a promising salvage regimen for ASCT-ineligible elderly patients with relapsed DLBCL after rituximab-containing chemotherapy and warrants further investigation.

This phase 1/2 study aimed to identify the maximum tolerated dose, the recommended phase 2 dose (RP2D), and efficacy of the clofarabine, etoposide, and cyclophosphamide combination regimen in adult patients with relapsed/refractory acute lymphoblastic leukemia (ALL). Patients aged ≥ 15 years with relapsed/refractory ALL were enrolled. Escalating doses of clofarabine (20–30 mg/m2/day × 5 days), etoposide (50–100 mg/m2/day × 5 days), and cyclophosphamide (200–440 mg/m2/day × 5 days) were administered. Dose-limiting toxicity was defined as Grade 3 or more non-hematological toxicities and others. A total of 18 patients (B-ALL; n = 13, T-ALL; n = 5) were recruited in phase 1; however, the protocol was amended to close study without proceeding to phase 2. Three patients were enrolled in cohort 1, three in cohort 2, six in cohort 3, and six in cohort 4. The RP2D of clofarabine, etoposide, and cyclophosphamide was 30, 100, and 440 mg/m2 daily, respectively. Complete remission (CR) was achieved in four patients (22%) and CR without platelet recovery in four patients (22%), with an overall response rate of 44%. The RP2D of the combination therapy was successfully determined in this study.

Cytomegalovirus (CMV) infection is a major infectious complication following an allogeneic hematopoietic stem cell transplantation (allo-HSCT). Recent large-scale retrospective studies reported that CMV reactivation is an independent risk factor for poor post-transplant outcomes, although the development of CMV end-organ disease is suppressed by the CMV antiviral preemptive therapy, which has been mainly analyzed for hematopoietic malignancies, such as acute leukemia. However, it remains unclear whether CMV reactivation also has a negative effect on post-transplant outcomes in aplastic anemia (AA). Therefore, we evaluated the clinical relevance of CMV reactivation in patients with AA using the registry database of the Japan Society for Hematopoietic Cell Transplantation. Adult patients with AA who underwent their first allo-HSCT between 2005 and 2017 and who survived with neutrophil engraftment until 100 days post-transplantation were analyzed (n = 672). Patients were monitored using pp65 antigenemia since the time of engraftment, and CMV reactivation in the analysis of this study was defined as the beginning of CMV preemptive or definitive therapy within 100 days post-transplantation. CMV reactivation occurred in 372 (55%) patients, including 19 with CMV end-organ disease. In time-dependent multivariate analysis, patients aged ≥40 years (hazard ratio [HR], 1.89; P = .003) who underwent transplantation from HLA-matched related peripheral blood stem cells (HR, 2.85; P = .008), HLA-matched unrelated bone marrow (BM) (HR, 2.01; P = .036), and other stem cell sources (HR, 2.32; P = .007) compared to HLA-matched related BM, CMV reactivation (HR 1.65; P = .042), grade II to IV acute graft-versus-host disease (HR 1.73; P = .013), and secondary graft failure (HR 7.09; P.001) had independent risk factors that significantly decreased overall survival, indicating that CMV reactivation, one of the early events at post-transplantation, had a significant negative impact on the long-term prognosis at post-transplantation. This effect was more pronounced in patients aged ≥40 years who received a graft from other than HLA-matched related BM. Comparing the causes of death with and without CMV reactivation, no significant difference in the frequency of each cause of death was observed between the 2 groups (P = .453). Improvement of post-transplant CMV management that effectively suppresses CMV reactivation in the early stage at post-transplantation will be required to improve post-transplant outcomes, especially in high-risk patients.

Sinusoidal obstruction syndrome (SOS) is a lethal complication after hematopoietic stem cell transplantation (HSCT). Defibrotide (DF) is the only drug internationally recommended for SOS treatment in Western countries. Recombinant human soluble thrombomodulin (rhTM), which is promising for the treatment of patients with disseminated intravascular coagulation, is also reported to be potentially effective for SOS. To clarify the safety and efficacy of DF and rhTM, we conducted a retrospective survey of these agents in Japan. Data from 65 patients who underwent allogeneic HSCT and received DF (n = 24) or rhTM (n = 41) for SOS treatment were collected. The complete response rates for SOS on day 100 were 50% and 54% in the DF and rhTM groups, respectively. The 100-day overall survival rates were 50% in the DF group, and 48% in the rhTM group. Several severe hemorrhagic adverse events were observed in one patient in the DF group and five patients in the rhTM group. The main causes of death were SOS-related death, and no patient died of direct adverse events of DF or rhTM. Our results suggest that rhTM, as well as DF, can be effective as a novel treatment option for SOS.

Standard therapy for idiopathic thrombocytopenic purpura (ITP) has not been established. We are conducting a multicenter, prospective trial to determine the efficacy and safety of short-term, high-dose dexamethasone therapy in ITP patients aged 18-80 years with platelet counts of

Introduction: Graft failure (GF) is a fatal complication after allogeneic stem cell transplantation (SCT). Although salvage SCT is the only curative therapy for GF, optimal donors and strategies for this procedure have not yet been established. Although in the last decade haploidentical donors have emerged as alternative donors, only limited data are available regarding the outcomes after haploidentical salvage SCT using post-transplant cyclophosphamide (PTCy). Therefore, this nationwide retrospective study aimed to evaluate the transplant outcomes and risk factors for survival after haploidentical salvage SCT using PTCy on behalf of the Transplant Complications Working Group of the Japan Society for Transplantation and Cellular Therapy. Methods: Clinical data were provided by the nationwide database of the Japanese Data Center for Hematopoietic Cell Transplantation. Patients who were diagnosed with GF and underwent a second or higher allogeneic SCT from the haploidentical related donor (≥2 antigen-mismatch), using PTCy as graft-versus-host disease (GVHD) prophylaxis, between 2011 and 2019 were included. Organ failure was defined as either ejection fraction ≤50%, serum creatinine ≥2 mg/dL, bilirubin ≥1.5 × upper limit of normal, or aspartate aminotransferase/alanine aminotransferase ≥2.5 × upper limit of normal. Overall survival (OS) probabilities were estimated using the Kaplan-Meier method and differences among groups were analyzed using the log-rank test. The multivariate analysis for OS was performed using the Cox proportional hazard regression model. Factors from the univariate analysis that demonstrated significance with P values < 0.1 were included in the multivariate analysis. Results: A total of 33 patients were included in the study. The median age was 34 years (range, 2-67), while performance status (PS) was 0-1 in 21 patients (64%). At salvage transplantation, 12 (36%) were receiving treatment for active infection, and 5 (15%) had organ failure. The median interval from SCT to salvage SCT was 49 days (range, 26-1,468), and 21 patients (68%) underwent salvage SCT within 100 days after previous SCT. Conditioning regimens consisted of fludarabine (Flu)/ cyclophosphamide (Cy)-based in 10 (31%), Flu/melphalan (Mel)-based in 10 (31%), and Flu/busulfan (Bu)-based in 7 (21%). The total dose of PTCy was 75-100 mg/kg in 26 patients (84%) and 40-50 mg/kg in 5 patients (16%). Most patients (84%) received tacrolimus plus mycophenolate mofetil as GVHD prophylaxis in addition to PTCy. Previous SCT was cord blood transplantation in 22 patients (67%) and haploidentical transplantation in 6 patients (19%), of which 4 patients (13%) received PTCy. The median time for neutrophil engraftment was 18 days, and the cumulative incidence of neutrophil engraftment at 30 days was 82%. Specifically, a patient who had donor-specific human-leukocyte antigen-antibody successfully achieved neutrophil engraftment at 22 days after salvage SCT. The median OS was 359 days, while the OS at 1 year was 47% (Figure A). In the univariate analysis, the OS of patients who received 75-100 mg/kg PTCy was significantly better than those who received 40-50 mg/kg PTCy (61% vs. 0% at 1 year, P = 0.022, Figure B). After adjusting for PS and the presence of active infection and organ failure, 75-100 mg/kg PTCy was significantly associated with better OS (hazard ratio, 0.30; P = 0.036). Although the differences were not significant, patients who received Flu/Mel-based conditioning exhibited numerically better OS than those who received Flu/Cy- or Flu/Bu-based conditioning (80% vs. 40% vs. 57%, P = 0.21). Conclusions: Haploidentical salvage SCT using PTCy offers promising survival outcomes and can be a substantial option for GF after allogeneic SCT. An adequate dose of PTCy (i.e., 75-100 mg/kg) needs to be administered to achieve long-term survival. Figure 1 Figure 1. Disclosures Nakamae: PPD-SNBL K.K: Research Funding; Bristol-Myers Squibb Company: Honoraria, Research Funding; Alexion: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Simon-Kucher & Partners: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria; Astellas Pharma Inc.: Honoraria; Otsuka Pharmaceutical Co., Ltd: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria; CMIC HOLDINGS Co., Ltd: Research Funding; Novartis: Honoraria, Research Funding; Pfizer Japan Inc.: Honoraria. Ichinohe: Celgene: Honoraria; Novartis Pharma K.K.: Honoraria; Repertoire Genesis Inc.: Honoraria, Research Funding; Takara Bio Inc.: Research Funding; Zenyaku Kogyo Co.: Research Funding; Taiho Pharmaceutical Co.: Research Funding; Sumitomo Dainippon Pharma Co.: Honoraria, Research Funding; Otsuka Pharmaceutical Co.: Research Funding; Nippon Shinyaku Co: Research Funding; Ono Pharmaceutical Co.: Honoraria, Research Funding; Kyowa Kirin Co.: Honoraria, Research Funding; FUJIFILM Wako Chemicals.: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; Eisai Co.: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Chugai Pharmaceutical: Research Funding; Bristol-Myers Squibb: Honoraria; Takeda Pharmaceutical Co.: Honoraria; AbbVie Pharma: Research Funding; Astellas Pharma: Honoraria, Research Funding. Atsuta: Mochida Pharmaceutical Co., Ltd.: Speakers Bureau; Astellas Pharma Inc.: Speakers Bureau; AbbVie GK: Speakers Bureau; Kyowa Kirin Co., Ltd: Honoraria; Meiji Seika Pharma Co, Ltd.: Honoraria. Nakasone: Takeda Pharmaceutical: Honoraria; Otsuka Pharmaceutical: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Eisai: Honoraria; Chugai Pharmaceutical: Honoraria; Nippon Shinyaku: Honoraria.

Therapy-related acute myeloid leukemia and myelodysplastic syndrome (t-AML/MDS) represent severe late effects in patients receiving hematopoietic cell transplantation (HCT) for lymphoma. The choice between high-dose therapy with autologous HCT and allogeneic HCT with reduced-intensity conditioning remains controversial in patients with relapsed lymphoma. We retrospectively analyzed incidence and risk factors for the development of t-AML/MDS in lymphoma patients treated with autologous or allogeneic HCT. A total of 13 810 lymphoma patients who received autologous (n=9963) or allogeneic (n=3847) HCT between 1985 and 2012 were considered. At a median overall survival (OS) of 52 and 46 months in autologous and allogeneic HCT groups, respectively, lymphoma patients receiving autologous HCT (1.38% at 3 years after autologous HCT) had a significant risk for developing t-AML/MDS compared to allogeneic HCT (0.37% at 3 years after allogeneic HCT, P

Diarrhea after hematopoietic stem cell transplantation (HSCT) can be life-threatening, and its etiology includes conditioning regimens, graft-versus-host disease (GVHD), infections, and transplantation-associated microangiopathy (iTAM). Cord colitis syndrome (CCS) has been described as a syndrome of culture-negative and antibiotic-responsive persistent watery and non-bloody diarrhea of uncertain pathogenesis and occurs in umbilical cord blood transplantation (UCBT) recipients. We encountered a case similar to CCS that developed severe watery diarrhea after UCBT without any signs of GVHD or infection and responded well to metronidazole (MNZ) treatment. Since CCS is very rare, we herein describe a case of MNZ-effective diarrhea after UCBT.

Summary Background Fungal infections are a major complication of neutropaenia following chemotherapy. Their early diagnosis is difficult, and empirical antifungal treatment is widely used, and uses of less toxic drugs that reduce breakthrough infection are required. Objective We conducted a multicentre, open‐label, randomised, non‐inferiority trial to compare the safety and efficacy of intravenous itraconazole (ivITCZ) and liposomal amphotericin B (LAmB) as empirical antifungal therapy in patients with haematological malignancies with neutropaenia and persistent fever. Methods Patients with haematological malignancies who developed fever refractory to broad‐spectrum antibacterial agents under neutropaenia conditions were enrolled. Patients were randomised for treatment with LAmB (3.0 mg/kg/d) or ivITCZ (induction: 400 mg/d, maintenance: 200 mg/d). Results Observed overall favourable response rates of 17/52 (32.7%) and 18/50 (36.0%) in the LAmB and ivITCZ groups, with a model‐based estimate of a 4% difference (90% CI, −12% to 20%), did not fulfil the statistical non‐inferiority criterion. In the LAmB group, there were two cases of breakthrough infection and five cases of probable invasive fungal disease, whereas in the itraconazole group, neither breakthrough infection nor probable invasive fungal disease occurred. Patients in the ivITCZ group had significantly fewer grade 3‐4 hypokalaemia‐related events than LAmB group patients (P

Acute promyelocytic leukemia (APL) in human immunodeficiency virus (HIV)-infected individuals is very rare. There is currently no consensus regarding the use of anti-cancer drugs with highly active anti-retroviral therapy (ART) in these patients due to their small number. We herein report two cases of APL with HIV-infected patients. Both cases received all-trans-retinoic acid-containing chemotherapies and achieved complete remission. ART was continued throughout the treatment course. The clinical course of these cases suggests that it is preferable to perform standard chemotherapy for APL with ART if patients have an adequate performance status.

Background/aim Neuroblastoma (NB) is the most common extracranial solid tumor in childhood; treatments with greater effectiveness are required for NB, especially in advanced cases. This study aimed at evaluating the combined effect of anaplastic lymphoma kinase (ALK) inhibitor alectinib and histone deacetylase inhibitor vorinostat on NB cell lines harboring wild-type or mutated ALK. Materials and methods Cytotoxicity was examined using the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay. Protein expression was analyzed using western blotting. Results Combination treatment with alectinib and vorinostat had a synergistic effect on growth inhibition of the NB cell line with ALK R1275Q mutation. Cleavage of caspase-3 and poly-(ADP-ribose) polymerase increased, indicating enhanced caspase-dependent apoptosis. In addition, this combination reduced the protein levels of MYCN proto-oncogene and nuclear factor kappa B, both of which are important for NB tumorigenesis and progression. Conclusion Combined treatment with alectinib and vorinostat might be a novel therapeutic option for NB harboring the ALK R1275Q mutation.

Invasive fungal infections, especially those caused by Aspergillus, can be fatal in patients who have undergone allogeneic hematopoietic stem cell transplantation. Fluconazole, itraconazole and micafungin can be used to prevent fungal infections in patients undergoing allogeneic hematopoietic stem cell transplantation, but fluconazole is not effective against Aspergillus, and itraconazole has less tolerability from gastrointestinal toxicity. Micafungin is approved for prophylaxis at a dose of 50 mg/day, less than a therapeutic dose. Voriconazole, the current preferred agent for invasive Aspergillus infection, is available in both oral and intravenous preparations, and has recently been approved for prophylaxis in Japan. Some US and European studies have reported on the prophylactic use of voriconazole, but the efficacy and safety of this has not been confirmed in Japan. Hence, this prospective study of voriconazole as prophylaxis against invasive fungal infections in patients who have received allogeneic hematopoietic stem cell transplantation is being performed to evaluate its efficacy and safety, including incidence rate of proven/probable invasive aspergillosis and other fungal infections, and adverse event(s) due to voriconazole administration. We are also investigating potential interactions between voriconazole and immunosuppressive drugs by monitoring the blood concentration of a calcineurin inhibitor in Japanese patients. Further, this study aims to improve the clinical outcomes of allogeneic hematopoietic stem cell transplantation recipients.

Eltrombopag, an oral thrombopoietin-receptor agonist, stimulates hematopoiesis in patients with acquired aplastic anemia (AA) and has higher exposure in patients of East Asian origin. We evaluated the pharmacokinetics, efficacy, and safety of eltrombopag in Japanese patients with AA refractory or intolerant to immunosuppressive therapy (IST). Twenty-one patients (15 with non-severe AA, six with severe AA) with platelet counts

Ganciclovir (GCV) and foscarnet (FCN) are effective anti-cytomegalovirus (CMV) preemptive therapies; however, the impact of the 2 agents on various clinical outcomes of allogeneic hematopoietic stem cell transplantation (HSCT) remains unclear. We retrospectively analyzed data on 532 patients undergoing allogeneic HSCT from unrelated donors and administered FCN (n = 86) or GCV (n = 446) as first-line anti-CMV preemptive therapy. Overall survival, relapse, and nonrelapse mortality (NRM) did not differ between the FCN and GCV groups, whereas the GCV group had a higher risk of chronic graft-versus-host disease (cGVHD) (hazard ratio [HR], 2.38; 95% confidence interval [CI], 1.28 to 4.39; P = .006) and extensive cGVHD (HR, 3.94; 95% CI, 1.43 to 10.9; P = .008). All 13 patients with cGVHD in the FCN group survived. Switching to the other agent was done mainly due to hematologic adverse events in the GCV group and mainly due to insufficient efficacy in the FCN group. The incidence of end-organ CMV disease was similar in the 2 groups. Selection of FCN or GCV as first-line preemptive anti-CMV therapy did not affect survival, relapse, or NRM. Physicians can select either of the agents, depending on the clinical situation; however, the selection may influence the cGVHD-related clinical course in HSCT recipients.

Gilteritinib, a novel, highly specific, potent fms-like tyrosine kinase 3/AXL inhibitor, demonstrated antileukemic activity in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). In this open-label phase 1 study (NCT02181660), Japanese patients (aged ≥18 years) with R/R AML received once-daily gilteritinib, escalating from 20 to 300 mg/d. Primary endpoints were safety/tolerability, including the maximum tolerated dose (MTD) and the recommended dose (RD); secondary endpoints were antileukemic activity and pharmacokinetics (PK). Twenty-four Japanese patients with R/R AML received once-daily oral gilteritinib in 1 of 6 dose-escalation cohorts (20, 40, 80, 120, 200, and 300 mg/d). Gilteritinib was well tolerated. The MTD was 200 mg/d; dose-limiting toxicities were grade 3 tumor lysis syndrome (120 mg/d; n = 1); and grade 3 elevated blood lactate dehydrogenase, amylase, blood creatine phosphokinase levels, and syncope (all n = 2; 300 mg/d). The RD was 120 mg/d. The most common drug-related grade ≥3 adverse events were thrombocytopenia (n = 4 [16.7%]) and increased blood creatine phosphokinase (n = 3 [12.5%]). Gilteritinib had a dose-proportional PK profile. Among patients with mutated fms-like tyrosine kinase 3, the overall response rate (ORR) was 80% (n = 4 of 5; complete remission [CR] with incomplete platelet recovery, 1 [20%]; CR with incomplete hematologic recovery, 2 [40%]; partial remission (PR), 1 [20%]). Among patients with wild-type fms-like tyrosine kinase 3, ORR was 36.4%; (n = 4 of 11; CR, 1 [9.1%]; CR with incomplete platelet recovery, 2 [18.2%]; PR, 1 [9.1%]). In conclusion, gilteritinib was well tolerated and demonstrated antileukemic activity in a Japanese R/R AML population.

Clinical information regarding non-Hodgkin lymphoma (NHL) in adolescents and young adults (AYA) is lacking. We retrospectively analyzed 1426 consecutively registered patients with newly diagnosed NHL. Of 798 DLBCL patients, 42 (5.3%) were identified as AYA (16–39 years). The characteristics of AYA DLBCL patients showed no significant differences compared to older adult DLBCL patients (age ≥ 40 years). Progression-free survival (PFS) and overall survival (OS) in AYA were similar to those in patients aged 40–60 years. However, in older adult groups, PFS and OS were significantly different according to the age group (40–60, 61–79, and ≥ 80 years). In univariate analysis in AYA, performance status, clinical stage, International Prognostic Index (IPI), and age-adjusted IPI significantly affected both PFS and OS. In multivariate analysis, only clinical stage was identified as an independent predictor among AYA. In conclusion, disease characteristics and outcomes of DLBCL in AYA were nearly the same as those in older adults.

Influence of melphalan plus fludarabine-conditioning regimen in elderly patients aged ⩾ 55 years with hematological malignancies

Mantle cell lymphoma (MCL) is a B cell malignancy characterized by aberrant expression of cyclin D1 due to a t(11;14) translocation. MCL is refractory to conventional chemotherapy, and treatment remains challenging. We investigated the efficacy of the histone deacetylase (HDAC) inhibitor vorinostat combined with one of several B-cell receptor (BCR) signaling inhibitors on MCL cell death and the underlying mechanisms, using MCL cell lines. The Bruton’s tyrosine kinase inhibitor PCI-32765 and the spleen tyrosine kinase inhibitor R406 showed synergistic effects with vorinostat on growth inhibition. Treatment with PCI-32765 or R406 alone induced 27.3 ± 2.1 or 25.1 ± 3.2 % apoptosis. When combined with vorinostat, these apoptotic fractions significantly increased to 50.8 ± 4.9 and 63.1 ± 5.0 %, respectively. Activation of caspase-3 and poly-(ADP-ribose) polymerase cleavage were markedly increased. We performed gene expression profiling following treatment with the combination of vorinostat and individual BCR signaling inhibitors using a microarray, and differentially expressed genes were identified. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis showed that the nuclear factor (NF)-κB signaling pathway was significantly enriched following treatment with the combination of vorinostat and R406. Protein expression analysis confirmed the down-regulation of NF-κB1/p105 and cyclin D1, suggesting inhibition of the NF-κB pathway. Taken together, the combination of an HDAC inhibitor and a BCR signaling inhibitor may be a novel therapeutic strategy for MCL.

Little is known regarding the chimerism status after reduced-intensity conditioning transplantation when bone marrow is used as a stem cell source. We prospectively analyzed lineage-specific chimerism and retrospectively evaluated clinical outcomes in 80 adult patients who underwent unrelated donor bone marrow transplantation (URBMT) with fludarabine plus melphalan (FM) as the conditioning regimen. Mixed donor chimerism (MDC) was seen in 43 and 10 % of patients at days 14 and 28, respectively. Melphalan at ≤130 mg/m(2) was associated with an increased incidence of MDC at day 28 (P = 0.03). Patients with MDC at day 14 showed a marginally increased risk of primary graft failure and a marginally decreased risk of graft-versus-host disease. In multivariate analysis, MDC at day 14 was associated with higher overall mortality (hazard ratio (HR) = 2.1; 95 % confidence interval (CI), 1.1-4.2; P = 0.04) and relapse rate (HR = 3.0; 95 % CI, 1.2-7.5; P = 0.02), but not with non-relapse mortality (HR = 1.8; 95 % CI, 0.70-4.6; P = 0.23). Thus, the FM regimen yields prompt complete donor chimerism after URBMT, but the melphalan dose significantly impacts the kinetics of chimerism. Chimerism status evaluation at day 14 may be instrumental in predicting relapse after URBMT with the FM regimen.

The term cryoglobulinemia (CG) is used to refer to vasculitis due to so-called mixed cryoglobulins containing immune complexes. Although most cases of monoclonal CG, called type I CG, are asymptomatic, purpura, skin ulcers, and renal failure develop in some cases. Hematological disorders are the underlying diseases in most cases, on which the therapeutic strategies available and the prognosis of patients depends. We here report a case of a 47-year-old man who had pain in both his ankles, with palpable purpura and epistaxis, and presented with acute renal failure. Monoclonal immunoglobulin (Ig) G-κ protein was detected and cryoglobulin was also positive. Renal biopsy revealed emboli with a fibrillar structure in the glomeruli and renal tubule lumina. The complication of thrombotic microangiopathy (TMA) occurred during the course. Therefore, plasma exchange and hemodialysis were added to methylprednisolone pulse therapy. The treatment was successful, dissipating the purpura. However, the purpura relapsed and renal dysfunction progressed when the administration of oral steroids was tapered. Bone marrow biopsy was performed again, which indicated an increase in abnormal plasma cells. The patient was finally diagnosed as multiple myeloma. Then, bortezomib-dexamethasone therapy was initiated. This is the first case of type I CG with monoclonal IgG complicated by TMA during the course; it provides insight into the pathogenesis of renal dysfunction associated with type I CG.