Utility of allogeneic stem cell transplantation for adult Ph+ALL with complete molecular remission.

This study aimed to investigate the usefulness of allogeneic stem cell transplantation (allo-SCT) for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) in the first complete remission (CR1) with complete molecular remission (CMR). We compared the outcomes between Ph+ALL patients who did or did not undergo allo-SCT in CR1. We included patients enrolled in the prospective clinical studies in the tyrosine kinase inhibitor era conducted by the Japan Adult Leukemia Study Group, who achieved CMR within 3 months. A total of 147 patients (allo-SCT: 101; non-SCT: 46) were eligible for this analysis. In the multivariate analyses, allo-SCT was significantly associated with both superior overall survival (OS) (adjusted hazard ratio (aHR): 0.54; 95% CI: 0.30-0.97; p = .04) and relapse-free survival (RFS) (aHR: 0.21; 95% CI: 0.12-0.38; p < .001). The 5-year adjusted OS and RFS were 73% and 70% in the allo-SCT cohort, whereas they were 50% and 20% in the non-SCT cohort. Despite the higher non-relapse mortality (aHR: 3.49; 95% CI: 1.17-10.4; p = .03), allo-SCT was significantly associated with a lower relapse rate (aHR: 0.10; 95% CI: 0.05-0.20; p < .001). In addition, allo-SCT was also associated with superior graft-versus-host disease-free, relapse-free survival (aHR: 0.43; 95% CI: 0.25-0.74; p = .002). Propensity score-matched analyses confirmed the results of the multivariate analyses. In patients who achieved CMR within 3 months, allo-SCT in CR1 had superior survival and lower relapse compared with the non-SCT cohort.

Safety and Pharmacokinetics of Quizartinib Combination Therapy With Standard Induction and Consolidation Chemotherapy in Patients With Newly Diagnosed Acute Myeloid Leukemia: Results from Two Phase 1 Trials in Japan and China.

Quizartinib is a potent, oral, second-generation, selective type II FMS-like receptor tyrosine kinase 3 (FLT3) inhibitor. It has shown improved overall survival in a randomized, multinational, Phase 3 (QuANTUM-First) study in patients with FLT3-internal tandem duplication (ITD)-positive newly diagnosed acute myeloid leukemia. We conducted 2 Phase 1b studies in Japan and China to evaluate the safety, pharmacokinetics, and efficacy of quizartinib in combination with standard induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia. Quizartinib was started at a dose level of 20 mg/day and then escalated to 40 mg/day, the dose used in the Phase 3 study. Seven patients were enrolled according to the 3 + 3 dose-escalation method in each study, including 3 patients who were FLT3-ITD positive. No dose-limiting toxicities were observed at dose levels up to 40 mg/day in both studies. Grade 3 or higher, quizartinib-related, treatment-emergent adverse events included febrile neutropenia, hematologic toxicities, and infections. QT prolongation on electrocardiogram was observed in 5 patients. The pharmacokinetics of quizartinib and its metabolite AC886 were similar between the studies and consistent with previous findings in the United States. We confirmed the tolerability of Japanese and Chinese patients to the dose of quizartinib and chemotherapy regimens used in the QuANTUM-First study.

Development and evaluation of a rapid one-step high sensitivity real-time quantitative PCR system for minor BCR-ABL (e1a2) test in Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL).

OBJECTIVE: Minimal residual disease assessment of BCR-ABL messenger ribonucleic acid levels is crucial in Philadelphia chromosome-positive acute lymphoblastic leukemia for prognosis and treatment planning. However, accurately quantifying minor BCR-ABL transcripts, which comprise 70% of Philadelphia chromosome-positive acute lymphoblastic leukemia cases, lacks a national-approved method. METHODS: We developed the "Otsuka" minor BCR-ABLmessenger ribonucleic acid assay kit with exceptional precision (0.00151%). Minor BCR-ABL messenger ribonucleic acid levels were analyzed in 175 adults, 36 children with acute lymphoblastic leukemia and 25 healthy individuals to evaluate the kit's performance. RESULTS: The "Otsuka" kit showed high concordance with a commonly used chimeric gene screening method, indicating reliable detection of positive cases. Quantitative results demonstrated a robust correlation with both a laboratory-developed test and a diagnostic research product. The "Otsuka" kit performs comparably or even surpass to conventional products, providing valuable insights into Philadelphia chromosome-positive acute lymphoblastic leukemia pathology. CONCLUSIONS: The 'Otsuka" minor BCR-ABL messenger ribonucleic acid assay kit exhibits excellent performance in quantifying minor BCR-ABL transcripts in Philadelphia chromosome-positive acute lymphoblastic leukemia patients. Our results align well with established screening methods and show a strong correlation with laboratory-developed tests and diagnostic research products. The "Otsuka" kit holds great promise as a valuable tool for understanding Philadelphia chromosome-positive acute lymphoblastic leukemia pathology and guiding effective treatment strategies.

Autologous peripheral blood stem cell transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia is safe but poses challenges for long-term maintenance of molecular remission: Results of the Auto-Ph17 study.

Autologous hematopoietic stem cell transplantation (SCT) is not a standard treatment option for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL); however, its position has been reassessed since the introduction of tyrosine kinase inhibitors (TKIs). We prospectively analyzed the efficacy and safety of autologous peripheral blood SCT (auto-PBSCT) for Ph+ALL patients aged between 55 and 70 years who had achieved complete molecular remission. Melphalan, cyclophosphamide, etoposide, and dexamethasone were used for conditioning. A total of 12 courses of maintenance therapy, including dasatinib, were performed. The required number of CD34+ cells was harvested in all five patients. No patient died within 100 days after auto-PBSCT, and no unexpected serious adverse events were observed. Although 1-year event-free survival was 100%, hematological relapse was observed in three patients at a median of 801 days (range, 389-1088 days) after auto-PBSCT. Molecular progressive disease was observed in the other two patients, although they maintained their first hematological remission at the last visit. Auto-PBSCT can be safely performed for Ph+ALL with TKIs. A limitation of auto-PBSCT was suggested, despite the increase in the intensity of a single treatment. The development of long-term therapeutic strategies by including new molecular targeted drugs is warranted to maintain long-term molecular remission.

End-of-Life Care of Acute Myeloid Leukemia Compared with Aggressive lymphoma in Patients Who Are Eligible for Intensive Chemotherapy: An Observational Study in a Japanese Community Hospital.

Background: Patients with hematological malignancies (HMs) are reported to receive more aggressive care at the end of life (EOL) than patients with solid tumors. However, the reasons behind this occurrence are not fully understood. Objectives: To examine whether the care at EOL for HMs is mainly because of the disease characteristics or hematologists' attitudes and systems of care, we compared the EOL care of patients with acute myeloid leukemia (AML) and diffuse large B cell lymphoma (DLBCL). Design: We retrospectively analyzed the EOL care of patients with AML and DLBCL younger than 80 years who were receiving combination chemotherapy at a city hospital in Japan. Results: Fifty-nine patients with AML and 65 with DLBCL were included. Those with AML received chemotherapy more often within their last 30 days (48% vs. 19%, p < 0.001) and 14 days (37% vs. 1.5%, p < 0.001) of life, and consulted the palliative team less frequently (5.3% vs. 29%, p < 0.001). In the last 3 years, the mortality rate in hematological wards decreased from 74% to 29% in the DLBCL group, but only from 95% to 90% in the AML group. In multivariate analysis, AML (odds ratio [OR] 0.065) and death before 2018 (OR, 0.077) were significant factors associated with reduced referrals to specialized palliative teams. Conclusion: Patients with AML tend to have lesser access to specialized palliative care and fewer options for their place of death than those with DLBCL. Detailed EOL care plans are needed for these patients, considering the characteristics of the disease.

Pomalidomide, dexamethasone, and daratumumab in Japanese patients with relapsed or refractory multiple myeloma after lenalidomide-based treatment.

In cohort C of the phase 2 MM-014 trial, the efficacy and safety of pomalidomide, dexamethasone, and daratumumab therapy were investigated in 18 Japanese patients with relapsed/refractory multiple myeloma (RRMM) after their most recent regimen of lenalidomide-based therapy (NCT01946477). Patients received oral pomalidomide (4 mg daily), oral dexamethasone (20-40 mg weekly), and intravenously infused daratumumab (16 mg/kg). Median age was 67.5 years. All patients received prior lenalidomide per protocol; 89% received prior bortezomib. Twelve patients (67%) had lenalidomide-refractory disease, and 6 (33%) had lenalidomide-relapsed disease. Ten patients (56%) had only 1 prior treatment line. As of August 3, 2020, 15 patients (83%) were still on treatment; median follow-up was 8.1 months. Three patients (17%) discontinued treatment (2 for adverse events; 1 for major protocol deviation). Overall response rate (primary endpoint) was 83% (very good partial response or better, 61%). All patients had ≥ 1 grade 3/4 treatment-emergent adverse events, most commonly neutropenia (78%; febrile, 6%), leukopenia (28%), and lymphopenia (22%). Grade 3/4 infections occurred in 17%; 11% had pneumonia. In Japanese patients with RRMM, a triplet regimen of pomalidomide, dexamethasone, and daratumumab after early-line lenalidomide treatment failure showed high efficacy and safety consistent with the known safety profile.

A Retrospective Analysis of R-MPV Plus Response-adapted Whole-brain Radiotherapy for Elderly Patients with Primary Central Nervous System Lymphoma.

Objective Few reports have described the real-world outcomes of rituximab, methotrexate (MTX), procarbazine, and vincristine (R-MPV) plus response-adapted whole-brain radiotherapy (WBRT) for elderly patients with primary central nervous system lymphoma (PCNSL). We evaluated the outcome of this regimen. Methods We evaluated >60-year-old patients with newly diagnosed PCNSL who received R-MPV plus WBRT from January 2010 to December 2019 at Toyohashi Municipal Hospital. The patients' characteristics, regimen enforcement, response rate, survival, and toxicity were analyzed. Patients Ten patients were consecutively enrolled. Their median age was 69 years old, and 60% had a performance status of 3 or 4 before induction therapy. Results Seven patients achieved a complete response after induction, and all 10 patients achieved a complete response after consolidation. Seven received reduced-dose WBRT at 23.4 Gy, and 2 received WBRT at 45 Gy. The median follow-up was 44.4 months; the 3-year progression-free survival and overall survival rates were 60% and 80%, respectively; and the cumulative incidence of relapse was 40%. The incidence of symptomatic delayed neurotoxicity was 70%. Of the 7 patients who received reduced-dose WBRT, 4 (57%) developed delayed neurotoxicity, including 1 severely affected patient. Only one patient survived without relapse and delayed neurotoxicity. The ratio of patients who developed relapse or delayed neurotoxicity that impaired daily life was 33% and 100% in the MTX high- and low-intensity groups, respectively. Conclusion This regimen in elderly patients is unsatisfactory because of delayed neurotoxicity. We should consider maintaining an adequate MTX intensity, postponing or minimizing WBRT, and choosing high-dose consolidation therapy for select patients.

Dasatinib-based 2-step induction for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia.

The standard treatment for adults with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in Japan is imatinib-based chemotherapy followed by allogeneic hematopoietic stem cell transplantation (HSCT). However, ∼40% of patients cannot undergo HSCT in their first complete remission (CR1) because of chemotherapy-related toxicities or relapse before HSCT or older age. In this study, we evaluated dasatinib-based 2-step induction with the primary end point of 3-year event-free survival (EFS). The first induction (IND1) was dasatinib plus prednisolone to achieve CR, and IND2 was dasatinib plus intensive chemotherapy to achieve minimal residual disease (MRD) negativity. For patients who achieved CR and had an appropriate donor, HSCT during a consolidation phase later than the first consolidation, which included high-dose methotrexate, was recommended. Patients with pretransplantation MRD positivity were assigned to receive prophylactic dasatinib after HSCT. All 78 eligible patients achieved CR or incomplete CR after IND1, and 52.6% achieved MRD negativity after IND2. Nonrelapse mortality (NRM) was not reported. T315I mutation was detected in all 4 hematological relapses before HSCT. Fifty-eight patients (74.4%) underwent HSCT in CR1, and 44 (75.9%) had negative pretransplantation MRD. At a median follow-up of 4.0 years, 3-year EFS and overall survival were 66.2% (95% confidence interval [CI], 54.4-75.5) and 80.5% (95% CI, 69.7-87.7), respectively. The cumulative incidence of relapse and NRM at 3 years from enrollment were 26.1% and 7.8%, respectively. Dasatinib-based 2-step induction was demonstrated to improve 3-year EFS in Ph+ ALL. This study was registered in the UMIN Clinical Trial Registry as #UMIN000012173.

Long-term follow-up after rituximab plus bendamustine in a patient with relapsed or refractory hairy cell leukemia variant: A case report.

INTRODUCTION: Hairy cell leukemia variant (HCL-v) is a rare lymphoproliferative disorder regarded as a splenic B-cell lymphoma/leukemia, unclassifiable tumor in the 2017 World Health Organization classification of lymphoid tumors. The prognosis of HCL-v is much worse than that of classical hairy cell leukemia and there is no consensus regarding the optimal treatment strategy for HCL-v. For patients with indolent lymphoma, rituximab plus bendamustine (RB) has proven effective in several clinical trials. Thus, RB is expected to be a treatment option for patients with HCL-v, but there have been few reports of its use in these patients. PATIENT CONCERNS: A 64-year-old man presented with leukocytosis and abnormal lymphocytes in peripheral blood in a medical examination. Computed tomography revealed mild splenomegaly, but no lymph node enlargement. DIAGNOSIS: The patient was initially diagnosed with low-grade B-cell lymphoma. After he experienced a second relapse, his clinical data were reviewed again; subsequently, he was diagnosed with HCL-v on the basis of clinical presentation, flow cytometry findings, and cytogenetic abnormalities. INTERVENTIONS: The patient was first treated with the cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen. After the regimen was ineffective, he received six cycles of RB. After relapse, the patients received an additional six cycles of RB. OUTCOMES: The patients exhibited a slight reduction of the abnormal lymphocyte level but insufficient therapeutic efficacy during CHOP therapy. After the first cycle of RB, the patient exhibited an immediate response with the absence of minimal residual disease. He remained relapse-free for approximately 67 months. After a second relapse, complete response was again achieved with the absence of minimal residual disease following RB re-administration. He remained relapse-free for approximately 29 months after the second RB. CONCLUSION: RB could be a treatment option for patients with relapsed or refractory HCL-v. Further research is needed to establish the optimal treatment regimen for patients of HCL-v.

Machine learning-aided risk stratification in Philadelphia chromosome-positive acute lymphoblastic leukemia.

We used the eXtreme Gradient Boosting algorithm, an optimized gradient boosting machine learning library, and established a model to predict events in Philadelphia chromosome-positive acute lymphoblastic leukemia using a machine learning-aided method. A model was constructed using a training set (80%) and prediction was tested using a test set (20%). According to the feature importance score, BCR-ABL lineage, polymerase chain reaction value, age, and white blood cell count were identified as important features. These features were also confirmed by the permutation feature importance for the prediction using the test set. Both event-free survival and overall survival were clearly stratified according to risk groups categorized using these features: 80 and 100% in low risk (two or less factors), 42 and 47% in intermediate risk (three factors), and 0 and 10% in high risk (four factors) at 4 years. Machine learning-aided analysis was able to identify clinically useful prognostic factors using data from a relatively small number of patients.

Combination of clofarabine, etoposide, and cyclophosphamide in adult relapsed/refractory acute lymphoblastic leukemia: a phase 1/2 dose-escalation study by the Japan Adult Leukemia Study Group.

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.

Once-weekly vs. twice-weekly carfilzomib dosing in a subgroup of Japanese relapsed and refractory multiple myeloma patients from a randomized phase 3 trial (A.R.R.O.W.) and comparison with ENDEAVOR.

A.R.R.O.W. evaluated the superiority of once-weekly carfilzomib plus dexamethasone (Kd) 20/70 mg/m2 vs. twice-weekly Kd 20/27 mg/m2 based on progression-free survival (PFS) in relapsed and/or refractory multiple myeloma patients. Forty Japanese patients (once-weekly arm, n = 26; twice-weekly arm, n = 14) were randomized in A.R.R.O.W. In the Japanese subgroup of A.R.R.O.W., median PFS was 14.8 months (95% confidence interval [CI], 7.5-not evaluable [NE]) and 9.7 months (95% CI, 3.8-NE) in the once- and twice-weekly arms, respectively. The overall response rate (ORR) was 73.1% (19/26; 95% CI, 52.2-88.4) and 57.1% (8/14; 95% CI, 28.9-82.3) in each arm. The adverse events (AEs) incidence was 100% in both arms. Grade ≥ 3 AE incidence was 80.8% (21/26) and 78.6% (11/14) in each arm. Two fatal treatment-related AEs (acute lung injury and acute respiratory distress syndrome) occurred in the once-weekly arm. In exploratory unadjusted analyses of A.R.R.O.W. (once-weekly Kd 20/70 mg/m2) vs. ENDEAVOR (twice-weekly Kd 20/56 mg/m2), median PFS was 14.8 months vs. NE due to not yet being reached, and ORR was 73.1% (19/26) vs. 42.9% (3/7). In the Japanese subgroup, once-weekly Kd tended to improve ORR vs. twice-weekly Kd. Results from A.R.R.O.W. tended to be consistent with results from ENDEAVOR.

Multi-Lineage BCR-ABL Expression in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Is Associated With Improved Prognosis but No Specific Molecular Features.

BACKGROUND: Recently, various blood cell lineages expressing the BCR-ABL fusion gene in Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) have been reported. However, the biological and clinical significance of these BCR-ABL lineages has not been established; therefore, we aimed to clarify the impacts of these different BCR-ABL-expressing lineages. PATIENTS: Multi-lineage BCR-ABL expression (multi-Ph) was defined as BCR-ABL expression outside of the B-lineage compartment, as determined by fluorescence in situ hybridization (FISH) in peripheral blood neutrophils and bone marrow clots, and flow cytometry-sorted polymerase chain reaction (PCR). We analyzed IKZF1 deletion patterns by PCR, examined gene expression profiles using RNA sequencing, and compared treatment outcomes across different BCR-ABL-expressing lineages. RESULTS: Among the 21 multi-Ph patients in our 59-patient cohort (36%), BCR-ABL expression was detected at the multipotential progenitor level. However, no IKZF1 deletion patterns or gene expression profiles were identified that were specific for multi-Ph. However, multi-Ph patients were found to have better survival rates than patients with uni-lineage BCR-ABL expression [event-free survival (EFS): 74 vs. 33%, P = 0.01; overall survival (OS): 79 vs. 44% at 4 years, P = 0.01]. In multivariate analyses, multi-Ph was identified as a good prognostic factor for both EFS and OS. CONCLUSION: We confirmed that more than one-third of Ph+ALL patients could be classified as mutli-Ph. Although no specific molecular characteristics were identified for multi-Ph, this phenotype was associated with better treatment outcomes.

[Lupus anticoagulant-hypoprothrombinemia syndrome associated with follicular lymphoma].

A 56-year-old woman was referred to our hospital with symptoms of swelling, purpura, and pain in her limbs. Prior to referral, bleeding in her limbs had spontaneously appeared and disappeared several times. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) were prolonged, and the factor II level was 17%. The plasma-mixing test indicated lupus anticoagulant (LA), which was confirmed using aPTT-LA and dilute Russell's viper venom time (dRVVT). Therefore, she was diagnosed with lupus anticoagulant-hypoprothrombinemia syndrome (LAHPS). During screening for underlying disorders, chest computed tomography (CT) revealed a retrosternal mass. Biopsy was not performed because the administration of freshly frozen plasma failed to correct her coagulopathy. Prednisolone (PSL) treatment (1 mg/kg) was initiated, which normalized the coagulation tests. The retrosternal mass also disappeared. PSL was tapered without LAHPS recurrence; however, the follow-up CT revealed systemic lymphadenopathy. Follicular lymphoma was diagnosed using lymph-node biopsy. Considering the subsequent LAHPS recurrence, six cycles of bendamustine + rituximab were administered. Complete response with no LAHPS recurrence was observed at the time of drafting this report. LAHPS is rare and distinct from antiphospholipid syndrome because it can cause severe bleeding. Underlying disorders should be evaluated in cases of LAHPS.

Ultra-high sensitivity HBsAg assay can diagnose HBV reactivation following rituximab-based therapy in patients with lymphoma.

BACKGROUND & AIMS: HBV reactivation is a risk in patients receiving anti-CD20 antibodies for the treatment of lymphoma. The purpose of this post hoc analysis was to evaluate the efficacy of an ultra-high sensitivity HBsAg assay to guide preemptive antiviral treatment in patients with lymphoma and resolved HBV infections using prospectively stored samples from an HBV DNA monitoring study. METHODS: HBV reactivation (defined as HBV DNA levels of ≥11 IU/ml) was confirmed in 22 of 252 patients. A conventional HBsAg assay (ARCHITECT, cut-off value: 0.05 IU/ml) and an ultra-high sensitivity HBsAg assay employing a semi-automated immune complex transfer chemiluminescence enzyme technique (ICT-CLEIA, cut-off value: 0.0005 IU/ml) were performed at baseline, at confirmed HBV reactivation and monitored after HBV reactivation. RESULTS: Baseline HBsAg was detected using ICT-CLEIA in 4 patients; in all of whom precore mutants with high replication capacity were reactivated. Of the 6 patients with HBV DNA detected below the level of quantification at baseline, 5 showed HBV reactivation and 3 of the 5 had precore mutations. Sensitivity for detection by ARCHITECT and ICT-CLEIA HBsAg assays at HBV reactivation or the next sampling after HBV reactivation was 18.2% (4 of 22) and 77.3% (17 of 22), respectively. Of the 5 patients undetectable by ICT-CLEIA, HBV reactivation resolved spontaneously in 2 patients. All 6 patients reactivated with precore mutations including preS deletion could be diagnosed by ICT-CLEIA HBsAg assay at an early stage of HBV reactivation. Multivariate analysis showed that an anti-HBs titer of less than 10 mIU/ml, HBV DNA detected but below the level of quantification, and HBsAg detected by ICT-CLEIA at baseline were independent risk factors for HBV reactivation (adjusted hazard ratios, 15.4, 31.2 and 8.7, respectively; p <0.05). CONCLUSIONS: A novel ICT-CLEIA HBsAg assay is an alternative method to diagnose HBV reactivation. CLINICAL TRIAL NUMBER: UMIN000001299. LAY SUMMARY: Hepatitis B virus can be reactivated in lymphoma patients receiving anti-CD20 antibodies such as rituximab. Currently, reactivation requires the monitoring of HBV DNA, but monitoring of the surface antigen (HBsAg) could provide a relatively inexpensive, quick and easy alternative. We assessed the performance of an ultra-high sensitivity HBsAg assay and showed that it could be effective for the diagnosis and monitoring of HBV reactivation.

A survey of blood transfusion errors in Aichi Prefecture in Japan: Identifying major lapses threatening the safety of transfusion recipients.

BACKGROUND: Despite recent progress in blood systems, transfusion errors can occur at any time from the moment of collection through to the transfusion of blood and blood products. This study investigated the actual statuses of blood transfusion errors at institutions of all sizes in Aichi prefecture. MATERIALS AND METHODS: We investigated 104 institutions that perform 98 % of the blood transfusions in Aichi prefecture, and investigated the errors (incidents/accidents) that occurred at these facilities over 6 months (April to September, 2017). Incident/accident data were collected from responses to questionnaires sent to each institution; these were classified according to the categories and risk levels. RESULTS: Ninety-seven of the 104 institutions (93.3 %) responded to the questionnaire; a total of 688 incidents/accidents were reported. Most (682 cases; 99.2 %), were classified as risk level 2; however, 6 were level 3 and over, which included problems with autologous transfusion and inventory control. Approximately one-half of the incidents/accidents (394 cases; 57.3 %), were related to verification and the actual administration of blood products at the bedside; more than half of these incidents/accidents occurred at large-volume institutions. Meanwhile, a high frequency of incidents/accidents related to transfusion examination and labeling of blood products was observed at small- or medium-sized institutions. The reasons for most of these errors were simple mistakes and carelessness by the medical staff. CONCLUSIONS: Our results emphasize the importance of education, operational training, and compliance instruction for all members of the medical staff despite advances in electronic devices meant to streamline transfusion procedures.

Prospective evaluation of prognostic impact of KIT mutations on acute myeloid leukemia with RUNX1-RUNX1T1 and CBFB-MYH11.

The prognostic impact of KIT mutation on core-binding factor acute myeloid leukemia (CBF-AML) remains controversial. We registered 199 newly diagnosed de novo CBF-AML patients, aged 16 to 64 years, who achieved complete remission. They received 3 courses of high-dose cytarabine therapy and no further treatment until hematological relapse. Mutations in exons 8, 10-11, and 17 of the KIT gene were analyzed. Furthermore, we analyzed mutations in 56 genes that are frequently identified in myeloid malignancies and evaluated minimal residual disease (MRD). The primary end point was relapse-free survival (RFS) according to KIT mutations. The RFS in KIT-mutated patients was inferior to that in unmutated patients (hazard ratio, 1.92; 95% confidence interval, 1.23-3.00; P = .003). Based on subgroup analysis, KIT mutations had a prognostic impact in patients with RUNX1-RUNX1T1, but not in those with CBFB-MYH11, and only exon 17 mutation had a significant prognostic impact. Multivariate Cox regression analysis with stepwise selection revealed that the KIT exon 17 mutation and the presence of extramedullary tumors in patients with RUNX1-RUNX1T1, and loss of chromosome X or Y and NRAS mutation in patients with CBFB-MYH11 were poor prognostic factors for RFS. MRD was evaluated in 112 patients, and it was associated with a poorer RFS in the patients with CBFB-MYH11, but not in those with RUNX1-RUNX1T1. These results suggested that it is necessary to separately evaluate AML with RUNX1-RUNX1T1 or CBFB-MYH11 according to appropriate prognostic factors. This study was registered at www.umin.ac.jp/ctr/ as #UMIN000003434.

Final results of a phase I study of carfilzomib, lenalidomide, and dexamethasone for heavily pretreated multiple myeloma.

We report the final results from a multicenter, open-label phase I study of carfilzomib plus lenalidomide and dexamethasone in Japanese patients with heavily pretreated relapsed and/or refractory multiple myeloma (RRMM). Twenty-six RRMM patients were enrolled and received a median of 4.0 prior regimens; 12/26 patients (46.2%) completed the planned 18 administration cycles (mean number of cycles: 14.5 ± 4.9). The safety profile was consistent with that of previous carfilzomib studies. All patients experienced adverse events (AEs), but no new safety concerns were observed. The most common grade ≥ 3 AEs (incidence: ≥ 10%) were lymphocyte count decreased (46.2%), platelet count decreased (42.3%), and neutrophil count decreased (34.6%). The overall response rate was 88.5% (23/26; 90% confidence interval: 72.8-96.8). Complete response (CR) or better was achieved by 30.8% of patients compared with 3.8% in the interim analysis. The median time to CR or better response was 9.4 months. Median progression-free survival and duration of response were 19.5 months and 20.3 months, respectively. Median overall survival was not reached. Long-term administration of carfilzomib produced deep response and long-term disease control. The combination of carfilzomib plus lenalidomide and dexamethasone was well tolerated and showed promising clinical efficacy for heavily pretreated RRMM patients. CLINICAL TRIAL REGISTRATION: This clinical trial was registered in the database clinicaltrials.jp (clinical trial registration number: Japic CTI 142677).

Diffuse large B cell lymphoma primarily presenting as acute liver failure in a surviving patient.

Acute liver failure (ALF) is a relatively rare presentation of non-Hodgkin lymphoma, often found only during postmortem examination in patients. We treated a 33-year-old woman with prominent jaundice who was diagnosed with diffuse large B-cell lymphoma presenting as ALF. We could not perform liver biopsy during the critical phase because of coagulopathy, but gastric biopsy showed the infiltration of lymphoma cells. The patient was successfully treated with rituximab and chemotherapy and she survived. Malignant lymphoma should be considered in the differential diagnosis of patients who show liver dysfunction, and biopsy should be performed.