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Refractoriness to platelet transfusion is a major problem in a small group of patients, and large-scale manufacturing of clinical grade functional platelets ex vivo has remained an elusive goal. Sugimoto et al report on the results of the first clinical trial of an autologous transfusion of induced pluripotent stem cell (iPSC)-derived platelets in a patient who had severe aplastic anemia but no compatible platelet donor. Using methodology described in a complementary article in Blood Advances, the results provide proof-of-principle and illustrate the challenges to be faced in taking this approach further.

Acute erythroid leukemia (AEL) is a unique subtype of acute myeloid leukemia characterized by prominent erythroid proliferation whose molecular basis is poorly understood. To elucidate the underlying mechanism of erythroid proliferation, we analyzed 121 AEL using whole-genome, whole-exome, and/or targeted-capture sequencing, together with transcriptome analysis of 21 AEL samples. Combining publicly available sequencing data, we found a high frequency of gains and amplifications involving EPOR/JAK2 in TP53-mutated cases, particularly those having >80% erythroblasts designated as pure erythroid leukemia (10/13). These cases were frequently accompanied by gains and amplifications of ERG/ETS2 and associated with a very poor prognosis, even compared with other TP53-mutated AEL. In addition to activation of the STAT5 pathway, a common feature across all AEL cases, these AEL cases exhibited enhanced cell proliferation and heme metabolism and often showed high sensitivity to ruxolitinib in vitro and in xenograft models, highlighting a potential role of JAK2 inhibition in therapeutics of AEL.Significance:This study reveals the major role of gains, amplifications, and mutations of EPOR and JAK2 in the pathogenesis of pure erythroleukemia. Their frequent response to ruxolitinib in patient-derived xenograft and cell culture models highlights a possible therapeutic role of JAK2 inhibition for erythroleukemia with EPOR/JAK2-involving lesions.This article is highlighted in the In This Issue feature, p. 369

Supplementary Figure from Amplified EPOR/JAK2 Genes Define a Unique Subtype of Acute Erythroid Leukemia

Supplementary Table from Amplified EPOR/JAK2 Genes Define a Unique Subtype of Acute Erythroid Leukemia

Graft-versus-host-disease-free, relapse-free survival (GRFS) is a useful composite endpoint that measures survival without relapse or significant morbidity after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We aimed to develop a novel analytical method that appropriately handles right-censored data and competing risks to understand the risk for GRFS and each component of GRFS. This study was a retrospective data-mining study on a cohort of 2207 adult patients who underwent their first allo-HSCT at the Kyoto Stem Cell Transplantation Group (KSCTG), a multi-institutional joint research group of 17 transplantation centers in Japan. The primary endpoint was GRFS. A stacked ensemble of Cox proportional hazard regression and seven machine learning algorithms was applied to develop a prediction model. The median age of patients was 48 years. For GRFS, the stacked ensemble model achieved better predictive accuracy evaluated by C-index than other top-of-the-art competing risk models (ensemble model: 0.670, Cox-PH: 0.668, Random Survival Forest: 0.660, Dynamic DeepHit: 0.646). The probability of GRFS after 2 years was 30.54% for the high-risk and 40.69% for the low-risk group, respectively (hazard ratio [HR] compared to the low-risk group: 2.127; 95% CI: 1.19-3.80). We developed a novel predictive model for survival analysis that showed superior risk stratification to existing methods using a stacked ensemble of multiple machine learning algorithms., アンサンブル学習を用いた造血幹細胞移植予後予測モデルの開発 --機械学習を用いた新規生存時間解析手法の実装--. 京都大学プレスリリース. 2021-12-28.

Shwachman-Diamond syndrome (SDS) is an autosomal recessive inherited disorder characterized by bone marrow failure, exocrine pancreatic dysfunction, and skeletal abnormalities. SDS is typically caused by a pathogenic mutation in the Shwachman-Bodian-Diamond Syndrome (SBDS) gene. Patients with SDS have an increased risk of developing acute myeloid leukemia (AML) and myelodysplastic syndromes. We identified germline biallelic SBDS mutations (p.K62X and p.I167M) in a 50-year-old AML patient who had never experienced the typical symptoms of SDS. The K62X mutation is one of the most common pathogenic mutations, whereas the significance of the I167M mutation was unclear. Based on cellular experiments, we concluded that the I167M mutation contributed to the development of AML, and chemotherapy including topoisomerase inhibitors, which induce DNA double-strand breaks, may have been toxic to this patient. Our experience indicates that some asymptomatic Shwachman-Bodian-Diamond syndrome mutations contribute to the development of leukemia, and that careful treatment selection may be warranted for patients harboring these mutations.

TAFRO syndrome and POEMS syndrome are lymphoproliferative disorders with elevated interleukin-6 and vascular endothelial growth factor (VEGF) levels; however, their underlying pathogenic mechanisms remain unclear. Similarities have been reported in the pathological findings of the lymph nodes of TAFRO syndrome, Multicentric Castleman disease (MCD), and some cases of POEMS syndrome. However, there is no consensus on the relationship among them. We encountered a case of lymphoproliferative disorder that presented with manifestations of both TAFRO syndrome and POEMS syndrome. This case may be a subtype of idiopathic MCD and will be very important for establishing the disease concept of TAFRO syndrome and POEMS syndrome.

Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the key strategy to cure patients with mature T and natural killer (NK) cell lymphomas/leukemia, especially those with relapsed/refractory diseases, there is no consensus strategy for donor selection. We retrospectively analyzed the outcomes of allo-HSCT in 111 patients in 15 Japanese institutions as a multi-institutional joint research project. Thirty-nine patients received bone marrow or peripheral blood stem cell transplantation from related donors (rBMT/rPBSCT), 37 received BMT/PBSCT from unrelated donors (uBMT/uPBSCT), and 35 received cord blood transplantation (CBT). Overall survival (OS) and progression-free survival (PFS) at 4 years were 42% and 34%, respectively. The cumulative incidences of relapse and nonrelapse mortality were 43% and 25%. In multivariate analysis, CBT showed comparable OS with rBMT/rPBSCT (rBMT/rPBSCT versus CBT: hazard ratio [HR], 1.63; P = .264) and better OS compared with uBMT/uPBSCT (HR, 2.99; P = .010), with a trend toward a lower relapse rate (rBMT/rPBSCT versus CBT: HR, 2.60; P = .010; uBMT/uPBSCT versus CBT: HR, 2.05; P = .082). This superiority of CBT was more definite in on-disease patients (OS: rBMT/rPBSCT versus CBT: HR, 5.52; P = .021; uBMT/uPBSCT versus CBT: HR, 6.80; P = .007). Better disease control was also strongly associated with better OS and PFS with lower relapse rate. In conclusion, allo-HSCT is beneficial for the survival of patients with mature T and NK cell lymphomas/leukemia if performed in a timely fashion. Since CBT showed favorable survival with a lower relapse risk, it could be a preferred alternative, especially in on-disease patients.

Benefit of high-dose cytarabine (HD-AraC) for acute myeloid leukemia (AML) prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains unknown. We retrospectively analyzed data ...

Methotrexate, hydrocortisone, vincristine, sobuzoxane, and etoposide (MTX-HOPE) chemotherapy was originally reported in 2007 as a salvage regimen for relapsed or refractory non-Hodgkin's lymphoma. To clarify the safety and efficacy of this regimen, we retrospectively analyzed patients at our institute. We analyzed 18 patients, including 16 with diffuse large B-cell lymphoma (DLBCL), one with follicular lymphoma (FL), and one with T-cell lymphoma. The median age at MTX-HOPE therapy was 79 (range: 68-87). Ten patients received more than 3 previous chemotherapy regimens. The median period from the initial treatment to the first MTX-HOPE administration was 53 months. No patient had severe renal dysfunction. The overall response rate was 78%, with 39% achieving CR and 39% achieving PR. The median OS and PFS after the initiation of MTX-HOPE were 10 months (range: 0.5-86 months) and 7 months (range: 0.2-86 months), respectively. The one-year OS rate was 44% and the two-year OS rate was 22%. The median number of treatment cycles was 7 (range: 1-46), and 6 patients received more than 10 cycles. Among eight patients who were over 80 years of age, 7 responded to the therapy, and the median OS and PFS of this subgroup were 19 months and 11 months, respectively. All patients tolerated the treatment well, mostly on an outpatient basis, except for one who died from infection and one who developed intracranial hemorrhage. MTX-HOPE may be a promising treatment option for elderly patients with refractory or relapsed malignant lymphoma.

Viral infection is one of the lethal adverse events after cord blood transplantation (CBT). Human leukocyte antigen (HLA) and killer immunoglobulin-like receptor (KIR) ligand divergences can increase the risk of viral infection due to conflicting interactions between virus-infected cells and immune cells. However, the relationship between these disparities and the frequency of viral infection after CBT remains to be evaluated. Herein, we have conducted a retrospective multicenter study to assess the effect of HLA and KIR ligand mismatches on viral infections after CBT. The study included 429 patients, among which 126 viral infections occurred before day 100. Viral infection was significantly associated with poorer overall survival (OS; hazard ratio [HR] 1.74, p 0.01). Patients harboring ≥3 mismatches in the HLA allele and inhibitory KIR ligand mismatches (HLAKIR mismatches) had a significantly greater prevalence of viral infection (HR 1.66, p = 0.04). Thus, patients with HLAKIR mismatches had poorer outcomes in terms of non-relapse mortality (HR 1.61, p = 0.05). Our study demonstrates the unfavorable impacts of HLAKIR mismatches on viral infections and non-relapse mortality after CBT. Evaluating the viral infection risk and performance of an appropriate and early intervention in high-risk patients and optimizing the graft selection algorithm could improve the outcome of CBTs.

Acute erythroid leukemia (AEL) is a unique subtype of acute myeloid leukemia characterized by prominent erythroid proliferation whose molecular basis is poorly understood. To elucidate the underlying mechanism of erythroid proliferation, we analyzed 121 AEL using whole-genome/exome and/or targeted-capture sequencing, together with transcriptome analysis of 21 AEL samples. Combining publicly available sequencing data, we found a high frequency of gains/amplifications involving EPOR/JAK2 in TP53-mutated cases, particularly those having >80% erythroblasts designated as pure erythroid leukemia (10/13). These cases were frequently accompanied by gains/amplifications of ERG/ETS2 and associated with a very poor prognosis, even compared with other TP53-mutated AEL. In addition to activation of the STAT5 pathway, a common feature across all AEL cases, these AEL cases exhibited enhanced cell proliferation and heme metabolism and often showed high sensitivity to ruxolitinib in vitro and in xenograft models, highlighting a potential role of JAK2 inhibition in therapeutics of AEL., ゲノム解析から急性赤白血病の変異プロファイルと治療標的を解明 --特定の遺伝子変異群の組み合わせと、特徴となる遺伝子の増幅が鍵--. 京都大学プレスリリース. 2022-08-05.

Chronic active Epstein-Barr virus infection (CAEBV) is a systemic T- or NK-lymphoproliferative disorder (LPD) caused by EBV. Allogenic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for CAEBV, but relapse sometimes occurs. Relapse is generally attributed to proliferation of recipient-derived CAEBV cells. We herein report a case of donor-derived CAEBV-like NK-cell post-transplant lymphoproliferative disease (PTLD) in a 41-year-old female after the first allogenic HSCT for CAEBV from an HLA-matched sibling donor. A second HSCT from an HLA-matched unrelated donor successfully controlled the disease, but EBV infection of cells derived from the second donor continued to be detected. Although the mechanisms underlying CAEBV and CAEBV-like NK-cell PTLD have not yet been elucidated in detail, the findings of the present case imply that host genetic factors, including familial factors, may be important in disease development.

Shwachman-Diamond syndrome (SDS) is an autosomal recessive inherited disorder characterized by bone marrow failure, exocrine pancreatic dysfunction, and skeletal abnormalities. SDS is typically caused by a pathogenic mutation in the Shwachman-Bodian-Diamond Syndrome (SBDS) gene. Patients with SDS have an increased risk of developing acute myeloid leukemia (AML) and myelodysplastic syndromes. We identified germline biallelic SBDS mutations (p.K62X and p.I167M) in a 50-year-old AML patient who had never experienced the typical symptoms of SDS. The K62X mutation is one of the most common pathogenic mutations, whereas the significance of the I167M mutation was unclear. Based on cellular experiments, we concluded that the I167M mutation contributed to the development of AML, and chemotherapy including topoisomerase inhibitors, which induce DNA double-strand breaks, may have been toxic to this patient. Our experience indicates that some asymptomatic Shwachman-Bodian-Diamond syndrome mutations contribute to the development of leukemia, and that careful treatment selection may be warranted for patients harboring these mutations.

Primary central nervous system lymphoma (PCNSL) and chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) can share clinical features and may be indistinguishable, even after brain biopsy. We encountered a case of Epstein-Barr virus-positive (EBV+) PCNSL recurrence in a patient with clinical features of CLIPPERS, and repeat brain biopsy was required to reach the correct diagnosis. Four years after the initial diagnosis and treatment of PCNSL, "peppering" punctate enhanced lesions with transient steroid responsiveness were detected during brain magnetic resonance imaging (MRI). A second brain biopsy supported a diagnosis of CLIPPERS, while a third biopsy confirmed the diagnosis of recurrent PCNSL.

We report a case of acquired hypofibrinogenemia with multiple myeloma presenting λ-type IgG monoclonal protein. The patient had anemia and renal deficiency, and also developed bleeding tendency due to severe coagulopathy. Her fibrinogen level was under the detectable limits in a functional assay. Enzyme-linked immunosorbent assay (ELISA) and immunoblotting analysis results were consistent with functional assay results, and deficiency patterns observed in cross-mixing tests for PT and aPTT confirmed the diagnosis of hypofibrinogenemia. To determine the cause of hypofibrinogenemia, we purified the patient’s immunoglobulin via protein A agarose, and confirmed that fibrinogen was included in the bound fraction, strongly indicating paraprotein interference with fibrinogen. As accelerated removal of fibrinogen was indicated, we incubated the patient’s plasma up to 48 h, but did not observe significant loss of fibrinogen. In sharp contrast, fibrinogen returned to below the detection level 12 h after infusion of fresh frozen plasma. These findings support leukocyte-mediated fibrinogen removal, rather than paraprotein-triggered fibrinogen instability. Surprisingly, the patient’s paraprotein was IgG2, but we speculate the amount of paraprotein (IgG 5346 mg/dL) compensated for lower affinity to Fcγ receptors.

Autologous stem cell transplantation (ASCT) with high-dose thiotepa and busulfan is a treatment option for patients with central nervous system (CNS) lymphoma. We report here the occurrence of secondary failure of platelet recovery (SFPR) in three out of 24 patients who received high-dose thiotepa and busulfan followed by ASCT. Although there was no obvious abnormality in the primary platelet engraftment as well as the recovery of other blood cells, they developed SFPR with a median time to onset of day 38, and the platelets gradually recovered over several months with steroid therapy. During the same period, there was no development of SFPR among 50 patients who received ASCT with a conditioning regimen of MEAM (ranimustine, etoposide, cytarabine, and melphalan) or high-dose melphalan. However, one of the two patients who received a conditioning regimen of busulfan and melphalan developed SFPR, suggesting that the use of a busulfan-based conditioning regimen may be one of the risk factors for SFPR. It is important to be aware of this possible adverse effect of ASCT with high-dose thiotepa and busulfan to ensure timely diagnosis and prevention of subsequent serious complications.

In 2003, a 60-year-old man presenting with thrombocytosis was referred to our hospital. Laboratory tests revealed normal white blood cell count and hemoglobin level. Bone marrow examination showed an increased number of megakaryocytes with dysplasia. G-banded karyotype analysis revealed del (5q). Initially, the patient was diagnosed with myelodysplastic/myeloproliferative neoplasm (MDS/MPN), and it was treated with aspirin and hydroxyurea. During the treatment course, fluorescence in situ hybridization for CSF1R and EGR1 was performed to detect del (5q), which showed negative results. In 2017, the patient had increased platelet count despite receiving treatment. A comprehensive genomic profiling revealed that the deleted region in this case was present in 5q14-5q23, which was different from the common deleted region of 5q- syndrome (5q32-5q33, where CSF1R was present) and that of high-risk MDS or acute myeloid leukemia (5q31, where EGR1 was present). Moreover, a CALR mutation was also detected. This case met the diagnostic criteria of essential thrombocythemia. The platelet count decreased with the administration of anagrelide. In conclusion, comprehensive genetic profiling is very important, and it leads to accurate diagnosis and therapy.

The intestinal microbiota plays an important role in the pathogenesis of acute graft-versus-host disease (aGVHD). During the course of hematopoietic stem cell transplantation (HSCT), the intestinal microbiota is influenced by the use of broad-spectrum antibiotics. However, the impact of the use and type of antibiotics on the microbiota composition and, subsequently, the onset of aGVHD remain poorly understood. We hypothesized that the use and type of antibiotics had an impact on the occurrence of aGVHD. We assessed 275 patients who underwent their first allogeneic HSCT between January 2005 and June 2015 at Kyoto University Hospital. We monitored the 6 most frequently administered antibiotics (fourth-generation cephalosporins, glycopeptides, piperacillin-tazobactam, carbapenems, aminoglycosides, and quinolones) administered between days –14 and +14 relative to HSCT and its duration. The primary endpoint was the cumulative incidence of grades II to IV aGVHD. The cumulative incidence of aGVHD was significantly higher in patients administered fourth-generation cephalosporins than in patients not receiving fourth-generation cephalosporins (grades II to IV: hazard ratio, 1.98; 95% confidence interval, 1.19 to 3.29; P = .0087; grades III to IV: hazard ratio, 8.03; 95% confidence interval, 1.07 to 60.51; P = .043). In contrast, there was no significant association between administration of other antibiotics and aGVHD incidence. As for organ-specific aGVHD, the cumulative incidence of gut aGVHD was significantly higher in patients who received fourth-generation cephalosporins than in those who did not (31% versus 16%, P = .018). In conclusion, we demonstrated that the administration of fourth-generation cephalosporins had a strong impact on the development of aGVHD.

A 61-year-old man was admitted to our hospital with fever and massive leukocytosis. A bone marrow smear revealed an increased density of myeloid cells in various stages of maturation as well as dysplasia in the neutrophils. There was no proliferation of blasts, eosinophils, or basophils. Genomic analysis of the bone marrow cells revealed no detectable abnormalities associated with myeloproliferative neoplasms, including BCR-ABL1. Therefore, the patient was diagnosed with atypical chronic myeloid leukemia (aCML). Chromosomal analysis revealed the presence of 1-17 double minute chromosomes (dmin) in 20 of 20 tumor cells examined. Multiple MYC signals were detected via interphase fluorescence in situ hybridization, indicating MYC gene amplification in the dmins. Three months after the oral administration of hydroxyurea, leukocytosis reoccurred. Therefore, induction therapy followed with umbilical cord blood transplantation was performed. However, MYC signals remained detectable in the bone marrow sample obtained immediately after neutrophil engraftment, indicating the presence of residual tumor cells. To the best of our knowledge, this is the first case report of aCML with dmin gene amplification, suggesting that the dmin MYC amplification exacerbated the patient's disease.

Background: Acute erythroid leukemia (AEL) is a rare subtype of AML characterized by erythroid predominant proliferation and classified into two subtypes with pure erythroid (PEL) and myeloid/erythroid (MEL) phenotypes. Although several reports described gene mutations in AEL, genotype phenotype correlations have not fully been elucidated with little knowledge about feasible molecular targets for therapy. Methods: To understand the mechanism of the erythroid dominant phenotype of AEL and identify potential therapeutic targets for AEL, we analyzed a total of 121 adult AEL cases with the median age of 60 (23-87), using whole genome/exome sequencing of 35 cases, followed by targeted-capture sequencing of 387 genes together with 1,279 SNP loci for copy number measurements in all cases. Among these, 21 were also analyzed by RNA sequencing. Genetic profiles of these AEL cases were compared to those of 409 cases with non-erythroid AML (non-AEL) including 195 cases from The Cancer Genome Atlas. Six patient-derived xenografts (PDX) were established from AEL with JAK2 and/or EPOR focal gain/amplification/mutation. PDX cells were inoculated into immune-deficient mice and tested for their response to JAK1/2 inhibitor. Results: According to unique genetic alterations, AEL was classified into 4 genomic groups (A-D). Characterized by TP53 mutations and complex karyotype, Group A was the most common subtype (48/121; 40%) and showed very poor prognosis. Remarkably, almost all the PEL cases (12/13; 92%) were categorized into Group A. Conspicuously, 75% of PEL cases with TP53 mutation had focal gain/amplifications/mutations of JAK2 (5/12; 42%), EPOR (7/12; 58%), and ERG/ETS2 (1/12; 8%) loci on chromosomes 9p, 19q, and 21q, respectively, while 34% of MEL cases with TP53 mutation had focal gain/amplifications/mutations of JAK2 (2/29; 7%), EPOR (7/29;24%), and ERG/ETS2 (7/29;24%) loci, frequently in combination. Group B was characterized by frequent NPM1 mutations, in contrast to the frequent co-mutation of FLT3 in the corresponding subgroup of NPM1-mutated cases in non-AEL, whereas NPM1-mutated patents in this group lacked FLT3 mutations but had frequent PTPN11 mutations (8/16; 50%), which were much less common in non-AEL (15/101; 15%). All cases in Group C (n=22, 18%), another prevalent form of AEL, had STAG2 mutations and classified in MEL. Prominently, 68% (17/25) of STAG2-mutated AEL cases had KMT2A-PTD, which was rarely found in non-AEL cases. The remaining cases were categorized into Group D, which was enriched for mutations in ASXL1, BCOR, PHF6, RUNX1 and TET2. We also identified recurrent loss-of-function USP9X mutations in this group, which were previously reported in ALL with an upregulated JAK-STAT pathway. In RNA sequencing analysis, AEL cases exhibited gene expression profiles implicated in an upregulated STAT5 signaling pathway, which was seen not only in those cases with JAK2 or EPOR focal gain/amplification/mutation, but also in AEL without these amplifications, suggesting that aberrantly upregulated STAT5 activation might represent a common molecular signature of AEL. Survival analysis revealed that TP53 mutation is a poor prognostic factor in AEL and non-AEL and no statistically significant difference between AEL and non-AEL with TP53 mutation. Intriguingly, 19p gains/amplifications were associated with a significantly poor prognostic prognosis in TP53-mutated AEL cases. Based on this finding, we evaluated the effect of a JAK inhibitor, ruxolitinib, on 6 PDX models established from AEL having TP53 mutations and JAK2 and EPOR mutation/amplification. Of interest , ruxolitinib significantly suppressed cell growth and prolonged overall survival in mice engrafted with 4 PDX models with STAT5 downregulation, although the other 2 models were resistant to JAK2 inhibition with persistent STAT5 activation. Conclusion: AEL is a heterogeneous group of AML, of which PEL is characterized by frequent amplifications/mutations in JAK2 and/or EPOR. Frequent involvement of EPOR/JAK/STAT pathway is a common feature of AEL, in which a therapeutic role of JAK inhibition was suggested. Disclosures Nakagawa: Sumitomo Dainippon Pharma Oncology, Inc.: Research Funding. Yoda: Chordia Therapeutics Inc.: Research Funding. Morishita: Chordia Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Miyazaki: Sumitomo-Dainippon: Honoraria, Research Funding; Astellas: Honoraria; Chugai: Honoraria; Abbvie: Honoraria; Novartis: Honoraria; Nippon-Shinyaku: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Daiichi-Sankyo: Honoraria; Kyowa-Kirin: Honoraria; Eisai: Honoraria; Janssen: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria. Usuki: Alexion: Speakers Bureau; Eisai: Speakers Bureau; MSD: Speakers Bureau; PharmaEssentia: Speakers Bureau; Yakult: Speakers Bureau; Mundipharma: Research Funding; Astellas-Amgen-Biopharma: Research Funding; Nippon Boehringer Ingelheim: Research Funding; Takeda: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Janssen: Research Funding; Ono: Research Funding, Speakers Bureau; Otsuka: Research Funding, Speakers Bureau; Sumitomo Dainippon: Research Funding; Daiichi Sankyo: Research Funding, Speakers Bureau; Symbio: Research Funding, Speakers Bureau; Gilead: Research Funding; Abbvie: Research Funding; Nippon shinyaku: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Pfizer: Research Funding; Kyowa Kirin: Research Funding, Speakers Bureau; Brisol-Myers Squibb: Research Funding, Speakers Bureau; Astellas: Research Funding, Speakers Bureau. Maciejewski: Bristol Myers Squibb/Celgene: Consultancy; Regeneron: Consultancy; Novartis: Consultancy; Alexion: Consultancy. Ohyashiki: Novartis Pharma: Other: chief clinical trial; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Ganser: Celgene: Honoraria; Novartis: Honoraria; Jazz Pharmaceuticals: Honoraria. Heuser: Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Pharma AG: Research Funding; Karyopharm: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Research Funding; BergenBio: Research Funding; Janssen: Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolremo: Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Thol: Astellas: Honoraria; Abbvie: Honoraria; Novartis: Honoraria; Jazz: Honoraria; BMS/Celgene: Honoraria, Research Funding; Pfizer: Honoraria. Shih: PharmaEssentia Co: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene Ltd: Research Funding; Ltd: Research Funding; Novartis: Research Funding. Takaori-Kondo: Celgene: Research Funding; Bristol-Myers K.K.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Research Funding. Ogawa: Otsuka Pharmaceutical Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Kan Research Laboratory, Inc.: Consultancy, Research Funding; Dainippon-Sumitomo Pharmaceutical, Inc.: Research Funding; ChordiaTherapeutics, Inc.: Consultancy, Research Funding; Ashahi Genomics: Current holder of individual stocks in a privately-held company.

Introduction: Unrelated cord blood (UCB) and haploidentical related donor transplantation using post-transplant cyclophosphamide (PTCy-haplo) have become alternative options to treat patients with hematological malignancies without a human leukocyte antigen (HLA)-matched donor. Although a previous phase III study showed better outcomes after bone marrow transplantation (BMT) using PTCy-haplo than those after double unit UCB, a donor selection algorithm including peripheral blood stem cell transplant (PBSCT) using PTCy-haplo or high-risk patients remains to be clarified. With the aim to assess the relative efficacies of UCB and PTCy-haplo transplant, we performed a multi-center retrospective analysis to compare the clinical outcomes in patients with hematologic malignancies. Methods: We included 517 patients aged 16 years to 70 years with hematological malignancies who received a first stem cell transplantation using a single UCB unit or PTCy-haplo between 2013 and 2019 in Kyoto Stem Cell Transplantation Group (KSCTG), which is a multi-center group of 18 transplantation centers in Japan. The primary endpoint was to compare overall survival (OS) between the UCB and PTCy-haplo groups. Secondary endpoints were relapse-free survival (RFS), GVHD- and relapse-free survival (GRFS), relapse, non-relapse mortality (NRM), neutrophil engraftment, platelet engraftment, grade II-IV acute graft-versus-host disease (GVHD), grade III-IV acute GVHD, chronic GVHD, and extensive chronic GVHD. Results: Among 517 patients, 460 received single UCB transplant and 57 received PTCy-haplo related donor transplant (53 PBSCT and 4 BMT). The median age of the UCB and PTCy-haplo groups was 55 and 52 years, respectively (P= 0.770). Myeloablative conditioning (MAC) was used more often in the UCB group than in the PTCy-haplo group (P< 0.001). In the PTCy-haplo cohort, the total dose of Cy was 80mg/m 2 (43.9%) or 100mg/m 2 (56.1%), and the median duration of tacrolimus and mycophenolate mofetil use was 173 and 34 days, respectively. The median follow-up periods of survivors were 2.2 and 2.4 years, respectively. OS in the UCB group was comparable to that in the PTCy-haplo group (2-year OS; 53.7%, 53.6%, P= 0.71 and adjusted hazard ratio (aHR) 1.00, P= 0.99), with similar risks of relapse (aHR 0.91, P= 0.99) and NRM (aHR 0.93, P= 0.69). This result was consistent regardless of disease risk. Neutrophil and platelet engraftment were significantly lower (92.2% vs 94.7%, P= 0.042 and 79.8% vs 82.5%, P= 0.003) and the incidence of acute GVHD in the UCB group tended to be higher (gradeⅡ-Ⅳ; aHR 1.64, p= 0.055, grade III-IV; aHR 3.60, P= 0.073) in the UCB group than those in the PTCy-haplo group. However, the incidences of chronic or extensive chronic GVHD after UCB transplant were comparable (chronic; aHR 0.89, p=0.68, extensive chronic; aHR 0.69, P= 0.35) to those after PTCy-haplo transplant. In the subgroup analysis of disease-specific comparison, acute leukemia patients have a significantly lower risk of relapse with UCB transplant (UBC vs PTCy-haplo, HR 0.55, P= 0.030) and lymphoma patients tended to have good results after PTCy-haplo transplant in terms of higher OS (UCB vs PTCy-haplo, aHR 2.13, P= 0.162) and lower relapse (aHR 3.43, P= 0.100). In terms of Cy toxicity in the PTCy-haplo group, transplant with a reduced dose of Cy (80 mg/m 2) tended to show higher OS (2-year OS, 64.8% vs 45.0%) and significantly lower NRM (2-year NRM, 8.0% vs 31.2%) without an increase in gradeⅡ-IV acute GVHD compared to those after standard-dose Cy (100 mg/m 2). Conclusion: Our findings suggest that UCB transplant gives outcomes comparable to PTCy-haplo transplant for patients without an HLA-matched sibling or unrelated donor. Disclosures Kanda: Amgen Astellas BioPharma: Honoraria; Astellas Pharma Inc.: Consultancy, Honoraria; Bristol-Myers Squibb Co: Honoraria; CHUGAI PHARMACEUTICAL Co., Ltd.: Honoraria; DAIICHI SANKYO Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eisai: Research Funding; Janssen Pharmaceutical K.K.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin Co., Ltd.: Honoraria; Megakaryon Co: Honoraria, Membership on an entity's Board of Directors or advisory committees; NextGeM Inc: Patents & Royalties; Novartis Pharma K.K.: Honoraria; Ono Pharma Inc.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Sanofi K.K.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; SymBio Pharmaceuticals, Ltd.: Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceutical Company Limited: Honoraria, Membership on an entity's Board of Directors or advisory committees; TEIJIN PHARMA LIMITED.: Honoraria. Imada: Celgene Co., Ltd.: Honoraria; Bristol-Myers Squibb K.K.: Honoraria; Astellas Pharma Inc.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Otsuka Pharmaceutical Co. Ltd.: Honoraria; Takeda Pharmaceutical Co. Ltd.: Honoraria; Novartis Pharma K.K.: Honoraria. Kondo: Asahi Kasei Pharmaceutical: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Chugai Pharma: Honoraria; MSD Pharmaceutical: Honoraria; Sumitomo Dainippon Pharma: Honoraria. Takaori-Kondo: Bristol-Myers K.K.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Research Funding; Celgene: Research Funding.

Introduction: Platelet transfusion have saved lives of patients with thrombocytopenia through preventing or treating bleeding complications. Currently, platelet products are provided from blood banks which collect blood from healthy donors. However, our ageing society bears the risk of supply in the future. Furthermore, although the rate is decreasing, alloimmune platelet transfusion refractoriness (allo-PTR) is still found in 5% of platelet transfusion patients. Gestation and previous platelet transfusion cause sensitization to produce alloantibodies mostly against class I human leukocyte antigens (HLA-I) and less frequently against human platelet antigens (HPA), resulting in allo-PTR. In these cases, platelets from compatible donors are transfused, but for patients with rare HLA or HPA, donors are difficult to find. As a possible solution, we proposed the application of platelets from induced pluripotent stem cells (iPSC-platelets), which we have succeeded in the ex vivo production at clinical scale. iPSC-platelets are produced from expandable megakaryocyte cell lines (imMKCLs) as master cells and using a "turbulent flow" bioreactor and various new drugs. imMKCLs are established from iPSCs during megakaryocytic differentiation by overexpression of c-MYC, BMI1 and BCL-XL under the doxycycline control promoter. Switching off these transgenes leads to the maturation of imMKCLs. Turbulent flow was found to be a crucial factor in efficient ex vivo production of healthy iPSC-platelets from imMKCLs. We also developed TA-316, a thrombopoietin mimetic compound, KP-547, an ADAM17 inhibitor that inhibits CD42b shedding and stores platelet function, and also found the combination of AhR antagonist and ROCK inhibitor enables feeder-free liquid culture in imMKCL maturation. Aim: To evaluate the safety of autologous iPS-platelets administered to an aplastic anemia patient with allo-PTR due to anti-HPA alloantibody, who experienced systemic post-transfusion purpura-like complication and have no compatible donor in Japan. Methods and Results: Preclinical studies showed that iPSC-platelets were competent in in vitro assays and mouse and rabbit models for circulation and hemostasis, and pathogen and tumorigenicity free. The clinical study was approved by the Certified Special Committee for Regenerative Medicine of the Kyoto University and by the Health Sciences Council of the Japan Ministry of Health, Labour and Welfare as meeting the Act on the Safety of Regenerative Medicine. The clinical study started in March 2019. Using imMKCL master cells derived from the patient, iPS-platelets were manufactured at the Facility for iPS Cell Therapy (FiT) in Center for iPS Cell Research and Application (CiRA), Kyoto University according to the GMP standard. Three doses of 1x10^10, 3x10^10 and 1x10^11 were administered in a dose escalation single-center open-label uncontrolled study at Kyoto University Hospital. The primary endpoint was safety as measured by frequency and extent of adverse events, which were evaluated by the Efficacy Safety Assessment Committee for each dose cohort. Three doses of the administration of autologous iPS-platelets have been completed. No significant adverse event was observed during the full observation period of one year after the last dose. Conclusion: The iPLAT1 study completed the administration of iPSC-platelets for the first time and confirmed the safety in an allo-PTR patient who would otherwise have no HPA-compatible platelet product. The insights gained from the current study should further contribute to development of allogeneic iPSC-platelet products that can be readily administered to wide range of patients. (Japan Registry of Clinical Trials number jRCTa050190117) Figure 1 Figure 1. Disclosures Sugimoto: Astellas Pharma Inc.: Honoraria; Ebara Corporation: Honoraria; Kyowa Kirin Co., Ltd.: Honoraria; Megakaryon Co: Consultancy, Honoraria; Novartis Pharma K.K.: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria. Kanda: Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; SymBio Pharmaceuticals, Ltd.: Membership on an entity's Board of Directors or advisory committees; Sanofi K.K.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Ono Pharma Inc.: Honoraria; Novartis Pharma K.K.: Honoraria; NextGeM Inc: Patents & Royalties; Megakaryon Co: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eisai: Research Funding; DAIICHI SANKYO Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees; CHUGAI PHARMACEUTICAL Co., Ltd.: Honoraria; Bristol-Myers Squibb Co: Honoraria; Astellas Pharma Inc.: Consultancy, Honoraria; Amgen Astellas BioPharma: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria, Membership on an entity's Board of Directors or advisory committees; TEIJIN PHARMA LIMITED.: Honoraria. Kondo: Asahi Kasei Pharmaceutical: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Chugai Pharma: Honoraria; MSD Pharmaceutical: Honoraria; Sumitomo Dainippon Pharma: Honoraria. Shimizu: Megakaryon co: Consultancy. Hirai: Kyowa Kirin: Patents & Royalties, Research Funding; Bristol-Myers K.K.: Research Funding; CSL Behring: Research Funding; Mitsubishi Tanabe Pharma: Research Funding; Sumitomo Dainippon Pharma: Research Funding; Novartis Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding. Takaori-Kondo: Bristol-Myers K.K.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Research Funding; Celgene: Research Funding. Eto: Megakaryon co: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Kyowa Kirin Co., Ltd.: Honoraria; Takeda Pharmaceutical Co Ltd: Honoraria; Kowa Co Ltd: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; TEIJIN PHARMA LIMITED.: Honoraria; Kyoto Manufacturing Co., Ltd.: Research Funding.

Key Clinical Message We report here a patient with extremely indolent mantle cell lymphoma (MCL) who had progressed and required immunochemotherapy 20 years after diagnostic splenectomy. Non‐nodal, indolent MCL patients may progress after such an extraordinary long indolent phase, and we recommend lifelong follow up for such cases.

Autoimmune neutropenia (AIN) is a rare disorder that may cause life-threatening infections. In adults, most cases are secondary to other pathological conditions, and primary AIN is extremely rare. We herein report a case involving a 57-year-old woman diagnosed with AIN. A granulocyte immunofluorescence test detected autoantibodies against human neutrophil antigens in her serum, while various examinations revealed no other causes of neutropenia, suggesting her AIN was primary. She was refractory to granulocyte-colony-stimulating factor but responded to prednisolone. Her neutrophil count remained normal after gradual discontinuation of prednisolone. Diagnostic procedures and optimal treatments for this disorder need to be established.

Background: Acute erythroid leukemia (AEL) is a rare subtype of AML characterized by erythroid predominant proliferation and classified into two subtypes with pure erythroid (PEL) and myeloid/erythroid (MEL) phenotypes. Although gene mutations in AEL have been described in several reports, genotype phenotype correlations are not fully understood with little knowledge about the feasible molecular targets for therapy. Methods: To understand the mechanism of the erythroid dominant phenotype of AEL and identify potential therapeutic targets for AEL, we analyzed a total of 105 AEL cases with the median age of 60 (23-86), using targeted-capture sequencing of commonly mutated genes in myeloid neoplasms, together with 1,279 SNPs for copy number measurements. Among these 105 cases, 13 were also analyzed by RNA sequencing. Genetic profiles of these 105 AEL cases were compared to those of 775 cases with non-erythroid AML (NEL) including 561 cases from The Cancer Genome Atlas and Beat AML study. An immature erythroid cell line (TF1) and three patient-derived xenografts (PDX) established from AEL with JAK2 and/or EPOR amplification. Cell line and samples from patients were inoculated into immune-deficient mice and tested for their response to JAK1/2 inhibitor. Results: According to unique genetic alterations, AEL was classified into 4 subgroups (A-D). Characterized by TP53 mutations and complex karyotype, Group A was the most common subtype and showed very poor prognosis. Remarkably, all PEL cases were categorized into Group A. Conspicuously, 80% of PEL cases had amplifications of JAK2 (6/10; 60%), EPOR (7/10;70%), and ERG (6/10;60%) loci on chromosomes 9p, 19q, and 21q, respectively, frequently in combination, although they were rarely seen in NEL cases. All cases in Group B (n=19, 18%), another prevalent form of AEL, had STAG2 mutations and classified in MEL. To further characterize this subgroup, we compared genetic profiles of STAG2-mutated AEL and NEL. Prominently, 70% (14/20) of STAG2-mutated cases in AEL had KMT2A-PTD, whereas it was found only in 8.8% (3/34) of NEL. CEBPA mutations were also more common in AEL (6/21; 29%) than NEL (4/34; 12%). While Group C was characterized by frequent NPM1 mutations, in contrast to the frequent co-mutation of FLT3 in the corresponding subgroup of NPM1-mutated cases in NEL, NPM1-mutated patents in this subgroup lacked FLT3 mutations but had frequent PTPN11 mutations (8/16; 50%), which were much less common in NEL (25/209; 12%). The remaining cases were categorized into Group D, which was enriched for mutations in ASXL1, BCOR, PHF6, U2AF1 and KMT2C. Recurrent loss-of-function mutations in USP9X were unique to this subtype, although USP9X mutations have been reported in ALL with upregulation of JAK-STAT pathway. In RNA sequencing analysis, AEL cases exhibited gene expression profiles implicated in an upregulated STAT5 signaling pathway, which was seen not only those cases with JAK2 or EPOR amplification, but also those without, suggesting that aberrantly upregulated STAT5 activation might represent a common defect in AEL. Based on this finding, we evaluated the effect of a JAK inhibitior, ruxolitinib, on an AEL-derived cell line and three PDX models established from AEL having TP53 mutations and JAK2 and EPOR mutation/amplification. Of interest, ruxolitinib significantly suppressed cell growth and prolonged overall survival in mice engrafted with TF1 and 2 PDX models with STAT5 downregulation, although the other model was resistant to JAK2 inhibition with persistent STAT5 activation. Conclusion: AEL is a heterogeneous group of AML, of which PEL is characterized by frequent amplifications/mutations in JAK2, EPOR and/or ERG. Frequent involvement of EPOR/JAK/STAT pathway is a common feature of AEL, in which a role of JAK inhibition was suggested. Disclosures Yoda: Chordia Therapeutics Inc.: Research Funding. Shih:Novartis: Research Funding; Celgene: Research Funding; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ishiyama:Alexion: Research Funding; Novartis: Honoraria. Miyazaki:Astellas Pharma Inc.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; NIPPON SHINYAKU CO.,LTD.: Honoraria; Celgene: Honoraria; Otsuka Pharmaceutical: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Novartis Pharma KK: Honoraria; Kyowa Kirin Co., Ltd.: Honoraria. Nakagawa:Sumitomo Dainippon Pharma Co., Ltd.: Research Funding. Takaori-Kondo:Celgene: Honoraria, Research Funding; Ono Pharmaceutical: Research Funding; Thyas Co. Ltd.: Research Funding; Takeda: Research Funding; CHUGAI: Research Funding; OHARA Pharmaceutical: Research Funding; Sanofi: Research Funding; Novartis Pharma: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Research Funding; Otsuka Pharmaceutical: Research Funding; Eisai: Research Funding; Astellas Pharma: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Nippon Shinyaku: Research Funding; MSD: Honoraria. Kataoka:Asahi Genomics: Current equity holder in private company; Otsuka Pharmaceutical: Research Funding; Takeda Pharmaceutical Company: Research Funding; CHUGAI PHARMACEUTICAL CO., LTD.: Research Funding. Usuki:Alexion: Research Funding, Speakers Bureau; Apellis: Research Funding; Novartis: Research Funding, Speakers Bureau; Chugai: Research Funding. Maciejewski:Novartis, Roche: Consultancy, Honoraria; Alexion, BMS: Speakers Bureau. Ganser:Novartis: Consultancy; Celgene: Consultancy. Thol:Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Ogawa:Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Asahi Genomics Co., Ltd.: Current equity holder in private company; Eisai Co., Ltd.: Research Funding; Chordia Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; KAN Research Institute, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Ruxolitinib is used for drug efficacy test using patient-derived xenografts established from acute erythroid leukemia.

Iron overload is considered a risk factor for mortality in patients with hematopoietic malignancies. Hepcidin is a key regulator of systemic iron balance. We previously reported dynamic changes of serum hepcidin‐25 levels in patients with hematologic malignancies after allogeneic hematopoietic stem cell transplantation (allo‐HSCT). In this study, we retrospectively analyzed the association of pretransplant hepcidin‐25 levels with overall survival (OS), engraftment, and other clinical outcomes of allo‐HSCT in patients with hematologic malignancies. A total of 166 patients were divided into two groups depending on their pretransplant serum hepcidin‐25 levels; their median age was 49.5 years, and the median follow‐up time was 46.8 months. At 3 years, the patients in the high‐hepcidin group had a significantly lower OS than those in the low‐hepcidin group (49.2 vs. 69.0%, respectively; P = 0.006). Multivariate analysis revealed that pretransplant serum hepcidin‐25 level, sex, and disease status were independently associated with OS. The incidence of platelet engraftment was significantly lower in the high‐hepcidin group than in the low‐hepcidin group, whereas no significant differences were observed in neutrophil and reticulocyte engraftments between these groups. Hence, pretransplant serum hepcidin levels can be a marker for predicting delayed platelet recovery after allo‐HSCT.

Therapeutic antibodies have heterogeneities in their structures, although its structural alteration in the body is unclear. Here, we analyzed the change of amino acid modifications and carbohydrate chains of rituximab after administration to patients. Twenty B cell non-Hodgkin’s lymphoma patients who were treated with rituximab for the first time or after more than one year’s abstinence were recruited. Structural analysis of rituximab was carried out at 1 h after administration and at the trough by using liquid chromatography/time-of-flight-mass spectrometry. Plasma rituximab concentration and pharmacodynamic markers were also determined. Of recruited twenty, 3 patients exhibited rapid rituximab clearance. Nine types of carbohydrate chains were detected in rituximab isolated from the blood. The composition ratios in some glycoforms were significantly different between at 1 h after administration and at the trough, although consisted amino acids remained unchanged. The patients with high clearance showed extensive alterations of glycoform composition ratios. However, pharmacodynamics makers were not different. Inter-individual variations in plasma concentrations of rituximab were found in some B-NHL patients. We could analyze a change in glycoforms of rituximab in the patients, and this finding may affect the pharmacokinetics of rituximab.

In this multicenter, single-arm, phase II study, the efficacy and safety of ibrutinib were examined in Japanese patients with relapsed or refractory mantle cell lymphoma (MCL). Patients (age ≥20 years) with relapsed or refractory MCL who had progressed after receiving at least one prior treatment regimen, were enrolled. Patients were treated with oral ibrutinib (560 mg once daily; 28-day cycle) until disease progression (or relapse), unacceptable toxicity, or study end. The primary end-point was overall response rate. Secondary end-points included duration of response (DOR), time to response, progression-free survival (PFS), overall survival, and safety. Of the 16 patients who received treatment, 5 patients discontinued the study (progressive disease, 4; sepsis, 1). Median duration of ibrutinib exposure was 6.5 months (range, 2.8-8.3 months). The overall response rate was 87.5% (90% confidence interval, 65.6-97.7; complete response = 2 [12.5%]; partial response = 12 [75.0%]). Median time to response for all responders (n = 14) was 1.8 months (range, 0.7-5.3 months). The median DOR and PFS were not estimable due to censoring (range: DOR, 1.1-6.4+ months; PFS, 2.8-8.0+ months). Overall survival data were immature due to the limited observation period. A total of 8/16 patients (50%) had at least one grade 3 adverse event (AE), and 5 (31.3%) patients reported serious AEs. The most commonly reported AEs were diarrhea and stomatitis (37.5% each), platelet count decrease (31.3%), and anemia (25%). Overall, orally administered single agent ibrutinib was efficacious with an acceptable safety profile in Japanese patients with relapsed or refractory MCL. Clinical trial registration NCT02169180 (ClinicalTrials.gov).

Neurolymphomatosis (NL) is a rare condition involving the infiltration of lymphoma cells into the peripheral nervous system. NL can be primary or secondary in the setting of an unknown or known hematologic malignancy, respectively. Here, we report five cases in which F-18 2-fluoro-2-deoxy-glucose positron emission tomography/computed tomography (F-18 FDG-PET/CT) had great value for diagnosing NL. Two cases were rare primary NL, and the other three were secondary NL. Clinical presentations were asymmetric sensorimotor disturbances in the extremities with or without involvement of cranial nerves. Furthermore, all patients experienced spontaneous pain in the face or affected extremities. Cerebrospinal fluid analysis was cytologically negative in two of five cases. Gadolinium (Gd)-enhanced magnetic resonance imaging (MRI) detected abnormalities in the cranial nerves, nerve roots, and cauda equina in all cases except case 1 and the recurrent stage of case 2. F-18 FDG-PET/CT showed clear visualization of almost all the lymphomatous involvement of peripheral nerves and other tissues in all patients. Furthermore, F-18 FDG-PET/CT detected abnormalities including asymptomatic lesions that were not detected with MRI, and also identified the appropriate lesion for diagnostic biopsy. However, as in case 3, the lesions in the left oculomotor nerve and the cauda equina were detected only with Gd-enhanced MRI, which has superior spatial resolution. In conclusion, F-18 FDG-PET/CT is a sensitive modality that can suggest the presence of malignancy and identify appropriate places for diagnostic biopsies. It is especially useful when combined with Gd-enhanced MRI, even in patients with primary NL that is usually difficult to diagnose.

Angioimmunoblastic T-cell lymphoma (AITL) is a common subtype of peripheral T-cell lymphoma with an aggressive clinical course and poor prognosis after conventional chemotherapy, for which there is no current standard of care. We describe here an 87-year-old woman with AITL, whose clinical diagnosis was complicated by the presence of B immunoblasts positive for Epstein–Barr virus in the lymph nodes and monoclonal plasma cells in the bone marrow at initial presentation. Rebiopsy of the lymph node led to the correct diagnosis of AITL with concurrent smoldering plasma cell myeloma. She was treated with several courses of conventional chemotherapy, resulting in progressive disease, and then switched to the immunomodulatory drug lenalidomide, which used in Japan for the treatment of multiple myeloma. Lenalidomide was effective in controlling both AITL and plasma cell myeloma.

Background Staphylococcus epidermidis can cause nosocomial meningitis in the presence of prosthetic devices. We describe a case of Staphylococcus epidermidis meningitis in a patient with neutropenia who had no intracranial foreign body, and we review the literature on meningitis that is caused by coagulase-negative Staphylococcus spp. without a neurosurgical device. Case presentation A 47-year-old Japanese man with acute myeloid leukemia receiving chemotherapy through a totally implantable central venous catheter developed fever and headache. The patient had a history of craniotomy for anaplastic oligodendroglioma without an indwelling neurosurgical device. The results of two blood cultures and a cerebrospinal fluid culture were positive for Staphylococcus epidermidis. Clinical improvement was observed with treatment with vancomycin and removal of the central venous catheter despite prolonged neutropenia. Conclusions To the best of our knowledge, this is the first reported case of Staphylococcus epidermidis meningitis in a patient with neutropenia without a neurosurgical device who was successfully treated.

Key Clinical Message Currently, there is no standard treatment for neurolymphomatosis because of the scarcity of clinical studies. Here, we report the successful treatment of neurolymphomatosis caused by follicular lymphoma with bendamustine, which could be an effective treatment option for this condition.

A 59-year-old woman presented with high serum total protein, detected on a screening examination. Laboratory tests revealed high plasma levels of M-protein (IgG-λ), and FDG-PET/CT revealed systemic lymph node swelling and a large tumorous mass in the abdominal cavity. Bone marrow aspirates contained 8.4% plasma cells and approximately 30% abnormal small lymphocytes. A biopsy of the left supraclavicular lymph node was initially interpreted as lymphoplasmacytic lymphoma (LPL). However, chromosomal analysis of the lymph node demonstrated an unusual karyotype with t (14;18) (q32;q21). FISH analysis for the IgH-BCL2 fusion gene was positive. Furthermore, the MYD88 L265P mutation was not detected in tumor cells. Based on these findings, this case was determined to be a type of follicular lymphoma with plasmacytic differentiation. We considered that this case was an important example emphasizing the importance of karyotypic examination for lymphoma classification.

The number of patients eligible for allogeneic stem cell transplantation (allo-HSCT) has increased because of improvements in transplantation procedures. Among long-term survivors of allo-HSCT, chronic kidney disease (CKD) is a major cause of morbidity. We retrospectively analyzed the clinical data of 106 consecutive patients with a median age of 43 years (range, 17 to 73) who had undergone allo-HSCT at our institution between January 2001 and September 2009. Patients who died within 5 years after transplantation or had CKD at the time of transplantation were excluded from study. CKD was defined as a persistent decrease in the estimated glomerular filtration rate to below 60 mL/min/1.73 m2. CKD occurred in 32 patients (30.2%) at a median time of 55 months after transplantation. Three patients required maintenance hemodialysis. In multivariate analysis older age at the time of transplantation (hazard ratio [HR], 1.07/year; 95% confidence interval [CI], 1.02 to 1.13) and a history of acute kidney injury (AKI) within 100 days after transplantation (HR, 6.30; 95% CI, 2.21 to 17.9) were significant risk factors for CKD. Conditioning regimen, stem cell source, or the presence of acute/chronic GVHD was not significantly associated with CKD in this study. Patients with CKD had a lower overall survival rate (HR, 4.11; 95% CI, 1.3 to 13.0) than patients without CKD. Careful monitoring of renal function is required for long-term survivors after allo-HSCT, especially in patients who have experienced AKI and in older patients.

Late-onset neutropenia after rituximab (RTX) therapy (R-LON) has been widely reported, but clinical studies on a large number of cases are limited. In this study, we aimed to investigate the incidence and risk factors of R-LON.In this study, we retrospectively analyzed data of 213 enrolled B-cell lymphoma patients (male 114; female 99) treated with RTX at a single institution. R-LON was defined as otherwise unexplained grade III-IV neutropenia after RTX. The median age of the patients was 62 years, and 129 of them were initially diagnosed at advanced stages (stage III-IV).R-LON occurred in 19 patients within a median of 121 (range, 49-474) days after the last RTX administration. The 1-year cumulative incidence was 9.0%. On univariate analysis, older age (60 years), advanced stage, and purine analog or methotrexate administration were significant or borderline significant risk factors for R-LON, whereas sex, disease type, bone marrow invasion, combination with cytotoxic chemotherapeutic drugs, intensified therapy (compared with R-CHOP), prior autologous transplantation, and repeated RTX administration were not. On multivariate analysis, older age (hazard ratio (HR), 2.95) and advanced stage (HR, 3.56) were significant risk factors. Treatment with granulocyte colony-stimulating factor was feasible in grade IV R-LON patients with high risk of infection.Careful follow-up is therefore necessary after B-cell lymphoma treatment, especially in high-risk patients with advanced disease or of older age.