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Objectives: Hemorrhagic events are a rare but potentially fatal complication in patients with polycythemia vera (PV)., Methods: We analyzed the characteristics of hemorrhagic events in 267 patients with PV., Results: A median follow-up of 4.8 years revealed that 23 (8.6%) hemorrhagic events occurred. Significantly more hemorrhagic events occurred in younger patients aged below 60 years (n = 72) than in older patients aged 60 years or above (n = 191) (n = 12 [16.7%] vs. n = 11 [5.8%], respectively, P  = 0.012). In univariate analysis among the younger patients, white blood cell (WBC) count ≥ 15 × 10 9 /L (hazard ratio [HR] = 7.746, 95% confidence interval [CI] 2.082-28.830, P  = 0.002), palpable splenomegaly (HR = 5.629, 95% CI 1.193-26.550, P  = 0.029), and JAK2 V617F allele burden ≥ 80% (HR = 22.850, 95% CI 2.885-181.00, P  = 0.003) were associated with an increased risk of hemorrhagic events. In multivariate analysis, JAK2 V617F allele burden ≥ 80% (HR = 9.394, 95% CI 1.046-84.380, P  = 0.046) was a significant risk factor., Conclusions: There is an increased risk of hemorrhagic events after diagnosis in younger PV patients with a high JAK2 V617F allele burden, high WBC count or palpable splenomegaly. It is important to consider treatment options that aim to avoid hemorrhagic events by reducing the JAK2 V617F allele burden in younger PV patients.

Ropeginterferon alfa-2b (ropegIFN), a new-generation interferon-based agent, has been approved in Japan for patients with polycythemia vera (PV) who are ineligible for or respond inadequately to conventional treatment. However, long-term outcomes with ropegIFN in Japanese patients have not been reported. This extension of a phase 2 study of ropegIFN in Japanese patients with PV aimed to determine its long-term safety/efficacy, and changes over time in JAK2 V617F allele burden. Here, we report data from the phase 2 study and subsequent extension over a period of 36 months. The primary endpoint was the complete hematologic response (CHR) maintenance rate without phlebotomy (hematocrit value < 45% without phlebotomy during the previous 12 weeks, platelet count ≤ 400 × 10 9 /L, and white blood cell count ≤ 10 × 10 9 /L). The CHR maintenance rates were 8/27 (29.6%), 18/27 (66.7%), and 22/27 (81.5%) at 12, 24, and 36 months, respectively. No thrombotic or hemorrhagic events occurred. The median allele burden change from baseline was - 74.8% at 36 months. All patients experienced adverse events; 25/27 (92.6%) experienced adverse drug reactions (ADRs), but no serious ADRs or deaths occurred. This interim analysis demonstrated the safety and efficacy of ropegIFN over 36 months in Japanese patients with PV., Competing Interests: Declarations. Conflict of interest: KK reports honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AbbVie G.K., Novartis Pharma K.K., PharmaEssentia Japan KK, Sanofi K.K., and Takeda Pharmaceutical Co., Ltd. YS reports research funding from Astellas Pharma Inc., Incyte Biosciences Japan G.K., Kyowa Kirin Co., Ltd., Ono Pharmaceutical Co., Ltd., and Toyo Kohan Co., Ltd.; grants from Shojunkai Takeuchi Hospital; honoraria from Novartis Pharma K.K.; and participation on a data safety monitoring board or advisory board for Novartis Pharma K.K. AG reports research funding from Bayer Yakuhin, Ltd., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., MSD K.K., Nihon Pharmaceutical Co., Ltd., Nippon Shinyaku Co., Ltd., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Sumitomo Pharma Co., Ltd., Taiho Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd.; consulting fees from Alexion Pharmaceuticals, Inc., Chugai Pharmaceutical Co., Ltd., and PharmaEssentia Japan KK; honoraria from Alexion Pharmaceuticals, Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Janssen Pharmaceutical K.K., Kyowa Kirin Co., Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Nihon Pharmaceutical Co., Ltd., Nippon Shinyaku Co., Ltd., Pfizer Japan Inc., Sanofi K.K., Sumitomo Pharma Co., Ltd., Taiho Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd.; and participation on a data safety monitoring board or advisory board for Alexion Pharmaceuticals, Inc., Chugai Pharmaceutical Co., Ltd., and PharmaEssentia Japan KK. KT reports research funding and consulting fees from Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Otsuka Pharmaceutical Co., Ltd., PharmaEssentia Japan KK, and Takeda Pharmaceutical Co., Ltd.; and honoraria from Alexion Pharmaceuticals, Inc., Kyowa Kirin Co., Ltd., MSD K.K., and Novartis Pharma K.K. M Ichii reports payments for presentations from Novartis Pharmaceuticals and payments for speakers bureaus from Sumitomo Pharma Co., Ltd. TI reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Asahi Kasei Pharma Co., Ltd., Chugai Pharmaceutical Co., Ltd., Novartis Pharma K.K., and PharmaEssentia Japan KK. SS reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AbbVie G.K., Amgen K.K., Asahi Kasei Pharma Co., Ltd., Novartis Pharma K.K., and Ono Pharmaceutical Co., Ltd. M Ito reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca K.K., Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Incyte Biosciences Japan G.K., Janssen Pharmaceutical K.K., Novartis Pharma K.K., PharmaEssentia Japan KK, and Takeda Pharmaceutical Co., Ltd. OZ is an employee of PharmaEssentia Corporation USA. AQ is an employee of PharmaEssentia Corporation Taiwan. HK is an employee of PharmaEssentia Japan KK. TS is a board member of PharmaEssentia Japan KK. NK reports grants from Chugai Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Perseus Proteomics Inc., PharmaEssentia Japan KK, and Sumitomo Pharma Co., Ltd.; research funding from Meiji Seika Pharma Co., Ltd. and Takeda Pharmaceutical Co., Ltd.; consulting fees from Japan Tobacco Inc., PharmaEssentia Japan KK, and Torii Pharmaceutical Co., Ltd.; honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Novartis Pharma K.K. and Takeda Pharmaceutical Co., Ltd.; and is a board member of PharmaEssentia Japan KK. KS reports research funding from AbbVie G.K., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Mochida Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Shionogi & Co., Ltd., Sumitomo Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd.; honoraria from Novartis Pharma K.K. and Takeda Pharmaceutical Co., Ltd.; and participation on a data safety monitoring board or advisory board for AbbVie G.K., (© 2024. The Author(s).)

Disease recurrence remains the principal cause of treatment failure after allogeneic hematopoietic stem cell transplantation. Post-transplant maintenance therapy with azacitidine (AZA) is promising to prevent relapse but the outcomes are unsatisfactory in patients at high risk of recurrence. Herein, we evaluated the outcome in patients who received AZA and gemtuzumab ozogamicin (GO), anti-CD33 antibody-calicheamicin conjugate, as post-transplant maintenance therapy. Twenty-eight patients with high-risk hematologic malignancies harboring CD33-positive leukemic blasts received the maintenance therapy. AZA (30 mg/m 2 ) was administered for 7 days, followed by GO (3 mg/m 2 ) on day 8. The maximum number of cycles was 4. At transplant, 21 patients (75.0%) had active disease. Their 2-year overall survival, disease-free survival, relapse, and non-relapse mortality rates were 53.6%, 39.3%, 50.0%, and 10.7%, respectively. Of these patients, those with minimal residual disease at the start of maintenance therapy (n = 9) had a higher recurrence rate (66.7% vs. 42.1% at 2 years, P = 0.069) and shorter disease-free survival (11.1% vs. 52.6% at 2 years, P = 0.003). Post-transplant maintenance therapy with AZA and GO was generally tolerable but more than half of the patients eventually relapsed. Further improvements are needed to prevent relapse after transplantation in patients with high-risk hematologic malignancies., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Persistent COVID-19 is a well recognized issue of concern in patients with hematological malignancies. Such patients are not only at risk of mortality due to the infection itself, but are also at risk of suboptimal malignancy-related outcomes because of delays and terminations of chemotherapy. We report two lymphoma patients with heavily pretreated persistent COVID-19 in which ensitrelvir brought about radical changes in the clinical course leading to rapid remissions. Patient 1 was on ibrutinib treatment for mantle cell lymphoma when he developed COVID-19 pneumonia which was severe and ongoing for 2 months despite therapy with molnupiravir, multiple courses of remdesivir, one course of sotrovimab, tocilizumab, and steroids. Patient 2 was administered R-CHOP therapy for diffuse large B-cell lymphoma when he developed COVID-19 which was ongoing for a month despite treatment with multiple courses of remdesivir and one course of sotrovimab. A 5-day administration of ensitrelvir promptly resolved the persistent COVID-19 accommodated by negative conversions of RT-qPCR tests in both patients within days. Ensitrelvir is a novel COVID-19 therapeutic that accelerates viral clearance through inhibition of the main protease of SARS-CoV-2, 3-chymotrypsin-like protease, which is vital for viral replication. Ensitrelvir is a promising treatment approach for immunocompromised lymphoma patients suffering from persisting and severe COVID-19., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Furuya, Yasuda, Hiki, Shirane, Yamana, Uchimura, Inano, Takaku, Hamano and Ando.)

Background: Acute graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with significant morbidity and mortality, and efficacy of currently available therapeutics are limited. Acute and chronic GVHD are similar in that both are initiated by antigen presenting cells and activation of alloreactive B-cells and T-cells, subsequently leading to inflammation, tissue damage, and organ failure. One difference is that acute GVHD is mostly attributed to T-cell activation and cytokine release, whereas B-cells are the key players in chronic GVHD. Ibrutinib is an irreversible inhibitor of the Bruton's tyrosine kinase (BTK), which is part of B-cell receptor signaling. Ibrutinib is currently used for treating chronic GVHD, but its efficacy towards acute GVHD is unknown. Besides BTK, ibrutinib also inhibits interleukin-2 inducible T-cell kinase (ITK), which is predominantly expressed in T-cells and a crucial enzyme for activating the downstream pathway of TCR signaling. ITK activates PLCγ2 and facilitates signaling through NF-κB, NFAT, and MAPK, leading to activation and proliferation of T-cells and enhanced cytokine production. Therefore, the TCR signaling pathway is indispensable for development of acute GVHD, and ITK inhibition by ibrutinib would be a rational therapeutic approach., Case Presentation: A 56-year-old male acute myeloid leukemia patient with Myeloid neoplasms with germline DEAD-box RNA helicase 41 ( DDX41 ) mutation underwent cord blood transplantation and developed severe gastrointestinal (GI) acute GVHD which was refractory to steroids and mesenchymal stem cell therapy. While acute GVHD accommodated by multiple life-threatening GI bleeding events persisted, chronic cutaneous GVHD developed, and ibrutinib 420 mg/day was initiated from day 147 of transplant. Although ibrutinib was commenced targeting the chronic GVHD, unexpected and abrupt remission of acute GVHD along with remission of chronic GVHD was observed., Conclusion: Ibrutinib is a promising therapeutic for treating acute GVHD, and further studies are warranted., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Risk-adapted therapy is recommended to prevent major clinical complications, such as thrombo-haemorrhagic events, in patients with essential thrombocythaemia (ET). In this study, we analysed the association between non-driver gene mutations and thrombo-haemorrhagic events in 579 patients with ET. ASXL1 and TP53 mutations were frequently identified in patients with ET complicated by thrombosis (22.7% and 23.1%, respectively), and the DNMT3A mutation was frequently identified in patients who experienced haemorrhage (15.2%). Multivariate analyses of thrombosis-free survival (TFS) revealed that ASXL1 and TP53 mutations are associated with thrombosis (hazard ratio [HR] = 3.140 and 3.752 respectively). Patients harbouring the ASXL1 or TP53 mutation had significantly worse TFS rates than those without mutation (p = 0.002 and p < 0.001 respectively). Furthermore, JAK2V617F-mutated patients with accompanying ASXL1 mutations showed significantly shorter TFS compared with those without ASXL1 mutations (p = 0.003). Multivariate analyses of haemorrhage-free survival (HFS) revealed that the DNMT3A mutation (HR = 2.784) is associated with haemorrhage. DNMT3A-mutated patients showed significantly shorter HFS than those without the mutation (p = 0.026). Non-driver gene mutations should be considered in treatment strategies and may provide important information for personalised treatment approaches., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

Budd-Chiari syndrome (BCS) is a rare vascular disorder characterized by obstruction of hepatic venous outflow, culminating in elevated hepatic and portal venous pressure. BCS is associated with myeloproliferative neoplasms (MPN) in 40% of cases, which is significantly higher than the rate observed in other venous thrombotic conditions, and suggests that MPN may contribute to the etiology of BCS. In particular, the JAK2 V617F mutation has recently attracted substantial attention, given its profound association with thrombogenesis, mechanically implicated through endothelial damage, increased blood cell adhesion, and facilitation of neutrophil extracellular trap formation. A common treatment approach consists of anticoagulation for prevention and treatment of thrombosis, and cytoreductive therapy targeting MPN. However, as no definitive evidence exists for this approach, a bespoke therapeutic strategy tailored to individual patient profiles is required.

Objectives: Since MPL mutation is a rare driver gene mutation found in a small number of essential thrombocythemia (ET) patients, the clinical characteristics of patients with MPL mutations and their association with thrombotic events have not yet been elucidated in Japan., Methods: We enrolled 579 Japanese ET patients based on the diagnostic criteria of the WHO classification 2017 and compared clinical characteristics of MPL -mutated patients ( n  = 22; 3.8%) to JAK2 V617F-mutated ( n  = 299; 51.6%), CALR -mutated ( n  = 144; 24.9%), and triple-negative (TN) ( n  = 114; 19.7%) patients., Results: Thrombosis during follow up was observed in 4 out of 22 (18.2%) in the MPL -mutated group, which was the highest among all driver gene mutation groups ( JAK2 V617F-mutated, 8.7%; CALR -mutated, 3.5%; TN,1.8%). The MPL- and JAK2 V617F-mutated groups had worse thrombosis-free survival (TFS) than the CALR -mutated ( p  = 0.043) and TN groups ( p  = 0.006). Univariable analysis revealed that a history of thrombosis was a possible risk factor for thrombosis among MPL -mutated patients (hazard ratio: 9.572, p  = 0.032)., Conclusions: MPL -mutated ET patients should require more intensive management to prevent recurrence of thrombosis.

Myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) is a rare disease, which presents with features of myelodysplastic syndromes with ring sideroblasts and essential thrombocythemia, as well as anemia and marked thrombocytosis. SF3B1 and JAK2 mutations are often found in patients, and are associated with their specific clinical features. This study was a retrospective analysis of 34 Japanese patients with MDS/MPN-RS-T. Median age at diagnosis was 77 (range, 51-88) years, and patients had anemia (median hemoglobin: 9.0 g/dL) and thrombocytosis (median platelet count: 642 × 109/L). Median overall survival was 70 (95% confidence interval: 68-not applicable) months during the median follow-up period of 26 (range: 0-91) months. A JAK2V617F mutation was detected in 46.2% (n = 12) of analyzed patients (n = 26), while an SF3B1 mutation was detected in 87.5% (n = 7) of analyzed patients (n = 8). Like those with myelodysplastic syndromes or myeloproliferative neoplasms, patients often received erythropoiesis-stimulating agents and aspirin to improve anemia and prevent thrombosis. This study, which was the largest to describe the real-world characteristics of Japanese patients with MDS/MPN-RS-T, showed that the patients had similar characteristics to those in western countries., (© 2023. Japanese Society of Hematology.)

Objectives: A proportion of patients with polycythemia vera (PV) and essential thrombocythemia (ET) harbor non-driver mutations associated with poor prognosis. In this study, we analyzed the frequency of non-driver mutations in a large Japanese PV and ET cohort. Furthermore, we studied the relationship of these mutations and prognosis in Japanese patients., Methods: We enrolled 843 Japanese patients with PV or ET. Non-driver mutations were analyzed by target resequencing using next-generation sequencing. The association of the mutations with the prognosis was estimated using multivariable logistic regression analysis and log-rank test., Results: Non-driver mutations were detected in 31.1% and 24.5% patients with PV and ET, respectively. Among them, ASXL1 mutations were identified as a risk factor for leukemic/myelofibrotic transformation in PV and ET patients (hazard ratio: 4.68, p = .006). The higher-risk groups of the mutation-enhanced international prognostic system (MIPSS)-PV and MIPSS-ET incorporating non-driver mutations exhibited significantly shorter overall survival compared with the low-risk group (p < .001)., Conclusions: These results implicate the importance of studying non-driver mutations for predicting the prognosis and survival of Japanese PV and ET patients., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Risk-adapted therapy is recommended to prevent thrombosis in essential thrombocythemia (ET) patients. An advanced age, a history of thrombosis, and the presence of the JAK2V617F mutation are well-defined risk factors for thrombosis in ET; however, the impact of cardiovascular risk (CVR) factors on thrombosis in ET remains elusive. Therefore, we herein investigated the impact of CVR factors on thrombosis in 580 ET patients who met the 2017 World Health Organization Classification diagnostic criteria. A univariate analysis identified hypertriglyceridemia and multiple CVR factors as strong risk factors for thrombosis (hazard ratio [HR] 3.530, 95% confidence interval [CI] 1.630-7.643, P = 0.001 and HR 3.368, 95% CI 1.284-8.833, P = 0.014, respectively) and hyper-LDL cholesterolemia as a potential risk factor (HR 2.191, 95% CI 0.966-4.971, P = 0.061). A multivariate analysis revealed that hypertriglyceridemia was an independent risk factor for thrombosis (HR 3.364, 95% CI 1.541-7.346, P = 0.002). Furthermore, poor thrombosis-free survival was observed in patients with a serum triglyceride level ≥ 1.2 mmol/L (HR = 2.592, P = 0.026 vs. < 1.2 mmol/L) or two or more CVR factors (P = 0.011 vs. no CVR factors and P = 0.005 vs. one CVR factor). These results revealed the impact of CVR factors on thrombosis in ET. Since CVR factors are manageable, lifestyle interventions, such as the control of serum triglyceride levels, may effectively prevent thrombosis in ET patients., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Acquired erythrocytosis can be classified into polycythemia vera (PV) and non-neoplastic erythrocytosis (NNE). The vast majority of PV patients harbor JAK2 mutations, but differentiating JAK2 mutation-negative PV from NNE is challenging due to a lack of definitive molecular markers., Methods: We studied the clinical features of 121 patients with erythrocytosis of which 47 (38.8%) were JAK2 mutation-positive and also fulfilled the diagnostic criteria for PV, and 67 (55.4%) JAK2 mutation-negative erythrocytosis patients who were diagnosed as NNE. Diagnosis was strictly based on driver mutation analysis and central pathology review., Results: No JAK2 mutation-negative PV patients were found in our cohort. The NNE group showed significantly younger (p < 0.01) age with higher frequency of smoking (p < 0.001), alcohol consumption (p < 0.001), and diabetes mellitus (p < 0.05), whereas the PV group (n = 47) showed significantly higher white blood cell count, platelet count, and lactate dehydrogenase (p < 0.001). Although serum erythropoietin (EPO) levels were significantly higher in NNE compared to PV (p < 0.001), approximately 40% of the NNE patients had EPO levels below the lower range of normal, fulfilling a minor diagnostic criterion of PV and raising the possibility of PV misdiagnosis., Conclusion: Low EPO levels in JAK2 mutation-negative erythrocytosis may not be a reliable diagnostic criterion for distinguishing PV from NNE., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: Current guidelines for essential thrombocythemia (ET) patients recommend different treatment approaches based on thrombosis risk stratification models. However, these recommendations may not be applicable to some patients under real clinical settings. Therefore, we carried out a retrospective real-world validation study., Methods: Thrombosis-free survival (TFS) was compared between treatment naïve ET patients receiving different treatment approaches. ET patients were stratified by three representative risk models, the conventional, the International Prognostic Score for thrombosis in ET (IPSET-thrombosis), and revised IPSET-thrombosis. Treatment decisions were largely made by individual physicians, taking into account patient preferences and backgrounds., Results: A total of 179 ET patients were included, and thrombotic events were observed in 26 patients. TFS was significantly longer in high-risk patients of all risk models receiving a combination of cytoreductive therapy (CRT) and antiplatelet therapy (APT) compared to CRT alone. Similar results were seen in intermediate-risk patients stratified by IPSET-thrombosis. In contrast, in very low- and low-risk patients of all risk models, TFS was not affected by addition of CRT, indicating that observation or APT alone is an appropriate treatment approach for these patients., Conclusion: We demonstrate that current guidelines provide optimal treatment approaches for Japanese ET patients under real-world clinical settings.

Invasive mucormycosis is a refractory fungal infection. Central nervous system (CNS) mucormycosis is a rare complication caused by infiltration from the paranasal sinuses or hematogenous dissemination. Here, we present a case of a brain abscess, due to mucormycosis, diagnosed using burr craniotomy. A 25-year-old Japanese woman with relapsed-refractory acute lymphoblastic leukemia underwent cord blood transplantation (CBT). The patient experienced prolonged and profound neutropenia, and oral voriconazole was administered as primary antifungal prophylaxis. The patient received a conditioning regimen on day -11 and complained of aphasia and right hemiparesis on day -6. Magnetic resonance imaging (MRI) revealed a T2-weighted high-intensity area in the left frontal cortex. A brain abscess was suspected, and liposomal amphotericin B (L-AMB) administration was started. The patient underwent CBT as scheduled and underwent neutrophil engraftment on day 14. Although the patient achieved complete remission on day 28, her consciousness level gradually deteriorated. MRI revealed an enlarged brain lesion with a midline shift sign, suggesting brain herniation. Craniotomy was performed to relieve intracranial pressure and drain the abscess on day 38, and a diagnosis of cerebral mucormycosis was confirmed. The L-AMB dose was increased to 10 mg/kg on day 43. Although the patient's consciousness level improved, she died of hemorrhagic cystitis and aspiration pneumonia. Cerebral mucormycosis should be suspected if neurological symptoms are observed in stem cell transplant recipients. Prompt commencement of antifungal therapy and debridement are crucial because mucormycosis has a poor prognosis., Competing Interests: Declaration of competing interest None., (Copyright © 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: The etiology of POEMS syndrome and its associated polyneuropathy have not been fully elucidated. The clinical picture of POEMS-associated polyneuropathy and nutritional polyneuropathy due to vitamin B6 (VB6) deficiency are strikingly similar, both being typically sensorimotor, symmetrical, stocking and glove distribution, and more severe in the lower extremities., Case Presentation: We report two consecutive POEMS patients with VB6 deficiency who showed unusual rapid and drastic recovery of polyneuropathies within 6-8 weeks after oral VB6 supplementation. Case 1 was supplemented with VB6 from time of autologous stem cell transplantation. Polyneuropathy began to improve within one week, and he became walker-free and could walk unaided with a cane within 6 weeks. Case 2 was supplemented with VB6 from time of stem cell harvest, and he became cane-free and his gait almost normalized within two months. Nerve conduction studies were also confirmatory of neurologic recovery in both cases., Conclusions: Objective physical improvement of POEMS-associated polyneuropathy has been reported to typically require approximately a year after autologous stem cell transplantation, and together with our observations of VB6 deficiency and supplementations leading to accelerated recoveries of polyneuropathy, VB6 deficiency most probably contributes to POEMS-associated polyneuropathy. VB6 acts as a coenzyme in approximately 150 biochemical reactions. VB6 has been reported to inhibit the hypoxia-inducible factor/vascular endothelial growth factor (VEGF) pathway, and VEGF levels are known to corollate with disease activity of POEMS syndrome. Therefore, VB6 deficiency may contribute not only to POEMS-associated polyneuropathy, but also to the etiology of POEMS syndrome itself.

The concept of allogeneic cell therapy was first presented over 60 years ago with hematopoietic stem cell transplantation. However, complications such as graft versus host disease (GVHD) and regimen-related toxicities remained as major obstacles. To maximize the effect of graft versus leukemia, while minimizing the effect of GVHD, donor lymphocyte infusion was utilized. This idea, which was used against viral infections, postulated that adoptive transfer of virus-specific cytotoxic T lymphocytes could reconstitute specific immunity and eliminate virus infected cells and led to the idea of banking third party cytotoxic T cells (CTLs). T cell exhaustion sometimes became a problem and difficulty arose in creating robust CTLs. However, the introduction of induced pluripotent stem cells (iPSCs) lessens such problems, and by using iPSC technology, unlimited numbers of allogeneic rejuvenated CTLs with robust and proliferative cytotoxic activity can be created. Despite this revolutionary concept, several concerns still exist, such as immunorejection by recipient cells and safety issues of gene editing. In this review, we describe approaches to a feasible "off-the-shelf" therapy that can be distributed rapidly worldwide. We also offer perspectives on the future of allogeneic cell cancer immunotherapy.

Immunosuppressive therapies, including antithymocyte globulin and cyclosporine (CsA), are used for the treatment of aplastic anemia, but they reportedly cause lymphoproliferative diseases. Here, we report two cases of aplastic anemia in which diffuse large B-cell lymphoma developed during treatment with CsA. In both the cases, CsA was discontinued and combination therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisolone) plus the thrombopoietin receptor agonist eltrombopag was initiated. Furthermore, supportive care, including blood transfusion and granulocyte colony-stimulating factor, was provided. After six or eight courses of R-CHOP therapy, a complete metabolic response was achieved without serious adverse events. These cases illustrate the safety of combining R-CHOP with eltrombopag therapy in patients at a high risk of severe pancytopenia.

Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Trio-next generation sequencing is useful to identify undiagnosed inherited diseases. We have attended a patient with trigenic ADH5 / ALDH2 / ADGRV1 pathogenic variants, which caused two distinct diseases, myelodysplastic syndrome and Usher syndrome. Whole genome sequencing of peripheral blood from the patient and his parents were applied to identify disease-causing genes. Sanger sequencing was performed to validate the identified ADH5 / ALDH2 / ADGRV1 variants. Our results identified disease-associated variants in ADGRV1 (disease inheritance autosomal recessive) and in ADH5 (disease inheritance also autosomal recessive) and a variant in ALDH2 (disease inheritance autosomal dominant). Although the variants identified in ADH5 and ALDH2 have been reported, their co-existence in association with disease-causing variation in a third gene has not. They broaden the spectrum of ADGRV1 in Usher syndrome. Findings on next generation sequencing guided rapid and accurate diagnosis, resulting in patient-tailored therapeutic intervention., Competing Interests: The authors declare no conflict of interest., (© 2021 The Author(s).)

We report about a 48-year-old woman diagnosed with primary central nervous system lymphoma (PCNSL). After chemotherapy and autologous stem cell transplantation, she presented with a continuous high-grade fever. Positron emission tomography-computed tomography revealed prominent hepatosplenomegaly and high diffuse uptake of 18F-fluorodeoxyglucose in the liver, spleen, and lungs. Intravascular large B-cell lymphoma (IVLBCL) was diagnosed using random skin biopsy. There were no symptoms of IVLBCL at the time of diagnosis of PCNSL. The histopathological features of PCNSL and IVLBCL were nearly similar. These findings suggest that IVLBCL was the recurrence of PCNSL rather than a separate entity., Competing Interests: The authors declare no conflict of interest regarding this report., (© 2021 The Author(s).)

We report the case of a 58-year-old woman with multiple myeloma who relapsed after the first autologous peripheral blood stem cell transplantation. She was refractory to new drugs and underwent a haploidentical allogeneic hematopoietic stem cell transplantation (haplo-HSCT) by administering post-transplantation cyclophosphamide (PTCy) after the second autologous peripheral blood stem cell transplantation. Neutrophil and platelet engraftment were achieved on days 22 and 55, respectively. Grade II cutaneous acute graft-versus-host disease was observed, which was resolved by systemic steroid treatment. Post-transplant bone marrow examination confirmed donor chimerism replacement and immunophenotypic complete response, and the patient is alive and disease-free. Although haplo-HSCT using PTCy for multiple myeloma has not been reported in Japan, it could be performed safely. Here, we report our results with literature review.

Bone turnover markers (BTMs) are useful parameters for assessing fracture risk and unlike bone mineral density (BMD), can be measured at any institution. However, BTM values have not been established in patients post-allogeneic hematopoietic stem cell transplantation (allo-HSCT). We investigated the practicality of BTMs in patients who underwent allo-HSCT by measuring levels of the serum bone resorption marker, tartrate-resistant acid phosphatase-5b (TRACP-5b), and the bone formation marker, bone-specific alkaline phosphatase (BAP), together with BMD, 1 month before and 6 months after allo-HSCT. Patients were classified into either the alendronate group (n = 14) if alendronate treatment (35 mg orally per week) was administered before allo-HSCT or within 1 month after allo-HSCT, or the control group (n = 16), in which patients did not receive alendronate treatment. Despite the high frequency of corticosteroids users in the alendronate group (71.4 vs. 18.9%; p < 0.01), the mean percentage changes in BMD at the lumbar spine (- 2.9 vs. - 3.1%; p = 0.44) and femoral neck (- 3.2 vs. - 4.1%; p = 1.00), TRACP-5b levels (- 4.8 vs. 9.9%; p = 0.45), and BAP levels (6.9 vs. 1.0%; p = 0.85) during 6 months did not differ significantly between the alendronate and control groups. Additionally, the percentage changes in BMD at the lumbar spine were negatively associated with the TRACP-5b levels 6 months after allo-HSCT (p = 0.03, r = 0.40). Our results indicate the possible effectiveness of alendronate treatment in allo-HSCT patients. BTM levels could be useful to monitor the BMD changes.

There have been many reports regarding tyrosine kinase inhibitor (TKI) administration to prevent relapse following allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). However, there are no commonly accepted standards for the choice of TKIs. We retrospectively analyzed the clinical features of Ph+ALL patients who received TKIs after allo-HSCT at our institution. The prophylactic administration of TKIs (pro) occurred in eight patients, and six patients received preemptive TKI administration (pre). The median follow-up period after allo-HSCT was 1,427 (range, 161-2,428) days in the pro group and 773.5 (range, 156-2,243) days in the pre group. Only one patient with non-hematological complete remission before allo-HSCT relapsed among the patients in the pro group. In the pre group, four patients treated with only TKIs achieved negativity of minimal residual disease. The 2-year overall survival rate after allo-HSCT was 85.7% in the pro group and 100% in the pre group. We used lower doses of TKIs compared with previous reports and this analysis shows that the dose is safe and effective as the treatment.

Objective Little information is available about the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) for patients with secondary myelofibrosis from essential thrombocythemia (ET) and polycythemia vera (PV). A nationwide retrospective study of the outcome of HSCT for post-ET and post-PV myelofibrosis was conducted in Japan. Patients and Methods Clinical data for patients with post-ET (n=29) and post-PV (n=9) myelofibrosis who had received first allogeneic HSCT were extracted from the Transplant Registry Unified Management Program, which is a registry of the outcomes of HSCT in Japan. Results Five patients died without neutrophil recovery within 60 days after transplantation. The incidence of neutrophil recovery was significantly lower in umbilical cord blood (UCB) transplantation than in related donor transplantation (40% vs. 92%, p=0.010). The 1-year non-relapse mortality for post-ET and post-PV myelofibrosis was 35% and 27%, respectively (p=0.972). No patient or transplantation characteristics were associated with non-relapse mortality. The 4-year overall survival for post-ET and post-PV myelofibrosis was 46% and 65%, respectively (p=0.362). A univariate analysis identified UCB transplantation (vs. related donor, p=0.017) and ≥10 times red blood cell transfusions before transplantation (vs. <10 times, p=0.037) as predictive of a lower overall survival. Conclusion Allogeneic HSCT provides a long-term survival for at least some patients with post-ET and post-PV myelofibrosis. Further studies with more patients are required to determine the best alternative donor.

Objective: The purpose of this study was to describe the clinical features of nocardiosis after allogeneic hematopoietic stem cell transplantation (allo-HSCT), focusing on new Nocardia species., Methods: We retrospectively reviewed data from patients with nocardiosis after allo-HSCT treated at our hospital and documented cases in the medical literature., Results: Fifty-seven cases were identified from our institution and the literature review. Although 51 patients (89.5%) responded to initial treatment, 28 (49.1%) patients were switched over to other treatment regimens due to the recurrence of nocardiosis or adverse events of antimicrobials. Nocardiosis-attributed mortality occurred in ten patients (17.5%). Antimicrobial susceptibilities varied among intra- and inter-species except linezolid (LZD). In the present study, five species were newly discovered after 2000, including N. cyriacigeorgica, N. veterana, N. abscessus, N. aobensis, and N. mexicana. All isolates of N. cyriacigeorgica, N. veterana, N. abscessus, and N. aobensis were sensitive to trimethoprim/sulfamethoxazole, amikacin (AMK), imipenem (IPM), and LZD; however, N. mexicana was resistant to AMK and IPM., Conclusion: Newly identified Nocardia species have various antimicrobial susceptibility patterns. Long-term maintenance therapy could be challenging due to the adverse events of antimicrobials, especially in the allo-HSCT setting. Prudent evaluation is crucial for selecting a second-line or further treatment options., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Vitamin B6 (VB6) deficiency contributes to oncogenesis and tumor progression in certain cancers, and is prevalent in cancer patients in general. VB6 is also an essential element of heme synthesis, and deficiency can lead to anemia. Primary myelofibrosis (PMF) and secondary myelofibrosis (sMF) are myeloproliferative neoplasms often presenting with anemia along with other cytopenias. We performed a prospective study to determine whether PMF and sMF patients suffer from VB6 deficiency, and whether VB6-deficient patients show improvement of anemias with VB6 supplementation. Twelve PMF patients and 11 sMF patients were analyzed. A total of 16 of 23 patients (69.6%) were found to have VB6 deficiency, but VB6 supplementation with pyridoxal phosphate hydrate did not elevate hemoglobin levels in deficient patients. None of the patients presented with vitamin B12, iron, or copper deficiencies. Four patients showed serum folate levels below the lower limit of normal and eight patients showed serum zinc levels below the lower limit of normal; however, these deficiencies were marginal and unlikely to contribute to anemia. Compared to VB6-sufficient patients, VB6-deficient patients showed significantly lower serum folate levels and higher serum copper levels. Studies elucidating the relationship of VB6 deficiency and etiology of PMF/sMF are warranted.

Dasatinib induces lymphocytosis of large granular lymphocytes (LGLs) in a proportion of patients with chronic myelogenous leukemia (CML), and is associated with better clinical outcomes. LGLs consist of cytotoxic T lymphocytes and natural killer cells; however, the context and phenotypic/functional features of each type of LGL are unknown. To better define features of these LGLs, we investigated lymphocytosis in CML patients treated with dasatinib. D57-positive and CD4-positive type I T-helper (Th) cells (CD57+ Th cells) rarely occur in CML patients without lymphocytosis and in healthy individuals; however, a substantial increase in the proportion of CD57+ Th cells was observed in CML patients treated with dasatinib. In addition, these cells showed appreciable levels of cytocidal activity via cytotoxic degranulation. Analysis of T-cell receptor α and β sequences showed a skewed T-cell repertoire in the CD57+ Th cells. Furthermore, patients with LGLs and CD57+ Th lymphocytosis achieved stronger molecular responses than did those without lymphocytosis. While further studies are warranted, our observations suggest that dasatinib induces the expansion of CD57+ Th-LGLs, which may play a crucial role in the dasatinib-induced response against Philadelphia chromosome-positive leukemia.

Objective: There are currently 2 representative diagnostic criteria for essential thrombocythemia (ET), the 2014 British Committee for Standards in Hematology Guidelines (BCSH) criteria and the 2016 World Health Organization (WHO) criteria. We compare and discuss the advantages and disadvantages of the 2 criteria., Method: We applied the 2 criteria to 403 patients with thrombocytosis and suspected myeloproliferative neoplasms (MPN) and compared patient populations., Results: The BCSH criteria diagnosed ET in 279 patients (BCSH-ET) whereas the WHO criteria diagnosed ET in 203 patients (WHO-ET). There were 83 patients diagnosable only by the BCSH criteria (BCSH-only-ET), of which under the WHO classification, 69 patients fell under the category of MPN, unclassifiable (MPN-u), 12 patients were PMF, prefibrotic/early stage (pre-PMF), and 2 patients were polycythemia vera. Patient characteristics such as age, hemoglobin, hematocrit, platelet counts, lactate dehydrogenase levels, JAK2V617F allele burdens, prevalence of myelofibrosis and splenomegaly, and frequencies of thrombotic events and treatment did not differ between WHO-ET and BCSH-only-ET, but BCSH-only-ET patients showed higher WBC counts and higher JAK2V617F mutation frequencies., Conclusion: The BCSH criteria diagnosed ET in a broader range of patients encompassing a significant number of patients who would otherwise be diagnosed as pre-PMF or MPN-u., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The majority of patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) harbor JAK2, CALR, or MPL mutations. We compared clinical manifestations of different subtypes of JAK2 and CALR mutations in Japanese patients with MPNs. Within our cohort, we diagnosed 166 patients as polycythemia vera (PV), 212 patients as essential thrombocythemia (ET), 23 patients as pre-primary myelofibrosis (PMF), 65 patients as overt PMF, and 27 patients as secondary myelofibrosis following the 2016 WHO criteria. Compared to patients with JAK2V617F-mutated PV, JAK2 exon 12-mutated PV patients were younger, showed lower white blood cell (WBC) counts, lower platelet counts, higher red blood cell counts, and higher frequency of thrombotic events. Compared to JAK2-mutated ET patients, CALR-mutated ET patients were younger, showed lower WBC counts, lower hemoglobin levels, higher platelet counts, and fewer thrombotic events. CALR type 1-like mutation was the dominant subtype in CALR-mutated overt PMF patients. Compared with JAK2V617F-mutated ET patients, JAK2V617F-mutated pre-PMF patients showed higher LDH levels, lower hemoglobin levels, higher JAK2V617F allele burden, and higher frequency of splenomegaly. In conclusion, Japanese patients with MPNs grouped by different mutation subtypes exhibit characteristics similar to those of their Western counterparts. In addition, ET and pre-PMF patients show different characteristics, even when restricted to JAK2V617F-mutated patients.

Exophiala dermatitidis infections in patients with hematological malignancies are very rare. Our patient had a blood stream infection caused by E. dermatitidis following the second umbilical cord blood transplantation (UCBT) after graft failure during the first UCBT. To our knowledge, this is the first report describing a breakthrough fungal infection caused by E. dermatitidis during the prophylactic administration of micafungin (MCFG). Therefore, MCFG-treated patients should be monitored for breakthrough E. dermatitidis infection during hematopoietic stem cell transplantation., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Recurrent somatic mutations of calreticulin (CALR) have been identified in patients harboring myeloproliferative neoplasms; however, their role in tumorigenesis remains elusive. Here, we found that the expression of mutant but not wild-type CALR induces the thrombopoietin (TPO)-independent growth of UT-7/TPO cells. We demonstrated that c-MPL, the TPO receptor, is required for this cytokine-independent growth of UT-7/TPO cells. Mutant CALR preferentially associates with c-MPL that is bound to Janus kinase 2 (JAK2) over the wild-type protein. Furthermore, we demonstrated that the mutant-specific carboxyl terminus portion of CALR interferes with the P-domain of CALR to allow the N-domain to interact with c-MPL, providing an explanation for the gain-of-function property of mutant CALR. We showed that mutant CALR induces the phosphorylation of JAK2 and its downstream signaling molecules in UT-7/TPO cells and that this induction was blocked by JAK2 inhibitor treatment. Finally, we demonstrated that c-MPL is required for TPO-independent megakaryopoiesis in induced pluripotent stem cell-derived hematopoietic stem cells harboring the CALR mutation. These findings imply that mutant CALR activates the JAK2 downstream pathway via its association with c-MPL. Considering these results, we propose that mutant CALR promotes myeloproliferative neoplasm development by activating c-MPL and its downstream pathway., (© 2016 by The American Society of Hematology.)

To investigate the current situation and issues regarding the diagnosis of Philadelphia-negative myeloproliferative neoplasms (MPN) in Japan, we retrospectively analyzed an accumulated cohort consisting of 1,081 patients with suspected MPN. Based on WHO2008 diagnostic criteria, we diagnosed 101 of these patients with polycythemia vera, 179 with essential thrombocythemia, 36 with primary myelofibrosis, 45 with unclassifiable MPN, and 4 with myelodysplastic syndromes. Out of 716 patients, 235 were not diagnosed with MPN despite the detection of a JAK2, CALR, or MPL mutation. Among 156 patients with undefined MPN receiving further follow-up, none underwent bone marrow examination and screening for BCR-ABL1 was not performed in 88 cases. Thus, diagnosis was not possible in these cases due to a lack of essential examinations. Since the prognosis and treatment strategy associated with MPN differ among disease types, in addition to mutation analysis, the importance of bone marrow examination and screening for BCR-ABL1 must be re-recognized.

Neurological symptoms induced by the infiltration of malignant lymphoma into the nervous systems are subsumed under the term neurolymphomatosis (NL). Here, we report the case of a 30-year-old Japanese man with primary testicular lymphoma complicated, as seen in various neurological findings, by secondary NL prior to testicular swelling. Painless right scrotal enlargement was noticed more than 1 month after the appearance of neurological complications such as right upper extremity numbness, dysarthria, facial palsy, and diplopia. Proactive investigation and biopsies of extranodal sites at high risk of central nervous system infiltration of malignant lymphoma, such as the testes, should be considered when secondary NL is suspected based on imaging findings.

Patients diagnosed with polycythemia vera (PV) or essential thrombocythemia (ET) sometimes suffer transformation of the disease into myelofibrosis (MF), which is associated with a poorer prognosis. This study investigated the prognostic value of the allele burden of JAK2V617F, a somatic driver mutation in these diseases, by comparing the allele burden between formalin-fixed paraffin-embedded bone marrow collected at initial diagnosis and peripheral blood from follow-up visits. Although the annual changes in the JAK2V617F allele burden were comparable between MF-transformed (n = 11) and untransformed (n = 23) patients, the burden was significantly increased in MF-transformed patients exhibiting a longer disease duration than untransformed patients. Furthermore, MF transformation was only observed in patients whose JAK2V617F allele burden exceeded the mean values for each disease (PV, 71.7 %; ET, 35.5 %) at initial diagnosis or during follow-up. Finally, we showed that hydroxycarbamide treatment exerted neither a preventive effect on MF transformation nor a suppressive effect on the increased JAK2V617F allele burden. In conclusion, a high JAK2V617F allele burden at initial diagnosis or during follow-up is predictive of MF transformation in PV and ET. Therefore, routine measurement of the JAK2V617F allele burden using an accurate assay system is recommended to predict MF transformation.

JAK2V617F, a gain-of-function mutation in the tyrosine kinase JAK2, is frequently detected in classical myeloproliferative neoplasms (MPNs). In the present study, we determined the JAK2V617F allele burden in Japanese MPN patients using alternately binding probe competitive-polymerase chain reaction, a highly quantitative method recently developed by our group. Although we observed strong similarities in terms of epidemiological parameters associated with the JAK2V617F allele burden between our cohort and others, we found a higher JAK2V617F allele burden in Japanese polycythemia vera (PV) patients and lower frequencies of thrombosis in Japanese MPN patients compared with previous reports. In addition, despite the presence of high red blood cell counts, some patients bearing the JAK2V617F mutation were not diagnosed as PV, as their hemoglobin values were lower than the WHO PV criterion. In these patients, the JAK2V617F allele burden was strikingly similar to that in PV patients fulfilling the 2008 WHO criteria, suggesting that these patients can be classified as PV. Although isotopic measurement of red cell mass (RCM) is required for definitive diagnosis of PV, our data suggest that precise measurement of the JAK2V617F allele burden may improve the diagnosis of PV when RCM has not been determined.