[Rinsho ketsueki] The Japanese journal of clinical hematology

A 76-year-old woman with stage IIIB squamous cell lung carcinoma developed pancytopenia following maintenance therapy with durvalumab. She was diagnosed with squamous cell lung carcinoma (T4N2M0, stageIIIB) in December 2023. Following a favorable response to chemoradiotherapy, maintenance therapy with durvalumab was initiated in June 2024. Thrombocytopenia was observed starting in August, and platelet count had decreased to 22,000/µl in October, leading to the discontinuation of durvalumab. However, the condition progressed to pancytopenia. Bone marrow biopsy revealed hypocellular marrow without dysplasia, fibrosis, or hemophagocytosis. Additional findings included paroxysmal nocturnal hemoglobinuria-type blood cells and fatty marrow replacement on spinal MRI. Based on these comprehensive findings, the patient was diagnosed with aplastic anemia (AA) in January 2025. Immunosuppressive therapy combining antithymocyte globulin, cyclosporine A, and eltrombopag was initiated in February 2025, resulting in a favorable response. AA is a relatively rare immune-related adverse event, and reports of AA induced by durvalumab are extremely limited. This case highlights the importance of considering AA in the differential diagnosis of persistent thrombocytopenia or pancytopenia during immune checkpoint inhibitor therapy.

Central nervous system (CNS) viral infections after allogeneic hematopoietic stem cell transplantation are associated with poor prognosis and have limited therapeutic options. We report three cases of refractory CNS viral infection treated by combination therapy with antiviral agents and intrathecal immunoglobulin administration. Case 1 involved cytomegalovirus encephalitis, Case 2 varicella zoster virus meningitis, and Case 3 human herpesvirus 6 encephalitis; all were resistant to antiviral agents. Two patients achieved viral DNA negativity in cerebrospinal fluid, and none experienced adverse events related to intrathecal injection. Although no intrathecal immunoglobulin products have been approved for use in Japan, our findings suggest that this treatment may be a viable option in selected refractory cases. Further studies are warranted to clarify the optimal agent, dosage, and schedule.

The complement system, which plays a key role in innate immunity, facilitates the elimination of foreign and endogenous substances in the body. Consequently, while a balance between complement activation and regulation is typically maintained, a disruption of this balance can lead to various diseases. Paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome (aHUS) are diseases in which abnormal complement regulatory factors cause excessive complement activation. To accurately diagnose diseases such as aHUS, international standard complement tests including activation markers such as Ba and sC5b-9 are used. The Japanese Society for Complement Research has contributed to the standardization of the International Complement Society and has established this testing system in Japan. In the present study, we revealed that the Ba level serves as a good predictive marker for the onset of thrombotic microangiopathy, a complication that typically occurs following hematopoietic stem cell transplantation. We also showed that complement activation levels rise more frequently postpartum than during pregnancy. Considering the growing number of drugs targeting the complement pathway, it is speculated that these complement markers will become available for testing in clinical settings in Japan.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an established curative treatment for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Advances in supportive care, infection control, and graft-versus-host disease management have substantially reduced non-relapse mortality, leading to improved transplant outcomes. However, post-transplant relapse remains the leading cause of treatment failure, particularly in patients with adverse genetic abnormalities or active disease at transplantation. Post-transplant maintenance therapy has emerged as a strategy to prevent relapse by providing a "third anti-leukemic effect" that complements the cytotoxic effect of conditioning regimens and the graft-versus-leukemia immune response. Maintenance approaches can be broadly categorized into prophylactic therapy administered during molecular remission and preemptive therapy initiated upon detection of measurable residual disease (MRD). This review summarizes the current concepts of post-transplant maintenance therapy in AML/MDS, with a particular focus on hypomethylating agents such as azacitidine and FLT3 inhibitors. It also discusses emerging evidence supporting MRD-guided treatment strategies and molecularly targeted maintenance approaches, highlighting future perspectives for optimizing relapse prevention after allo-HSCT.

BACKGROUND:Myelodysplastic syndromes (MDS) are classified into de novo and secondary forms. MDS among atomic bomb survivors (A-bomb-related MDS) is considered radiation-associated secondary MDS, whereas therapy-related MDS (t-MDS) develops after cytotoxic therapy and generally has a poor prognosis. However, differences between these two secondary MDS entities remain unclear. METHODS:We analyzed patients registered in the Nagasaki MDS cohort who were diagnosed between January 1985 and December 2023. Sixty A-bomb-related MDS and 150 t-MDS cases were included. Clinical characteristics, IPSS-R risk categories, overall survival (OS), and cytogenetic abnormalities at diagnosis were compared. RESULTS:The distribution of IPSS-R risk and cytogenetic risk categories did not differ significantly between groups. Nevertheless, median OS was significantly longer in A-bomb-related MDS than in t-MDS (65 vs. 19 months). Cytogenetic profiling revealed different features between groups, including a significantly higher frequency of monosomy 7 in t-MDS and of balanced structural abnormalities in A-bomb-related MDS. Balanced structural abnormalities were not clearly associated with prognosis. CONCLUSIONS:Although both A-bomb-related MDS and t-MDS are both classified as secondary MDS, they showed distinct prognostic and cytogenetic features. These findings suggest that the two conditions represent clinically distinct entities with different pathophysiology.

A 37-year-old man presented with recurrent fever. Diagnosis was challenging due to the lack of localized physical findings; however, subcutaneous panniculitis-like T-cell lymphoma (SPTCL) was eventually confirmed through multiple bone marrow biopsies. The patient developed rapidly progressive liver failure and hemophagocytic lymphohistiocytosis (HLH), resulting in a severe bleeding tendency. Despite receiving massive blood transfusions and sequential treatments with corticosteroids, etoposide, and CHP chemotherapy even before the definitive diagnosis, the patient died of cerebral hemorrhage approximately one month after admission. Autopsy revealed tumor infiltration in systemic adipose tissue and bone marrow. Genetic testing identified a homozygous germline HAVCR2 mutation (p.Y82C). While SPTCL is a rare subtype of cytotoxic T-cell lymphoma generally associated with a favorable prognosis, cases harboring HAVCR2 mutations can be complicated by severe HLH and follow a fulminant course. Detailed clinical reports of such severe cases are scarce. Our findings suggest that early diagnosis and prompt initiation of chemotherapy are crucial for managing severe SPTCL.

Cancer immunotherapy using patient-derived T cells genetically modified in vitro has been demonstrated to be effective. However, issues such as cost, time, and unstable quality must be resolved. To overcome these barriers, we developed the TCR-PS cell method, in which a specific TCR gene is introduced into pluripotent stem cells (PS cells), such as ES cells or iPS cells, and T cells are generated from those PS cells. We are currently preparing for a clinical trial in acute myeloid leukemia, targeting the WT1 antigen, with iPS cells provided by the CiRA Foundation as the starting material. In parallel, we are also investigating this approach for viral infections and preparing for clinical trials in COVID-19, with HLA-deficient ES cells as the starting material. This method should enable stockpiling of T cell therapies against known viruses such as SARS or avian influenza. Even for outbreaks caused by unknown viruses, it should be possible to produce T cell therapies within 100 days after the virus genome is defined.

INTRODUCTION:Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative option for blast-phase myeloproliferative neoplasms (BP-MPN), although relapse rates remain high. Recently, conditioning with thiotepa, busulfan, and fludarabine (TBF) has shown promising anti-leukemic activity in acute myeloid leukemia. CASE REPORT:A 64-year-old man with essential thrombocythemia that progressed to secondary myelofibrosis and subsequently BP-MPN underwent allo-HSCT after cytoreduction with azacitidine plus venetoclax. Peripheral blood stem cells were obtained from an HLA allele-matched unrelated donor, and TBF was used as the conditioning regimen. Low-dose anti-thymocyte globulin was administered for graft-versus-host disease (GVHD) prophylaxis. Full donor chimerism was achieved on day 28 after transplantation. Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) improved with defibrotide, and acute GVHD was manageable. CONCLUSION:This case suggests that a multidisciplinary treatment strategy incorporating TBF conditioning may improve relapse-free survival in patients with BP-MPN.

We report the case of an 80-year-old woman in which marked prolongation of prothrombin time (PT) and activated partial thromboplastin time (APTT) noted upon diagnosis of autoimmune hemolytic anemia revealed severe factor V (FV) deficiency. A mixing study showed a downward-convex pattern and the Bethesda assay for inhibitors was negative, which initially suggested congenital FV deficiency. Although the patient had concomitant early-stage esophageal cancer, infusions of fresh frozen plasma (FFP) failed to correct the coagulopathy, necessitating postponement of endoscopic therapy. Subsequently, a comprehensive evaluation by the Standardization Committee of the Japanese Ministry of Health, Labour and Welfare detected anti- FV IgG, establishing the diagnosis of hyperclearance-type autoimmune FV deficiency (AiFVD). Despite corticosteroid therapy, conventional coagulation screening test results remained markedly abnormal, complicating periprocedural management. In contrast, viscoelastic testing (VET) and thrombin generation testing (TGT), including ex vivo supplementation assays, indicated that adequate hemostasis could be achieved, allowing the endoscopic treatment to proceed safely. This case underscores that, even in FV deficiency with a negative inhibitor screen, testing for anti-FV IgG is essential for identifying hyperclearance-type AiFVD. Furthermore, ex vivo VET and TGT provided actionable assessments of hemostatic capacity and proved useful for guiding management in AiFVD.

Mature NK/T-cell lymphomas are a rare group of lymphoma subtypes, represented by extranodal NK/T-cell lymphoma (ENKL) and aggressive NK-cell leukemia (ANKL). Both subtypes are strongly associated with Epstein-Barr virus and show a high prevalence, particularly in East Asia and Central and South America. In Japan, ENKL currently accounts for approximately 1% of all malignant lymphomas, whereas ANKL is even rarer, accounting for approximately 0.1%. ENKL and ANKL share many clinical and pathological features. However, as evidence regarding differences in molecular biological characteristics, including genetic and chromosomal abnormalities, has gradually accumulated, they have been recognized as distinct disease entities since the 2001 WHO classification (3rd edition). Since the 2000s, the treatment of ENKL has markedly advanced with the development of non-anthracycline-based regimens. In Japan, RT-2/3DeVIC for localized-stage ENKL and SMILE for stage IV and relapsed/refractory ENKL were developed and remain the current standard of care. In contrast, because ANKL is a rare disease and reports on its treatment are limited, it is usually treated using strategies for advanced-stage ENKL. This review focuses on ENKL and ANKL, providing an overview of their disease characteristics, evolving treatment and prognosis, and future challenges and perspectives.

The introduction of tyrosine kinase inhibitors (TKIs) has made long-term survival achievable for patients with chronic myeloid leukemia (CML). In patients who achieve a deep molecular response, treatment-free remission (TFR), defined as sustained remission without molecular relapse after TKI discontinuation, has emerged as an important therapeutic goal. Accumulating evidence indicates that the establishment and maintenance of TFR are strongly influenced by host immunity, particularly immune surveillance mediated by natural killer (NK) cells. This review summarizes the clinical and immunological factors associated with successful TFR and discusses the potential of killer immunoglobulin-like receptor/human leukocyte antigen genetic polymorphisms as predictive biomarkers that regulate NK cell function and TFR outcomes. It also highlights immunomodulatory strategies using interferon-α, the feasibility of second attempts at TFR after initial discontinuation failure, and emerging therapeutic approaches targeting CML stem cells to achieve more durable disease control.

A 55-year-old man was diagnosed with chronic myeloid leukemia (CML) in the chronic phase and achieved a major molecular response (MMR) 3 months after dasatinib induction. Seven months later, he noticed left cervical lymphadenopathy, and 18-fluorodeoxyglucose positron emission tomography (FDG-PET) showed marked 18F-FDG uptake at the left cervical and supraclavicular lymph nodes. Left cervical lymph node biopsy showed reactive follicular hyperplasia and increased numbers of large B-cells between the follicles. Based on the clinical course, dasatinib-associated lymphadenopathy (DAL) was diagnosed. The treatment was switched to bosutinib, and lymph node enlargement resolved after 4 weeks. Lymphoproliferative disorder during CML treatment is a rare adverse event of dasatinib and is classified in the category of immune deficiency and dysregulation-associated LPDs (IDD-LPDs) in the WHO Classification of Tumours, 5th Edition. As more new drugs associated with IDD-LPDs are used across various indications, the scope of iatrogenic immune deficiency-related LPDs continues to broaden. Although the pathogenesis of DAL remains unclear, the immune dysregulation mechanisms of dasatinib may contribute. Since spontaneous remission can be expected with dasatinib discontinuation, observation should be considered even when differentiation from de novo lymphoma is difficult, and the decision to initiate chemotherapy should be made carefully.

Mitochondrial metabolism actively and precisely contributes to hematopoietic stem cell (HSC) fate determination by ensuring proper segregation of mitochondria and by modulating fatty acid oxidation (FAO) activity and mitochondrial NADPH during asymmetric (or symmetric) cell division. Elevated NADPH levels in HSCs promote anabolic processes, notably cholesterol biosynthesis, redirecting acetyl-CoA away from the TCA cycle toward cholesterol production, which in turn supports multiple downstream biosynthetic pathways essential for HSC maintenance. The NADPH-cholesterol axis facilitates the biogenesis of extracellular vesicles (EVs) to sustain HSC properties. EVs from diverse cell types can influence HSC survival and clonogenic potential, contributing to the maintenance of HSC capacity, including autocrine and paracrine signaling that further reinforces intrinsic regulatory circuits. Targeting the mechanisms that regulate the fate of HSCs remains a central aim of ongoing research in HSC-based therapies, including ex vivo expansion, genetic editing strategies, and the treatment of hematological malignancies, with the potential to enhance transplantation outcomes and patient recovery.

Growing evidence has revealed that mitochondria are not merely bioenergetic organelles but also critical regulators of inflammation, cell death, and stem cell maintenance. Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are myeloid malignancies that arise from hematopoietic stem and progenitor cells harboring genetic alterations; however, their fundamental disease phenotypes are distinct. Notably, hematopoietic stem and progenitor cells in MDS, which are characterized by chronic inflammation and ineffective hematopoiesis, exhibit excessive mitochondrial fragmentation independent of the underlying mutational profile. In contrast, AML, a malignancy driven primarily by uncontrolled proliferation, is associated with mitochondrial fusion and an increase in mitochondrial mass. These distinct mitochondrial dynamics appear to reflect disease-specific biological demands rather than incidental cellular abnormalities. This review focuses on the differences in mitochondrial dynamics and function between MDS and AML and discusses how these mitochondrial alterations contribute to the pathogenesis of myeloid neoplasms.

A 51-year-old woman with classical Hodgkin lymphoma refractory to multiple chemotherapy regimens, including an immune check inhibitor (ICI), was admitted to our hospital for autologous stem cell transplantation (auto-SCT). On day 7, she presented with a fever, skin rash, and elevated monocyte counts. We diagnosed engraftment syndrome (ES) and initiated corticosteroid therapy. Her symptoms resolved quickly, and we continued hydrocortisone until day 10. On day 11, she developed a fever, skin rash, and hypoxia, which we recognized as a relapse of ES. We started prednisolone at 0.5 mg/kg/day, leading to rapid symptom resolution of her symptoms, then we tapered the prednisolone on day 18. On day 19, she presented with hypotension and hypoxia, prompting us to increase the prednisolone dose to 1 mg/kg/day. Her symptoms resolved, and we gradually tapered the prednisolone dosage; she did not experience any further relapses of ES. Prior usage of ICIs has been reported to increase the risk of immune-related toxicity during allogeneic stem cell transplantation. Based on our experience, patients who have received ICIs before auto-SCT should also be closely monitored for immune-related toxicities in the early post-transplant period.

The introduction of tyrosine kinase inhibitors (TKIs) has greatly improved outcomes for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) undergoing allogeneic hematopoietic stem cell transplantation (HSCT). However, patients with measurable residual disease (MRD) positivity at the time of HSCT show a high relapse rate, making post-HSCT TKI administration a promising strategy. However, the indications, administration methods, and optimal duration of TKI therapy remain unclear. Retrospective studies from outside Japan have suggested that prophylactic TKIs may reduce relapse risk and improve survival. Although first- and second-generation TKIs demonstrate potential efficacy, tolerability issues persist. Ponatinib, a third-generation TKI, has shown promising results, especially in high-risk patients and those with the T315I mutation, although clinical evidence is limited due to small study populations. Although TKI administration after HSCT has generally demonstrated potential benefits, prospective trials are needed to provide robust evidence.

Venous thrombosis is initiated by endothelial cell activation triggered by reduced blood flow and venous stasis. Innate immune cells (neutrophils and monocytes) and platelets adhere to activated endothelial cells via P-selectin and von Willebrand factor multimers, respectively. Platelet activation involves integrin activation, P-selectin expression, and the release of ADP, polyphosphates, and soluble complement regulators. Neutrophils bind to the activated platelets and endothelial cells and release neutrophil extracellular traps. Activated monocytes express tissue factor. The interplay of these exacerbated immune and thrombotic events ultimately results in thrombosis, a process now referred to as immunothrombosis. Atypical hemolytic uremic syndrome, aHUS, is a thrombotic microangiopathy caused by uncontrolled activation of the alternative pathway of complement. Genetic analyses of Japanese patients with aHUS predominantly identified a unique gain-of-function C3 variant, p.Ile1157Thr. Patients with this variant showed favorable outcomes despite frequent relapses.

Pola-R-CHP is becoming a standard therapy for DLBCL. We retrospectively compared the incidence of chemotherapy-induced peripheral neuropathy (CIPN)-related events (numbness and constipation) assessed by the nursing staff at our ambulatory therapy center (ATC) between these two regimens. Patients with DLBCL who received the 2nd (or 3rd) to 6th cycle of either regimen at ATC from Jan 2020 to Dec 2024 were analyzed. Twenty-six patients received Pola-R-CHP, and 35 received R-CHOP. Whereas 92% of patients treated with Pola-R-CHP received 100% of the planned polatuzumab dose, only 58% of those treated with R-CHOP received 100% of the planned vincristine dose. The incidence of numbness increased with the number of cycles and was more frequent with R-CHOP than with Pola-R-CHOP. The difference was most significant at the 4th cycle. In contrast, the incidence of constipation was comparable between the two regimens. Pola-R-CHP may be associated with a lower incidence of CIPN compared with R-CHOP. The high percentage of patients receiving the planned doses of polatuzumab further indicates that Pola-R-CHP could achieve better dose intensity with a lower risk of CIPN.

Chimeric antigen receptor (CAR)-natural killer (NK) cell therapy has attracted increasing attention in recent clinical studies as a promising alternative to CAR-T cell therapy. CAR-NK cells offer several advantages, including a markedly lower risk of severe cytokine release syndrome and neurotoxicity, as well as the feasibility of developing off-the-shelf products due to the minimal potential for graft-versus-host disease. However, NK cells constitute only a small fraction of peripheral blood and have a relatively short lifespan, raising concerns about the durability of therapeutic efficacy. Recent advances have highlighted that, as in T-cell biology, the acquisition of memory-like phenotypes is critical for sustaining NK-cell function. Strategies to enhance NK-cell persistence, such as cytokine-induced memory-like NK cells and cytokine-engineered NK cells, have progressed rapidly. In parallel, alternative cellular sources, including umbilical cord blood-derived and induced pluripotent stem cell (iPSC)-derived NK cells, are being actively developed, enabling standardized manufacturing and large-scale production of uniform off-the-shelf products. In this review, we summarize the latest developments in CAR-NK cell research and discuss how genetic modulation of NK-cell differentiation pathways may contribute to the establishment of next-generation CAR-NK cell therapies with improved durability and antitumor efficacy.

Allogeneic hematopoietic cell transplantation (allo-HCT) offers curative potential for acute myeloid leukemia (AML) through its graft-versus-leukemia (GVL) effects, but this same alloreactivity can cause graft-versus-host disease (GVHD), making separation of these effects a central challenge. Proposed mechanisms of post-allo-HCT immune evasion by AML cells include HLA loss via 6p loss of heterozygosity, epigenetic HLA class II silencing, upregulation of immune-suppressive ligands on AML cells, and persistence of leukemia stem cells (LSCs) after transplantation. In addition, donor T-cell exhaustion and an immunosuppressive tumor microenvironment may contribute to post-transplant relapse. We summarize emerging strategies to ameliorate GVHD without attenuating GVL, including intensified local therapy, selective trafficking blockade, S1PR modulators that limit pathogenic T-cell migration, and tissue-protective agents that enhance epithelial regeneration and prevent the establishment of inflammatory memory. We also outline maintenance approaches designed to restore leukemia immunogenicity without exacerbating GVHD, including inhibition of MDM2, EZH2, menin, and FLT3-ITD; IFN-α-based immune modulation; hypomethylating agents; and minor histocompatibility antigen-directed vaccines intended to selectively elicit anti-leukemia alloresponses. Finally, optimization of calcineurin inhibitor timing in post-transplant cyclophosphamide-based allo-HCT may help balance GVHD prevention and GVL preservation. Collectively, these growing mechanistic and clinical insights are making functional separation of GVL from GVHD increasingly feasible.