Hyperammonemic encephalopathy is a rare but often fatal complication in patients with hematological malignancies receiving intensive therapy, and its underlying mechanism is often unclear. We report the case of a woman in her 40 s with acute myeloid leukemia who developed fulminant nonhepatic hyperammonemia during high-dose cytarabine consolidation in association with previously unrecognized partial ornithine transcarbamylase (OTC) deficiency. On day 5 of consolidation, she developed rapidly progressive altered consciousness with marked hyperammonemia, preserved hepatic and renal function, and no evidence of active sepsis. Brain magnetic resonance imaging showed cortical abnormalities more consistent with metabolic encephalopathy than cytarabine-associated neurotoxicity or posterior reversible encephalopathy syndrome. Despite supportive therapy, serum ammonia increased further, followed by seizures, diffuse cerebral edema, and death. Metabolic evaluation suggested a urea cycle disorder, and genetic testing identified a heterozygous pathogenic OTC variant, indicating an underlying inherited metabolic predisposition. Reported adult cases of severe nonhepatic hyperammonemia in hematological malignancies have largely been considered idiopathic or infection-related, whereas genetically confirmed urea cycle disorders remain rare. This case expands the spectrum of chemotherapy-associated nonhepatic hyperammonemia and suggests that occult inherited metabolic predisposition may contribute to its pathogenesis, highlighting the importance of early recognition of hyperammonemia in unexplained encephalopathy during intensive chemotherapy.
Autologous CAR-T therapy has achieved notable success in B-cell malignancies, yet its broader application is constrained by high costs, protracted manufacturing timelines, and severe toxicities, including cytokine release syndrome (CRS) and graft-versus-host disease (GVHD). Natural killer (NK) cells offer a compelling off-the-shelf alternative, owing to their major histocompatibility complex-independent cytotoxicity and negligible GVHD risk. Among allogeneic NK sources, umbilical cord blood (UCB)-derived CAR-NK cells are distinguished by a CD56brightCD16−/dim phenotype, extended telomeres, and a transcriptional profile that facilitates >1,000-fold ex vivo expansion. These properties have supported extensive preclinical evaluation and early clinical translation. Preclinical studies have documented antitumor activity against CD19, CD123, PD-L1, ErbB3, and mesothelin, without evidence of CRS. In a landmark phase I/II trial (NCT03056339), 7 of 11 patients (64
Cellular immunotherapy has substantially changed the treatment of B-cell leukemias, lymphomas, and multiple myeloma. The success of chimeric antigen receptor (CAR)-T cell therapy in these diseases has been supported by suitable target antigens, including CD19 in B-cell malignancies and B-cell maturation antigen in multiple myeloma. In contrast, comparable progress has not yet been achieved in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), in part because an optimal target with clinically manageable on-target effects on normal cells has not been identified. Nevertheless, identification of an appropriate target could enable major therapeutic advances with CAR-T cell therapy in myeloid malignancies. To further harness the potential of cellular immunotherapy in AML/MDS, a multifaceted approach may be required. In parallel with CAR-T cell development, CAR-NK cells, T-cell receptor-engineered T cells, NK cells and other innate immune approaches are actively explored, while allogeneic hematopoietic stem cell transplantation remains an established form of cellular immunotherapy for AML/MDS. These approaches may be developed in parallel and, where appropriate, integrated with molecularly targeted and other pharmacologic therapies. This issue of Progress in Hematology reviews these emerging directions and their potential to expand cellular therapy for AML/MDS.
Current therapies for acute graft-versus-host disease (aGVHD) are limited by suboptimal efficacy or excessive immunosuppression. In this retrospective, exploratory, hypothesis-generating case series, we evaluated belumosudil, a selective Rho-associated coiled-coil kinase 2 inhibitor, in eight patients with aGVHD. All patients had gastrointestinal involvement, and 62.5
Quantitative Epstein–Barr virus (EBV)-DNA measurement is used in EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH), but the optimal sample type for risk assessment and monitoring remains unclear. We retrospectively analyzed 71 pediatric patients with newly diagnosed EBV-HLH from a Japanese multicenter cohort between April 2019 and May 2025. EBV-DNA loads in plasma, white blood cells, and T- and B-cell fractions were centrally quantified by real-time polymerase chain reaction. Patients were classified into remission and refractory/recurrent (R/R) groups. Baseline plasma EBV-DNA was higher in the R/R group than in the remission group (median, 5.762 vs. 5.366 log10 copies/mL; p = 0.024), whereas cellular EBV-DNA loads did not differ. A plasma cutoff of 5.560 log10 copies/mL showed modest discrimination for R/R disease (area under the curve, 0.667). Predominant EBV-detected cell fraction and baseline T-cell receptor (TCR) clonality were not associated with R/R, but TCR clonality at 2 weeks was more frequent in the R/R group (44.4
Primary and secondary central nervous system lymphomas (PCNSL and SCNSL, respectively) are aggressive non-Hodgkin lymphomas with high relapse risk. Methotrexate rarely achieves durable remission, necessitating combination therapy or consolidation. Although high-dose busulfan and thiotepa (BuTT) conditioning followed by autologous stem cell transplantation (ASCT) is a promising consolidation strategy, the optimal timing and real-world outcomes of ASCT remain unclear. We retrospectively analyzed 12 patients (eight with PCNSL and four with SCNSL) treated with BuTT/ASCT at a single center between 2019 and 2024. Nine patients underwent upfront ASCT shortly after achieving complete remission with rituximab, methotrexate, procarbazine, and vincristine and remained in remission at a median follow-up of 681 days (range, 147–1322 days). Three patients (two with PCNSL and one with SCNSL) who underwent salvage ASCT following multiple prior therapies experienced early relapse (51–125 days post-ASCT) and died of their disease. BuTT/ASCT is highly effective when administered promptly after remission, whereas salvage ASCT after multiple therapies is associated with poor outcomes. Timely clinical decision-making and upfront consolidation may be key to optimizing the therapeutic benefits of ASCT in CNSL, although further validation is warranted.
Graft-versus-host disease (GVHD) increases the risk of invasive fungal infection (IFI) after allogeneic hematopoietic cell transplantation (HCT). This randomized phase II selection trial evaluated protocol-defined prophylaxis success and safety of voriconazole (VRCZ) and itraconazole (ITCZ) prophylaxis in patients with GVHD. Allogeneic HCT recipients with grade II-IV acute GVHD or chronic GVHD requiring systemic corticosteroids were randomized to receive VRCZ or ITCZ for 60 days. Success was defined as survival without protocol-defined proven/probable IFI through day 60 and receipt of study drug for at least 48 days. Sixty-six patients (33 per group) were randomized. The success rate was 88
Minimal/measurable residual disease (MRD) analysis using multiparametric flow cytometry (MFC-MRD) is essential for therapy stratification in acute leukemia; however, conventional analysis is limited by analyst-dependent variability and complex manual gating. Although machine learning approaches have been proposed, their clinical implementation requires large reference datasets and standardized antibody panels. Therefore, we evaluated the feasibility of unsupervised dimensionality reduction as a practical reference-free strategy for single-sample MFC-MRD analysis. We retrospectively analyzed 58 bone marrow specimens from 32 patients with acute myeloid leukemia or B-lineage acute lymphoblastic leukemia with < 5
Disorders of intracellular cobalamin metabolism are rare but treatable conditions that mimic bone marrow failure syndromes. An eight-month-old male presented with macrocytic anemia, reticulocytopenia, neutropenia, infections, failure to thrive, and developmental delay. Bone marrow examination showed hypocellularity with paucity of myeloid precursors, dysplastic megakaryocytes, fibrosis, and cytoplasmic vacuolization of hematopoietic precursors. Whole-exome-sequencing identified a homozygous LMBRD1 variant (c.907C > A; p.Pro303Thr), confirmed by parental segregation. Treatment with parenteral hydroxocobalamin resulted in partial improvement. LMBRD1-related cblF deficiency is an exceptionally rare but treatable mimic of inherited bone marrow failure. Early recognition enables targeted therapy.
XPO1/CRM1 (also known as Exportin-1) is best known as a RanGTP-dependent nuclear export receptor and has been explored as a therapeutic target in various diseases, including acute myeloid leukemia (AML). Emerging evidence, however, indicates that XPO1 is also detectable on chromatin at active regulatory regions, including the HOX clusters and the MEIS1 locus—key transcriptional nodes in multiple AML subtypes. Recent studies support a “pre-bound XPO1 platform” model in which genetically diverse leukemia drivers, such as nucleoporin (NUP98/NUP214) fusions and mutant NPM1 (NPM1c), are recruited to these loci via phenylalanine–glycine (FG) repeat–XPO1 or nuclear export signal (NES)–XPO1 interactions, coupled with partner-encoded chromatin contacts. This dual engagement may stabilize locus-restricted assemblies and lower the threshold for liquid–liquid phase separation (LLPS)-linked condensate formation that sustains aberrant HOX/MEIS-driven transcriptional programs. By reframing XPO1 from a nuclear export receptor to a chromatin-associated interaction hub, this perspective provides a framework for understanding transcriptionally addicted AML subtypes and highlights opportunities to selectively target chromatin-associated XPO1 functions in HOX/MEIS-driven AML.
Bendamustine, etoposide, and busulfan (BEB) is a conditioning regimen used for autologous stem-cell transplantation (ASCT) in non-Hodgkin lymphoma (NHL). We investigated whether addition of melphalan (BEBM) could enhance this regimen. BEBM with melphalan at 50, 70, or 100 mg/m2 was assessed in 12 high-risk or relapsed/refractory NHL patients (10 in complete response before ASCT) in a phase I 3 + 3 dose-escalation study. The primary endpoint was dose-limiting toxicity (DLT). All patients experienced grade ≥ 3 hematologic toxicities. Cohort 1 (50 mg/m2) exhibited no grade ≥ 3 non-hematologic adverse events (AEs). Cohort 2 (70 mg/m2, n = 6) exhibited two DLTs (grade 4 mucositis; one sepsis-related death). Cohort 3 (100 mg/m2, n = 1) was prematurely terminated and had no severe non-hematologic AEs. The 3-month complete response rate was 90.9
Immune thrombocytopenia (ITP) is an acquired autoimmune disease characterized by increased platelet destruction and thrombocytopenia. Fostamatinib inhibits spleen tyrosine kinase and suppresses platelet destruction. However, clinical evidence of its efficacy in Japanese patients with ITP remains limited. In this study, we retrospectively evaluated the clinical outcomes of fostamatinib, with or without thrombopoietin receptor agonists (TPO-RAs), at a single center in Japan. The study included 11 patients. At week 1, all 3 evaluable patients (100.0
The development of several complement-inhibiting medicines has been a major advance in the management of paroxysmal nocturnal hemoglobinuria (PNH), a rare and life-threatening disease. Patients now have a life expectancy close to that of the general population, and the quality of life of most patients has improved substantially. In addition, by targeting either the proximal or the terminal complement pathway, we have also been able to improve our understanding of the pathophysiology of PNH. Within the landscape of this rather spectacular progress, a major drawback has been the rather astronomic price of all of these medicines: This means, in practice, that in many countries they are not available at all, and a conservative estimate is that at least one-half of the PNH patients in the world have no access to complement inhibitors. It is urgent to correct this inequality that is also an injustice. Very recently, the Max Foundation, a global nonprofit organization, has announced that it will collaborate with a pharmaceutical company to make 'innovative treatment for PNH' available in many countries: We may now hope that other companies will join such collaborations.
Primary central nervous system lymphoma (PCNSL) is a rare extranodal lymphoma, with diffuse large B cell lymphoma accounting for most cases. T cell variants are uncommon and associated with poor outcomes. We report a case of primary CNS T cell lymphoma with simultaneous brain and spinal cord involvement. A 37-year-old Japanese man presented with impaired consciousness, and brain magnetic resonance imaging revealed multiple contrast-enhancing parenchymal lesions. Histopathological examination of a brain biopsy specimen demonstrated medium- to large-sized atypical lymphoid cells, leading to a diagnosis of peripheral T cell lymphoma, not otherwise specified (PTCL-NOS). Comprehensive systemic evaluation showed no extracranial disease; however, contrast-enhanced spinal magnetic resonance imaging revealed extensive lesions from the cervical spinal cord to the thoracic spinal cord. Next-generation sequencing analysis identified a mutation in SETD2, possibly contributing to the aggressive disease behavior. The patient received methotrexate, procarbazine, and vincristine as first-line therapy and achieved an initial radiological complete response. However, rapid disease relapse occurred with newly developed lesions in the pineal gland and cranial nerves, and the patient died shortly after initiation of consolidation therapy. This case highlights the aggressive clinical course of primary CNS T cell lymphoma with spinal cord involvement and underscores the importance of molecular genetic profiling in this rare entity.
Relapsed or refractory B-cell acute lymphoblastic leukemia (r/r B-ALL) remains challenging, and allogeneic hematopoietic cell transplantation (allo-HCT) is often the only curative option. Inotuzumab ozogamicin (InO) has demonstrated high remission rates in salvage settings, but concerns regarding sinusoidal obstruction syndrome (SOS) have limited its use as a bridge to transplantation. We retrospectively evaluated post-transplant outcomes following an InO-based salvage strategy in adults with r/r B-ALL who underwent allo-HCT at a single center in Japan. Eighty-one patients were included (median age, 50 years). Twenty patients received InO before transplantation, while 61 patients previously treated with conventional chemotherapy served as a historical reference. Sequential immunotherapy was common in the InO group, with most receiving blinatumomab. The CR/CRi rate before HCT was higher in the InO group. With a median follow-up of 48 months, the estimated 3-year overall survival and disease-free survival in the InO group were 55.3
Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic infection of the central nervous system (CNS) observed in immunocompromised individuals. We retrospectively evaluated the clinical courses of PML in patients with hematological malignancies at North Japan Hematology Study Group institutions, using patients with human immunodeficiency virus (HIV) infection as a reference. Eight PML patients had hematological malignancies and 9 had HIV infection. CD4 + T cell counts were markedly low in patients with hematological malignancies (median 168/μl, range 48.4–330/μl) and did not differ significantly from those in patients with HIV infection (median 28/μl, range 8–225.4/μl). IgG levels were significantly lower in patients with hematological malignancies (median 643.5 mg/dL, range 205–2478 mg/dL) than in patients with with HIV infection (median 1691.5 mg/dL, range 1304–3014 mg/dL) (p < 0.01). Almost all patients with hematological malignancies died after progression of PML (median time from onset to death, 136 days). In contrast, seven patients with HIV infection were alive at the end of follow-up. The incidence of PML in patients with hematological malignancies may increase with the introduction of new antibody drugs and cellular therapies in future. Considering the poor prognosis, greater caution is warranted regarding this serious complication.
Immune effector cell-associated neurotoxicity syndrome (ICANS) is a serious early adverse event of chimeric antigen receptor T (CAR-T) cell therapy. ICANS typically occurs concurrently with or follows cytokine release syndrome (CRS), suggesting CRS can be considered the primary risk factor for ICANS onset. Therefore, CRS characteristics in an individual patient may predict their risk for subsequently developing ICANS. We analyzed 154 patients with B cell lymphoma treated with commercial CAR-T products between 2020 and 2024; 38 patients (24.7
Myeloproliferative neoplasms (MPNs) are associated with pulmonary hypertension (PH). Recent studies have demonstrated associations between PH and adverse cardiovascular outcomes and MPN disease progression. However, risk factors for development of PH and the pathophysiology of PH in MPNs remain unclear. We conducted an analysis of a multicenter retrospective cohort of patients with MPN with ≥ 2 transthoracic echocardiograms (TTEs) after MPN diagnosis. Patients with low probability of PH on the first TTE after MPN diagnosis were included. Backward stepwise Cox proportional hazards regression modeling was performed to identify risk factors for high probability of PH on subsequent TTE. Impact of incident high probability of PH on subsequent TTE, on major adverse cardiovascular event (MACE), hematologic progression, and death was examined using multivariable competing risk or Cox proportional hazards regression. After backward stepwise modeling, age at MPN, non-JAK2 driver mutations, polycythemia vera (PV) and myelofibrosis (versus essential thrombocythemia), leukocytosis, and elevated HFA-PEFF score were associated with increased risk of incident high probability of PH. Incident high probability of PH was associated with increased risk of MACE, hematologic progression, and death. Further studies are needed to evaluate the role of prospective screening for PH in patients with MPNs and further delineate pathophysiology of PH in patients with MPNs.
