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.

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.

We describe a unique case of SAMD9-associated myelodysplastic syndrome (MDS) with monosomy 7 that evolved over 16 years into BCR::ABL1-positive acute myeloid leukemia (AML) and subsequently manifested as B-cell acute lymphoblastic leukemia (B-ALL). Genomic analysis at AML diagnosis revealed a germline SAMD9 mutation together with somatic RUNX1 and PPM1D mutations, supporting stepwise clonal evolution, with BCR::ABL1 emerging as a late leukemogenic event. The dominant leukemic population at AML onset showed myeloid morphology and immunophenotype, whereas a minor CD19[+]CD10[+] population was already detectable. Following venetoclax and azacitidine therapy, the dominant leukemic phenotype shifted to B-ALL while retaining BCR::ABL1 positivity. Detection of the Philadelphia chromosome in mature neutrophils at both AML onset and ALL relapse supported multilineage involvement of a multipotent BCR::ABL1-positive clone. Ponatinib achieved disease control. This case highlights late acquisition of BCR::ABL1 during SAMD9-associated clonal evolution and therapy-driven phenotypic shift within a shared Ph-positive leukemic stem-cell hierarchy.

Fostamatinib was approved in Japan in December 2022 for primary immune thrombocytopenia (ITP). Given the limited clinical trial data, post-marketing surveillance (PMS) was conducted in Japan to collect safety and effectiveness data for fostamatinib. This interim analysis of PMS collected data between April 2023 and April 2025. Most of the 489 patients in the safety analysis set had received ≥ 3 treatment lines. Approximately 70% used fostamatinib with glucocorticoids and/or a thrombopoietin receptor agonist. Adverse drug reactions (ADRs) were reported in 49.5% (serious ADRs in 8.6%). The most common ADRs were diarrhoea (20.0%), hypertension (15.7%), hepatic function abnormal (9.6%), liver disorders (4.9%), and neutrophil count decreased (4.1%). Safety analysis revealed no major differences in the frequency of ADRs, including those of special interest, by combination treatment(s). Median platelet count increased at 2 weeks of treatment and remained above 50,000/μL thereafter, regardless of the ITP treatment combination. Further, complete response (platelet count ≥ 100,000/μL) was observed in 135 of 309 patients at 3 months and 128 of 241 patients at 6 months under continuous fostamatinib use. The results of this real-world PMS revealed no new safety concerns and support the effectiveness of fostamatinib in patients with primary ITP.

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.

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% and 56.3%, respectively. The favorable outcomes associated with InO-based therapy were more evident in Philadelphia chromosome-negative disease. SOS occurred more frequently in the InO group but was generally mild. These findings provide real-world evidence supporting the feasibility of an InO-based sequential salvage strategy as a bridge to allo-HCT in patients with r/r B-ALL.

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%) developed ICANS after CRS. The cohort was split into a derivation set and a validation set. In the derivation cohort, univariate analysis identified two CRS-related factors strongly associated with ICANS: CRS onset within 24h and grade 2-4 CRS by day 3. Using these two variables, we created a simple predictive model that stratified patients into high-, intermediate-, and low-risk groups, with ICANS incidences of 47.4%, 31.0%, and 8.2%, respectively. The validation cohort confirmed this trend. These findings suggest that early CRS characteristics provide a practical, clinically applicable method for estimating ICANS risk and may support timely management decisions in CAR-T therapy.

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.

Clonal hematopoiesis of indeterminate potential (CHIP) is the presence of hematologic malignancy-associated somatic mutations in patients without hematologic malignancies. In multiple myeloma (MM), the implications of CHIP on chimeric antigen receptor (CAR)-T cell outcomes and toxicities have yet to be fully explored. In a retrospective study at UCLA, we explored the association between CHIP and clinical outcomes of 68 adult patients with MM (31% with CHIP mutations) who were undergoing CAR-T cell therapy from 6/1/2021 to 12/31/2024. The overall (95% CHIP vs. 93% no CHIP; p = 0.99) and complete response rates (81% CHIP vs. 67% no CHIP; p = 0.15) did not differ by CHIP status. Similarly, CHIP mutations did not impact progression-free survival (HR 0.83; 95% CI 0.38-1.83; p = 0.65) or overall survival (HR 0.76; 95% CI 0.24-2.45; p = 0.65). Patients with CHIP mutations were more likely to develop CRS (100% vs. 70%; p = 0.007); however, there was no difference in the incidence of ICANS (33% CHIP vs. 17% no CHIP, p = 0.20). Our results show that although CHIP did not negatively influence response rate, complete response rate, survival, or progression-free survival in MM patients after CAR-T cell therapy, it did confer a higher risk of inflammatory response with increased frequency and grade of CRS.

Allogeneic hematopoietic stem cell transplantation remains the standard treatment for various hematologic genetic disorders resulting from single or multiple genes. However, this strategy is hindered by two main problems: failure to find a matching donor and the risk of graft-versus-host disease (GVHD) after transplantation. Recent advances in gene editing, particularly nucleases exemplified by clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) and related derivative tools, have overcome the limitations posed by the poor specificity of traditional gene modification techniques. A robust groundwork has been established for developing efficient, precise, and diverse gene editing strategies, facilitating the clinical application of ex vivo modified autologous hematopoietic stem cells (HSCs). In contrast, autologous HSC transplantation does not have the previously mentioned problems associated with allogeneic transplantation. Consequently, gene editing involving ex vivo genetic modification of HSCs and subsequent reinfusion in a single patient has emerged, with related research progressing from investigation into fundamental mechanisms and proof-of-concept studies to clinical trials.

The arterial occlusive events (AOEs) associated with ponatinib are dose-dependent. Although the phase II OPTIC trial showed that reducing the dose to 15 mg daily (QD) after achieving a response provided an optimal benefit-risk profile, this has not been adequately verified using plasma drug concentrations data. A 66-year-old woman with chronic-phase chronic myeloid leukemia (CP-CML) was switched to ponatinib because of nilotinib-induced grade 3 thrombocytopenia. For safety, ponatinib was initiated at 15 mg every other day (Q2D) and gradually increased to 45 mg QD. A major molecular response (MMR) was achieved 30.6 months after starting ponatinib. The dose was then reduced to 15 mg QD to mitigate cardiovascular risks, and the MMR was successfully sustained for approximately 2 years (21.2 months) at this reduced dose. The total overall observation period was more than 5 years (65.2 months). A strong correlation was observed between the ponatinib dose and plasma trough concentrations (R2 = 0.8132). Although 30 mg QD was required to reach the target concentration for suppressing resistant clones (23 ng/mL), MMR was sustained at 15 mg QD, with a trough level of 14.1 ng/mL. Once the tumor burden is significantly reduced, lower concentrations of ponatinib may be sufficient to maintain the molecular response.