[Rinsho ketsueki] The Japanese journal of clinical hematology最新文献

Background: Autologous peripheral blood stem cell (PBSC) collection can be challenging in pediatric patients with solid tumors following intensive chemotherapy. Plerixafor, a hematopoietic stem cell mobilizing agent, has been increasingly used in such cases; however, reports from Japan remain limited.

Methods: We conducted a single-center retrospective observational study to assess the efficacy and safety of plerixafor. Eight pediatric patients with solid tumors (nine mobilization attempts) who received plerixafor at our institution between 2015 and 2024 were included in the analysis.

Results: The median CD34-positive cell count collected was 10.8×10⁶/kg. In all cases, the target cell dose required for autologous transplantation was successfully achieved. Adverse events were mild, including transient headache, elevated liver enzymes, and diarrhea. No severe adverse events were observed.

Conclusion: Plerixafor was effective and well tolerated in pediatric patients with solid tumors, regardless of disease status (newly diagnosed or relapsed). These findings support its potential as a valuable stem cell mobilization option in pediatric transplant settings in Japan.

A 68-year-old man was diagnosed with multiple myeloma complicated by acute renal injury due to cast nephropathy in August 2018. Although induction therapy with bortezomib and dexamethasone achieved a hematological response, he remained dependent on hemodialysis. Extramedullary lesions developed in April 2024 during fifth-line treatment with daratumumab, pomalidomide, and dexamethasone. In July 2024, elranatamab was initiated on non-dialysis days with standard premedication and without dose adjustment. Elranatamab was well tolerated, with adverse effects limited to grade 1 cytokine release syndrome during the first cycle, and no immune-effector cell-associated neurotoxicity syndrome. PET/CT after 4 cycles demonstrated extramedullary mass regression. Elranatamab was continued through 8 cycles without significant adverse events, with sustained clinical response. Although data on bispecific antibodies in patients on hemodialysis are limited, our case demonstrates that elranatamab can be administered safely and effectively in this population. Consequently, elranatamab could be a feasible and effective therapeutic option for patients with multiple myeloma on hemodialysis.

This review focuses on the findings of the JSH-MPN-R18 study, a retrospective analysis of 596 patients with polycythemia vera (PV) and 1,152 patients with of essential thrombocythemia (ET). Among the four sub-analyses conducted, one focused on adolescents and young adults (AYA population) with PV and ET, demonstrating that the characteristics of thrombotic events in young Japanese patients differ from those observed in Western populations. Specifically, the proportion of venous thrombosis among all thrombotic events was lower in the Japanese AYA population compared to their Western counterparts. Additionally, an analysis focusing on absolute neutrophil count and neutrophil ratio at diagnosis revealed their utility as predictors of thrombotic events, particularly in low-risk ET patients. These findings should contribute to the development of appropriate management strategies for young PV and ET patients in Japan, as well as to the enhancement of thrombotic risk stratification for PV and ET patients overall.

Combination of immunosuppressive therapy (IST) and thrombopoietin receptor agonists has revolutionized the treatment of aplastic anemia. In this study, 18 patients with eltrombopag (EPAG)-refractory and intolerant AA, including 16 with severe AA, were switched from EPAG to romiplostim and continued with romiplostim for at least three months. Of the 18 patients (7 refractory and 11 intolerant to EPAG), 13 (72%) achieved a response, with a therapeutic response in at least one lineage within three months, and nine patients (50%) showed a trilineage response. All three patients who started romiplostim over three years after diagnosis failed to respond to romiplostim. In three of the four patients with adequate response to romiplostim, interruption of romiplostim resulted in relapsed thrombocytopenia, and early resumption of romiplostim resulted in recovered blood counts. These results suggest that romiplostim may achieve a response in IST+EPAG refractory/intolerant SAA.

We compared the International Prognostic Scoring System-Revised (IPSS-R) to the International Prognostic Scoring System-Molecular (IPSS-M) in 30 patients with myelodysplastic neoplasms (MDS) newly diagnosed at our institution from January 2021 to February 2023. Molecular analysis was performed by myeloid panel. The median age was 66 years (range: 35-80), and classifications were MDS-LB (n=18), MDS IB-1 (n=1), MDS IB-2 (n=2), MDS-SF3B1 (n=2), MDS-biTP53 (n=1), and MN-pCT (n=6). Each patient had 0 to 8 (median 1) mutations. The most frequently detected mutation was the TET2 mutation, and others detected in>5 patients were U2AF1, TP53, and RUNX1 mutations. IPSS-R classification indicated that 2, 14, 5, 3, and 6 patients were very low, low, intermediate (Int), high, and very high risk, respectively, whereas the IPSS-M classification indicated that 3, 9, 7, 2, 4, and 5 cases were very low, low, moderate-low (ML), moderate-high (MH), high, and very high risk, respectively. Considering IPSS-M ML and MH as the equivalent to IPSS-R Int, 13 (43%) patients had a different risk level in the IPSS-M compared to the IPSS-R. One patient was rated low-risk by IPSS-R, but reclassified as high risk by IPSS-M. It is important to be mindful of this potential for significant discrepancies between risk assessments using IPSS-R and IPSS-M in some cases when making treatment decisions.

In vivo expansion and long-term maintenance of CAR-T cells are considered to be the hallmark of treatment success after CD19 CAR-T cell therapy. Genome-wide CRISPR screening has emerged as a powerful tool for large-scale gene screens. Genome-wide CRISPR screening revealed that CUL5 gene knockout (KO) improved the proliferation of CD19 CAR-T cells. CUL5KO improved not only the proliferation but also the effector function of CAR-T cells. The JAK-STAT pathway was upregulated in CUL5KO CAR-T cells, and CUL5 was associated with the degradation of JAK3 upon activation through IL-2 signaling. CUL5KO CD19 CAR-T cells efficiently suppressed in vivo tumor progression as compared to control CD19 CAR-T cells.

Paroxysmal nocturnal hemoglobinuria (PNH) is a hematopoietic stem cell disease that results from clonal expansion of hematopoietic stem cells with gene mutations. Patients with PNH are known to have an increased risk of developing myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). We report a case of a 42-year-old woman diagnosed with AML 13 years after a diagnosis of PNH. Gene mutations associated with MDS were detected. She did not achieve complete remission (CR) after induction therapy with idarubicin and cytarabine. Unrelated bone marrow transplantation was performed with a myeloablative conditioning regimen with cyclophosphamide (120 mg/kg) and total body irradiation (12 Gy). Ravulizumab was administered until 47 days after transplantation. She achieved CR after transplantation with complete donor engraftment. The transplantation was successful without severe complications such as graft-versus-host disease or sinusoidal obstruction syndrome. Further accumulation of cases is necessary to determine the efficacy and safety of anti-complement inhibitors in allogeneic hematopoietic stem cell transplantation.

Aplastic anemia (AA) is a rare hematologic disorder characterized by bone marrow hypoplasia and pancytopenia, and is classified into idiopathic and secondary forms. Idiopathic AA is primarily treated with immunosuppressive therapy (IST), thrombopoietin receptor agonists (TPO-RAs), and hematopoietic stem cell transplantation (HSCT). Cyclosporine (CsA) monotherapy is recommended for patients who have mild disease or are moderately transfusion-independent, whereas the combination of anti-thymocyte globulin (ATG) and CsA is the standard treatment for severe disease. In 2023, equine ATG (ATGAM^®) was approved in Japan, expanding the options for IST. TPO-RA options for combination therapy with IST now include romiplostim in addition to eltrombopag, and studies have demonstrated the efficacy of triple combination therapy with ATG, CsA, and a TPO-RA has been demonstrated. In the context of HSCT, HLA-haploidentical transplantation using post-transplant cyclophosphamide is increasingly being considered as an option for patients without an HLA-matched donor due to its improved safety and efficacy. This review provides a comprehensive overview of the latest advances in AA treatment, including novel therapeutic strategies, and discusses future therapeutic directions to further improve patient outcomes.

MLL gene rearrangements cause malignant leukemia, and continue to pose challenges for both patients and their clinicians. Gene rearrangements result in fusion of MLL with more than 80 different partner genes, whose protein products constitutively activate MLL-target genes such as HOXA9 and MEIS1, thereby transforming hematopoietic progenitors into leukemia cells. Interactome analysis identified MENIN as a common associated factor for both MLL fusions and wild-type MLL. Domain mapping analysis of MLL fusion identified the MENIN binding motif and the CXXC domain as the crucial structures for leukemic transformation. The CXXC domain mediates interaction with unmethylated CpGs, which are clustered in the promoter regions. MLL-MENIN interaction leads to further association with LEDGF, which contains a PWWP domain that binds to di/tri-methylated histone H3 K36 (H3K36me2/3). The PWWP and CXXC domains confer stable binding to CpG-rich promoters containing H3K36me2/3 marks so that MLL fusion proteins are able to recognize their target genes. Thus, the protein complex assembly of MENIN, MLL fusion, and LEDGF is the critical event required for leukemia induction, which provides opportunities for drug-mediated inhibition of the MLL fusion protein complex. Small compounds that interfere with MENIN-MLL interaction have been developed by several pharmaceutical companies. Some are now in clinical trials, and one has even obtained FDA approval.