In acute myeloid leukemia (AML), EVI1 rearrangement represented by inv(3)(q21q26) or t(3;3)(q21;q26) causes EVI1 overexpression via structural rearrangement of an enhancer, and confers poor prognosis. My colleagues and I performed a mutational analysis of EVI1-rearranged myeloid neoplasms and identified SF3B1, a core RNA splicing factor, as the most commonly co-mutated gene. Indeed, latent leukemia development in transgenic mice bearing the humanized inv(3)(q21q26) allele was significantly accelerated by co-occurrence of Sf3b1 mutation. Intriguingly, we found that this SF3B1 mutant induced mis-splicing of EVI1 itself, which generated an aberrant EVI1 isoform with in-frame insertion of 6 amino acids near the DNA-binding domain of EVI1. This aberrant EVI1 isoform exhibited DNA-binding activity different from wild-type EVI1 and significantly enhanced the self-renewal capacity of murine hematopoietic stem cells. We also identified the cryptic branch point and exonic splicing enhancer required for this EVI1 mis-splicing induced by the SF3B1 mutant. These data provide a basis for further elucidation of the molecular mechanism and potential therapeutic candidates for EVI1-rearranged AML.

A 46-year-old man was diagnosed with chronic myeloid leukemia (CML) in chronic phase. He was treated with imatinib, nilotinib, and dasatinib, but failed to achieve a complete cytogenetic response (CCyR). After tyrosine kinase inhibitor therapy, F317L BCR-ABL1 kinase domain mutation was detected. At age 66, the patient started ponatinib (PON) at 45 mg/day, and achieved CCyR within three months. Subsequently, PON was tapered to 15 mg once weekly due to arterial-occlusive events. PON was discontinued after a 3-year deep molecular response (≥ MR^4.5). However, the patient lost MR^4.0 within two months, and PON (15 mg once weekly) was restarted. He achieved MR^4.0 again within one month, and then a deeper molecular response (MR^5.0) after starting dialysis therapy at the same PON dose. The trough value of PON (15 mg once weekly) was 5.8 ng/ml, which suppressed F317L mutation in the CML clone. Currently, the patient is 77 years old and is sustaining MR^5.0. Chronic renal failure may cause hyperabsorption and metabolic retardation in patients receiving PON. Initiation of hemodialysis may improve homeostasis resulting in enhanced anti-tumor immunity against CML.

A 75-year-old man was diagnosed with diffuse large B-cell lymphoma originating from the paranasal sinuses. Curative induction chemotherapy was initiated and pegfilgrastim was administered on day5 of the first cycle as primary prophylaxis. The patient developed headache on day7 and fever on day11. These symptoms persisted despite treatment with antibiotics and antifungal agents. Computed tomography (CT) after admission revealed wall thickening in the aortic arch. Chest contrast-enhanced CT also revealed contrast enhancement in the thickened aortic wall. Results of blood cultures and serological tests for autoantibodies were negative, indicating that the clinical manifestations were not due to infection or a specific collagen disease. The final diagnosis was drag-induced large vessel vasculitis induced by long-acting granulocyte colony-stimulating factor (G-CSF). The patient’s symptoms and large-vessel wall thickening immediately resolved after treatment with a glucocorticoid (prednisolone, 0.6 mg/kg/day). Aortitis should be considered as a differential diagnosis when fever is observed in a patient who received long-acting G-CSF during chemotherapy.

A 16-year-old boy received an unrelated bone marrow transplant while in second remission of acute myeloid leukemia. He suffered from severe oral mucosal complications and had difficulty taking oral drugs such as sulfamethoxazole/trimethoprim (ST). Engraftment was obtained on transplant day 35, and blurred vision and headache appeared around transplant day 60. Funduscopy revealed retinal hemorrhage and macular edema, and an MRI scan of the head revealed a nodular lesion in the left putamen. Toxoplasma gondii was detected by CSF PCR, and cerebral toxoplasmosis was diagnosed. Following therapy with ST and clindamycin, the patient was administered pyrimethamine, sulfadiazine, and leucovorin. Symptoms improved promptly, and CSF PCR was negative 45 days after the start of treatment. Since the prevalence of toxoplasma antibodies increases with age, it is crucial to avoid toxoplasma reactivation by ST after hematopoietic cell transplantation in postpubescent patients.

Guillain-Barré syndrome (GBS) is a rare neurological complication of allogeneic hematopoietic stem cell transplantation (HSCT). The pathogenesis of post-HSCT GBS is unclear. Here, we report a case of GBS coincident with Epstein-Barr virus (EBV) and cytomegalovirus (CMV) reactivation that occurred after HSCT in a patient with myelodysplastic syndrome. A 61-year-old man was admitted to our hospital because of gait disturbance due to lower limb muscle weakness, which arose during treatment for chronic graft-versus-host disease (GVHD) five months after allogeneic HSCT. He was diagnosed with GBS based on his clinical course, cerebrospinal fluid analysis, and a nerve conduction study. At that time, he exhibited EBV and CMV reactivation. GBS improved after intravenous injection of immunoglobulins. Our case suggests that reactivation of EBV and CMV during treatment for chronic GVHD may induce GBS, and that rapidly progressive muscular weakness coincident with EBV or CMV reactivation can be a diagnostic sign of GBS after allogeneic HSCT.

A 39-year-old woman with myotonic dystrophy (DM) presented with syncope and was diagnosed with primary mediastinal large B-cell lymphoma, clinical stage IA. PET-CT revealed an upper mediastinal mass with high FDG uptake (SUVmax, 14.8). She had muscle weakness associated with DM, but her performance status was preserved. She was treated with 6 cycles of dose-adjusted EPOCH-R therapy and localized irradiation for the residual mass, without severe adverse events or recurrence of syncope. Patients with DM should be monitored for cardiac events and muscle weakness when undergoing lymphoma treatment.

The effectiveness of interferon (IFN) in patients with myeloproliferative neoplasms (MPNs) including polycythemia vera (PV) has been reported for more than three decades. However, because of its toxicity and tolerability, the use of IFN has been restricted. With the recent development of pegylated-IFN, the use of IFN has been highlighted again for effectively treating MPNs. Guidelines in Western countries recommend IFN as the first choice for cytoreduction alongside hydroxyurea, particularly for young and pregnant patients. Furthermore, a novel IFN, ropeginterferon alfa-2b, allows biweekly injection and exhibits durable high hematological and molecular responses leading to the approvement of its use in Western countries. Although IFN is not yet been approved for use against PV in Japan’s National Health Insurance System as of February 2023, a phase 2 study has shown efficacy, safety, and tolerability of ropeginterferon alfa-2b in Japanese patients with PV, providing hope for future development.

Myelofibrosis (MF) is a chronic myeloproliferative tumor with a poor prognosis that not only impairs the quality of life because of splenomegaly and debilitating systemic symptoms but also has a high acute myeloid leukemia progression rate. Ruxolitinib, a JAK inhibitor, enhances systemic symptoms in MF and prolongs survival; however, it is not effective in suppressing bone marrow fibrosis and leukemia progression, and allogeneic hematopoietic stem cell transplantation remains needed for treatment. As a result, many new drugs for MF are presently being developed. Many similar drugs have been demonstrated to enhance therapeutic effectiveness if combined with ruxolitinib, particularly BCL-2/BCL-XL inhibitors, bromodomain and extra-terminal domain inhibitors, and human double-minute homolog 2 inhibitors, to improve bone marrow fibrosis. This study provides an overview of drugs currently employed in clinical trials being performed in Japan.

The median survival duration of myelofibrosis is about 5 years and at present, allogeneic hematopoietic cell transplantation is the only curative treatment. Although myelofibrosis’s clinical course and prognosis vary from patient to patient, the time and indication of transplantation should be determined in light of the likelihood of transplant-related death or long-term prognosis, as well as any information on each patient’s gene mutation risk. Previous reports have demonstrated that allogeneic hematopoietic cell transplantation can be a curative treatment for myelofibrosis. However, the transplant-related mortality rate is as high as 30-50%, and the overall survival rate is only around 40%. Future research should clarify how to decide between JAK2 inhibitors and allogeneic hematopoietic cell transplantation, how to lower high transplant-related mortality, how to choose a stem cell source, how to create the best pretransplant treatment, and how to incorporate JAK2 inhibitors before transplantation.

Philadelphia chromosome-negative myeloproliferative neoplasms (Ph⁻ MPN) in children, adolescents, and young adults (AYA) attract attention from hematologists because they are identified more than before due to the recognition and advancement of diagnostic capacity for Ph⁻ MPN. The clinical features of Ph⁻ MPN diagnosed in children and AYA are found to be different from those of Ph⁻ MPN that occur in patients in their 60s, peak age of onset. Ph⁻ MPN diagnosed in children and AYA has more triple-negative cases with no identifiable driver genes and a larger proportion of venous thrombosis in thrombotic events. In terms of treatment, there are still problems to be resolved that are unique to younger patients, such as choosing cytoreductive agents for long-term use and the development of optimal prevention of thrombotic or bleeding events during pregnancy and childbirth. In this paper, we will discuss the clinical research supporting these claims and offer some practical advice for treating young children with Ph⁻ MPN daily.

Chronic neutrophilic leukemia (CNL) is a clonal disorder that is characterized by increasing mature neutrophils. Colony stimulating factor 3 receptor (CSF3R) T618I mutation was frequently identified in patients with CNL and is defined as a molecular marker of the disease. Ruxolitinib, a JAK2 inhibitor, provided a promising therapeutic effect in a phase II study. In particular, ruxolitinib was more efficient for patients with CSF3R mutation. Allogeneic stem cell transplantation (Allo-SCT) may be a curative treatment for CNL. On the other hand, further studies are needed to define the optimal method of transplantation, source of donor, conditioning therapy, and timing of transplantation. Chronic eosinophilic leukemia (CEL) is a clonal disorder that is characterized by increasing eosinophils. In the World Health Organization Classification 5th edition, diagnostic criteria for CEL are renewed. Because the new criteria will be more specific for CEL than criteria in the older edition, “not otherwise specified (NOS) ” is removed from the name of the disease. Anti-CD52 antibody, alemtuzumab, or anti-IL-5 antibody, mepolizumab, are promising drugs to control symptoms that are associated with hypereosinophilic syndrome. Allo-SCT is anticipated as a curative treatment for CEL, but the evidence of Allo-SCT for CEL is still limited. Further study is required to define the treatment strategy.