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

Although vaccination against coronavirus infection 2019 (COVID-19) has been found to be effective, reports of adverse reactions continue to appear. We report the development of severe aplastic anemia post BTN162b2 mRNA COVID-19 vaccination in patient undergoing dialysis. The pathogenesis and risk factors for post-vaccination aplastic anemia remain unclear. We must remain vigilant to aplastic anemia following COVID-19 vaccination. The risk of aplastic anemia should be identified, and management methods should be established.

Chronic myeloid leukemia (CML) is a hematological malignancy characterized by the Philadelphia (Ph) chromosome, which is formed by a t (9;22)(q34;q11) translocation. The aberrant activation of the ABL1 tyrosine kinase is caused by the BCR::ABL1 fusion gene on the Ph chromosome, leading to significant leukemic cell proliferation. CML is typically diagnosed in the chronic phase with few clinical symptoms and progresses to a blast crisis within years. CML acquires additional genetic abnormalities on top of BCR::ABL1 fusion during clonal evolution. ASXL1 mutations are found in the chronic phase, with a frequency of approximately 20%, whereas other mutations are rare. Most blast crisis cases have additional genetic abnormalities, including frequent ASXL1 and RUNX1 mutations. Recent studies have revealed that a subset of these genetic mutations affects the sensitivity of tyrosine kinase inhibitors to leukemic cells as well as patient prognosis, indicating applications for patient stratification and individualized treatment.

Enhancer of zeste homolog (EZH), a subunit of polycomb repressive complex 2 (PRC2), suppresses gene expression by methylation of H3K27. EZH is closely associated with B-cell development and pathogenesis of certain malignant lymphomas. In follicular lymphoma (FL), gain-of-function mutation and upregulation of EZH2 are observed in approximately 30% and 15% of cases, respectively. Moreover, one-third of diffuse large B-cell lymphomas carry an EZH2 mutation, mostly co-existing with translocation involving Bcl-2. Genome-wide trimethylation of H3K27 is a unique characteristic induced by upregulation of both EZH2 and EZH1, and is responsible for more than half of the gene suppression that occurs in adult T-cell leukemia/lymphoma (ATL). Inhibition of EZH can reduce H3K27 methylation and subsequently restore epigenetically suppressed genes. Currently, an EZH2 inhibitor and dual EZH1/2 inhibitor have been clinically used to treat relapsed/refractory FL and ATL, respectively. EZH-targeted treatment for lymphoma has only just begun, and further development of these drugs for various other malignancies, both alone and in combination with other therapeutics, is ongoing.

Adult T-cell leukemia-lymphoma (ATL) is a highly aggressive peripheral T-cell neoplasm caused by human T-cell leukemia virus type 1 (HTLV-1) infection occurring in approximately 5% of patients after prolonged latent period. ATL relapses within a short period despite its transient response to multiagent chemotherapy and the prognosis is extremely poor due to anticancer drug resistance and immunodeficiency. Although novel agents with different mechanisms, such as molecular targeted agents, have improved the prognosis, the number of cured patients remains limited. Hematopoietic stem cell transplantation resulted in long-term remission, whereas its indication is limited due to treatment-related mortality. As most ATL patients are of advanced age, development of a lesser toxic treatment is necessary. Therefore, we developed a novel therapeutic dendritic cell vaccine targeting the HTLV-1 Tax antigen. The safety profile has been confirmed in a pilot and phase I clinical studies, and a promising long-term clinical efficacy has also been obtained. This novel vaccine is a noninvasive, long-lasting therapy for ATL and can potentially be extended to different applications for low-grade ATL and high-risk HTLV-1 carriers.

Invasive pneumococcal diseases (IPDs) after allogeneic hematopoietic stem cell transplantation have high fatality rates and often develop late after transplantation. The patient was a 58-year-old female. Fourteen years ago, she underwent bone marrow transplantation from a HLA-DR 1-antigen mismatched unrelated donor for myelodysplastic syndrome. She developed pneumonia, chronic graft-versus-host disease, and hypogammaglobulinemia. She received 23-valent pneumococcal capsular polysaccharide vaccine 11 and 6 years earlier. She was presented to our emergency room with fever. Her blood culture was positive for pneumococcus, and she was diagnosed with an IPD. The patient received antibiotic treatment but died on the third day of hospitalization. Because of its seriousness, pneumococcal infection should receive attention even 10 or more years after transplantation. Preventive approaches such as vaccination and early intervention at the time of diagnosis are important.

Double minute chromosomes (dmin) are small, acentric, and extrachromosomal fragments that frequently mediate oncogene amplification and induce rapid disease progression with poor prognosis, although they are infrequent in myeloid neoplasms. An 81-year-old woman with anemia and thrombocytopenia was admitted to our hospital. Bone marrow examination showed 54.0% of the blasts. She was diagnosed with acute myeloid leukemia (French-American-British classification, M2; World Health Organization classification, acute myeloid leukemia [AML], not otherwise specified, AML with maturation). Chromosomal analysis revealed the presence of 3-45 dmin in the background of 46 and XX in 14 out of 20 metaphases examined. Spectral karyotyping examination demonstrated that the dmins were derived from chromosome 8. Fluorescence in situ hybridization (FISH) targeting the MYC gene demonstrated that dmins contained full-length MYC genes with multiple signals. Finally, she was diagnosed with AML with dmin via MYC amplification and was administered with venetoclax plus azacitidine chemotherapy. After two cycles of the regimen, FISH found no MYC amplification signals, indicating her state being in cytogenetic remission. At present, she has finished four cycles of the regimen and remained in complete remission. Venetoclax plus azacitidine could be an effective regimen for the poor prognosis of AML with dmin through MYC amplification.

A 55-year old female patient was treated with methotrexate (MTX) and infliximab (IFX) for rheumatoid arthritis (RA). She experienced unknown fever, generalized lymphadenopathy, and liver tumors. Histological examination of the inguinal lymph node and a liver tumor resulted in the pathological diagnosis of classic Hodgkin lymphoma, with many Reed-Sternberg cells with the positivity of Epstein-Barr virus (EBV). She was diagnosed with MTX-related lymphoproliferative disorders (MTX-LPDs). She received chemotherapy after the cessation of MTX and IFX and achieved complete remission. RA showed recurrence after a while, and she was treated with steroids or other drugs. Six years after the chemotherapy, she experienced low-grade fever and anorexia. Whole computed tomography images showed an appendix tumor and enlargement of the surrounding lymph nodes. Appendectomy with the radical lymph nodes dissection was performed. The pathological diagnosis was diffuse large B-cell lymphoma, resulting in the clinical diagnosis of the relapse of MTX-LPD. EBV was negative at this point. The pathological findings of MTX-LPD may change at relapse; thus, biopsy should be considered when the relapse of MTX-LPD is suggested.

A 71-year-old woman complained of nausea and anorexia. Laboratory tests revealed significant neutrophilia and immunoglobulin A-kappa type M proteinemia, as well as increased plasma cells on bone marrow examination. Furthermore, the serum granulocyte-colony stimulating factor (G-CSF) concentration was high at 160 pg/ml, and the colony stimulating factor 3 receptor (CSF3R)-T618I mutation was negative. Immunohistochemical (IHC) analysis of bone marrow specimens using the anti-G-CSF antibody revealed immunopositivity of some myeloma cells. The patient was diagnosed using G-CSF-producing myeloma and was treated with daratumumab, lenalidomide, and dexamethasone. Her treatment resulted in a very good partial response, with normalization of both serum G-CSF levels and neutrophil count. There have been a few cases of G-CSF -producing myeloma reported, and it has previously been reported as chronic neutrophilic leukemia with M proteinemia. According to previous reports, techniques such as serum G-CSF measurements, IHC with an anti-G-CSF antibody, and CSF3R gene mutation analysis are useful for differentiating G-CSF-producing myeloma. However, the clinical characteristics and long-term prognosis of G-CSF-producing myeloma remain unknown. Additional case gathering and investigations are required.

Immunosuppressive therapy (IST) is the first-line treatment for patients with aplastic anemia (AA) who require blood transfusion when a human leukocyte antigen-matched related donor is unavailable. However, the proportion of patients with AA who are refractory to IST remains high (30%). IST in combination with eltrombopag has been studied in adults, but its efficacy and safety in children have not been established. We present three cases of AA that were initially refractory to IST but improved with additional eltrombopag administration. These patients were successfully managed using this strategy without the use of hematopoietic cell transplantation (HCT). The first patient achieved a complete response within one month after receiving eltrombopag. When the second and third patients were given eltrombopag, they were able to safely reduce the amount of cyclosporin they were given. They avoided blood transfusions, but no measurable response was obtained. The conjunctival icterus was detected and treated using a dose reduction of eltrombopag. Eltrombopag may be effective in children with AA who are refractory to IST, allowing them to avoid blood transfusions and HCT. More cases treated with this strategy are needed to confirm its efficacy and safety for children with AA.

Hematopoietic cell transplantation (HCT) is the only curative therapy for juvenile myelomonocytic leukemia (JMML). Meanwhile, an established conventional chemotherapy before HCT remains unavailable. Studies have shown that azacitidine (AZA), which is a DNA methyltransferase inhibitor, is clinically effective for JMML as a bridging therapy for HCT; a prospective clinical trial in Japan is ongoing. Herein, we present a case of a patient with JMML who was administered AZA as bridging therapy for both first and second HCT. A 3-year-old boy with neurofibromatosis type 1 was administered with intravenous AZA (75 mg/m²/day for 7 days, intervals of 28 days, and four cycles) and received myeloablative HCT (unrelated bone marrow). When relapse occurred on day 123, four additional AZA therapy cycles were administered, and the patient received a second nonmyeloablative HCT (cord blood). After seven AZA therapy cycles as post HCT consolidation, hematological remission was sustained for 16 months after the second HCT. No severe adverse events occurred. AZA is effective for JMML as a bridging therapy for HCT and has robust cytoreductive potential despite the risk of relapse.