Taichiro Tokura

We report the case of a 76-year-old man with follicular lymphoma who developed cancer-associated thrombosis (CAT) presenting as multiple brain infarctions during complete remission (CR). After the fourth cycle of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) and pegfilgrastim, the patient presented with dysarthria and right upper-limb paresis. Brain magnetic resonance imaging demonstrated multiple brain infarctions with a positive three-territory sign, specific for cancer-associated brain infarctions. Laboratory tests revealed leukocytosis and thrombocytopenia. Whole-body computed tomography demonstrated CR without thrombosis. Anticoagulation with unfractionated heparin, followed by apixaban, resulted in neurological improvements. The patient was discharged without bleeding or any neurological sequelae. This case highlights that CAT can occur even in indolent lymphoma during CR and that anticoagulation is effective and safe despite the presence of thrombocytopenia.

The KMT2A gene is frequently altered in acute myeloid leukemia (AML). KMT2A abnormalities include partial tandem duplication (PTD), single-nucleotide variants (SNVs), and chromosomal rearrangements such as t(9;11)(p21.3;q23.3) and t(v;11q23.3). However, with the widespread adoption of next-generation sequencing (NGS), PTD has been assessed less frequently. We evaluated the clinical features and prognostic impact of PTD and other KMT2A abnormalities. We analyzed the KMT2A abnormalities and coexisting genetic alterations in 585 patients with de novo AML diagnosed across 25 institutions (1991–2020). Using bone marrow and/or peripheral blood samples, we identified PTD by targeted polymerase chain reaction-based assay, chromosomal rearrangements by karyotyping, and SNVs and other genetic alterations by targeted NGS. KMT2A abnormalities were detected in 18.3% of de novo AML, comprising PTD in 6.7%, SNVs in 5.1%, t(9;11)(p21.3;q23.3) in 2.2%, and t(v;11q23.3) in 4.8%; 0.5% had concurrent KMT2A abnormalities. Patients with PTD, t(9;11)(p21.3;q23.3), or t(v;11q23.3) had significantly shorter relapse-free survival (RFS) than the KMT2A wild-type group (hazard ratio [HR] 1.99, p = 0.048; HR 3.13, p = 0.009; HR 2.41, p = 0.006, respectively). Patients with PTD, t(9;11)(p21.3;q23.3), or t(v;11q23.3) had significantly shorter overall survival (OS) than the KMT2A wild-type group (HR 3.92, p < 0.001; HR 4.58, p < 0.001; HR 3.73, p < 0.001, respectively). Within the PTD group, older age (p = 0.030) and higher lactate dehydrogenase (p = 0.005) remained independent adverse prognostic factors. KMT2A-PTD is associated with inferior RFS and OS in de novo AML. Our findings support routine PTD testing at diagnosis and the incorporation of KMT2A-PTD into prognostic risk stratification and clinical decision-making.

Transplant-associated thrombotic microangiopathy (TA-TMA) is a life-threatening complication of hematopoietic stem cell transplantation in which systemic complement activation induces endothelial injury, leading to microangiopathic hemolytic anemia, thrombocytopenia, and organ dysfunction. TA-TMA often progresses rapidly and has historically been associated with high mortality. Over the last decade, increasing recognition of complement activation as a central driver of TA-TMA has shifted management from largely empirical supportive care toward mechanism-based therapy. This review summarizes recent advances in complement-targeted therapies for TA-TMA and outlines key aspects of pathophysiology, risk factors, and monitoring that inform therapeutic decision-making. Earlier non–complement-directed therapies, including calcineurin inhibitor modification, plasma exchange, defibrotide, and rituximab, showed limited and inconsistent benefit. In contrast, complement-targeted therapies have advanced the treatment of TA-TMA. Prospective and large cohort data support the clinical activity of eculizumab (C5 inhibitor), with meaningful improvements in survival and organ recovery. Ravulizumab (long-acting C5 inhibitor) has shown encouraging phase 3 results, and narsoplimab (MASP-2 inhibitor), which became the first approved treatment for TA-TMA, has demonstrated promising outcomes, including activity in some patients previously exposed to C5 inhibition. In addition, newer agents targeting C5, C3, or factor B are expanding the therapeutic horizon for TA-TMA, although efficacy data are still limited for some of these therapies. Overall, complement-targeted therapies represent a therapeutic advance in TA-TMA, and ongoing prospective studies will be crucial to define optimal agent selection, sequencing, and integration into clinical practice.

Background and Clinical Significance: Mantle cell lymphoma (MCL) frequently involves bone marrow, gastrointestinal tract, and hepatosplenomegaly, whereas pleural effusions are uncommon. Cases requiring invasive mechanical ventilation and thoracic drainage are rare. We report a case of MCL with persistent massive pleural effusions requiring invasive mechanical ventilation and bilateral continuous thoracic drainage. Case Presentation: A 71-year-old woman presented with dyspnea and was found to have bilateral pleural effusions and generalized lymphadenopathy. Shortly after admission, she developed acute respiratory failure due to pleural effusions and required invasive mechanical ventilation. Right-sided continuous thoracic drainage was initiated. Thereafter, more than 1 L of pleural fluid was drained each day. Flow cytometry of the pleural fluid showed CD5-positive B cells with kappa light-chain restriction. Bone marrow examination revealed abnormal lymphocyte infiltration. Cervical lymph node biopsy demonstrated diffuse proliferation of medium-sized, abnormal B lymphocytes with an immunophenotype of CD5⁺, CD19⁺, CD20⁺, cyclin D1⁺, SOX11⁺, and κ⁺, with a Ki-67 index of 20%, confirming MCL, stage IV. Immunochemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) was commenced under mechanical ventilation. Shortly thereafter, left-sided continuous thoracic drainage was also initiated. However, in response to immunochemotherapy, the bilateral pleural effusions gradually subsided, enabling extubation, and there was no reaccumulation after removal of both chest tubes. Furthermore, generalized lymphadenopathy regressed, and bone marrow examination revealed resolution of lymphoma infiltration, resulting in complete remission. Conclusions: De novo MCL complicated by persistent massive pleural effusions requiring invasive mechanical ventilation and bilateral continuous thoracic drainage is rare. A thorough diagnostic workup followed by prompt initiation of immunochemotherapy can arrest pleural output, enable extubation, and be lifesaving. Clinicians should recognize that MCL rarely presents with persistent massive pleural effusions.

We report the case of a 61-year-old man with chronic myelomonocytic leukemia, who underwent unrelated peripheral blood stem cell transplantation. Fusariosis was suspected prior to identification of the fungal species, and voriconazole and liposomal amphotericin B combination therapy were administered. The patient developed fusarium-related endophthalmitis, accompanied by eye pain. Despite vitrectomy, the endophthalmitis was poorly controlled, and the left eye was enucleated. No recurrence of fusariosis was observed until death following multiple-organ failure due to steroid-resistant graft-versus-host disease.

Transplant-associated thrombotic microangiopathy (TA-TMA) generally occurs after allogeneic hematopoietic stem cell transplantation (HSCT) and has a high mortality rate. However, TA-TMA after autologous HSCT is rare. In particular, there are almost no accurate reports of TA-TMA after autologous HSCT in adults. Furthermore, there are no reports of such patients being treated with complement-targeting agents, including eculizumab. We report the first adult case of TA-TMA after autologous HSCT treated with eculizumab. A 66-year-old woman in complete remission after the second relapse of follicular lymphoma received autologous HSCT following the MEAM regimen (ranimustine [MCNU], etoposide, cytarabine [Ara-C], and melphalan). Trilineage engraftment was confirmed. However, she developed new-onset hypertension, hemolytic anemia, thrombocytopenia, and renal failure. The screening results were notable for normal coagulation, normal ADAMTS13 activity and inhibitor levels, and negative direct and indirect Coombs tests. No variants appeared in complement regulatory genes such as CFH, CFB, CFHR5, CFI, CD46, C3, THBD, and DGKE. In addition, all other microbiological and autoimmune screening tests were negative. Based on comprehensive diagnostic findings and the onset within 100 days post-HSCT, TA-TMA was diagnosed. She also developed acute respiratory failure requiring >15 L/min of oxygen. Transthoracic echocardiography revealed pulmonary hypertension (PH) and right-sided heart failure (RHF) as complications of TA-TMA. Following the administration of eculizumab, clinical improvement was observed. In conclusion, TA-TMA after first-time autologous HSCT in adults is extremely rare but can occur. Even with serious complications such as PH and RHF, TA-TMA after autologous HSCT may improve with early diagnosis and prompt initiation of complement-targeting agents, such as eculizumab. These findings suggest that complement inhibition may play a critical therapeutic role even in patients with cardiopulmonary complications and raise the possibility that the prognosis of TA-TMA after autologous HSCT may be more favorable than previously reported in allogeneic HSCT, with a lower mortality rate.

Aim: The MEAM regimen consisting of ranimustine (MCNU), etoposide (ETP), cytarabine (Ara‐C), and melphalan (MEL) is widely used before auto‐peripheral blood stem cell transplantation (auto‐PBSCT) for malignant lymphoma in Japan. The MEAM regimen generally consists of 200–400 mg/m² for 4 days, but we decided to increase the dosage of Ara‐C from the standard to 2 g/m² for 2 days with the aim of increasing drug transferability to the central nervous system. We evaluate the safety and therapeutic efficacy of high‐dose Ara‐C MEAM therapy.Methods: The high‐dose Ara‐C MEAM protocol consisted of MCNU 300 mg/m² on day –7, ETP 200 mg/m² on days –6, –5, –4, –3 and Ara‐C 2 g/m² on day –4 –3, and MEL 140 mg/m² on day –2. We retrospectively analyzed 37 cases of malignant lymphoma at our institution between May 2014 and July 2020.Results: All patients got engraftment and there were no cases of treatment‐related mortality. In all cases, the 3‐year overall survival (OS) and progression‐free survival (PFS) after transplantation were 80.6% and 65.7%, respectively. Twenty‐one cases of diffuse large B‐cell lymphoma recurrence, for which there is proven usefulness of auto‐PBSCT, showed good results after transplantation, with the 3‐year OS and PFS after transplantation being 100% and 74.3%, respectively.Conclusion: The safety and efficacy of high‐dose Ara‐C MEAM therapy were demonstrated, but the expected therapeutic effect on central nervous system lesions could not be fully evaluated owing to the small number of cases.

Histiocytic sarcoma is a relatively new disease category and the gastrointestinal origin is sporadic. We report a case of a 74-year-old woman who underwent chemotherapy and proximal gastrectomy for extremely rare, advanced gastric histiocytic sarcoma. The resected specimen was subjected to numerous immunostainings to meet the diagnostic criteria of histiocytic sarcoma and was positive for the histiocyte markers’ cluster of differentiation 68 and lysozyme. The markers of Langerhans cells, follicular dendritic cells, and myelocyte were all negative. Six reports of surgical resection of histiocytic sarcoma originating in the stomach exist, including our case. We reviewed the clinical course and the histological and immunohistochemical diagnostic features of surgically resected gastric histiocytic sarcoma.

Introduction: Acute myelogenous leukemia (AML) in elderly patients is associated with an increased incidence of complications and treatment‐related toxicity because of the frequency of comorbid disease and age‐related deterioration in organ function. Despite advances in AML treatment in recent years, elderly patients have experienced limited benefit, and their outcomes remain poor. This study aimed to perform a comprehensive gene mutation analysis in elderly AML patients and identify gene mutations that could serve as prognostic factors.Methods: An analysis of gene mutations was performed for 281 AML patients, including 98 elderly patients aged 65 years or above.Results: Compared to younger AML patients, elderly patients showed a higher frequency of the following gene mutations: TP53 (P = 0.026), PTPN11 (P = 0.006), RUNX1 (P = 0.024), TET2 (P = 0.002), and ASXL1 (P = 0.023). The complete remission rate was significantly lower in DNMT3A mutation‐positive cases (4.26%, P = 0.011) and TP53 mutation‐positive cases (2.13%, P = 0.031) than in negative cases. The overall survival rate was significantly poorer in cases with FLT3‐ITD (P = 0.003), DNMT3A (P = 0.033), or TP53 mutation (P < 0.001). Conversely, cases with PTPN11 mutation (P = 0.014) had a significantly more favorable prognosis. In multivariate analysis, FLT3‐ITD (P = 0.011) and TP53 mutation positivity (P = 0.002) were independent poor prognostic factors, as were a performance status of 3 or above (P < 0.001) and poor cytogenetic prognosis (P = 0.001). In contrast, PTPN11 mutation positivity (P = 0.023) was an independent favorable prognosis factor.Conclusion: Analysis of gene mutations in elderly AML patients is very important, not only for establishing prognosis, but also for introducing appropriate molecular‐targeted treatments.