Optimal timing of apheresis for the efficient mobilization of peripheral blood progenitor cells recruited by high-dose granulocyte colony-stimulating factor in healthy donors.

Predictors of peripheral blood stem cell (PBSC) yield can potentially improve the comfort, safety, and efficacy of CD34+ cell collection from donors treated with recombinant human granulocyte colony-stimulating factor (G-CSF). We investigated 181 apheresis procedures on 109 healthy allogeneic donors to identify factors correlating with efficient PBSC collection. Apheresis started on Day 4 or 5 and continued up to Day 6 of G-CSF administration. CD34+ cell　yields on Days 4 and 5 were comparable, and significantly higher than on Day 6. This suggests that starting apheresis on Day 4 rather than Day 5 may be preferable, to reduce G-CSF exposure and optimize yield, even if multi-day collection is required. More CD34+ cells were collected from male and cytomegalovirus (CMV)-seronegative donors than from female and CMV-seropositive donors, respectively. The yields of CD34+ cells were similarly high in both male and female donors aged 20-29 years; yields decreased in female donors in their thirties, and were comparably low in both male and female donors in their forties and thereafter. These findings should guide decision-making about when to begin apheresis, and encourage careful consideration of donor factors such as gender, age, and CMV serostatus when collecting PBSCs.

[Airway obstruction due to localized tracheal lesion of extranodal NK/T-cell lymphoma, nasal type].

A 76-year-old man presented with a tracheal tumor associated with severe respiratory obstruction. A tracheotomy was performed due to respiratory failure. F-fluorodeoxyglucose (FDG) -positron emission tomography/computed tomography revealed an abnormal accumulation of FDG (maximum standardized uptake value: 16) in the trachea. A histopathological examination of the tracheal biopsy revealed extranodal NK/T-cell lymphoma, nasal type (ENKL). He was treated with concurrent radiotherapy (50 Gy) for the tracheal tumor and three courses of two-thirds dose ofdexamethasone, etoposide, ifosfamide, and carboplatin. Although the tumor responded remarkably well to this therapy, the patient died of an ENKL recurrence in the lungs and liver 11 months post therapy.

A possible role of low regulatory T cells in anti-acetylcholine receptor antibody positive myasthenia gravis after bone marrow transplantation.

BACKGROUND: Chronic graft-versus-host disease (GVHD) appears several months following allogenic hematopoietic stem cell transplantation (HSCT) and is clinically analogous to autoimmune disorder. Polymyositis is a common neuromuscular disorder in chronic GVHD, but myasthenia gravis (MG) is extremely rare. Hence, its pathophysiology and treatment have not been elucidated. CASE PRESENTATION: A 63-year-old man with a history of chronic GVHD presented with ptosis, dropped head, and dyspnea on exertion, which had worsened over the previous several months. He showed progressive decrement of compound muscle action potential in the deltoid muscle evoked by 3-Hz repetitive nerve stimulation, a positive edrophonium test, and elevated levels of serum anti-acetylcholine receptor antibodies, which suggested a diagnosis of generalized MG. No thymoma was found. Flow cytometric analysis revealed a remarkable depletion of peripheral Tregs (CD4+CD25highFOXP3+ cells, 0.24% of the total lymphocytes). Administration of prednisolone and tacrolimus was insufficient to alleviate his symptoms; however, the use of rituximab successfully improved his condition. CONCLUSIONS: Myasthenic symptoms appeared in the process of tapering prednisolone for the treatment of chronic GVHD, supporting the diagnosis of MG associated with chronic GVHD. The present case proposes a possibility that reduction of Tregs might contribute to the pathogenesis of MG underlying chronic GVHD. Immunotherapy with rituximab is beneficial for treatment of refractory MG and GVHD.

Cancer-associated thrombosis in hematologic malignancies.

Patients with hematologic malignancies are often complicated not only by severe bleeding due to thrombocytopenia and disseminated intravascular coagulation but also by thromboembolic events, just like in patients with solid cancers, and these events can negatively impact patient outcomes. Nevertheless, the prevention and treatment of cancer-associated thrombosis (CAT) in hematologic malignancies has not been adequately investigated due to the limited size, heterogeneity, and unique pathophysiology of the patient population. This article summarizes the current understanding, risk factors, prediction models, and optimal prevention and treatment strategies of CAT in hematologic malignancies on a disease-by-disease basis, including acute leukemia, lymphoma, myeloma, and myeloproliferative neoplasms. Specific considerations of novel molecular targeted therapeutics introduced in recent years, such as immunomodulatory drugs and tyrosine kinase inhibitors, are also discussed based on the latest clinical trials.

A systematic review and meta-analysis of recombinant human soluble thrombomodulin for the treatment of DIC associated with hematological malignancies.

BACKGROUND: Recombinant human soluble thrombomodulin (rhTM) is commonly used in Japan to treat disseminated intravascular coagulation (DIC), but its efficacy compared with other anticoagulants is unclear. We conducted a systematic review and meta-analysis to investigate this issue in DIC patients with hematological malignancies. METHODS: We searched PubMed, Cochrane, and Scopus for prospective and retrospective studies evaluating the efficacy and safety of rhTM in DIC patients with hematological malignancies between April 2008 and April 2023. We performed a systematic review and meta-analysis evaluating recovery from DIC, hemorrhagic adverse events (AEs), and overall survival (OS). RESULTS: We analyzed one prospective (64 patients) and seven retrospective studies (209 patients). Use of rhTM was associated with a higher rate of recovery from DIC (OR: 2.25 [1.09-4.63] and 1.98 [1.12-3.50] in prospective and retrospective studies, respectively; same order below) and fewer hemorrhagic AEs (OR: 0.83 [0.30-2.30] and 0.21 [0.08-0.57]). rhTM did not improve OS (OR: 1.06 [0.42-2.66] and 1.72 [0.87-3.39]), although the incidence of hemorrhagic death was lower in the rhTM group (0 of 94 patients). CONCLUSION: Use of rhTM in patients with hematological malignancy-associated DIC is strongly expected to be effective and safe.

Myeloid sarcoma with plasmacytoid dendritic cell-like proliferation associated with IKZF1, ETV6 and DNMT3A mutations.

The classification of clonal plasmacytoid dendritic cell (pDC) proliferation associated with myeloid neoplasms remains a topic of ongoing debate. Although the fifth edition of the World Health Organization classification classifies clonal pDC proliferation into two categories, it is unclear whether this classification adequately captures the complexities of clonal pDC pathogenesis. We present a clinical case featuring myeloid sarcoma with pDC-like cells in cervical lymph nodes and bone marrow (BM). Analysis of biopsy specimens and BM aspirate revealed two distinct cellular populations expressing myeloid and pDC markers. One population exhibited myeloid leukemia and monocyte markers, including MPO, CD13, CD33, CD11b, and CD14, while the other manifested an immunophenotype reminiscent of pDCs, characterized by expression of CD56 and CD123. Additionally, whole exome sequencing and RNA sequencing of BM mononuclear cells were conducted to explore the pathophysiology of this rare malignancy, and unveiled pDC-like cell proliferation driven by IKZF1 and ETV6 mutations originating from clonal hematopoiesis initiated by a DNMT3A mutation. Notably, venetoclax-based therapy exhibited efficacy for achieving and sustaining complete remission. This case provides pivotal insights into the mechanistic aspects of pDC/pDC-like cell proliferation in myeloid sarcoma, offering valuable perspectives on therapeutic strategies.

High Efficacy and Safety of Asciminib in a Chronic Myeloid Leukemia Patient with Chronic Kidney Disease Following Renal Transplantation.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm driven by the BCR::ABL1 tyrosine kinase. Tyrosine kinase inhibitors (TKIs) have been established as standard therapies for CML. However, some CML patients experience TKI intolerance. Asciminib was approved for CML patients either intolerant or refractory to TKI therapy. We herein report a 63-year-old CML patient who underwent renal transplantation and exhibited TKI intolerance. He was switched to asciminib, which achieved a deep molecular response without exacerbation of the renal function. Our experience revealed that asciminib is effective and safe for CML patients complicated with chronic kidney disease.

A case of cold agglutinin syndrome associated with chronic lymphocytic leukaemia harbouring mutations in CARD11 and KMT2D.

Cold agglutinin disease (CAD) is a rare cold autoimmune haemolytic anaemia (cAIHA) caused by IgM antibodies recognizing I antigens on erythrocytes. cAIHA is now mainly classified into two types: primary CAD and cold agglutinin syndrome (CAS). CAS develops in association with the underlying disease, which is most commonly malignant lymphoma. Recent studies have identified gene mutations in CARD11 and KMT2D in a high proportion of patients with CAD, which has led to recognition of CAD as an indolent lymphoproliferative disorder. We herein report a case of cAIHA without lymphocytosis or lymphadenopathy in whom bone marrow was infiltrated by a small population of clonal lymphocytes (6.8%) expressing cell surface markers consistent with chronic lymphocytic leukaemia (CLL). Whole-exome sequencing of bone marrow mononuclear cells revealed mutations in the CARD11 and KMT2D genes. This patient also had somatic hypermutation with overrepresentation of IGHV4-34, which is prevalent in CLL harbouring the KMT2D mutation. These observations suggest that CAS caused by early-phase CLL could be misinterpreted as primary CAD.

A case of delayed postoperative bleeding after excision of endometrial polyp using resectoscope in an infertile woman with von Willebrand disease:a case report and literature review.

Von Willebrand disease (VWD) is a bleeding disorder caused by a congenital quantitative reduction, deficiency, or qualitative abnormality of the von Willebrand factor (VWF). Here, we report a case of delayed postoperative bleeding in an infertile woman with endometrial polyps complicated by VWD. The patient was a 39-year-old infertile woman with type 2A VWD. At 38 years of age, she was referred to our hospital for infertility and heavy menstrual bleeding. Hysteroscopy revealed a 15-mm polyp lesion in the uterus. The patient was scheduled for transcervical resection (TCR) of the endometrial polyp. Gonadotropin-releasing hormone agonists were preoperatively administered to prevent menstruation. The VWF-containing concentrate was administered for 3 days according to guidelines. The patient was discharged on postoperative day 3 after confirming the absence of uterine bleeding. Uterine bleeding began on postoperative day 6. The patient was readmitted on postoperative day 7 and treated with VWF-containing concentrate for 5 days, after which hemostasis was confirmed. TCR surgery for endometrial lesions is classified as a minor surgery, and guidelines recommend short-term VWF-containing concentrate replacement. However, it should be kept in mind that only short-term VWF-containing concentrate replacement may cause rebleeding postoperatively.

Acquired von Willebrand Syndrome in a Patient with Multiple Comorbidities, Including MALT Lymphoma with IgA Monoclonal Gammopathy and Hyperviscosity Syndrome.

Acquired von Willebrand syndrome (aVWS) develops with various underlying diseases. We herein report an individual with aVWS associated with mucosa-associated lymphoid tissue lymphoma in the lungs complicated by hyperviscosity syndrome, Sjögren's syndrome, and hypothyroidism. This patient developed life-threatening hemorrhaging during a lung biopsy despite transfusion of concentrate of plasma-derived VWF/factor VIII. The use of rituximab caused remission of the lymphoma and hyperviscosity syndrome in parallel with the resolution of aVWS. Thus, lymphoma and hyperviscosity might result in aVWS. Invasive procedures with a risk of bleeding should be avoided in individuals with aVWS.

Mutated ZRSR2 and CUL3 accelerate clonal evolution and confer venetoclax resistance via RAS signaling pathway in blastic plasmacytoid dendritic cell neoplasm.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive subtype of myeloid malignancy characterized by skin, lymph node and central nervous system (CNS) involvement. Although various regimens are used, a standard therapeutic strategy for BPDCN has not been established. Recent studies revealed that BPDCN patients frequently have a mutation in ZRSR2, which is a minor spliceosome component. However, the association between the clinical features of BPDCN and ZRSR2 mutational status remains unknown. A 70-year-old man was referred to our hospital with skin rash and enlarged lymph nodes, as well as blasts in the peripheral blood. BPDCN was diagnosed based on the immunophenotype of the blasts derived from bone marrow. Whole exome sequencing revealed that BPDCN cells collected at diagnosis had mutations in ZRSR2, ZBTB33, CUL3, TET2 and NRAS. RNA sequencing analysis indicated that U12-type intron retention occurred in LZTR1, caused by ZRSR2 loss. After seven cycles of venetoclax combined with azacitidine therapy, BPDCN cells appeared in the peripheral blood and infiltrated the CNS. Two KRAS mutated clones appeared at BPDCN recurrence. These findings are important for understanding the pathogenesis of BPDCN, which will inform development of novel therapeutic strategies.

Successful allogeneic hematopoietic stem cell transplantation for myelodysplastic neoplasms complicated with secondary pulmonary alveolar proteinosis and Behçet's disease harboring GATA2 mutation.

Myelodysplastic neoplasms (MDS) are defined by cytopenia and morphologic dysplasia originating from clonal hematopoiesis. They are also frequently complicated with diseases caused by immune dysfunction, such as Behçet's disease (BD) and secondary pulmonary alveolar proteinosis (sPAP). MDS with both BD and sPAP is extremely rare, and their prognosis is poor. In addition, haploinsufficiency of the hematopoietic transcription factor gene GATA2 is recognized as a cause of familial MDS and is frequently complicated by sPAP. Herein, we report a case of MDS combined with both BD and sPAP in association with GATA2 deficiency in a Japanese woman. Because she developed progressive leukopenia and macrocytic anemia during BD treatment at the age of 61, she underwent a bone-marrow examination and was diagnosed with MDS. She subsequently developed sPAP. At the age of 63, she underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). Since allo-HSCT, she has maintained complete remission of MDS as well as the symptoms of BD and sPAP. Furthermore, we performed whole exome sequencing and identified the GATA2 Ala164Thr germline mutation. These findings suggest that patients with MDS, BD and sPAP should be considered for early allo-HSCT.

Outcomes of adult patients with early T-cell precursor (ETP) acute lymphoblastic leukemia/lymphoma (ALL) and non-ETP T-ALL.

Early T-cell precursor (ETP) acute lymphoblastic leukemia/lymphoma (ALL) is generally considered to be a high-risk subtype. We retrospectively analyzed the clinical outcomes of adult patients diagnosed with ETP-ALL or other T-cell ALL (non-ETP T-ALL). The subjects were 82 patients (ETP-ALL: n = 18, non-ETP T-ALL: n = 64) for whom relevant immunophenotype data needed for classification were available. ETP-ALL patients were older (median age, 50.5 vs. 33.5 years, P = 0.042) and had less mediastinal involvement (27.8 vs. 73.4%, P < 0.001). The rate of complete remission (CR) with the first induction therapy was significantly lower in the ETP group (33.3 vs. 64.0%, P = 0.03), but the CR rate within 2 cycles of chemotherapy did not differ significantly (61.1 vs. 76.6%, P = 0.232). The 3-year overall survival (OS) rate was also similar in both groups (43.2 vs. 45.8%, P = 0.992). The ETP phenotype had no impact on survival in the transplant group or the non-transplant group. A multivariate analysis identified the male sex as a poor prognostic factor (HR: 4.43, P < 0.01), but not the immunophenotype of ETP. The prognosis for adult patients with ETP-ALL was comparable to that of non-ETP T-ALL patients. However, further studies aimed at improving the remission rate for ETP-ALL are needed.

Successful management of unstable angina in a ravulizumab-treated patient with paroxysmal nocturnal hemoglobinuria.

Ravulizumab is an anti-C5 antibody approved for treating paroxysmal nocturnal hemoglobinuria (PNH). In August 2019, a 77-year-old Japanese man with PNH, who had been on ravulizumab treatment for 2 years, was hospitalized for chest discomfort and malaise. Electrocardiography identified a right bundle block, and elevated serum troponin I and d-dimer suggested ischemic heart disease. Cardiac catheterization revealed severe stenosis in the left anterior descending coronary artery, and intracoronary stenting relieved his chest discomfort. The final diagnosis was unstable angina unrelated to ravulizumab, and the patient's ravulizumab treatment was uninterrupted with no significant complications of PNH. This case report highlights the importance of continuing complement inhibition therapy during acute coronary events.

The suppressive effects of Mer inhibition on inflammatory responses in the pathogenesis of LPS-induced ALI/ARDS.

The pathogenesis of sepsis-induced acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) has not yet been fully elucidated. Growth arrest-specific 6 (Gas6) has marked effects on hemostasis and reduces inflammation through its interaction with receptor tyrosine kinases of the TAM family: Tyro3, Axl, and Mer. Here, we found that plasma concentrations of Gas6 and soluble Mer were greater in patients with severe sepsis or septic ALI/ARDS compared with those in normal healthy donors. To determine whether the Gas6-Mer axis was critical in the pathogenesis of ALI/ARDS, we investigated the effects of intravenous administration of the selective Mer inhibitor UNC2250 on lipopolysaccharide (LPS)-induced ALI in mouse models subjected to inhalation of LPS. UNC2250 markedly inhibited the infiltration into the lungs of neutrophils and monocytes with increased amounts of Gas6 and Mer proteins, severe lung damage, and increased amounts of reactive oxygen species (ROS) in LPS-induced ALI in mice. In human pulmonary aortic endothelial cells, LPS induced decreases in the amounts of endothelial nitric oxide synthase, thrombomodulin, and vascular endothelial-cadherin, which was blocked by treatment with UNC2250. UNC2250 also inhibited the LPS-dependent increases in cell proliferation and enhanced apoptosis in HL-60 cells, a human neutrophil-like cell line, and RAW264.7 cells, a mouse monocyte/macrophage cell line. These data provide insights into the potential multiple beneficial effects of the Mer inhibitor UNC2250 as a therapeutic reagent to treat inflammatory responses in ALI/ARDS.

Case Report: Coexistence of Multiple Myeloma and Auricular Chondritis in VEXAS Syndrome.

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is an inflammatory disorder caused by somatic UBA1 variants, which are sometimes associated with hematological disorders, including myelodysplastic syndrome (MDS). VEXAS syndrome often overlaps with rheumatic diseases, including relapsing polychondritis. Here, we describe a case of VEXAS syndrome with auricular chondritis and exceptional multiple myeloma (MM). An 83-year-old man was diagnosed with MM, which was treated once by lenalidomide hydrate obtaining a partial response, but the patient did not desire further aggressive therapy. Although the treatment was effective, progressive macrocytic anemia and inflammation of both the ears emerged over the following 2 months. The histological examination of the auricle skin revealed that the perichondrial area was infiltrated by inflammatory cells, leading to the diagnosis of auricular chondritis. He was treated with oral prednisolone 40 mg/day, and his symptoms rapidly resolved. The re-evaluation of the histopathological bone marrow findings revealed vacuoles in the myeloid precursor cells without myelodysplasia-related changes. Sanger sequencing of UBA1 was performed using genomic DNA from peripheral blood leukocytes and revealed a somatic variant (c.122T>C:p.Met41Thr) consistent with VEXAS syndrome. This demonstrates that patients with chondritis can have complications with MM despite the absence of underlying MDS. A strong association exists between UBA1 variants and the risk of MDS; however, it remains elusive whether somatic UBA1 variants contribute to the development of plasma cell dyscrasia without MDS. Hence, we discuss the possible relationship between auricular chondritis and MM on a background of VEXAS syndrome.

Dasatinib induces endothelial-to-mesenchymal transition in human vascular-endothelial cells: counteracted by cotreatment with bosutinib.

Adverse vascular events have become a serious clinical problem in chronic myeloid leukemia (CML) patients who receive certain BCR/ABL1 tyrosine kinase inhibitors (TKIs). Studies have shown that endothelial-to-mesenchymal transition (EndMT) can contribute to various vascular diseases. We investigated the effects of TKIs on the development of EndMT in human vascular-endothelial cells (VECs). Exposure of VECs to dasatinib, but not to other TKIs, produced a significant increase in the formation of spindle-shaped cells. This effect was accompanied by a significant increase in expression of the EndMT inducer transforming growth factor-ß (TGF-ß) and mesenchymal markers vimentin, smooth muscle alpha-actin, and fibronectin, as well as a significant decrease in expression of vascular-endothelial markers CD31 and VE-cadherin attributable at least in part to activation of ERK signaling. Inhibitors of TGF-ß and ERK partially attenuated dasatinib-induced EndMT. Interestingly, bosutinib efficiently counteracted dasatinib-induced EndMT and attenuated dasatinib-induced phosphorylation of ERK. Taken together, these results show that dasatinib induces EndMT, which might contribute to the development of vascular toxicity, such as the pulmonary hypertension observed in CML patients receiving dasatinib. Bosutinib could play a distinct role in protecting VECs from EndMT.

Heterogeneity in the diagnosis of plasmablastic lymphoma, plasmablastic myeloma, and plasmablastic neoplasm: a scoping review.

The diagnosis of plasmablastic lymphoma (PBL), plasmablastic myeloma (PBM), and plasmablastic neoplasm (PBN) may be arbitrary in some cases because these entities can be indistinct. We conducted this scoping review to investigate heterogeneity in diagnostic criteria used in previous studies and validate the diagnostic results of previous diagnostic algorithms and the algorithm we developed, which also includes diagnosis of PBN. Using the PRISMA Extension for Scoping Reviews, we analyzed literature published between September 2017 and April 2020. We identified a total of 163 cases (128 PBL, 32 PBM, and 3 PBN) from 77 case reports and 8 case series. We found that diagnostic criteria in the literature varied for PBL but were consistent for PBM. Our algorithm was the first attempt to include PBN in a complete structure. The results of the three diagnostic algorithms varied significantly. Hematologists and pathologists should pay more attention to the differential diagnosis of PBL, PBM, and PBN.