Characteristics and long-term outcome in a large series of chronic myelomonocytic leukaemia patients including 104 formerly referred to as oligomonocytic.

Recently modified diagnostic criteria for chronic myelomonocytic leukaemia (CMML) have lowered the cut-off for absolute monocytosis. In the largest series to date, we have analysed 313 CMML patients, including 104 with oligomonocytic (OM)-CMML. Five-year survival was longer for OM-CMML than for other patients (p < 0.001). Multivariate analysis identified OM-CMML as a favourable prognostic factor (HR 0.58; p = 0.002). The 5-year cumulative incidence of progression to classical CMML was 47%. Older age and transfusion dependence were adverse prognostic factors for OM-CMML. Our results support the inclusion of OM-CMML in the CMML category as a subtype with superior outcomes.

Diagnosis of Bone Marrow Necrosis following Severe Vaso-Occlusive Crisis in Patient with Compound Heterozygous Sickle Cell Disease.

Introduction: Bone marrow necrosis is a rare entity that can develop in context of a sickle cell disease vaso-occlusive crisis. Its physiopathology is related to an endothelial dysfunction taking place in bone marrow microvasculature. Case Presentation: A 30-year-old patient with history of compound heterozygous sickle cell disease was admitted following SARS-CoV-2 infection with fever and diarrhea. After initial favorable evolution, he developed a severe vaso-occlusive crisis with intense hemolysis and multi-organ ischemic complications. Patient then developed high fever and hypoxemia. With the suspicion of acute thoracic syndrome, a red blood cell exchange was performed. Respiratory symptoms ceased but patient persisted febrile with very high levels of acute phase reactants, persistent pancytopenia, and leucoerythroblastic reaction. An infectious cause was ruled out. Afterward, bone marrow aspiration and bone marrow biopsy showed a picture of bone marrow necrosis, which is an extremely rare complication of vaso-occlusive crisis but, paradoxically, more frequent in milder heterozygote cases of sickle cell disease. Ultimately, large deposits of complement membrane attack complex (particles C5b-9) were demonstrated after incubation of laboratory endothelial cells with activated plasma from the patient. Discussion: The clinical presentation and findings are consistent with a case of bone marrow necrosis. In this setting, the demonstration of complement as a potential cause of the endothelial dysfunction mimics the pattern of atypical hemolytic uremic syndrome and other microangiopathic anemias. This dysregulation may be a potential therapeutic target for new complement activation blockers.

Germ line variants in patients with acute myeloid leukemia without a suspicion of hereditary hematologic malignancy syndrome.

Germ line predisposition in acute myeloid leukemia (AML) has gained attention in recent years because of a nonnegligible frequency and an impact on management of patients and their relatives. Risk alleles for AML development may be present in patients without a clinical suspicion of hereditary hematologic malignancy syndrome. In this study we investigated the presence of germ line variants (GVs) in 288 genes related to cancer predisposition in 47 patients with available paired, tumor-normal material, namely bone marrow stroma cells (n = 29), postremission bone marrow (n = 17), and saliva (n = 1). These patients correspond to 2 broad AML categories with heterogeneous genetic background (AML myelodysplasia related and AML defined by differentiation) and none of them had phenotypic abnormalities, previous history of cytopenia, or strong cancer aggregation. We found 11 pathogenic or likely pathogenic variants, 6 affecting genes related to autosomal dominant cancer predisposition syndromes (ATM, DDX41, and CHEK2) and 5 related to autosomal recessive bone marrow failure syndromes (FANCA, FANCM, SBDS, DNAJC21, and CSF3R). We did not find differences in clinical characteristics nor outcome between carriers of GVs vs noncarriers. Further studies in unselected AML cohorts are needed to determine GV incidence and penetrance and, in particular, to clarify the role of ATM nonsense mutations in AML predisposition.

The evolution of hematopoietic cells under cancer therapy.

Chemotherapies may increase mutagenesis of healthy cells and change the selective pressures in tissues, thus influencing their evolution. However, their contributions to the mutation burden and clonal expansions of healthy somatic tissues are not clear. Here, exploiting the mutational footprint of some chemotherapies, we explore their influence on the evolution of hematopoietic cells. Cells of Acute Myeloid Leukemia (AML) secondary to treatment with platinum-based drugs show the mutational footprint of these drugs, indicating that non-malignant blood cells receive chemotherapy mutations. No trace of the 5-fluorouracil (5FU) mutational signature is found in AMLs secondary to exposure to 5FU, suggesting that cells establishing the leukemia could be quiescent during treatment. Using the platinum-based mutational signature as a barcode, we determine that the clonal expansion originating the secondary AMLs begins after the start of the cytotoxic treatment. Its absence in clonal hematopoiesis cases is consistent with the start of the clonal expansion predating the exposure to platinum-based drugs.

Outcomes of CD19 Chimeric Antigen Receptor T Cell Therapy in Patients with Gastrointestinal Tract Involvement of Large B Cell Lymphoma.

CD19-directed chimeric antigen receptor (CAR) T cell therapy with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) is approved for the standard of care treatment of relapsed or refractory large B cell lymphoma (LBCL). Patients with LBCL involving the gastrointestinal (GI) tract are at risk of perforation after lymphoma-directed therapy. The outcomes of CAR T cell therapy in patients with GI involvement have not been reported previously. This study aimed to determine the safety and efficacy of CD19 CAR T cell therapy in patients with LBCL involvement of the GI tract. This was a single-center retrospective study of 130 consecutive patients treated with standard of care or expanded-access axi-cel or tisa-cel for LBCL. Twenty-four of these patients had radiologic involvement of the GI tract before CAR T infusion. Incidence rates of severe immune effector cell-mediated toxicities and clinical outcomes were compared between the GI involvement and non-GI involvement groups. Three of the 24 patients with GI tract involvement experienced perforation. One patient had a contained gastric perforation after leukapheresis while receiving bridging radiation therapy to the stomach. This patient was eventually able to proceed with lymphodepletion and product infusion. In the other 2 patients, GI tract perforation occurred at day +13 and day +35 after CAR T infusion. All 3 patients subsequently died while experiencing lymphoma progression. Upper GI bleeding occurred in 1 other patient in the context of progressive disease at 6 months after product infusion. The incidence rates of severe cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, length of hospital stay, and use of anti-IL-6 and steroids were similar in the 24 patients with GI tract involvement and the 106 patients without GI tract involvement. No significant between-group differences were seen in the best overall response rate, progression-free survival, or overall survival. Our data show that outcomes of patients with GI tract involvement before CAR T cell therapy are similar to those without GI involvement, and that durable remissions can be observed. However, patients with preexisting GI tract involvement are at risk of perforation from disease progression before and after CAR T cell infusion.