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Key Points TCM-derived CD19 CAR T–cell therapy is safe for treatment of poor-risk NHL patients undergoing autologous HSCT. Addition of a CD28 costimulatory domain to the CAR, plus changes to T-cell product manufacturing, resulted in improved T-cell expansion.

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Post-transplant thrombotic microangiopathy (TMA) is a multi-factorial complication of allogeneic hematopoietic cell transplantation (allo-HCT) whose incidence is increased when using a sirolimus plus tacrolimus regimen for acute graft-versus-host disease (aGVHD) prophylaxis. We evaluated the incidence and possible risk factors for TMA in a case series of 177 patients who received allo-HCT using SIR/TAC-based GVHD prophylaxis. Donors were either sibling (n=82) or matched unrelated (n=95). Within the first 100 days post-HCT, 30 (17%) patients were diagnosed with TMA, and an additional nine patients (5%) were classified as probable TMA cases. The median time to TMA onset was 4.6 weeks (range: 1.6-10.6). Thirty-four patients developed both TMA and aGVHD, with the majority of patients (81%) developing aGVHD first. By multivariable analysis, the following factors were found to be associated with increased risk of TMA: day 14 serum sirolimus: ≥9.9 ng/ml (HR: 2.19, 95% CI: 1.13-4.27, p=0.02), presence of prior aGVHD grades II-IV (HR: 3.04, 95% CI: 1.38-6.71, p<0.01), and fully myeloablative conditioning (HR: 3.47, 95% CI: 1.60-7.53, p<0.01). The risk factors for TMA suggest that when using sirolimus/tacrolimus for GVHD prophylaxis, careful monitoring and adjustment of sirolimus dosages is critical, particularly in patients with active aGVHD.

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Key Points The incidence of IFIs during VEN-HMA therapy is low, and the used antifungal prophylaxis approach did not influence the risk of IFIs. The risk of IFIs is higher in nonresponders and those who were treated in the r/r AML setting.

FLT3-ITD-mutated acute myeloid leukemia (AML) has very high risk of relapse and is associated with poor outcome following allogeneic hematopoietic-cell transplant (allo-HCT). This two-part, phase 1, multicenter, open-label, sequential-group, dose-escalation study aimed to determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and safety/tolerability of quizartinib, a selective and highly potent FLT3 inhibitor, when administered as maintenance therapy after allo-HCT. Thirteen subjects with documented FLT3-ITD-mutated AML in morphological remission following allo-HCT received one of two quizartinib dihydrochloride dose levels (DL): 40 mg/d (DL1; n 5 7) and 60 mg/d (DL2; n 5 6), administered orally in 28-day cycles for up to 24 cycles. Median age of participants was 43 years. All subjects received human leukocyte antigen (HLA)-matched allo-HCT. One subject treated at DL1 and 1 treated at DL2 had DLTs that required drug interruption (grade 3 gastric hemorrhage and grade 3 anemia, respectively). Ten subjects (77%) received quizartinib for >1 year; 5 (38%) completed 24 cycles. Four subjects (31%) discontinued quizartinib due to adverse events. One subject (8%) experienced relapse during cycle 1 and discontinued treatment. Most common grade 3/4 adverse events were neutropenia (23%), anemia (15%), leukopenia (15%), lymphopenia (15%), and thrombocytopenia (15%). This study demonstrated acceptable tolerability and early evidence of reduced relapse rate following allo-HCT with quizartinib maintenance compared to historical cohorts. No MTD was identified, but 60 mg daily was selected as highest dose for continuous daily administration based on randomized comparison of daily 30 and 60 mg doses in relapsed/refractory AML. | I N TR ODU C TI ONAML is the most common acute leukemia in adults and a heterogenous malignancy involving clonal proliferation of abnormally or poorly differentiated hematopoietic cells of myeloid lineage. 1,2 Despite recent progress in the understanding of the biology of AML, improvements in patient outcomes have been limited over the last 30 years, and 5-year survival rate remains poor ( 25%). [2][3][4] While approximately 60% to 80% of subjects with AML achieve complete remission (CR) in response to standard of care induction/consolidation chemotherapy, disease relapse occurs in a majority of patients and is a major cause of treatment failure. Subjects with relapsed AML have poor outcomes. 1,2,4,5 Mutations of the FMS-like tyrosine kinase 3 (FLT3) receptor are among the most common molecular alterations in subjects with AML, particularly in individuals presenting with normal karyotype. 6-9 Internal tandem duplication (ITD) mutations of FLT3 occur in approximately 25% of subjects with newly diagnosed AML, resulting in constitutive activation of FLT3 kinase activity and the promotion of cellular proliferation and survival that is associated with high leukemic burden. [10][11][12][13][14] Importantly, FLT3-ITD is a driver mutation in AML, and its presence identifies a high-risk po...

Therapy-related acute lymphoblastic leukemia remains poorly defined due to a lack of large data sets recognizing the defining characteristics of this entity. We reviewed all consecutive cases of adult acute lymphoblastic leukemia treated at our institution between 2000 and 2017 and identified therapy-related cases - defined as acute lymphoblastic leukemia preceded by prior exposure to cytotoxic chemotherapy and/or radiation. Of 1022 patients with acute lymphoblastic leukemia, 93 (9.1%) were classified as therapy-related. The median latency for therapy-related acute lymphoblastic leukemia onset was 6.8 years from original diagnosis, and this was shorter for patients carrying the MLL gene rearrangement compared to those with other cytogenetics. When compared to de novo acute lymphoblastic leukemia, therapy-related patients were older (P<0.01), more often female (P<0.01), and had more MLL gene rearrangement (P<0.0001) and chromosomes 5/7 aberrations (P=0.02). Although therapy-related acute lymphoblastic leukemia was associated with inferior 2-year overall survival compared to de novo cases (46.0% vs. 68.1%, P=0.001), prior exposure to cytotoxic therapy (therapy-related) did not independently impact survival in multivariate analysis (HR=1.32; 95% CI: 0.97–1.80, P=0.08). There was no survival difference (2-year = 53.4% vs. 58.9%, P=0.68) between the two groups in patients who received allogenic hematopoietic cell transplantation. In conclusion, therapy-related acute lymphoblastic leukemia represents a significant proportion of adult acute lymphoblastic leukemia diagnoses, and a subset of cases carry clinical and cytogenetic abnormalities similar to therapy-related myeloid neoplasms. Although survival of therapy-related acute lymphoblastic leukemia was inferior to de novo cases, allogeneic hematopoietic cell transplantation outcomes were comparable for the two entities.