Tisagenlecleucel therapy has shown promising efficacy for relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, relapses occur in 30-50% of patients. ...Determinants for CD19
versus CD19
relapses are poorly characterized. We report on 51 patients with R/R BCP-ALL (median age 17 years) infused with tisagenlecleucel after lymphodepletion. Complete remission rate at D28 was 96%. Prior blinatumomab increased the risk of early failure at D28. The 18-month cumulative incidence of relapse (CIR), event-free survival (EFS), and overall survival (OS) were 51%, 44%, and 74%, respectively, at a median follow-up of 15.5 months. Factors associated with a high tumor burden (occurrence of cytokine release syndrome) and prior blinatumomab were associated with an increased CIR, and a shorter EFS and OS. Pre-lymphodepletion high disease burden (MRD ≥ 10
, SHR 10.4, p = 0.03) and detectable MRD at D28 (SHR 7.2, p = 0.006) correlated with an increased risk of CD19
relapse. Low disease burden (SHR 5.3, p = 0.03) and loss of B-cell aplasia (BCA) (SHR 21.7, p = 0.004) predicted an increased risk of CD19
relapses. These data highlight the impact of prior therapy on patient outcome. Finally, detectable MRD at D28 and loss of BCA both define patients at high risk of relapse for whom additional interventions are needed.
Background
Hepatitis‐associated aplastic anemia (AA) is a rare syndrome combining acute hepatitis of variable severity and AA. Hepatitis may be severe enough to require urgent liver transplantation ...(LT). Herein, we describe clinical presentation and management of a cohort of pediatric patients diagnosed with AA after undergoing LT for nonviral hepatitis.
Methods
To describe this rare clinical situation, we performed a national survey and identified nine children treated for AA following LT during the last 10 years in France.
Results
All patients were treated first for hepatic failure with urgent LT. AA was diagnosed with a median delay of 34 days 21‐200 from the diagnosis of hepatitis. Seven children were treated with antithymocyte globulin/cyclosporine, one with CSA alone and one received bone marrow transplantation. At the last visit (median follow‐up: 4 years), outcomes were excellent: all patients were alive and in hematological remission (complete remission: 7; partial remission: 2). Immunosuppressive therapy was pursued in all patients due to the liver transplant. No unusual toxicities were reported.
Conclusion
AA after LT is considered a therapeutic challenge. Nevertheless, hematological outcome is good using a standard immunosuppressive approach.
T-cell acute lymphoblastic leukemia (T-ALL) has a dismal prognosis in case of relapsed or refractory disease. Contrary to B-ALL, few immunotherapies are available for T-ALL. Use of autologous CAR ...T-cells is challenging due to shared antigen between leukemic and normal T-cells responsible for fratricide and T-cell aplasia in case of persistence of CAR T-cells. Moreover, risk of contamination of the apheresis product by lymphoblasts remains an issue. To counteract these challenges several methods are used to edit T-cell such as protein expression blocker, CRISPR/Cas9 and base-editing. Other possibility is to use autologous T-cells naturally selected in vitro or donor-derived T-cells allowing gene edition and reduction of the risk of graft vs host disease. Encouraging results are obtained in preclinical and clinical studies for early response rate but several questions remain. Is the persistence of these cells requiring for maintaining the remission? Is it feasible to recover a target-negative T-cell population without risk of profound immunosuppression? Has an allogeneic stem cell transplantation to be planned for patients after CAR T-cells infusion? What about the risk of engineered T-cells in the long term?
•CAR T-cells in T-ALL is challenging due to fratricide and T-cell aplasia.•Several methods are already used to edit CAR T-cells to counteract these obstacles.•Donor-derived T-cells could be an option to obtain CAR T-cells for T-ALL.•The role of persistence of CAR T-cells in T-ALL is not yet well identified.
Summary
In a patient with severe microcephaly, congenital bone marrow failure, growth retardation, and renal hypoplasia, we identified a likely pathogenic variant in NUF2 that impairs the cell's ...ability to properly complete mitosis. Interestingly, these clinical features as well as the observed cellular alterations are highly reminiscent of what is reported in Fanconi Anaemia supporting a unifying causal role of the variant in the disease. This case provides the first evidence that a kinetochore defect, previously associated with microcephaly, can be responsible for an inherited bone marrow failure syndrome, highlighting the unique pathological link between neurogenesis and haematopoiesis.
T-cell acute lymphoblastic leukemias (T-ALL) represent 15% of pediatric and 25% of adult ALL. Since they have a particularly poor outcome in relapsed/refractory cases, identifying prognosis factors ...at diagnosis is crucial to adapting treatment for high-risk patients. Unlike acute myeloid leukemia and BCP ALL, chromosomal rearrangements leading to chimeric fusion-proteins with strong prognosis impact are sparsely reported in T-ALL. To address this issue an RT-MPLA assay was applied to a consecutive series of 522 adult and pediatric T-ALLs and identified a fusion transcript in 20% of cases. PICALM-MLLT10 (4%, n = 23), NUP214-ABL1 (3%, n = 19) and SET-NUP214 (3%, n = 18) were the most frequent. The clinico-biological characteristics linked to fusion transcripts in a subset of 235 patients (138 adults in the GRAALL2003/05 trials and 97 children from the FRALLE2000 trial) were analyzed to identify their prognosis impact. Patients with HOXA trans-deregulated T-ALLs with MLLT10, KMT2A and SET fusion transcripts (17%, 39/235) had a worse prognosis with a 5-year EFS of 35.7% vs 63.7% (HR = 1.63; p = 0.04) and a trend for a higher cumulative incidence of relapse (5-year CIR = 45.7% vs 25.2%, HR = 1.6; p = 0.11). Fusion transcripts status in T-ALL can be robustly identified by RT-MLPA, facilitating risk adapted treatment strategies for high-risk patients.
The reintegration of excised signal joints resulting from human V(D)J recombination was described as a potent source of genomic instability in human lymphoid cancers. However, such molecular events ...have not been recurrently reported in clinical patient lymphoma/leukemia samples. Using a specifically designed NGS-capture pipeline, we here demonstrated the reintegration of T-cell receptor excision circles (TRECs) in 20/1533 (1.3%) patients with T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL). Remarkably, the reintegration of TREC recurrently targeted the tumor suppressor gene, ZFP36L2, in 17/20 samples. Thus, our data identified a new and hardly detectable mechanism of gene deregulation in lymphoid cancers providing new insights in human oncogenesis.
IDH1 and IDH2 mutations (IDH1/2
) are recognized as recurrent genetic alterations in acute myeloid leukemia (AML) and associated with both clinical impact and therapeutic opportunity due to the ...recent development of specific IDH1/2
inhibitors. In T-cell acute lymphoblastic leukemia (T-ALL), their incidence and prognostic implications remain poorly reported. Our targeted next-generation sequencing approach allowed comprehensive assessment of genotype across the entire IDH1 and IDH2 locus in 1085 consecutive unselected and newly diagnosed patients with T-ALL and identified 4% of, virtually exclusive (47 of 49 patients), IDH1/2
. Mutational patterns of IDH1/2
in T-ALL present some specific features compared to AML. Whereas IDH2
mutation was frequent in T-ALL (25 of 51 mutations), the IDH2
AML hotspot was absent. IDH2 mutations were associated with older age, an immature phenotype, more frequent RAS gain-of-function mutations and epigenetic regulator loss-of-function alterations (DNMT3A and TET2). IDH2 mutations, contrary to IDH1 mutations, appeared to be an independent prognostic factor in multivariate analysis with the NOTCH1/FBXW7/RAS/PTEN classifier. IDH2
were significantly associated with a high cumulative incidence of relapse and very dismal outcome, suggesting that IDH2-mutated T-ALL cases should be identified at diagnosis in order to benefit from therapeutic intensification and/or specific IDH2 inhibitors.
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