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Among adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia, treatment with the bispecific anti-CD19 and anti-CD3 monoclonal antibody blinatumomab resulted in longer overall survival and higher remission rates than did chemotherapy. The prognosis for adults with newly diagnosed acute lymphoblastic leukemia (ALL) has improved over the past three decades. With the use of intensive chemotherapy regimens, complete remission rates are 85 to 90% and long-term survival rates are 30 to 50%. 1 – 4 Still, most adults with B-cell precursor ALL will have a relapse and will die from complications of resistant disease or associated treatment. Among adults with relapsed or refractory ALL, remission rates are 18 to 44% with the use of standard salvage chemotherapy, but the duration of remission is typically short. 5 – 10 A major goal in this population is to . . .

Recent advances in antibody technology to harness T cells for cancer immunotherapy, particularly in the difficult-to-treat setting of relapsed/refractory acute lymphoblastic leukemia (r/r ALL), have led to innovative methods for directing cytotoxic T cells to specific surface antigens on cancer cells. One approach involves administration of soluble bispecific (or dual-affinity) antibody-based constructs that temporarily bridge T cells and cancer cells. Another approach infuses ex vivo- engineered T cells that express a surface plasma membrane-inserted antibody construct called a chimeric antigen receptor (CAR). Both bispecific antibodies and CARs circumvent natural target cell recognition by creating a physical connection between cytotoxic T cells and target cancer cells to activate a cytolysis signaling pathway; this connection allows essentially all cytotoxic T cells in a patient to be engaged because typical tumor cell resistance mechanisms (such as T-cell receptor specificity, antigen processing and presentation, and major histocompatibility complex context) are bypassed. Both the bispecific T-cell engager (BiTE) antibody construct blinatumomab and CD19-CARs are immunotherapies that have yielded encouraging remission rates in CD19-positive r/r ALL, suggesting that they might serve as definitive treatments or bridging therapies to allogeneic hematopoietic cell transplantation. With the introduction of these immunotherapies, new challenges arise related to unique toxicities and distinctive pathways of resistance. An increasing body of knowledge is being accumulated on how to predict, prevent, and manage such toxicities, which will help to better stratify patient risk and tailor treatments to minimize severe adverse events. A deeper understanding of the precise mechanisms of action and immune resistance, interaction with other novel agents in potential combinations, and optimization in the manufacturing process will help to advance immunotherapy outcomes in the r/r ALL setting.

Activating mutations in the NOTCH1 pathway are frequent in pediatric T-cell acute lymphoblastic leukemia (T-ALL) but their role in refining risk stratification is unclear. We screened 162 pediatric T-ALL patients treated on the MRC UKALL2003 trial for NOTCH1/FBXW7 gene mutations and related genotype to response to therapy and long-term outcome. Overall, 35% were wild-type (WT) for both genes ( NOTCH1 WT FBXW7 WT ), 38% single NOTCH1 mutant ( NOTCH1 Single FBXW7 WT ), 3% just FBXW7 mutant ( NOTCH1 WT FBXW7 MUT ) and 24% either double NOTCH1 mutant ( NOTCH1 Double FBXW7 WT ) or mutant in both genes ( NOTCH1 MUT FBXW7 MUT ), hereafter called as NOTCH1 ± FBXW7 Double . There was no difference between groups in early response to therapy, but NOTCH1 ± FBXW7 Double patients were more likely to be associated with negative minimal residual disease (MRD) post-induction than NOTCH1 WT FBXW7 WT patients (71% versus 40%, P =0.004). Outcome improved according to the number of mutations, overall survival at 5 years 82%, 88% and 100% for NOTCH1 WT FBXW7 WT , NOTCH1 Single FBXW7 WT and NOTCH1 ± FBXW7 Double patients, respectively (log-rank P for trend=0.005). Although 14 NOTCH1 ± FBXW7 Double patients were classified as high risk (slow response and/or MRD positive), only two had disease progression and all remain alive. Patients with double NOTCH1 and/or FBXW7 mutations have a very good outcome and should not be considered for more intensive therapy in first remission, even if slow early responders or MRD positive after induction therapy.

Abstract Background Advances in care have led to improvements in survival for adolescents and young adults (AYAs) diagnosed with cancer; however, the risk of early death remains high for certain cancers, particularly acute leukemias. Risk factors for early death in AYAs diagnosed with acute leukemia have not been well studied. Methods The Surveillance, Epidemiology, and End Results registry was used to assess risk of early death (within 2 months of diagnosis) in AYAs diagnosed with acute leukemia (n = 16 153). Early death proportion, by year, for AYAs diagnosed between 2006 and 2020 was described. Associations between incidence of early death and age at diagnosis, sex, race and ethnicity, socioeconomic status, rurality, acute leukemia type, and year of diagnosis were evaluated with logistic regression. Results Overall, 6.0% of AYAs experienced early death and there was a significant annual decrease in the odds of early death (odds ratio [OR] = 0.96, 95% confidence interval [CI] = 0.95 to 0.98, P < .0001) across the study period. Over the entire study period, AYAs diagnosed with acute promyelocytic leukemia (9.6%, 95% CI = 8.4 to 11.1) or other acute leukemias (13.3%, 95% CI = 10.5 to 16.7) had the highest proportion of early death and AYAs diagnosed with T lymphoblastic leukemia/lymphoma had the lowest (2.6%, 95% CI = 1.9 to 3.7). Older age at diagnosis, male sex, and Hispanic ethnicity were all associated with increased risk of early death. Conclusions A high proportion of AYAs with acute leukemia experience early death and risk varies by leukemia type and sociodemographic factors. A better understanding of the complex interplay between disease biology and sociodemographic factors is needed to guide risk prediction and prevention.

In this study, adoptively transferred T cells transfected with anti-CD19 and activating signal–generating molecules led to complete remission in 90% of patients with relapsed and refractory acute leukemia, and overall survival at 6 months was 78%. Engineered T-cell therapy is a new strategy for the treatment of relapsed and refractory acute lymphoblastic leukemia (ALL), which is associated with an extremely poor prognosis in adults and remains a leading cause of death from childhood cancer. 1 – 3 In initial proof-of-principle clinical trials involving patients with chronic lymphocytic leukemia (CLL), chimeric antigen receptor–modified T cells that target CD19 produced a durable complete remission in a small number of patients. 4 – 6 Our group and others then extended these findings to relapsed and refractory B-cell ALL, and we found profound responses in a small number of children and adults. 7 , 8 Chimeric . . .

CD19-specific CAR T cells were produced centrally for a global study in young people with relapsed B-cell ALL. The overall remission rate was 81%, and patients with a response were negative for minimal residual disease. High-grade toxic effects were frequent but treatable.

Dramatic progress in the treatment of childhood acute lymphoblastic leukemia (ALL) has been achieved during the last two decades in Western countries, where the 5-year event-free survival (EFS) rate has risen from 30 to 85 %. However, similarly high cure rates have not always been achieved in all centers in developing countries due to limited sources. We evaluated the treatment results of the ALL-Berlin–Frankfurt–Münster (BFM) 95 protocol as used between 1995 and 2009 in the pediatric hematology departments of two university hospitals. A retrospective analysis of 343 children newly diagnosed with ALL (M/F 200/143, median age 6.8 years) was performed. The overall survival (OS) and EFS according to age, initial leukocyte count, immunophenotype, chemotherapy responses (on days 8, 15, and 33), and risk groups were analyzed by Kaplan–Meier survival analysis. Median follow-up time was 6.4 years. Complete remission was achieved in 97 % of children. Five-year EFS and OS were found to be 78.4 and 79.9 %, respectively. Children younger than 6 years old had significantly better EFS and OS (83.7 and 85.2 %) than children aged ≥6 years (71.4 and 72.8 %). Adolescents achieved 63 % EFS and 65 % OS. Patients who had initial leukocyte counts of <20 × 10 9 /L had better EFS and OS (82.2 and 84.6 %) than children with higher initial leukocyte counts (72.6 and 72.6 %). EFS for B-cell precursor and T-cell ALL was 81.5 and 66.7 %, respectively. Children with a good response to prednisolone on day 8 (87 %) achieved significantly better EFS and OS (81.2 and 81.9 % vs. 55.3 and 60.5 %). Children whose bone marrow on day 15 was in complete remission had higher EFS and OS (83.7 and 86.6.1 % vs. 56.4 and 61.5 %). Children in the standard-risk and medium-risk groups obtained statistically significantly higher EFS (95.5 and 82.7 %) and OS (97.7 and 82.3 %) compared to the high-risk group (EFS 56.3 %, OS 63.4 %). The relapse rate was 14.8 %. The median relapse time from diagnosis was 23.2 months. Death occurred in 69 of 343 patients (20.1 %). The major causes of death were infection and relapse. None of the patients died of drug-related toxicity. The ALL-BFM 95 protocol was applied successfully in these two centers. In developing countries in which minimal residual disease cannot be monitored, this protocol can still be used with high survival rates.

CAR T cells expressing anti-CD19 and signaling molecules CD28 and CD3-zeta chain induced complete remission in 83% of patients with refractory ALL. Patients with a low disease burden had longer survival and a lower rate of toxic effects than those with a high disease burden.

The most frequent targets of genetic alterations in human leukemias are transcription factor genes with essential functions in normal blood cell development. The Interferon Regulatory Factor 4 (IRF4) gene encodes a transcription factor important for key developmental stages of hematopoiesis, with known oncogenic implications in multiple myeloma, adult leukemias and lymphomas. Very few studies have reported an association of IRF4 with childhood malignancy, whereas high transcript levels have been observed in the more mature immunophenotype of ALL. Our aim was to investigate the expression levels of IRF4 in the diagnostic samples of pediatric leukemias and compare them to those of healthy controls, in order to determine aberrant gene expression and whether it extends to leukemic subtypes other than the relatively mature ALL subpopulation. Quantitative real-time RT-PCR methodology was used to investigate IRF4 expression in 58 children with acute leukemias, 4 leukemic cell lines and 20 healthy children. We show that aberrant IRF4 gene expression is implicated in a variety of leukemic subtypes; higher transcript levels appear in the more immature B-common ALL subtype and in T-cell than in B-cell leukemias, with the highest expression levels appearing in the AML group. Interestingly, we show that childhood leukemia, irrespective of subtype or cell maturation stage, is characterised by a minimum of approximately twice the amount of IRF4 gene expression encountered in healthy children. A statistically significant correlation also appeared to exist between high IRF4 expression and relapse. Our results show that ectopic expression of IRF4 follows the reverse expression pattern of what is encountered in normal B-cell development and that there might be a dose-dependency of childhood leukemia for aberrantly expressed IRF4, a characteristic that could be explored therapeutically. It is also suggested that high IRF4 expression might be used as an additional prognostic marker of relapse at diagnosis.

T‐cell acute lymphoblastic leukemia (T‐ALL) is a clonal proliferative malignant disease characterized by abnormal T‐cell development. The classification of T‐ALL primarily hinges on immunophenotype, encompassing early T‐cell precursor (ETP)‐ALL, near‐ETP‐ALL, and non‐ETP‐ALL. We summarized clinical information from 117 patients, with genetic data available for 77 patients and transcriptomic data available for 24 patients. An ETP‐like score model was established based on transcriptome, aiming to address the subjectivity in the current T‐ALL immunophenotype classification. The retrospective analysis indicated that ETP immunophenotype was not a prognostic factor for T‐ALL patients. Compared to non‐ETP‐ALL patients, ETP‐like patients including ETP‐ALL and near‐ETP‐ALL were more likely to carry MED12 gene mutations, which may predict a dismal outcome. Transcriptomic analysis suggested that T‐ALL patients with different immunophenotypes were in accordance with the T‐cell development trajectory, while ETP‐like patients exhibited characteristics of early T‐cell development. Finally, we established an ETP‐like score model and confirmed its efficiency across four independent cohorts, with sensitivity exceeding 80%. And T‐ALL patients with high ETP‐like score were associated with poor prognosis. In conclusion, our study elucidated the clinical and molecular features of distinct subtypes of T‐ALL patients, providing new valuable insights for T‐ALL classification. This study categorized T‐ALL patients into 3 distinct subgroups: ETP‐like group, immature T‐ALL group, and mature T‐ALL group based on transcriptome. ETP‐like patients exhibited characteristics of early T‐cell development, which can be identified by the ETP‐like score model.