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Leukemia Sep 2023Polyethylene glycol (PEG)-asparaginase (pegaspargase) is a key agent in chemotherapy for acute lymphoblastic leukemia (ALL), but recipients frequently experience... (Randomized Controlled Trial)
Randomized Controlled Trial
Polyethylene glycol (PEG)-asparaginase (pegaspargase) is a key agent in chemotherapy for acute lymphoblastic leukemia (ALL), but recipients frequently experience allergic reactions. We hypothesized that by decreasing antibody-producing CD20-positive B cells, rituximab may reduce these reactions. Children and adolescents (aged 1-18 years) with newly diagnosed B-ALL treated on the St. Jude Total XVII study were randomized to induction therapy with or without rituximab on day 3 (cohort 1) or on days 6 and 24 (cohort 2). Patient clinical demographics, CD20 expression, minimal residual disease (MRD), rituximab reactions, pegaspargase allergy, anti-pegaspargase antibodies, and pancreatitis were evaluated. Thirty-five patients received rituximab and 37 did not. Among the 35 recipients, 16 (45.7%) experienced a grade 2 or higher reaction to rituximab. There were no differences between recipients and non-recipients in the incidence of pegaspargase reactions (P > 0.999), anti-pegaspargase antibodies (P = 0.327), or pancreatitis (P = 0.480). CD20 expression on day 8 was significantly lower in rituximab recipients (P < 0.001), but there were no differences in MRD levels on day 8, 15, or at the end of induction. Rituximab administration during induction in pediatric patients with B-ALL was associated with a high incidence of infusion reactions with no significant decrease in pegaspargase allergies, anti-pegaspargase antibodies, or MRD.
Topics: Adolescent; Child; Humans; Rituximab; Asparaginase; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Polyethylene Glycols; Pancreatitis; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Antineoplastic Combined Chemotherapy Protocols; Antineoplastic Agents
PubMed: 37543655
DOI: 10.1038/s41375-023-01992-z -
American Journal of Obstetrics &... Sep 2023
Topics: Humans; Birth Weight; Gestational Age; Mendelian Randomization Analysis; Risk Factors; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 37330008
DOI: 10.1016/j.ajogmf.2023.101058 -
Genome Medicine Oct 2023Mixed phenotype acute leukemia (MPAL), a rare subgroup of leukemia characterized by blast cells with myeloid and lymphoid lineage features, is difficult to diagnose and...
BACKGROUND
Mixed phenotype acute leukemia (MPAL), a rare subgroup of leukemia characterized by blast cells with myeloid and lymphoid lineage features, is difficult to diagnose and treat. A better characterization of MPAL is essential to understand the subtype heterogeneity and how it compares with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Therefore, we performed single-cell RNA sequencing (scRNAseq) on pediatric MPAL bone marrow (BM) samples to develop a granular map of the MPAL blasts and microenvironment landscape.
METHODS
We analyzed over 40,000 cells from nine pediatric MPAL BM samples to generate a single-cell transcriptomic landscape of B/myeloid (B/My) and T/myeloid (T/My) MPAL. Cells were clustered using unsupervised single-cell methods, and malignant blast and immune clusters were annotated. Differential expression analysis was performed to identify B/My and T/My MPAL blast-specific signatures by comparing transcriptome profiles of MPAL with normal BM, AML, and ALL. Gene set enrichment analysis (GSEA) was performed, and significantly enriched pathways were compared in MPAL subtypes.
RESULTS
B/My and T/My MPAL blasts displayed distinct blast signatures. Transcriptomic analysis revealed that B/My MPAL profile overlaps with B-ALL and AML samples. Similarly, T/My MPAL exhibited overlap with T-ALL and AML samples. Genes overexpressed in both MPAL subtypes' blast cells compared to AML, ALL, and healthy BM included MAP2K2 and CD81. Subtype-specific genes included HBEGF for B/My and PTEN for T/My. These marker sets segregated bulk RNA-seq AML, ALL, and MPAL samples based on expression profiles. Analysis comparing T/My MPAL to ETP, near-ETP, and non-ETP T-ALL, showed that T/My MPAL had greater overlap with ETP-ALL cases. Comparisons among MPAL subtypes between adult and pediatric samples showed analogous transcriptomic landscapes of corresponding subtypes. Transcriptomic differences were observed in the MPAL samples based on response to induction chemotherapy, including selective upregulation of the IL-16 pathway in relapsed samples.
CONCLUSIONS
We have for the first time described the single-cell transcriptomic landscape of pediatric MPAL and demonstrated that B/My and T/My MPAL have distinct scRNAseq profiles from each other, AML, and ALL. Differences in transcriptomic profiles were seen based on response to therapy, but larger studies will be needed to validate these findings.
Topics: Adult; Humans; Child; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Acute Disease; Phenotype; Sequence Analysis, RNA; Tumor Microenvironment
PubMed: 37845689
DOI: 10.1186/s13073-023-01241-z -
Nature Reviews. Disease Primers Jun 2024
Topics: Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 38871713
DOI: 10.1038/s41572-024-00531-z -
Cancer Immunology, Immunotherapy : CII Sep 2023Immunotherapy has revolutionized cancer therapy. Two recently FDA-approved immunotherapies for B-cell malignancies target CD19, in the form of a Bispecific T-Cell...
A Novel bispecific T-cell engager (BiTE) targeting CD22 and CD3 has both in vitro and in vivo activity and synergizes with blinatumomab in an acute lymphoblastic leukemia (ALL) tumor model.
Immunotherapy has revolutionized cancer therapy. Two recently FDA-approved immunotherapies for B-cell malignancies target CD19, in the form of a Bispecific T-Cell Engager (BiTE) antibody construct or chimeric antigen receptor T (CAR-T) cells. Blinatumomab, an FDA-approved BiTE, binds to CD19 on B cells and to CD3 on T cells, mediating effector-target cell contact and T-cell activation that results in effective elimination of target B cells. Although CD19 is expressed by essentially all B-cell malignancies at clinical presentation, relapses with loss or reduction in CD19 surface expression are increasingly recognized as a cause of treatment failure. Therefore, there is a clear need to develop therapeutics for alternate targets. We have developed a novel BiTE consisting of humanized anti-CD22 and anti-CD3 single chain variable fragments. Target binding of the anti-CD22 and anti-CD3 moieties was confirmed by flow cytometry. CD22-BiTE promoted in vitro cell-mediated cytotoxicity in a dose and effector: target (E:T)-dependent fashion. Additionally, in an established acute lymphoblastic leukemia (ALL) xenograft mouse model, CD22-BiTE demonstrated tumor growth inhibition, comparable to blinatumomab. Further, the combination of blinatumomab and CD22-BiTE yielded increased efficacy in vivo when compared to the single agents. In conclusion, we report here the development of a new BiTE with cytotoxic activity against CD22 cells which could represent an alternate or complementary therapeutic option for B-cell malignancies.
Topics: Humans; Animals; Mice; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Antineoplastic Agents; T-Lymphocytes; Antibodies, Bispecific; Antigens, CD19
PubMed: 37247022
DOI: 10.1007/s00262-023-03444-0 -
Current Hematologic Malignancy Reports Feb 2024Acute lymphoblastic leukemia (ALL) is a widely heterogeneous disease in terms of genomic alterations, treatment options, and prognosis. While ALL is considered largely... (Review)
Review
PURPOSE OF REVIEW
Acute lymphoblastic leukemia (ALL) is a widely heterogeneous disease in terms of genomic alterations, treatment options, and prognosis. While ALL is considered largely curable in children, adults tend to have higher risk disease subtypes and do not respond as favorably to conventional chemotherapy. Identifying genomic drivers of leukemogenesis and applying targeted therapies in an effort to improve disease outcomes is an exciting focus of current ALL research. Here, we review recent updates in ALL targeted therapy and present promising opportunities for future research.
RECENT FINDINGS
With the utilization of next-generation sequencing techniques, the genomic landscape of ALL has greatly expanded to encompass novel subtypes characterized by recurrent chromosomal rearrangements, gene fusions, sequence mutations, and distinct gene expression profiles. The evolution of small molecule inhibitors and immunotherapies, and the exploration of unique therapy combinations are some examples of recent advancements in the field. Targeted therapies are becoming increasingly important in the treatment landscape of ALL to improve outcomes and minimize toxicity. Significant recent advancements have been made in the detection of susceptible genomic drivers and the use of novel therapies to target them.
Topics: Adult; Child; Humans; Leukemia, Myeloid, Acute; Prognosis; Mutation; Biomarkers, Tumor; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 38048037
DOI: 10.1007/s11899-023-00718-3 -
Mathematical Biosciences and... Jan 2024The timely diagnosis of acute lymphoblastic leukemia (ALL) is of paramount importance for enhancing the treatment efficacy and the survival rates of patients. In this...
The timely diagnosis of acute lymphoblastic leukemia (ALL) is of paramount importance for enhancing the treatment efficacy and the survival rates of patients. In this study, we seek to introduce an ensemble-ALL model for the image classification of ALL, with the goal of enhancing early diagnostic capabilities and streamlining the diagnostic and treatment processes for medical practitioners. In this study, a publicly available dataset is partitioned into training, validation, and test sets. A diverse set of convolutional neural networks, including InceptionV3, EfficientNetB4, ResNet50, CONV_POOL-CNN, ALL-CNN, Network in Network, and AlexNet, are employed for training. The top-performing four individual models are meticulously chosen and integrated with the squeeze-and-excitation (SE) module. Furthermore, the two most effective SE-embedded models are harmoniously combined to create the proposed ensemble-ALL model. This model leverages the Bayesian optimization algorithm to enhance its performance. The proposed ensemble-ALL model attains remarkable accuracy, precision, recall, F1-score, and kappa scores, registering at 96.26, 96.26, 96.26, 96.25, and 91.36%, respectively. These results surpass the benchmarks set by state-of-the-art studies in the realm of ALL image classification. This model represents a valuable contribution to the field of medical image recognition, particularly in the diagnosis of acute lymphoblastic leukemia, and it offers the potential to enhance the efficiency and accuracy of medical professionals in the diagnostic and treatment processes.
Topics: Humans; Bayes Theorem; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Algorithms; Health Personnel; Neural Networks, Computer
PubMed: 38454670
DOI: 10.3934/mbe.2024087 -
Journal of Clinical Oncology : Official... Dec 2023Systemic combination chemotherapy and intrathecal chemotherapy markedly increased the survival rate of children with ALL. In the past two decades, the use of minimal... (Review)
Review
Systemic combination chemotherapy and intrathecal chemotherapy markedly increased the survival rate of children with ALL. In the past two decades, the use of minimal (measurable) residual disease (MRD) measurements early in therapy improved risk group stratification with subsequent treatment intensifications for patients at high risk of relapse, and enabled a reduction of treatment for low-risk patients. The recent development of more sensitive MRD technologies may further affect risk stratification. Molecular genetic profiling has led to the discovery of many new subtypes and their driver genetic alterations. This increased our understanding of the biological basis of ALL, improved risk classification, and enabled implementation of precision medicine. In the past decade, immunotherapies, including bispecific antibodies, antibody-drug conjugates, and cellular therapies directed against surface proteins, led to more effective and less toxic therapies, replacing intensive chemotherapy courses and allogeneic stem-cell transplantation in patients with relapsed and refractory ALL, and are now being tested in newly diagnosed patients. It has taken 50-60 years to increase the cure rate in childhood ALL from 0% to 90% by stepwise improvements in chemotherapy. This review provides an overview of how the developments over the past 10-15 years mentioned above have significantly changed the diagnostic and treatment approach in ALL, and discusses how the integrated use of molecular and immunotherapeutic insights will very likely direct efforts to cure those children with ALL who are not cured today, and improve the quality of life for survivors who should have decades of life ahead. Future efforts must focus on making effective, yet very expensive, new technologies and therapies available to children with ALL worldwide.
Topics: Child; Humans; Quality of Life; Neoplasm Recurrence, Local; Antineoplastic Combined Chemotherapy Protocols; Hematopoietic Stem Cell Transplantation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Neoplasm, Residual
PubMed: 37820294
DOI: 10.1200/JCO.23.01286 -
Journal of Clinical Oncology : Official... Jul 2023Failure to respond to induction chemotherapy portends a poor outcome in childhood acute lymphoblastic leukemia (ALL) and is more frequent in T-cell ALL (T-ALL) than...
PURPOSE
Failure to respond to induction chemotherapy portends a poor outcome in childhood acute lymphoblastic leukemia (ALL) and is more frequent in T-cell ALL (T-ALL) than B-cell ALL. We aimed to address the limited understanding of clinical and genetic factors that influence outcome in a cohort of patients with T-ALL induction failure (IF).
METHODS
We studied all cases of T-ALL IF on two consecutive multinational randomized trials, UKALL2003 and UKALL2011, to define risk factors, treatment, and outcomes. We performed multiomic profiling to characterize the genomic landscape.
RESULTS
IF occurred in 10.3% of cases and was significantly associated with increasing age, occurring in 20% of patients age 16 years and older. Five-year overall survival (OS) rates were 52.1% in IF and 90.2% in responsive patients ( < .001). Despite increased use of nelarabine-based chemotherapy consolidated by hematopoietic stem-cell transplant in UKALL2011, there was no improvement in outcome. Persistent end-of-consolidation molecular residual disease resulted in a significantly worse outcome (5-year OS, 14.3% 68.5%; HR, 4.10; 95% CI, 1.35 to 12.45; = .0071). Genomic profiling revealed a heterogeneous picture with 25 different initiating lesions converging on 10 subtype-defining genes. There was a remarkable abundance of TAL1 noncoding lesions, associated with a dismal outcome (5-year OS, 12.5%). Combining TAL1 lesions with mutations in the MYC and RAS pathways produces a genetic stratifier that identifies patients highly likely to fail conventional therapy (5-year OS, 23.1% 86.4%; HR, 6.84; 95% CI, 2.78 to 16.78; < .0001) and who should therefore be considered for experimental agents.
CONCLUSION
The outcome of IF in T-ALL remains poor with current therapy. The lack of a unifying genetic driver suggests alternative approaches, particularly using immunotherapy, are urgently needed.
Topics: Humans; Young Adult; Adolescent; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Treatment Outcome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Hematopoietic Stem Cell Transplantation; T-Lymphocytes; Prognosis
PubMed: 37098241
DOI: 10.1200/JCO.22.02734 -
Expert Review of Hematology 2024This study evaluated the benefits and risks of patients with refractory or relapsed acute lymphocytic leukemia (R/R ALL) treated with anti-CD19 chimeric antigen receptor... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
This study evaluated the benefits and risks of patients with refractory or relapsed acute lymphocytic leukemia (R/R ALL) treated with anti-CD19 chimeric antigen receptor (CAR) T-cell therapy and blinatumomab.
METHODS
PubMed, Web of Science, Embase, and the Cochrane Library were searched for relevant studies.
RESULTS
The pooled complete remission (CR) rate and minimal residual disease (MRD) negative rate were 48%, 31% for blinatumomab, and 86% and 80% for CAR T-cell therapy.
CONCLUSIONS
The CAR T-cell therapy group exhibited a higher likelihood of CR rate than the blinatumomab group in every analysis regardless of adjustment subgroups. CAR T-cell therapy was associated with a significantly prolonged overall survival (OS) and relapse-free survival (RFS) compared with blinatumomab (2-year OS 55% vs 25%; 2-year RFS 40% vs 22%). CAR T-cell therapy was more effective for achieving CR and bridging to allogeneic hematopoietic stem cell transplantation (allo-SCT) than blinatumomab (2-year OS 75% vs. 57%). An emerging role for blinatumomab is as a bridging agent pre-SCT, and for patients who achieve an MRD-negative state pre-SCT, post-SCT outcomes are expected to be the same as CAR-T. For adverse effects (AEs), blinatumomab was associated with a lower rate of grade ≥3 hematological toxicity, CRS, and neurological events.
Topics: Humans; Immunotherapy, Adoptive; Hematopoietic Stem Cell Transplantation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Antibodies, Bispecific; Recurrence; Antigens, CD19
PubMed: 38135295
DOI: 10.1080/17474086.2023.2298732