-
Virchows Archiv : An International... Jan 2023The updated International Consensus Classification (ICC) of B-acute lymphoblastic leukemia (B-ALL) and T-acute lymphoblastic leukemia (T-ALL) includes both revisions to... (Review)
Review
The updated International Consensus Classification (ICC) of B-acute lymphoblastic leukemia (B-ALL) and T-acute lymphoblastic leukemia (T-ALL) includes both revisions to subtypes previously outlined in the 2016 WHO classification and several newly described entities. The ICC classification incorporates recent clinical, cytogenetic, and molecular data, with a particular emphasis on whole transcriptome analysis and gene expression (GEX) clustering studies. B-ALL classification is modified to further subclassify BCR::ABL1-positive B-ALL and hypodiploid B-ALL. Additionally, nine new categories of B-ALL are defined, including seven that contain distinguishing gene rearrangements, as well as two new categories that are characterized by a specific single gene mutation. Four provisional entities are also included in the updated B-ALL classification, although definitive identification of these subtypes requires GEX studies. T-ALL classification is also updated to incorporate BCL11B-activating rearrangements into early T-precursor (ETP) ALL taxonomy. Additionally, eight new provisional entities are added to the T-ALL subclassification. The clinical implications of the new entities are discussed, as are practical approaches to the use of different technologies in diagnosis. The enhanced specificity of the new classification will allow for improved risk stratification and optimized treatment plans for patients with ALL.
Topics: Humans; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Consensus; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Lymphoma
PubMed: 36422706
DOI: 10.1007/s00428-022-03448-8 -
Haematologica Nov 2020The last decade has witnessed great advances in our understanding of the genetic and biological basis of childhood acute lymphoblastic leukemia (ALL), the development of... (Review)
Review
The last decade has witnessed great advances in our understanding of the genetic and biological basis of childhood acute lymphoblastic leukemia (ALL), the development of experimental models to probe mechanisms and evaluate new therapies, and the development of more efficacious treatment stratification. Genomic analyses have revolutionized our understanding of the molecular taxonomy of ALL, and these advances have led the push to implement genome and transcriptome characterization in the clinical management of ALL to facilitate more accurate risk-stratification and, in some cases, targeted therapy. Although mutation- or pathway-directed targeted therapy (e.g., using tyrosine kinase inhibitors to treat Philadelphia chromosome [Ph]-positive and Phlike B-cell-ALL) is currently available for only a minority of children with ALL, many of the newly identified molecular alterations have led to the exploration of approaches targeting deregulated cell pathways. The efficacy of cellular or humoral immunotherapy has been demonstrated with the success of chimeric antigen receptor T-cell therapy and the bispecific engager blinatumomab in treating advanced disease. This review describes key advances in our understanding of the biology of ALL and optimal approaches to risk-stratification and therapy, and it suggests key areas for basic and clinical research.
Topics: Antibodies, Bispecific; Child; Humans; Immunotherapy; Immunotherapy, Adoptive; Lymphoma, B-Cell; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 33054110
DOI: 10.3324/haematol.2020.247031 -
American Society of Clinical Oncology... May 2020Acute lymphoblastic leukemia (ALL) is characterized by chromosomal translocations and somatic mutations that lead to leukemogenesis. The incorporation of pediatric-type... (Review)
Review
Acute lymphoblastic leukemia (ALL) is characterized by chromosomal translocations and somatic mutations that lead to leukemogenesis. The incorporation of pediatric-type regimens has improved survival in young adults, and the incorporation of tyrosine kinase inhibitors for patients with Philadelphia chromosome-positive disease has led to further improvements in outcomes. However, older patients often have poor-risk biology and reduced tolerance to chemotherapy, leading to lower remission rates and overall survival. Regardless of age, patients with relapsed or refractory ALL have extremely poor outcomes. The advent of next-generation sequencing has facilitated the revolution in understanding the genetics of ALL. New genetic risk stratification together with the ability to measure minimal residual disease, leukemic blasts left behind after cytotoxic chemotherapy, has led to better tools to guide postremission approaches-that is, consolidation chemotherapy or allogeneic stem cell transplantation. In this article, we discuss the evolving and complex genetic landscape of ALL and the emerging therapeutic options for patients with relapsed/refractory ALL and older patients with ALL.
Topics: Drug Resistance, Neoplasm; Humans; Immunotherapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence
PubMed: 32421447
DOI: 10.1200/EDBK_280175 -
Blood Oct 2020Relapsed acute lymphoblastic leukemia (ALL) has remained challenging to treat in children, with survival rates lagging well behind those observed at initial diagnosis.... (Review)
Review
Relapsed acute lymphoblastic leukemia (ALL) has remained challenging to treat in children, with survival rates lagging well behind those observed at initial diagnosis. Although there have been some improvements in outcomes over the past few decades, only ∼50% of children with first relapse of ALL survive long term, and outcomes are much worse with second or later relapses. Recurrences that occur within 3 years of diagnosis and any T-ALL relapses are particularly difficult to salvage. Until recently, treatment options were limited to intensive cytotoxic chemotherapy with or without site-directed radiotherapy and allogeneic hematopoietic stem cell transplantation (HSCT). In the past decade, several promising immunotherapeutics have been developed, changing the treatment landscape for children with relapsed ALL. Current research in this field is focusing on how to best incorporate immunotherapeutics into salvage regimens and investigate long-term survival and side effects, and when these might replace HSCT. As more knowledge is gained about the biology of relapse through comprehensive genomic profiling, incorporation of molecularly targeted therapies is another area of active investigation. These advances in treatment offer real promise for less toxic and more effective therapy for children with relapsed ALL, and we present several cases highlighting contemporary treatment decision-making.
Topics: Age Factors; Algorithms; Child; Clinical Decision-Making; Clinical Trials as Topic; Combined Modality Therapy; Disease Management; Female; Humans; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Recurrence; Retreatment; Treatment Outcome
PubMed: 32589723
DOI: 10.1182/blood.2019004043 -
International Journal of Molecular... Feb 2020Minimal residual disease (MRD) refers to a chemotherapy/radiotherapy-surviving leukemia cell population that gives rise to relapse of the disease. The detection of MRD... (Review)
Review
Minimal residual disease (MRD) refers to a chemotherapy/radiotherapy-surviving leukemia cell population that gives rise to relapse of the disease. The detection of MRD is critical for predicting the outcome and for selecting the intensity of further treatment strategies. The development of various new diagnostic platforms, including next-generation sequencing (NGS), has introduced significant advances in the sensitivity of MRD diagnostics. Here, we review current methods to diagnose MRD through phenotypic marker patterns or differential gene patterns through analysis by flow cytometry (FCM), polymerase chain reaction (PCR), real-time quantitative polymerase chain reaction (RQ-PCR), reverse transcription polymerase chain reaction (RT-PCR) or NGS. Future advances in clinical procedures will be molded by practical feasibility and patient needs regarding greater diagnostic sensitivity.
Topics: Flow Cytometry; High-Throughput Nucleotide Sequencing; Humans; Neoplasm Recurrence, Local; Neoplasm, Residual; Neoplastic Cells, Circulating; Polymerase Chain Reaction; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 32033444
DOI: 10.3390/ijms21031054 -
Frontiers of Medicine Dec 2020The cure rate of childhood acute lymphoblastic leukemia (ALL) has exceeded 90% in some contemporary clinical trials. However, the dose intensity of conventional... (Review)
Review
The cure rate of childhood acute lymphoblastic leukemia (ALL) has exceeded 90% in some contemporary clinical trials. However, the dose intensity of conventional chemotherapy has been pushed to its limit. Further improvement in outcome will need to rely more heavily on molecular therapeutic as well as immuno-and cellular-therapy approaches together with precise risk stratification. Children with ETV6-RUNX1 or hyperdiploid > 50 ALL who achieve negative minimal residual disease during early remission induction are suitable candidates for reduction in treatment. Patients with Philadelphia chromosome (Ph)-positive or Ph-like ALL with ABL-class fusion should be treated with dasatinib. BH3 profiling and other preclinical methods have identified several high-risk subtypes, such as hypodiplod, early T-cell precursor, immature T-cell, KMT2A-rearranged, Ph-positive and TCF-HLF-positive ALL, that may respond to BCL-2 inhibitor venetoclax. There are other fusions or mutations that may serve as putative targets, but effective targeted therapy has yet to be established. For other high-risk patients or poor early treatment responders who do not have targetable genetic lesions, current approaches that offer hope include blinatumomab, inotuzumab and CAR-T cell therapy for B-ALL, and daratumumab and nelarabine for T-ALL. With the expanding therapeutic armamentarium, we should start focus on rational combinations of targeted therapy with non-overlapping toxicities.
Topics: Child; Dasatinib; Humans; Neoplasm, Residual; Philadelphia Chromosome; Precision Medicine; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 33074527
DOI: 10.1007/s11684-020-0759-8 -
Blood Jan 2023Despite recent progress in identifying the genetic drivers of acute lymphoblastic leukemia (ALL), prognosis remains poor for those individuals who experience disease... (Review)
Review
Despite recent progress in identifying the genetic drivers of acute lymphoblastic leukemia (ALL), prognosis remains poor for those individuals who experience disease recurrence. Moreover, acute leukemias of ambiguous lineage lack a biologically informed framework to guide classification and therapy. These needs have driven the adoption of multiple complementary single-cell sequencing approaches to explore key issues in the biology of these leukemias, including cell of origin, developmental hierarchy and ontogeny, and the molecular heterogeneity driving pathogenesis, progression, and therapeutic responsiveness. There are multiple single-cell techniques for profiling a specific modality, including RNA, DNA, chromatin accessibility and methylation; and an expanding range of approaches for simultaneous analysis of multiple modalities. Single-cell sequencing approaches have also enabled characterization of cell-intrinsic and -extrinsic features of ALL biology. In this review we describe these approaches and highlight the extensive heterogeneity that underpins ALL gene expression, cellular differentiation, and clonal architecture throughout disease pathogenesis and treatment resistance. In addition, we discuss the importance of the dynamic interactions that occur between leukemia cells and the nonleukemia microenvironment. We discuss potential opportunities and limitations of single-cell sequencing for the study of ALL biology and treatment responsiveness.
Topics: Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Lymphocytes; Acute Disease; Prognosis; Single-Cell Analysis; Tumor Microenvironment
PubMed: 35926109
DOI: 10.1182/blood.2022016954 -
Blood Jun 2023T-cell lymphoblastic lymphoma (T-LLy) and T-cell acute lymphoblastic leukemia (T-ALL) have historically been considered a spectrum of the same disease. However, recent...
T-cell lymphoblastic lymphoma (T-LLy) and T-cell acute lymphoblastic leukemia (T-ALL) have historically been considered a spectrum of the same disease. However, recent evidence demonstrating differential responses to chemotherapy raise the possibility that T-LLy and T-ALL are distinct clinical and biologic entities. Here, we examine differences between the 2 diseases and use illustrative cases to highlight key recommendations on how to best treat patients with newly diagnosed and relapsed/refractory T-LLy. We discuss results of recent clinical trials incorporating use of nelarabine and bortezomib, choice of induction steroid, role of cranial radiotherapy, and risk stratification markers to identify patients at highest risk of relapse and to further refine current treatment strategies. Because prognosis for relapsed or refractory T-LLy patients is poor, we discuss ongoing investigations incorporating novel therapies, including immunotherapeutics, into upfront and salvage regimens and the role of hematopoietic stem cell transplantation.
Topics: Humans; Child; Young Adult; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia-Lymphoma, Adult T-Cell; Recurrence; T-Lymphocytes
PubMed: 37018730
DOI: 10.1182/blood.2022016503 -
Blood Mar 2023The central nervous system (CNS) is the most important site of extramedullary disease in adults with acute lymphoblastic leukemia (ALL). Although CNS disease is... (Review)
Review
The central nervous system (CNS) is the most important site of extramedullary disease in adults with acute lymphoblastic leukemia (ALL). Although CNS disease is identified only in a minority of patients at the time of diagnosis, subsequent CNS relapses (either isolated or concurrent with other sites) occur in some patients even after the delivery of prophylactic therapy targeted to the CNS. Historically, prophylaxis against CNS disease has included intrathecal (IT) chemotherapy and radiotherapy (RT), although the latter is being used with decreasing frequency. Treatment of a CNS relapse usually involves intensive systemic therapy and cranial or craniospinal RT along with IT therapy and consideration of allogeneic hematopoietic cell transplant. However, short- and long-term toxicities can make these interventions prohibitively risky, particularly for older adults. As new antibody-based immunotherapy agents have been approved for relapsed/refractory B-cell ALL, their use specifically for patients with CNS disease is an area of keen interest not only because of the potential for efficacy but also concerns of unique toxicity to the CNS. In this review, we discuss data-driven approaches for these common and challenging clinical scenarios as well as highlight how recent findings potentially support the use of novel immunotherapeutic strategies for CNS disease.
Topics: Humans; Aged; Hematopoietic Stem Cell Transplantation; Central Nervous System; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Central Nervous System Diseases; Recurrence; Central Nervous System Neoplasms
PubMed: 36548957
DOI: 10.1182/blood.2022017035 -
Leukemia Jul 2022Maintenance therapy (MT) with oral methotrexate (MTX) and 6-mercaptopurine (6-MP) is essential for the cure of acute lymphoblastic leukemia (ALL). MTX and 6-MP interfere... (Review)
Review
Maintenance therapy (MT) with oral methotrexate (MTX) and 6-mercaptopurine (6-MP) is essential for the cure of acute lymphoblastic leukemia (ALL). MTX and 6-MP interfere with nucleotide synthesis and salvage pathways. The primary cytotoxic mechanism involves the incorporation of thioguanine nucleotides (TGNs) into DNA (as DNA-TG), which may be enhanced by the inhibition of de novo purine synthesis by other MTX/6-MP metabolites. Co-medication during MT is common. Although Pneumocystis jirovecii prophylaxis appears safe, the benefit of glucocorticosteroid/vincristine pulses in improving survival and of allopurinol to moderate 6-MP pharmacokinetics remains uncertain. Numerous genetic polymorphisms influence the pharmacology, efficacy, and toxicity (mainly myelosuppression and hepatotoxicity) of MTX and thiopurines. Thiopurine S-methyltransferase (encoded by TPMT) decreases TGNs but increases methylated 6-MP metabolites (MeMPs); similarly, nudix hydrolase 15 (encoded by NUDT15) also decreases TGNs available for DNA incorporation. Loss-of-function variants in both genes are currently used to guide MT, but do not fully explain the inter-patient variability in thiopurine toxicity. Because of the large inter-individual variations in MTX/6-MP bioavailability and metabolism, dose adjustments are traditionally guided by the degree of myelosuppression, but this does not accurately reflect treatment intensity. DNA-TG is a common downstream metabolite of MTX/6-MP combination chemotherapy, and a higher level of DNA-TG has been associated with a lower relapse hazard, leading to the development of the Thiopurine Enhanced ALL Maintenance (TEAM) strategy-the addition of low-dose (2.5-12.5 mg/m/day) 6-thioguanine to the 6-MP/MTX backbone-that is currently being tested in a randomized ALLTogether1 trial (EudraCT: 2018-001795-38). Mutations in the thiopurine and MTX metabolism pathways, and in the mismatch repair genes have been identified in early ALL relapses, providing valuable insights to assist the development of strategies to detect imminent relapse, to facilitate relapse salvage therapy, and even to bring about changes in frontline ALL therapy to mitigate this relapse risk.
Topics: Humans; Mercaptopurine; Methotrexate; Methyltransferases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Thioguanine
PubMed: 35654820
DOI: 10.1038/s41375-022-01591-4