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Lancet (London, England) Apr 2020Acute lymphoblastic leukaemia develops in both children and adults, with a peak incidence between 1 year and 4 years. Most acute lymphoblastic leukaemia arises in... (Review)
Review
Acute lymphoblastic leukaemia develops in both children and adults, with a peak incidence between 1 year and 4 years. Most acute lymphoblastic leukaemia arises in healthy individuals, and predisposing factors such as inherited genetic susceptibility or environmental exposure have been identified in only a few patients. It is characterised by chromosomal abnormalities and genetic alterations involved in differentiation and proliferation of lymphoid precursor cells. Along with response to treatment, these abnormalities are important prognostic factors. Disease-risk stratification and the development of intensified chemotherapy protocols substantially improves the outcome of patients with acute lymphoblastic leukaemia, particularly in children (1-14 years), but also in adolescents and young adults (15-39 years). However, the outcome of older adults (≥40 years) and patients with relapsed or refractory acute lymphoblastic leukaemia remains poor. New immunotherapeutic strategies, such as monoclonal antibodies and chimeric antigen receptor (CAR) T cells, are being developed and over the next few years could change the options for acute lymphoblastic leukaemia treatment.
Topics: Adolescent; Adult; Child; Child, Preschool; Humans; Infant; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Young Adult
PubMed: 32247396
DOI: 10.1016/S0140-6736(19)33018-1 -
[Rinsho Ketsueki] the Japanese Journal... 2017Acute lymphoblastic leukemia (ALL) is seen in both children and adults, but its incidence peaks between 2 and 5 years and also increases in the older population....
Acute lymphoblastic leukemia (ALL) is seen in both children and adults, but its incidence peaks between 2 and 5 years and also increases in the older population. Although most children can be cured, the prognosis of adults with ALL remains poor. Recent identification of novel genetic alterations and sequence mutations has contributed to the elucidation of the pathogenesis of ALL. The World Health Organization classification was revised in 2016. ALL was included within the subgroup of myeloid neoplasms and acute leukemia. New provisional entities with recurrent abnormalities have been recognized and incorporated into the classification. Treatment of ALL involves some of the most complex chemotherapy combinations and treatment schedules used in oncology. Two main chemotherapy regimens are being used. The Berlin-Frankfurt-Münster framework consists of an induction regimen, consolidation regimen, reintensification regimen, and maintenance therapy and is mostly used in Europe for adult ALL trials. Another approach is to alternatively repeat two different intensive chemotherapy cycles, such as the hyper-CVAD regimen designed by investigators at the MD Anderson Cancer Center. Furthermore, the treatment of older patients with ALL is an unmet medical need. Novel targeted therapies, immunotherapies, and reduced-intensity SCT are promising approaches.
Topics: Cytogenetics; Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Risk Factors; World Health Organization
PubMed: 28592761
DOI: 10.11406/rinketsu.58.460 -
The Lancet. Haematology Dec 2022Blinatumomab is effective in relapsed or refractory B-cell acute lymphocytic leukaemia and results in high rates of minimal residual disease negativity. We aimed to...
Hyper-CVAD and sequential blinatumomab for newly diagnosed Philadelphia chromosome-negative B-cell acute lymphocytic leukaemia: a single-arm, single-centre, phase 2 trial.
BACKGROUND
Blinatumomab is effective in relapsed or refractory B-cell acute lymphocytic leukaemia and results in high rates of minimal residual disease negativity. We aimed to establish whether the incorporation of blinatumomab into front-line therapy for acute lymphocytic leukaemia could improve outcomes.
METHODS
We conducted a single-arm, phase 2 trial at The University of Texas MD Anderson Cancer Center (Houston, TX, USA). Patients aged 14 years or older with confirmed, newly diagnosed Philadelphia chromosome (Ph)-negative B-cell acute lymphocytic leukaemia were eligible, including patients who had received up to one course of chemotherapy before enrolment. Patients received four cycles of intensive chemotherapy (hyper-CVAD [hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone] alternating with high-dose methotrexate and cytarabine), followed by four cycles of blinatumomab consolidation (up to 28 μg/day by continuous intravenous infusion for 28 days, given every 42 days). Maintenance consisted of 15 cycles of alternating blocks of three cycles of POMP (6-mercaptopurine, vincristine, methotrexate, and prednisone) chemotherapy and one of blinatumomab. The primary endpoint was relapse-free survival evaluated in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT02877303, and is still enrolling patients.
FINDINGS
Between Nov 14, 2016, and Aug 27, 2020, 38 patients with newly diagnosed B-cell acute lymphocytic leukaemia were treated (median age 37 years [IQR 29-45]; 26 [68%] male; 21 [55%] White, non-Hispanic). With a median follow-up of 37 months (IQR 28-49), estimated 3-year relapse-free survival was 73% (95% CI 56-85). No patients relapsed more than 2 years after the start of therapy. One (3%) patient developed transient grade 3 cytokine release syndrome, and four (11%) patients had a grade 3 blinatumomab-related neurological event. The most common non-haematological grade 3-4 adverse events were infections, which occurred in 14 (37%) of 38 patients during induction and in 27 (71%) of 38 patients during consolidation chemotherapy cycles. One (3%) patient discontinued therapy because of treatment-related neurotoxicity. There were two deaths-one due to infection and one due to respiratory failure-which were not considered treatment-related.
INTERPRETATION
Front-line sequential chemotherapy with blinatumomab resulted in encouraging long-term survival. Future randomised studies should evaluate the routine incorporation of blinatumomab in the treatment of patients with Ph-negative B-cell acute lymphocytic leukaemia.
FUNDING
Amgen.
Topics: Male; Humans; Adult; Female; Philadelphia Chromosome; Vincristine; Methotrexate; Antineoplastic Combined Chemotherapy Protocols; Neoplasm Recurrence, Local; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 36279879
DOI: 10.1016/S2352-3026(22)00285-X -
Current Oncology Reports Jan 2022Lymphoblastic lymphoma (LBL) is a rare, highly aggressive non-Hodgkin lymphoma variant virtually indistinguishable from acute lymphoblastic leukemia (ALL). We review the... (Review)
Review
PURPOSE OF REVIEW
Lymphoblastic lymphoma (LBL) is a rare, highly aggressive non-Hodgkin lymphoma variant virtually indistinguishable from acute lymphoblastic leukemia (ALL). We review the advancements in diagnostics, staging, treatment, and response assessment.
RECENT FINDINGS
T-LBL displays a mediastinal mass with pleuro-pericardic effusions as key distinctive features and is far more frequent than B-LBL. LBL is exquisitely sensitive to ALL-type chemotherapy, achieving cure rates in the order of 70% in adults and even more in children. Positron-emission tomography, genetic risk classifications, and minimal disseminated/residual disease assays are increasingly used to detect occult sites of involvement and predict treatment outcome. Stem cell transplantation is effective and should be considered for very high-risk subsets and/or at salvage. Although curable in the majority of patients, about 25-30% of adults with LBL patients experience resistance or relapse following first-line therapy. It is essential to identify these cases early on and to explore new modalities of precision medicine with targeted agents.
Topics: Adult; Child; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma, B-Cell; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Prognosis
PubMed: 35059993
DOI: 10.1007/s11912-021-01168-x -
Blood Jan 2020Improved personalized adjustment of primary therapy to the perceived risk of relapse by using new prognostic markers for treatment stratification may be beneficial to... (Review)
Review
Improved personalized adjustment of primary therapy to the perceived risk of relapse by using new prognostic markers for treatment stratification may be beneficial to patients with acute lymphoblastic leukemia (ALL). Here, we review the advances that have shed light on the role of IKZF1 aberration as prognostic factor in pediatric ALL and summarize emerging concepts in this field. Continued research on the interplay of disease biology with exposure and response to treatment will be key to further improve treatment strategies.
Topics: Animals; Child; Drug Resistance, Neoplasm; Gene Deletion; Humans; Ikaros Transcription Factor; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis
PubMed: 31821407
DOI: 10.1182/blood.2019000813 -
Acta Biochimica Et Biophysica Sinica Jun 2023Leukaemia is the common name for a group of malignant diseases of the haematopoietic system with complex classifications and characteristics. Remarkable progress has... (Review)
Review
Leukaemia is the common name for a group of malignant diseases of the haematopoietic system with complex classifications and characteristics. Remarkable progress has been made in basic research and preclinical studies for acute leukaemia compared to that of the many other types/subtypes of leukaemia, especially the exploration of the biological basis and application of immunotherapy in acute myeloid leukaemia (AML) and B-cell acute lymphoblastic leukaemia (B-ALL). In this review, we summarize the basic approaches to immunotherapy for leukaemia and focus on the research progress made in immunotherapy development for AML and ALL. Importantly, despite the advances made to date, big challenges still exist in the effectiveness of leukaemia immunotherapy, especially in AML. Therefore, we use AML as an example and summarize the mechanisms of tumour cell immune evasion, describe recently reported data and known therapeutic targets, and discuss the obstacles in finding suitable treatment targets and the results obtained in recent clinical trials for several types of single and combination immunotherapies, such as bispecific antibodies, cell therapies (CAR-T-cell treatment), and checkpoint blockade. Finally, we summarize novel immunotherapy strategies for treating lymphocytic leukaemia and clinical trial results.
Topics: Immunotherapy; Humans; Bone Marrow Transplantation; Cancer Vaccines; Tumor Escape; Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 37272727
DOI: 10.3724/abbs.2023101 -
British Journal of Haematology Jun 2019Lymphoblastic lymphoma (LBL) is the second most common type of Non-Hodgkin Lymphoma (NHL) in childhood and adolescence, accounting for 25-35% of all cases. The majority,... (Review)
Review
Lymphoblastic lymphoma (LBL) is the second most common type of Non-Hodgkin Lymphoma (NHL) in childhood and adolescence, accounting for 25-35% of all cases. The majority, 70-80%, is of T-lymphoblastic origin while 20-25% arise from B lymphoblasts. With current therapy, the event-free and overall survivals for paediatric LBL patients now exceeds 80%. Therapy, especially in T-LBL with large mediastinal tumours, is challenging, with both significant morbidity and late sequela. An additional challenge is the dismal prognosis of patients with refractory or relapsed disease. This review article will focus on the growing knowledge of the pathogenesis and biology of LBL, recent advances and challenges in the therapy of LBL, and ongoing and future efforts and opportunities in optimizing therapy and developing novel targeted treatment approaches.
Topics: Adolescent; Child; Combined Modality Therapy; Disease Management; Disease Susceptibility; Drug Resistance, Neoplasm; Humans; Neoplasm Staging; Phenotype; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Symptom Assessment; Treatment Outcome
PubMed: 30809797
DOI: 10.1111/bjh.15793 -
Nature Medicine Jul 2023In the context of relapsed and refractory childhood pre-B cell acute lymphoblastic leukemia (R/R B-ALL), CD19-targeting chimeric antigen receptor (CAR)-T cells often...
In the context of relapsed and refractory childhood pre-B cell acute lymphoblastic leukemia (R/R B-ALL), CD19-targeting chimeric antigen receptor (CAR)-T cells often induce durable remissions, which requires the persistence of CAR-T cells. In this study, we systematically analyzed CD19 CAR-T cells of 10 children with R/R B-ALL enrolled in the CARPALL trial via high-throughput single-cell gene expression and T cell receptor sequencing of infusion products and serial blood and bone marrow samples up to 5 years after infusion. We show that long-lived CAR-T cells developed a CD4/CD8 double-negative phenotype with an exhausted-like memory state and distinct transcriptional signature. This persistence signature was dominant among circulating CAR-T cells in all children with a long-lived treatment response for which sequencing data were sufficient (4/4, 100%). The signature was also present across T cell subsets and clonotypes, indicating that persisting CAR-T cells converge transcriptionally. This persistence signature was also detected in two adult patients with chronic lymphocytic leukemia with decade-long remissions who received a different CD19 CAR-T cell product. Examination of single T cell transcriptomes from a wide range of healthy and diseased tissues across children and adults indicated that the persistence signature may be specific to long-lived CAR-T cells. These findings raise the possibility that a universal transcriptional signature of clinically effective, persistent CD19 CAR-T cells exists.
Topics: Humans; Antigens, CD19; Immunotherapy, Adoptive; Leukemia, Lymphocytic, Chronic, B-Cell; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Receptors, Antigen, T-Cell; Remission Induction; T-Lymphocytes
PubMed: 37407840
DOI: 10.1038/s41591-023-02415-3 -
BioMed Research International 2015
Topics: Child; Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 26078962
DOI: 10.1155/2015/787194 -
Current Hematologic Malignancy Reports Apr 2022While the treatment of acute lymphoblastic leukemia (ALL) has improved significantly over the last 30 years, the majority of adult patients will have their disease... (Review)
Review
PURPOSE OF REVIEW
While the treatment of acute lymphoblastic leukemia (ALL) has improved significantly over the last 30 years, the majority of adult patients will have their disease relapse. The BCL-2 gene was initially discovered from follicular lymphoma research; however, the BH3 family of proteins has is emerging to be crucial in patients with ALL due to their reliance on the balance of these pro-apoptotic and anti-apoptotic proteins in the BH3 family. We discuss apoptosis in ALL, the reliance mechanisms, drug development in this space, and areas for future research.
RECENT FINDINGS
The first drugs that were developed to inhibit the BCL-2 pathway include both venetoclax (BCL-2 specific inhibitor) and navitoclax (BCL-2, BCL-XL, and BCL-W). These drugs show promise and have obtained complete remissions, minimal residual disease negative status, and have been used as a bridge to allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia and chronic lymphocytic leukemia. There are multiple ongoing clinical trials looking to assess the use of BCL-2 inhibition with chemotherapy, targeted therapies, and bi-specific T-cell engager therapies not only in both frontline and relapsed refractory ALL but also in consolidation and maintenance phases. There is still a large need for improvement of ALL outcomes in adult patients. Research has shown that ALL depends on the BCL-2 family of proteins for cell survival and proliferation. Targeting this pathway with BCL-2 inhibition has led to encouraging results, and future research is aimed at incorporating this targeted therapy into current treatment paradigms.
Topics: Adult; Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Proto-Oncogene Proteins c-bcl-2
PubMed: 35538391
DOI: 10.1007/s11899-022-00661-9