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Best Practice & Research. Clinical... Sep 2023One of the consistent features in development of hematopoietic stem cell transplant (HCT) for Acute Lymphoblastic Leukemia (ALL) is the rapidity with which discoveries... (Review)
Review
One of the consistent features in development of hematopoietic stem cell transplant (HCT) for Acute Lymphoblastic Leukemia (ALL) is the rapidity with which discoveries in the laboratory are translated into innovations in clinical care. Just a few years after murine studies demonstrated that rescue from radiation induced marrow failure is mediated by cellular not humoral factors, E. Donnall Thomas reported on the transfer of bone marrow cells into irradiated leukemia patients. This was followed quickly by the first descriptions of Graft versus Leukemia (GvL) effect and Graft versus Host Disease (GvHD). Despite the pivotal nature of these findings, early human transplants were uniformly unsuccessful and identified the challenges that continue to thwart transplanters today - leukemic relapse, regimen related toxicity, and GvHD. While originally only an option for young, fit patients with a matched family donor, expansion of the donor pool to include unrelated donors, umbilical cord blood units, and more recently the growing use of haploidentical donors have all made transplant a more accessible therapy for patients with ALL. Novel agents for conditioning, prevention and treatment of GvHD have improved outcomes and investigators continue to develop novel treatment strategies that balance regimen related toxicity with disease control. Our evolving understanding of how to prevent and treat GvHD and how to prevent relapse are incorporated into novel clinical trials that are expected to further improve outcomes. Here we review current considerations and future directions for both adult and pediatric patients undergoing HCT for ALL, including indication for transplant, donor selection, cytoreductive regimens, and outcomes.
Topics: Adult; Humans; Animals; Child; Mice; Hematopoietic Stem Cell Transplantation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Graft vs Host Disease; Bone Marrow Cells; Recurrence
PubMed: 37611999
DOI: 10.1016/j.beha.2023.101485 -
American Journal of Hematology Apr 2024
Topics: Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Antibodies, Bispecific; Antineoplastic Agents; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 38366135
DOI: 10.1002/ajh.27253 -
Pediatric Blood & Cancer Nov 2023Cyclin D has been shown to play an essential role in acute lymphoblastic leukemia (ALL) initiation and progression, providing rationale for targeting the CDK4/6-cyclin D...
Palbociclib in combination with chemotherapy in pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia and lymphoma: A Children's Oncology Group study (AINV18P1).
BACKGROUND
Cyclin D has been shown to play an essential role in acute lymphoblastic leukemia (ALL) initiation and progression, providing rationale for targeting the CDK4/6-cyclin D complex that regulates cell cycle progression.
PROCEDURE
The Children's Oncology Group AINV18P1 phase 1 trial evaluated the CDK4/6 inhibitor, palbociclib, in combination with standard four-drug re-induction chemotherapy in children and young adults with relapsed/refractory B- and T-cell lymphoblastic leukemia (ALL) and lymphoma. Palbociclib (50 mg/m /dose) was administered orally once daily for 21 consecutive days, first as a single agent (Days 1-3) and subsequently combined with re-induction chemotherapy. This two-part study was designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D), followed by an expansion pharmacokinetic cohort.
RESULTS
Twelve heavily pretreated patients enrolled, all of whom were evaluable for toxicity. One dose-limiting hematologic toxicity (DLT) occurred at the starting dose of 50 mg/m /dose orally for 21 days. No additional DLTs were observed in the dose determination or pharmacokinetic expansion cohorts, and overall rates of grade 3/4 nonhematologic toxicities were comparable to those observed with the chemotherapy platform alone. Five complete responses were observed, two among four patients with T-ALL and three among seven patients with B-ALL. Pharmacokinetic studies showed similar profiles with both liquid and capsule formulations of palbociclib.
CONCLUSIONS
Palbociclib in combination with re-induction chemotherapy was well tolerated with a RP2D of 50 mg/m /day for 21 days. Complete responses were observed among heavily pretreated patients.
Topics: Child; Humans; Young Adult; Antineoplastic Combined Chemotherapy Protocols; Lymphoma; Lymphoma, B-Cell; Maximum Tolerated Dose; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 37553297
DOI: 10.1002/pbc.30609 -
Nature Cancer Aug 2023Children with acute lymphoblastic leukemia (ALL) undergoing anti-CD19 therapy occasionally develop acute myeloid leukemia (AML). The clonal origin of such lineage-switch...
Children with acute lymphoblastic leukemia (ALL) undergoing anti-CD19 therapy occasionally develop acute myeloid leukemia (AML). The clonal origin of such lineage-switch leukemias remains unresolved. Here, we reconstructed the phylogeny of multiple leukemias in a girl who, following multiply relapsed ALL, received anti-CD19 cellular and antibody treatment and subsequently developed AML. Whole genome sequencing unambiguously revealed the AML derived from the initial ALL, with distinct driver mutations that were detectable before emergence. Extensive prior diversification and subsequent clonal selection underpins this fatal lineage switch. Genomic monitoring of primary leukemias and recurrences may predict therapy resistance, especially regarding anti-CD19 treatment.
Topics: Child; Female; Humans; Leukemia, Myeloid, Acute; Antibodies, Bispecific; Precursor Cell Lymphoblastic Leukemia-Lymphoma; T-Lymphocytes
PubMed: 37474833
DOI: 10.1038/s43018-023-00604-0 -
Hematology. American Society of... Dec 2023Hematopoietic stem cell transplantation (HSCT) represents a consolidated therapeutic strategy for high-risk pediatric acute lymphoblastic leukemia (ALL), offering the... (Review)
Review
Hematopoietic stem cell transplantation (HSCT) represents a consolidated therapeutic strategy for high-risk pediatric acute lymphoblastic leukemia (ALL), offering the potential for curative treatment. This manuscript delves into the debate around the more universal application of HSCT for pediatric ALL in the modern era, considering the ubiquitous availability of suitable donors. In fact, despite significant advancements in chemotherapy, targeted therapy, and immunotherapy, a subset of pediatric patients with ALL with high-risk features or relapse continue to encounter poor prognostic outcomes. For this subgroup of patients, HSCT often remains the only potentially curative measure, leveraging the graft-versus- leukemia effect for long-term disease control. Nevertheless, the procedure's complexity and associated risks have traditionally curtailed its widespread use. However, the scenario is shifting with improvements in HLA matching, availability of alternative donor sources, less toxic conditioning regimens, and improved supportive care protocols. Concurrently, emerging therapies like CD19+ CAR T cells present new considerations for definitive therapy selection in relapsed/ refractory ALL. This article reviews critical current evidence and debates the potential of HSCT as a more universal treatment for ALL, reevaluating traditional treatment stratification in light of the constant availability of stem cell donors.
Topics: Humans; Child; Hematopoietic Stem Cell Transplantation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tissue Donors; Prognosis; Transplantation Conditioning; Graft vs Host Disease
PubMed: 38066901
DOI: 10.1182/hematology.2023000423 -
Clinical Neurophysiology : Official... Oct 2023Vincristine is a mainstay treatment for paediatric cancers, particularly acute lymphoblastic leukemia (ALL), with common toxicity including vincristine-induced...
OBJECTIVE
Vincristine is a mainstay treatment for paediatric cancers, particularly acute lymphoblastic leukemia (ALL), with common toxicity including vincristine-induced peripheral neuropathy (VIPN). The present study comprehensively assessed VIPN outcomes in patients receiving vincristine treatment for ALL.
METHODS
Children diagnosed with ALL commencing vincristine treatment were prospectively evaluated (baseline, post-induction, pre-reinduction, post-reinduction, follow-up). VIPN was examined clinically using the Balis sensory/motor scale, neurophysiologically using axonal excitability techniques and quality-of-life using Pediatric Quality of Life Inventory.
RESULTS
Thirty-one patients were recruited to this study (age = 6.8 ± 4.4; 61.3% female). Incidence of motor VIPN (motor Balis grade > 0) symptoms were higher than sensory VIPN (sensory Balis grade > 0) at post-induction (92.0% vs 36.0%) and post-reinduction (81.8% vs 22.7%) vincristine treatment. Neurophysiological assessment also demonstrated greater change in motor axonal excitability parameters compared to sensory parameters including changes in depolarising threshold electrotonus (P < 0.0125), superexcitability and subexcitability parameters (all P < 0.0125). Follow-up assessment demonstrated persisting VIPN symptoms with reduced quality-of-life scores compared to baseline.
CONCLUSIONS
Clinical and neurophysiological evaluation of VIPN suggests vincristine produces a motor-prominent sensorimotor neuropathy in children which persisted at follow-up.
SIGNIFICANCE
VIPN signs and symptoms develop early in the treatment course, in line with axonal excitability profiles. Early detection of significant nerve changes may support timely implementation of neuroprotection strategies.
Topics: Child; Humans; Female; Child, Preschool; Male; Vincristine; Antineoplastic Agents, Phytogenic; Quality of Life; Prospective Studies; Peripheral Nervous System Diseases; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 37633123
DOI: 10.1016/j.clinph.2023.08.002 -
International Journal of Laboratory... Aug 2023To report a series of acute lymphoblastic leukemia (ALL) cases with spontaneous remission and provide presenting clinical and pathologic information and details of... (Review)
Review
AIMS
To report a series of acute lymphoblastic leukemia (ALL) cases with spontaneous remission and provide presenting clinical and pathologic information and details of clinical course to raise awareness among oncologists and patients.
METHODS
We identified and analyzed nine patients with ALL and spontaneous remission. Review of literature reveals an additional nine previously reported cases with similar clinical course.
RESULTS
All of these patients, ranging in age from 2 to 12 years of age, presented with inciting signs and symptoms of viral or bacterial infection. All of the patients showed varying percentages of lymphoblasts (.2% to 90%) in diagnostic bone marrow biopsy. All B-ALL cases shared a similar blast phenotype on flow cytometry with coexpression of CD19, CD10 and TdT and variable CD20 expression. All nine patients achieved spontaneous remission of their leukemia as confirmed by flow cytometry and/or bone marrow biopsy without chemotherapeutic intervention. Time to remission from presentation ranged from 1 to 8 weeks. After remission, all patients redeveloped ALL, and time from remission to reemergence ranged from 2 to 24 weeks.
CONCLUSION
Our series of cases and cases identified in literature show that ALL diagnosed with modern methods of flow cytometry and molecular analysis will recur within weeks to months from disappearance, usually with cytopenias, which provides a template for oncologic follow-up and testing in these patients.
Topics: Humans; Remission, Spontaneous; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Bone Marrow; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Lymphoma, B-Cell; Flow Cytometry; Immunophenotyping
PubMed: 36806637
DOI: 10.1111/ijlh.14042 -
Blood Cancer Discovery May 2024Myeloid neoplasms arise from preexisting clonal hematopoiesis (CH); however, the role of CH in the pathogenesis of acute lymphoblastic leukemia (ALL) is unknown. We...
UNLABELLED
Myeloid neoplasms arise from preexisting clonal hematopoiesis (CH); however, the role of CH in the pathogenesis of acute lymphoblastic leukemia (ALL) is unknown. We found that 18% of adult ALL cases harbored TP53, and 16% had myeloid CH-associated gene mutations. ALL with myeloid mutations (MyM) had distinct genetic and clinical characteristics, associated with inferior survival. By using single-cell proteogenomic analysis, we demonstrated that myeloid mutations were present years before the diagnosis of ALL, and a subset of these clones expanded over time to manifest as dominant clones in ALL. Single-cell RNA sequencing revealed upregulation of genes associated with cell survival and resistance to apoptosis in B-ALL with MyM, which responds better to newer immunotherapeutic approaches. These findings define ALL with MyM as a high-risk disease that can arise from antecedent CH and offer new mechanistic insights to develop better therapeutic and preventative strategies.
SIGNIFICANCE
CH is a precursor lesion for lymphoblastic leukemogenesis. ALL with MyM has distinct genetic and clinical characteristics, associated with adverse survival outcomes after chemotherapy. CH can precede ALL years before diagnosis, and ALL with MyM is enriched with activated T cells that respond to immunotherapies such as blinatumomab. See related commentary by Iacobucci, p. 142.
Topics: Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Clonal Hematopoiesis; Mutation; Adult; Male; Female; Middle Aged; Aged; Young Adult; Adolescent
PubMed: 38150184
DOI: 10.1158/2643-3230.BCD-23-0106 -
Haematologica Jul 2023Cure rates in adult acute lymphoblastic leukemia (ALL) improved using pediatric-based chemotherapy and stem cell transplantation (SCT). However, limited data on the...
Cure rates in adult acute lymphoblastic leukemia (ALL) improved using pediatric-based chemotherapy and stem cell transplantation (SCT). However, limited data on the health condition of cured adults are available whereas pediatric data cannot be transferred. The GMALL analyzed the health status in survivors of adult ALL retrospectively. Physicians answered a questionnaire on general condition (Eastern Cooperative Oncology Group [ECOG] status) and comorbidity or syndrome occurrence observed after treatment. Five hundred and thirty-eight patients with a median age of 29 (range, 15-64) years at diagnosis were analyzed, median follow-up was 7 (range, 3-24) years. Thirty-one percent had received SCT. ECOG status was 0-1 in 94%, 34% had not developed significant comorbidities. Most frequent comorbidities involved the neurologic system (27%), endocrine system (20%), skin (18%), graft-versus-host-disease (15%), cardiac system (13%), fatigue (13%). SCT impacted ECOG status and comorbidity occurrence significantly. ECOG 0-1 was observed in 86% of SCT and 98% of non-SCT patients (P<0.0001); comorbidity was observed in 87% and 57% respectively (P<0.0001). Our analysis elucidates the spectrum of comorbidities in cured adult ALL patients, with higher risk for transplanted patients, providing stimulations for the design of adequate aftercare programs. Overall, a large proportion of non-SCT patients achieved unrestricted general condition. The data provide a reference for new patient-centered endpoints in future trials.
Topics: Humans; Adult; Child; Adolescent; Young Adult; Middle Aged; Retrospective Studies; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Hematopoietic Stem Cell Transplantation; Survivors; Comorbidity
PubMed: 36779593
DOI: 10.3324/haematol.2022.281820 -
Pediatric Blood & Cancer Sep 2023Cure rates for acute lymphoblastic leukemia (ALL), the most common childhood cancer have steadily improved over the past five decades. This is due to intensifying...
Cure rates for acute lymphoblastic leukemia (ALL), the most common childhood cancer have steadily improved over the past five decades. This is due to intensifying systemic therapy, recognizing and treating the central nervous system as a sanctuary site, and implementing modern risk stratification to deliver varying intensities of therapy based on age, presenting white blood count, sentinel somatic genetics, and therapy response. Recently, numerous Children's Oncology Group trials have demonstrated the lack of benefit of intensifying traditional chemotherapy, providing evidence that new approaches are needed to cure the patients for whom cure has been elusive. Distinguishing those who require intensive or novel therapeutic approaches from others who will be cured with minimal therapy is key for future trials. Incorporating new genomic biomarkers and more sensitive measures of minimal/measurable residual disease provide opportunities to achieve these goals.
Topics: Humans; Child; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Central Nervous System; Antineoplastic Combined Chemotherapy Protocols; Treatment Outcome
PubMed: 37489549
DOI: 10.1002/pbc.30585