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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 Reviews Sep 2021Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm caused by a reciprocal translocation [t(9;22)(q34;q11.2)] that leads to the fusion of ABL1 gene sequences... (Review)
Review
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm caused by a reciprocal translocation [t(9;22)(q34;q11.2)] that leads to the fusion of ABL1 gene sequences (9q34) downstream of BCR gene sequences (22q11) and is cytogenetically visible as Philadelphia chromosome (Ph). The resulting BCR/ABL1 chimeric protein is a constitutively active tyrosine kinase that activates multiple signaling pathways, which collectively lead to malignant transformation. During the early (chronic) phase of CML (CP-CML), the myeloid cell compartment is expanded, but differentiation is maintained. Without effective therapy, CP-CML invariably progresses to blast phase (BP-CML), an acute leukemia of myeloid or lymphoid phenotype. The development of BCR-AB1 tyrosine kinase inhibitors (TKIs) revolutionized the treatment of CML and ignited the start of a new era in oncology. With three generations of BCR/ABL1 TKIs approved today, the majority of CML patients enjoy long term remissions and near normal life expectancy. However, only a minority of patients maintain remission after TKI discontinuation, a status termed treatment free remission (TFR). Unfortunately, 5-10% of patients fail TKIs due to resistance and are at risk of progression to BP-CML, which is curable only with hematopoietic stem cell transplantation. Overcoming TKI resistance, improving the prognosis of BP-CML and improving the rates of TFR are areas of active research in CML.
Topics: Animals; Antineoplastic Agents; Disease Management; Disease Models, Animal; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Models, Molecular; Protein Kinase Inhibitors
PubMed: 33773846
DOI: 10.1016/j.blre.2021.100825 -
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 -
The evolution of acute lymphoblastic leukemia research and therapy at MD Anderson over four decades.Journal of Hematology & Oncology Mar 2023Progress in the research and therapy of adult acute lymphoblastic leukemia (ALL) is accelerating. This analysis summarizes the data derived from the clinical trials... (Review)
Review
Progress in the research and therapy of adult acute lymphoblastic leukemia (ALL) is accelerating. This analysis summarizes the data derived from the clinical trials conducted at MD Anderson between 1985 and 2022 across ALL subtypes. In Philadelphia chromosome-positive ALL, the addition of BCR::ABL1 tyrosine kinase inhibitors (TKIs) to intensive chemotherapy since 2000, improved outcomes. More recently, a chemotherapy-free regimen with blinatumomab and ponatinib resulted in a complete molecular remission rate of 85% and an estimated 3-year survival rate of 90%, potentially reducing the role of, and need for allogeneic stem cell transplantation (SCT) in remission. In younger patients with pre-B Philadelphia chromosome-negative ALL, the integration of blinatumomab and inotuzumab into the frontline therapy has improved the estimated 3-year survival rate to 85% across all risk categories. Our future strategy is to evaluate the early integration of both immunotherapy agents, inotuzumab and blinatumomab, with low-dose chemotherapy (dose-dense mini-Hyper-CVD-inotuzumab-blinatumomab) into the frontline setting followed by CAR T cells consolidation in high-risk patients, without any further maintenance therapy. In older patients, using less intensive chemotherapy (mini-Hyper-CVD) in combination with inotuzumab and blinatumomab has improved the 5-year survival rate to 50%. Among patients ≥ 65-70 years, the mortality in complete remission (CR) is still high and is multifactorial (old age, death in CR with infections, development of myelodysplastic syndrome or acute myeloid leukemia). A chemotherapy-free regimen with inotuzumab and blinatumomab is being investigated. The assessment of measurable residual disease (MRD) by next-generation sequencing (NGS) is superior to conventional assays, with early MRD negativity by NGS being associated with the best survival. We anticipate that the future therapy in B-ALL will involve less intensive and shorter chemotherapy regimens in combination with agents targeting CD19 (blinatumomab), CD20, and CD22 (inotuzumab). The optimal timing and use of CAR T cells therapy may be in the setting of minimal disease, and future trials will assess the role of CAR T cells as a consolidation among high-risk patients to replace allogeneic SCT. In summary, the management of ALL has witnessed significant progress during the past four decades. Novel combination regimens including newer-generation BCR::ABL1 TKIs and novel antibodies are questioning the need and duration of intensive chemotherapy and allogeneic SCT.
Topics: Adult; Humans; Aged; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Antineoplastic Combined Chemotherapy Protocols; Antibodies, Bispecific; Cardiovascular Diseases
PubMed: 36927623
DOI: 10.1186/s13045-023-01409-5 -
Blood Advances Jan 2020Philadelphia chromosome-like B-cell acute lymphoblastic leukemia (Ph-like ALL) accounts for 15% to 30% of B-cell acute lymphoblastic leukemia in older children,... (Review)
Review
Philadelphia chromosome-like B-cell acute lymphoblastic leukemia (Ph-like ALL) accounts for 15% to 30% of B-cell acute lymphoblastic leukemia in older children, adolescents, and adults and is associated with high rates of conventional treatment failure and relapse. Current clinical trials are assessing the efficacy of the addition of tyrosine kinase inhibitors (TKIs) to chemotherapy for children and adults with Ph-like ALL harboring ABL class translocations or CRLF2 rearrangements and other JAK pathway alterations. However, real-time diagnosis of patients can be quite challenging given the genetic heterogeneity of this disease and the often cytogenetically cryptic nature of Ph-like ALL-associated alterations. In this review, we discuss the complex biologic and clinical features of Ph-like ALL across the age spectrum, available diagnostic testing modalities, and current clinical treatment strategies for these high-risk patients. We further propose a practical and step-wise approach to Ph-like ALL genetic testing to facilitate the identification and allocation of patients to appropriate clinical trials of TKI-based therapies or commercially available drugs. Although the majority of patients with Ph-like ALL can be successfully identified via current clinical assays by the end of induction chemotherapy, increasing diagnostic efficiency and sensitivity and decreasing time to test resulting will facilitate earlier therapeutic intervention and may improve clinical outcomes for these high-risk patients.
Topics: Adolescent; Adult; Child; Humans; Induction Chemotherapy; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinase Inhibitors
PubMed: 31935290
DOI: 10.1182/bloodadvances.2019000163 -
American Journal of Hematology Mar 2023The combination of ponatinib, a third-generation BCR::ABL1 tyrosine kinase inhibitor, with hyper-CVAD chemotherapy resulted in high rates of complete molecular...
The combination of ponatinib, a third-generation BCR::ABL1 tyrosine kinase inhibitor, with hyper-CVAD chemotherapy resulted in high rates of complete molecular remissions and survival, without the need for stem cell transplantation (SCT) in most patients with Philadelphia chromosome(Ph)-positive acute lymphocytic leukemia (ALL). Confirming these results in a large cohort of patients with longer follow-up would establish this regimen as a new standard of care. Adults with newly diagnosed Ph-positive ALL were treated with the hyper-CVAD regimen. Ponatinib was added as 45 mg daily × 14 during induction, then 45 mg daily continuously (first 37 patients) or 30 mg daily continuously, with dose reduction to 15 mg daily upon achievement of a complete molecular response (CMR; absence of a detectable BCR::ABL1 transcript by quantitative reverse transcription polymerase-chain reaction at a sensitivity of 0.01%). Maintenance therapy consisted of daily ponatinib and vincristine-prednisone monthly for 2 years, followed by daily ponatinib indefinitely. Twelve intrathecal injections of cytarabine alternating with methotrexate were given as central nervous system prophylaxis. The trial is registered on clinicaltrials.gov with the identifier NCT01424982. Eighty-six patients were treated. Their median age was 46 years (range, 21-80). All 68 patients with active disease at the initiation of therapy achieved complete response (CR) The cumulative CMR rate was 86%. Twenty- patients (23%) underwent allogeneic SCT. With a median follow-up of 80 months (range, 16-129 months), the estimated 6-year event-free survival rate was 65% and the overall survival rate was 75%. There was no difference in outcome by performance of allogeneic SCT in first CR. Common grade 3-5 adverse events included infection (n = 80, 93%), increased liver transaminases (n = 26, 31%) and total bilirubin (n = 13, 15%), hypertension (n = 15, 17%), pancreatitis (n = 13, 15%), hemorrhage (n = 12, 13%), and skin rash (n = 9, 10%). Two ponatinib-related deaths from myocardial infarction (3%; at months 2.6 and 4.3, respectively; both in CR) in the first 37 patients treated led to the ponatinib dose-modifications mentioned earlier, with no further ponatinib-related deaths observed. The long-term results of ponatinib and hyper-CVAD continue to demonstrate excellent outcome results and acceptable safety data, indicating that this strategy is another standard of care approach in frontline Ph-positive ALL.
Topics: Adult; Humans; Middle Aged; Cyclophosphamide; Doxorubicin; Philadelphia Chromosome; Follow-Up Studies; Dexamethasone; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Vincristine; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36600670
DOI: 10.1002/ajh.26816 -
Blood Advances Sep 2022Promising results have been shown with the combination of ponatinib and chemotherapy in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+...
Promising results have been shown with the combination of ponatinib and chemotherapy in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). The PONALFIL (Ponatinib With Chemotherapy for Young Adults Ph Positive Acute Lymphoblastic Leukemia) trial combined ponatinib (30 mg/d) with standard induction and consolidation chemotherapy followed by allogeneic hematopoietic stem cell transplant (alloHSCT) in newly diagnosed Ph+ ALL patients aged 18 to 60 years. Ponatinib was only given pre-emptively after alloHSCT. Primary end points were hematologic and molecular response before alloHSCT and event-free survival (EFS), including molecular relapse as event. Thirty patients (median age, 49 years; range, 19-59 years) entered the trial. All exhibited hematologic response, and alloHSCT was performed in 26 patients (20 in complete molecular response and 6 in major molecular response). Only 1 patient died (of graft-versus-host disease), and 5 patients exhibited molecular relapse after alloHSCT. No tyrosine kinase inhibitor was given after HSCT in 18 of 26 patients. Twenty-nine patients are alive (median follow-up, 2.1 years; range, 0.2-4.0 years), with 3-year EFS and overall survival (OS) of 70% (95% confidence interval, 51-89) and 96% (95% confidence interval, 89-100), respectively. Comparison of the PONALFIL and the ALLPh08 (Chemotherapy and Imatinib in Young Adults With Acute Lymphoblastic Leukemia Ph [BCR-ABL] Positive; same schedule, using imatinib as the tyrosine kinase inhibitor) trials by propensity score showed significant improvement in OS for patients in PONALFIL (3-year OS, 96% vs 53%; P = .002). The most frequent grade 3 to 4 adverse events were hematologic (42%), infectious (17%), and hepatic (22%), with only one vascular occlusive event. The combination of chemotherapy with ponatinib followed by alloHSCT is well tolerated, with encouraging EFS in adults with newly diagnosed Ph+ ALL. Cross-trial comparison suggests improvement vs imatinib (clinicaltrials.gov identifier #NCT02776605).
Topics: Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Humans; Imatinib Mesylate; Imidazoles; Middle Aged; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinase Inhibitors; Pyridazines; Recurrence; Young Adult
PubMed: 35675590
DOI: 10.1182/bloodadvances.2022007764 -
Journal of Blood Medicine 2023Chronic myeloid leukemia (CML) is one of the most common leukemias occurring in the adult population. The course of CML is divided into three phases: the chronic phase,... (Review)
Review
Chronic myeloid leukemia (CML) is one of the most common leukemias occurring in the adult population. The course of CML is divided into three phases: the chronic phase, the acceleration phase, and the blast phase. Pathophysiology of CML revolves around Philadelphia chromosome that constitutively activate tyrosine kinase through BCR-ABL1 oncoprotein. In the era of tyrosine kinase inhibitors (TKIs), CML patients now have a similar life expectancy to people without CML, and it is now very rare for CML patients to progress to the blast phase. Only a small proportion of CML patients have resistance to TKI, caused by BCR-ABL1 point mutations. CML patients with TKI resistance should be treated with second or third generation TKI, depending on the BCR-ABL1 mutation. Recently, many studies have shown that it is possible for CML patients who achieve a long-term deep molecular response to stop TKIs treatment and maintain remission. This review aimed to provide an overview of CML, including its pathophysiology, clinical manifestations, the role of stem cells, CML treatments, and treatment-free remission.
PubMed: 37051025
DOI: 10.2147/JBM.S382090