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Blood Reviews Jul 2024There have been major paradigm shifts in the treatment of Philadelphia chromosome negative (Ph-) acute lymphoblastic leukemia (ALL) in the last decade with the... (Review)
Review
There have been major paradigm shifts in the treatment of Philadelphia chromosome negative (Ph-) acute lymphoblastic leukemia (ALL) in the last decade with the introduction of new immunotherapies and targeted agents, adoption of pediatric-type chemotherapy protocols in younger adults as well as chemotherapy light approaches in older adults and the incorporation of measurable residual disease (MRD) testing to inform clinical decision making. With this, treatment outcomes in adult Ph- ALL have improved across all age groups. However, a subset of patients will still develop relapsed disease, which can be challenging to treat and associated with poor outcomes. Here we review the treatment of Ph- ALL in both younger and older adults, including the latest advancements and future directions.
Topics: Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Philadelphia Chromosome; Neoplasm, Residual; Disease Management; Antineoplastic Combined Chemotherapy Protocols; Treatment Outcome
PubMed: 38734488
DOI: 10.1016/j.blre.2024.101208 -
Best Practice & Research. Clinical... Dec 2021Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a subset of high-risk B-ALL associated with high relapse risk and inferior clinical outcomes... (Review)
Review
Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a subset of high-risk B-ALL associated with high relapse risk and inferior clinical outcomes across the pediatric-to-adult age spectrum. Ph-like ALL is characterized by frequent IKZF1 alterations and a kinase-activated gene expression profile similar to that of Philadelphia chromosome-positive (Ph+) ALL, yet lacks the canonical BCR-ABL1 rearrangement. Advances in high-throughput sequencing technologies during the past decade have unraveled the genomic landscape of Ph-like ALL, revealing a diverse array of kinase-activating translocations and mutations that may be amenable to targeted therapies that have set a remarkable precision medicine paradigm for patients with Ph + ALL. Collaborative scientific efforts to identify and characterise Ph-like ALL during the past decade has directly informed current precision medicine trials investigating the therapeutic potential of tyrosine kinase inhibitor-based therapies for children, adolescents, and adults with Ph-like ALL, although the most optimal treatment paradigm for this high-risk group of patients has yet to be established. Herein, we describe the epidemiology, clinical features, and biology of Ph-like ALL, highlight challenges in implementing pragmatic and cost-effective diagnostic algorithms in the clinic, and describe the milieu of treatment strategies under active investigation that strive to decrease relapse risk and improve long-term survival for patients with Ph-like ALL as has been successfully achieved for those with Ph + ALL.
Topics: Adolescent; Adult; Child; Fusion Proteins, bcr-abl; Humans; Molecular Targeted Therapy; Mutation; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Translocation, Genetic
PubMed: 34865703
DOI: 10.1016/j.beha.2021.101331 -
Cancer Dec 2023Since the introduction of BCR::ABL1 tyrosine kinase inhibitors (TKIs) in 2000, the treatment of Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML) has...
Outcome of Philadelphia chromosome-positive chronic myeloid leukemia in the United States since the introduction of imatinib therapy-The Surveillance, Epidemiology, and End Results database, 2000-2019.
BACKGROUND
Since the introduction of BCR::ABL1 tyrosine kinase inhibitors (TKIs) in 2000, the treatment of Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML) has improved significantly.
METHODS
This study aimed to evaluate Ph-positive CML outcomes in the TKI therapy era, considering factors like age, ethnicity, and income. Using the Surveillance, Epidemiology, and End Results (SEER) database, 2857 patients with Ph-positive CML diagnosed from 2000 to 2019 were analyzed.
RESULTS
The overall 5-year survival rates in Ph-positive CML increased to above 80%, compared with pre-TKIs historical data reporting 5-year overall survival (OS) rates of less than 50%. The 5-year OS rate was 73% for patients diagnosed in 2000-2004, 82% in 2005-2009, and 78% in 2010-2014; the 4-year OS rate was 83% in 2015-2019. The 5-year OS rate for younger patients (<60 years old) was 88% in 2000-2009 and 90% in 2010-2019 (p value .426). In older patients (60+ years old), the 5-year OS rates were 64% and 65%, respectively (p value, .303). Lower household income was associated with inferior survival across the 2000-2019. These results are inferior to European studies where TKIs are universally available and affordable, and relative OS in CML is similar to age-matched normal populations.
CONCLUSIONS
Although the outcome of Ph-positive CML has improved significantly since 2000, the SEER data still shows differences in outcomes among patient subsets, some anticipated (worse OS in older patients accounted by the relative OS), but others that suggest less than universal access and affordability of this therapy (among poorer patients) in the United States.
Topics: Humans; United States; Aged; Middle Aged; Imatinib Mesylate; Philadelphia Chromosome; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Income; Protein Kinase Inhibitors
PubMed: 37769040
DOI: 10.1002/cncr.35038 -
Expert Review of Clinical Pharmacology Mar 2024Tyrosine kinase inhibitors (TKIs) have revolutionized survival rates of chronic myeloid leukemia (CML) and Philadelphia chromosome positive (Ph+) acute lymphoblastic... (Review)
Review
INTRODUCTION
Tyrosine kinase inhibitors (TKIs) have revolutionized survival rates of chronic myeloid leukemia (CML) and Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) and replaced hematopoietic stem cell transplantation (hSCT) as the key treatment option for these patients. More recently, the so-called Philadelphia chromosome-like (Ph-like) ALL has similarly benefitted from TKIs. However, many patients shift from the first generation TKI, imatinib, due to treatment-related toxicities or lack of treatment efficacy. A more personalized approach to TKI treatment could counteract these challenges and potentially be more cost-effective. Therapeutic drug monitoring (TDM) has led to higher response rates and less treatment-related toxicity in adult CML but is rarely used in ALL or in childhood CML.
AREAS COVERED
This review summarizes different antileukemic treatment indications for TKIs with focus on imatinib and its pharmacokinetic/-dynamic properties as well as opportunities and pitfalls of TDM for imatinib treatment in relation to pharmacogenetics and co-medication for pediatric and adult Ph+/Ph-like leukemias.
EXPERT OPINION
TDM of imatinib adds value to standard monitoring of ABL-class leukemia by uncovering non-adherence and potentially mitigating adverse effects. Clinically implementable pharmacokinetic/-dynamic models adjusted for relevant pharmacogenetics could improve individual dosing. Prospective trials of TDM-based treatments, including both children and adults, are needed.
Topics: Adult; Humans; Child; Imatinib Mesylate; Philadelphia Chromosome; Drug Monitoring; Prospective Studies; Protein Kinase Inhibitors; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Drug Resistance, Neoplasm
PubMed: 38345044
DOI: 10.1080/17512433.2024.2312256 -
Leukemia Research Aug 2022Cyclic AMP-response element-binding protein 3-like 1 (CREB3L1) is a gene involved in the unfolded protein response (UPR). Recently, we demonstrated that CREB3L1 is...
Cyclic AMP-response element-binding protein 3-like 1 (CREB3L1) is a gene involved in the unfolded protein response (UPR). Recently, we demonstrated that CREB3L1 is specifically overexpressed in the platelets of patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). In this study, we aimed to show the clinical and biological relevance of CREB3L1 in these hematological diseases. Overexpression of CREB3L1 was specific to platelets in MPNs and associated with a higher risk of thrombosis and fibrotic transformation in essential thrombocythemia (ET) and polycythemia vera (PV) cases, respectively. Furthermore, we found that UPR genes were downregulated in platelets of patients with ET and PV, which were more pronounced in patients harboring the JAK2 V617F mutation. However, CREB3L1 overexpression does not alter UPR gene expression or cell proliferation in UT-7/TPO/CALRm cells exogenously expressing mutated calreticulin and HEL cells harboring endogenous JAK2 V617F. Furthermore, CREB3L1 overexpression did not modulate sensitivity to endoplasmic reticulum stress in these cell lines. Taken together, our data show 1) a potential role of CREB3L1 expression in platelets as a new marker of high-risk MPNs and 2) an association between CREB3L1 overexpression and UPR gene downregulation in these patients' platelets, with CREB3L1 not altering UPR in our in vitro models and possibly further in vivo mechanisms being involved.
Topics: Calreticulin; Cyclic AMP Response Element-Binding Protein; Humans; Janus Kinase 2; Mutation; Myeloproliferative Disorders; Nerve Tissue Proteins; Philadelphia Chromosome; Polycythemia Vera; Thrombocythemia, Essential
PubMed: 35689957
DOI: 10.1016/j.leukres.2022.106883 -
International Journal of Molecular... Aug 2020Philadelphia chromosome (Ph) results from a translocation between the breakpoint cluster region () gene on chromosome 9 and ABL proto-oncogene 1 () gene on chromosome... (Review)
Review
Philadelphia chromosome (Ph) results from a translocation between the breakpoint cluster region () gene on chromosome 9 and ABL proto-oncogene 1 () gene on chromosome 22. The fusion gene, , is a constitutively active tyrosine kinase which promotes development of leukemia. Depending on the breakpoint site within the gene, different isoforms of BCR-ABL1 exist, with p210 and p190 being the most prevalent. P210 isoform is the hallmark of chronic myeloid leukemia (CML), while p190 isoform is expressed in majority of Ph-positive B cell acute lymphoblastic leukemia (Ph+ B-ALL) cases. The crucial component of treatment protocols of CML and Ph+ B-ALL patients are tyrosine kinase inhibitors (TKIs), drugs which target both BCR-ABL1 isoforms. While TKIs therapy is successful in great majority of CML patients, Ph+ B-ALL often relapses as a drug-resistant disease. Recently, the high-throughput genomic and proteomic analyses revealed significant differences between CML and Ph+ B-ALL. In this review we summarize recent discoveries related to differential signaling pathways mediated by different BCR-ABL1 isoforms, lineage-specific genetic lesions, and metabolic reprogramming. In particular, we emphasize the features distinguishing Ph+ B-ALL from CML and focus on potential therapeutic approaches exploiting those characteristics, which could improve the treatment of Ph+ B-ALL.
Topics: Cell Lineage; Clinical Trials as Topic; Humans; Leukemia; Lymphocytes; Myeloid Cells; Philadelphia Chromosome; Proto-Oncogene Mas
PubMed: 32806528
DOI: 10.3390/ijms21165776 -
Clinical Lymphoma, Myeloma & Leukemia Nov 2023The therapeutic landscape of Philadelphia chromosome positive acute lymphoblastic leukemia (ALL) for adults has dramatically changed over the past 2 decades; the... (Review)
Review
The therapeutic landscape of Philadelphia chromosome positive acute lymphoblastic leukemia (ALL) for adults has dramatically changed over the past 2 decades; the emergence of newer generations of tyrosine kinase inhibitors and incorporation of targeted immunotherapies into front-line therapy have significantly improved outcomes to the point where an argument can be made that this entity may no longer be considered a high-risk ALL subgroup. In this review article, we discuss different front-line regimens (both intensive and deintensified regimens including chemotherapy-free regimens). We also review disease monitoring strategies, discuss the role of allogeneic hematopoietic stem cell transplantation, and discuss the rapidly changing therapeutic landscape for patients with relapsed disease.
Topics: Humans; Adult; Protein Kinase Inhibitors; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Hematopoietic Stem Cell Transplantation
PubMed: 37438208
DOI: 10.1016/j.clml.2023.06.007 -
Hamostaseologie Jun 2021Philadelphia chromosome-negative myeloproliferative neoplasms are hematopoietic stem cell disorders characterized by dysregulated proliferation of mature myeloid blood... (Review)
Review
Philadelphia chromosome-negative myeloproliferative neoplasms are hematopoietic stem cell disorders characterized by dysregulated proliferation of mature myeloid blood cells. They can present as polycythemia vera, essential thrombocythemia, or myelofibrosis and are characterized by constitutive activation of signaling. They share a propensity for thrombo-hemorrhagic complications and the risk of progression to acute myeloid leukemia. Attention has also been drawn to mutant clonal hematopoiesis of indeterminate potential as a possible precursor state of MPN. Insight into the pathogenesis as well as options for the treatment of MPN has increased in the last years thanks to modern sequencing technologies and functional studies. Mutational analysis provides information on the oncogenic driver mutations in , , or in the majority of MPN patients. In addition, molecular markers enable more detailed prognostication and provide guidance for therapeutic decisions. While inhibitors represent a standard of care for MF and resistant/refractory PV, allogeneic hematopoietic stem cell transplantation remains the only therapy with a curative potential in MPN so far but is reserved to a subset of patients. Thus, novel concepts for therapy are an important need, particularly in MF. Novel inhibitors, combination therapy approaches with ruxolitinib, as well as therapeutic approaches addressing new molecular targets are in development. Current standards and recent advantages are discussed in this review.
Topics: Aged; Allografts; Calreticulin; Combined Modality Therapy; DNA Mutational Analysis; Female; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Janus Kinase 2; Janus Kinase Inhibitors; Male; Middle Aged; Mutation; Myeloproliferative Disorders; Nitriles; Philadelphia Chromosome; Polycythemia Vera; Primary Myelofibrosis; Pyrazoles; Pyrimidines; Receptors, Thrombopoietin; Thrombocythemia, Essential
PubMed: 34192778
DOI: 10.1055/a-1447-6667 -
Expert Review of Anticancer Therapy Oct 2020Despite the significant progress that has been made over the last years in the front-line treatment of Philadelphia (Ph) chromosome-positive acute lymphoblastic leukemia... (Review)
Review
INTRODUCTION
Despite the significant progress that has been made over the last years in the front-line treatment of Philadelphia (Ph) chromosome-positive acute lymphoblastic leukemia (ALL), relapses are frequent and their treatment remains a challenge, especially among patients with resistant mutations.
AREAS COVERED
This manuscript reviews available data for the treatment of adult patients with relapsed/refractory Ph-positive ALL, with a focus on the role of tyrosine kinase inhibitors (TKIs), monoclonal antibodies, and immunotherapy.
EXPERT OPINION
Although a majority of patients with first relapsed Ph-positive ALL respond to subsequent salvage chemotherapy plus TKI combination, their outcomes remain poor. The main predictor of survival is the achievement of major molecular response anytime during the morphological response. More treatment strategies to improve survival are under investigation. Monoclonal antibodies and bispecific antibody constructs hold considerable promise in improving the outcomes of patients with relapsed ALL including Ph-positive ALL.
Topics: Adult; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Fusion Proteins, bcr-abl; Humans; Immunotherapy; Mutation; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinase Inhibitors; Recurrence
PubMed: 33016157
DOI: 10.1080/14737140.2020.1832890 -
Hematology/oncology Clinics of North... Apr 2021Polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) comprise the BCR-ABL-negative classical myeloproliferative neoplasms (MPNs).... (Review)
Review
Polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) comprise the BCR-ABL-negative classical myeloproliferative neoplasms (MPNs). These clonal myeloid diseases are principally driven by well-described molecular events; however, factors leading to their acquisition are not well understood. Beyond increasing age, male sex, and race/ethnicity differences, few consistent risk factors for the MPNs are known. PV and ET have an incidence of 0.5 to 4.0 and 1.1 to 2.0 cases per 100,000 person-years, respectively, and predict similar survival. PMF, which has an incidence of about 0.3 to 2.0 cases per 100,000 person-years, is associated with the shortest survival of the MPNs.
Topics: Humans; Male; Myeloproliferative Disorders; Philadelphia Chromosome; Polycythemia Vera; Primary Myelofibrosis; Thrombocythemia, Essential
PubMed: 33641862
DOI: 10.1016/j.hoc.2020.11.005