-
International Journal of Molecular... Sep 2021Philadelphia chromosome negative myeloproliferative neoplasms (MPN) are composed of polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis... (Review)
Review
Philadelphia chromosome negative myeloproliferative neoplasms (MPN) are composed of polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF). The clinical picture is determined by constitutional symptoms and complications, including arterial and venous thromboembolic or hemorrhagic events. MPNs are characterized by mutations in , , or , with additional mutations leading to an expansion of myeloid cell lineages and, in PMF, to marrow fibrosis and cytopenias. Chronic inflammation impacting the initiation and expansion of disease in a major way has been described. Neutrophilic granulocytes play a major role in the pathogenesis of thromboembolic events via the secretion of inflammatory markers, as well as via interaction with thrombocytes and the endothelium. In this review, we discuss the molecular biology underlying myeloproliferative neoplasms and point out the central role of leukocytosis and, specifically, neutrophilic granulocytes in this group of disorders.
Topics: Hematologic Neoplasms; Humans; Myeloproliferative Disorders; Neoplasm Proteins; Neutrophils; Philadelphia Chromosome
PubMed: 34502471
DOI: 10.3390/ijms22179555 -
Current Hematologic Malignancy Reports Dec 2020The treatment of acute lymphoblastic leukemia (ALL) in adolescent and young adult (AYA) patients has markedly improved with the adoption of pediatric-inspired protocols.... (Review)
Review
PURPOSE OF REVIEW
The treatment of acute lymphoblastic leukemia (ALL) in adolescent and young adult (AYA) patients has markedly improved with the adoption of pediatric-inspired protocols. However, there remain several subtypes of ALL that represent significant therapeutic challenges. Here, we review the current evidence guiding treatment of Philadelphia chromosome-positive (Ph+), Philadelphia chromosome-like (Ph-L), and early T-precursor (ETP) ALL in the AYA population.
RECENT FINDINGS
Clinical trials in Ph + ALL have demonstrated the superior efficacy of second- and third-generation tyrosine kinase inhibitors (TKIs) to induce and maintain remission. Current efforts now focus on determining the durability of these remissions and which patients will benefit from transplant. For Ph-like and ETP ALL, recent studies are investigating the addition of novel agents to standard treatment. The treatment of Ph + ALL has significantly improved with the addition of potent TKIs. However, the treatment of Ph-like and ETP ALL remains a challenge. At this time, the judicious use of allogenic transplant is the only current approach to modify this increased risk.
Topics: Adolescent; Biomarkers, Tumor; Clinical Decision-Making; Clinical Trials as Topic; Combined Modality Therapy; Disease Management; Disease Susceptibility; Drug Evaluation, Preclinical; Humans; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Treatment Outcome; Young Adult
PubMed: 32920736
DOI: 10.1007/s11899-020-00597-y -
Modern Pathology : An Official Journal... Jul 2018The Philadelphia chromosome resulting from t(9;22)(q34;q11.2) or its variants is a defining event in chronic myeloid leukemia. It is also observed in several types of de...
The Philadelphia chromosome resulting from t(9;22)(q34;q11.2) or its variants is a defining event in chronic myeloid leukemia. It is also observed in several types of de novo acute leukemia, commonly in B lymphoblastic leukemia, and rarely in acute myeloid leukemia, acute leukemia of ambiguous lineage, and T lymphoblastic leukemia. Acquisition of the Philadelphia chromosome during therapy of acute leukemia and myelodysplastic syndrome is rare. We reported 19 patients, including 11 men and 8 women with a median age of 53 years at initial diagnosis. The diagnoses at initial presentation were acute myeloid leukemia (n = 11), myelodysplastic syndrome (n = 5), B lymphoblastic leukemia (n = 2), and T lymphoblastic leukemia (n = 1); no cases carried the Philadelphia chromosome. The Philadelphia chromosome was detected subsequently at relapse, or at refractory stage of acute leukemia or myelodysplastic syndrome. Of 14 patients evaluated for the BCR-ABL1 transcript subtype, 12 had the e1a2 transcript. In 11 of 14 patients, the diseases before and after emergence of the Philadelphia chromosome were clonally related by karyotype or shared gene mutations. Of 15 patients with treatment information available, 7 received chemotherapy alone, 5 received chemotherapy plus tyrosine kinase inhibitors, 2 received tyrosine kinase inhibitors only, and 1 patient was not treated. Twelve patients had follow-up after acquisition of the Philadelphia chromosome; all had persistent/refractory acute leukemia. Thirteen of 15 patients died a median of 3 months after the emergence of the Philadelphia chromosome. In summary, secondary Philadelphia chromosome acquired during therapy is rare, and is associated with the e1a2 transcript subtype, terminal disease stage, and poor outcome.
Topics: Acute Disease; Adolescent; Adult; Aged; Antineoplastic Agents; Female; Humans; Leukemia; Male; Middle Aged; Myelodysplastic Syndromes; Neoplasm Recurrence, Local; Philadelphia Chromosome; Young Adult
PubMed: 29449681
DOI: 10.1038/s41379-018-0014-x -
Hematology. American Society of... Nov 2018Acute lymphoblastic leukemia (ALL) is characterized by genetic alterations that block differentiation, promote proliferation of lymphoid precursor cells, and are... (Review)
Review
Acute lymphoblastic leukemia (ALL) is characterized by genetic alterations that block differentiation, promote proliferation of lymphoid precursor cells, and are important for risk stratification. Although ALL is less common in adolescents and young adults (AYAs) and adults than children, survival rates are inferior, and long-term prognosis for adults is poor. Thus, ALL remains a challenging disease to treat in the AYA and adult populations. A major contributing factor that influences prognosis in this population is the reduced prevalence of genetic subtypes associated with favorable outcome and a concomitant increase in subtypes associated with poor outcome. Recent advances in genomic profiling across the age spectrum continue to enhance our knowledge of the differences in disease biology between children and adults and are providing important insights into novel therapeutic targets. Philadelphia chromosome-like (Ph-like) ALL is one such subtype characterized by alterations that deregulate cytokine receptor or tyrosine kinase signaling and are amenable to inhibition with approved tyrosine kinase inhibitors. One of the greatest challenges now remaining is determining how to implement this breadth of genomic information into rapid and accurate diagnostic testing to facilitate the development of novel clinical trials that improve the outcome of AYAs and adults with ALL.
Topics: Adolescent; Adult; Child; Child, Preschool; Female; Humans; Infant; Male; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis
PubMed: 30504302
DOI: 10.1182/asheducation-2018.1.137 -
Biologics : Targets & Therapy 2016Chronic myelogenous leukemia (CML) is a pluripotent stem cell disease characterized by the presence of the Philadelphia chromosome and the bcr-abl gene. The discovery of... (Review)
Review
Chronic myelogenous leukemia (CML) is a pluripotent stem cell disease characterized by the presence of the Philadelphia chromosome and the bcr-abl gene. The discovery of tyrosine kinase inhibitors (TKIs) revolutionized therapy for CML, such that durable response, increased overall survival, and increased progression-free survival of patients in chronic phase CML is now possible. Due to resistance and intolerance to imatinib, there was need for development of second- and third-generation TKIs for the treatment of CML. This review examines the role of nilotinib, an oral second-generation TKI, in the treatment of Philadelphia positive CML. The pharmacology, efficacy, and safety of nilotinib are critically evaluated. Patient-related issues, including tolerance, drug interactions, and quality of life issues are also examined.
PubMed: 27013862
DOI: 10.2147/BTT.S67844 -
Hematology. American Society of... Dec 2017Treatment of Philadelphia chromosome positive acute lymphoblastic leukemia exemplifies how the addition of potent targeted agents, directed at the molecular aberrations... (Review)
Review
Treatment of Philadelphia chromosome positive acute lymphoblastic leukemia exemplifies how the addition of potent targeted agents, directed at the molecular aberrations responsible for leukemic transformation, can overcome resistance mechanisms to traditional regimens and lead to improved outcomes. The introduction of targeted tyrosine kinase inhibitors (TKIs) has significantly improved the outcomes not only by allowing more patients to undergo allogeneic hematopoietic cell transplantation (alloHCT) but also by decreasing our reliance on this potentially toxic strategy, particularly in the less fit population. Long-term data using chemotherapy and TKI combinations demonstrate that a proportion of patients treated can achieve durable relapse-free survival without undergoing alloHCT. Furthermore, the availability of sensitive minimal residual disease monitoring assays may allow early detection of the patients who are more likely to relapse and who are likely candidates for early alloHCT. The emergence of more potent TKIs with significant activity against resistant mutations has allowed deintensification of chemotherapy regimens. Available data indicate that complete reliance on TKIs, alone or with minimal additional therapy, and elimination of more intensive chemotherapy or alloHCT is unlikely to achieve long term cure in most patients. However, introduction of other highly effective agents that can be combined with TKIs may allow further minimization of chemotherapy and alloHCT in the future, as we have witnessed in acute promyelocytic leukemia.
Topics: Allografts; Fusion Proteins, bcr-abl; Humans; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinase Inhibitors; Stem Cell Transplantation
PubMed: 29222233
DOI: 10.1182/asheducation-2017.1.22 -
Hematology. American Society of... Dec 2022Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) carried a very poor prognosis prior to the advent of tyrosine kinase inhibitors (TKIs) that...
Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) carried a very poor prognosis prior to the advent of tyrosine kinase inhibitors (TKIs) that block the activity of the BCR-ABL1 oncoprotein. With improvements in TKI efficacy and allogeneic hematopoietic cell transplantation (HCT), survival has improved over the past 3 decades, and the role of chemotherapy and allogeneic HCT is now changing. Better risk stratification, the application of the third-generation TKI ponatinib, and the use of immunotherapy with the CD19-CD3 bifunctional T-cell engaging antibody blinatumomab in place of chemotherapy has made therapy for Ph+ ALL more tolerable and arguably more efficacious, especially for older patients who comprise most patients with Ph+ ALL.
Topics: Humans; Protein Kinase Inhibitors; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Hematopoietic Stem Cell Transplantation; Philadelphia Chromosome
PubMed: 36485090
DOI: 10.1182/hematology.2022000338 -
Life (Basel, Switzerland) Oct 2021Chronic myeloproliferative neoplasms (MPNs) are hematopoietic stem cell neoplasms with driver events including the translocation leading to a diagnosis of chronic... (Review)
Review
Chronic myeloproliferative neoplasms (MPNs) are hematopoietic stem cell neoplasms with driver events including the translocation leading to a diagnosis of chronic myeloid leukemia (CML), or somatic mutations in , , or MPL resulting in Philadelphia-chromosome-negative MPNs with constitutive activation of the JAK-STAT signaling pathway. In the Philadelphia-chromosome-negative MPNs, modern sequencing panels have identified a vast molecular landscape including additional mutations in genes involved in splicing, signal transduction, DNA methylation, and chromatin modification such as , , , and . These additional mutations often influence prognosis in MPNs and therefore are increasingly important for risk stratification. This review focuses on the molecular alterations within the WHO classification of MPNs and laboratory testing used for diagnosis.
PubMed: 34833034
DOI: 10.3390/life11111158 -
Cancer Medicine Jan 2021The epidemiology, genetics, and thrombosis risk of MPNs among Arabs are largely unknown. This may be attributed to scarce epidemiological data, particularly from our...
The epidemiology, genetics, and thrombosis risk of MPNs among Arabs are largely unknown. This may be attributed to scarce epidemiological data, particularly from our region. Our study included 381 Kuwaiti nationals with Ph-negative MPNs and a confirmed driver mutation involving JAK2 (exon 12 14), CALR, or MPL. This first regional study examines the demographics, clinical parameters, and thrombosis-related attributes of the participants. This study reported a median age of 58 years, with females and males representing 54.9% and 45.1%, respectively. ET was the most frequent subtype of Ph-negative MPNs in our population, accounting for 52.0% of the cases, followed by PV, found in 34.6% of the participants, and PMF, found in 8.4% of participants. The crude annual cumulative incidence of Ph-negative MPNs in Kuwait ranged from 0.674 to 3.177 per 100,000 population across the study period. The most common driver mutation was JAK2V617F, with a frequency of 89.5%. At diagnosis, 19.2% of the patients presented with unexplained thrombosis, and almost half were of arterial origins. Males were more likely to present with arterial thrombosis than females (61.5% vs. 35.3%), whereas venous thrombotic events were more common in females than in males (47.1% vs. 17.9%; p-value = 0.025). Ph-negative MPNs in Kuwait are rare; however, thrombosis is a frequent complication, being documented in up to 19.2% of cases at presentation, more commonly at arterial sites. These findings call for thorough evaluation of patients with unexplained derangements in their hematological parameters during follow-ups.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Arterial Occlusive Diseases; Calreticulin; Child; Child, Preschool; Female; Genetic Predisposition to Disease; Humans; Incidence; Infant; Infant, Newborn; Janus Kinase 2; Kuwait; Male; Middle Aged; Mutation; Myeloproliferative Disorders; Philadelphia Chromosome; Receptors, Thrombopoietin; Registries; Risk Assessment; Risk Factors; Thrombosis; Venous Thromboembolism; Young Adult
PubMed: 33280271
DOI: 10.1002/cam4.3633 -
American Journal of Cancer Research 2022Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) is a high-risk disease subtype with a dismal prognosis. Inhibiting BCR-ABL kinase alone is...
Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) is a high-risk disease subtype with a dismal prognosis. Inhibiting BCR-ABL kinase alone is insufficient to eradicate Ph+ALL clones, and alternative BCR-ABL-dependent and -independent pathways need to be targeted as an effective strategy. Our study revealed that the combination of dasatinib and interferon-α showed synergistic activity against Ph+ALL, inducing mitochondrial dysfunction and causing necrosis-like cell lysis. Mechanistic studies showed that the induced cell death was caspase-3-independent. Canonical necroptosis signals, such as RIP1 and MLKL, were not activated; instead, the pyroptosis executor Gasdermin D was upregulated expression and activated. The expression levels of extracellular ATP and IL-1β were also upregulated, both of which are markers of pyroptotic cell death. In a murine Ph+ALL model, the dual drug treatment prolonged the survival of tumor-bearing mice. More importantly, we incorporated the dual drugs to maintenance therapy in 39 patients who were unfit for allogeneic stem cell transplantation (allo-HSCT). The median follow-up was 28.5 months, the 4-year disease-free survival and overall survival rates were 52.2% and 65.2%, respectively. Our data suggest that the combination of dasatinib and interferon-α has potential synergistic activity against Ph+ALL and shows promise as a maintenance therapy for Ph+ALL patients who are unfit for allo-HSCT.
PubMed: 35812060
DOI: No ID Found