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Cancer Oct 2016Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a standard of care for patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia... (Review)
Review
Use of tyrosine kinase inhibitors to prevent relapse after allogeneic hematopoietic stem cell transplantation for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: A position statement of the Acute Leukemia Working Party of the European Society for Blood and Marrow...
Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a standard of care for patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). The introduction of tyrosine kinase inhibitors (TKIs) to first-line therapy has improved overall outcomes; however, a significant proportion of patients still relapse after alloHSCT. Posttransplant TKI maintenance was demonstrated to reduce the risk of relapse in a large retrospective study and, therefore, should be considered a valuable option. This consensus paper, written on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation, presents an overview of clinical studies on the use of TKIs after alloHSCT and proposes practical recommendations regarding the choice of TKI, treatment timing, and dosage. It is hoped that these recommendations will become the state of art in this field and, more importantly, lead to a reduction of Ph-positive ALL relapse after alloHSCT. Cancer 2016;122:2941-2951. © 2016 American Cancer Society.
Topics: Hematopoietic Stem Cell Transplantation; Humans; Neoplasm Recurrence, Local; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinase Inhibitors; Societies, Medical
PubMed: 27309127
DOI: 10.1002/cncr.30130 -
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 -
The National Medical Journal of India 1992Chronic myelogenous leukaemia is a clonal neoplasm of the pluripotent haematopoietic stem cell which is characterized in most patients by a consistent cytogenetic... (Review)
Review
Chronic myelogenous leukaemia is a clonal neoplasm of the pluripotent haematopoietic stem cell which is characterized in most patients by a consistent cytogenetic abnormality known as the Philadelphia chromosome. This chromosome occurs as a consequence of a reciprocal translocation between the long arms of chromosomes 9 and 22 which results in the creation of a new gene comprising sequences from the c-abl gene on chromosome 9 and the bcr gene on chromosome 22. The protein encoded by this structurally altered hybrid gene differs from the normal c-abl gene product in both molecular weight and in tyrosine kinase activity. It is likely that these alterations in the c-abl gene product play a central role in the pathogenesis of this leukaemia.
Topics: Genes, abl; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Philadelphia Chromosome; Translocation, Genetic
PubMed: 1302582
DOI: No ID Found -
PloS One 2021Hematopoietic stem cell transplantation (HSCT) is the current mainstay treatment for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). However,... (Meta-Analysis)
Meta-Analysis
Is stem cell transplantation still needed for adult Philadelphia chromosome-positive acute lymphoblastic leukemia receiving tyrosine kinase inhibitors therapy?: A systematic review and meta-analysis.
BACKGROUND
Hematopoietic stem cell transplantation (HSCT) is the current mainstay treatment for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). However, tyrosine kinase inhibitors (TKI) also play a significant role in the treatment of these patients. We conducted this systematic review and meta-analysis to compare the efficacy of allogeneic (allo-) HSCT, autologous (auto-) HSCT, and chemotherapy (CMT) alone-all in combination with TKIs in adult Ph+ ALL patients.
MATERIALS AND METHODS
This systematic review identified studies from the EMBASE and MEDLINE databases from inception to April 2021 using search terms related to "ALL" and "HSCT." Eligible studies could be randomized controlled trials or cohort studies that included adult Ph+ ALL patients who received a TKI and either allo-HSCT, auto-HSCT, or CMT alone, and that reported the number of patients in each group for each of our primary outcomes of interest: overall survival (OS) or disease-free survival (DFS). Point estimates and associated 95% confidence intervals (CI) from each study were combined using the Hantel-Maenszel method.
RESULTS
After two rounds of review, 26 cohort studies were determined to be eligible for the meta-analysis. Adult Ph+ ALL patients who received HSCT had better survival outcomes than those who did not receive any HSCT (pooled odds ratio [OR] for OS of 1.61, 95%CI: 1.08-2.40; I2 = 59%, and for DFS of 3.23, 95%CI: 2.00-5.23; I2 = 62% for allo-HSCT; and, pooled OR for OS of 7.04, 95%CI: 1.97-25.15; I2 = 0%, and for DFS of 5.78, 95%CI: 1.04-32.19; I2 = 42% for auto-HSCT). Allo-HSCT recipients had comparable OS and DFS, but lower relapse rate compared to auto-HSCT recipients. Funnel plot generally demonstrated no presence of publication bias.
CONCLUSIONS
This systematic review and meta-analysis demonstrated superior results of HSCT in Ph+ ALL patients compared to CMT alone. Moreover, auto-HSCT could be implemented with comparable survival outcomes to allo-HSCT in patients with no available donor or when haploidentical HSCT is not feasible.
Topics: Allografts; Disease-Free Survival; Hematopoietic Stem Cell Transplantation; Humans; Molecular Targeted Therapy; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinase Inhibitors
PubMed: 34181696
DOI: 10.1371/journal.pone.0253896 -
BMJ (Clinical Research Ed.) Feb 2002
Review
Topics: Child; Child, Preschool; Chromosomes, Human, Pair 12; Chromosomes, Human, Pair 21; Genetic Markers; Genetic Predisposition to Disease; Humans; Infant; Infections; Leukemia, Myeloid, Acute; Oncogene Proteins, Fusion; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Translocation, Genetic; Twin Studies as Topic
PubMed: 11823363
DOI: 10.1136/bmj.324.7332.283 -
The Journal of Clinical Investigation Aug 2007Almost 50 years ago, David Hungerford and I noticed an abnormally small chromosome in cells from patients with chronic myelogenous leukemia (CML). This article is a... (Review)
Review
Almost 50 years ago, David Hungerford and I noticed an abnormally small chromosome in cells from patients with chronic myelogenous leukemia (CML). This article is a personal perspective of the events leading to the discovery of this chromosome, which became known as the Philadelphia chromosome. As technology advanced over subsequent decades, the translocation resulting in the Philadelphia chromosome has been identified, its role in the development of CML has been confirmed, and a therapy directed against the abnormal protein it produces has shown promising results in the treatment of patients with CML.
Topics: History, 20th Century; History, 21st Century; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Neoplasm Proteins; Philadelphia Chromosome
PubMed: 17671636
DOI: 10.1172/JCI31771 -
Medicine May 2024The Philadelphia chromosome (Ph) is seen in most patients with chronic myeloid leukemia and some patients with acute lymphoblastic leukemia. However, Ph-positive acute... (Review)
Review
Philadelphia chromosome-positive acute myeloid leukemia successfully treated by allogeneic hematopoietic stem cell transplantation: A case report and review of the literature.
RATIONAL
The Philadelphia chromosome (Ph) is seen in most patients with chronic myeloid leukemia and some patients with acute lymphoblastic leukemia. However, Ph-positive acute myeloid leukemia (Ph + AML) is a rare entity with a poor prognosis and a short median survival period. To date, there have been few clinical reports on this disease. And the treatment regimen of this disease has not been uniformly determined.
PATIENT CONCERNS
We report a case of a Ph + AML. A 32-year-old male who was admitted to our hospital with weakness for 2 months.
DIAGNOSIS
Philadelphia chromosome-positive acute myeloid leukemia.
INTERVENTIONS
The patient achieved complete remission by the administration of a tyrosine kinase inhibitor, combined with low-intensity chemotherapy and a B-cell lymphoma 2 inhibitor. Then, allogeneic hematopoietic stem cell transplantation (allo-HSCT) from his sister was successfully performed.
OUTCOMES
The patient has been in a continuous remission state for 6 months after transplantation.
LESSONS
We reported a rare Ph + AML case, successfully treated with allo-HSCT. This case provided strong support for treating Ph + AML with allo-HSCT.
Topics: Humans; Male; Hematopoietic Stem Cell Transplantation; Adult; Leukemia, Myeloid, Acute; Philadelphia Chromosome; Transplantation, Homologous; Remission Induction
PubMed: 38728478
DOI: 10.1097/MD.0000000000038110 -
BMJ Open Jan 2021To investigate the effectiveness and safety of tyrosine kinase inhibitors (TKIs) in the management of paediatric Philadelphia chromosome-positive acute lymphoblastic... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
To investigate the effectiveness and safety of tyrosine kinase inhibitors (TKIs) in the management of paediatric Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ALL).
DESIGN
A systematic review and meta-analysis.
DATA SOURCES
Electronic searches were conducted on CENTRAL, MEDLINE, EMBASE, SIOP, ASPHO, ASCO, ASH and four Chinese databases from inception to 8 March 2020. Language of publications was restricted in English and Chinese.
ELIGIBILITY CRITERIA
Prospective and retrospective comparative studies were included.
DATA EXTRACTION AND SYNTHESIS
Two authors independently assessed and extracted data. Quality of studies was assessed by the Cochrane Collaboration's tool and Newcastle-Ottawa Scale. Subgroup analysis was performed by comparing different types of TKIs. Quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation approach.
RESULTS
Two randomised controlled trials (RCTs) and four cohort studies enrolling 536 patients were included. For RCTs, the pooled HR was 0.68 (95% CI 0.26 to 1.78) in overall survival (OS), 0.63 (95% CI 0.28 to 1.42) in event-free survival (EFS), respectively, comparing TKI arm with non-TKI arm for treatment of paediatric Ph+ALL. There was significant difference in OS and EFS between imatinib arm and dasatinib arm (HR 2.26, 95% CI 1.02 to 5.01; HR 2.36; 95% CI 1.27 to 4.39, respectively). For cohort studies, the pooled HR was 0.25 (95% CI 0.14 to 0.47) in OS, 0.25 (95% CI 0.12 to 0.56) in EFS, respectively, comparing TKI arm with non-TKI arm. There was no significance difference in adverse drug reaction between TKI group and without TKI group (risk ratio (RR) 0.82, 95% CI 0.63 to 1.08 in RCT; RR 1.01, 95% CI 0.64 to 1.59 in cohort studies; respectively), and imatinib versus dasatinib (RR 0.97, 95% CI 0.77 to 1.23). The quality of evidence was rated as low for OS, EFS and adverse drug reaction (ADR).
CONCLUSIONS
The combination of TKIs with chemotherapy is likely to improve the OS and EFS rates in paediatric Ph+ALL, and dasatinib is superior than imatinib. Large sample size and prospective controlled studies are warranted.
PROSPERO REGISTRATION NUMBER
CRD42018104107.
Topics: Child; Disease-Free Survival; Humans; Imatinib Mesylate; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinase Inhibitors; Randomized Controlled Trials as Topic
PubMed: 33468532
DOI: 10.1136/bmjopen-2020-042814 -
Current Hematologic Malignancy Reports Oct 2017The prognosis for patients with Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPNs) is highly variable. All Ph-negative MPNs carry an increased... (Review)
Review
PURPOSE OF REVIEW
The prognosis for patients with Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPNs) is highly variable. All Ph-negative MPNs carry an increased risk for thrombotic complications, bleeding, and leukemic transformation. Several clinical, biological, and molecular prognostic factors have been identified in recent years, which provide important information in guiding management of patients with Ph-negative MPNs. In this review, we critically evaluate the recent published literature and discuss important new developments in clinical and molecular factors that impact survival, disease transformation, and thrombosis in patients with polycythemia vera, essential thrombocythemia, and primary myelofibrosis.
RECENT FINDINGS
Recent studies have identified several clinical factors and non-driver mutations to have prognostic impact on Ph-negative MPNs independent of conventional risk stratification and prognostic models. In polycythemia vera (PV), leukocytosis, abnormal karyotype, phlebotomy requirement on hydroxyurea, increased bone marrow fibrosis, and mutations in ASXL1, SRSF2, and IDH2 were identified as additional adverse prognostic factors. In essential thrombocythemia (ET), JAK2 V617F mutation, splenomegaly, and mutations in SH2B3, SF3B1, U2AF1, TP53, IDH2, and EZH2 were found to be additional negative prognostic factors. Bone marrow fibrosis and mutations in ASXL1, SRSF2, EZH2, and IDH1/2 have been found to be additional prognostic factors in primary myelofibrosis (PMF). CALR mutations appear to be a favorable prognostic factor in PMF, which has not been clearly demonstrated in ET. The prognosis for patients with PV, ET, and PMF is dependent upon the presence or absence of several clinical, biological, and molecular risk factors. The significance of additional risk factors identified in these recent studies will need further validation in prospective studies to determine how they may be best utilized in the management of these disorders.
Topics: Disease-Free Survival; Hematologic Neoplasms; Humans; Mutation; Myeloproliferative Disorders; Neoplasm Proteins; Philadelphia Chromosome; Survival Rate
PubMed: 28948488
DOI: 10.1007/s11899-017-0401-2 -
American Society of Clinical Oncology... 2016Acute lymphoblastic leukemia (ALL) remains an important cause of morbidity in children and adults. In this article, we highlight advances in the genetics and therapy of... (Review)
Review
Acute lymphoblastic leukemia (ALL) remains an important cause of morbidity in children and adults. In this article, we highlight advances in the genetics and therapy of three key subtypes of ALL: T-cell ALL, BCR-ABL1 (Philadelphia [Ph] chromosone-positive), and Ph-like ALL. T-ALL is an aggressive disease that accounts for about 15% and 25% of ALL among pediatric and adult cohorts, respectively, and exhibits a multistep nature of cancer initiation and progression. The integration of cytogenetics, molecular biology, and immunophenotype analyses has led to the identification of defined T-ALL subgroups, such as early T-cell precursor ALL and novel lesions with a prognostic role, for which specific inhibitors are being developed. Ph-positive ALL was historically regarded as a subtype of ALL with a poor prognosis, and allogeneic stem cell transplant was recommended for all patients who could undergo this procedure. The deep complete responses seen with combination tyrosine kinase inhibitors (TKIs) and chemotherapy in Ph-positive ALL, and the reports of long-term survival among some patients not undergoing allogeneic stem cell transplant, has raised the question of whether there is a subset of patients who could be cured without this intervention. Ph-like ALL is a subtype of B-progenitor ALL common among older children and adults and associated with a diverse range of genetic alterations that activate kinase signaling. Ph-like ALL is also associated with poor outcome, for which precision medicine trials identifying kinase alterations and testing TKI therapy are being developed.
Topics: Adult; Child; Hematopoietic Stem Cell Transplantation; Humans; Philadelphia Chromosome; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Protein Kinase Inhibitors; Remission Induction
PubMed: 27249738
DOI: 10.1200/EDBK_156628