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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 -
Cancer Medicine Dec 2021This study seeks to clarify whether allogeneic hematopoietic stem cell transplantation (allo-HSCT) is necessary for adult patients with Philadelphia chromosome-positive... (Meta-Analysis)
Meta-Analysis
Comparison of allogeneic hematopoietic stem cell transplantation and TKI combined with chemotherapy for adult philadelphia chromosome positive acute lymphoblastic leukemia: a systematic review and meta-analysis.
OBJECTIVE
This study seeks to clarify whether allogeneic hematopoietic stem cell transplantation (allo-HSCT) is necessary for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in post-remission based on a comparison with tyrosine kinase inhibitor (TKI) combined with chemotherapy.
METHODS
We searched the Pubmed, Embase, and Web of Science databases and limited the date range for the studies from January 2010 to August 2020. A hazard ratio (HR) with a 95% confidence interval (CI) was employed to assess overall survival (OS) and relapse-free survival (RFS), and an odds ratio (OR) with a 95% CI was used to evaluate the ratio of non-relapsed mortality (NRM) and non-relapsed survival (NRS). All analyses were conducted with Stata software 16.0 and Revman 5.3.
RESULTS
Fifteen studies, totaling 959 patients, were included in our analysis. Among those patients, 473 underwent allo-HSCT, and 486 received TKI plus chemotherapy. The pooled results showed no difference in OS between outcomes for patients receiving TKI plus chemotherapy and those treated with allo-HSCT (HR = 0.76, 95% CI [0.51-1.12], p = 0.16). Patients undergoing allo-HSCT did better than those receiving TKI plus chemotherapy regarding RFS (HR = 0.48, 95% CI [0.37-0.63], p = 0.00), and NRS (OR = 2.64, 95% CI [1.25-5.57], p = 0.00). The NRM rate of the TKI plus chemotherapy group was significantly lower than the allo-HSCT group (OR = 2.33, 95% CI [1.51-3.59], p = 0.00).
CONCLUSION
TKI combined with chemotherapy can be considered a post-remission treatment option for adult Ph+ ALL patients who are ineligible for allo-HSCT. However, more prospective studies with large sample sizes should be carried out in the future.
Topics: Acute Disease; Adolescent; Adult; Aged; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Middle Aged; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinase Inhibitors; Transplantation Conditioning; Transplantation, Homologous; Young Adult
PubMed: 34761879
DOI: 10.1002/cam4.4413 -
Leukemia Research Oct 2022Philadelphia-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk molecular subtype with a gene expression profile similar to Philadelphia-positive ALL, but... (Review)
Review
Philadelphia-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk molecular subtype with a gene expression profile similar to Philadelphia-positive ALL, but not harboring the BCR-ABL1 gene fusion. We aimed to investigate the efficacy of target therapy with the Janus kinase inhibitor, ruxolitinib, in patients with Ph-like ALL and molecular signature of JAK-STAT signaling pathway. A systematic search of the literature was performed to identify reports concerning administration of ruxolitinib in Ph-like ALL patients. Additionally, Polish Pediatric ALL registries were searched for patients with Ph-like ALL treated with ruxolitinib. Extracted information included epidemiological background, somatic aberrations, treatment response, and patient outcome. After PubMed database search, twelve patients were identified, and one was identified in the Polish Pediatric ALL registry. In nine patients gene fusions affecting JAK2 (n = 7) and EPOR (n = 2) were detected. Surface overexpression of CRLF2 and IKZF1 deletions were observed in two and three patients, respectively. Induction failure occurred in all the patients. Therapy with ruxolitinib led to complete (n = 7) and partial (n = 2) remission, in three individuals no information was found. Based on the limited number of studies describing the efficacy of ruxolitinib as an additional compound administrated with standard ALL therapy, we conclude that this approach can be considered in patients with aberrations activating JAK-STAT pathway.
Topics: Child; Humans; Janus Kinase Inhibitors; Janus Kinases; Nitriles; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrazoles; Pyrimidines; STAT Transcription Factors; Signal Transduction
PubMed: 35939887
DOI: 10.1016/j.leukres.2022.106925 -
BMC Cancer Feb 2019Philadelphia (Ph) chromosome-negative myeloproliferative neoplasms (MPNs) are a heterogeneous group of hematopoietic stem cell clonal diseases. Most patients with MPN... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Philadelphia (Ph) chromosome-negative myeloproliferative neoplasms (MPNs) are a heterogeneous group of hematopoietic stem cell clonal diseases. Most patients with MPN are asymptomatic at diagnosis although some of them suffer from constitutional symptoms. Thrombosis and bleeding can also be one of the initial manifestations although the reported prevalence varied considerably across the studies. This systematic review and meta-analysis was conducted with the aims to better understand the prevalence and characteristics of thrombosis and bleeding among patients with newly-diagnosed MPN.
METHODS
Using a search strategy that included the terms for myeloproliferative neoplasms, thrombosis, and bleeding, two investigators independently searched for published articles indexed in the MEDLINE and EMBASE databases from inception to August 2018. The pooled prevalence was calculated using the DerSimonian-Laird random-effects model with a double arcsine transformation.
RESULTS
A total of 29 cohort studies (8 prospective and 21 retrospective) with 13,436 patients with MPN were included into this meta-analysis. At diagnosis, the pooled prevalence of overall thrombosis among patients with MPN was 20.0% (95% CI, 16.6-23.8%; I 96%), with the pooled prevalence of arterial thrombosis of 16.2% (95% CI, 13.0-20.0%; I 95%) and the pooled prevalence of venous thrombosis of 6.2% (95% CI, 4.9-7.8%; I 89%). Common thrombotic events included cerebrovascular disease/transient ischemic attack, coronary heart disease, and deep venous thrombosis. The pooled prevalence of hemorrhagic complications among patients who were newly diagnosed with MPN patients was 6.2% (95% CI, 5.0-7.8%; I 85%). Common sites of bleeding included gastrointestinal, mucosal, and cutaneous bleeding.
CONCLUSIONS
Thrombosis and bleeding are common initial manifestations of MPN. Investigations for MPN should be considered for patients who present with unexplained thrombosis or abnormal bleeding.
Topics: Hemorrhage; Humans; Myeloproliferative Disorders; Philadelphia Chromosome; Prevalence; Thrombosis
PubMed: 30819138
DOI: 10.1186/s12885-019-5387-9 -
Cancers Aug 2023Chronic myeloid leukemia (CML) is treated with tyrosine kinase inhibitors (TKI) that target the pathological BCR-ABL1 fusion oncogene. The objective of this statistical... (Review)
Review
Chronic myeloid leukemia (CML) is treated with tyrosine kinase inhibitors (TKI) that target the pathological BCR-ABL1 fusion oncogene. The objective of this statistical meta-analysis was to assess the prevalence of other hematological adverse events (AEs) that occur during or after predominantly first-line treatment with TKIs. Data from seventy peer-reviewed, published studies were included in the analysis. Hematological AEs were assessed as a function of TKI drug type (dasatinib, imatinib, bosutinib, nilotinib) and CML phase (chronic, accelerated, blast). AE prevalence aggregated across all severities and phases was significantly different between each TKI ( < 0.05) for anemia-dasatinib (54.5%), bosutinib (44.0%), imatinib (32.8%), nilotinib (11.2%); neutropenia-dasatinib (51.2%), imatinib (29.8%), bosutinib (14.1%), nilotinib (14.1%); thrombocytopenia-dasatinib (62.2%), imatinib (30.4%), bosutinib (35.3%), nilotinib (22.3%). AE prevalence aggregated across all severities and TKIs was significantly ( < 0.05) different between CML phases for anemia-chronic (28.4%), accelerated (66.9%), blast (55.8%); neutropenia-chronic (26.7%), accelerated (63.8%), blast (36.4%); thrombocytopenia-chronic (33.3%), accelerated (65.6%), blast (37.9%). An odds ratio (OR) with 95% confidence interval was used to compare hematological AE prevalence of each TKI compared to the most common first-line TKI therapy, imatinib. For anemia, dasatinib OR = 1.65, [1.51, 1.83]; bosutinib OR = 1.34, [1.16, 1.54]; nilotinib OR = 0.34, [0.30, 0.39]. For neutropenia, dasatinib OR = 1.72, [1.53, 1.92]; bosutinib OR = 0.47, [0.38, 0.58]; nilotinib OR = 0.47, [0.42, 0.54]. For thrombocytopenia, dasatinib OR = 2.04, [1.82, 2.30]; bosutinib OR = 1.16, [0.97, 1.39]; nilotinib OR = 0.73, [0.65, 0.82]. Nilotinib had the greatest fraction of severe (grade 3/4) hematological AEs (30%). In conclusion, the overall prevalence of hematological AEs by TKI type was: dasatinib > bosutinib > imatinib > nilotinib. Study limitations include inability to normalize for dosage and treatment duration.
PubMed: 37686630
DOI: 10.3390/cancers15174354 -
Annals of Hematology Nov 2020In the era of tyrosine kinase inhibitors (TKIs), allogeneic hematopoietic stem cell transplantation (allo-HSCT) is recommended as a standard approach for Philadelphia... (Comparative Study)
Comparative Study Meta-Analysis
Comparative study on allogeneic with autologous hematopoietic stem cell transplantation in adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia in the era of TKIs: a systematic review and meta-analysis.
In the era of tyrosine kinase inhibitors (TKIs), allogeneic hematopoietic stem cell transplantation (allo-HSCT) is recommended as a standard approach for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) achieving complete remission (CR). However, the role of autologous hematopoietic stem cell transplantation (auto-HSCT) in adult patients achieving complete molecular remission (CMR) is an alternative, less toxic treatment options, especially for the patients who lack suitable donors and are unfit for allo-HSCT. Thus, we conducted a systematic review and meta-analysis to compare the efficacy of allo-HSCT and auto-HSCT for the treatment of adult patients with Ph+ ALL. We searched the PubMed, Embase, Scopus, and Cochrane Library for studies published before June 2019 without language restriction. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for overall survival (OS) and relapse-free survival (RFS) and odds ratios (ORs) and 95% CIs for relapse rate (RR) and treatment-related mortality (TRM). Four prospective studies and one retrospective study were included with a total of 810 patients. We found auto-HSCT was superior to allo-HSCT in OS (HR = 1.42, 95% CI: 1.06-1.91, P = 0.02), and there was no difference between allo-HSCT and auto-HSCT for RFS (HR = 1.10, 95% CI: 0.86-1.40, P = 0.44) and RR (OR = 0.53, 95% CI: 0.22-1.26, P = 0.15). The risk of TRM for patients undergoing allo-HSCT was significantly higher than that of the patients who received auto-HSCT (OR = 5.06, 95% CI: 1.03-24.75, P = 0.05). Our meta-analysis shows that auto-HSCT may be an attractive and alternative treatment option for adult Ph+ ALL patients achieving CMR, with similar or better outcomes than allo-HSCT in the era of TKIs.
Topics: Adult; Allografts; Autografts; Disease-Free Survival; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Survival Rate
PubMed: 32960314
DOI: 10.1007/s00277-020-04258-1 -
Cancer Control : Journal of the Moffitt... 2021Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders characterized by the overproduction of mature myeloid cells and are often associated...
Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders characterized by the overproduction of mature myeloid cells and are often associated with an acquired genetic mutation of . Various epidemiological studies have indicated associations between environmental factors, lifestyle factors, and host characteristics with developing MPNs. This review aims to collect and summarize the existing information on these risk factors and establish their association with pathogenesis MPNs. Medline, Embase, PubMed, and grey literature were systematically searched using key terms for MPNs, and epidemiological study designs, that is, cross-sectional studies, case-control, and cohort, that investigated the risk factors for MPNs published were identified. Out of the 4621 articles identified, 20 met the selection criteria and were included in this review. Heterogeneity, study reliability, and bias were assessed. A significant association was found between smoking and the development of MPNs. This relationship has been explained by the substantial increase in several proinflammatory mediators and systematic oxidative stress causing hyperstimulation of myeloid compartments leading to the development of MPNs. Obesity was modestly linked with an increased risk of MPNs. The underlying mechanisms have been linked to changes in endocrine, metabolic, and inflammatory systems. No strong association was found between exposure to hazardous substances, that is, benzene and MPNs, but further investigation on the effects of increased levels and duration of exposure on hematopoietic stem cells will be beneficial. Unique individual and host variations have been determined as a modifier of disease pathogenesis and phenotype variations. There is a higher incidence rate of females developing MPNs, specifically ET, than males with higher PV incidence. Therefore, gender contributes to the heterogeneity in myeloproliferative neoplasm. Studies identified as part of this review are very diverse. Thus, further in-depth assessment to explore the role of these etiological factors associated with MPNs is warranted.
Topics: Cigarette Smoking; Environment; Environmental Exposure; Female; Humans; Inflammation Mediators; Life Style; Male; Myeloproliferative Disorders; Obesity; Oxidative Stress; Philadelphia Chromosome; Risk Factors; Sex Distribution; Sociodemographic Factors
PubMed: 34645293
DOI: 10.1177/10732748211046802 -
The Annals of Pharmacotherapy Oct 2021To assess the current literature for blinatumomab in the treatment of adult and pediatric B-cell acute lymphoblastic leukemia (ALL).
OBJECTIVE
To assess the current literature for blinatumomab in the treatment of adult and pediatric B-cell acute lymphoblastic leukemia (ALL).
DATA SOURCES
We conducted a PubMed (inception to December 11, 2020) and ClinicalTrials.gov systematic literature search using the following terms: , and .
STUDY SELECTION AND DATA EXTRACTION
All relevant published articles, package inserts, and meeting abstracts evaluating the use of blinatumomab in ALL were considered for inclusion.
DATA SYNTHESIS
Blinatumomab, a first-in-class bispecific T-cell engager monoclonal antibody, facilitates cytotoxic T-cell activation and subsequent eradication of CD19-positive B cells. The confirmatory phase III TOWER trial demonstrated superior overall survival (OS) with blinatumomab compared with standard chemotherapy (7.7 months vs 4.0 months) in relapsed and refractory (R/R) B-cell ALL. In the phase II BLAST trial, blinatumomab achieved a complete measurable residual disease (MRD) response in 78% of evaluable patients, with a median OS of 36.5 months. Potentially life-threatening cytokine release syndrome and neurotoxicity occurred in approximately 15% and 65% of patients, respectively.
RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE
Following initial Food and Drug Administration approval in 2014, blinatumomab gained expanded approval in pediatric patients and in Philadelphia chromosome-positive R/R ALL. In 2018, blinatumomab became the first and only drug approved for the treatment of persistent MRD in any hematologic malignancy. Emerging data demonstrate promising efficacy with blinatumomab in specific ALL settings, including frontline therapy, as a bridge to transplantation, and in "chemotherapy-free" combination regimens.
CONCLUSIONS
Blinatumomab provides a paradigm-shifting treatment option; however, many questions surrounding optimal patient selection, sequencing, and cost-effectiveness remain.
Topics: Antibodies, Bispecific; Antineoplastic Agents; Child; Humans; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction
PubMed: 33435716
DOI: 10.1177/1060028020988411 -
Frontiers in Genetics 2022We aim to determine the spectrum of cytogenetic abnormalities and outcomes in unbalanced offspring of asymptomatic constitutional balanced t(9;22) carriers through a...
We aim to determine the spectrum of cytogenetic abnormalities and outcomes in unbalanced offspring of asymptomatic constitutional balanced t(9;22) carriers through a systematic literature review. We also include a case of a constitutional balanced t(9;22) carrier from our institution. Among the 16 balanced t(9;22) carriers in our review, 13 were maternal and 3 were paternal. Of the 15 unbalanced translocation cases identified, 13 were live births, one was a missed abortion, and one resulted in pregnancy termination. The spectrum of established syndromes reported among the live births was the following: trisomy 9p syndrome (6/13), dual trisomy 9p and DiGeorge syndrome (3/13), dual 9q subtelomere deletion syndrome and DiGeorge syndrome (1/13), 9q subtelomere deletion syndrome (1/13), and DiGeorge syndrome (1/13). One unbalanced case did not have a reported syndrome. The phenotype of the unbalanced cases included cardiac abnormalities (5/13), neurological findings (7/13), intellectual disability (6/10), urogenital anomalies (3/13), respiratory or immune dysfunction (3/13), and facial or skeletal dysmorphias (13/13). Any constitutional balanced reciprocal t(9;22) carrier should be counseled regarding the increased risk of having a child with an unbalanced translocation, the spectrum of possible cytogenetic abnormalities, and predicted clinical phenotype for the unbalanced derivative.
PubMed: 35991550
DOI: 10.3389/fgene.2022.921910 -
Acta Haematologica 2020The treatment of chronic myeloid leukaemia (CML) requires quantitative polymerase chain reaction (qPCR) to monitor BCR-ABL1 in International Scale (IS). Some normal...
The treatment of chronic myeloid leukaemia (CML) requires quantitative polymerase chain reaction (qPCR) to monitor BCR-ABL1 in International Scale (IS). Some normal subjects were found to harbour BCR-ABL1. We performed a systematic review on normal subjects harbouring BCR-ABL1. A literature search was done on July 16, 2017 using EBSCOhost Research Databases interface and Western Pacific Region Index Medicus. Two authors selected the studies, extracted the data, and evaluated the quality of studies using the modified Appraisal Tool for Cross-Sectional Studies independently. The outcomes were prevalence, level of BCR-ABL1IS, proportion, and time of progression to CML. The initial search returned 4,770 studies. Eleven studies, all having used convenient sampling, were included, with total of 1,360 subjects. Ten studies used qualitative PCR and one used qPCR (not IS). The mean prevalence of M-BCR was 5.9, 15.5, and 15.9% in cord blood/newborns/infants (CB/NB/I) (n = 170), children (n = 90), and adults (n = 454), respectively, while m-BCR was 15, 26.9, and 23.1% in CB/NB/I (n = 786), children (n = 67), and adults (n = 208), respectively. No study reported the proportion and time of progression to CML. Nine studies were graded as moderate quality, one study as poor quality, and one study as unacceptable. The result of the studies could neither be inferred to the general normal population nor compared. Follow-up data were scarce.
Topics: Acute Disease; Blast Crisis; Chronic Disease; Databases, Factual; Fusion Proteins, bcr-abl; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Philadelphia Chromosome
PubMed: 31401626
DOI: 10.1159/000501146