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British Journal of Haematology Jan 2020The past decade has witnessed tremendous progress in the treatment of acute lymphoblastic leukaemia (ALL), primarily due to the development of targeted therapies,... (Review)
Review
The past decade has witnessed tremendous progress in the treatment of acute lymphoblastic leukaemia (ALL), primarily due to the development of targeted therapies, including tyrosine kinase inhibitors targeting BCR-ABL1 tyrosine kinase, monoclonal antibodies targeting cell surface antigens (CD19, CD20 and CD22), bispecific antibodies and chimeric antigen receptor T- cell therapy. A number of new therapies have been approved by the US Food and Drug Administration in the past 5 years, including blinatumomab in 2014, inotuzumab ozagamicin in 2017 and tisagenlecleucel in 2017 for relapsed/refractory ALL. This has led to tremendous improvement in long-term survival, of more than 50% in patients with precursor B-ALL [50-70% in patients with Philadelphia chromosome (Ph)-positive ALL)], 50-60% in T-ALL and 80% in mature B-ALL. Research is ongoing to optimize the benefit of targeted therapeutics with the goal of decreasing the use of cytotoxic therapies.
Topics: Antineoplastic Agents, Immunological; Humans; Middle Aged; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 31566728
DOI: 10.1111/bjh.16207 -
American Journal of Hematology Oct 2021
Randomized Controlled Trial
Impact of Philadelphia chromosome-like alterations on efficacy and safety of blinatumomab in adults with relapsed/refractory acute lymphoblastic leukemia: A post hoc analysis from the phase 3 TOWER study.
Topics: Adult; Antibodies, Bispecific; Antineoplastic Agents; Humans; Neoplasm Recurrence, Local; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Treatment Outcome
PubMed: 34161631
DOI: 10.1002/ajh.26281 -
Blood Mar 1991During an 8-year period, 3,638 children from institutions of the Pediatric Oncology Group (POG) were diagnosed with acute lymphoblastic leukemia (ALL). Fifty-seven...
During an 8-year period, 3,638 children from institutions of the Pediatric Oncology Group (POG) were diagnosed with acute lymphoblastic leukemia (ALL). Fifty-seven patients had Philadelphia chromosome-positive (Ph1) ALL. Blast cells obtained at diagnosis from 13 of these 57 cases (23%) were also found to have partial or complete monosomy 7 (-7). This subgroup of children with Ph1/-7 ALL was comprised primarily of older males with early B-lineage ALL. Bone marrow specimens from six Ph1/-7 patients were studied further using the polymerase chain reaction and primers that flank the ALL, and chronic myelogenous leukemia breakpoints to determine the molecular characteristic of the 9;22 translocation. Rearrangements were detected in RNA from bone marrow and/or peripheral blood cells of six patients, although four were in hematologic remission at the time of the analysis. Five cases showed the ALL breakpoint, while one child with Ph1/-7 showed the chronic myelogenous leukemia breakpoint. The induction failure rate was much higher in this subgroup (31%) as compared with Ph1-negative cases, and the projected duration of event-free survival reflected the aggressive nature of this subgroup because no children are projected to remain in remission at 2 years. ALL with both the 9;22 translocation and -7 appears to represent a unique and previously undescribed subgroup of childhood ALL associated with a particularly adverse outcome. Leukemic transformation in such patients may involve the interaction of a dominant oncogene (Ph1) and a tumor suppressor gene (-7).
Topics: Adolescent; Antigens, CD; Antineoplastic Combined Chemotherapy Protocols; Base Sequence; Child; Chromosomes, Human, Pair 7; Humans; Infant; Karyotyping; Molecular Sequence Data; Monosomy; Oligonucleotides; Philadelphia Chromosome; Polymerase Chain Reaction; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Translocation, Genetic
PubMed: 1995090
DOI: No ID Found -
Transplantation and Cellular Therapy Sep 2021Molecular relapse after allogeneic hematopoietic cell transplantation (allo-HCT) has been thought to predict clinical relapse in patients with Philadelphia...
Molecular relapse after allogeneic hematopoietic cell transplantation (allo-HCT) has been thought to predict clinical relapse in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (PhALL). Tyrosine kinase inhibitor (TKI) administration after allo-HCT may dynamically change the status from molecular relapse to molecular remission, but these state changes cannot be accurately represented by conventional survival indicators such as relapse-free survival, where events are usually considered irreversible. We aimed to develop novel indicators of transplant outcomes for allo-HCT recipients with PhALL and to visualize current molecular-relapse-free survival (CMRFS) and current on-TKI status (CTKI), treating molecular relapse or TKI administration after allo-HCT as a reversible event. We retrospectively analyzed 286 patients with PhALL who received allo-HCT between 2000 and 2016 in order to develop the indicators. CMRFS was defined as the probability of molecular remission without clinical relapse or death at any time after allo-HCT. Similarly, CTKI was defined as the probability of TKI administration without clinical relapse or death at any time after allo-HCT. The 1- and 5-year CMRFS rates were 67% and 59%, respectively, whereas the 1- and 5-year conventional molecular relapse-free survival rates were 42% and 37%. The 1- and 5-year CTKI rates were 14% and 8%, respectively. In a post hoc analysis focusing on patients who had achieved a molecular complete remission within 6 weeks (n = 201), the 5-year CMRFS rate (71%) was similar to the 5-year conventional molecular relapse-free survival (molRFS) rate (70%) in the non-TKI group. On the other hand, the 5-year CMRFS rate in the TKI group was 61%, whereas the 5-year conventional molRFS rate was only 38%. CMRFS and CTKI might become useful indicators of transplant success in terms of survival, leukemia-free status, and treatment-free status at any time point. Future extension of these survival models to other clinical situations is warranted.
Topics: Humans; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Retrospective Studies; Transplantation, Homologous
PubMed: 34171522
DOI: 10.1016/j.jtct.2021.06.020 -
British Journal of Haematology Jun 2020
An oral, chemotherapy-free regimen (dasatinib plus prednisone) as induction and consolidation for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia.
Topics: Administration, Oral; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Consolidation Chemotherapy; Dasatinib; Female; Humans; Imatinib Mesylate; Induction Chemotherapy; Male; Middle Aged; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Retrospective Studies
PubMed: 32314800
DOI: 10.1111/bjh.16661 -
Biology of Blood and Marrow... Sep 2018The aim of this study was to examine the value of minimal residual disease (MRD) detection by multiparameter flow cytometry (MFC) and real-time quantitative PCR (RQ-PCR)...
Comparative Analysis of Flow Cytometry and RQ-PCR for the Detection of Minimal Residual Disease in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia after Hematopoietic Stem Cell Transplantation.
The aim of this study was to examine the value of minimal residual disease (MRD) detection by multiparameter flow cytometry (MFC) and real-time quantitative PCR (RQ-PCR) at the early stage after hematopoietic stem cell transplantation for predicting relapse and leukemia-free survival (LFS) in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+-ALL). Patients who maintained complete molecular remission (BCR-ABL <.01%) status at 1 and 3 months were associated with a lower relapse rate (P = .02 and <.001) and better LFS (P = .014 and .013) than were those without a complete molecular remission. Negative MFC at 1, 2, and 3 months was associated with a lower relapse rate (P = .01, .004, and .04, respectively) and better LFS (P = .044, <.0001, and .013, respectively). Multivariate analysis showed that MRD positivity identified by MFC or RQ-PCR at 3 months was an independent risk factor for relapse (hazard ratio [HR], 6.042 (95% confidence interval [CI], 2.283 to 15.988), P < .001), LFS (HR, 3.614 (95% CI, 1.610 to 8.111), P = .002), and overall survival (HR, 2.547, 95% CI, 1.008 to 6.443), P = .048). In summary, MRD detection by MFC and RQ-PCR detection of BCR-ABL at the early stage were important predictors of outcome in patients with Ph+-ALL, and these tests played complementary roles in predicting prognosis.
Topics: Adolescent; Adult; Child; Child, Preschool; Female; Flow Cytometry; Hematopoietic Stem Cell Transplantation; Humans; Male; Middle Aged; Neoplasm, Residual; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Real-Time Polymerase Chain Reaction; Transplantation Conditioning; Young Adult
PubMed: 29572111
DOI: 10.1016/j.bbmt.2018.03.015 -
Cancer Genetics Apr 2011This report summarizes highlights of the Philadelphia Chromosome Symposium: Past, Present and Future, held September 28, 2010, to commemorate the 50th anniversary of the...
This report summarizes highlights of the Philadelphia Chromosome Symposium: Past, Present and Future, held September 28, 2010, to commemorate the 50th anniversary of the discovery of the Philadelphia chromosome. The symposium sessions included presentations by investigators who made seminal contributions concerning the discovery and molecular characterization of the Ph chromosome and others who developed a highly successful therapy based on the specific molecular alteration observed in chronic myeloid leukemia. Additional presentations highlighted future opportunities for the design of molecularly targeted therapies for various types of cancer. Also included here are reminiscences connected with the discovery of the Ph chromosome by David Hungerford and Peter Nowell, the discovery that the abnormality arises from a chromosomal translocation, by Janet Rowley, and the cloning of the 9;22 translocation breakpoints by Nora Heisterkamp, John Groffen, and colleagues.
Topics: Antineoplastic Agents; Benzamides; Cloning, Molecular; Cytogenetics; History, 20th Century; History, 21st Century; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Philadelphia Chromosome; Piperazines; Pyrimidines; Translocation, Genetic
PubMed: 21536234
DOI: 10.1016/j.cancergen.2011.03.002 -
Blood Jan 1988Philadelphia chromosome-positive (Ph1) acute leukemia is a heterogeneous subset of acute leukemia with a poor prognosis. We studied five patients to determine the...
Philadelphia chromosome-positive (Ph1) acute leukemia is a heterogeneous subset of acute leukemia with a poor prognosis. We studied five patients to determine the potential for phenotypic and molecular heterogeneity. Cellular characterization studies included light myeloperoxidase (L-MPO), terminal deoxynucleotidyl transferase (TdT), ultrastructural MPO (U-MPO), and immunophenotyping by flow cytometry using T11, T3, T4, T8, Leu 1, B1, Leu 12, HLA-DR (la), CALLA (J5), OKM1, My4, My7, My8, My9, and My10. DNA was analyzed for rearrangements of the breakpoint cluster region (bcr), immunoglobulin heavy chain, joining region (JH), immunoglobulin kappa light chain constant region (C kappa), and T cell receptor (TcR beta). RNA dot blots were hybridized by using molecular probes for MPO and TdT. We found that four of five cases were acute mixed-lineage leukemia (AMLL). One patient had acute unclassifiable leukemia. Of the four patients classified as having AMLL, three showed myeloid and lymphoid features, with one patient showing myeloid, T cell, and B cell features. The last case showed T cell and B cell features only. In one patient MPO/RNA was positive in spite of insufficient L-MPO or U-MPO to diagnose acute myelogenous leukemia (AML), thereby suggesting significant MPO gene expression before the production of sufficient MPO protein to meet the French-American-British criteria for AML. Three of the five patients showed rearrangement of bcr (cases 1, 2, and 5). Studies of these five patients support the concepts of molecular and phenotypic heterogeneity in Ph1 acute leukemia, demonstrate a high incidence of AMLL in this subset of acute leukemia, and support the use of lineage-associated molecular probes to define lineage at an earlier stage than previously possible.
Topics: Acute Disease; Adult; Antigens, Neoplasm; Female; Humans; Leukemia; Male; Middle Aged; Neoplasm Proteins; Neoplastic Stem Cells; Phenotype; Philadelphia Chromosome; RNA, Neoplasm
PubMed: 3334895
DOI: No ID Found -
International Journal of Clinical and... 2014Precursor B acute lymphoblastic leukemia (B-ALL) is the most common cancer in children and overall, has an excellent prognosis. However, the Philadelphia chromosome...
BACKGROUND
Precursor B acute lymphoblastic leukemia (B-ALL) is the most common cancer in children and overall, has an excellent prognosis. However, the Philadelphia chromosome translocation (Ph+), t(9;22)(q34;q11), is present in a small subset of patients and confers poor outcomes. CD25 (IL-2 receptor alpha chain) expression has been associated with Ph+ B-ALL in adults, but no similar study has been performed in pediatric B-ALL.
METHODS
A retrospective analysis of 221 consecutive pediatric patients with a diagnosis of B-ALL (blood and/or bone marrow) from 2009 to 2012 was performed to determine an association between Ph+ B-ALL and CD25 expression. A threshold of 25% was used to define positive cases for CD25 expression by flow cytometry.
RESULTS
There were 221 patients with a diagnosis of B-ALL ranging from 2 to 22 years (median, 6 years). Eight (3.6%) B-ALL patients were positive for the Philadelphia chromosome translocation (Ph+ B-ALL) and 213 were negative (Ph-negative B-ALL). CD25 expression was observed in 6 of 8 (75%) Ph+ B-ALL patients and 6 of 213 (2.8%) Ph-negative B-ALL patients. CD25 expression was significantly higher in Ph+ B-ALL compared to Ph-negative B-ALL, with median CD25 expression of 64% (range 0-93%) and 0.1% (range 0-91%), respectively (P ≤ 0.0002). Therefore, CD25 expression as a predictor of Ph+ B-ALL had 75% sensitivity, 97% specificity, 50% positive predictive value and 99% negative predictive value.
CONCLUSIONS
CD25 expression is a specific and relatively sensitive marker for the identification of Ph+ B-ALL in the pediatric population.
Topics: Adolescent; Age Factors; Biomarkers, Tumor; Child; Child, Preschool; Female; Flow Cytometry; Fusion Proteins, bcr-abl; Humans; Interleukin-2 Receptor alpha Subunit; Male; Philadelphia Chromosome; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Predictive Value of Tests; Prognosis; Retrospective Studies; Translocation, Genetic; Up-Regulation; Young Adult
PubMed: 25337274
DOI: No ID Found -
Leukemia & Lymphoma Mar 2020Incorporation of asparaginase (ASNase) and pegylated asparaginase (PEG-ASP) into pediatric-inspired regimens for adults with acute lymphoblastic leukemia (ALL) has led...
Incorporation of asparaginase (ASNase) and pegylated asparaginase (PEG-ASP) into pediatric-inspired regimens for adults with acute lymphoblastic leukemia (ALL) has led to improved treatment outcomes albeit with increased toxicities. This study compared the efficacy and safety of the Children's Oncology Group standard PEG-ASP (SD) dosing (>1000, median 2500 IU/m/dose) in adult Philadelphia chromosome-negative ALL patients receiving multiagent chemotherapy vs reduced dose PEG-ASP (RED) (≤1000, median 500 IU/m/dose) during induction. 51 patients were included, 26 in RED and 25 in SD (median age 49 vs 37 years, = .027). Median day 7 ASNase activity level for RED was 0.16 IU/mL. All 11 patients who received PEG-ASP 1000 IU/m and 9/11 patients who received 500 IU/m achieved an ASNase level ≥0.1 IU/mL. Patients receiving RED experienced fewer total grade 3/4 toxicities during induction compared to SD ( = .02) while still attaining therapeutic ASNase levels. RED permits safer ASNase use in adults with ALL and should be tested in a larger cohort prospectively.
Topics: Adult; Antineoplastic Agents; Asparaginase; Child; Humans; Middle Aged; Philadelphia Chromosome; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Reference Standards
PubMed: 31680584
DOI: 10.1080/10428194.2019.1680839