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American Journal of Hematology Feb 2018Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukemia (ALL) is a biologically, clinically, and genetically distinct subtype of precursor-B ALL. The... (Review)
Review
Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukemia (ALL) is a biologically, clinically, and genetically distinct subtype of precursor-B ALL. The Ph chromosome, results from a reciprocal translocation of the ABL1 kinase gene on chromosome 9 to the breakpoint cluster region (BCR) gene on chromosome 22. Depending on the translocation breakpoint, typically a p210 BCR-ABL1 or a p190 BCR-ABL onc protein are generated; both are constitutively active tyrosine kinases that play a central role to alter signaling pathways of cell proliferation, survival, and self-renewal, leading to leukemogenesis. In Ph-positive ALL, the p190-BCR-ABL (minor [m]-bcr) subtype is more frequent than the p210-BCR-ABL (major [M]-bcr) subtype, commonly found in chronic myeloid leukemia. The Philadelphia chromosome is the most frequent recurrent cytogenetic abnormality in elderly patients with ALL. Its incidence increases with age, reaching ∼50% in patients with ALL aged 60 years and over. Patients traditionally had a very poor outcome with chemotherapy, particularly if they do not undergo allogeneic hematopoietic cell transplantation (allo-HCT) in first complete remission (CR1). With the availability of multiple tyrosine kinase inhibitors (TKI), the therapeutic armamentarium is expanding quickly. However, there is no consensus on how to best treat Ph-positive ALL. With modern therapy, improved outcomes have led to the emergence of a number of controversies, including the need for intensive chemotherapy, the ideal TKI, and whether all eligible patients should receive an allo-HSCT, and if so, what type. Here, we discuss these controversies in light of the available literature.
Topics: Adult; Disease Management; Fusion Proteins, bcr-abl; Humans; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 28971501
DOI: 10.1002/ajh.24926 -
Journal of Cellular and Molecular... Sep 2022Chronic myelogenous leukaemia (CML) has a special phenomenon of chromosome translocation, which is called Philadelphia chromosome translocation. However, the detailed...
Chronic myelogenous leukaemia (CML) has a special phenomenon of chromosome translocation, which is called Philadelphia chromosome translocation. However, the detailed connection of this structure is troublesome and expensive to be identified. Low-coverage whole genome sequencing (LCWGS) could not only detect the previously unknown chromosomal translocation, but also provide the breakpoint candidate small region (with an accuracy of ±200 bases). Importantly, the sequencing cost of LCWGS is about US$300. Then, with the Sanger DNA sequencing, the precise breakpoint can be determined at a single base level. In our project, with LCWGS, BCR and ABL1 are successfully identified to be disrupted in three CML patients (at chr22:23,632,356 and chr9:133,590,450; chr22:23,633,748 and chr9:133,635,781; chr22: 23,631,831 and chr9:133,598,513, respectively). Due to the reconnection after chromosome breakage, classical fusion gene (BCR::ABL1) was found in bone marrow and peripheral blood. The precise breakpoints were helpful to investigate the pathogenic mechanism of CML and could better guide the classification of CML subtypes. This LCWGS method is universal and can be used to detect all diseases related to chromosome variation, such as solid tumours, liquid tumours and birth defects.
Topics: Bone Marrow; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Philadelphia Chromosome; Translocation, Genetic
PubMed: 35903038
DOI: 10.1111/jcmm.17500 -
Advances in Therapy Jul 2023Efficacy of ponatinib-based treatment for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) has not been compared to...
INTRODUCTION
Efficacy of ponatinib-based treatment for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) has not been compared to imatinib-based treatments in head-to-head clinical trials. We evaluated its efficacy versus imatinib-based regimens using a matching adjusted indirect comparison.
METHODS
Two ponatinib studies were used: the phase 2 MDACC study of ponatinib + hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) in adult patients and the phase 2 GIMEMA LAL1811 study of ponatinib + steroids in patients > 60 years/unfit for intensive chemotherapy and stem cell transplant. Studies on imatinib as first-line treatment in adults with Ph + ALL were identified using a systematic literature search. Population adjustment was based on the prognostic factors and effect modifiers identified by clinical experts. Hazard ratios (HRs) were calculated for overall survival (OS) and odds ratios (ORs) for complete molecular response (CMR).
RESULTS
The systematic literature search identified two studies (GRAAPH-2005 and NCT00038610) reporting the efficacy of first-line imatinib + hyper-CVAD and one study reporting the efficacy of first-line imatinib monotherapy induction + imatinib-based consolidation (CSI57ADE10). Ponatinib + hyper-CVAD prolonged OS and gave a higher CMR rate than imatinib + hyper-CVAD. The adjusted HR [95% confidence interval (CI)] for OS was 0.35 (0.17-0.74) for MDACC vs. GRAAPH-2005 and 0.35 (0.18-0.70) for MDACC vs. NCT00038610; the adjusted OR (95% CI) for CMR was 12.11 (3.77-38.87) for MDACC vs. GRAAPH-2005 and 5.65 (2.02-15.76) for MDACC vs. NCT00038610. Ponatinib + steroids prolonged OS and gave a higher CMR rate than imatinib monotherapy induction + imatinib-containing consolidation. The adjusted HR (95% CI) for OS was 0.24 (0.09-0.64) and the adjusted OR (95% CI) for CMR was 6.20 (1.60-24.00) for GIMEMA LAL1811 vs. CSI57ADE10.
CONCLUSION
In adults with newly diagnosed Ph + ALL, first-line treatment with ponatinib was associated with better outcomes than first-line treatment with imatinib.
Topics: Adult; Humans; Imatinib Mesylate; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Cyclophosphamide; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone
PubMed: 37208556
DOI: 10.1007/s12325-023-02497-y -
Cancer Mar 2010Acute lymphoblastic leukemia (ALL), a clonal expansion of hematopoietic blasts, is a highly heterogeneous disease comprising many entities for which distinct treatment... (Review)
Review
Acute lymphoblastic leukemia (ALL), a clonal expansion of hematopoietic blasts, is a highly heterogeneous disease comprising many entities for which distinct treatment strategies are pursued. Although ALL is a success story in pediatric oncology, results in adults lag behind those in children. An expansion of new drugs, more reliable immunologic and molecular techniques for the assessment of minimal residual disease, and efforts at more precise risk stratification are generating new aspects of adult ALL therapy. For this review, the authors summarized pertinent and recent literature on ALL biology and therapy, and they discuss current strategies and potential implications of novel approaches to the management of adult ALL. Cancer 2010. (c) 2010 American Cancer Society.
Topics: Adult; Chromosome Aberrations; Hematopoietic Stem Cell Transplantation; Humans; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Recurrence
PubMed: 20101737
DOI: 10.1002/cncr.24862 -
International Journal of Molecular... May 2020Since myeloproliferative neoplasms (MPN) pose a significant risk for vascular and thrombotic complications, cytoreductive therapies, such as hydroxyurea (HU), interferon... (Review)
Review
Since myeloproliferative neoplasms (MPN) pose a significant risk for vascular and thrombotic complications, cytoreductive therapies, such as hydroxyurea (HU), interferon (IFN) inhibitors, and Janus kinase (JAK) inhibitors are recommended for patients at high risk. However, these agents also place patients at increased risk for drug-related cutaneous adverse events. Herein, we review the literature on skin toxicity related to the use of drugs for the treatment of MPN. Overall, the cytoreductive agents used for MPN are generally well tolerated and considered to be safe, except IFN, for which dropout rates as high as 25% have been reported. While IFN is known to give rise to flu syndrome, it rarely leads to hematological alterations. The most common hematological side effects of HU are mild and include granulocytopenia, anemia, and thrombocytopenia. The JAK inhibitor ruxolitinib has been associated with cytopenia and a higher incidence of viral infections, as well as increased risk for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Based on the present analysis, it can be concluded that cutaneous toxicity is not a negligible complication of commonly used treatments for MPN. While further research is needed, patients on these agents, and especially those with a history of cutaneous malignancies, should undergo thorough skin examination before and during therapy. In addition, detailed history is critical since many patients who develop non-melanoma skin cancer have multiple preexisting risk factors for cutaneous carcinogenesis.
Topics: Humans; Hydroxyurea; Interferons; Janus Kinase Inhibitors; Keratosis, Actinic; Myeloproliferative Disorders; Nitriles; Philadelphia Chromosome; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Risk; Skin Diseases; Skin Neoplasms
PubMed: 32486130
DOI: 10.3390/ijms21113900 -
Medical Oncology (Northwood, London,... Aug 2018Classical Philadelphia- negative myeloproliferative neoplasms (MPNs) encompass three main myeloid malignancies: polycythemia vera (PV), essential thrombocythemia (ET),... (Review)
Review
Classical Philadelphia- negative myeloproliferative neoplasms (MPNs) encompass three main myeloid malignancies: polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). Phenotype-driver mutations in Janus kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukemia virus oncogene (MPL) genes are mutually exclusive and occur with a variable frequency. Driver mutations influence disease phenotype and prognosis. PV patients with JAK2 exon 14 mutation do not differ in number of thrombotic events, risk of leukemic and fibrotic transformation, and overall survival to those with JAK2 exon 12 mutation. Type 2-like CALR-mutated ET patients have lower risk of thrombosis if compared with those carrying JAK2 or type 1-like CALR mutation. For ET, overall survival is comparable between patients with JAK2 and either type 1-like and type 2-like CALR mutations. For MF, better OS is demonstrated for patients harboring a type 1-like CALR mutation than those with type 2-like CALR or JAK2. The discovery of driver mutations in MPNs has prompted the development of molecularly targeted therapy. Among JAK2 inhibitors, ruxolitinib (RUX) has been approved for (1) treatment of intermediate-2 and high-risk MF and (2) PV patients who are resistant to or intolerant to hydroxyurea. RUX reduces spleen size and alleviates disease symptoms in a proportion of MF patients. RUX in MF leads to prolonged survival and reduces risk of death. RUX controls hematocrit, reduces spleen size and alleviates symptoms in PV. Adverse events of RUX are moderate, however, its long-term use may be associated with opportunistic infections. Trials with other JAK2 inhibitors are ongoing.
Topics: Antineoplastic Agents; Calreticulin; Humans; Janus Kinase 2; Molecular Targeted Therapy; Mutation; Myeloproliferative Disorders; Nitriles; Philadelphia Chromosome; Pyrazoles; Pyrimidines
PubMed: 30074114
DOI: 10.1007/s12032-018-1187-3 -
Blood Apr 2021The need for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in adults with Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL) with... (Clinical Trial)
Clinical Trial
The need for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in adults with Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL) with high-risk (HR) features and adequate measurable residual disease (MRD) clearance remains unclear. The aim of the ALL-HR-11 trial was to evaluate the outcomes of HR Ph- adult ALL patients following chemotherapy or allo-HSCT administered based on end-induction and consolidation MRD levels. Patients aged 15 to 60 years with HR-ALL in complete response (CR) and MRD levels (centrally assessed by 8-color flow cytometry) <0.1% after induction and <0.01% after early consolidation were assigned to receive delayed consolidation and maintenance therapy up to 2 years in CR. The remaining patients were allocated to allo-HSCT. CR was attained in 315/348 patients (91%), with MRD <0.1% after induction in 220/289 patients (76%). By intention-to-treat, 218 patients were assigned to chemotherapy and 106 to allo-HSCT. The 5-year (±95% confidence interval) cumulative incidence of relapse (CIR), overall survival (OS), and event-free survival probabilities for the whole series were 43% ± 7%, 49% ± 7%, and 40% ± 6%, respectively, with CIR and OS rates of 45% ± 8% and 59% ± 9% for patients assigned to chemotherapy and of 40% ± 12% and 38% ± 11% for those assigned to allo-HSCT, respectively. Our results show that avoiding allo-HSCT does not hamper the outcomes of HR Ph- adult ALL patients up to 60 years with adequate MRD response after induction and consolidation. Better postremission alternative therapies are especially needed for patients with poor MRD clearance. This trial was registered at www.clinicaltrials.gov as # NCT01540812.
Topics: Adolescent; Adult; Consolidation Chemotherapy; Female; Hematopoietic Stem Cell Transplantation; Humans; Induction Chemotherapy; Maintenance Chemotherapy; Male; Middle Aged; Neoplasm, Residual; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Transplantation, Homologous; Treatment Outcome; Young Adult
PubMed: 33150388
DOI: 10.1182/blood.2020007311 -
BMC Health Services Research Jun 2023Tyrosine kinase inhibitors combined with conventional chemotherapy (CC) in treating Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) has...
Cost-effectiveness analysis of imatinib versus dasatinib in the treatment of pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia when combined with conventional chemotherapy in China.
BACKGROUND
Tyrosine kinase inhibitors combined with conventional chemotherapy (CC) in treating Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) has achieved promising efficacy and safety outcomes. The study was conducted to compare the cost-effectiveness between imatinib (HANSOH Pharma, Jiangsu, China) and dasatinib (CHIATAI TIANQING Pharma, Jiangsu, China) in treating pediatric Ph-positive ALL when combined with CC from the perspective of the health system in China.
METHODS
A Markov model was established to simulate a hypothetical cohort of pediatric Ph-positive ALL patients receiving imatinib or dasatinib, combined with CC. The model was designed using a 10-year horizon, a 3- month cycle, and a 5% discount rate. Three health states were included: alive with progression-free survival, progressed disease, and death. Patient characteristics and transition probabilities were estimated based on clinical trials. Other relevant data, such as direct treatment costs and health utility data were extracted from published literature and Sichuan Province's centralized procurement and supervision platform. One-way sensitivity analysis and probabilistic sensitivity analysis were performed to assess the robustness of the results. The willingness-to-pay (WTP) was set as three times China's GDP per capita in 2021.
RESULTS
In the base-case analysis, the total medical costs were $89,701 and $101,182, and the quality-adjusted life years (QALYs) gained were 1.99 and 2.70, for imatinib and dasatinib regimens, respectively. The incremental cost-effectiveness ratio for dasatinib versus imatinib was $16,170/QALY. The probabilistic sensitivity analysis indicated that treatment with dasatinib combined with CC achieved a 96.4% probability of cost-effectiveness at a WTP threshold of $37,765/QALY.
CONCLUSIONS
Dasatinib combined with CC is likely to be a cost-effective strategy compared to imatinib combination therapy for pediatric Ph-positive ALL in China at a WTP threshold of $37,765/QALY.
Topics: Humans; Child; Imatinib Mesylate; Dasatinib; Cost-Effectiveness Analysis; Philadelphia Chromosome; Pyrimidines; Protein Kinase Inhibitors; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Cost-Benefit Analysis; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 37331932
DOI: 10.1186/s12913-023-09600-7 -
Biology of Blood and Marrow... Dec 2019We performed a nationwide registry-based analysis to describe the clinical outcome of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia... (Clinical Trial)
Clinical Trial
Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Adult Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia in the Era of Tyrosine Kinase Inhibitors: A Registry-Based Study of the Italian Blood and Marrow Transplantation Society (GITMO).
We performed a nationwide registry-based analysis to describe the clinical outcome of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph ALL) who underwent an allogeneic hematopoietic stem cell transplantation (HSCT) after a tyrosine kinase inhibitor (TKI)-based treatment A total of 441 patients were included in the study. The median age at HSCT was 44 years (range, 18 to 70 years). All 441 patients (100%) received TKI before HSCT (performed between 2005 and 2016). Of these 441 patients, 404 (92%) were in cytologic complete remission (CR), whereas the remaining 37 (8%) had active disease at the time of HSCT. Molecular minimal residual disease (MRD) was negative in 147 patients (36%) at the time of HSCT. The donor was unrelated in 46% of patients. The most prevalent source of stem cells was peripheral blood (70%). The conditioning regimen was myeloablative in 82% of cases (total body irradiation-based in 50%) and included antithymocyte globulin in 51% of patients. With a median follow-up after HSCT of 39.4 months (range, 1 to 145 months), the probability of overall survival (OS) at 1, 2, and 5 years was 69.6%, 61.1% and 50.3%, respectively, with a median OS of 62 months. Progression-free survival (PFS) at 1, 2, and 5 years was 60.2%, 52.1% and 43.7%, respectively. OS and PFS were significantly better in patients who were in CR and MRD-negative at the time of HSCT compared with patients who were in CR but MRD-positive (50% OS not reached versus 36 months; P = .015; 50% PFS not reached versus 26 months, P = .003). The subgroup of MRD-negative patients both at HSCT and at 3 months after HSCT had a better outcome (5-year OS, 70%). Conversely, the 37 patients who underwent a HSCT with active Ph ALL had a median OS of 7 months and a median PFS of 5 months. The 5-year cumulative incidence of relapse was significantly lower in MRD-negative patients (19.5% versus 35.4%; P = .001). Nonrelapse mortality (NRM) after 1, 2, and 5 years was 19.1% (95% confidence interval [CI], 15.5% to 22.9%), 20.7% (95% CI, 17% to 24.7%), and 24.1% (95% CI, 20% to 28.5%), respectively. NRM was significantly lower with a modified European Society for Blood and Marrow Transplantation (mEBMT) risk score of 0 to 2 compared with ≥3 (15% versus 25%; P = .016). The median OS for Ph ALL patients who underwent a TKI-based treatment followed by an allogeneic HSCT, in recent years at the GITMO centers, was 62 months. Evaluation of the mEBMT risk score can be useful to predict NRM. Our data confirm that HSCT is a potentially curative treatment for Ph ALL with an excellent outcome for the subgroup of MRD-negative patients both at HSCT and at 3 months after HSCT (5-year OS, 70%).
Topics: Adolescent; Adult; Aged; Allografts; Disease-Free Survival; Female; Hematopoietic Stem Cell Transplantation; Humans; Italy; Male; Middle Aged; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Registries; Societies, Medical; Survival Rate
PubMed: 31400502
DOI: 10.1016/j.bbmt.2019.07.037 -
Haematologica Jan 2010
Topics: Animals; Bone Marrow Transplantation; Humans; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinase Inhibitors
PubMed: 20065078
DOI: 10.3324/haematol.2009.015974