Imatinib Plus Vincristin & Prednisolone Induces Complete Remission and Prolonged Survival in Elderly Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4339-4339
Author(s):  
Ashis Mukhopadhyay ◽  
Soma Mukhopadhyay ◽  
Pinaki Ranjan Gupta ◽  
Ujjal Kanti Roy ◽  
Ajoy Sinha
Keyword(s):  
Overall Survival ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Disease Free Survival ◽  
Induction Treatment ◽  
Molecular Testing ◽  
Molecular Response ◽  
Highly Active ◽  
Philadelphia Chromosome Positive

Abstract Introduction: Acute lymphoblastic Leukemia (ALL) in elderly patients (50yrs or older) carries a poor prognosis. In survival studies using in variety of therapeutic regimens. This may be because of relatively high frequency of the Philadelphia chromosome (Ph). With the advent of dose intensive chemotherapy regimen such as hyper CVAD (Fractionated Cyclophosphamide, Vincristin, Doxorubicin, Dexamethasone) overall survival has not improved. The aim of our study was to see the effectiveness of Imatinib plus Vincristin & Prednisolone in Philadelphia Chromosome positive in elderly acute lymphoblastic leukemia patients. Material & Methods: During period from January 2006 December 2006 we selected 10 consecutive elderly (more than 50yrs) Ph+ ALL patients in the haemato-oncology department Netaji Subhash Chandra Bose Cancer Research Institute. There were 4 males & 6 females. The median age of the patient was 64years (range 51 to 77yrs). All patients were started with Imatinib mesylate (Natco pharma) 400mg daily. Prednisolone was given 40mg /m2 over 6weeks & followed by 2weeks tapering dose. Vincristin was given 2mg/m2 weekly for 6weeks. All patients were evaluated by bone marrow and molecular testing done every 3monthly for 1year then 6monthly. Result: All patients (100%) obtained complete haematological & partial molecular response at 3month. Three patient (30%) achieved complete molecular response at 9month. With median follow-up of 8months (range 6–15months) the disease free survival and overall survival were 80% & 90% respectively. Most of the induction treatment was done as OPD basis, no hospitalization required. The therapy was tolerated well. Conclusion: We concluded that Imatinib plus Vincristin & Prednisolone is a feasible, highly active protocol for elderly Philadelphia Chromosome positive acute lymphoblastic leukemia patients. It is well tolerated & associated with good quality of life.

Imatinib plus steroids induces complete remissions and prolonged survival in elderly Philadelphia chromosome–positive patients with acute lymphoblastic leukemia without additional chemotherapy: results of the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) LAL0201-B protocol

Blood ◽  
2007 ◽  
Vol 109 (9) ◽  
pp. 3676-3678 ◽  
Author(s):  
Marco Vignetti ◽  
Paola Fazi ◽  
Giuseppe Cimino ◽  
Giovanni Martinelli ◽  
Francesco Di Raimondo ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Treatment Strategies ◽  
Induction Treatment ◽  
Highly Active ◽  
Additional Chemotherapy ◽  
Frontline Treatment ◽  
Philadelphia Chromosome Positive

AbstractThirty elderly (> 60 years) Philadelphia chromosome–positive (Ph+) patients with acute lymphoblastic leukemia (ALL) received imatinib, 800 mg daily, associated to steroids without further chemotherapy as frontline treatment. Median age was 69 years (range, 61-83 years). Twenty-nine patients were evaluable for response and all of them obtained a hematologic complete remission, with a median BCR-ABL reduction of 2.9 and 2.0 logs in p190+ and p210+ cases, respectively. Most of the induction treatment did not require admission of the patients. No major toxicities occurred and the treatment was well tolerated. Median survival from diagnosis was 20 months. This study shows that elderly Ph+ patients with ALL—often considered eligible only for palliative treatment strategies—may benefit from an imatinib-steroids protocol, which does not require chemotherapy nor a long hospitalization, is feasible, highly active, and associated with a good quality of life.

Treatment Selection for Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia in the Era of Tyrosine Kinase Inhibitors

Chemotherapy ◽  
2019 ◽  
Vol 64 (2) ◽  
pp. 81-93 ◽  
Author(s):  
Yingying Ma ◽  
Quanchao Zhang ◽  
Peiyan Kong ◽  
Jingkang Xiong ◽  
Xi Zhang ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Molecular Response ◽  
Term Survival ◽  
Hematopoietic Stem ◽  
Philadelphia Chromosome Positive

With the advent of tyrosine kinase inhibitors (TKIs), the treatment of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) has entered a new era. The efficacy of TKIs compared with other ALL treatment options is emphasized by a rapid increase in the number of TKI clinical trials. Subsequently, the use of traditional approaches, such as combined chemotherapy and even allogeneic hematopoietic stem cell transplantation (allo-HSCT), for the treatment of ALL is being challenged in the clinic. In light of the increased use of TKIs in the clinic, several questions have been raised. First, is it necessary to use intensive chemotherapy during the induction course of therapy to achieve a minimal residual disease (MRD)-negative status? Must a patient reach a complete molecular response/major molecular response before receiving allo-HSCT? Does MRD status affect long-term survival after allo-HSCT? Is auto-HSCT an appropriate alternative for allo-HSCT in those Ph+ ALL patients who lack suitable donors? Here, we review the recent literature in an attempt to summarize the current status of TKI usage in the clinic, including several new therapeutic approaches, provide answers for the above questions, and speculate on the future direction of TKI utilization for the treatment of Ph+ ALL patients.

Dasatinib (SPRYCEL®) in Patients (pts) with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Who Are Imatinib-Resistant (im-r) or -Intolerant (im-i): Updated Results from the CA180-015 ‘START-L’ Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 286-286 ◽  
Author(s):  
Herve Dombret ◽  
O.G. Ottmann ◽  
G. Rosti ◽  
B. Simonsson ◽  
R.A. Larson ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Median Duration ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Cell Transplant ◽  
Hematologic Response ◽  
Grade 3 ◽  
Philadelphia Chromosome Positive

Abstract Dasatinib (SPRYCEL®, formerly BMS-354825) is a novel, oral, multi-targeted kinase inhibitor of BCR-ABL and SRC. Relapsing pts with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) who have been previously treated with chemotherapy including im have a very poor prognosis. START-L is an open label, multi-center, global phase-II study, which treated 46 im-r or im-i pts with Ph(+) ALL from January through June 2005. Dasatinib was given orally, 70 mg twice daily (BID) with escalation to 100 mg BID for poor response or reductions to 50 mg and 40 mg BID for toxicity. Response was assessed on weekly blood counts and monthly bone marrow exams, including cytogenetics. Mutation analysis was conducted at baseline and at end of study. Quantitative PCR was carried out pretreatment and at the time of complete cytogenetic response (CCyR). At the time of this update, all 46 pts had a minimum of 9 months (mo) of follow-up. Of these, 44 (96%) were im-r; due to the small number of im-i pts, data for all pts are presented. 59% of patients were male and median age was 48 years. The median time from initial Ph(+) ALL diagnosis to first dose was 18 mo. All patients had been pretreated with im including 46% with 600 mg per day or more, and 52% whose duration of im treatment was more than 12 mo. 37% of the pts had received a stem cell transplant. At baseline, 67% of pts had WBC <2000/mm3, 74% had platelets <100 × 103/mm3, and 24% had extramedullary disease outside of the spleen. In the 40 pts with baseline mutation data, im-resistant BCR-ABL mutations were observed in 78%, one with T315I. The median duration of therapy was 3.0 mo (range 0.03–16.5) for all pts and was 13.0 mo (9.2–16.5) for pts still on study. The overall complete hematologic response rate was 35%. The major cytogenetic response was 57%, including 54% CCyR. The major hematologic response (MHR) in the 31 pts with baseline mutations was 45%. The median duration of MHR was 11 mo and the median progression-free survival was 3.7 mo (95% CI 1.6–6.1). Grades 3 and 4 thrombocytopenia occurred in 13% and 67%, respectively and grades 3 and 4 neutropenia occurred in 27% and 52% of pts, respectively. Most frequent non-hematologic toxicities included diarrhea in 30% (grade 3–4, 7%), nausea in 22% (no grade 3–4), pyrexia in 22% (grade 3–4, 2%), and pleural effusion in 22% (grade 3–4, 7%) of pts. Dose was reduced in 30% and interrupted in 43% of pts, primarily due to non-hematologic toxicities. Dasatinib has important efficacy in this Ph(+) ALL pt population. Updated efficacy (including molecular response), safety, and mutational analysis data will be presented at the meeting.

Imatinib combined with induction or consolidation chemotherapy in patients with de novo Philadelphia chromosome–positive acute lymphoblastic leukemia: results of the GRAAPH-2003 study

Blood ◽  
2006 ◽  
Vol 109 (4) ◽  
pp. 1408-1413 ◽  
Author(s):  
Adrienne de Labarthe ◽  
Philippe Rousselot ◽  
Françoise Huguet-Rigal ◽  
Eric Delabesse ◽  
Francis Witz ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
De Novo ◽  
Lymphoblastic Leukemia ◽  
Quantitative Polymerase Chain Reaction ◽  
Philadelphia Chromosome ◽  
Disease Free Survival ◽  
Free Survival ◽  
Prospective Trials ◽  
Polymerase Chain ◽  
Philadelphia Chromosome Positive

AbstractThe combination of imatinib with chemotherapy has been recently reported as very promising in patients with Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL). During 2004 and 2005, 45 patients with newly diagnosed Ph+ ALL were treated in the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAAPH) 2003 study, in which imatinib was started with HAM (mitoxantrone with intermediate-dose cytarabine) consolidation in good early responders (corticosensitive and chemosensitive ALL) or earlier during the induction course in combination with dexamethasone and vincristine in poor early responders (corticoresistant and/or chemoresistant ALL). Imatinib was then continuously administered until stem cell transplantation (SCT). Overall, complete remission (CR) and BCR-ABL real-time quantitative polymerase chain reaction (RQ-PCR) negativity rates were 96% and 29%, respectively. All of the 22 CR patients (100%) with a donor actually received allogeneic SCT in first CR. At 18 months, the estimated cumulative incidence of relapse, disease-free survival, and overall survival were 30%, 51%, and 65%, respectively. These 3 end points compared very favorably with results obtained in the pre-imatinib LALA-94 trial. This study confirms the value of the combined approach and encourages prospective trials to define the optimal chemotherapy that has to be combined with imatinib and to carefully reevaluate the place of allogeneic SCT in this new context.

scholarly journals The role of stem cell transplantation in the management of Philadelphia chromosome-positive acute lymphoblastic leukemia

2018 ◽  
Vol 9 (12) ◽  
pp. 357-368 ◽  
Author(s):  
Jose-Maria Ribera ◽  
Jordi Ribera ◽  
Eulalia Genescà
Keyword(s):  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Molecular Response ◽  
Hematopoietic Stem ◽  
Philadelphia Chromosome Positive

The concurrent administration of tyrosine kinase inhibitors (TKIs) with standard chemotherapy together with allogeneic hematopoietic stem cell transplantation (alloHSCT) has improved the outcome of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Although to date, no study has shown alloHSCT to be inferior to chemotherapy plus TKIs in any subgroup of adult Ph+ ALL, there is some evidence suggesting no additional benefit of alloHSCT in patients with deep molecular responses to intensive chemotherapy with a second-generation, and especially, third-generation TKI. As none of these positive and negative studies are controlled, randomized trials are needed to fully define the role of alloHSCT in Ph+ ALL, especially in those with deep molecular response. However, if studies combining TKIs with new approaches such as immunotherapy lead to durable responses, alloHSCT in the first complete remission could be avoided in the near future in the majority of patients with Ph+ ALL.

CD34+CD38-CD58- Candidate Leukemia-Initiating Cells Are Clinically Relevant With The Unfavorable Prognosis In Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 354-354
Author(s):  
Yuan kong ◽  
Ying-Jun Chang ◽  
Yan-rong Liu ◽  
Ya-zhe Wang ◽  
Qian Jiang ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Philadelphia Chromosome ◽  
Disease Free Survival ◽  
Mrna Levels ◽  
Imatinib Resistance ◽  
Self Renewal ◽  
Philadelphia Chromosome Positive

Abstract Background The prognosis of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) has been greatly improved in the modern era of imatinib. Nevertheless, relapse is still a major cause of treatment failure in human Ph+ALL. Leukemia-initiating cells (LICs) are presumed to be responsible for relapse in leukemia. Therefore, we conducted a study to identify the candidate LICs that are responsible for disease progression and its clinical significance in patients with Ph+ALL. Aims To investigate the leukemia-initiating and self-renewal capacities of CD34+CD38-CD58- cells and determine the prognostic significance of CD34+CD38-CD58- phenotype in patients with Ph+ALL treated in Peking University Institute of Hematology. Methods The leukemia-initiating potential and self-renewal capacity of the sorted CD34+CD38-CD58-, CD34+CD38-CD58+,CD34+CD38+CD58- and CD34+CD38+CD58+ compartments were investigated in vivo using sublethally irradiated and anti-mouse CD122 monoclonal antibody conditioned NOD/SCID mice by intra-bone marrow–injection. Furthermore, we prospectively analyzed whether the identified CD34+CD38-CD58- compartment at diagnosis correlates with minimal residual disease (MRD) after therapy and clinical outcomes in 63 adult patients (18-60 years) with de novo Ph+ALL. Results Xenotransplantation of the sorted CD34+CD38-CD58- cells led to a repopulation of human B-ALL in primary and secondary recipient mice, which were phenotypically and clonally derived from the original Ph+ALL patients analyzed by flow cytometry, as well as quantitative real-time RT-PCR and fluorescence in situ hybridization for leukemia-specific cytogenetic abnormalities. Furthermore, the candidate CD34+CD38-CD58- LICs phenotype at diagnosis (n=16) significantly correlated with a lower complete remission rate and higher MRD frequency monitored by BCR-ABL mRNA levels in BM of Ph+ALL patients. Additionally, it directly correlated with higher cumulative incidence of relapse (CIR, 60% ± 1.97% vs. 15.51% ± 0.30%, P=0.002) and unfavorable disease-free survival (DFS, 33.75%±12.64% vs. 71.31%±7.17%, P=0.009) at 3-year. The CD34+CD38-CD58- group exhibited a higher rate of BCR-ABL mutations conferring higher level imatinib resistance than the other group (43.75% vs. 17.02%, P=0.04). Multivariate analyses revealed that CD34+CD38-CD58- phenotype at diagnosis was an independent risk factor for relapse (HR=4.35, P=0.009) and DFS (HR=3.38, P=0.008) in adult Ph+ALL. Summary/Conclusion Both the xenotransplantation data as well as the clinical correlation studies show that CD34+CD38-CD58- compartment enrich for leukemia-initiating cells in adult Ph+ALL. CD34+CD38-CD58- phenotype at diagnosis independently correlates with an adverse prognosis, which promises to be an efficient tool for relapse prediction and risk-stratification treatment in adult Ph+ALL patients. Acknowledgments This work was supported by grants from National Natural Science Foundation of China (grants no. 30800483&81230013) and Beijing Municipal Science and Technology Program (grant no.Z111107067311070). Disclosures: No relevant conflicts of interest to declare.

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