Poor Treatment Outcome of Philadelphia Chromosome-Positive Pediatric Acute Lymphoblastic Leukemia Despite Intensive Chemotherapy

Purpose Addition of imatinib to intensive chemotherapy improved survival for children and young adults with Philadelphia chromosome–positive acute lymphoblastic leukemia. Compared with imatinib, dasatinib has increased potency, CNS penetration, and activity against imatinib-resistant clones. Patients and Methods Children’s Oncology Group (COG) trial AALL0622 (Bristol Myers Squibb trial CA180-204) tested safety and feasibility of adding dasatinib to intensive chemotherapy starting at induction day 15 in patients with newly diagnosed Philadelphia chromosome–positive acute lymphoblastic leukemia age 1 to 30 years. Allogeneic hematopoietic stem-cell transplantation (HSCT) was recommended for patients at high risk based on slow response and for those with a matched family donor regardless of response after at least 11 weeks of therapy. Patients at standard risk based on rapid response received chemotherapy plus dasatinib for an additional 120 weeks. Patients with overt CNS leukemia received cranial irradiation. Results Sixty eligible patients were enrolled. Five-year overall (OS) and event-free survival rates (± standard deviations [SD]) were 86% ± 5% and 60% ± 7% overall, 87% ± 5% and 61% ± 7% for standard-risk patients (n = 48; 19% underwent HSCT), and 89% ± 13% and 67% ± 19% for high-risk patients (n = 9; 89% underwent HSCT), respectively. Five-year cumulative incidence (± SD) of CNS relapse was 15% ± 6%. Outcomes (± SDs) were similar to those in COG AALL0031, which used the same chemotherapy with continuous imatinib: 5-year OS of 81% ± 6% versus 86% ± 5% ( P = .63) and 5-year disease-free survival of 68% ± 7% versus 60% ± 7% ( P = 0.31) for AALL0031 versus AALL0622, respectively. IKZF1 deletions, present in 56% of tested patients, were associated with significantly inferior OS and event-free survival overall and in standard-risk patients. Conclusion Dasatinib was well tolerated with chemotherapy and provided outcomes similar to those with imatinib in COG AALL0031, where all patients received cranial irradiation. Our results support limiting HSCT to slow responders and suggest a potential role for transplantation in rapid responders with IKZF1 deletions.

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Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia in the Elderly: Prognostic Factors and Treatment Outcome

Hematology ◽

10.1080/10245330400001983 ◽

2004 ◽

Vol 9 (5-6) ◽

pp. 369-376 ◽

Cited By ~ 13

Author(s):

Roch Houot ◽

Emmanuelle Tavernier ◽

Quoc-Hung Le ◽

Véronique Lhéritier ◽

Anne Thiebaut ◽

...

Keyword(s):

Treatment Outcome ◽

Prognostic Factors ◽

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

The Elderly ◽

Philadelphia Chromosome Positive

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Dasatinib for a child with Philadelphia chromosome–positive acute lymphoblastic leukemia and persistently elevated minimal residual disease during imatinib therapy

Current Oncology ◽

10.3747/co.22.2719 ◽

2015 ◽

Vol 22 (4) ◽

pp. 303 ◽

Cited By ~ 1

Author(s):

K.H. Wu ◽

H.P. Wu ◽

T. Weng ◽

C.T. Peng ◽

Y.H Chao

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Minimal Residual Disease ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Intensive Chemotherapy ◽

Molecular Remission ◽

Allogeneic Hsct ◽

Minimal Residual ◽

Philadelphia Chromosome Positive

Imatinib has improved outcomes in patients with Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (all). Minimal residual disease (mrd) is a useful tool for predicting leukemia relapse. However, there is no consensus on how to treat children with elevation of BCR-ABL transcripts but no evidence of hematologic relapse during chemotherapy combined with imatinib. Here, we report the case of a child with Ph+ all who had persistent elevation of mrd, but no evidence of hematologic relapse while receiving imatinib plus intensive chemotherapy. Dasatinib was substituted for imatinib because no suitable donor for allogeneic hematopoietic stem-cell transplantation (hsct) was available. Less-intensive chemotherapy with methotrexate and 6-mercaptopurine was administered concomitantly. No serious adverse events were encountered. With continuous dasatinib combined with chemotherapy, but no allogeneic hsct, our patient reached complete molecular remission and has been in complete molecular remission for more than 13 months. This report is the first about the long-term use of dasatinib in patients with Ph+ all and mrd elevation but hematologic remission during imatinib chemotherapy. In a similar situation, chemotherapy combined with dasatinib instead of allogeneic hsct could be considered to avoid hsct-related mortality and morbidity. Clinical trials are needed.

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Improved Early Event-Free Survival With Imatinib in Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia: A Children's Oncology Group Study

Journal of Clinical Oncology ◽

10.1200/jco.2008.21.2514 ◽

2009 ◽

Vol 27 (31) ◽

pp. 5175-5181 ◽

Cited By ~ 449

Author(s):

Kirk R. Schultz ◽

W. Paul Bowman ◽

Alexander Aledo ◽

William B. Slayton ◽

Harland Sather ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Early Event ◽

Intensive Chemotherapy ◽

Event Free Survival ◽

Free Survival ◽

The Impact ◽

Improved Outcome ◽

Philadelphia Chromosome Positive

Purpose Imatinib mesylate is a targeted agent that may be used against Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL), one of the highest risk pediatric ALL groups. Patients and Methods We evaluated whether imatinib (340 mg/m2/d) with an intensive chemotherapy regimen improved outcome in children ages 1 to 21 years with Ph+ ALL (N = 92) and compared toxicities to Ph− ALL patients (N = 65) given the same chemotherapy without imatinib. Exposure to imatinib was increased progressively in five patient cohorts that received imatinib from 42 (cohort 1; n = 7) to 280 continuous days (cohort 5; n = 50) before maintenance therapy. Patients with human leukocyte antigen (HLA) –identical sibling donors underwent blood and marrow transplantation (BMT) with imatinib given for 6 months following BMT. Results Continuous imatinib exposure improved outcome in cohort 5 patients with a 3-year event-free survival (EFS) of 80% ± 11% (95% CI, 64% to 90%), more than twice historical controls (35% ± 4%; P < .0001). Three-year EFS was similar for patients in cohort 5 treated with chemotherapy plus imatinib (88% ± 11%; 95% CI, 66% to 96%) or sibling donor BMT (57% ± 22%; 95% CI, 30.4% to 76.1%). There were no significant toxicities associated with adding imatinib to intensive chemotherapy. The higher imatinib dosing in cohort 5 appears to improve survival by having an impact on the outcome of children with a higher burden of minimal residual disease after induction. Conclusion Imatinib plus intensive chemotherapy improved 3-year EFS in children and adolescents with Ph+ ALL, with no appreciable increase in toxicity. BMT plus imatinib offered no advantage over BMT alone. Additional follow-up is required to determine the impact of this treatment on long-term EFS and determine whether chemotherapy plus imatinib can replace BMT.

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