Impact of tyrosine kinase inhibitors on minimal residual disease and outcome in childhood Philadelphia chromosome-positive acute lymphoblastic leukemia.

Abstract

BACKGROUND:

Breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL1) tyrosine kinase inhibitors (TKIs) improve the outcome of patients with childhood Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) when they are incorporated into postremission induction chemotherapy. To date, no data are available on the impact of TKIs on minimal residual disease (MRD) at the end of induction therapy among patients who have a poor early response to 2 weeks of induction therapy that does not include TKIs.

METHODS:

The authors analyzed the early response to TKIs during remission induction in children with Ph-positive ALL who were treated at St. Jude Children's Research Hospital. MRD was measured on days 15 and 42 of induction. TKIs were incorporated into induction therapy on day 22 in the post-TKI era.

RESULTS:

TKIs produced a marked drop in MRD levels: at the end of remission induction, 9 of 11 patients who received imatinib or dasatinib and conventional induction chemotherapy achieved MRD-negative status compared with only 2 of 16 patients who received chemotherapy alone (P < .001). The 5-year event-free survival rate (± standard deviation) was 68.6% ± 19.2% for the 11 patients who received TKIs versus 31.6% ± 9.9% for the 19 patients who did not (P = .022); notably, 2 of the former group underwent hematopoietic stem cell transplantation versus 15 of the latter group (P = .002). MRD levels and outcomes did not differ significantly among 498 patients with standard-risk/high-risk, Ph-negative ALL who were treated in the pre-TKI or post-TKI eras.

CONCLUSIONS:

TKIs administered in the early phases of therapy can dramatically reduce MRD and improve the outcome of childhood Ph-positive ALL.

• Authors: Sima Jeha, Elaine Coustan-Smith, Deqing Pei, John T Sandlund, Jeffrey E Rubnitz, Scott C Howard, Hiroto Inaba, Deepa Bhojwani, Monika L Metzger, Cheng Cheng, John K Choi, Jeffrey Jacobsen, Sheila A Shurtleff, Susana Raimondi, Raul C Ribeiro, Ching-Hon Pui, Dario Campana
• Journal: Cancer (Cancer) Vol. 120 Issue 10 Pg. 1514-9 (May 15 2014) ISSN: 1097-0142 [Electronic] United States
• PMID: 24501014 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 American Cancer Society.

Chemical References

• Antineoplastic Agents
• Benzamides
• Piperazines
• Protein Kinase Inhibitors
• Pyrimidines
• Thiazoles
• Imatinib Mesylate
• Protein-Tyrosine Kinases
• Dasatinib

Topics

• Adolescent
• Antineoplastic Agents (administration & dosage, therapeutic use)
• Benzamides (administration & dosage, therapeutic use)
• Child
• Child, Preschool
• Dasatinib
• Drug Administration Schedule
• Female
• Flow Cytometry
• Genes, T-Cell Receptor
• Humans
• Imatinib Mesylate
• Induction Chemotherapy
• Infant
• Male
• Neoplasm, Residual (drug therapy, genetics, prevention & control)
• Philadelphia Chromosome
• Piperazines (administration & dosage, therapeutic use)
• Polymerase Chain Reaction
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, genetics)
• Protein Kinase Inhibitors (administration & dosage, therapeutic use)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Pyrimidines (administration & dosage, therapeutic use)
• Thiazoles (administration & dosage, therapeutic use)
• Treatment Outcome