September 2013, Vol 2, No 6

← Back to Issue

Ponatinib Given Early May Stem Resistance in CML

Alice Goodman

Uncategorized

Mutation analysis at baseline and at the end of treatment (EOT) provides information about the response to ponatinib in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome–positive (Ph+) acute lymphocytic leukemia (ALL) enrolled in the phase 2 PACE study. Results were presented at the 2013 Annual Meeting of ASCO.

Ponatinib is an oral pan-BCR-ABL1 tyrosine kinase inhibitor (TKI) with potent activity against native and mutated BCR-ABL1 and other kinases. The drug has demonstrated activity against all clinically relevant mutations associated with resistance to TKI therapy in vitro, including the T315I mutation. Ponatinib is the first TKI in phase 2 studies that is active against the T315I mutation.

The study included patients with CML or Ph+ ALL resistant or intolerant to dasatinib or nilotinib (n=203) or with a confirmed T315I mutation at baseline (n=64). Patients were heavily pretreated, with 93% having received 2 or more prior TKIs and 58% having received 3 or more prior TKIs.

“We observed that the overall rate of mutations increases with stage, and so does the number of mutations for each individual,” noted lead author Michael W. N. Deininger, MD, PhD, University of Utah’s Huntsman Cancer Institute, Salt Lake City.

When ponatinib was given at therapeutic doses, no single mutation was found to confer resistance to ponatinib during the study. In studies of other TKIs in CML, the T315I mutation is typically associated with resistance.

Responses to ponatinib were observed regardless of mutation status or disease stage (ie, chronic, accelerated, or blast phase/Ph+ ALL). Durable responses to ponatinib were observed in chronic phase CML, with 91% achieving a major cytogenetic response (MCyR) that persisted at 12 months (MCyR was the primary end point for chronic phase patients, and major hematologic response was used for accelerated and blast crisis phases).

Chronic phase patients with T315I mutations tend to do very well, but those with no single demonstrable mutation do slightly worse, with only 25% MCyR in chronic phase, Deininger noted.

Overall results of the study were reported separately according to disease stage. In chronic phase CML, few patients who discontinued treatment with ponatinib gained single mutations at EOT, and many patients who did gain mutations had been treated with ponatinib at low-dose intensity. Few of these patients developed compound mutations, and there was no change in mutation status for the majority of patients at EOT.

In the accelerated phase, the majority of patients – approximately 80% – had no change in mutation status at EOT.

The situation in blast crisis CML was different. Slightly more than 50% of patients who discontinued treatment with ponatinib developed multiple or compound mutations, but still there was no change in mutation status for a significant proportion of patients.

“These findings suggest that mechanisms other than compound mutations are responsible for resistance to ponatinib in patients in blast crisis,” Deininger told listeners.

“If we introduce ponatinib early in the course of therapy, this drug may be able to suppress the emergence of single BCR-ABL1 mutations, and as a result, the development of compound mutations,” he stated.

Reference
Deininger MWN, Cortes JE, Kim D-W, et al. Impact of baseline mutations on response to ponatinib and end of treatment mutation analysis in patients with chronic myeloid leukemia. J Clin Oncol. 2013;31(suppl):Abstract 7001.

Uncategorized - September 23, 2013

Pathways Creating More and More Value

Hollywood, FL – Pathways continue to be refined toward value-based care, adapting to the challenges of a rapidly shifting oncology landscape, as 2 speakers at the Third Annual Conference of the Association for Value-Based Cancer Care described. Michael A. Kolodziej, MD, National Medical Director for Oncology Strategies at Aetna, Hartford, [ Read More ]

Uncategorized - September 23, 2013

Olaparib Maintenance Therapy Slows Progression in Patients With Ovarian Cancer and BRCA Mutations

Olaparib maintenance therapy prolonged progression-free survival (PFS) and the time to disease progression after a second subsequent therapy (PFS2) in patients with platinum-sensitive relapsed serous ovarian cancer (SOC). The effect of olaparib was particularly robust in patients with a BRCA mutation in an updated analysis of Study 19 presented at [ Read More ]