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CML: Third-Line Therapy with Ponatinib May Be Better than Second-Line for Patients with Highly Resistant Disease

Fuerst, Mark

doi: 10.1097/01.COT.0000419310.28482.30


CHICAGO—Third-line therapy with ponatinib may prove to be better than second-line therapy for chronic myeloid leukemia (CML) and Philadelphia-positive acute lymphocytic leukemia (Ph+ ALL) patients who are resistant or intolerant to dasa-tinib or nilotinib or those who carry the difficult-to-treat T315I mutation, according to data reported at the ASCO Annual Meeting here.

“There are no available treatment options for CML patients who have failed to respond to the second-generation tyrosine kinase inhibitors nilotinib or dasatinib, or both, or have the T315I mutation—ponatinib would be a welcome alternative,” said Jorge Cortes, MD, Chair of the CML Section at the University of Texas MD Anderson Cancer Center.

Speaking in an interview after the meeting, he noted that 35 to 40 percent of CML patients who take imatinib become resistant or intolerant. “We can rescue about 35 percent of these patients with second-generation TKIs. The rest are candidates for other options.” About 15 to 20 percent of CML patients do not respond to imatinib or a second-generation TKI, he added.

JORGE CORTES, MD, said that so far, the results with ponatinib have been “spectacular,” with about 50 percent of patients who had not responded to three TKIs achieving a major cytogenetic response

JORGE CORTES, MD, said that so far, the results with ponatinib have been “spectacular,” with about 50 percent of patients who had not responded to three TKIs achieving a major cytogenetic response

Cortes, who presented the results of a pivotal phase II trial of ponatinib (Abstract 6503), said that so far, the results with ponatinib are “spectacular.”

“About 50 percent of patients who have failed three TKIs achieve a major cytogenetic response. This fairly safe, oral drug is well-tolerated, and captures the bulk of patients who fail multiple TKIs. It will be the first choice in this setting.”

The Discussant, Michael Mauro, MD, Professor of Medicine in the Division of Hematology and Medical Oncology at Oregon Health Sciences University, said: “Ponatinib is revolutionizing CML and provides remarkable ability to salvage resistant disease, especially T315I patients. Earlier use may prove even better, as seen in the less-treated T315I cohort. And it may have activity in mutation-negative patients.”

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Potent, Oral, Pan-BCR-ABL Inhibitor

Ponatinib is a potent, oral, pan-BCR-ABL inhibitor active against the native enzyme and all tested resistant mutants, including the uniformly resistant T315I mutation. Cortes presented results of the PACE (Ponatinib Ph+ALL and CML Evaluation) trial that enrolled 449 patients, median age of 59, including 270 chronic phase (CP) CML patients, 85 accelerated phase (AP) CML patients, and 95 blast crisis CML or Ph+ALL patients who were resistant or intolerant to imatinib, dasatinib, or nilotinib, or who had T315I mutations. The patients received 45 mg ponatinib once daily.

Nearly two-thirds of this heavily pretreated group had received all three available TKIs. Two-thirds with the T315I mutation had received two TKIs. “Surprisingly, only 30 percent had one mutation,” Cortes said. About 80 percent of patients had T315I-only mutations.

Only one-quarter of chronic-phase patients had achieved a major cytogenetic response (MCyR) with dasatinib or nilotinib. One-third of those in accelerated phase had achieved major hematologic response with therapy.

After a median of 10 months of follow-up, more than half of the chronic-phase (CP) CML patients achieved a MCyR, as did nearly three-quarters of those with the T315I mutation. The median time to MCyR was 12 weeks. About two-thirds of accelerated-phase CML patients and one-third of blast-crisis/Ph+ALL patients achieved a major hematologic response after a median of six months of follow-up.

More than one-third of the CP CML cytogenetic responses were complete cytogenetic responses (CCyR), Cortes noted. Again, those with a T315I mutation did better—two-thirds achieved CCyR. For those with advanced disease, overall 20 percent achieved CCyR, including one-third of those with T315I mutations.

MICHAEL MAURO, MD: “Ponatinib is revolutionizing CML and provides remarkable ability to salvage resistant disease, especially T315I patients

MICHAEL MAURO, MD: “Ponatinib is revolutionizing CML and provides remarkable ability to salvage resistant disease, especially T315I patients

Responses continued to improve over time, going from about one-third of responders at three months of follow-up to more than half of the responders at nine months.

“Those who had received all three TKIs had a robust CCyR in early follow-up,” he said. In addition, more than one-third of those with no mutations achieved CCyR.

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Adverse Effects ‘Mild and Manageable’

Adverse events included primarily rash and dry skin in about one-third of patients (grade 3/4 events were rare). About one-quarter of patients had abdominal pain, and 10 percent had grade 3 lipase increases.

Grade 3 or higher thrombocytopenia was observed in about one-quarter of patients, and was the major reason for discontinuations. About two-thirds of the CP CML and AP CML patients remain on study.

In conclusion, Cortes said, “Ponatinib shows robust anti-leukemic activity in this heavily pretreated population. Responses were observed regardless of mutation status or disease stage, and improved over time. The responses are durable, with 93 percent of CP CML patients projected to remain in MCyR at one year. The drug is well-tolerated, and adverse events are mild and manageable.”

Olatoyosi Odenike, MD, a leukemia and MDS specialist at the University of Chicago and a member of the ASCO Communications Committee, agreed that the results point to a new treatment option for the heavily pretreated patients with CML, including patients with the T315I mutation.

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‘Continue to Build’

Mauro added that the “PACE phase II results continue to build on phase I efficacy, but this is early reporting with 10 months median follow-up for CP CML patients. This is mainly a resistant population, about 80 percent or more, and a highly resistant one, about two-thirds had up to three TKI therapies and only about 25 percent of patients had achieved MCyR on second-line therapy. Only a small population was multi-intolerant patients.”

He noted that the T315I subset was slightly less heavily treated. The majority (about 60%) of the non-T315I patients had no mutation.

“Ponatinib in third line is out ‘PACE'ing response rates we saw in second-line with nilotinib and dasatinib,” he continued. “The T315I cohort consistently has higher response rates than the overall CP CML population. There was some loss of cytogenetic response efficacy with increasing exposure and in the subset of CP CML T315I cases with additional mutations.”

The cytogenetic and molecular responses appear similar in the CP CML overall population, irrespective of the number of prior TKIs used, he said.

The impact of mutations in the overall chronic-phase CML population is minimal, Mauro said. In accelerated-phase patients, T315I response is better than the non-T315I response; and in blast-phase and acute lymphocytic leukemia patients, the results appear similar.

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How Will It Be Used?

Now that ponatinib is rapidly moving towards FDA approval, how will it be used? Mauro said: “The drug is built for T315I patients. This gives justification for mutation analysis in resistant CML to find this subset of patients. Its performance overall and durability of response justify approval and rapid implementation for better salvage.”

He added that as second-line therapy, ponatinib may be used for a subset of resistant patients after primary treatment with dasatinib and nilotinib, including those defined early on (at three months) based on having more than 10 percent residual Bcr-Abl levels—“These patients have unfavorable odds of CCyR and no rationale to move back to imatinib.”

And even for patients without a T315I mutation, ponatinib might be used after imatinib, he said. “There may be other mechanisms for resistance beyond mutations yet to be discovered.”

Cortes said that “clinical data allow us to investigate other mutations or means of resistance,” noting that analysis is under way in blast-phase patients to see about the emergence of other mutations.

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‘Monitor Carefully, Avoid Temptation to Switch from One Drug Too Soon’

Jorge Cortes, MD, said his message to clinicians is to monitor patients carefully, but avoid the temptation to switch from one drug to another too soon: “Even though we have several options, let the drug you are using do its job. All of these drugs have adverse events. It's better to manage the adverse events than to switch to another drug too quickly.”

How can a clinician know when a drug has failed? Follow the defined criteria now established in treatment guidelines, he said. “That's the way to know what's appropriate for your patient. If you follow the guidelines, the majority of CML patients will live normal lives.”

© 2012 Lippincott Williams & Wilkins, Inc.
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