As tyrosinse kinase inhibitors become increasingly effective in treating chronic myeloid leukemia (CML), major molecular responses (≥ 3-log reduction in BCR-ABL transcripts) are being achieved for a growing percentage of patients.
“In the new era of tyrosinse kinase inhibitors, we are learning how to achieve better, deeper response durations,” said Attaya Suvannasankha, MD, of Indiana University School of Medicine, Indianapolis, who discussed recent data on the three currently available tyrosine kinase inhibitors and one on the horizon at the Best of ASCO Boston meeting.
DASISION 3-Year Data
The DASISION phase III trial established that in newly diagnosed chronic phase CML patients, dasatinib (Sprycel) at 100 mg daily has superior efficacy over imatinib (Gleevec) at 400 mg daily and achieves faster, deeper responses by 3 months, which are known to improve outcomes. Major molecular responses were achieved by 68% receiving dasatinib and 55% receiving imatinib; the probability of achieving a major molecular response was 64% higher with dasatinib (P < .0001), and there was less transformation to accelerated or blast phase with dasatinib.1
More importantly, response rates were deeper with dasatinib, as indicated by 4-log (MR4) and 4.5-log (MR4.5) reductions in BCR-ABL. At 3 years, the MR4 was 35% with dasatinib vs 22% with imatinib (P = .00635) and the MR4.5 was 22% vs 12% (P = .00069), respectively. In an exploratory analysis, deeper response at 3 months was associated with a higher probability of progression-free survival and overall survival at 3 years, and decreased transformation to accelerated phase or blast crisis.
In the study, however, overall and progression-free survival remained similar, with approximately 92% of patients in each arm alive. Side effects were usually mild but differed between the arms, with dasatinib associated with more pleural effusion and imatinib associated with more superficial edema and gastrointestinal effects.
Speaking to the issue of continuing on a drug or switching therapy, Dr. Suvannasankha described the 12-month follow-up of the ENESTcmr trial (Evaluating Nilotinib Efficacy and Safety in Clinical Trials—complete molecular response), which evaluated 207 CML patients achieving a complete cytogenetic response but not a molecular response, on imatinib (ie, remaining BCR-ABL–positive after 2 years). The study found that twice as many patients achieved deep molecular responses after switching to nilotinib (Tasigna) at 400 mg twice daily, vs staying on imatinib, 400 to 600 mg/d.2 Patients who switched also demonstrated improvements in MR4 and MR4.5 and were less likely to progress or transform.
This means, according to Dr. Suvannasankha, “that after 1 or 2 years, if there is no major molecular response, you can assume the patient is unlikely to become more responsive. If you don’t see this response right away, there may not be an advantage to waiting.”
When Imatinib, Dasatinib, and Nilotinib Fail
For patients whose disease progresses after therapy with first- and second-generation tyrosine kinase inhibitors, clinicians can expect to have a new treatment option: the third-generation tyrosinse kinase inhibitor ponatinib. Ponatinib was designed to target not only native BCR-ABL but also its isoforms that carry mutations conferring resistance to treatment with existing tyrosinse kinase inhibitors, including the T315I mutation for which no effective therapy currently exists. Ariad Pharmaceuticals filed for accelerated approval of the drug in August.
Ponatinib showed robust efficacy in the 10-month follow-up of the phase II PACE trial, an open-label study of 499 patients with CML or Philadelphia chromosome–positive acute lymphoblastic leukemia who were resistant to or intolerant of nilotinib or dasatinib, or who had the T315I mutation.3
Major cytogenetic response was achieved by 54% of chronic phase patients, including 70% of patients with the T315I mutation and 49% of refractory/intolerant patients. In the accelerated phase, the primary endpoint of major hematologic response was achieved by 58%, including 60% refractory/intolerant and 50% with the T315I mutation. In blast phase CML, a major hematologic response was reached by 34%, 35%, and 33%, respectively. Responses improved over time. The best responses were seen in patients who had received no more than two tyrosine kinase inhibitors.
“This was a highly resistant population, and only about 25% had achieved a major cytogenetic response on second-line therapy. We saw significant responses of about 54% across the board, whether in chronic phase or more advanced phases of the disease. In blast phase, whether mutated or not, response rates were about 34%. Also we saw many major molecular repsonses, which we do not see with the earlier-generation tyrosine kinase inhibitors,” she pointed out. “Importantly, the T315I mutation cohort consistently shows higher response rates than the overall chronic phase population.” ■
Disclosure: Dr. Suvannasankha reported no potential conflicts of interest.
References
1. Hochhaus A, Shah NP, Cortes JE, et al: Dasatinib versus imatinib in newly diagnosed chronic myeloid leukemia in chronic phase: DASISION 3-year follow-up. 2012 ASCO Annual Meeting. Abstract 6504. Presented June 4, 2012.
2. Lipton JH, Hughes TP, Leber B, et al: Switch to nilotinib versus continued imatinib in patients with chronic myeloid leukemia in chronic phase with detectable BCR-ABL after 2 or more years on imatinib: ENESTcmr 12-month follow-up. 2012 ASCO Annual Meeting. Abstract 6505. Presented June 4, 2012.
3. Cortes JE, Kim D-W, Pinilla-Ibarz J, et al: PACE: A pivotal phase II trial of ponatinib in patients with CML and Ph+ ALL resistant or intolerant to dasatinib or nilotinib, or with the T315I mutation. 2012 ASCO Annual Meeting. Abstract 6503. Presented June 4, 2012.
