Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 52nd Annual Meeting and Exposition of the American Society of Hematology

Orlando, Florida / December 4-7, 2010

As long predicted, the maturing data with second-generation tyrosine kinase inhibitors (TKIs) in first-line therapy of Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) are validating a change in the standard of care. A phase III trial, conducted with nilotinib, has now reached 24 months of minimum follow-up and the data continue to demonstrate greater, faster and more profound responses. Although the types of adverse events differ markedly between TKIs, the newer-generation agents have been at least as well tolerated.

ENESTnd: Data After 24 Months

The 24-month follow-up from ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials—Newly Diagnosed Patients) demonstrates why second-generation agents are now emerging as first-line treatment.

“At 24 months, the conclusions that we can draw are that nilotinib is superior to imatinib for major molecular response (MMR), complete cytogenetic response (CCyR) and complete molecular response (CMR). On nilotinib relative to imatinib, there was a lower rate of failure, a significant improvement in progression-free survival (PFS) and fewer adverse events. These data support the superiority of nilotinib as the first-line treatment,” reported Prof. Timothy P. Hughes, Royal Adelaide Hospital, Australia.

Perhaps one of the most telling observations from the most recent follow-up from ENESTnd was generated by an evaluation of MMR kinetics. Previous studies have shown that there is a positive correlation between the speed at which MMR is reached and favourable outcomes such as PFS. The MMR response on nilotinib at 6 months was comparable to the MMR response to imatinib at 18 months.

All of the 24-month results from ENESTnd expand on and reinforce the 12-month data published earlier this year (N Engl J Med 2010;362:2251-9). In ENESTnd, 846 patients with chronic-phase Ph+ CML were randomized to 1 of 2 doses of nilotinib (300 mg b.i.d. or 400 mg b.i.d.) or imatinib 400 mg. The primary end point of MMR at 12 months was achieved in almost twice as many patients taking either dose of nilotinib vs. imatinib (44% and 43% for nilotinib vs. 22% for imatinib; P<0.001). The 12-month CCyR responses of 80% on nilotinib 300 mg and 78% on 400 mg were both significantly greater than the 65% on imatinib (P<0.001 for both comparisons).

At 24 months, MMR rates had climbed to 62% and 59% on the 300-mg and 400-mg doses, respectively, and to 37% on imatinib (P<0.001 for both doses of nilotinib relative to imatinib). Similarly, CCyR rates by 24 months had risen to 87% and 88% for the nilotinib doses, respectively, and to 77% on imatinib (P<0.05 for both doses vs. imatinib). On an intention-to-treat analysis, the progression to acute-phase/blast crisis (AP/BC) was 0.7% on 300 mg nilotinib (P=0.0059 vs. imatinib), 1.1% on 400 mg nilotinib (P=0.0196 vs. imatinib) and 4.2% on imatinib. On progression to AP/BC with clonal evolution, the rates were 0.7% (P=0.0003 vs. imatinib), 1.8% (P=0.0089 vs. imatinib) and 6%, respectively.

At 24 months, rates of grade 3 and 4 neutropenia, like those at 12 months, remained higher on imatinib (21% vs. 12% and 11% for 300 mg and 400 mg nilotinib, respectively) but rates of grade 3 and 4 thrombocytopenia and anemia were similar. Grade 3 and 4 gastrointestinal toxicities remained more common on imatinib, but hyperbilirubinemia (4% and 8% vs. <1%) and lipase elevations (7% and 8% vs. 3%) were higher on nilotinib. Grade 3 and 4 ALT elevations were similar on 300 mg nilotinib and imatinib (4% vs. 3%) but higher on 400 mg nilotinib (9%).

DASISION and Other Results

The other second-generation TKI, dasatinib, also reinforced a clinical advantage over imatinib in an 18-month update of previously published data. That phase III trial, called DASISION (Dasatinib versus Imatinib Study in Treatment-Naive CML Patients), was published simultaneously with ENESTnd (N Engl J Med 2010;362:2260-70). In DASISION, dasatinib 100 mg q.d. was compared to imatinib 400 mg q.d. in 519 treatment-naive CML patients. According to Dr. Neil Shah, University of California, San Francisco, who presented DASISION updated results, the advantage of dasatinib has persisted.

“Based on time-to-response analysis, patients on dasatinib were 1.84-fold more likely to achieve a MMR than those on imatinib (HR 1.84; P<0.0001). Rates of CCyR in dasatinib-treated patients with low, intermediate and high risk were 92%, 71% and 73%, respectively. The corresponding rates in the imatinib arm were 72%, 71% and 64%,” Dr. Shah told delegates. However, he reported that the progression to AP/BC at 12 months, which was 2.3% on dasatinib and 3.5% on imatinib, was not statistically different.

Side effects at 18 months were generally lower but different on dasatinib relative to imatinib. For example, while the rates of fluid retention (23% vs. 43%) and superficial edema (10% vs. 36%) were lower on dasatinib, the rate of pleural effusion was higher (12% vs. 0%). Rates of nausea (9% vs. 21%), vomiting (5% vs. 10%), muscle inflammation (4% vs. 19%) and myalgia (6% vs. 12%) were all lower on dasatinib, but the differences in the rates of musculoskeletal pain (12% vs. 16%), diarrhea (18% vs. 19%) and fatigue (8% vs. 11%) were relatively modest.

While Dr. Shah, like Dr. Hughes, also concluded that the long-term follow-up is solidifying the conclusion that second-generation TKIs should be employed as first-line therapy, even longer-term data provided even greater support for this contention. In data from a phase II trial with 3-year follow-up on 73 treatment-naive CML patients initiated on nilotinib, only 1 patient has progressed to AP/BC and no patient who achieved MMR has progressed. The rates of PFS and overall survival are both 97%, while the event-free survival is 91%. The 4 discontinuations were due to lipase or amylase elevations, but there has been no pancreatitis and there have been no discontinuations for other side effects. At 3 years, the daily dose of nilotinib is 800 mg in 71% of the patients, 400 mg in 28% of patients and 200 mg in 1 patient.

“The very high rates of response that we observed in this study and that were also observed in the ENESTnd study at 12 months are translating into the types of outcomes predicted by the greater degree of earlier control that we see with this agent relative to imatinib,” reported Dr. Gianantonio Rosti, Department of Hematology and Oncology, University of Bologna, Italy. Presenting these phase II data, he remarked, “We remain impressed with how stable the responses have been.”

The reason for the greater control provided by second-generation TKIs is that they provide a far more potent suppression of BCR-ABL, an advantage first demonstrated in vitro and now shown to be clinically significant. Here at ASH, one small study graphically demonstrated this advantage by evaluating BCR-ABL kinetics after switching patients with a suboptimal molecular response on imatinib to nilotinib.

“Overall, the 14 patients in this study achieved a median 3.11 log reduction in BCR-ABL transcription levels by 3 months after the switch to nilotinib,” reported Dr. Carole Miller, St. Agnes Hospital, Baltimore, Maryland, who noted that there were further incremental reductions in transcription levels at 6 and 12 months. Perhaps most importantly, 86% of the patients treated for at least 12 months, despite a suboptimal response on imatinib, reached MMR after switching to nilotinib.

Summary

The data on second-generation TKIs in the first-line treatment of CML have matured, providing validation of the results produced after 12 months. These agents, previously known to be more effective against the molecular target on an experimental basis, produced faster, higher and deeper responses in the clinical setting, and these are translating into better long-term disease control. The longest follow-up is with nilotinib, which has provided effective and sustained control of CML for periods of up to 3 years in treatment-naive patients with an acceptable safety profile. The data appear to be setting the stage for a new standard of care in chronic-phase CML.

Note: At time of printing, neither nilotinib nor dasatinib is approved as first-line therapy in Canada.