Two separate phase III randomized, controlled trials showed superiority of dasatinib (Sprycel) and nilotinib (Tasigna), respectively, compared with imatinib, the current standard of care for newly diagnosed, chronic-phase chronic myelogenous leukemia (CML). Even though these studies were positive, experts were hesitant to weigh in about which drug would be preferable as first-line therapy if both new drugs are approved by the FDA in this setting as expected. (See page 45 for news of nilotinib's recent FDA approval.)

Both second-generation tyrosine kinase inhibitors (TKI)-dasatinib and nilotinib-almost doubled the 12-month molecular response rates compared with imatinib, and presenters of both studies hailed dasatinib and nilotinib, respectively, as new standards of care for front-line therapy of CML.  The studies were published online in The New England Journal of Medicine to coincide with the presentations at the 2010 ASCO Annual Meeting.

Dasatinib vs Imatinib

The Dasatinib versus Imatinib Study in Treatment-Naïve CML Patients (DASISION) trial, funded by Bristol-Myers Squibb, randomized 519 newly diagnosed patients with chronic-phase CML to open-label treatment with dasatinib at 100 mg/d or imatinib at 400 mg/d.^1,2 Planned follow-up is 5 years. Patients were recruited from 108 centers in 26 countries.

Treatment arms were well balanced for demographic and disease characteristics. Median age was about 47 years, median time from diagnosis was 1 year, and 19% of patients enrolled in the trial were deemed high risk. Median treatment duration in the trial was 14 months. The dose was escalated for suboptimal response in 5% of the dasatinib group compared with 14% of the imatinib group.

The primary endpoint of confirmed complete cytogenetic response (CCyR) by 12 months was achieved in 77% of the dasatinib group vs 66% of the imatinib group (P = .0067). The CCyR rate by 12 months on at least one assessment was 83% vs 72%, respectively (P = .0011). Major molecular response (MMR) rate was 46% vs 28%, respectively (P < .0001).

"Dasatinib was superior to imatinib at all time points over the first year, with about a 50% higher response," said lead investigator Hagop Kantarjian, MD, Chairman of the Department of Leukemia at The University of Texas M. D. Anderson Cancer Center in Houston.

Progression to accelerated/blastic phase occurred in 1.9% of the dasatinib group vs 3.5% of those treated with imatinib. Dr. Kantarjian pointed out that no patient who achieved MMR experienced disease progression, but progression was seen in two patients with a CCyR.

Treatment was discontinued in 15.5% of the dasatinib group vs 18.6% of the imatinib group. Reasons for discontinuation included progression, toxicity, and other unrelated events.

Hematologic toxicity was similar between the two arms, with the exception of more grade 3 or 4 thrombocytopenia with dasatinib: 19% vs 10%, respectively. Regarding nonhematologic adverse events that occurred in 10% or more of patients, more nausea, vomiting, and rash were seen with imatinib, whereas mild to moderate pleural effusions were more common with dasatinib (10% vs 0%). However, 24 of 26 patients with pleural effusions achieved CCyR by 12 months, and only 3 patients discontinued dasatinib because of pleural effusions.

Nilotinib vs Imatinib

Eighteen-month and continuous follow-up of the Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients (ENESTnd) trial, funded by Novartis, found that nilotinib was superior to imatinib in newly diagnosed chronic-phase CML. 3,4 The study enrolled 846 patients in a 1:1:1 ratio to nilotinib at 300 mg twice daily, nilotinib at 400 mg twice daily, and imatinib at 400 mg daily. Planned follow-up is 5 years.

"With longer follow-up, the rates of MMR and CCyR are superior with nilotinib, and continue to deepen over time. Fewer progressions and deaths were seen with nilotinib. Both doses of nilotinib were well tolerated. These data support nilotinib as a new standard of care in CML," said lead author Richard A. Larson, MD, Professor of Medicine and Director of the Hematologic Malignancies Program at the University of Chicago Medical Center.

ENESTnd's primary endpoint was MMR at 12 months, analyzed by intention to treat. Both doses of nilotinib were significantly better than imatinib: 44% for the lower dose of nilotinib, 43% for the 400-mg dose, and 22% for imatinib (P < .001 for both comparisons with imatinib).

For the 145 patients who have already had polymerase chain reaction (PCR) assessment at 24 months, MMR at 24 months was 86% and 88%, vs 48%, respectively.

More nausea, muscle spasms, diarrhea, and vomiting were seen with imatinib, whereas rash, headache, pruritus, and alopecia were more common with nilotinib. Grade 3 and 4 adverse events were rare on all three arms.

When asked which drug a clinician should choose for first-line therapy, Dr. Larson appeared to be on the fence. "Now we have three excellent choices for newly diagnosed CML," he said. ■

References

1. Kantarjian H, Shah NP, Hochhaus A, et al: Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. June 5, 2010 (epub ahead of print).

2. Kantarjian H, Shah NP, Hochhaus A, et al: Dasatinib compared to imatinib (IM) in patients (pts) with newly diagnosed chronic-phase chronic myelogenous leukemia in chronic phase (CML-CP): Twelve-month efficacy and safety from the phase III DASISION study. 2010 ASCO Annual Meeting. Abstract LBA6500. Presented June 7, 2010.

3. Saglio G, Kim D-W, Issaragrisil S, et al: Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. June 5, 2010 (epub ahead of print).

4. Larson RA, le Coutre PD, Reiffers J, et al: Comparison of nilotinib and imatinib in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): ENESTnd beyond one year. 2010 ASCO Annual Meeting. Abstract 6501. Presented June 7, 2010.