Updated Findings Further Define Role of Tyrosine Kinase Inhibitors in CML

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At all levels of response, outcomes were twice as good with nilotinib.

—Jeffrey H. Lipton, MD

With three available tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia (CML), attention has turned from the ability to achieve a sustained response to the possibility of “curing” patients. Updates of pivotal trials presented at ASCO may help define the role of the tyrosine kinase inhibitors in this endeavor.

DAISION 3-Year Data Reported

Three-year follow-up of the phase III DASISION study was presented by Andreas Hochhaus, MD, of the Universitätsklinikum Jena in Germany.1 DASISION compared dasatinib (Sprycel) at 100 mg/d to imatinib (Gleevec/Glivec) at 400 mg/d in 519 newly diagnosed CML patients in chronic phase. Previous analyses established dasatinib as superior, “with faster, deeper responses occurring early, at 3 months,” said Dr. Hochhaus.

Major molecular responses were observed at 1 year in 46% of patients receiving dasatinib and in 23% of those receiving imatinib, while at 3 years this improved to 68% and 55%, respectively. In the updated analysis, the probability of achieving a major molecular response was 64% higher in patients receiving dasatinib (P < .0001), and this was true for all risk groups, he said.

“More important is the deeper response rate—4.0-log and 4.5-log reductions in BCR-ABL,” he said. Molecular response (MR) in this setting is measured in terms of log reduction from baseline as defined in the International Randomised Study of Interferon versus STI571 (IRIS). Thus, “MR4” represents at least a 4.0-log reduction in BCR-ABL from the standardized IRIS trial baseline.2,3

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. “This difference is increasing over time, and we expect wider differences after 4 years.” Overall survival and progression-free survival, however, are not yet different, with approximately 92% of patients in each arm alive.

“The 3-year follow-up of DASISION continues to support dasatinib at 100 mg daily as first-line treatment for newly diagnosed CML chronic-phase patients,” Dr. Hochhaus concluded.

ENESTcmr: It Pays to Switch

Twice as many patients achieved deeper molecular responses after switching to nilotinib (Tasigna), vs staying on imatinib, in the 12-month follow-up of the ENESTcmr study (Evaluating Nilotinib Efficacy and Safety in clinical Trials–complete molecular response), which was reported by Jeffrey H. Lipton, MD, of Princess Margaret Hospital in Toronto.4 “At all levels of response, outcomes were twice as good with nilotinib,” Dr. Lipton said.

The study of 207 patients evaluated whether patients achieving a complete cytogenetic response, but not a molecular response (ie, remained BCR-ABL–positive after 2 years), could achieve a complete cytogenetic molecular response by switching to nilotinib at 400 mg twice daily, as opposed to continuing on imatinib 400–600 mg/d.

Indeed, cytogenetic molecular response was significantly more likely among patients who switched: 23.1% vs 10.7% (P = .02); cytogenetic molecular responses were confirmed in 12.5% vs 5.8% (P = .108). He said the difference in confirmed cytogenetic molecular responses is not statistically significant because patients coming off study due to adverse events were calculated as failures in the intent-to-treat analysis.

“But if you look only at patients achieving an evaluable response, ie, those who are present, there is a significant difference,” he noted. Of evaluable patients still on treatment, 14.9% on nilotinib and 6.1% on imatinib achieved a confirmed cytogenetic molecular response (P = .04) by 12 months.

Patients who switched also demonstrated improvements in MR4 and MR4.5. Patients switching to nilotinib had a median 0.5-log reduction in BCR-ABL from baseline, while no change was observed in patients who continued on imatinib, he added.

“Deeper molecular responses on nilotinib may increase patient eligibility for future tyrosine kinase inhibitor discontinuation studies,” he said, “though it remains to be assessed whether switching results in patients being able to stop treatment.” ■

Disclosure: Dr. Lipton is on the advisory board of Novartis, Bristol-Myers Squibb, Pfizer, and Teva. He also receives research funds from Novartis and Bristol-Myers Squibb, and is a speaker for Novartis and Bristol-Myers Squibb. Dr. Hochhaus reported no potential conflicts of interest.


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. Hughes TP, Kaeda J, Branford S, et al: Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med 349:1423-1432, 2003.

3. Cross NC, White HE, Muller MC, et al: Standardized definitions of molecular response in chronic myeloid leukemia. Leukemia. April 16, 2012 (early release online).

4. 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.