Defining therapy goals for major molecular remission in chronic myeloid leukemia: results of the randomized CML Study IV

Abstract

Major molecular remission (MMR) is an important therapy goal in chronic myeloid leukemia (CML). So far, MMR is not a failure criterion according to ELN management recommendation leading to uncertainties when to change therapy in CML patients not reaching MMR after 12 months. At monthly landmarks, for different molecular remission status Hazard ratios (HR) were estimated for patients registered to CML study IV who were divided in a learning and a validation sample. The minimum HR for MMR was found at 2.5 years with 0.28 (compared to patients without remission). In the validation sample, a significant advantage for progression-free survival (PFS) for patients in MMR could be detected (p-value 0.007). The optimal time to predict PFS in patients with MMR could be validated in an independent sample at 2.5 years. With our model we provide a suggestion when to define lack of MMR as therapy failure and thus treatment change should be considered. The optimal response time for 1% BCR-ABL at about 12-15 months was confirmed and for deep molecular remission no specific time point was detected. Nevertheless, it was demonstrated that the earlier the MMR is achieved the higher is the chance to attain deep molecular response later.

Trial registration: ClinicalTrials.gov NCT00055874.

Conflict of interest statement

The authors declare that they have no conflict of interest. S.S.: Novartis: Honoraria, Research Funding, Travel Other; B.-M.S.: Honoraria, Research Funding, Travel, Travel Other; Pfizer: Honoraria, Travel, Travel Other. R.H.: B.-M.S.: Research Funding; Novartis: Research Funding. S.J.: MLL Munich Leukemia Laboratory: Equity Ownership. A.N.: MedUpdate: Honoraria, Speakers Bureau. M.K.: Novartis: Consultancy, Equity Ownership, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. M.Pfi.: Novartis: Consultancy; B.-M.S.: Honoraria. A.H.: Novartis: Consultancy, Honoraria, Research Funding; B.-M.S.: Consultancy, Honoraria; ARIAD: Honoraria, Research Funding; Pfizer: Consultancy, Research Funding. M.C.M.: Novartis: Honoraria, Research Funding; B.-M.S.: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding.

Figures

Fig. 1

Consort diagram

Fig. 2

Distribution of patients according to remission status achieved at different landmarks from 6 months to 5 years (a) and respective percentages of these states (b)

Fig. 3

Median hazard ratio functions for the comparison of patients who had achieved a MMR resp. MR2 to those who did not have any remission at different landmarks with respect to PFS from 6 months to 5 years together with the 95% confidence intervals. On the y axis, the hazard ratio for PFS is plotted on a logarithmic scale. Note that on the x axis the landmark time is plotted instead of the event time. A hazard ratio of, e.g., 0.5 at landmark 6 months indicates that patients with MMR have only half the risk of patients with no MMR before or at 6 months

Fig. 4

Median hazard ratio function for the comparison of patients who had achieved an MMR to those who did not have any remission at different landmarks with respect to MR4.5 from 6 months to 5 years together with the 95% confidence intervals. On the y axis, the hazard ratio for MR4.5 is plotted on a logarithmic scale. Note that on the x axis the landmark time is plotted instead of the event time