Abstract
The use of tyrosine kinase inhibitors (TKIs) in CML CP has extended survival to a near-normal life expectancy. The concept of ‘optimal biologic dose’, defined hypothetically as the lowest dose that maintains similar efficacy, good compliance, with reduced toxicity, led to studies of upfront 50 mg OD dasatinib to ascertain the efficacy of the lower dose of dasatinib in CML CP. After a thorough review of literature, our study was planned to compare the use of three agents in patients with newly diagnosed CML CP - imatinib 400 mg OD, dasatinib 100 mg OD, and dasatinib 50 mg OD.
We carried out a randomized open-label study in three arms- patients with newly diagnosed CML CP were randomly assigned to receive either of the above three drugs at diagnosis. The guiding principles for experimental procedures found in the Declaration of Helsinki of the World Medical Association were followed in both spirit and letter. The trial was registered at the Clinical Trials Registry of India, with the registration number - CTRI/2023/05/053188. The primary objective was to compare the number of patients achieving early molecular response (EMR) after three months of therapy among the three arms. The study also had these secondary objectives: assessing the velocity of initial response to TKI therapy among the three arms, the cost-effectiveness of dasatinib 50 mg OD, as compared to the other two agents, and the rates of major molecular response (MMR) at 12 months in three arms.
The patients in the three arms were similar at the baseline. A total of 205 evaluable patients were assessed for the primary objective, 154 had attained EMR at the end of three months of therapy. The percentages of patients among the three groups (group-1: dasatinib 50 mg OD, group-2: dasatinib 100 mg OD, group-3: imatinib 400 mg OD) who had achieved the primary objective were 88.06%, 78.26%, and 59.42% respectively. Evaluation of this data as a categorical variable yielded a statistically significant difference among the three groups.
The analysis of BCR::ABL1 kinetics by the means of halving time (HT) did not reveal any statistically significant difference among the three arms. The comparison of the mean reduction ratio (RR) of BCR::ABL1IS for the three groups, analyzed by ANOVA, showed a statistically significant difference between the three groups. It was difficult to place a fiscal value on the clinical benefit due to lack of standardized definitions and parameters for our outcome of interest – cost-effectiveness - in CML. Therefore, a direct cost analysis was performed for dasatinib 50 mg OD by analyzing direct out-of-pocket cost, an important metric in our setting of low and middle income country (LMIC). For evaluating the rates of MMR at 12 months of therapy, the evaluable data were analyzed. The differences between groups-1 and 2 were statistically not significant, while those between group -1 and group-3, and between group-2 and group-3 were found to be statistically significant.
The majority of the treatment-related adverse effects were hematological, the rates of anemia were the highest. Bleeding manifestations were highest among the patients treated with dasatinib 100 mg OD. Pleural effusion was seen in eight patients treated with dasatinib 100 mg OD- three of whom required treatment discontinuation, as compared to two patients in the low-dose dasatinib group and none in the imatinib group. The findings were not statistically significant.
In our study, better EMR responses at three months of therapy were seen with dasatinib 50 mg OD as compared to the other two arms. Dasatinib 50 mg OD also had better safety profile with lower treatment interruptions and discontinuations and is cheaper. Kinetics analyzed in our study favored the use of upfront dasatinib 50 mg OD. We also found that both dasatinib 50 mg OD and 100 mg OD were able to induce significantly more MMR at 12 months of therapy than imatinib 400 mg OD. However, our study was not powered to detect these effects.
In view of our findings, we suggest that the lower dose of dasatinib is a promising alternative to standard dose of dasatinib as upfront therapy in patients with newly diagnosed CML CP. We also suggest that a larger study with longer follow-up be planned, with standardized drugs and industry assistance, to answer this question. Double blinded RCTs with longer follow-up should be done to assess BCR::ABL1 kinetics and their relationship to defined molecular responses.
