Early BCR-ABL1 Transcript Decline after 1 Month of Tyrosine Kinase Inhibitor Therapy as an Indicator for Treatment Response in Chronic Myeloid Leukemia

Abstract

In chronic myeloid leukemia (CML), early treatment prediction is important to identify patients with inferior overall outcomes. We examined the feasibility of using reductions in BCR-ABL1 transcript levels after 1 month of tyrosine kinase inhibitor (TKI) treatment to predict therapy response. Fifty-two first-line TKI-treated CML patients were included (imatinib n = 26, dasatinib n = 21, nilotinib n = 5), and BCR-ABL1 transcript levels were measured at diagnosis (dg) and 1, 3, 6, 12, 18, 24, and 36 months. The fold change of the BCR-ABL1 transcripts at 1 month compared to initial BCR-ABL1 transcript levels was used to indicate early therapy response. In our cohort, 21% of patients had no decrease in BCR-ABL1 transcript levels after 1 month and were classified as poor responders. Surprisingly, these patients had lower BCR-ABL1 transcript levels at dg compared to responders (31% vs. 48%, p = 0.0083). Poor responders also significantly more often had enlarged spleen (55% vs. 15%; p<0.01) and a higher percentage of Ph+ CD34+CD38- cells in the bone marrow (91% vs. 75%, p<0.05). The major molecular response rates were inferior in the poor responders (at 12m 18% vs. 64%, p<0.01; 18m 27% vs. 75%, p<0.01; 24m 55% vs. 87%, p<0.01). In conclusion, early treatment response analysis defines a biologically distinct patient subgroup with inferior long-term outcomes.

Early BCR-ABL1 decline in imatinib-treated patients with chronic myeloid leukemia: results from a multicenter study of the Chinese CML alliance

“…Since prognostic information available even as early as 3 months may be too late for effective intervention in patients who experience early transformation 24 , we evaluated this optimal time point as being 22 days after the start of treatment in our cohort. Patients with a more rapid decline (BCR-ABL1 halving time ≤22 days) had a higher chance of ultimately achieving MMR and therefore a better prognosis.…”

Treatment and monitoring of Philadelphia chromosome-positive leukemia patients: recent advances and remaining challenges

“…This reflects the fact that the actual baseline level of BCR-ABL1 transcripts varies greatly among individual patients, and the presence of similar levels at 3 months can therefore either mirror a substantial decline of BCR-ABL1 transcripts or only a minimal (if any) reduction of the pre-TKI value. Two more recent studies have reported similar observations in patients on first-line treatment with second-generation TKIs: a Japanese study indicated that patients with a halving time of 14 days or less had a higher likelihood to achieve major molecular response (MMR; BCR-ABL1 ≤ 0.1% IS ) and MR 4 (4-log reduction in transcript level on the IS) on dasatinib therapy [45], and a Nordic study from Finland, Sweden, and Norway suggested that a greater than 1-fold decline of BCR-ABL1 transcripts after 1 month of therapy with imatinib, nilotinib, or dasatinib is associated with better responses at 3 months and significantly higher rates of MMR [46]. To assess the early response to TKI treatment by determining the kinetics of BCR-ABL1 transcripts, a minimum of two, but preferentially more consecutive measurements would be required, e.g., at baseline and subsequently at monthly intervals during the first 3 months.…”

Evaluation of Molecular Response to Imatinib Mesylate Treatment in Iranian Patients With Chronic Myeloid Leukemia

“…Several studies have demonstrated that the BCR-ABL1 transcript level at 3 and 6 months after starting imatinib has prognostic significance. [18][19][20][21][22][23][24]30 In a cohort of 1303 patients in the study by Hanfstein et al, 72% of patients had a BCR-ABL IS %10 after 3 months of imatinib treatment. In their study, the 5-year OS in patients with a BCR-ABL IS 10% by the third month was significantly higher than patients with a BCR-ABL IS > 10% (95.2% vs. 87%; P < .0001).…”