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.

Fig 1. A proportion of CML patients do not respond during the first month of TKI therapy.

A) The 1-month BCR-ABL1 transcript value was divided by the BCR-ABL1 transcript value at dg, and poor responders were identified as patients with fold change (FC) >1 (no decrease in the BCR-ABL1 transcript level after 1 month). The patients with an FC lower than 1 were defined as responders. Furthermore, we used the median FC (0.31) of the responders to divide these patients into an intermediate responders group (0.31<FC<1) and good responders group (FC<0.31). B) The initial BCR-ABL1 transcript level at dg was significantly lower for the poor responders than for the responders (p<0.01). Statistical significance was analyzed with an unpaired two-tailed t-test, and median values are noted with lines.

Fig 2. The poor responders have a higher percentage of Ph+CD34+CD38- cells and an enlarged spleen at diagnosis (dg).

The proportion of Ph+ cells in the CD34+CD38- and CD34+CD38+ cell compartments was analyzed by sorting and FISH. A) The poor responders had a higher proportion of Ph+CD34+CD38- cells at dg when compared to the responder group (p<0.05). B) The proportion of Ph+CD34+CD38+ cells at dg. C) Difference in the size of the spleen (measured as the palpable part under the costal margin) between the poor responder and responder groups (p<0.05). D) Proportion of patients with enlarged spleen (pchi square <0.01). E) Hemoglobin levels in poor responders and responders. Statistical significance was analyzed with an unpaired two-tailed t-test, and median values are noted with lines. In panel D, the chi-square test was used.

Fig 3. The Ph+CD34+CD38- cells are eradicated more slowly in poor responders.

A) At 1 month, the BCR-ABL1 transcript level was significantly higher in poor responders (median 40.2%, range 11–98.7) compared to responders (median 13.9%, range 0.9–106.6) (p<0.01) B) At 1 month, the proportion of Ph+CD34+CD38- cells in poor responders (median 56.2%, range 1.1–97) and responders (11.1%, range 0–98.0) C) At 3 months, poor responders had a significantly higher proportion of Ph+CD34+CD38- cells (median 2.8%, range 0–34.9) versus responders (0.2%, range 0–7.8) (p<0.01). D) Poor responders have a significantly higher percentage of Ph+CD34+CD38+ cells at 1 month (median 86.5%, range 34.2–94.8) compared to responders (median 32.0%, range 0.9–98.8) (p<0.01). Statistical significance was analyzed with an unpaired two-tailed t-test, and median values are noted with lines.

Fig 4. Ph+ in CD34+CD38- and CD34+CD38+ fractions decrease more slowly in the poor responders.

The figure presents the proportions of Ph+ cells in CD34+CD38- (A and B) and CD34+CD38+ (C and D) fractions in responders (A and C) and poor responders (B and D) at the time of dg and during follow-up (1, 3, and 6 months). Imatinib-treated patients are presented with dashed lines and dasatinib-treated patients with solid lines. Medians in each group are marked with bold lines.

Fig 5. A third of the poor responders do not achieve a BCR-ABL1 transcript level<10% at 3 months.

Using the 3-month BCR-ABL1 transcript 10% classification, 36% of the poor responders had BCR-ABL1 transcripts>10%, whereas 0% of good responders (FC<0.31) and 24% of the intermediate responders (0.31<FC<1) were categorized into this group (see Fig 1A for classification of patients). Statistical significance was analyzed with a chi-square test.

Fig 6. Poor responders have an inferior outcome at 12 and 18 months.

A-B) The poor responders achieved MMR more seldom at 12 months (p<0.01) and 18 months (p<0.01) compared to responders. C–D) Poor responders had a higher BCR-ABL1 transcript level at 12 months compared to the responders (p<0.05), whereas no difference was observed at 18 months. E) According to the ELN 12-month classification, the poor responders were significantly more often classified as warning and failures than the responders (p<0.05). In panels A, B, and E, statistical significance was analyzed with a chi-square test. In C and D, an unpaired two-tailed t-test was applied, and median values are noted with lines.

Fig 7. Poor responders have significantly worse long-term outcomes.

The patients were divided into three groups based on the 1-month FC (poor responders FC>1, intermediate 0.31<FC<1, good FC<0.3; Fig 1A). A–B) The comparison of the three groups showed differences in the MMR rates at 12 (p<0.05) and 18 months (p<0.05). C–D) The BCR-ABL1 transcript value at 12 and 18 months in the three response groups. In A and B, statistical significance was analyzed with a chi-square test. In C and D, an unpaired two-tailed t-test was applied, and median values are noted with lines.