Contributions
Abstract: S426
Type: Oral Presentation
Presentation during EHA22: On Saturday, June 24, 2017 from 12:30 - 12:45
Location: Hall D
Background
With imatinib (IM), most patients with chronic myeloid leukemia (CML) achieve deep molecular responses. Six months after stopping tyrosine kinase inhibitor in deep response in the EURO-SKI trial, 61% of the patients were in molecular relapse-free survival (RFS) i.e. alive and in major molecular remission (3-log reduction in BCR-ABL1 levels) (Mahon ASH 2016). Between patients with and without BCR-ABL1, the difference in RFS at 6 months was not significant when assessing BCR-ABL1 detectability at the MR4.5 level (at least a 4.5-log reduction in BCR-ABL1) (Pfirrmann ASH 2016).
Aims
For 91 of 448 patients of the EURO-SKI learning sample, the sensitivity to claim undetectable disease at the MR4.5 level was not given. Aim was to investigate whether RFS probabilities would be different when comparing detectable and undetectable disease at the MR4 level.
Methods
Detectability of BCR-ABL1 depends on the number of control gene transcripts. To reduce bias when comparing “MR4 detectable disease” (MR4 but still detectable BCR-ABL1 transcripts; i.e. 0.01- 0.0033% IS) and “MR4 undetectable disease” (MR4 without detectable BCR-ABL1; based on 10,000-31,999 ABL1 or 24,000-76,999 GUSB copies), two samples with similar sensitivity of identifying BCR-ABL1 were to be identified using propensity score (PS) matching (Rosenbaum, Rubin 1983). Apart from type (ABL1 or GUSB) and number of control gene transcripts, matching variables were interferon alpha pre-treatment, duration of MR4, and the IM treatment time before observation of MR4. Logistic regression was used to compare RFS at 6 months. Significance level was 0.05.
Results
A total of 448 patients had eligible, complete, and sufficient molecular data prior to and within the first 6 months after stopping IM treatment. All molecular results had sensitivity at the MR4 level with yet detectable disease in 196 patients (44%). With small differences in GUSB copy numbers (used in 96 of 448 cases, U test (detectable vs. undetectable): P>0.5), prior to PS matching, median numbers of ABL1 transcripts were higher with MR4 detectable disease (78,975 vs. 68,925 with undetectable disease; P=0.0511, not significant (n .s.)). In 196 patients with detectable disease, RFS at 6 months was 52% (95% confidence interval (CI): 45-59%) and in 252 patients with undetectable disease 63% (CI: 58-69%). Relapse was significantly higher in patients with detectable disease (odds ratio: 1.603 (CI: 1.096-2.343). PS matching resulted in 173 patients per group. Median numbers of ABL1 transcripts changed to 82.142 (detectable) and 75.750 (undetectable disease; n. s.). At 6 months, patients with detectable disease again had 52% (95% confidence interval (CI): 45-59%) RFS probability, and patients with undetectable disease 59% (CI: 52-66%). In the logistic model stratified for the matched pairs, for relapse at 6 months, the odds ratio for MR4 with detectable to undetectable disease was 1.308 (CI: 0.862-1.984, n. s.).
Conclusion
Using the MR4 threshold, after matching on number of control transcripts and other factors, results suggest little or no impact of detectability of BCR-ABL1 on RFS. Time in deep response seems to be more important. In daily routine, many labs produce reliable outcome at the MR4 but not always at the MR4.5 level. Discontinuation at the MR4 level, irrespective of detectability of BCR-ABL1 residual disease, appears safe, with a good chance of success when performed as in EURO-SKI. With PS matching, bias and differences but also power was reduced. To judge whether molecular response on the MR4 level is sufficient, further data is welcome.
Session topic: 8. Chronic myeloid leukemia - Clinical
Keyword(s): prognosis, Molecular relapse, Chronic myeloid leukemia
Abstract: S426
Type: Oral Presentation
Presentation during EHA22: On Saturday, June 24, 2017 from 12:30 - 12:45
Location: Hall D
Background
With imatinib (IM), most patients with chronic myeloid leukemia (CML) achieve deep molecular responses. Six months after stopping tyrosine kinase inhibitor in deep response in the EURO-SKI trial, 61% of the patients were in molecular relapse-free survival (RFS) i.e. alive and in major molecular remission (3-log reduction in BCR-ABL1 levels) (Mahon ASH 2016). Between patients with and without BCR-ABL1, the difference in RFS at 6 months was not significant when assessing BCR-ABL1 detectability at the MR4.5 level (at least a 4.5-log reduction in BCR-ABL1) (Pfirrmann ASH 2016).
Aims
For 91 of 448 patients of the EURO-SKI learning sample, the sensitivity to claim undetectable disease at the MR4.5 level was not given. Aim was to investigate whether RFS probabilities would be different when comparing detectable and undetectable disease at the MR4 level.
Methods
Detectability of BCR-ABL1 depends on the number of control gene transcripts. To reduce bias when comparing “MR4 detectable disease” (MR4 but still detectable BCR-ABL1 transcripts; i.e. 0.01- 0.0033% IS) and “MR4 undetectable disease” (MR4 without detectable BCR-ABL1; based on 10,000-31,999 ABL1 or 24,000-76,999 GUSB copies), two samples with similar sensitivity of identifying BCR-ABL1 were to be identified using propensity score (PS) matching (Rosenbaum, Rubin 1983). Apart from type (ABL1 or GUSB) and number of control gene transcripts, matching variables were interferon alpha pre-treatment, duration of MR4, and the IM treatment time before observation of MR4. Logistic regression was used to compare RFS at 6 months. Significance level was 0.05.
Results
A total of 448 patients had eligible, complete, and sufficient molecular data prior to and within the first 6 months after stopping IM treatment. All molecular results had sensitivity at the MR4 level with yet detectable disease in 196 patients (44%). With small differences in GUSB copy numbers (used in 96 of 448 cases, U test (detectable vs. undetectable): P>0.5), prior to PS matching, median numbers of ABL1 transcripts were higher with MR4 detectable disease (78,975 vs. 68,925 with undetectable disease; P=0.0511, not significant (n .s.)). In 196 patients with detectable disease, RFS at 6 months was 52% (95% confidence interval (CI): 45-59%) and in 252 patients with undetectable disease 63% (CI: 58-69%). Relapse was significantly higher in patients with detectable disease (odds ratio: 1.603 (CI: 1.096-2.343). PS matching resulted in 173 patients per group. Median numbers of ABL1 transcripts changed to 82.142 (detectable) and 75.750 (undetectable disease; n. s.). At 6 months, patients with detectable disease again had 52% (95% confidence interval (CI): 45-59%) RFS probability, and patients with undetectable disease 59% (CI: 52-66%). In the logistic model stratified for the matched pairs, for relapse at 6 months, the odds ratio for MR4 with detectable to undetectable disease was 1.308 (CI: 0.862-1.984, n. s.).
Conclusion
Using the MR4 threshold, after matching on number of control transcripts and other factors, results suggest little or no impact of detectability of BCR-ABL1 on RFS. Time in deep response seems to be more important. In daily routine, many labs produce reliable outcome at the MR4 but not always at the MR4.5 level. Discontinuation at the MR4 level, irrespective of detectability of BCR-ABL1 residual disease, appears safe, with a good chance of success when performed as in EURO-SKI. With PS matching, bias and differences but also power was reduced. To judge whether molecular response on the MR4 level is sufficient, further data is welcome.
Session topic: 8. Chronic myeloid leukemia - Clinical
Keyword(s): prognosis, Molecular relapse, Chronic myeloid leukemia