Editorial Comment Acta Haematol 2015;134:246–247 DOI: 10.1159/000433413
Received: May 18, 2015 Accepted: May 19, 2015 Published online: July 4, 2015
Chronic Myeloid Leukemia Monitoring after Imatinib Failure: Still More Questions than Answers Rony Schaffel Division of Hematology, Medical School, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
© 2015 S. Karger AG, Basel 0001–5792/15/1344–0246$39.50/0 E-Mail [email protected] www.karger.com/aha
6 months in 54 CML patients that were started on secondline dasatinib or nilotinib due to imatinib resistance (n = 35) or intolerance (n = 17). The patients were divided according to BCR-ABL1 transcripts levels into 3 subgroups (10%) and their rates of survival were compared. The OS, PFS and EFS were inferior in patients who still had BCR-ABL1 levels >10% at 3 months of therapy or >1% at 6 months of therapy. These results raise several points that are worth addressing. The cut-off of 1% is more stringent than that reported in the European LeukemiaNet recommendations for patients on second-line therapy [2]. Currently, only patients with >10% BCR-ABL1 transcripts at 6 months are considered as failures to second-line therapy. However, this cut-off is derived from the experience with the less potent imatinib. In the largest study reported so far, on 321 CML patients treated with nilotinib after imatinib, the patients with BCR-ABL1 transcripts ≤1% at 3 or 6 months had a better OS and PFS [4]. Boquimpani et al. [5] evaluated 115 CML patients on second-line therapy with dasatinib or nilotinib and who were resistant to imatinib. The patients with BCR-ABL1 transcripts >10% at 3 months and ≥1% at 6 months had worse OS and PFS. Interestingly, the patients with BCR-ABL1 transcripts ≥1% at 3 months had inferior FFS and a complete molecular response; these are surrogate markers for PFS. So, are we ready to name as failures the patients who did not achieve the 10% cut-off at 3 months? Should we recommend changing the 6-month cut-off value to 1% Rony Schaffel Division of Hematology, Medical School Federal University of Rio de Janeiro Rio de Janeiro 21941-913 (Brazil) E-Mail rony @ hucff.ufrj.br
Downloaded by: NYU Medical Center Library 198.143.38.1 - 7/12/2015 3:55:21 AM
The introduction of imatinib had a major impact on the prognosis of patients with chronic myeloid leukemia (CML). In the 8-year follow-up analysis of the IRIS study, one of the first CML randomized studies with imatinib therapy, the rate of event-free survival (EFS) was 81%, that of freedom from progression to accelerated phase or blastic crisis (PFS) was 92% and estimated overall survival (OS) was 85% [1]. The management of CML relies upon surrogate prognostic markers of progression, such as BCR-ABL transcript levels in the peripheral blood. Recommendations for the proper management of patients on first-line treatment with imatinib are well established [2]. For instance, a BCR-ABL1 transcript level >10% as early as 6 months into therapy is considered a failure and should lead to a change of therapy, i.e. to nilotinib or dasatinib. The importance of obtaining an early molecular response is further highlighted by the finding that most of the progression to accelerated phase and blastic crisis occurs in the first 2–3 years of therapy with imatinib [1]. There is a great degree of uncertainty as to how to monitor CML patients on second-line therapy after imatinib. In the IRIS study, only 55% of the patients remained on imatinib therapy [1]. Second-line therapy was started due to failure (in 16% of the patients) but also due to intolerance to imatinib (in 45%). These 2 groups of patients are the subject of the study by Ribeiro et al. [3] reported in this issue of Acta Haematologica. They report on the prognostic impact of BCR-ABL1 transcript levels at 3 and
instead of 10%? Unfortunately, we cannot make such recommendations until important issues pertaining only to patients on second-line therapy have been addressed. First, should we manage patients who are failures to imatinib therapy similarly to patients intolerant to this drug? Ribeiro et al. [3] have shown that the latter group seems to have a better response to dasatinib and nilotinib. Second, how does the initial tumor load at the time of switching to second-line therapy relate to the early molecular responses? In other words, should a patient with baseline BCR-ABL1 transcripts of 50% and a 3-month evaluation of 11% be managed in the same way as a patient with a baseline BCR-ABL1 of 11% and a 3-month evaluation of 10%? The halving time may well be applied to this setting [6]. Third, what is the probability that a patient who did not reach the 10% cut-off at 3 months will improve significantly at 6 months? No such cases appear in the study by Ribeiro et al. [3] but they were reported in other series. For instance, Boquimpani et al. [5] found that 4 out of 23 patients who did not reach a BCR-ABL1 transcript level
Received: May 18, 2015 Accepted: May 19, 2015 Published online: July 4, 2015
Chronic Myeloid Leukemia Monitoring after Imatinib Failure: Still More Questions than Answers Rony Schaffel Division of Hematology, Medical School, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
© 2015 S. Karger AG, Basel 0001–5792/15/1344–0246$39.50/0 E-Mail [email protected] www.karger.com/aha
6 months in 54 CML patients that were started on secondline dasatinib or nilotinib due to imatinib resistance (n = 35) or intolerance (n = 17). The patients were divided according to BCR-ABL1 transcripts levels into 3 subgroups (10%) and their rates of survival were compared. The OS, PFS and EFS were inferior in patients who still had BCR-ABL1 levels >10% at 3 months of therapy or >1% at 6 months of therapy. These results raise several points that are worth addressing. The cut-off of 1% is more stringent than that reported in the European LeukemiaNet recommendations for patients on second-line therapy [2]. Currently, only patients with >10% BCR-ABL1 transcripts at 6 months are considered as failures to second-line therapy. However, this cut-off is derived from the experience with the less potent imatinib. In the largest study reported so far, on 321 CML patients treated with nilotinib after imatinib, the patients with BCR-ABL1 transcripts ≤1% at 3 or 6 months had a better OS and PFS [4]. Boquimpani et al. [5] evaluated 115 CML patients on second-line therapy with dasatinib or nilotinib and who were resistant to imatinib. The patients with BCR-ABL1 transcripts >10% at 3 months and ≥1% at 6 months had worse OS and PFS. Interestingly, the patients with BCR-ABL1 transcripts ≥1% at 3 months had inferior FFS and a complete molecular response; these are surrogate markers for PFS. So, are we ready to name as failures the patients who did not achieve the 10% cut-off at 3 months? Should we recommend changing the 6-month cut-off value to 1% Rony Schaffel Division of Hematology, Medical School Federal University of Rio de Janeiro Rio de Janeiro 21941-913 (Brazil) E-Mail rony @ hucff.ufrj.br
Downloaded by: NYU Medical Center Library 198.143.38.1 - 7/12/2015 3:55:21 AM
The introduction of imatinib had a major impact on the prognosis of patients with chronic myeloid leukemia (CML). In the 8-year follow-up analysis of the IRIS study, one of the first CML randomized studies with imatinib therapy, the rate of event-free survival (EFS) was 81%, that of freedom from progression to accelerated phase or blastic crisis (PFS) was 92% and estimated overall survival (OS) was 85% [1]. The management of CML relies upon surrogate prognostic markers of progression, such as BCR-ABL transcript levels in the peripheral blood. Recommendations for the proper management of patients on first-line treatment with imatinib are well established [2]. For instance, a BCR-ABL1 transcript level >10% as early as 6 months into therapy is considered a failure and should lead to a change of therapy, i.e. to nilotinib or dasatinib. The importance of obtaining an early molecular response is further highlighted by the finding that most of the progression to accelerated phase and blastic crisis occurs in the first 2–3 years of therapy with imatinib [1]. There is a great degree of uncertainty as to how to monitor CML patients on second-line therapy after imatinib. In the IRIS study, only 55% of the patients remained on imatinib therapy [1]. Second-line therapy was started due to failure (in 16% of the patients) but also due to intolerance to imatinib (in 45%). These 2 groups of patients are the subject of the study by Ribeiro et al. [3] reported in this issue of Acta Haematologica. They report on the prognostic impact of BCR-ABL1 transcript levels at 3 and
instead of 10%? Unfortunately, we cannot make such recommendations until important issues pertaining only to patients on second-line therapy have been addressed. First, should we manage patients who are failures to imatinib therapy similarly to patients intolerant to this drug? Ribeiro et al. [3] have shown that the latter group seems to have a better response to dasatinib and nilotinib. Second, how does the initial tumor load at the time of switching to second-line therapy relate to the early molecular responses? In other words, should a patient with baseline BCR-ABL1 transcripts of 50% and a 3-month evaluation of 11% be managed in the same way as a patient with a baseline BCR-ABL1 of 11% and a 3-month evaluation of 10%? The halving time may well be applied to this setting [6]. Third, what is the probability that a patient who did not reach the 10% cut-off at 3 months will improve significantly at 6 months? No such cases appear in the study by Ribeiro et al. [3] but they were reported in other series. For instance, Boquimpani et al. [5] found that 4 out of 23 patients who did not reach a BCR-ABL1 transcript level
