Stopping Imatinib: When is Enough Enough?

Abstract & Commentary

Synopsis:Imatinib therapy was discontinued in 40 patients who had sustained undetectable BCR-ABL transcripts for 2 or more years, and close follow-up revealed approximately 50% remained with undetectable disease off treatment at 24 months. For those who developed evidence for recurrence, imatinib reinduced deep molecular responses. However, using a highly sensitive research assay, patients in treatment-free remission still have detectable BCR-ABL DNA. Thus, continued vigilance to diagnose and treat early relapse remains clinically relevant, even for those off therapy for several years.

Source:Ross DM, et al. Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: Results from the TWISTER study. Blood 2013;122:515-522.

Imatinib treatment for chronic myelogenous leukemia (CML) commonly induces a major molecular response (MMR) with very low levels of BCR-ABL transcripts (minimal residual disease, MRD) detected by sensitive RT/PCR assays. In approximately 40% who receive the drug for 5 or more years, the BCR-ABL transcript is undetectable (UMRD).1,2 Yet, prior studies have shown that stopping imatinib in patients with UMRD is typically followed by the reappearance of detectable BCR-ABL.3,4 It has been speculated that for those with UMRD evident for several years, stopping may be possible without subsequent molecular relapse.5 In fact, in the French Stop Imatinib (STIM) study, 100 imatinib-treated CML patients with sustained (> 2 years) undetectable disease were taken off drug. After a 12-month follow-up, approximately 40% of patients remained with undetectable BCR-ABL transcripts, raising the hopeful expectation that for certain individuals the disease might indeed be cured by imatinib.5

In the current study, Ross and colleagues report findings from the Australasian Leukemia & Lymphoma Group TWISTER study. They conducted a prospective clinical trial of imatinib withdrawal in 40 chronic-phase CML patients on imatinib for a minimum of 3 years who had sustained undetectable minimal residual disease (UMRD) by conventional quantitative polymerase chain reaction (PCR) for at least 2 years. Patients stopped imatinib and were monitored regularly for molecular relapse. After 24 months, the actuarial estimate of stable treatment-free remission (TFR) was 47.1%. Most relapses occurred within 4 months of stopping imatinib, and no relapses beyond 27 months were seen. In the 21 patients treated with interferon before imatinib, a shorter duration of interferon treatment before imatinib was significantly associated with relapse risk, as was slower achievement of UMRD after switching to imatinib. Using a highly sensitive, patient-specific BCR-ABL DNA PCR assay, as previously reported from this group,6 showed persistence of the original CML clone in all patients with stable UMRD, even several years after imatinib withdrawal. For those who did relapse, recommencement of imatinib therapy was generally effective in producing deep molecular responses. Further, none of the patients had developed BCR-ABL mutations (median follow-up, 42 months).

COMMENTARY

This is an important contribution because in a prospective study it confirms the conclusions from the STIM trial that imatinib therapy may be discontinued safely in those with stable UMRD, with the provision that subsequent management would include frequent and sensitive molecular monitoring and early rescue if molecular relapse occurs. Important features include the reassurance that all patients who experienced molecular relapse remained sensitive to imatinib therapy. Another important finding was the demonstration that peripheral blood was equally effective to bone marrow sampling in predicting or identifying early relapse. However, the demonstration of patient-specific, very low levels of BCR-ABL DNA transcripts (using a research methodology not available outside the research setting) in all patients with traditional laboratory-diagnosed UMRD was somewhat disconcerting. This would imply the persistence of the leukemia clone, even without evidence for active proliferation based on the traditional RT/PCR methodology and raises a specter of caution concerning late relapse, even in patients off therapy for several years.

Beyond imatinib, second- and third-generation tyrosine kinase inhibitors are now currently available and are used by many as first-line treatment based on their superiority in inducing more rapid and deeper molecular responses.7,8 Sustained response to these agents are likely to produce at least comparable results to those demonstrated in the STIM and TWISTER studies, raising once again that hopeful expectation that the leukemia clone may be eradicated completely. However, patients and clinicians await the results from similarly conducted clinical trials examining the potential for these newer agents to produce sustained undetectable disease years after the discontinuation of therapy.

References

1.Branford S, et al. BCR-ABL messenger RNA levels continue to decline in patients with chronic phase chronic myeloid leukemia treated with imatinib for more than 5 years and approximately half of all first-line treated patients have stable undetectable BCR-ABL using strict sensitivity criteria. Clin Cancer Res 2007;13:7080-7085.

2.Hughes T, et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: Review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood 2006;108:28-37.

3.Rousselot P, et al. Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years. Blood 2007;109:58-60.

4.Yhim HY, et al. Imatinib mesylate discontinuation in patients with chronic myeloid leukemia who have received front-line imatinib mesylate therapy and achieved complete molecular response. Leuk Res 2012;36:689-693.

5.Mahon FX, et al. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol 2010;11:1029-1035.

6.Ross DM, et al. Patients with chronic myeloid leukemia who maintain a complete molecular response after stopping imatinib treatment have evidence of persistent leukemia by DNA PCR. Leukemia 2010;24:1719-1724.

7.Kantarjian HM, et al. Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood 2012;119:1123-1129.

8.Larson RA, et al. Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up. Leukemia 2012;26:2197-2203.