Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study

Abstract

Key Points• Approximately 40% of patients with undetectable minimal residual disease on imatinib can stop treatment without loss of molecular response.• Patients in treatment-free remission still have detectable BCR-ABL DNA several years after stopping imatinib.Most patients with chronic myeloid leukemia (CML) treated with imatinib will relapse if treatment is withdrawn. We conducted a prospective clinical trial of imatinib withdrawal in 40 chronic-phase CML patients who had sustained undetectable minimal residual disease (UMRD) by conventional quantitative polymerase chain reaction (PCR) on imatinib for at least 2 years. Patients stopped imatinib and were monitored frequently for molecular relapse. At 24 months, the actuarial estimate of stable treatment-free remission 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. Highly sensitive patient-specific BCR-ABL DNA PCR showed persistence of the original CML clone in all patients with stable UMRD, even several years after imatinib withdrawal. No patients with molecular relapse after discontinuation have progressed or developed BCR-ABL mutations (median follow-up, 42 months). All patients who relapsed remained sensitive to imatinib re-treatment. These results confirm the safety and efficacy of a trial of imatinib withdrawal in stable UMRD with frequent, sensitive molecular monitoring and early rescue of molecular relapse. (Blood. 2013;122(4):515-522)

Age and dPCR can predict relapse in CML patients who discontinued imatinib: The ISAV study

“…The majority of the relapses (58%) occurred in the first 6 months after imatinib interruption. The TWISTER study confirmed that stable treatment free remission at 24 months after imatinib interruption could be achieved in 47.1% of patients [18]. In both studies, all patients but 1 who relapsed, did not progress or develop BCR-ABL1 mutations and all of them remained sensitive to imatinib re-treatment.…”

“…In the ISAV study 48% of patients relapsed, with an overall risk of relapse at 36 months of 52%. The fact that imatinib can be interrupted was already demonstrated in other trials such as the STIM and the TWISTER studies [16][17][18]22,23]. The relapse of approximately 50% of patients after 2 years of FUP is now a consistent figure across several studies, including patients treated with second generation TKIs [24].…”

De-escalation of tyrosine kinase inhibitor dose in patients with chronic myeloid leukaemia with stable major molecular response (DESTINY): an interim analysis of a non-randomised, phase 2 trial

“…Early studies were confined to patients with undetectable BCR-ABL1 transcripts by standard reverse transcriptase polymerase chain reaction (RT-PCR), and defined molecular recurrence as the reappearance of BCR-ABL1 transcript positivity 6,7 . More recent studies have specified recurrence as the loss of major molecular response (MMR, defined as BCR-ABL1/ABL1 transcript ratio of >0.1%, also called MR3 [molecular response of 3 logs below an arbitrary standard baseline]).…”

Molecular monitoring to improve outcomes in patients with chronic myeloid leukemia in chronic phase: Importance of achieving treatment‐free remission

“…The definition of CMR as the complete absence of detectable BCR-ABL1 transcripts is limited by the sensitivity of the assay used for transcript measurement [24,25,27,28]. Thus, ELN recommends use of the term molecularly undetectable leukemia, together with the number of control gene transcripts, over the term CMR [11].…”