Timing and deepness of response to tyrosine kinase inhibitors as a measure of potential treatment discontinuation in chronic myeloid leukemia patients managed in the real-life
Authors: Massimo Breccia, Gioia Colafigli, Matteo Molica, Emilia Scalzulli, Daniela Diverio, Roberto Latagliata, Anna Guarini, Robin Foà
Journal: American Journal of Hematology (2017)

Discontinuation of treatment and maintenance of response (treatment-free remission or TFR) has become a new endpoint in the management of chronic myeloid leukemia patients in chronic phase (CP-CML) after achievement of a stable and deep molecular response.1 To date, only in one sponsored clinical trial—the ENESTnd study2—the number of patients who may undergo a discontinuation has been estimated. In this study, which compared nilotinib 300 mg BID versus imatinib 400 mg/day, after a long-term follow-up of 6 years, a quantification of patients with sustained deep molecular response (MR4 or BCR-ABL1/ABL ratio <0.01% and MR4.5 or BCR-ABL1/ABL ratio <0.0032%) was reported. It was found that 37.9% of patients who received nilotinib 300 mg BID for more than 3 years had a sustained deep MR lasting for more than 1 year, being therefore potential candidates to TFR, compared to less than 20% of patients treated with imatinib.2 A real-life quantification of patients outside clinical trials who can attempt a treatment discontinuation strategy has never been reported. Aim of this study was to estimate the percentage of CP-CML patients who reached a deep MR and consequently met the criteria for discontinuation when treated frontline with the available tyrosine kinase inhibitors (TKIs) in a real-life setting. We evaluated 397 CP-CML patients treated frontline with imatinib (320 patients, median follow-up 9 years) or with second generation TKIs (24 patients with dasatinib and 53 with nilotinib, median follow-up 3 years) that continued therapy without interruptions, excluding patients lost to follow-up, who died for reasons related or not to CML or in second line. RQ-PCR was performed according to the standard international procedures suggested by the European LeukemiaNet.3 We also evaluated the impact of control gene amplification in the stability of the MR. Monitoring was performed every 3 months according to the ELN recommendations.4 A stable MR was defined as the persistence of the same response in three consecutive RQ-PCR tests performed every 3 months. The rate of patients candidate to treatment discontinuation was evaluate considering patients who maintain a deep MR (MR4.5) for more than 1 year (3–4 consecutive molecular test with the same level of response),5 and according to the STIM criteria (undetectable BCR-ABL1 transcript for at least two years).6 In patients treated with imatinib, the cumulative incidence of MR4.0 and MR4.5 was 51% and 34.6%, respectively, obtained after a median time of 3.8 and 5.4 years. After a median follow-up of 9 years, 133 imatinib-treated patients (41.5%) could attempt a treatment discontinuation, because they had maintained a deep MR for more than 1 year. A fluctuation of deep MR due to amplification of the control gene was observed over time in 49 patients (25.7%). If we considered only patients with undetectable responses at the level of MR4.5, according to the STIM criteria, the rate of patients decreased to 29% at 9 years. In the cohort of dasatinib-treated patients, 11/24 patients (46%) reached MR4.5 after a median time of 23 months: 7 patients maintained the same stable response at the last follow-up (undetectable in 4 patients). Only 2 patients had fluctuations due to control gene amplification during longitudinal monitoring. After a median follow-up of 3 years, 29% of dasatinib-treated patients can be defined candidates for discontinuation (17% considering undetectable responses according to the STIM criteria). In the cohort of nilotinib-treated patients, 26/53 (49%) patients reached MR4.5 after a median time of 25 months. Twenty-four patients maintained the same stable response at the last follow-up, being undetectable in 12. Two patients had an unstable response due to amplification of the control gene. After a median follow-up of 3 years, 45% of nilotinib-treated patients could attempt a treatment discontinuation (23% if we consider only undetectable responses). Comparing the imatinib-treated cohort at the same median follow-up of 3 years reported for both second generation TKIs, we detect that only 13% could be considered as candidate to TFR (Figure 1). Patients eligible for TFR after a median time treatment of 3 years Several trials have demonstrated the safety and feasibility of treatment discontinuation: the STIM1 study reported that 39% of patients in deep MR treated with imatinib maintained a TFR after a median time of 77 months, considering the reoccurrence of molecular disease as relapse.7 These results were confirmed by the TWISTER study,8 whereas the A-STIM, that considered the loss of major molecular response (MR3) as a relapse threshold, showed an improvement of the TFR rate to 61% at 36 months.9 The large analysis performed in the EURO-SKI trial, which involved 750 patients who discontinued treatment in sustained MR4, showed a molecular relapse-free survival of 50% at 36 months and highlighted that a prolonged median treatment of more than 6 years and the duration of deep MR were the independent prognostic factors associated to maintenance of response at 6 months after discontinuation.10 This is the first report that defines in the real-life practice how many CML patients treated with a TKI can be eligible for a treatment discontinuation program. Data from the literature indicate that after 3.5 years from the start of therapy, about 40% of patients treated with second generation TKIs frontline may be eligible to TFR2, 5 compared to 6% after treatment with imatinib.11 Our data, observed outside of clinical trial, are perfectly in line showing that imatinib induced a deep MR over a longer median time as compared to second-generation TKIs that increased the percentage of possible candidate to discontinuation in a median shorter time. Appropriate selection of patients at baseline, considering safety related to different TKI, can improve the rate of discontinuation over time. Fluctuations of the molecular levels due to amplifications of the control gene may influence the estimated rate of patients who could be defined as candidates to treatment discontinuation. Work partly supported by Associazione Italiana per la Ricerca sul Cancro (AIRC) Special Program Molecular Clinical Oncology, 5 × 1000, MCO1007, Milan and by Ministero dell'Università e Ricerca (MIUR), Fondo per gli Investimenti della Ricerca di Base (FIRB), Rome, Italy. MB received honoraria by Novartis, BMS, Pfizer, Incyte. MB designed the study, analyzed data and wrote the manuscript; MM, GC and RL followed patients; DD, AG performed molecular analysis; RF critically reviewed the paper and approved the final version.