Treatment-free remission after two-year consolidation therapy with nilotinib in patients with chronic myeloid leukemia: STAT2 trial in Japan

Abstract

The purpose of this trial was to evaluate the efficacy of 2-year consolidation therapy with nilotinib, at a dose of 300 mg twice daily, for achieving treatment-free remission in chronic myeloid leukemia patients with a deep molecular response (BCR-ABL1IS ≤0.0032%). Successful treatment-free remission was defined as no confirmed loss of deep molecular response. We recruited 96 Japanese patients, of whom 78 sustained a deep molecular response during the consolidation phase and were therefore eligible to discontinue nilotinib in the treatment-free remission phase; of these, 53 patients (67.9%; 95% confidence interval: 56.4–78.1%) remained free from molecular recurrence in the first 12 months. The estimated 3-year treatment-free survival was 62.8%. Nilotinib was readministered to all patients (n=29) who experienced a molecular recurrence during the treatment-free remission phase. After restarting treatment, rapid deep molecular response returned in 25 patients (86.2%), with 50% of patients achieving a deep molecular response within 3.5 months. Tyrosine kinase inhibitor withdrawal syndrome was reported in 11/78 patients during the early treatment-free remission phase. The treatment-free survival curve was significantly better in patients with undetectable molecular residual disease than in patients without (3-year treatment-free survival, 75.6 versus 48.6%, respectively; P=0.0126 by the log-rank test). There were no significant differences in treatment-free survival between subgroups based on tyrosine kinase inhibitor treatment before the nilotinib consolidation phase, tyrosine kinase inhibitor-withdrawal syndrome, or absolute number of natural killer cells. The results of this study indicate that it is safe and feasible to stop tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia who have achieved a sustained deep molecular response with 2 years of treatment with nilotinib. This study was registered with UMIN-CTR (UMIN000005904).

Digital PCR improves the quantitation of DMR and the selection of CML candidates to TKIs discontinuation

“…In our cohort of patients, the TFR rate was higher than the one currently reported in the IM and second‐generation TKI discontinuation studies but, as expected, the loss of MR occurred in 24/111 (22%) cases early after TKIs discontinuation (3 months). This highly positive selection could be explained, as above reported, by the prolonged treatment and the DMR duration . Furthermore, the major part of the patients (75%) who underwent TKIs discontinuation was characterized by the presence of the transcript b3a2.…”

“…This highly positive selection could be explained, as above reported, by the prolonged treatment and the DMR duration. 30,31 Furthermore, the major part of the patients (75%) who underwent TKIs discontinuation was characterized by the presence of the transcript b3a2. This transcript has been recently associated with a better response to the TKIs treatment, resulting in higher sustained DMR rate, 39 and a longer TFR.…”

Managing chronic myeloid leukemia for treatment-free remission: a proposal from the GIMEMA CML WP

“…In the case of nonoptimal response, the change from a TKI to another TKI is optional, if it is believed that it may help to achieve a deeper molecular response and to bring the patient to TFR. There are some data, 20,26,32,43 and there is some experience, of switching from imatinib to a 2GTKI, not from a 2GTKI to another TKI. All studies suggest that such a switch may increase the rate of deep molecular response (DMR), hence the number of patients eligible for treatment discontinuation and TFR, but, regrettably, all of these studies are single-arm and do not allow for calculation of the benefit of a switching policy against the risk of increased toxicity.…”

“…Many studies, some retrospective and some prospective, have shown beyond any doubt that a consistent proportion, ranging between 30% and 70%, of the patients who discontinue treatment after having achieved a DMR (MR 4.0, BCR-ABL1 #0.01% IS , or MR 4.5, BCR-ABL1 #0.0032% IS ) may remain treatment-free for an as-yet undefined period of time. [36][37][38][39][40][41][42][43][44][45][46][47][48] It is important to underline that the patients with molecular relapse after discontinuation do not progress, and are almost all able to achieve DMR again upon retreatment, and that some of them can become eligible for a second attempt of treatment discontinuation. The probability of achieving TFR may depend on several factors: leukemia or patient characteristics, TKI type, treatment duration, DMR duration, etc.…”

“…It is uncertain whether treating for TFR may be allowed in all centers and to every doctors, or if it is still investigational and should be limited to referral centers, but the possibility of achieving TFR can no longer be denied to any patient. The results of several phase 2 single-arm TFR studies, [36][37][38][39][40][41][42][43][44] individual experience, patient will, as well as commercial pressure, may bias the choice of treatment. 13,24,26,[45][46][47][48] For these reasons, the CML Working Party (WP) of Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA; Italian Group for Hematologic Diseases of the Adult) has developed a project that has involved the representatives of 50 hematologic centers, with the purpose of suggesting a treatment policy aiming to the achievement of TFR.…”