Interim Analysis of a Pan European Stop Tyrosine Kinase Inhibitor Trial in Chronic Myeloid Leukemia : The EURO-SKI study

Abstract

Background: The tyrosine kinase inhibitors (TKIs) have dramatically changed the natural history of chronic myeloid leukemia (CML) leading to significant improvement in clinical outcome and survival rates. The option of treatment cessation has recently become of utmost importance. Indeed, prospective trials suggest that imatinib therapy may be safely and successfully discontinued in CML pts with deep and sustained molecular responses (Mahon Lancet Oncol 2010, Ross Blood 2013). The major aim of the EURO-SKI study (European Leukemia Net Stop TKI study) was to define prognostic markers to increase the rate of patients in durable deep MR after stopping TKI. Further aims were the evaluation of harmonized methods of molecular monitoring, assessment of quality of life, and calculation of saved treatment costs per country. Methods: Adult CML patients in chronic phase CML on TKI treatment in confirmed deep molecular response (MR4, BCR-ABL <0.01%) for at least one year (>4 log reduction on TKI therapy for >12 months confirmed by three consecutive PCR tests) and under TKI treatment for at least 3 years were eligible. MR4confirmation was performed in a standardized laboratory (n=6). Primary endpoint was the assessment of the duration of MR (defined by continuous MMR) after stopping TKI. Patients (pts) after a prior TKI failure were excluded. According to protocol, an interim analysis was planned after 200 patients with eligible molecular results at month (mo) 6 were available to test the null hypothesis that relapse-free survival at 6 mo is less or equal 40%. Results: From June 2012 to June 2014, 498 CML pts in chronic phase from 10 countries were enrolled and included in the trial. From June 2012 to July 2013, 254 pts from 8 countries were registered; 54 were excluded (consent withdrawal n=1, protocol violation n=1, not eligible n=34, restart of TKI without relapse n=4, atypical or unknown transcript n=6, missing data n=8). Of the eligible 200 pts, 41.5% were female. Median age at diagnosis was 53.3 years (range, 13.8 to 85.5). In assessable pts 8.7% and 18.2 % were high-risk according to EUTOS and Sokal Scores. 103 pts were treated prior to the start TKI therapy, mostly with hydroxyurea or interferon. 1st-line TKI was imatinib in 97%, dasatinib in 1.5%, and nilotinib in 1.5% of pts. Twenty-four pts switched to second-line TKI therapy due to intolerance, 16 to dasatinib, 2 to imatinib, and 6 to nilotinib. The median time from diagnosis of CML to TKI cessation was 8 years (range, 3-19 years). TKI treatment duration was less than 5 years in 16%, 5-8 years in 36% and > 8 years in 48% of pts. Median duration of TKI treatment was 8 years (range, 3-12.6 years) and median duration of MR4 before TKI cessation was 5.4 years (range, 1-11.7 years). MR4duration was less than 2 years in 8%, 2-5 years in 37%, 5-8 years in 39% and >8 years in 16% of pts. For all eligible pts, a standardized European laboratory confirmed MR4 assessment. Since 123 of the 200 pts (61.5%, 95% CI: [54.4%; 68.3%]) remained without relapse the first 6 mo, the null hypothesis could be discarded (p<0.0001). Recurrence of CML, defined as loss of MMR, was observed in 43/92 pts (47%) treated <8 years, as compared to 23/87 pts (26%) treated for >8 years (p= 0.005). So far, there was a trend for prognostic significance of MR4 duration: 33/71 pts with MR4 <5 years (46%) lost MMR within 6 mo as compared to 28/87 pts (32%) with MR4duration >5 years (p=0.07). No significant difference was observed for relapse within 6 mo according to depth of molecular response at discontinuation (MR4 vs MR4.5 vs MR5). TKI cessation was a safe procedure but a substantial proportion of pts reported transitory musculoskeletal pain starting within weeks after imatinib discontinuation. The phenomenon was described in 30% of Swedish patients as a “TKI withdrawal syndrome” (Richter JCO 2014). Taking into account the cost of imatinib in Europe and time without treatment in the total study population at the most recent analysis, total savings for the community within the EURO-SKI trial were estimated at 7 million Euros. Conclusion: Employing a standardized molecular testing for patient selection within a TKI cessation trial in CML the chance to stay in treatment-free remission could be higher than previously reported. The EURO-SKI trial will further elucidate the prognostic factors but the preliminary results confirm (as reported in the STIM Study) the prognostic impact of the duration of TKI therapy before stopping. Disclosures Mahon: NOVARTIS PHARMA: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BRISTOL MYERS SQUIBB: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ARIAD: Honoraria; PFIZER: Honoraria. Porkka:BMS: Honoraria; BMS: Research Funding; Novartis: Honoraria; Novartis: Research Funding; Pfizer: Research Funding. Hjorth-Hansen:Novartis: Honoraria; Bristol-myers Squibb: Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Mayer:Janssen Research & Development: Research Funding; Roche: Research Funding; GlaxoSmithKline: Research Funding; Celgene: Research Funding. Almeida:Celgene: Consultancy; Novartis: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Bristol-Meyer Squibb: Membership on an entity's Board of Directors or advisory committees. Berger:Genzyme/Sanofi and Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mustjoki:Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Hochhaus:ARIAD Pharmaceuticals, Inc.: Research Funding. Saussele:Novartis: Honoraria, Research Funding, Travel Other; Bristol-Myers Squibb: Honoraria, Research Funding, Travel, Travel Other; Pfizer: Honoraria, Travel, Travel Other.

Dasatinib cessation after deep molecular response exceeding 2 years and natural killer cell transition during dasatinib consolidation

“…14 15 and attempts to discontinue nilotinib yielded similar observations. 16,17 Therefore, the second-generation TKI appear to better enable chronic-phase CML patients to achieve therapy discontinuation.…”

Chronic myeloid leukemia: 2016 update on diagnosis, therapy, and monitoring

“…A pan‐European Stop Tyrosine Kinase Inhibitor trial (The EURO‐SKI study) aimed to define factors associated with durable deep molecular response (MR) after stopping TKI. An interim analysis on 200 patients with 6‐month follow‐up of molecular events was reported . Adult CML patients in CML‐CP on TKI treatment in confirmed deep MR (MR4, BCR‐ABL1 transcripts [IS] <0.01%) for at least 1 year (>4 log reduction on TKI therapy for >12 months confirmed by three consecutive PCR tests) and under TKI treatment for at least 3 years were eligible.…”

Recommendations from a Portuguese Expert Group for Discontinuation of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia Patients in Clinical Practice

“…18 Several clinical trials have shown that some Chronic Phase-CML (CP-CML) patients who achieved sustained DMR on TKI therapy can safely interrupt TKIs and attempt TFR. 11,[19][20][21][22][23][24][25][26] Most of these trials included patients treated with imatinib. 11,[19][20][21][22][23]26,27 Other studies involve patients treated with 2 nd generation TKIs nilotinib 6,22,24,[26][27][28][29][30] and dasatinib.…”