ALBERT

Description: Background Treatment-free remission (TFR) in patients with chronic myeloid leukemia (CML), who achieve a sustained and deep molecular response (DMR, MR4 or MR4.5) after treatment with BCR-ABL1 tyrosine kinase inhibitors (TKIs), is possible after TKI discontinuation (Rea and Cayuela. 2018). Nilotinib has been shown to elicit deeper and faster molecular responses compared to imatinib. More than 50% of patients who responded to imatinib, but did not achieve a DMR, achieved a DMR 1 year after they switched to nilotinib (Hughes et al. 2017). On attempting TFR, about 50% of patients lose response early and relapse (Mahon et al. 2019). The reason for this loss of response after achieving sustained DMR in patients has been attributed to residual and quiescent LSCs (Houshmand, et al. 2019). LSC for CML arises from the transformation of a hematopoietic stem cell through a t(9;22) translocation, leading to the Philadelphia chromosome [Ph1], and is characterized by the presence of the unregulated tyrosine kinase activity of the chimeric BCR-ABL1 protein together with specific surface antigens including CD26 and/or other aberrant markers (Bocchia, et al. 2018). The ENESTPath study is designed to evaluate the impact of duration of 24 or 36 months (mos) of consolidation treatment with nilotinib after switching from imatinib, on the rate of TFR. The LSC sub-study was designed to evaluate the correlation between duration of nilotinib therapy and LSCs. This interim analysis of the LSC sub-study presents preliminary data on characteristics of LSC-positive patients and their response after 24 mos of nilotinib therapy. Objectives To assess factors impacting LSCs and the effect of nilotinib therapy in patients with CML who switched from imatinib to nilotinib. Methods Patients from the ENESTPath study who switched from imatinib received 24 mos of nilotinib therapy (12 mos of induction and consolidation therapy, each). Patients who achieved stable MR4 (4/5 preceding quarterly real-time quantitative polymerase chain reaction [RT-PCR] assessments were ≥MR4 and last assessment was ≥MR4) at the end of the consolidation phase were randomized 1:1 to receive either an additional 1 year of nilotinib treatment or to start TFR, while those without stable MR4 were not randomized (NR), and followed-up until end of the study (5 years after baseline visit). For the current analysis, bone marrow samples collected at screening and at 24 mos were evaluated for the presence of Ph+ on fluorescence-activated cell sorting-purified CD34+CD38-/+ cells by fluorescence in situ hybridization and/or RT-PCR techniques. Results Of the 60 patients enrolled in the sub-study, 34 were randomized, 25 were NR, and 1 had protocol deviation (not included in the analysis). Overall, the mean age of the patients was 49.4 years. All patients had been previously treated with imatinib for a median duration of 59.7 mos. When analyzed for LSCs by RT-PCR or histone (HIS) at baseline, 10 patients were found to be positive, 23 were negative, 25 patients had data missing, and 1 was not evaluable. Sokal score categories and duration of prior imatinib therapy for LSC-positive and negative patients at baseline are presented in Table 1. More patients with low Sokal risk and longer duration of prior imatinib therapy (≥ 5 years) were negative for LSCs at baseline (Table 1). After treatment with nilotinib, the number of patients with Ph+ among CD34+CD38-, CD34+CD38+, and CD34+CD38-/+ LSCs was lower at 24 mos compared to baseline, except for aberrant CD34+ cells in the NR group (Figure 1). A decrease in the percentage of CD34+/CD38+ and immunophenotypically aberrant CD34+/- cells was observed for most of the patients analyzed at baseline and at 24 mos by HIS or RT-PCR. Overall, 11 and 10 patients in the randomized and NR groups, respectively, had ≥1 dose reduction/interruptions; adverse events led to dose reduction/interruptions in 9 patients each, in both arms. Conclusion This analysis indicates that treatment of CML patients with nilotinib after switching from imatinib may play a role in the reduction of LSCs over time. As the number of patients with available Sokal score at baseline and prior imatinib exposure was low, meaningful conclusions cannot be drawn, and further investigations are needed. Results of patients attempting TFR are awaited, and it would be interesting to analyze the correlation between the LSC count and rate of TFR in the final analysis of the sub-study. Disclosures Sanchez-Guijo: BMS: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Amgen: Honoraria; Roche: Honoraria. Plata:Novartis: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Crugnola:Novartis: Honoraria; Incyte: Honoraria. Caocci:Novartis: Honoraria; Celgene: Honoraria. Oakervee:Novartis: Honoraria; Bristol Myers-Squibb: Honoraria; Pfizer: Honoraria. Jedrzejczak:Amgen: Consultancy; Takeda: Consultancy; Novartis: Research Funding; Amgen: Other: Travel support for hematology meetings (ASH, EBMT, EHA) ; Celgene: Other: Travel support for hematology meetings (ASH, EBMT, EHA); Roche: Other: Travel support for hematology meetings (ASH, EBMT, EHA). Kiani:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Supekar:Novartis: Employment. Ferreira:Novartis: Employment. Shah:Novartis: Other: Service Provider. Steegmann:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Baccarani:Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Takeda: Consultancy.

Description: Background Tyrosine kinase inhibitors (TKIs) are the standard of care for patients (pts) with CML-CP. The current recommendation is to continue TKI therapy indefinitely.1 Results of several clinical trials indicate that pts achieving sustainable deep molecular response (DMR; defined as molecular response ≥ MR4) on imatinib (IM) may achieve long-lasting TFR. Nilotinib (NIL) at 300 mg bid induces higher rates of DMRs compared to IM.2 Also, DMRs can be achieved in pts with NIL (400 mg bid) who are switched after long-term IM.3 However, the optimal duration of consolidation treatment with NIL to increase the chances for successful and continuous TFR (≥ MR4) after stopping treatment is not yet known. Objective ENESTPath was designed to assess the proportion of pts (pretreated with IM and subsequently treated with NIL 300 mg bid) who can achieve a sustained DMR and maintain TFR without relapse for 12 months (mo) upon treatment discontinuation after different durations of treatment in consolidation phase. Methods ENESTPath is a randomized, phase 3 study enrolling pts with CML-CP who achieved a complete cytogenetic response (CCyR), but not MR4, after at least 24 mo of treatment with IM. After enrollment, pts were assigned to receive NIL at 300 mg bid for either 24 mo or 36 mo (arm 1 and arm 2, respectively). Pts with stable MR4 or better for at least 12 mo will enter the TFR phase. A stable MR4 was defined by 4 of the 5 preceding quarterly real-time quantitative RT-PCR (RQ-PCR) assessments ≥ MR4 and ≥ MR4 inthe last assessment performed by IS certified EUTOS laboratories. Results A total of 619 pts were enrolled in the study between May 2013 and June 2015. The present analysis reports the results of the first 300 pts (mean age, 50.8 years; 63.7% of males) enrolled and treated with NIL for 24 mo in induction and consolidation phase or who had discontinued earlier. Details of the baseline characteristics are given in Table 1. At data cutoff, 108 pts were in stable MR4; 101 (33.7%) were randomized and 7 (2.3%) were scheduled for randomization at that time point. 192 pts (64%) were not eligible for randomization, primarily due to lack of stable MR4 in 126 pts (42%), adverse events (AEs) or abnormal laboratory values in 44 pts (14.7%), and for other reasons in 22 pts (7.3%). The rates of MR4 at baseline*, 6 mo, 12 mo, 18 mo, and 24 mo were 14.3%, 43.3%, 45.7%, 43.7%, and 46%, respectively. By 24 mo of treatment with NIL, cumulative incidences of major molecular response (MMR), MR4, and MR4.5 of all treated pts not in respective MR at baseline were 93.2%, 69.3% and 42.1%, respectively (Figure 1). Further analysis showed that pts with MMR at baseline had a higher probability of achieving an MR4 than those lacking MMR at baseline, with a cumulative incidence of MR4 by 24 mo of 75.8% and 44.2%, respectively. No new safety signals were observed during the 24 mo consolidation with NIL. The majority of the AEs were low grade. Most common AEs irrespective of the relationship to the study drug were pruritus (19%), hypercholesterolemia (14.0%), rash (10.7%), asthenia (10%), and arthralgia (10%). The most common newly occurring or worsening all-grade biochemistry laboratory abnormalities included increase in total cholesterol (68.7%), increased ALT (54%), hyperglycemia (32.7%), and hyperbilirubinemia (37%); majority of them were grade 1 and 2. Newly occurring or worsening all-grade cytopenias include anemia (12.7%), thrombocytopenia (2.3%), leukopenia (2%), and neutropenia (1%). Grade 3 or 4 cardiovascular events (CVEs) were experienced by 6.7% of pts including ischemic heart disease (4.7%), peripheral artery occlusive disease (1.7%), and ischemic cerebrovascular events (0.7%) (Table 2). Conclusions This analysis of the first 300 pts after 24 mo of NIL treatment showed a cumulative incidence of MR4 in ~ 70% of pts who were not in MR4 at baseline with an advantage in favor of MMR at baseline. 108 pts (36%) were with stable MR4 at data cutoff and 192 pts (64%) discontinued the study due to very stringent protocol definitions of eligibility for randomization and AEs. Grade 3 or 4 AEs were consistent with the previous reports.4 References 1. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Chronic Myelogenous Leukemia V.1.2016 ©2016 National Comprehensive Cancer Network, Inc. 2. Hochhaus A, et al. Leukemia. 2016;30:1044-1054. 3. Hughes TP, et al. Blood. 2014;124:729-736. 4. Rea D, et al. Blood. 2015;125:[abstract 4040]. Disclosures Rea: Ariad: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria. Rosti:Roche: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; Incyte: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Cross:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Niederwieser:Novartis: Research Funding, Speakers Bureau; Amgen: Research Funding, Speakers Bureau. Pregno:Novartis: Honoraria; BMS: Honoraria; ARIAD: Honoraria. Orlandi:Ariad: Honoraria; BMS: Honoraria; Novartis: Honoraria. Almeida:Celgene: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; BMS: Speakers Bureau; Shire: Speakers Bureau; Alexion: Speakers Bureau. Illes:University of Debrecen faculty of medicine department of hematology: Employment. Sagues:ICO-Girona/hospital Universtiari de Girona Dr. Josep Trueta: Employment. Haenig:Novartis: Employment. Supekar:Novartis: Employment. Shah:Cognizant: Employment; Novartis: Other: Vendor. Saglio:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Steegmann:Aria: Honoraria, Other: Research funding for Spanish CML Group; BMS: Honoraria, Other: Research funding for Spanish CML Group; Novartis: Honoraria, Other: Research funding for Spanish CML Group; Pfizer: Honoraria, Other: Research funding for Spanish CML Group. Baccarani:Pfizer: Consultancy, Honoraria, Speakers Bureau; Ariad: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau.