Kinase Inhibitor Discontinuation Research Articles

Treatment-free remission (TFR) in patients with chronic myeloid leukemia (CML) following the discontinuation of tyrosine kinase inhibitors.

7050 Background: Tyrosine kinase inhibitors (TKIs) discontinuation in patients (pts) with CML is increasingly considered. We evaluated the outcome of pts with CML who discontinued TKIs and determined the factors associated with differences in the success rates of TFR. Methods: We reviewed data from 284 pts with CML treated with TKIs at our institution between October 1999 and February 2017 and who subsequently discontinued therapy. Major molecular response (MMR) was defined as a BCR-ABL1/ABL1 transcripts ratio ≤0.1% as determined by real time (RT)-PCR, MR4 as a ratio ≤0.01% IS, and MR4.5 as a ratio ≤0.0032%. TFR failure was defined as the loss of MMR on any single test. We analyzed TFR rates according to duration and depth of response and conducted a multivariate analysis for factors associated with loss of MMR. Results: Median age was 63 years (range, 25-93). 199 pts (70%) had electively discontinued their TKI while 70 pts (24%) stopped therapy because of adverse events. 92 pts (32%) had switched ≥1 TKI prior to discontinuation due to drug intolerance or resistance. The median time from the initiation of frontline TKI to discontinuation was 117 months (range, 16-242). The median duration of MR4 and MR4.5 before TKI discontinuation was 74 months (range, 2-207) and 64 months (range, 0-207), respectively. At a median follow-up of 36 months (95% CI, 32-40) after TKI discontinuation, 53 pts (19%) lost MMR, translating into a 5-year TFR rate of 79%. 50 pts (94%) resumed TKI therapy and, among 47 evaluable pts, all but one pt regained MMR, with 41 pts (88%) achieving MR4.5. The estimated 5-year TFR rates were 91%, 76% and 70% in pts achieving MR4.5 for ≥6 years, between 5 and 6 years, and < 5 years, respectively (P < 0.0001). The estimated 5-year TFR rates were higher with MR4 and MR4.5 ≥5 years, compared with MR4 < 5 years (87% vs 92% vs 64%; P < 0.0001). Pts who remained on their frontline TKI at the time of discontinuation had a 5-year TFR rate of 82%, compared with 75% and 72% among pts who switched to a second line TKI or beyond because of intolerance or resistance, respectively (P = 0.417). TFR rates did not vary according to the type of frontline TKI used (P = 0.761). By multivariate analysis, only durations in MR4 or MR4.5 ≥5 years before stopping treatment were associated with a lower risk of loss of MMR, with hazard ratios of 0.37 (95% CI, 0.18-0.76; P = 0.007) and 0.20 (95% CI, 0.09-0.45; P < 0.0001), respectively. We evaluated the impact of the frequency of molecular monitoring on the success rate of TFR. The estimated 5-year TFR rate was 79% for pts monitored monthly compared with 85% for pts monitored every 6-8 weeks following discontinuation (P = 0.263). Conclusions: Our findings suggest that achieving MR4 for ≥5 years was associated with a very high probability of maintaining TFR, and that less frequent molecular monitoring could be more cost-effective without any negative impact on outcomes.

KI Intolerance Study: A Phase 2 Study to Assess the Safety and Efficacy of Umbralisib (TGR-1202) in Patients with Chronic Lymphocytic Leukemia (CLL) Who Are Intolerant to Prior BTK or PI3K-δ Inhibitor Therapy

Background: Although kinase inhibitor (KI) therapies such as ibrutinib are generally well tolerated, intolerance is the most common reason for discontinuation in practice (~50%, Mato et al, Blood 2016). KI intolerance is of significance as interruptions ≥ 8 days may shorten overall survival (OS) (Barr et al, Blood 2017). Therefore, patients (pts) who respond to a KI but discontinue due to intolerance represent a pt population with an unmet medical need. In a Ph 1/2 study, 27% of ibrutinib (BTK) intolerant pts treated with the BTK inhibitor acalabrutinib discontinued therapy (Awan et al, ASH 2016), while data suggest that alternate-target KIs can have non-overlapping toxicity profiles. Umbralisib (TGR-1202) is a next generation, highly-specific PI3K-δ inhibitor with nanomolar inhibitory potency. Umbralisib is well-tolerated with a discontinuation rate due to AEs of 8% as demonstrated in an integrated safety analysis of 165 treated pts (Burris et al, ASCO 2016).Methods: We report results of a Phase 2, multicenter study to assess the safety and activity of umbralisib in CLL pts who are KI intolerant, defined as: ≥ 1 grade 3 or ≥ 2 grade 2 non-heme toxicities, ≥ 1 grade 3 neutropenia with infection or fever, and/or ≥ 1 grade 4 heme toxicity leading to KI (BTK and/or PI3K inhibitor) discontinuation. Toxicities must resolve to ≤ grade 1 prior to umbralisib dosing. Prior KI must be discontinued for ≥ 14 days without CLL progression; however, pts could have progressed after 14 days of KI discontinuation. Pts must start umbralisib within 12 mos of discontinuing prior KI. All eligible pts are treated with umbralisib (800mg oral daily) until PD, toxicity, or study conclusion. The primary endpoint is progression-free survival (PFS). Secondary endpoints include ORR, duration of response, time to treatment failure, and umbralisib safety profile. Peripheral blood (PB) samples are collected prior to umbralisib, Cycle 2, and at PD for correlative analyses to identify markers associated with KI intolerance. The trial commenced on 10/1/2016.Results: 22 pts who met study enrollment criteria for KI intolerance were treated as of 7/15/2017. 20 pts were ibrutinib intolerant and 2 were idelalisib intolerant. One idelalisib intolerant pt was deemed ineligible due to Richter transformation discovered 26 days after enrollment but thought present at study entry. Baseline demographics were as follows: median age 66 years (range 53-83), median prior therapies 2 (1-7), 55% female, 64% ECOG 1, stage III-IV (%), bulky disease (45%), del(17p) (14%), del(11q) (27%), IGHV unmutated (59%). Median duration of prior KI exposure was 8 months (range 1-36 months) and median duration from end of KI to start of umbralisib was 2.5 months. 68% experienced progression of CLL within 6 months of first KI discontinuation (prior to enrolling in this study). AEs that led to first KI discontinuation (ibrutinib or idelalisib) are defined in Table 1.On umbralisib treatment: Grade 3-4 AEs (≥ 10% patients) were limited to neutropenia (23%, n=5) and leukocytosis (14%, n=3, none related to CLL progression). Common Grade 3-4 AE's associated with other PI3K-δ inhibitors were rare as follows: AST/ALT (0% G 3/4); diarrhea (9% G 3/4); pneumonitis (0%). With a median follow up of 6 months, no pt has discontinued umbralisib due to intolerance, with 1 pt with ongoing clinical benefit discontinuing due to study noncompliance. No pt has experienced a recurrence of an AE on umbralisib that previously led to KI discontinuation (non-overlapping toxicity profile), including common AEs associated with PI3K-δ discontinuation. One pt experienced microscopic lymphocytic colitis possibly infectious or medication-related with grade 3 diarrhea and has been re-challenged with umbralisib. Median PFS has not been reached (Figure 1).Conclusions: Umbralisib is safe and effective in a KI intolerant CLL pt population. These are the first prospective data to confirm that switching from ibrutinib or idelalisib to an alternate PI3K-δ (umbralisib) can result in durable responses in the absence of recurrence of KI intolerance toxicities. These data are indicative of non-overlapping toxicity profiles with an alternate KI. Pre-umbralisib dosing samples are currently being analyzed for BTK, PLC gamma 2 mutations, IGHV mutation status, driver mutations of interest (Notch1, TP53) and CYP-3A4 polymorphisms. Study enrollment is ongoing and additional follow up on study outcomes will be reported. [Display omitted] DisclosuresMato:AstraZeneca: Consultancy; Kite: Consultancy; Regeneron: Research Funding; DTRM: Research Funding; Portola: Research Funding; Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Pharmacyclics: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. Cheson:AbbVie, Roche-Genentech, Pharmacyclics, Acerta: Consultancy; Acerta, Pharmacyclics, Epizyme, Gilead, Roche, AbbVi: Other: Institution receives research support . Lamanna:Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding. Pagel:Actinium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Lansigan:Seattle Genetics: Consultancy; Spectrum Pharmaceuticals: Consultancy, Research Funding. Barr:Gilead: Consultancy; AbbVie: Consultancy, Research Funding; Celgene: Consultancy; Infinity: Consultancy; Seattle Genetics: Consultancy; Novartis: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. Dorsey:TG Therapeutics, Inc.: Consultancy. Svoboda:Kite: Consultancy; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Research Funding; BMS: Consultancy, Research Funding; Celgene: Research Funding; Merck: Research Funding. Schuster:Seattle Genetics: Consultancy; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Nordic Nanovector: Consultancy; Celgene: Consultancy, Research Funding. Ujjani:Genentech: Consultancy; Abbvie: Research Funding, Speakers Bureau; Gilead: Consultancy; Pharmacyclics: Consultancy, Research Funding. Paskalis:TG Therapeutics, Inc.: Employment, Equity Ownership. Sportelli:TG Therapeutics, Inc.: Employment, Equity Ownership. Miskin:TG Therapeutics, Inc.: Employment, Equity Ownership. Weiss:TG Therapeutics, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Brander:Teva Pharmaceuticals, Genentech, AbbVie, Pharmacyclics: Consultancy; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Phase 2 study of the safety and efficacy of umbralisib in patients with CLL who are intolerant to BTK or PI3Kδ inhibitor therapy

AbstractIntolerance is the most common reason for kinase inhibitor (KI) discontinuation in chronic lymphocytic leukemia (CLL). Umbralisib, a novel highly selective phosphatidylinositol 3-kinase δ (PI3Kδ)/CK1ε inhibitor, is active and well tolerated in CLL patients. In this phase 2 trial (NCT02742090), umbralisib was initiated at 800 mg/d in CLL patients requiring therapy, who were intolerant to prior BTK inhibitor (BTKi) or PI3K inhibitor (PI3Ki) therapy, until progression or toxicity. Primary end point was progression‐free survival (PFS). Secondary end points included time to treatment failure and safety. DNA was genotyped for CYP3A4, CYP3A5, and CYP2D6 polymorphisms. Fifty-one patients were enrolled (44 BTKi intolerant and 7 PI3Kδi intolerant); median age was 70 years (range, 48‐96), with a median of 2 prior lines of therapy (range, 1‐7), 24% had del17p and/or TP53 mutation, and 65% had unmutated IGHV. Most common adverse events (AEs) leading to prior KI discontinuation were rash (27%), arthralgia (18%), and atrial fibrillation (16%). Median PFS was 23.5 months (95% CI, 13.1–not estimable), with 58% of patients on umbralisib for a longer duration than prior KI. Most common (≥5%) grade ≥3 AEs on umbralisib (all causality) were neutropenia (18%), leukocytosis (14%), thrombocytopenia (12%), pneumonia (12%), and diarrhea (8%). Six patients (12%) discontinued umbralisib because of an AE. Eight patients (16%) had dose reductions and were successfully rechallenged. These are the first prospective data to confirm that switching from a BTKi or alternate PI3Ki to umbralisib in this BTKi- and PI3Ki–intolerant CLL population can result in durable well-tolerated responses.

The Impact of Comorbidity on Quality of Life in Chronic Myeloid Leukemia Patients with Deep Molecular Response Who Stopped Therapy By Tyrosine Kinase Inhibitors: Results of the RU-SKI Trial

Background The data on quality of life (QoL) in chronic myeloid leukemia (CML) patients (pts) with deep molecular response (DMR) in the treatment-free remission (TFR) studies are limited. The influence of comorbidities on QoL in CML pts before and after tyrosine kinase inhibitors (TKIs) discontinuation has not been studied. Aim We aimed to study the impact of comorbidities on QoL in CML pts before and after the stop therapy by TKIs. Patients and methods The chronic phase (CP) CML pts who had received therapy by any TKI ≥3 years (yrs) with sustained DMR (BCR-ABL ≤0.01% IS) during ≥2 yrs were enrolled into the prospective TFR study RU-SKI. A regular qPCR with BCR-ABL IS evaluation was performed after TKI cessation. TKI were resumed in pts with major molecular response loss (MMR loss, BCR-ABL>0,1%). The QoL was evaluated by RAND SF-36 questionnaire at baseline before TKI stop and at 1, 3, 6, 12 mo during TFR. Eight functional scales were assessed: physical functioning, role limitations physical, bodily pain, general health perceptions, energy/vitality, social functioning, role limitations emotional, mental health. The Integral QoL Index (IQoLI) was calculated based on the scales. Mann-Whitney test, paired Wilcoxon test χ2 were used for the statistical analysis. Molecular relapse free survival (MRFS) was evaluated by Kaplan-Meier method, log-rank test was used for comparison. Results The analysis was performed in the group of 97 CML pts. Median (Me) age was 47±14.5 (yrs), 48.5% were males. The TKI before treatment cessation were as follows: imatinib and second-generation (2G) TKIs in 67 (70%) and 30 (30%) pts accordingly; 9 (30%) pts received 2G TKIs in 1st line and 21 (70%) pts in 2nd line. Me time of observation was 25 mo (range 12-42). Comorbidities were present in 81 pts (82%) at baseline. The most frequent comorbidities were cardiovascular (38.4%), gastroenterological (29.3%) and musculoskeletal disorders (27.3%). First we compared baseline QoL in 2 pts groups: group 1 - pts with acute comorbidity status at baseline (n=42), group 2 - pts with stable comorbidity status (n=29) and with no comorbidity (n=16). QoL in group 1 was significantly worse by all functional scales, except mental health (p<0.05). The IQoLI at baseline was significantly lower in group 1 vs group 2: 0.477 vs 0.589 (p<0.001). Then we evaluated QoL at 3 mo after TKI stop in 72 available pts, as acute status comorbidity remained in 30 pts. The majority of pts exhibited QoL improvement or stabilization by all SF-36 scales. The most pronounced positive changes were observed by SF-36 scales in pts with acute comorbidity status (group 1).The proportion of pts with QoL improvement at 3 mo after TKI stop was higher in group 1 as compared to group 2 by physical functioning (57% vs 29%), role physical functioning (30% vs 5%) and social functioning (40% vs 24%), p<0.05. Increasing of social functioning was statistically significant: ∆20.2 in group 1 vs ∆12.6 in group 2 (p=0.005). The proportion of pts with QoL worsening at 3 mo after TKI stop was similar in both groups. MRFS at 24 mo was 62% (CI 46-77%) and 45% (CI 32-58%) in groups 1 and 2 respectively, with no significant differences between the groups (p=0.107). Conclusion CML pts with DMR and acute comorbidity status had a worse QoL before TKI therapy cessation compared to pts without comorbidity or with comorbidity in remission. The majority of pts exhibited QoL improvement or stabilization in early terms after TKI stop. Pts with acute comorbidity status had more pronounced positive QoL changes after treatment cessation than other pts. Possible explanation is that TKI therapy could increase the clinical symptoms manifestation by overlapping with the treatment toxicity effects. The molecular relapse rate was similar in pts with and without acute comorbidity status. Thus, comorbidity is not a factor which may have negative impact on the outcomes of stop TKI therapy in CML pts. Disclosures Ionova: Takeda, BMS: Other: Principal Investigator of IISR, Research Funding. Chelysheva:Novartis: Consultancy, Honoraria; Fusion Pharma: Consultancy. Shukhov:Novartis: Consultancy; Pfizer: Consultancy. Turkina:Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; fusion pharma: Consultancy; Novartis: Consultancy, Speakers Bureau.

Tyrosine kinase inhibitor therapy treatment and discontinuation in patients with chronic myeloid leukemia in chronic phase in the United States: a clinical practice perspective

Tyrosine kinase inhibitor (TKI) therapy discontinuation practice in patients with chronic myeloid leukemia chronic phase (CML-CP) was assessed in real-world practice prior to the release of recommendations on discontinuation. Data were collected from US oncologists/hematologists (through web-based physician survey and patient chart review) on TKI therapy discontinuation practice including monitoring, adequate response for discontinuation, relapse, and symptoms following discontinuation. From the physician survey, 34% of oncologists/hematologists attempted discontinuation, with two-thirds doing so outside of a trial. From the chart review, TKI therapy was discontinued in 3.4% of patients after they achieved an adequate response with the intention to remain CML-therapy-free until disease relapse. Among these patients, 21% relapsed and 17% had symptoms following discontinuation. There was a lack of consensus on the definition of adequate response suggesting that discontinuation was attempted without clear guidelines and under suboptimal conditions underscoring the need for physician education regarding guidelines for TKI therapy discontinuation.

Analysis of PET-CT to Identify Richter's Transformation in 167 Patients with Disease Progression Following Kinase Inhibitor Therapy

▪Introduction: Positron emission tomography-computed tomography (PET-CT) has been utilized in CLL to help identify patients (pts) with Richter's transformation (RT). Data from kinase inhibitor (KI)-naïve pts suggest that maximum standardized uptake value (SUVmax) of ≥10 on PET can distinguish RT from CLL with 91% sensitivity, 95% specificity (Michallet, 2014). Additionally, in the setting of CLL progression, SUVmax ≥10 identified pts with inferior survival, independent of RT diagnosis (Falchi, 2014). Whether PET can accurately identify and risk-stratify pts failing KI therapy with RT vs. CLL is unknown. In a phase 2 trial (NCT021412820), treatment with the BCL-2 inhibitor venetoclax (VEN) was evaluated in pts in whom prior ibrutinib or idelalisib had failed. All consented pts were required to undergo PET imaging to identify and exclude RT. Therefore, this represents the largest, uniform dataset of KI-treated pts who have undergone PET imaging and were subsequently uniformly treated.Methods: Pts were evaluated at screening by PET and excluded from the study if RT was confirmed on core biopsy of the most suspicious node. Biopsy of the suspicious area was mandatory if PET SUVmax was ≥10 or for pts with CD38+, ZAP 70+, TP 53 mutated and IGHV unmutated CLL with an SUVmax 4-10 with ≥1 of the following: B symptoms, nodes >5 cm, and/or LDH elevation. We used descriptive methods, logistic regression, and receiver operator characteristic (ROC) analysis to define post-KI PET test characteristics.Results: 167 pts were screened, of whom 84 (50%) had PET SUV ≥5 and 25 (15%) had SUV ≥10. 57 pts met protocol criteria for biopsy at screening to evaluate for RT (SUV ≥10, n=18; SUV <10 with other factors, n=17): 35 underwent biopsy and 22 did not meet enrollment criteria for other reasons so no biopsy was performed. Of these 35 pts, 8 had RT (failed screening due to confirmed RT [all with large B-cell lymphoma]), 2 had other malignancies (metastatic anal cancer and neuroendocrine tumor), and 25 had biopsy demonstrating CLL. Based on a logistic regression analysis of 35 pts who underwent biopsy (Table 1), PET SUVmax ≥10 did not adequately distinguish RT post-KI therapy vs. CLL (OR, 1.79 [95% CI: 0.4-9]; p=.5) with 26% sensitivity, 82% specificity, 63% positive predictive value, and 50% negative predictive value. ROC area for SUVmax ≥10 was 56%.For pts who failed screening, median number of FDG-avid nodes with an SUV >3 was 4 (range: 1-11) and median SUVmax was 8 (range: 2-28), with 12 (39%) who had SUV ≥10 (Table 2). For 127 enrolled pts, median number of FDG-avid nodes was 5 (range: 1-13) and median SUVmax was 5 (range: 0-73), with 13 (10%) who had SUV ≥10. There was a statistical trend for higher SUVmax for pts who did not meet screening criteria vs enrolled (p=.0607). The objective response rate to VEN was similar for pts when stratified by screening PET SUV ≥10 (62%, 8/13) vs <10 (56%, 53/94). Median PFS was also similar for pts when stratified by screening PET SUV ≥10 (19.2 months [95% CI: 0.4, -]) vs <10 (21.9 months [95% CI: 15.9, -]).Fifty-six (44%) pts discontinued VEN, with 28 (22%) due to CLL progression and 6 (5%) due to biopsy-confirmed RT following both imaging and clinical changes. Median time to CLL progression was 8.4 months (range: .1-22.8) and to RT was 11.5 months (range: 4.4-19.7). For pts who discontinued VEN due to RT, median number of FDG-avid nodes at screening (pre-VEN) was 3 (range: 1-6) and SUVmax was 5.5 (range: 2-15). PET SUV ≥10 at screening did not predict development of subsequent RT when on VEN (OR, 1.483 [95% CI: .2-13.8]; p=.7289). Compared with 127 enrolled pts, pts who developed RT while on VEN were older, had a higher median number of prior therapies, and the majority had at least 1 poor-risk prognostic feature at study enrollment (Table 2).Conclusions: In the largest series of PET-CTs prospectively performed in pts following KI discontinuation, we conclude that PET SUV ≥10 alone lacks both sensitivity and specificity to distinguish CLL progression vs RT. CLL progression following KI exposure appears more metabolically active than previously reported following R-chemotherapy failure. RT was confirmed for 14% (8/57) of pts suspected of CLL progression with BCRi therapy, which suggests that screening for RT may be important upon BCRi failure. In addition, PET SUV ≥10 did not identify VEN-treated patients with an inferior ORR or PFS. Analysis to identify clinical factors distinguishing KI-treated pts with likely RT is ongoing. [Display omitted] DisclosuresMato:TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; DTRM: Research Funding; AbbVie: Consultancy, Research Funding; Portola: Research Funding; Kite: Consultancy; Pharmacyclics: Research Funding; Janssen: Consultancy; AstraZeneca: Consultancy; Regeneron: Research Funding; Acerta: Research Funding; Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wierda:Pharmacyclics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Acerta: Research Funding; GSK/Novartis: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria; Kite: Research Funding; Janssen: Research Funding; Sanofi: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Genentech/Roche: Consultancy, Honoraria, Research Funding; Emergent: Consultancy, Honoraria, Research Funding; Karyopharm: Research Funding; Juno: Research Funding; Merck: Consultancy, Honoraria; The University of Texas MD Anderson Cancer Center: Employment. Davids:Celgene: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy; Infinity: Consultancy, Research Funding; InCyte: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cheson:AbbVie, Roche-Genentech, Pharmacyclics, Acerta: Consultancy; Acerta, Pharmacyclics, Epizyme, Gilead, Roche, AbbVi: Other: Institution receives research support . Coutre:AbbVie: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Janssen: Consultancy; Novartis: Consultancy, Research Funding; Gilead: Consultancy, Research Funding. Choi:AbbVie, Genentech, and PCYC: Consultancy; AbbVie: Other: Institutional research funding; Gilead, Genentech, Abbvie, and PCYC: Speakers Bureau. Furman:AbbVie, Pharmacyclics, Janssen, Gilead, Genentech, Sunesis, Verastem: Consultancy. Heffner:ADC Therapeutics: Research Funding; Kite: Research Funding. Barr:Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Infinity: Consultancy; Celgene: Consultancy; Gilead: Consultancy; AbbVie: Consultancy, Research Funding; Novartis: Consultancy; Seattle Genetics: Consultancy. Eradat:AbbVie, Gilead, Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Speaker. Zhou:Abbvie: Employment, Equity Ownership. Verdugo:AbbVie: Employment, Equity Ownership. Potluri:Abbvie: Employment, Research Funding. Jones:Abbvie, Pharmacyclics, Genentech, Gilead, Janssen, Merck, and Acerta: Other: Institutional research funding; Sunesis: Other: Institutional research funding; Genentech, Abbvie, Pharmacyclics, Gilead, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Outcomes of CLL patients treated with sequential kinase inhibitor therapy: a real world experience

AbstractB-cell receptor kinase inhibitor (KI) therapy represents a paradigm shift in chronic lymphocytic leukemia (CLL) management, but data on practice patterns after KI discontinuation and optimal sequencing are limited. We conducted a multicenter, retrospective, comprehensive analysis on 178 patients with CLL (ibrutinib = 143; idelalisib = 35) who discontinued KI therapy. We examined responses, toxicity, post-KI therapies, and overall survival (OS). Patients had a median of 3 prior therapies (range 0-11); del17p (34%), p53 mutation (27%), del11q (33%), and complex karyotype (29%). Overall response rate (ORR) to first KI was 62% (complete response 14%). The most common reasons for KI discontinuation were toxicity (51%), CLL progression (29%), and Richter transformation (RT) (8%). Median progression-free survival (PFS) and OS from KI initiation were 10.5 and 29 months, respectively. Notably, initial KI choice did not impact PFS or OS; however, RT portended significantly inferior OS (P = .0007). One hundred fourteen patients received subsequent salvage therapy following KI discontinuation with an ORR to subsequent KI at 50% and a median PFS of 11.9 months. Median PFS in KI-intolerant patients treated with an alternate KI was not reached vs 7 months for patients with CLL progression. In summary, these data demonstrate that toxicity was the most common reason for KI discontinuation, that patients who discontinue KI due to toxicity can respond to an alternate KI, and that these responses may be durable. This trial was registered at www.clinicaltrials.gov as #NCT02717611 and #NCT02742090.

Favorable Outcomes in CLL Pts with Alternate Kinase Inhibitors Following Ibrutinib or Idelalisib Discontinuation: Results from a Large Multi-Center Study

Introduction: B cell receptor signal transduction kinase inhibitors (KI) represent a paradigm shift in CLL management; however, there are limited data regarding real world practice patterns of KI discontinuation and response to subsequent therapies. Two centers reported outcomes of ibrutinib (Ibr) failure patients (pts) treated on clinical trials (n=33, n=71) documenting an extremely poor prognosis (Jain 2014, Maddocks 2015). No analogous data in idelalisib (Ide) failure pts are available. Given the impressive activity of KI and the rarity of discontinuation events, 10 large US cancer centers collaborated to capture the experience of 123 CLL pts who discontinued Ibr- or Ide-based regimens focusing on reasons for discontinuation and response to subsequent KI therapies.Methods: We conducted a multicenter, retrospective analysis of CLL pts who discontinued Ibr- or Ide-based therapy for any reason. We examined demographics, reason for discontinuation, responses, survival data, toxicity, and post KI therapies. Primary endpoint was post KI PFS (time from post KI treatment to progression or last f/u) as determined by the Kaplan Meier method. Comparisons were made using log rank test. Each institution received IRB approval.Results: A total of 123 KI discontinuation pts (Ibr=93/Ide=30) were identified. Table 1 describes baseline characteristics at start of KI. Interestingly, 10% and 32% of Ibr (5% 140 mg, 5% 280 mg daily) and Ide pts (32% 100 mg BID), respectively, were initiated at doses less than FDA labeled dose. Further, 23% and 42% of Ibr pts and 30% and 65% Ide pts had doses modified or held, respectively, prior to discontinuation. Overall median time on KI therapy was 5 months (mos) (4.8 Ibr, 5.5 Ide). ORR to KI was 63% (CR 15%, PR 39%, PR-L 9%). Most common reasons for KI discontinuation were toxicity (58% Ibr, 60% Ide), CLL progression (24% Ibr, 30% Ide), and RT DLBCL (8% Ibr, 7% Ide). Table 2 describes the most common toxicities leading to KI discontinuation. Median PFS from KI initiation for the cohort was 9 mos (77 events, median f/u 6 mos, Figure A). When stratified by discontinuation reason (Figure B), PFS was significantly inferior in RT pts (5 mos RT vs 8 mos progression vs 9 mos toxicity, P=0.04). Median OS for the entire cohort has not been reached (34 deaths, med f/u 12 mos). Median OS was inferior in RT pts (10 mos in RT vs. not reached in CLL progression/toxicity pts; P=0.01). At the time of analysis, 66 (54%) pts following KI discontinuation (21 progression, 36 toxicity, 7 RT, 2 SCT) received a first salvage regimen: 20% R-chemotherapy, 18% Ibr-based, 17% Ide-based, 15% anti-CD20 mab, 14% BCL2-inhibitor, 5% cellular therapy, 5% experimental KI, 3% IMID, 3% other. In evaluable pts, ORR to non-KI therapies following Ibr/Ide discontinuation was 40%. ORR to Ide-based therapy (n=12) following Ibr discontinuation was 50% (42% PR, 8% PRL). ORR to Ibr-based therapy following Ide discontinuation (n=13) was 77% (54% PR, 23% PRL). Responses to alternate KI were similar in pts who discontinued KI for toxicity (ORR 60% PR+PRL) and progression (ORR 67% PR + PRL). PFS (median f/u 5 mos, Figure C) for pts treated with an alternate KI therapy (Ibr → Ide, Ide → Ibr) has not been reached vs 7 mos in non-KI therapies (Figure D).Conclusions: We describe the largest combined experience of practice patterns and outcomes post KI discontinuation in CLL. The majority of pts discontinued KI therapy due to toxicity or progression, not RT. For the first time, we demonstrate that the majority of pts who discontinue a KI due to toxicity or progression respond to other therapies, particularly alternate KI therapy. Collectively, these data provide supporting evidence that: (1) reason for KI discontinuation is toxicity in the majority of cases; (2) alternate KI therapy following KI discontinuation is efficacious; (3) non-overlapping toxicity profiles permit utilization of alternate KI following discontinuation due to toxicity; and (4) mechanisms of KI resistance may not overlap.Table 1Baseline CharacteristicsMedian time diagnosis to KI84 mos (1-333)Median age (range)61 yr (33 - 89)Median prior Therapies (range)2 (0 - 11)del17p (n)34% (36/107)del11q (n)31% positive (32/103)p53 mut (n)27% positive (22/81)Complex karyotype (n)31% (33/106)Table 2Reasons for KI DiscontinuationIbrutinibIdelalisibAfib 27%Pneumonitis 33%Infection 14%Colitis 28%Pneumonitis 10%Rash 17%Cytopenias 10%Transaminitis 11%Bleeding 10%Infection 5% [Display omitted] DisclosuresMato:Gilead: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Genentech: Consultancy; Pronai Pharmaceuticals: Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; Celgene Corporation: Consultancy, Research Funding; TG Therapeutics: Research Funding. Nabhan:Celgene Corporation: Honoraria, Research Funding. Barr:Abbvie: Consultancy; Gilead: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. Ujjani:Genentech: Membership on an entity's Board of Directors or advisory committees. Hill:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lamanna:Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding. Skarbnik:Genentech: Honoraria, Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Howlett:Teva: Speakers Bureau. Pu:Merck: Research Funding; BMS: Consultancy; Cyclacel: Research Funding; Medimmune: Research Funding; Ambit: Research Funding; Astellas: Research Funding. Rago:AbbVie: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Speakers Bureau. Zent:Genzyme-Sanofi: Research Funding; Biothera: Research Funding; GlaxoSmithKline: Research Funding; Novartis: Research Funding. Feldman:Celgene: Honoraria, Speakers Bureau; Pharmacyclics/JNJ: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau. Goy:Allos, Biogen Idec, Celgene, Genentech, and Millennium. Gilead: Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Claxton:Cyclacel: Research Funding; BMS: Consultancy; Merck: Research Funding; Astellas: Research Funding; Ambit: Research Funding; Medimmune: Research Funding. Svoboda:Celgene: Research Funding; Celldex: Research Funding; Immunomedics: Research Funding; Seattle Genetics: Research Funding. Dwivedy Nasta:BMS: Research Funding; Millenium: Research Funding. Porter:Genentech: Other: Spouse employment; Novartis: Other: IP interest, Research Funding. Schuster:Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Novartis: Research Funding; Genentech: Consultancy; Gilead: Research Funding; Hoffman-LaRoche: Research Funding; Celgene: Consultancy, Research Funding; Phamacyclics: Consultancy, Research Funding. Cheson:Celgene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Rochr-Genentech: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Astellas: Consultancy; Acerta: Research Funding.

Tyrosine Kinase Inhibitor Discontinuation in Chronic Myeloid Leukemia: Single US Center Experience

Imatinib (IM) can be safely discontinued in patients with chronic myeloid leukemia (CML) with sustained complete molecular remission. Previous publications from France and Australia have shown that overall 40% maintain MMR or MR5 for up to 5 years after IM is stopped. We report single US center experience with tyrosine kinase inhibitor (TKI) discontinuation. Between 06/2010 and 7/2015, 22 patients with CML in chronic (CP, n=19), accelerated (AP, n=2) and lymphoid blast phase (LBP, n=1) discontinued IM (n=17), dasatinib (DAS, n=3) or bosutinib (BOS, n=2), and were monitored by qPCR for BCR-ABL1 monthly for the first 3 months, quarterly for the following 2 years and then bi-annually. TKI was restarted in case of confirmed loss of MMR on a repeat qPCR. Reason for TKI discontinuation was predominantly driven by patients' request and TKI intolerance. Median age was 66 (range, 21-84). The 3 who discontinued DAS had IM-resistant (loss of CCyR; n=1), IM-intolerant CP (n=1), or received DAS as first-line agent (n=1). BOS was discontinued for IM-intolerant CP (n=1), or while in CR2 in a patient with LBP that transformed from IM resistant CP and relapsed following chemotherapy (HCVAD). Median duration of TKI therapy pre-discontinuation for the entire cohort was 89 months (range, 26-106). Three patients are not evaluable due to short follow-up (TKI stopped between 5/2015 and 7/2015). With a median follow-up of 40 months (range, 8-60), 7 (41%, 6 CP and 1 AP), all previously on IM lost MMR a median of 3 months (range, 3-24) after TKI was stopped and restarted IM. Loss of CHR occurred 13 months after loss of MMR in 1 patient who elected not to restart IM at the time MMR was lost, due to complications from cardiac transplant rejection. All 7 achieved MMR following restart of IM. Median duration of TKI therapy pre-discontinuation for these 7 patients was 60 months (range, 48-98). 12 patients (59%, 10 CP, 1 AP, 1 LBP) remain off TKI and have not lost MMR, 8 with continuously undetectable BCR-ABL1; and 4 had 1-2 transient detectable BCR-ABL1 at MR4 levels. Median duration of TKI therapy pre-discontinuation for these 12 patients was 87 months (range, 26-106). Loss of MMR-free survival is depicted in the Figure. We conclude that, similar to previous reports, TKI can be safely discontinued in patients with CML without reappearance of BCR-ABL1 in 50-60%. Figure 1. Figure 1. Disclosures Jillella: Seattle Genetics, Inc.: Research Funding. Kota:Leukemia Lymphoma Society: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees.