ALBERT

Description: Key Points A subset of DHL patients may be cured, and some patients may benefit from intensive induction. Further investigations into the roles of SCT and novel agents are needed.

Description: Key Points Toxicity was the most common reason for discontinuation of ibrutinib or idelalisib in treated patients with CLL. KI-intolerant patients, but less so those with CLL progression, can be successfully treated with an alternate KI.

Description: OBJECTIVE: According to standard protocol, the earliest post treatment marker of response following intensive induction therapy in patients with AML is a D14 marrow biopsy. Some controversy has surrounded this practice. This study aims to evaluate response to induction therapy based on D14 marrow assessment meeting genetic risk classifications as defined by the ELN. METHODS: In a single center, retrospective chart analysis subjects diagnosed with AML treated with 7+3 therapy were included if they had molecular and cytogenetic testing performed at baseline, day 14, and day 28. Baseline characteristics and treatment results at these time points were extracted. Sample demographics and treatment were described descriptively. Risk ratios were calculated to investigate the likelihood of achieving a chemo-ablated[1] bone marrow biopsy at Day 14 across the ELN risk classifications. All analyses were performed using SAS 9.4 (SAS Institute Inc., Cary, NC). RESULTS: One hundred thirty eight pts were included. The median age at diagnosis was 57 years (range 26 to 69). The median white blood cell count at diagnosis was 12,800 (range 0.1 to 122,000 per microliter). 6.5% of the pts had secondary AML and 8.7% had AML arising from an antecedent hematologic disorder. ELN risk classifications at diagnosis were 47.1%, 8.7%, 20.3% and 23.9% for favorable, intermediate-I, intermediate-II and adverse, respectively. Demographic variables and baseline characteristics did not differ across risk groups. The percentage of pts achieving a chemo-ablated marrow biopsy at Day 14 was 88%, 83%, 68% and 67% for the Favorable, Intermediate-I, Intermediate-II and Adverse group, respectively (Table 1, p=0.0385). Similarly, the percentage of patients achieving CR at Day 28 was highest for patients with a favorable ELN risk classification (92%) compared to intermediate-I (83%), intermediate-II (71%) and adverse (79%) (Table 2, p=0.0440). Re-induction rate was significantly different when stratified across ELN risk groups (p=0.0487). Risk ratio analysis showed a 26% increased likelihood of achieving a chemo-ablated marrow biopsy when comparing Favorable ELN risk pts to those to those in the non-favorable ELN risk group (RR:1.2552; 95% CI: 1.0526-1.468). A test of discordance comparing hypocellular/hypercellular results based on the Day 14 marrow biopsy with having CR/non CR at end of cycle 1 were not significant across the ELN risk classifications. CONCLUSION: With the advent of personalized therapy comes the potential to customize treatment and hope to optimize pt outcomes. Our results indicate that karyotype and a range of genetic mutations predict marrow morphology at Day 14. How these results predict long-term outcome needs to be further explored. [1] (defined as cellularity

Description: INTRODUCTION: Anticoagulant management of cancer-associated thrombosis is challenging since this patient population is concurrently at an increased risk for bleeding. The use of direct oral anticoagulants [(DOACs) dabigatran, rivaroxaban, apixaban] is not recommended for the treatment of venous thromboembolism (VTE) in cancer patients since there is limited data in this patient population. Despite limited evidence for use, DOACs are commonly prescribed due to ease of administration and lack of required laboratory monitoring. The objective of this study was to evaluate the practice and safety patterns of the DOACs when used for VTE treatment in the oncology population at Hackensack University Medical Center (HackensackUMC). METHODS: This study was a retrospective chart review of adult cancer patients treated at HackensackUMC who received dabigatran, rivaroxaban, or apixaban for the treatment of VTE. The protocol was reviewed and approved by the Institutional Review Board. Patients were identified through a computer generated report of the DOACs which included patients on all inpatient adult oncology floors at HackensackUMC from January 2013 to October 2015. Patients were included in this study if they were 18 years of age or older, admitted to an oncology floor, receiving a DOAC for VTE treatment for at least 48 hours, and had active cancer. Patients were excluded from this study if they were receiving hemodialysis or receiving a DOAC exclusively for the indication of atrial fibrillation. The primary outcomes of this study included the percentage of patients who were receiving a DOAC dosage consistent with that of the package insert and the percentage of patients who experienced clinically significant bleeding. The secondary outcomes of this study included the percentage of patients who had their DOAC held for thrombocytopenia and high risk procedures. Descriptive statistics were used to analyze study outcomes. RESULTS: Of the 126 patients screened, 39 patients were included. Thirty-five patients were on rivaroxaban and 4 patients were on apixaban (Table 1). Ten of 39 patients (26%) were not receiving a DOAC dosage consistent with that of the package insert. Of these 10 patients identified, the majority were receiving a lower DOAC dose than is recommended in the package insert. Our assumption is that these patients received a lower than recommended dose due to concerns for increased risk of bleeding. No patients experienced clinically significant bleeding. Four of 39 patients (10%) experienced a minor bleeding episode, all of which were gastrointestinal and/or genitourinary bleeds (Table 2). Four of 14 thrombocytopenic patients (29%) did not have their DOAC dose held for thrombocytopenia (none of which experienced a bleeding episode). All patients had their DOACs appropriately held for all procedures. CONCLUSION: Increased education and awareness on manufacturer recommended dosing of DOACs is warranted for oncology prescribers. Despite the increased risk for bleeding in cancer patients, no clinically significant bleeding events were identified in our patient cohort. To our knowledge, this is the first study to evaluate the use of DOACs for VTE treatment in patients with cancer at a high risk for bleeding. This data suggests that the use of DOACs may be safe to use for VTE treatment in the oncology population. This study may provide foundation for larger, randomized, controlled trials to determine whether DOACs should be used for VTE treatment in cancer patients. Disclosures Howlett: Eisai: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; Sandoz: Honoraria; Teva: Speakers Bureau. McCloskey:Ariad: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Novartis: Speakers Bureau.

Description: 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 1. Baseline Characteristics Median time diagnosis to KI 84 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 2. Reasons for KI Discontinuation Ibrutinib Idelalisib Afib 27% Pneumonitis 33% Infection 14% Colitis 28% Pneumonitis 10% Rash 17% Cytopenias 10% Transaminitis 11% Bleeding 10% Infection 5% Figure 1. Figure 1. Disclosures Mato: 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.

Description: Introduction: Ibrutinib (Ibr), idelalisib (Ide), andvenetoclax (Ven), are all now approved for treating CLL patients in the US. However, in the absence of head-to-head comparator trials, there is limited guidance as to the optimal sequence of these therapies and to the best choice upon failure of first selected agent. To address these gaps in current literature, 9 large US cancer centers and the Connect CLL Registry collaborated to capture the experience of 683 CLLpts treated with kinase inhibitors (KIs) - focusing on optimal sequencing and patterns of failure. Patients and Methods: We conducted a multicenter, retrospective analysis of CLLpts treated withIbr-, Ide- orVen-based therapy. We examined demographics, discontinuation rates, reasons for discontinuation, overall response rates (ORR), survival, and post kinase inhibitor (KI) salvage strategies. Primary endpoint was progression-free survival (PFS) (time from KI treatment to progression, death, or last follow-up) as determined by the Kaplan Meier (KM) method. Comparisons were made using the log rank (LR) test and COX regression analyses. Results: A total of 683 pts treated with KI therapy (Ibr=621/Ide=62) were identified (Table 1). Baseline characteristics were similar in theIbr and Ide-based groups. ORR toIbr as first KI was 69% [complete response (CR) 11%, partial response (PR) 45%, and PR-L 13%] and Ide was 81% (CR 5%, PR 71%,PR-L 5%). With a median follow-up from start of first KI of 17 months (range 1-60), median PFS and OS for the entire cohort from first KI was 35 months (216 events) and not reached respectively (107 events). Interestingly,pts treated withIbr (vs. Ide) as first KI had a significantly better PFS in all settings; front-line (figure a, HR 2.8, CI 1.3-6.3 p=.01), relapsed-refractory (figure b, HR 2.8, CI 1.9-4.1 p

Description: Introduction: Patients (pts) with double hit lymphoma (DHL) often experience poor outcomes due to chemotherapy resistance. Accordingly, DHL pts achieving first complete remission (CR1) may undergo consolidative stem cell transplant (SCT), but the benefit of this treatment remains unclear. Here we report the results of a retrospective analysis of DHL pt outcomes based on receipt of SCT in CR1. Methods: DHL was defined as high-grade B cell lymphoma (HGBL) with rearrangement of MYC/8q24as well as BCL2/18q21and/or BCL6/3q27 by fluorescence in situ hybridization or conventional karyotype. Pts received front-line therapy with either RCHOP or intensive induction, defined as REPOCH, RhyperCVAD or RCODOX-M/IVAC. To avoid confounding due to inclusion of pts with primary refractory or rapidly-relapsing disease who would not be eligible to receive SCT, all pts analyzed achieved CR1, defined as the absence of disease at ≥7.5 months (mo) from diagnosis. All included pts were also age ≤75 and deemed fit for SCT by the local investigator. A landmark analysis was carried out, with progression free survival (PFS) defined as the time from 7.5 mo post-diagnosis to relapse or last follow-up if in CR1 and overall survival (OS) defined as the time from 7.5 mo post-diagnosis to death or last follow-up if alive. Therapy, including SCT, was given at the discretion of the treating physician. Pts were treated from 2006-2016 and data were censored on 4/15/16. Results: A total of 163 pts treated at 17 US academic medical centers were included in this analysis. Sixty-eight pts (42%) received SCT in CR1 (SCT group) and 95 pts (58%) did not receive SCT in CR1 (no SCT group). In the SCT group, 57 pts received autologous (auto) SCT only, 10 pts allogeneic SCT only and 1pt both. Comparison of baseline clinicopathologic characteristics revealed higher frequency of male sex (p=0.05), transformed low-grade lymphoma (p60 (41% vs. 51%), stage 3-4 disease (81% vs. 74%), elevated lactate dehydrogenase (65% vs. 62%), ECOG performance status 〉1 (24% vs. 23%), International Prognostic Index score 3-5 (65% vs. 62%) bone marrow involvement (28% vs. 29%), extranodal disease (53% vs. 54%), Ki67 expression ≥90% (50% vs. 53%), germinal center cell of origin by Hans algorithm (93% vs. 83%), presence of BCL2 rearrangement (94% vs. 85%) and receipt of CNS prophylaxis (68% vs. 56%) were similar between SCT and no SCT pts, respectively. For all pts, the median length of follow-up from the time of landmark analysis was 23.5 mo (range 0.2-104.2 mo). Thirty-six mo PFS was 87% in SCT pts and 74% in no SCT pts (p=0.21) and 36 mo OS were 89% and 80%, respectively (p=0.49). No baseline characteristic was significantly associated with 36 mo OS; however, pts treated with R-CHOP (n=33) had a significantly higher hazard ratio (HR) for relapse at 36 mo (HR 3.45 95% confidence interval 1.59-7.45, p=0.002) as compared to that of pts treated with intensive induction (n=130). Additional analysis incorporating induction regimen and receipt of auto SCT revealed 36 mo PFS and OS as follows: 51% and 77% for pts receiving RCHOP induction and no auto SCT (RCHOP-, n=25), 75% and 83% for pts receiving RCHOP induction and auto SCT (RCHOP+, n=8), 85% and 81% for pts receiving intensive induction and no auto SCT (intensive-, n=70) and 90% and 93% for pts receiving intensive induction and auto SCT(intensive+, n=49) . Comparison of survival outcomes between groups revealed that RCHOP- pts experienced inferior 36 mo PFS to that of intensive- (p=0.006) and intensive+ (p=0.002) pts. However, 36 mo PFS was similar for RCHOP+, intensive- and intensive+ pts. Additionally, 36 mo PFS was similar between RCHOP- and RCHOP+ pts as well as intensive- and intensive+ pts. No difference in 36 mo OS was detected between groups. For 24 pts who relapsed, the median OS was 8.6 mo with 3 pts achieving OS 〉24 mo. Conclusion: The inferior rate of relapse at 36 mo experienced by pts treated with R-CHOP as compared to that of pts treated with intensive induction appears to be overcome by receipt of consolidative auto SCT. Neither 36 mo PFS in pts receiving intensive induction or 36 mo OS in any pt subgroup is significantly increased by receipt of consolidative auto SCT. DHL pts who relapse rarely experience prolonged OS, suggesting a need for novel therapies for these pts. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Reddy: INFINITY: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; KITE: Membership on an entity's Board of Directors or advisory committees; GILEAD: Membership on an entity's Board of Directors or advisory committees. Howlett:Amgen: Honoraria; Teva: Speakers Bureau; Eisai: Honoraria; Sandoz: Honoraria; Pfizer: Honoraria. Mato:Abbvie, Gilead Sciences, Pharmacyclics, TG Therapeutics: Consultancy; Abbvie, Acerta Pharma, Gilead Sciences, ProNAi, TG Therapeutics, Theradex: Research Funding. Kaplan:Seattle Genetics: Research Funding; Janssen: Research Funding. Petrich:AbbVie: Employment. Chavez:Janssen: Speakers Bureau. Barta:Janssen: Honoraria, Speakers Bureau; Celgene, Merck, Seattle Genetics: Research Funding. Lansigan:Pharmacyclics: Consultancy; Teva: Research Funding; Spectrum: Consultancy, Research Funding; Celgene: Consultancy. Calzada:Seattle Genetics: Research Funding. Cohen:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding. Amengual:Acetylon Pharmaceuticals: Research Funding; Bristol-Myers Squibb: Research Funding.

Description: Introduction: Salvage immunochemotherapy (IC), followed by high-dose chemotherapy with autologous stem cell transplantation if chemosensitive is standard-of-care second-line (2L) therapy (tx) for fit patients (pts) with relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL) when treated with first-line (1L) R-CHOP as shown in the CORAL study. Outcomes following receipt of salvage IC in the 2L setting for pts with DLBCL or high grade B cell lymphoma/B cell lymphoma unclassifiable (HGBL/BCLU) receiving intensive 1L tx remain unknown, and may be worse than those reported in CORAL given prior exposure to higher-dose IC in 1L setting. Here we report the results of a multicenter retrospective analysis of R/R DLBCL and HGBL/BCLU pts treated with intensive 1L tx who receive standard salvage 2L tx. Methods: Inclusion criteria were histologic diagnosis of DLBCL or HGBL/BCLU, R/R disease following 1L tx with R-EPOCH, R-HyperCVAD or R-CODOX-M/IVAC and receipt of 2L tx with R-ICE, R-DHAP, R-DHAC, R-ESHAP or R-GDP. Exclusion criteria were HIV positivity, post-transplant lymphoproliferative disorder, prior chronic lymphocytic leukemia and inadequate data. Therapy was given at the discretion of the treating physician. Progression free survival (PFS) was defined as the interval between time of first relapse or primary refractory disease and disease progression, change in therapy if no disease response or last follow-up in remission, and overall survival (OS) between time of first relapse or primary refractory disease and death or last follow-up while alive. Pts were treated from 2007-2017 and data were censored on 10/15/17. Results: A total of 195 pts treated at 20 US and Canadian academic medical centers were included. Clinicopathologic characteristics at time of R/R disease were 39% age 〉60 years, 62% male, 77% stage III-IV, 72% elevated LDH, 24% bone marrow (BM) involvement, 28% B symptoms present, 44% extranodal (EN) disease at 〉1 site, 19% ECOG performance status (PS) 〉1, 49% with International Prognostic Index score (IPI) ≥3, 46% HGBL/BCLU histology, 49% Ki67 ≥90%, and 61% germinal center (GCB) cell of origin (COO) by Hans algorithm. Of pts with available fluorescence in situ hybridization (FISH) data, 51%, 45% and 30% demonstrated MYC, BCL2 and BCL6 rearrangements (-R), respectively, and 37% were double hit lymphoma (DHL). Tx received in 1L were R-EPOCH in 82%, R-HyperCVAD in 16% and R-CODOX-M/IVAC in 2% of pts. R-ICE was received by 64% and other platinum-containing regimens by 36% as 2L tx. Most (86%) pts relapsed within 12 months (mo) of completion of 1L tx (early) and 58% of pts had primary refractory disease. For all pts, the median length of follow-up was 25.0 mo with a median PFS of 3.0 mo and median OS of 8.0 mo. Overall response rate to 2L tx among all pts was 44% (23% complete response [CR] and 21% partial response [PR]), and 48% with progressive disease. Pts achieving CR had significantly longer median PFS (32.0 vs 4.0 mo, p = 0.0001) and OS (not reached vs 13.0 mo, p = 0.0004) as compared to pts achieving PR. In pts who achieved CR or PR following 2L tx, 64% received consolidative transplant (42 autologous and 13 allogeneic) and achieved a median PFS and OS of 18.3 mo and 62.0 mo, respectively. As compared to pts relapsing ≥12 mo after completion of 1L tx (late), pts relapsing early were less likely to achieve CR (17% vs. 61%, p=0.0001) and experienced significantly shorter median PFS (2.8 vs. 23.0 mo, p1 and Ki67 ≥90%, but not BCL2-R, demonstrated a statistically significant increased HR for death. Multivariate analysis demonstrated only early relapse to have a statistically significant increased HR for progression (HR 2.47, p=0.024) and death (HR 5.90, p=0.001). Conclusion: Relapse

Description: Background: Imatinib revolutionized the treatment of chronic myelogenous leukemia (CML) demonstrating improved survival and durable response to treatment. Earlier and deeper response rates were observed with dasatinib and nilotinib in the front line setting compared to imatinib. Multiple clinical trials have revealed that carefully selected patients may safely discontinue TKI therapy. However, lifelong TKI therapy remains the standard of care outside of clinical trial. Methods: We reviewed the charts of patients with chronic phase CML treated with imatinib, dasatinib or nilotinib for chronic phase CML between January 2010 and April 2015 and identified 29 patients that had discontinued therapy. We collected data on their treatment history, response to therapy, and outcomes following TKI withdrawal. Results: At the time of TKI cessation all the patients had achieved an MMR (MR4) for at least 2 years. The median time in MMR prior to treatment withdrawal was 64 months. Twelve patients (41%) were treated with imatinib, 7 (24%) were treated with dasatinib, and 10 (35%) were treated with nilotinib. More than half of the patients had received prior treatment with an alternative TKI. At the time of data collection, 16 patients (55%) remained in MMR off therapy. The median time off treatment was 7 months (range: 3-24 months). The median time to loss of MMR was 5 months (range: 2-11 months). No significant difference was observed between TKI and time to loss of MMR (Table 1). Of those patients who lost MRR while off therapy, all achieved a second MMR upon resuming TKI therapy. Based on the average wholesale price, $3,149,576 was saved by cessation of TKI therapy during the observed period. The required follow up and PCR testing accounted for an additional cost of $84,200 for a net savings of $3,065,376. Conclusions: TKI therapy can be safely discontinued in patients with an MMR duration more than two years with close follow up. While this is a small retrospective study, the results are in keeping with those observed in larger trials. With the life expectancy of patients with chronic phase CML now approaching that of the healthy population, lifelong use of TKI has important implications for patients in terms of medical costs and quality of life. Table 1. Comparison of Patient Characteristics and Outcomes Off Treatment Variable Imatinib (n=12) Dastanib (n=7) Nilotinib (n=10) P-Value Age (years) Median (IQR) 55.5 (53.0 - 61.5) 68.0 (50.0 -72.0) 63.5 (51.0 - 72.0) 0.3811 Range 42.0 - 75.0 48.0 - 72.0 42.0 - 76.0 Gender Male n= 6 (50.0) n= 4 (57.1) n= 2 (20.0) 0.2266 Female n= 6 (50.0) n= 3 (42.9) n= 8 (80.0) Time on treatment prior to discontinuation Median (IQR) 98.0 (64.0- 110.5) 49.0 (39.0 - 69.0) 37.5 (27.0 - 60.0) 0.0016 Range 52.0 - 155.0 33.0 - 115.0 6.0 - 92.0 Time in MMR prior to stopping TKI Median (IQR) 52.5 (39.0 - 96.0) 37.0 (30.0 - 92.0) 71.0 (56.0 - 91.0) 0.6707 Minimum - Maximum 8.0 - 126.0 17.0 - 109.0 19.0 - 108.0 Time off treatment Median (IQR) 7.5 (3.0 - 12.0) 5.0 (2.0 - 9.0) 10.0 (6.0 - 12.0) 0.1599 Range 2.0 - 24.0 2.0 - 11.0 2.0 - 16.0 MMR status off treatment Remain in MMR N= 5 (41.7) N= 4 (57.1) N= 4 (40.0) 0.7970 Loss of MMR N= 7 (58.3) N= 3 (42.9) N= 6 (60.0) Time measured in months. Unless specified otherwise, data are presented as counts (percentages). Categorical variables were examined using Pearson's Chi-square test or Fisher's exact test, as appropriate. Continuous variables were examined using Kruskal-Wallis test or Proc mixed for one-way models, as appropriate. Any P

Description: Introduction: Ibrutinib (Ibr) is a kinase inhibitor (KI) indicated for treating CLL. Clinical trials that led to its approval showed that its unique side effects differ from traditional chemotherapy toxicities. We previously reported (Mato et al, ASH 2015) that intolerance was the most common reason for discontinuation of Ibr in 123 patients treated in a real world setting. Whether reasons for discontinuation reported in clinical trials mirror those encountered in the real world is unknown and has not been studied. Therefore, we conducted a retrospective analysis of 621 CLL patients treated with Ibr either on clinical studies or commercially. We aimed to compare the type and frequency of toxicities reported in either setting, assess discontinuation rates, and evaluate outcomes. Patients and Methods: This multicenter, retrospective analysis included Ibr-treated CLL patients at 9 US cancer centers or the Connect® CLL Registry. We examined demographics, dosing, discontinuation rates and reasons, toxicities, and outcomes. The primary endpoint was progression-free survival (PFS) (time from KI treatment to progression, death or last f/u) as determined by the Kaplan Meier method. Comparisons of outcomes data were made using the log rank (LR) test. All other comparisons were descriptive. Results: 621 patients treated with Ibr were identified. Table 1 includes available baseline characteristics stratified by line of therapy. A total of 546 (88%) patients were treated with commercial drug. Clinical trial patients were younger (median age 57 vs. 61 years), had a longer time from diagnosis to Ibr (median 85 vs. 72 months) and were more consistently initiated at 420 mg daily (100% vs. 89%). With a median f/u of 14.5 months, the Ibr discontinuation rate was estimated to be 42% (median time to Ibr discontinuation was 7 months). Reasons for discontinuation are listed in table 2. Notably, Ibr toxicity was the most common reason for discontinuation in all settings. Ibr starting dose (420 mg daily vs. 〈 420 mg daily) did not impact the proportion of patients who discontinued Ibr due to toxicity (51% vs. 50%). In relapsed CLL, the 5 most common Ibr-related toxicities as a reason for discontinuation included: atrial fibrillation (12.3%), infection (10.7%), pneumonitis (9.9%), bleeding (9%), and diarrhea (6.6%). In front line CLL, the 3 most common Ibr-related toxicities as a reason for discontinuation included arthralgia (41.6%), atrial fibrillation (25%), and rash (16.7%). Median times to discontinuation by toxicity were as follows: bleeding (8 months), diarrhea (7.5 months), atrial fibrillation (7 months), infection (6 months), arthralgia (5 months), pneumonitis (4.5 months), and rash (3.5 months). Median PFS and OS for the entire cohort were 35 months and not reached (median f/u 17 months) respectively. Figure 1 describes PFS for Ibr treated patients stratified by line of therapy (A), reason for discontinuation (B), clinical trial participation (C) and depth of response (D). In a multivariable model, complex karyotype was validated as an independent predictor of PFS (HR 1.6, CI 1.1-2.5 p=.04) but not OS (HR 1.6, CI .9-3.1 p=.1). Conclusions: In the largest reported series on Ibr-treated CLL patients, we show that 40% of patients have discontinued Ibr during this observation period. Intolerance as opposed to CLL progression or transformation was the most common reason for discontinuation. As compared to previous reports from clinical trials, the discontinuation rate appears to be higher suggesting (1) a learning curve in terms of toxicity management, (2) a higher incidence of toxicity in clinical practice, (3) or a lower threshold for discontinuation given alternative choices. Outcomes remain excellent and were not impacted by line of therapy and whether patients were treated on studies or commercially. These data strongly argue to find strategies to minimize Ibr intolerance so that efficacy can be further maximized. Figure 1 Figure 1. Disclosures Mato: Abbvie, Acerta Pharma, Gilead Sciences, ProNAi, TG Therapeutics, Theradex: Research Funding; Abbvie, Gilead Sciences, Pharmacyclics, TG Therapeutics: Consultancy. Lamanna:Acerta: Research Funding; TGR Therapeutics: Research Funding; Janssen: Honoraria; Pharmacyclics: Honoraria, Research Funding; Roche-Genentech: Honoraria, Research Funding; Celgene: Honoraria; AbbVie: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Infinity: Research Funding; Acerta: Research Funding; TGR Therapeutics: Research Funding. Ujjani:Gilead: Consultancy; Abbvie: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy. Brander:TG Therapeutics: Research Funding; Gilead: Honoraria. Howlett:Sandoz: Honoraria; Teva: Speakers Bureau; Amgen: Honoraria; Pfizer: Honoraria; Eisai: Honoraria. Skarbnik:Gilead Sciences: Speakers Bureau; Seattle Genetics: Speakers Bureau; Genentech: Speakers Bureau; Abbvie: Consultancy; Pharmacyclics: Consultancy. Cheson:Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kiselev:Celgene: Employment, Equity Ownership. Nasta:Millennium Pharmaceuticals: Research Funding. Schuster:Janssen Research & Development: Research Funding; Hoffman-LaRoche: Research Funding; Gilead: Research Funding; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Research Funding; Merck: Research Funding. Porter:Novartis: Patents & Royalties, Research Funding; Genentech: Employment. Nabhan:Seattle Genetics: Research Funding; Cardinal Health: Consultancy; Infinity: Consultancy; Abbvie: Consultancy; Genentech: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding; Astellas: Research Funding. Barr:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Consultancy.