ALBERT

Description: Introduction: Ponatinib is a potent oral tyrosine kinase inhibitor (TKI) approved for use in patients with refractory CML and Ph+ ALL, including patients with the resistant BCR-ABLT315I mutation. To evaluate whether patient characteristics and outcomes with ponatinib differed by extent of pretreatment with other TKIs, this post hoc analysis examines results among CP-CML patients enrolled in the phase 2 PACE trial (NCT01207440) according to the number of TKIs received prior to study entry. Updated data with 4 years of follow-up will be presented. Methods: Patients with CML or Ph+ ALL who were resistant or intolerant to dasatinib or nilotinib or who had the T315I mutation were enrolled (N=449). Ponatinib was initiated at 45 mg once daily. CP-CML patients were evaluated based on previous treatment with 1, 2, 3, or 4 prior TKIs approved for use in CP-CML (ie, imatinib, dasatinib, nilotinib, and bosutinib). Data reported in this abstract are as of February 2, 2015. Results: Overall, 270 CP-CML patients were enrolled and treated in PACE. Patient characteristics and disposition varied by number of prior TKIs (Table 1). Both median age and median time from diagnosis increased with number of prior TKIs; median dose intensity was highest in patients who had received only 1 prior TKI. The most common reasons for discontinuation across groups were adverse events (AEs) and withdrawal by patient request. Responses by number of prior TKIs are shown in Table 2. Rates of cytogenetic and molecular response to ponatinib were higher with fewer prior TKIs. While the frequency of individual AEs did not follow a consistent trend, the incidence of grade ≥3 AEs appeared to increase with the number of prior TKIs received (68%, 86%, 89%, and 100%, respectively); grade ≥3 AEs in ≥10% of CP-CML patients overall were thrombocytopenia (35%), neutropenia (17%), hypertension (13%), increased lipase (12%), and abdominal pain (10%). A similar frequency pattern was observed for serious AEs, which occurred in 58%, 53%, 62%, and 92% of patients who had previously received 1, 2, 3, and 4 approved TKIs, respectively. Serious AEs in ≥5% of CP-CML patients overall were pancreatitis (7%), angina pectoris (5%), and pneumonia (5%). The frequency of arterial occlusive events (AOEs) was 32% (6/19), 26% (25/98), 28% (39/141), and 42% (5/12) by increasing number of prior TKIs; exposure-adjusted incidence rates of new AOEs were 11.75, 10.4, 12.6, and 33.3 events per 100 patient-years, respectively. Conclusions: With 4 years of follow-up, ponatinib continues to provide benefit to ongoing CP-CML patients in the PACE trial. Analysis by treatment history indicates that patients who had received fewer TKIs prior to study entry appear to exhibit better efficacy and safety profiles. However, treatment decisions should be primarily guided by individual patient and disease factors, including mutation status, and physicians should weigh both the benefits and risks of prescribing ponatinib. Table 1. Patient Characteristics and Disposition by Number of Prior TKIs 1 TKI (n=19) 2 TKIs (n=98) 3 TKIs (n=141) 4 TKIs (n=12) Median age at baseline, years 52 58 63 67 Median time from diagnosis to first dose, years 2.8 5.2 7.9 12.4 Median dose intensity, mg/d 34.0 28.7 29.9 31.0 Mutations detected at baseline, % 68 51 43 75 T315I mutation detected at baseline, % 63 31 16 0 Prior TKI exposure, %, imatinib/dasatinib/nilotinib/bosutinib 68/21/5/5 97/66/36/1 100/96/96/7 100/100/100/100 Remain on study, % 53 48 40 8 Discontinued, % 47 52 60 92 Primary reason for discontinuation, % AE 16 18 17 33 Withdrawal by patient request 5 11 11 25 Disease progression 16 5 13 0 Lack of efficacy 0 2 9 8 Death 0 2 3 17 Othera 11 13 8 8 Median follow-up, months 42.3 42.9 42.1 28.2 aIncludes noncompliance, physician decision, protocol violation, and other reasons Table 2 Responses to Ponatinib by Number of Prior TKIs 1 TKI (n=16a) 2 TKIs (n=98) 3 TKIs (n=141) 4 TKIs (n=12) MCyR 12 (75) 69 (70) 69 (49) 7 (58) CCyR 12 (75) 63 (64) 63 (45) 4 (33) MMR 10 (63) 41 (42) 51 (36) 1 (8) MR4 6 (38) 30 (31) 38 (27) 1 (8) MR4.5 4 (25) 22 (22) 34 (24) 1 (8) All responses are n (%) a16/19 patients were evaluable for efficacy Disclosures Hochhaus: Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding. Cortes:ARIAD Pharmaceuticals Inc.: Other: Consulting & Advisory Role, Research Funding. Pinilla-Ibarz:Novartis: Consultancy, Other: Consulting & Advisory Role, Research Funding; ARIAD Pharmaceuticals, Inc.: Consultancy, Other: Consulting & Advisory Role, Research Funding; Teva: Consultancy, Speakers Bureau; Pfizer: Consultancy, Other: Consulting & Advisory Role, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Other: Consulting & Advisory Role, Speakers Bureau. le Coutre:Novartis: Honoraria; BMS: Honoraria; ARIAD Pharmaceuticals Inc.: Honoraria; Pfizer: Honoraria. Paquette:ARIAD Pharmaceuticals Inc.: Honoraria; BMS: Honoraria; Novartis: Honoraria. Chuah:Children International: Honoraria; Novartis: Honoraria; Bristol Meyers Squibb: Honoraria. Nicolini:Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Apperley:BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ARIAD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Talpaz:Pfizer: Other: CONSULTING OR ADVISORY ROLE; Novartis: Other: CONSULTING OR ADVISORY ROLE; ARIAD Pharmaceutical Inc.: Other: CONSULTING OR ADVISORY ROLE; Pfizer: Other: TRAVEL, ACCOMODATIONS, EXPENSES, Research Funding; Novartis: Other: TRAVEL, ACCOMODATIONS, EXPENSES, Research Funding; ARIAD Pharmaceutical Inc.: Other: TRAVEL, ACCOMODATIONS, EXPENSES, Research Funding; Incyte: Other: TRAVEL, ACCOMODATIONS, EXPENSES, Research Funding; Sanofi: Research Funding. DeAngelo:Incyte: Other: Consulting or Advisory Role; Pfizer: Other: Consulting or Advisory Role; Novartis: Other: Consulting or Advisory Role; BMS: Other: Consulting or Advisory Role; ARIAD Pharmaceuticals Inc.: Other: Consulting & Advisory Role; Amgen: Other: Consulting or Advisory Role. Abruzzese:BMS: Other: Consulting or Advisory Role; ARIAD Pharmaceuticals Inc.: Other: Consulting & Advisory Role; Novartis: Other: Consulting or Advisory Role; Pfizer: Other: Consulting or Advisory Role. Rea:Bristol-Myers Squibb: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Ariad: Honoraria. Baccarani:Pfizer: Other: Travel, Accommodations, Expenses; BMS: Other: Travel, Accommodations, Expenses; Novartis: Other: Travel, Accommodations, Expenses; ARAID Pharmaceutical Inc.: Other: Consulting or Advisory Role, Speakers Bureau; Pfizer: Honoraria, Other: Consulting or Advisory Role, Speakers Bureau; Novartis: Honoraria, Other: Consulting or Advisory Role, Speakers Bureau; BMS: Honoraria, Speakers Bureau; ARIAD Pharmaceutical Inc.: Other: Travel, Accommodations, Expenses. Muller:ARIAD Pharmaceuticals Inc.: Honoraria, Other: Consulting & Advisory Role, Research Funding; Novartis: Honoraria, Other: Consulting or Advisory Role, Research Funding; BMS: Honoraria, Other: Consulting or Advisory Role, Research Funding. Lustgarten:ARIAD Pharmaceuticals Inc.: Employment, Equity Ownership, Other: Stock. Conlan:ARIAD Pharmaceuticals Inc.: Other: Stock. Rivera:ARIAD Pharmaceuticals Inc.: Employment, Other: Full-time Employee & Shareholder (self-managed). Guilhot:Celgene: Consultancy, Other: CONSULTING OR ADVISORY ROLE; Pfizer: Honoraria; Novartis: Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES. Deininger:Incyte: Consultancy, Honoraria, Other: Consulting or Advisory Role; Pfizer: Consultancy, Honoraria, Other: Consulting or Advisory Role; ARIAD Pharmaceutical Inc.: Consultancy, Honoraria, Other: Consulting or Advisory Role; Gilead: Research Funding; Celgene: Research Funding; Novartis: Consultancy, Honoraria, Other: Consulting or Advisory Role, Research Funding; BMS: Consultancy, Honoraria, Other: Consulting & Advisory Role, Research Funding. Hughes:Bristol-Myers Squibb: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Shah:Pfizer: Research Funding; Bristol-Myers Squibb: Research Funding; Plexxikon Inc.: Research Funding. Kantarjian:Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Amgen: Research Funding.

Description: BACKGROUND: Ruxolitinib is a potent JAK1/JAK2 inhibitor that has proved superior to placebo and best available therapy in the phase 3 COMFORT studies for patients (pts) with intermediate (Int)-2- or high-risk myelofibrosis (MF). Ruxolitinib-treated pts demonstrated improvements in splenomegaly and MF-related symptoms as well as improved overall survival. JUMP is an expanded-access phase 3b trial designed to assess the safety and efficacy of ruxolitinib in pts with MF and includes those with no access to ruxolitinib outside of a clinical trial. Here, we report updated safety and efficacy findings for the full enrollment of JUMP, which includes 2233 pts in 26 countries. METHODS: Eligible pts had Int-2- or high-risk MF, with or without splenomegaly, or Int-1-risk MF with a palpable spleen (≥ 5 cm from the costal margin). Pts received starting doses of ruxolitinib based on platelet counts at baseline (5 mg twice daily [bid; ≥ 50 to 〈 100 × 109/L], 15 mg bid [100 to 200 × 109/L], 20 mg bid [〉 200 × 109/L]). The primary endpoint was assessment of safety and tolerability of ruxolitinib. Additional analyses included changes in palpable spleen length and symptom scores. The final analysis will be performed after all pts have completed 24 months of treatment or discontinued the study. RESULTS: This analysis includes 2233 pts (primary MF, 59.4% [n = 1326]) who started treatment ≥ 1 year before the data cutoff date (01 Jan 2016). At baseline, median age was 67 y (range, 18-89 y); 54.5% were male; median palpable spleen length was 12 cm below the costal margin; median time since diagnosis was 25.8 months. Median hemoglobin (Hb) was 106 g/L, and 38.3% of pts had Hb levels ˂ 100 g/L; median platelet count was 254 × 109/L; mean FACT-Lym TS and FACIT-Fatigue score were 113.9 and 33.4, respectively. At data cutoff, 15.8% of pts (353/2233) remained on treatment and 45.1% (1006/2233) completed treatment per protocol (ie, transitioned to commercial ruxolitinib). The primary reasons for treatment discontinuation were adverse events (AEs; 17.7%), disease progression (8.6%), and death (4.1%). Median exposure was 12.4 months; the median average daily dose of ruxolitinib was 23.1 mg for pts starting at 15 mg bid (n = 647 [29.0%]) and 36.5 mg for pts starting at 20 mg bid (n = 1384 [61.9%]). Overall 66.7% of pts had dose modifications and 26.3% had a dose interruption. Grade (G) 3/4 hematologic AEs included anemia (34.1%), thrombocytopenia (16.3%), and neutropenia (4.5%), which led to discontinuation in 1.5%, 2.7%, and 0.1% of pts, respectively. Nonhematologic AEs were primarily G1/2, and the most common (≥ 10%) were pyrexia (15.6%; G3/4, 2.3%), asthenia (14.9%; G3/4, 2.2%), and diarrhea (12.0%; G3/4, 1.1%). Rates of other G3/4 AEs were low (≤ 2%), except pneumonia (4.3%), which led to discontinuation in 10 pts (0.5%). Rates of infections were generally low; all-grade infections in ≥ 5% of pts included pneumonia (6.8%), urinary tract infection (5.6%), and nasopharyngitis (5.0%). Herpes zoster was reported in 4.6% of pts (G3/4, 0.5%), tuberculosis in 0.2% (G3/4, 0.04%) and hepatitis B in 1 pt (G3/4, 0.04%). At wk 24 and 48, 56.6% (874/1545) and 61.6% (658/1069) of pts with baseline splenomegaly achieved a ≥ 50% reduction from baseline in palpable spleen length; 23.3% (360/1545) and 18.9% (202/1069) had 25% to 50% reductions, respectively. Most pts (70.2% [1441/2054]) experienced a ≥ 50% reduction at any time; 23.7% had complete resolution of splenomegaly (Figure). At wk 24 and 48, 97.1% (67/69) and 92.3% (48/52) of evaluable pts without splenomegaly at baseline continued to have a nonpalpable spleen. A large proportion of pts achieved a response (ie, a clinically significant improvement) on the FACT-Lym TS and FACIT-Fatigue at wk 24 (42.4% [596/1406]; 46.6% [675/1447]) and wk 48 (42.9% [404/941]; 45.4% [434/957]). Overall, 221 patients received ESAs to manage anemia (G1, 7.2%; G2, 49.8%; G3, 38.9%; G4, 4.1%), and the majority had improved (32.6%) or resolved (31.7%) anemia (worsened, 16.3%; no change, 19.5%). CONCLUSIONS: This study includes the largest cohort of pts with MF treated with ruxolitinib to date. Consistent with findings from other studies, anemia and thrombocytopenia were the most common AEs but rarely led to discontinuation. As observed previously, most pts experienced reductions in splenomegaly and symptoms with ruxolitinib treatment. Overall, the safety and efficacy profile of ruxolitinib in JUMP is consistent with that in the COMFORT studies. Disclosures Foltz: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Palumbo:Celgene: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Honoraria; Roche: Honoraria. Al-Ali:Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Le Coutre:Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Other: travel, accomodations, expenses; Ariad: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: travel, accomocations, expenses, Research Funding. Vannucchi:Novartis: Consultancy, Research Funding, Speakers Bureau; Baxalta: Speakers Bureau; Shire: Speakers Bureau. Gupta:Novartis: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Research Funding. Bouard:Novartis Pharma AG: Employment. Perez Ronco:Novartis Pharma AG: Employment. Khanna:Novartis Healthcare Pvt. Ltd: Employment. Zaritskey:Janssen: Consultancy; Novartis: Consultancy.

Description: Background: Many patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) achieve a sustained deep molecular response (DMR) with frontline nilotinib (NIL) therapy. ENESTfreedom (NCT01784068) is an ongoing phase 2 study evaluating the potential for such pts to stop treatment and remain in treatment-free remission (TFR). Initial results from ENESTfreedom showed that 51.6% of pts who attempted TFR remained off treatment without loss of major molecular response (MMR [BCR-ABL1 ≤ 0.1% on the International Scale, BCR-ABL1IS]) at 48 weeks. Despite the enrollment of pts with established tolerance of NIL, the frequency of adverse events (AEs) decreased during the first 48 weeks of TFR compared with the year prior to stopping treatment (65.8% vs 83.2%, respectively), while AEs related to musculoskeletal pain were more common during TFR (24.7% vs 16.3%, respectively). The quality of life (QOL) of tyrosine kinase inhibitor-treated pts has gained increasing interest in recent years. To evaluate the impact of TFR on QOL, we analyzed patient-reported outcomes prior to and during TFR. Methods: Pts with CML-CP and ≥ 2 years of frontline NIL therapy (400 to 600 mg/day for the previous ≥ 1 year) who achieved MR4.5 (BCR-ABL1IS ≤ 0.0032%) on NIL were enrolled and entered a 1-year consolidation phase, during which they continued NIL with RQ-PCR assessments every 12 weeks. Pts with sustained DMR during the consolidation phase (no assessment worse than MR4 [BCR-ABL1IS ≤ 0.01%], ≤ 2 assessments between MR4 and MR4.5, and MR4.5 in the last assessment) entered the TFR phase and stopped treatment. Pts with loss of MMR during the TFR phase reinitiated NIL treatment (reinitiation phase). At specified time points, pts completed the MD Anderson Symptom Inventory for CML (MDASI-CML, in which pts rate the levels of severity and interference with daily life for a defined set of symptoms on a scale from 0 to 10, with 0 indicating the lowest severity/interference). At each time point, pts also completed the EQ-5D-5L questionnaire, in which they report the presence/absence and severity (slight, moderate, severe, or extreme) of problems related to mobility, self-care, usual activities, anxiety/depression, and pain/discomfort and rank their overall level of health from 0 to 100 using the EQ VAS scale, with 0 indicating the poorest level of health. Results: Among 215 pts enrolled, 190 remained in sustained DMR during the consolidation phase and entered the TFR phase. Mean MDASI-CML severity and interference scores and EQ VAS scores, respectively, among pts who completed each questionnaire were 1.4, 1.7, and 80.5 at week 48 of the consolidation phase; 1.1, 1.3, and 81.1 at week 12 of the TFR phase; and 1.2, 1.4, and 81.4 at week 48 of the TFR phase (Table). Among pts who sustained TFR and who had scores at both week 48 of the consolidation phase and week 12 or 48 of the TFR phase, no impact of stopping treatment on MDASI-CML or EQ VAS scores was detected. Among evaluable pts who lost MMR during the TFR phase and reinitiated NIL, mean scores at 24 weeks after treatment reinitiation were 1.3 (MDASI-CML severity), 1.5 (MDASI-CML interference), and 77.8 (EQ VAS). Among pts evaluable at both week 48 of the consolidation phase and week 24 of the reinitiation phase, mean scores were similar at both time points. Among pts who completed the EQ-5D-5L questionnaire, the proportions reporting problems (of any severity) at week 48 of the consolidation phase, weeks 12 and 48 of the TFR phase, and week 24 of the reinitiation phase tended to be similar. The proportion of pts reporting problems with anxiety/depression was lowest during the reinitiation phase (Table). Conclusion: Minimal changes in patient-reported outcomes were observed after stopping treatment. This may be related to pts having a relatively high QOL prior to stopping treatment, given that they had tolerated ≥ 2 years of NIL prior to enrollment. These data suggest that the higher frequency of musculoskeletal pain-related AEs in the TFR phase did not substantially impact pts' QOL; however, only a subset of pts were evaluable for changes in reported outcomes over time. Although many pts have fears about TFR, reported levels of anxiety/depression were similar before and after stopping treatment but decreased among pts who reinitiated treatment. Disclosures Hochhaus: BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding. Casares:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau. Stentoft:Pfizer: Research Funding; Ariad: Research Funding; Bristol-Myers-Squibb: Research Funding; Novartis: Research Funding. Conneally:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. García-Gutiérrez:Ariad: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Gattermann:Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: travel, accomodation expenses, Research Funding. Wiktor-Jedrzejczak:Sandoz: Consultancy; BMS: Research Funding; Novartis: Consultancy, Research Funding; Janssen-Cilag: Consultancy; Angelini: Consultancy; Novartis: Consultancy, Research Funding; Celgene: Consultancy; Amgen Inc.: Research Funding. Le Coutre:Ariad: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Other: travel, accomodations, expenses; Novartis: Consultancy, Honoraria, Other: travel, accomocations, expenses, Research Funding. Saussele:ARIAD: Honoraria; Novartis: Honoraria, Other: Travel grants, Research Funding; Pfizer: Honoraria, Other: Travel grants; BMS: Honoraria, Other: Travel grants, Research Funding. Giles:Novartis: Consultancy, Research Funding. Radich:Ariad: Consultancy; BMS: Consultancy; Novartis: Consultancy, Research Funding. Ross:BMS: Honoraria; Novartis Pharmaceuticals: Honoraria, Research Funding. Menssen:Novartis Pharma AG: Employment. Deng:Novartis Phamaceuticals Corp.: Employment. Brandt:Novartis: Employment. Gnanasakthy:Novartis: Consultancy, Equity Ownership, Research Funding. Bedoucha:Novartis: Employment. Saglio:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Roche: Consultancy, Honoraria.

Description: Key Points Ponatinib continued to provide deep, durable responses in heavily pretreated patients with CP-CML. Tolerability was acceptable in this heavily pretreated population with 5 years of follow-up.

Description: Introduction: The TIGER (CML V)-study* (NCT01657604) is a multicenter, randomized phase III trial to evaluate efficacy and tolerability of nilotinib (NIL) 2*300mg/d monotherapy vs NIL 2*300mg/d + pegylated interferon α2b (Peg-IFN) 30-50μg/week as first line therapy for chronic myeloid leukemia (CML) patients (pts) in chronic phase and discontinuation of therapy after Peg-IFN maintenance (Figure). Methods: In August 2012, recruitment started with a pilot phase, aiming to validate the recommended dose of Peg-IFN. 25 pilot phase patients were treated with the combination of NIL 2*300 mg daily and Peg-IFN (30-50μg/week according to tolerability and commenced after ≥6 weeks NIL monotherapy). During the main phase of the study, 692 newly diagnosed pts were randomized between NIL 2*300 mg/d and NIL/Peg-IFN combination according to the outcome of the pilot phase. Results: Within 5 years, a total of 717 pts (429 male; median age 51 years, range 18-85; 12.9% EUTOS high risk) were recruited from 109 sites in Germany, Switzerland, and the Czech Republic. 702 pts with typical BCR-ABL1 transcripts (97.9%) were eligible for molecular follow-up assessments according to the international scale (IS). Fifteen pts (2.1%) expressed atypical BCR-ABL1 transcripts. 692 pts were randomized after EUTOS risk stratification to receive NIL monotherapy (n=353) or NIL/PEG-IFN combination therapy (n=339). Median observation time since recruitment was 41 months. Up to now, 477 pts concluded the induction phase by achieving a confirmed major molecular response, MMR (BCR-ABL1 transcript levels ≤0.1% IS, which qualified for entering the maintenance phase of the study using NIL or Peg-IFN monotherapy. During the maintenance phase, 199 pts achieved or sustained MR4 (BCR-ABL1 ≤0.01% IS) for at least one year and then discontinued all therapy. While the rate of MMR at 12 and 18 mo - the first primary endpoint of the study - was not different between the treatment arms, adding Peg-IFN to upfront NIL significantly improved rates of MR4 and MR4.5, BCR-ABL1 ≤0.0032% IS) (Table). In competing risk analysis, median time to MMR was 5.7 vs 5.4 mo, to MR4 20.9 vs 12.5 mo, and to MR4.5 33.8 vs 23.2 mo for NIL vs NIL/Peg-IFN, respectively. After NIL discontinuation, during Peg-IFN maintenance therapy, rate of molecular recurrence (BCR-ABL1 〉1% IS) after 18 mo was 28%. From 199 pts who discontinued all therapy, 63 experienced a molecular relapse (BCR-ABL1 〉0.1%). Relapse free survival by 18 mo after treatment discontinuation was 61% in the total cohort. By protocol, it is too early to assign relapse rates to the randomized treatment arm. Frequencies of adverse events after 24 mo of therapy were 90 and 92% (grade 1-5) and 36 and 42% (grade 3-5) for NIL vs NIL/Peg-IFN, respectively. Adverse events of special interest (all grades) were fatigue in 34.6 vs 40.4%, thrombocytopenia in 13.3 vs 18.9% and elevation of the alanin aminotransferase (ALAT) in 11.0 vs 18.9% of pts in the NIL vs NIL/Peg-IFN arms, respectively. Fifteen pts (2.1%) progressed to accelerated phase or blast crisis; 22 pts (3.1%) received an allogeneic stem cell transplantation, 10 of them after disease progression. In total, 22 pts (3.1%) died, 16 during the induction phase, 4 in the maintenance phase and 2 in treatment free remission. Four deaths were related to CML, 3 to vascular complications. Conclusions: This per protocol interim analysis demonstrates feasibility of the first-line treatment with NIL 2*300 mg/d combined with PEG-IFN 30-50 μg/week. Peg-IFN, when added upfront to NIL further increases the rates of MR4 and MR4.5, which may translate into higher rates oftreatment free remission. *The study is being conducted on behalf of the German CML Study Group, the Swiss Group for Clinical Cancer Research (SAKK) and the East German Study Group on Hematology and Oncology (OSHO). Disclosures Hochhaus: Pfizer: Research Funding; Novartis: Research Funding; BMS: Research Funding; Incyte: Research Funding; MSD: Research Funding. Burchert:Novartis: Research Funding. Saussele:Novartis: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria. Baerlocher:Novartis: Research Funding. Brümmendorf:Janssen: Consultancy; Ariad: Consultancy; University Hospital of the RWTH Aachen: Employment; Pfizer: Consultancy, Research Funding; Merck: Consultancy; Novartis: Consultancy, Research Funding. La Rosée:Novartis: Research Funding; Bristol-Myers-Squibb: Consultancy, Other: Travel support, Speakers Bureau. Heim:Novartis: Research Funding. Krause:Siemens: Research Funding; Takeda: Honoraria; MSD: Honoraria; Gilead: Other: travel; Celgene Corporation: Other: Travel. le Coutre:Bristol-Myers Squibb: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Niederwieser:Daichii: Speakers Bureau; Cellectis: Consultancy. Lange:Novartis: Research Funding. Fabarius:Novartis: Research Funding. Hänel:Novartis: Honoraria; Amgen: Honoraria; Takeda: Other: advisory board; Celgene: Other: advisory board; Roche: Honoraria. Stegelmann:Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Mayer:AOP Orphan Pharmaceuticals AG: Research Funding. Hasford:Novartis: Research Funding. Hehlmann:Novartis: Research Funding. Ernst:Novartis: Research Funding. OffLabel Disclosure: Combination of Nilotinib and PEG-IFN alpha is being tested is off-label and being tested in the TIGER study.

Description: Introduction: Ponatinib, a potent oral tyrosine kinase inhibitor (TKI), is approved for use in patients with refractory CML and Ph+ ALL, including patients with the BCR-ABLT315I mutation. This post hoc analysis was undertaken to assess the evolution of the efficacy and safety of ponatinib over time in CP-CML patients in the ongoing phase 2 PACE trial (NCT01207440). Updated data with 4 years of follow-up, including an analysis of the management of select adverse events (AEs), will be presented. Methods: Patients with CML/Ph+ ALL who were resistant or intolerant to dasatinib or nilotinib or who had the T315I mutation (N=449) were enrolled and treated with ponatinib (starting dose 45 mg once daily). Accumulation of arterial occlusive events (AOEs) in the ponatinib program led to recommendations for dose reduction in PACE in October 2013. Efficacy and safety among CP-CML patients are reported as of February 2, 2015 in this abstract. Results: Included in the analysis were 270 CP-CML patients who received treatment, with a median follow-up of 42 (0.1-52.5) months. At the time of analysis, 42% of CP-CML patients (114/270) continued to receive ponatinib. Primary reasons for discontinuation were AEs (18%), withdrawal by patient (11%), and disease progression (10%). Characteristics of CP-CML patients continuing to receive ponatinib were similar to those of the overall cohort (Table 1). Of 267 CP-CML patients analyzed for efficacy, 59% and 53% achieved MCyR and CCyR at any time, and 39% and 23% achieved at least MMR and MR4.5, respectively; despite dose reductions from 45 mg/d at baseline, responses continued to deepen after the first year (Table 2). The probability of maintaining MCyR at 3 years was 83%, and the estimated PFS/OS rates were 60%/81% at 3 years. AEs in ≥20% of CP-CML patients were rash (46%), abdominal pain (46%), thrombocytopenia (45%), headache (43%), dry skin (41%), constipation (41%), hypertension (33%), arthralgia (32%), fatigue (30%), nausea (27%), increased lipase (26%), pyrexia (26%), myalgia (24%), pain in an extremity (21%), and back pain (20%). Most newly occurring AEs were observed within the first year. Rates of AOEs (any/serious) were 28%/23%, including cardiovascular (14%/11%), cerebrovascular (11%/9%), and peripheral vascular (11%/8%) events; median time to onset for AOEs was 14.1 (0.3-44.0) months. Exposure-adjusted incidence rates of new AOEs (events per 100 patient-years) have appeared to remain approximately stable or decrease over time; rates were 14.3 in Year 1, 15.2 in Year 2, 11.7 in Year 3, and 9.9 in Year 4 (analysis for Year 4 does not yet cover a full fourth year for all CP-CML patients). Conclusions: With longer follow-up in the PACE trial, the benefit/risk profile of ponatinib continues to evolve and remains favorable for many patients in this trial. In this analysis, the baseline characteristics of patients remaining on study did not differ substantially across the time points examined. Despite a decline from initial dose intensity, deep and lasting responses have continued to be observed after the first year in this trial of heavily pretreated patients. Most AEs have occurred early in treatment; AOEs have typically had a later onset-exposure-adjusted incidence rates of AOEs have not increased over time. Table 1. Characteristics of CP-CML Patients Continuing to Receive Ponatinib Over Time Baseline (n=270) Patients Receiving Ponatinib at 1 Year (n=179) Patients Receiving Ponatinib at 2 Years (n=156) Patients Receiving Ponatinib at 3 Years (n=125) Median age at baseline, years 60 58 58 58 ≥2 prior TKIs at baseline, % 93 91 92 92 ≥3 prior TKIs at baseline, % 60 55 54 54 Median time from diagnosis to first dose, years 7.0 6.9 7.0 6.7 Median dose intensity, mg/d 45.0 29.1 29.0 28.8 Mutations detected at baseline, % 49 49 48 47 T315I mutation detected at baseline, % 24 25 23 22 Table 2. Cumulative Response Rates in CP-CML Patients Receiving Ponatinib Over Time (n=267) By 1 Year, % By 2 Years, % By 3 Years, % Total, % MCyR 55 58 59 59 CCyR 50 53 53 53 MMR 30 36 39 39 MR4.5 9 16 22 23 Disclosures Cortes: Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; ARIAD Pharmaceuticals Inc.: Consultancy, Research Funding; Teva: Consultancy, Research Funding. Pinilla-Ibarz:Pfizer: Consultancy, Other: Consulting & Advisory Role, Research Funding, Speakers Bureau; Novartis: Consultancy, Other: Consulting & Advisory Role, Research Funding; Teva: Consultancy, Speakers Bureau; ARIAD Pharmaceuticals, Inc.: Consultancy, Other: Consulting & Advisory Role, Research Funding; BMS: Consultancy, Honoraria, Other: Consulting & Advisory Role, Speakers Bureau. le Coutre:Novartis: Honoraria; ARIAD Pharmaceuticals Inc.: Honoraria; BMS: Honoraria; Pfizer: Honoraria. Paquette:ARIAD Pharmaceuticals, Inc.: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Astra-Zeneca: Consultancy. Chuah:Children International: Honoraria; Novartis: Honoraria; Bristol Meyers Squibb: Honoraria. Nicolini:Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Apperley:BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ARIAD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Talpaz:Pfizer: Consultancy, Other: Travel/Expenses, Research Funding; Novartis: Consultancy, Other: Travel/Expenses, Research Funding; ARIAD Pharmaceuticals, Inc.: Consultancy, Other: Travel/Expenses, Research Funding; Sanofi: Research Funding; Incyte: Other: Travel/Expenses, Research Funding. DeAngelo:Incyte: Consultancy; Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Pfizer: Consultancy; Celgene: Consultancy; Ariad: Consultancy; Agios: Consultancy; Amgen: Consultancy. Abruzzese:Pfizer: Other: Consulting or Advisory Role; Novartis: Other: Consulting or Advisory Role; BMS: Other: Consulting or Advisory Role; ARIAD Pharmaceuticals Inc.: Other: Consulting & Advisory Role. Rea:Bristol-Myers Squibb: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Ariad: Honoraria. Baccarani:NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ARIAD Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Müller:BMS: Honoraria, Other: Consulting or Advisory Role, Research Funding; Novartis: Honoraria, Other: CONSULTING OR ADVISORY ROLE, Research Funding; ARIAD Pharmaceuticals Inc.: Honoraria, Other: Consulting & Advisory Role, Research Funding. Lustgarten:ARIAD Pharmaceuticals Inc.: Employment, Equity Ownership, Other: Stock. Conlan:ARIAD Pharmaceuticals Inc.: Other: Stock. Guilhot:Novartis: Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES; Pfizer: Honoraria; Celgene: Consultancy, Other: CONSULTING OR ADVISORY ROLE. Deininger:BMS: Consultancy, Honoraria, Other: Consulting & Advisory Role, Research Funding; Novartis: Consultancy, Honoraria, Other: Consulting or Advisory Role, Research Funding; Celgene: Research Funding; Gilead: Research Funding; ARIAD Pharmaceutical Inc.: Consultancy, Honoraria, Other: Consulting or Advisory Role; Pfizer: Consultancy, Honoraria, Other: Consulting or Advisory Role; Incyte: Consultancy, Honoraria, Other: Consulting or Advisory Role. Hochhaus:Bristol-Myers Squibb: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Hughes:ARIAD: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Kantarjian:Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Amgen: Research Funding. Shah:ARIAD Pharmaceuticals, Inc.: Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Plexxikon: Research Funding; Daiichi-Sankyo: Research Funding.

Description: Moxetumomab pasudotox-tdfk is a first-in-class recombinant CD22-directed cytotoxin approved in the US for the treatment of adult patients with relapsed/refractory hairy cell leukemia (HCL). The pivotal, multicenter, open-label, single-arm trial (Study 1053; NCT01829711) evaluated the efficacy, safety, immunogenicity, and pharmacokinetics of moxetumomab pasudotox-tdfk monotherapy in patients with relapsed/refractory HCL. Here we present the final analysis, describing the long-term follow-up of patients in Study 1053, with a median follow-up of 24.6 months (range 1.2-71.7). Eligible patients had received ≥ 2 prior systemic therapies, including ≥ 2 courses of a purine nucleoside analog (PNA) or 1 course of a PNA followed by ≥ 1 course of rituximab or a BRAF inhibitor. Patients received moxetumomab pasudotox-tdfk 40 µg/kg intravenously on days 1, 3, and 5 of each 28-day cycle for 6 cycles, or until minimal residual disease (MRD)-negative complete response (CR), disease progression, initiation of alternate therapy, or unacceptable toxicity. Disease response and immunohistochemistry MRD status were determined by blinded independent central review. The primary endpoint was durable CR (achieving CR and maintaining hematologic remission [HR] for 〉 180 days). Durable CR with HR ≥ 360 days was measured in this final analysis. HR was defined as hemoglobin ≥ 11.0 g/dL, absolute neutrophil count ≥ 1.5 × 103/µL, and platelet count ≥ 100 × 103/µL without receiving transfusions or growth factors within the 4 preceding weeks of assessment. Eighty patients (63 males; median age 60 years [range 34-84]) were enrolled and treated with moxetumomab pasudotox-tdfk. The median number of prior systemic therapies was 3 (range 2-11); 48.8% of patients were PNA-refractory and 37.5% were unfit for PNA retreatment. The median number of treatment cycles administered was 6 (range 1-7). The durable CR rate was 36.3% (29/80 patients; 95% confidence interval [CI]: 25.8-47.8%), durable CR rate with HR ≥ 360 days was 32.5% (26/80 patients; 95% CI: 22.4-43.9%), and the overall CR rate was 41.3% (33/80 patients; 95% CI: 30.4-52.8%) (Table). Overall, 27/33 (81.6%) patients who achieved a CR also achieved MRD-negative status (33.8% of all patients). HR was achieved by 64/80 patients (80.0%). The median duration of HR from CR was 62.8 months (Figure) and median progression-free survival was 41.5 months (range 0.0+ to 71.7). Per the primary analysis, the most frequent treatment-related adverse events (AEs) were nausea (28%), peripheral edema (26%), headache (21%), and pyrexia (20%). Treatment-related Grade 3/4 AEs were reported in 24 patients (30.0%) and serious AEs in 28 (35.0%). Treatment-related AEs led to study drug discontinuation in 8 patients (10.0%): hemolytic uremic syndrome (HUS), n = 4 (5.0%); capillary leak syndrome (CLS), n = 2 (2.5%); and increased blood creatinine, n = 2 (2.5%). Grade ≥ 3 CLS events occurred in 2 patients (2.5%) and Grade ≥ 3 HUS occurred in 5 patients (6.3%). In general, CLS and HUS events were manageable and reversible with appropriate supportive care and monitoring. Based on primary and follow-up analyses of serum creatinine, there was no decline in renal function over time; 12 months post-treatment all mean (SD) serum creatinine laboratory values stayed within normal limits, which suggests current management strategies for HUS (oral hydration, i.v. fluid supplementation on the day of infusion, and the use of dexamethasone) are adequate. With 24.6 months of follow-up, 4 deaths were reported: 2 due to study disease progression and 2 due to an AE (1 each of pneumonia and septic shock). Moxetumomab pasudotox-tdfk treatment was associated with a manageable safety profile. Moxetumomab pasudotox-tdfk achieved a high rate of durable responses, demonstrating the ability to achieve MRD negativity in heavily pretreated patients with HCL. Disclosures Kreitman: Genentech: Research Funding. Dearden:Abbvie: Honoraria; Genentech: Honoraria; Janssen: Honoraria; Sanofi: Honoraria. Zinzani:MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; VERASTEM: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CELLTRION: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GILEAD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; JANSSEN-CILAG: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; IMMUNE DESIGN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSAPHARMA: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ROCHE: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SERVIER: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SANDOZ: Membership on an entity's Board of Directors or advisory committees; KYOWA KIRIN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CELGENE: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SANOFI: Consultancy; PORTOLA: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Robak:Amgen: Consultancy, Other: Travel grant; UCB: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grant, Research Funding; Roche: Consultancy, Other: Travel grant, Research Funding; Abbvie: Consultancy, Honoraria, Other: Travel grant, Research Funding; Gilead: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Acerta: Research Funding; Morphosys AG: Research Funding; Takeda: Consultancy, Research Funding. le Coutre:Novartis: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Gjertsen:Research Council of Norway: Research Funding; Daiichi Sankyo: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; BerGenBio: Consultancy; KinN Therapeutics AS: Equity Ownership; Seattle Genetics: Consultancy; ERA PerMed: Research Funding; Haukeland University Hospital / University of Bergen: Employment; ACTII AS: Equity Ownership; Astellas: Consultancy; BerGenBio AS: Membership on an entity's Board of Directors or advisory committees; The Norwegian Cancer Society: Research Funding; Helse Vest Health Trust: Research Funding; EU Horizon 2020: Research Funding. Troussard:Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Other: Research Support; Sysmex: Other: Research Support. Roboz:Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: 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; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Karlin:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; AMGEN: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support. Kuptsova-Clarkson:AstraZeneca: Employment, Equity Ownership. Liu:Acerta Pharma: Employment. Patel:Acerta Pharma: Employment, Equity Ownership; AstraZeneca: Equity Ownership.

Description: Introduction: Bosutinib is a potent SRC/ABL tyrosine kinase inhibitor approved for treatment of adults with CML resistant or intolerant to prior therapy. Here we compare the efficacy and safety of first-line bosutinib versus imatinib in patients with chronic phase (CP) CML enrolled in BFORE after ≥18 months of follow-up. Methods: BFORE (NCT02130557) is an ongoing, multinational, open label phase 3 study that randomized 536 patients 1:1 to 400 mg QD bosutinib (n=268) or 400 mg QD imatinib (n=268 [3 not treated]). The prespecified primary endpoint was major molecular response (MMR) rate at 12 months in the modified intent-to-treat (mITT) population, defined as Philadelphia chromosome‒positive (Ph+) patients with e13a2/e14a2 transcripts, and excluding Ph- patients and those with unknown Ph status and/or BCR-ABL transcript type (mITT: BOS, n=246; IM, n=241). Efficacy results refer to the mITT population unless otherwise noted. Results: MMR rate was higher with bosutinib versus imatinib at 18 months (56.9% vs 47.7%; P=0.042). Among all randomized patients (ITT) 18-month MMR rates were higher for bosutinib (56.7% vs 46.6%; P