Egyed, Miklós

Abstract PAC203 is a randomized dose-finding study of pacritinib, an oral JAK2/IRAK1 inhibitor, in patients with advanced myelofibrosis who are intolerant of or resistant to ruxolitinib. Patients were randomized 1:1:1 to pacritinib 100 mg once per day, 100 mg twice per day, or 200 mg twice per day. Enhanced eligibility criteria, monitoring, and dose modifications were implemented to mitigate risk of cardiac and hemorrhagic events. Efficacy was based on ≥35% spleen volume response (SVR) and ≥50% reduction in the 7-component total symptom score (TSS) through week 24. Of 161 patients, 73% were intolerant of and 76% had become resistant to ruxolitinib; 50% met criteria for both. Severe thrombocytopenia (platelet count <50 × 103/μL) was present in 44%. SVR rates were highest with 200 mg twice per day (100 mg once per day, 0%; 100 mg twice per day, 1.8%; 200 mg twice per day, 9.3%), particularly among patients with baseline platelet counts <50 × 103/μL (17%; 4 of 24). Although TSS response rate was similar across doses (100 mg once per day, 7.7%; 100 mg twice per day, 7.3%; 200 mg twice per day, 7.4%), median percent reduction in TSS suggested a dose-response relationship (–3%, −16%, and −27%, respectively). Pharmacokinetic and pharmacodynamic modeling based on all available data showed greatest SVR and TSS reduction at 200 mg twice per day compared with lower doses. Common adverse events were gastrointestinal events, thrombocytopenia, and anemia. There was no excess of grade ≥3 hemorrhagic or cardiac events at 200 mg twice per day. Pacritinib 200 mg twice per day demonstrated clinical activity and an acceptable safety profile and was selected as the recommended dose for a pivotal phase 3 study in patients with myelofibrosis and severe thrombocytopenia. This trial was registered at www.clinicaltrials.gov as #NCT03165734.

Abstract Introduction Patients with mantle cell lymphoma (MCL) typically respond to initial therapy and almost inevitably relapse with frequent chemoresistance over time and poor outcome. Multiple phase II studies have established the efficacy and safety of lenalidomide, an immunomodulatory agent with tumoricidal and antiproliferative properties, in relapsed/refractory MCL. The prospective phase II multicenter MCL-001 “EMERGE” study led to FDA approval of lenalidomide for patients with relapsed/refractory MCL after 2 prior treatments, that included bortezomib. The activity of lenalidomide was seen regardless of MIPI, number of prior therapies, prior high dose therapy, bulky disease or high tumor burden. One of the most established prognostic factors in MCL is the proliferation index Ki67 (MIB1), now confirmed both in standard and dose-intensive high-dose therapy strategies. We present here longer follow-up of efficacy and safety from the MCL-001 study in patients relapsed/refractory to bortezomib and the potential relationship between Ki-67 and efficacy outcomes. Methods Patients with heavily pretreated MCL, that included prior bortezomib, received lenalidomide 25 mg/day PO, days 1-21 in 28-day cycles until disease progression or intolerability. Primary study endpoints were overall response rate (ORR) and duration of response (DOR); secondary endpoints included complete response (CR), time to response (TTR), progression-free survival (PFS), overall survival (OS), and safety. Response rates and time-to-event data were analyzed by independent central reviewers per modified IWG criteria and Kaplan-Meier estimates respectively (data cut-off March 20, 2013). Ki-67 was examined as an exploratory endpoint by immunohistochemistry for 81/134 patients (60%) either performed on biopsy samples for 24 patients, or based on the Ki-67 scores reported in local pathology reports for 57 patients. Results Median age for the enrolled intent-to-treat patient population (N=134) was 67 years (range, 43-83; 63% ≥65 years). The median number of previous therapies was 4 (range, 2-10; 78% received ≥3), 93% stage III/IV, and 72% were <6 months from last prior treatment. At a median follow-up of 13.2 months, the ORR was 28% (CR/CRu 8%), with a median DOR of 16.6 months (95% CI, 9.2-26.7; median not reached in patients with CR/CRu) by central review. Median TTR was 2.3 months (95% CI, 1.7-13.1), with a median time to CR/CRu of 4.1 months (95% CI, 1.9-13.2). Median PFS was 4.0 months (95% CI, 3.6-6.9), and median OS was 20.9 months (95% CI, 13.7-24.4). The average dose intensity of lenalidomide was 20 mg/day, for a median duration of 94.5 days (range, 1-1,256). Dose reductions or interruptions due to adverse events (AEs) occurred in 40% and 58% of patients, respectively. Neutropenia (44%), thrombocytopenia (28%), and anemia (11%) were the most common treatment-related grade 3/4 AEs. Ki-67 results were available in 81/134 patients, and efficacy data were categorized using 30% and 50% cut-off thresholds for Ki-67 expression (Table 1). Although patient numbers were limited, the ORR was similar in both lower and higher Ki-67 group, but those with lower Ki-67 levels demonstrated better CR rates, DOR and survival outcomes compared with patients with elevated Ki-67. Conclusions Single-agent lenalidomide in heavily pretreated patients with relapsed/refractory MCL post-bortezomib showed durable long-term efficacy with a consistent safety profile. Consistent with what is reported in the literature, high Ki-67 is associated with poor outcome in our cohort with shorter OS. Though based on retrospective evaluation and subsets of patients, the ORR to lenalidomide was similar in both low and high Ki-67 groups, suggesting lenalidomide can be active in patients expressing high levels of Ki67. Prospective studies are needed to confirm these findings. Disclosures: Goy: Celgene: Consultancy, Research Funding, Speakers Bureau. Off Label Use: This is a phase 2 clinical study of safety and efficacy for lenalidomide in patients with MCL. Williams:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Drach:Celgene: Honoraria. Ramchandren:Celgene: Research Funding. Zhang:Celgene: Employment. Cicero:Celgene: Employment. Fu:Celgene: Employment. Heise:Celgene: Employment, Equity Ownership. Witzig:Celgene: Research Funding.

Abstract Introduction: Despite recent advances in available treatments, chronic lymphocytic leukemia (CLL) remains an incurable disease, and the vast majority of patients (pts) will relapse and require additional lines of therapy. Thus, prolonging remission is a key treatment goal in CLL. This multicenter, randomized, double-blinded phase 3 trial (NCT00774345) was designed to evaluate the efficacy and safety of lenalidomide (LEN) vs placebo (PBO) as maintenance therapy in previously treated CLL pts. Methods: Eligible CLL pts must have had at least a partial response (PR) to second-line therapy. Pts were randomized 1:1 to receive either LEN 2.5 mg once daily on days 1-28 of the first 28-day cycle, or matching PBO. If LEN was well tolerated, escalation to 5 mg/day was permitted from cycle 2, and further escalation to 10 mg/day at cycle 7 and thereafter. Pts were stratified by their response at the end of second-line therapy (PR, nodular PR, complete response [CR], or CR with incomplete bone marrow recovery; vs minimal residual disease [MRD]-negative CR by flow cytometry); age (≤ 70 vs > 70 years); and presence of at least one of the following poor prognostic factors: del(11q), del(17p), unmutated IGHV, or b2M > 0.4 mg/L (Yes vs No vs Unknown). Co-primary endpoints were progression-free survival (PFS; IRAC assessed) and overall survival (OS). Secondary endpoints included: safety, tumor response, duration of response, second PFS (PFS2, time from randomization to second disease progression or death), and health-related quality of life (HRQoL). Results: Overall, 314 pts were enrolled (LEN, n = 160; PBO, n = 154). Baseline characteristics were balanced between the treatment arms: median age was 63 years (range 37-82) and 63 years (range 37-84), 71.9% and 72.1% were male, 9.4% and 11.7% had MRD-negative CR to second-line treatment, and 47.5% and 47.4% had at least one poor prognostic factor, in the LEN and PBO arms, respectively. On review of the primary analysis, 30 Sept 2015 data cutoff, the required number of progression events to complete the co-primary analysis had occurred, and the data monitoring committee recommended that the study be unblinded. Median follow-up time was 31.5 months, and the median PFS was significantly longer for LEN vs PBO: 33.9 vs 9.2 months, respectively (HR 0.40 [95% CI 0.29, 0.55]; P < 0.001). At the time of the analysis there were 86 deaths and there was no significant difference in the OS (HR 0.96 [95% CI 0.63, 1.48]; P = 0.856). Subsequent CLL therapy was received by 35.7% of pts in the LEN arm and 58.4% of pts in the PBO arm, of these pts 16% in the LEN arm and 20% in the PBO arm were treated with a BTK or PI3K inhibitor. Median PFS2 was significantly longer for LEN vs PBO: 57.5 vs 32.7 months, respectively (HR 0.46 [95% CI 0.29, 0.70]; P <0.001). Median number of treatment cycles received was 18 vs 9 cycles, for LEN vs PBO, respectively; a higher proportion of pts in the LEN arm started ≥25 cycles vs the PBO arm (38.9% vs 24.0%, respectively). Median dose intensity in the LEN arm was 4.2 mg/day. The most common adverse events (AEs) of all grades were neutropenia (66.2% vs 30.5%) and diarrhea (40.8% vs 16.2%) in the LEN vs PBO arm, respectively. Febrile neutropenia occurred in 1.9% vs 0%, deep vein thrombosis in 1.9% vs 0%, and pulmonary embolism in 2.5% vs 0.6% of pts in the LEN vs PBO arm, respectively. Most common grade 3/4 AEs were neutropenia (59.9% vs 22.7%), thrombocytopenia (16.6% vs 6.5%), and diarrhea (8.3% vs 0.6%) in the LEN vs PBO arm, respectively; all other grade 3/4 AEs occurred in <5% of pts in either arm. While there was a significant difference in the incidence of neutropenia, the rate of grade 3/4 infections was 16.6% for LEN vs 10.4% for PBO-treated pts. There were 13 (8.3%) vs 14 (9.1%) pts with at least one invasive second primary malignancy (SPM) in the LEN vs PBO arm, respectively. Hematologic invasive SPMs occurred in 7 vs 2 pts, and solid tumor invasive SPMs occurred in 7 vs 12 pts, in the LEN vs PBO arm, respectively. Overall, 44 pts in the LEN arm and 41 pts in the PBO arm died; 1 pt died on treatment in the LEN arm, and 2 pts in the PBO arm. There was no clinically meaningful difference in HRQoL for LEN vs PBO, as measured by FACT-Leu and EQ-5D, during maintenance treatment. Conclusions: LEN maintenance therapy significantly improved PFS from 9.2 to 33.9 months following second-line treatment in pts with CLL. The incidence of invasive SPMs was similar in both arms, and LEN maintenance treatment had an expected and acceptable safety profile. Disclosures Foà: Roche: Consultancy, Speakers Bureau; Janssen: Speakers Bureau; Gilead,: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Celgene Corporation: Consultancy, Speakers Bureau; Pfizer, Ariad: Speakers Bureau; Genentech, Janssen, BMS: Consultancy. Schuh:Gilead: Consultancy, Honoraria, Research Funding; Roche, Janssen, Novartis, Celgene, Abbvie: Consultancy, Honoraria. Zaritskey:Novartis: Consultancy; Janssen: Consultancy. Semochkin:Celgene, Sandoz, Novartis, Astellas, Janssen Pharmaceuticals, Bristol-Myers Squibb: Speakers Bureau; Celgene, Bayer Healthcare, Astellas Pharma Inc.: Research Funding; City Clinical Hospital 52, Moscow, Russia: Consultancy. Simpson:Amgen Pharmaceuticals: Research Funding; Celgene, Roche, Janssen: Honoraria. Vokurka:Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Zhang:Celgene Corporation: Employment, Equity Ownership. Purse:Celgene Corporation: Employment, Equity Ownership.

Abstract Background: The majority of pts with MF present with a mutation in exon 14 of the JAK2 gene (JAK2V617F). Studies have suggested that in pts with MF and this mutation, a lower AB is associated with a myelodepletive phenotype and shortened survival (Tefferi, Leukemia 2008; Guglielmelli Blood 2009; reviewed in Vannucchi, Ther Adv Hematol 2011). For example, in a Cox proportional hazard model for factors predictive of overall survival (OS) in pts with primary MF, a JAK2V617F AB of <25% was associated with a shortened OS (p=0.002; Guglielmelli, Blood 2009). In the phase III trials of ruxolitinib (RUX) therapy in JAK inhibitor-naïve MF, RUX-treated pts had a median decrease in AB of 16% (maximal) in COMFORT-I followed up to 216 weeks and 7% in COMFORT-II at 48 weeks. The median AB at the start of therapy was not reported for COMFORT-I and in COMFORT-II was 84.5% (Cervantes, Blood 2013; Deininger, Blood2015). Methods: In this communication, we report on clinical correlates of quantitative baseline JAK2 mutational status and the effect of treatment on JAK2V617Fmutational burden in the PERSIST-1 trial. This trial enrolled JAK inhibitor-naïve pts with primary or secondary MF without restrictions on baseline platelet counts, randomized 2:1 between PAC and BAT (excluding JAK2 inhibitors) arms. Stratifications included Dynamic International Prognostic Scoring System (DIPSS) risk category, and baseline platelet counts (<50,000/μL, 50,000-100,000/μL, >100,000/μL). Following the 24-week primary analysis, crossover was allowed by physician/pt choice and 90/107 BAT-treated pts (84%) crossed over to receive PAC. Baseline characteristics have been previously reported (Mesa, ASCO 2016) and included 203/327 (62%) pts with Primary MF, 42 (13%) with post-essential thrombocythemia MF and 81 (25%) with post-polycythemia vera MF. 320 of 327 pts had informative PCR testing for JAK2V617F. We report the baseline characteristics of pts with high (≥50%) AB of JAK2V617F, low (<50%) AB of JAK2V617Fand those without a detectable mutation at baseline (<0.1%), as well as the effect of PAC and BAT on AB and correlation with outcome measures. Results: 131 (40.9%) had AB >50% (high AB), 115 (35.9%) had an AB ≥0.1% and ≤50% (low AB), and 74 (23.1%) had AB <0.1% (wild-type JAK2). Median AB values were 80.3% for the high AB group and 30.3% for the low AB group. Baseline characteristics that were significantly different between high and low AB pts are shown in the Table. No differences were noted in the DIPSS risk category or baseline percentage of blasts between pts with low or high AB. There were a higher percentage of pts with a lower AB in the PAC arm (64% vs. 48%; p=0.01). PAC therapy resulted in a median decrement in AB at Week 24 of −15.8% vs −7.9% for pts in the BAT arm (Figure). The median greatest reduction from baseline in AB in PAC-treated pts was −31.6%. Decrease in AB was strongly correlated with spleen volume reduction (p=0.003) and trended towards correlation with improvement in total symptom score (p=0.07) in PAC-treated, but not in BAT-treated pts. Overall survival was shorter in PAC-treated pts with a minimal AB reduction vs pts with greater decreases in AB. Conclusions: In the PERSIST-1 trial, pts with a JAK2V617FAB of <50% had substantially different disease and demographic characteristics when compared with those pts with a >50% AB despite similar distribution of DIPSS scores. In this trial, reduction in AB associated with PAC, but not BAT correlated with clinical benefit. Disclosures Vannucchi: Novartis: Consultancy, Research Funding, Speakers Bureau; Baxalta: Speakers Bureau; Shire: Speakers Bureau. Mead:Baxalta: Consultancy, Honoraria. Perkins:Novartis Oncology: Consultancy, Honoraria; Bristol-Myers Squibb: Other: Travel, Accommodations, Expenses. Mayer:CTI BioPharma Corp.: Other: Travel, Accommodations, Expenses, Research Funding. Schouten:Sanofi: Consultancy; Novartis: Consultancy. Farber:Alexion: Equity Ownership; Celgene: Honoraria, Research Funding, Speakers Bureau; Genentech: Research Funding, Speakers Bureau; Acerta: Research Funding; Gilead: Research Funding, Speakers Bureau; TG Therapeutics: Research Funding; Seattle Genetics: Speakers Bureau; Pharmacyclics: Speakers Bureau. Kiladjian:Novartis: Honoraria, Research Funding; AOP Orphan: Consultancy, Research Funding. Nangalia:Novartis: Consultancy, Other: Travel, Accommodations, Expenses. Dean:CTI BioPharma Corp.: Employment, Equity Ownership. Zhou:CTI BioPharma Corp.: Employment, Equity Ownership. Singer:CTI BioPharma Corp.: Employment, Equity Ownership, Other: Leadership . Mesa:Novartis: Consultancy, Honoraria; Incyte: Research Funding; Gilead: Research Funding; CTI BioPharma: Research Funding; Celgene: Research Funding; Genetech: Research Funding; Promedior: Research Funding. Harrison:Novartis: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; CTI BioPharma: Consultancy, Honoraria, Speakers Bureau; Baxter: Consultancy, Honoraria; Shire: Speakers Bureau; Gilead: Speakers Bureau; Incyte: Speakers Bureau.

Abstract Abstract 905 Introduction: Though dose-intensive strategies using chemoimmunotherapy have significantly improved mantle cell lymphoma (MCL) outcomes with prolonged progression-free survival (PFS), most patients still relapse over time. In the relapsed setting, MCL patients often develop chemoresistance and have a poor overall prognosis. The immunomodulatory agent lenalidomide has demonstrated tumoricidal and antiproliferative effects in MCL and clinical activity and safety in multiple phase II studies in aggressive non-Hodgkin's lymphoma. The objective of the MCL-001 “EMERGE” study was to examine the safety and efficacy of single-agent lenalidomide in subjects with MCL who relapsed or were refractory to bortezomib. Methods: This phase II, multicenter, single-arm, open-label study examined single-agent lenalidomide administered at 25 mg/d PO on days 1–21 of a 28-day cycle until disease progression, unacceptable toxicity, or voluntary withdrawal. The subjects were required to have had prior treatment with rituximab, cyclophosphamide and anthracycline (or mitoxantrone), and to have relapsed or progressed (<12 months) after or were refractory to bortezomib. The primary endpoints were overall response rate (ORR) and duration of response (DOR); secondary endpoints included complete response (CR), PFS, time to progression (TTP), overall survival (OS) and safety. Efficacy data were measured by investigators and an independent central review committee according to modified International Working Group criteria and analyzed by SAS. Results: 134 subjects with relapsed or refractory MCL who were heavily pretreated (no limitation in number of prior therapies) were enrolled. The median age was 67 y (range, 43–83), two-thirds of them being 65 y or older and 93% with advanced stage disease (stage III-IV). The median number of prior therapies was 4 (range, 2– 10) with 78% of subjects having received ≥ 3 prior lines of treatment. The ORR to single-agent lenalidomide was 28% (CR/CRu 8%; Table 1) by independent central review, with a median DOR of 16.6 mo (95% CI, 7.7–26.7; Figure 1). The ORR was 32% (CR/CRu 16%) by investigator assessment, with a median DOR of 18.5 mo. Median time to response (central review) was 2.2 mo (3.7 mo to achieve CR). The median PFS was 4.0 mo (95% CI, 3.6–5.6); median OS was 19.0 mo (95% CI, 12.5–23.9). Subjects received an average dose of 20 mg/d of lenalidomide. Lenalidomide was dose reduced in 38% of subjects; treatment discontinuation due to an adverse event (AE; primarily myelosuppression) was reported in 19% of subjects. The most common grade 3/4 AEs were neutropenia (43%), thrombocytopenia (28%), anemia (11%), pneumonia (8%) and fatigue (7%). Other AEs (any grade) included tumor flare reaction (13 subjects, 10%), deep vein thrombosis (5 subjects, 4%), pulmonary embolism (3 subjects, 2%) and invasive second primary malignancies (3 subjects, 2%). Conclusions: The EMERGE study demonstrated rapid and durable efficacy of lenalidomide in MCL subjects who relapsed or progressed after or were refractory to bortezomib. These results in heavily pretreated MCL subjects (median of 4 prior treatments), and with an expected toxicity profile support single-agent lenalidomide in subjects with relapsed or refractory MCL after bortezomib. Disclosures: Goy: Pfizer: Advisory board member, Advisory board member Other; Seattle Genetics: Advisory board member Other; J&J: Advisory board member, Advisory board member Other; Pharmacyclics: Advisory board member, Advisory board member Other; Millenium: Advisory board member, Advisory board member Other, Speakers Bureau; Celgene: Advisory board member Other. Off Label Use: This is a phase 2 clinical study of safety and efficacy for lenalidomide in patients with MCL. Sinha:Celgene: Research Funding. Williams:Celgene: Clincial Trial Research Support, Advisory Boards, Data Safety Committee Member, Consultant Other, Consultancy. Drach:Celgene: Speakers Bureau; Janssen: Speakers Bureau; Roche: Research Funding. Ramchandren:Seattle Genetics: Speakers Bureau. Herbrecht:Pfizer: Advisory board member Other. Zhang:Celgene: Employment. Cicero:Celgene: Employment. Fu:Celgene: Employment. Witzig:Celgene : Research Funding.

7000 Background: MMB, an oral JAKi, has been shown in early trials to reduce spleen volume, improve disease associated symptoms (Sx) and improve RBC transfusion (Tx) requirements in patients (pts) with MF. This study was designed to test non-inferiority of MMB vs RUX in splenic volume reduction and Sx amelioration, and superiority in Tx requirement, in JAKi naïve MF pts. Methods: Eligibility: MF, IPSS high risk, Int-2, or symptomatic Int-1; palpable spleen ≥5cm; platelets ≥ 50 K/μl, and no Gr ≥2 peripheral neuropathy (PN). Stratification by Tx dependency and platelets (<100, 100-200 and >200 K/μl). Pts were randomized 1:1 to 24 wks of MMB 200 mg qd + RUX placebo or RUX 20 mg bid (or modified per label) + MMB placebo, after which all pts could receive open label MMB. Assessments: spleen volume by MRI, and pt reported Sx using a daily eDiary of modified MPN-SAF Total Sx Score (TSS). Primary endpoint was splenic response rate (SRR; ≥35% reduction in volume from baseline) at 24 wks. Secondary endpoints, evaluated sequentially at 24 wks, were rates of TSS response (≥50% reduction from baseline), RBC Tx independence (TI), RBC Tx dependence (TD) and of RBC Tx . Results: 175 of 215 (81%) and 201 of 217 (93%) pts randomized to MMB and RUX, respectively, completed the 24 wk DB phase. Efficacy results are shown in Table. Most common Gr ≥3 AEs in the DB phase with MMB were thrombocytopenia (7%) and anemia (6%), and with RUX were anemia (23%), thrombocytopenia (5%) and neutropenia (5%). Gr ≥3 infections occurred in 7% of MMB and 3% of RUX pts. Treatment emergent PN occurred in 22 (10%) of MMB (all Gr ≤2) and 10 (5%) of RUX (9 Gr ≤2, 1 Gr 3) pts in DB phase, none discontinuing study drug for PN. Overall, AEs led to study drug D/C in 13% of MMB and 6% of RUX pts in DB phase. Conclusions: In pts with JAKi naive MF, 24 weeks of MMB is non-inferior to RUX for spleen response but not for symptom response. MMB treatment is associated with a reduced transfusion requirement. NCT01969838. [Table: see text]