Kassis, Jeannine

Background: Patients with immune thrombocytopenia (ITP) may require treatment to raise the platelet count before surgery. Intravenous immune globulin (IVIG) is commonly used for this purpose, but eltrombopag, an oral thrombopoietin receptor agonist, may be a good alternative. We compared perioperative eltrombopag or IVIG for the achievement of platelet count targets for major or minor surgery. Methods: We conducted a randomized, non-inferiority trial at 8 centers in Canada.ITP patients with a platelet count <100 x109/L or <50 x109/L before elective major or minor surgery, respectively, were assigned to receive daily oral eltrombopag starting 3 weeks preoperatively or IVIG 1 week preoperatively. Eltrombopag was discontinued 1 week after surgical hemostasis, and a repeat dose of IVIG was permitted up to 1 week after surgical hemostasis. The primary endpoint was the achievement of platelet count targets (90 x109/L for major surgery, or 45 x109/L for minor surgery) immediately before surgery and for 7 days after surgical hemostasis without rescue treatment. Intention-to-treat and per-protocol analyses were done using a one-sided test for the difference in rates of achieving perioperative platelet count targets with a non-inferiority margin of 10% at a significance level of 0.05. Patients were followed for 4 weeks postoperatively. Secondary outcomes were thrombosis, adverse events and treatment satisfaction as measured using a validated patient questionnaire. Results: From 2013 to 2019, 38 patients were assigned to received eltrombopag and 36 patients were assigned to receive IVIG before major (n= 31) or minor (n= 43) surgery. Five patients did not complete the study. By intention to treat, 30/38 (78.9%) patients on eltrombopag achieved perioperative platelet count targets compared with 22/36 (61.1%) on IVIG (absolute risk difference, 17.8%; one-sided lower limit of the 95% confidence interval, 0.4%; p=0.005 for non-inferiority). Results were similar in the per protocol analysis (absolute risk difference: 15.8%; one-sided lower limit of the 95% CI, -2.1%; p=0.009). Eltrombopag was superior to IVIG in the intention-to-treat analysis (p=0.047) but not in the per-protocol analysis (p =0.074). One patient developed pulmonary embolism 14 days after minor surgery (skin biopsy) and 7 days after stopping eltrombopag when the platelet count was 135 x109/L. Of 18 patients who underwent splenectomy on study, marked post-splenectomy thrombocytosis (platelets >1,000 x109/L) occurred in 2 (11.1%) patients, both of whom were on eltrombopag. Global treatment satisfaction scores were higher for eltrombopag. Conclusion: Eltrombopag is non-inferior and may be superior to IVIG for achieving target platelet counts perioperatively for patients with ITP. Post-operative thromboprophylaxis should be considered with eltrombopag. Funding Source:This was an investigator-initiated trial funded by Novartis. Disclosures Arnold: Novartis: Honoraria, Research Funding; Rigel: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Principia: Consultancy. Heddle:Novartis: Research Funding. Hsia:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Jansen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sholzberg:Novartis: Honoraria; Amgen: Honoraria, Research Funding. Lin:Pfizer: Consultancy; Novartis: Research Funding; Octapharma: Research Funding; Amgen: Consultancy. Larratt:Novartis: Honoraria. Amini:Amgen NL: Research Funding; Novartis NL: Research Funding. Schipperus:Novartis: Research Funding. Lim:Pfizer Canada: Consultancy, Honoraria; Portola Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Honoraria. OffLabel Disclosure: Eltrombopag is not licenced for perioperative treatment in patients with ITP.

Abstract Abstract 1603 Background: We have previously reported similar outcomes for patients with bulky stage I or II mediastinal HL treated with combined modality therapy either with ABVD + radiotherapy or the Stanford V regimen in the North American Intergroup trial E2496 (Advani et al, ASH 2010 abstract 416). In the current analysis, we compare the patterns of failure between the two groups. Methods: Patients with stage I/II bulky mediastinal HL (maximum mediastinal mass width > 1/3 of intrathoracic diameter) were randomized to receive chemotherapy (CT) on either Arm A (ABVD x 6–8 cycles administered q 28 days) or Arm B (12 weeks of Stanford V administered weekly). Two-3 weeks after completion of chemotherapy all patients received modified involved field radiotherapy (RT) (36 Gy) delivered to the mediastinum, hila, and supraclavicular regions. Patients on Stanford V arm also received involved field RT to any other sites ≥ 5 cm at diagnosis. Patients were assessed 3, 6 and 12 months after completing RT with computed tomography scanning and then every 6 months for 5 years. The primary end points were failure free survival (FFS) and overall survival (OS). Disease progression was defined as 'in-field', 'distant' or both relative to the radiation fields prescribed in the E2496 protocol. Distant sites of failure were further characterized as intra-thoracic, intra-abdominal or other (bone, bone marrow and axillae, if not previously irradiated). Results: Two hundred and sixty-seven patients were randomized: 136 on the ABVD arm and 131 on the Stanford V arm. Patient characteristics were well matched with no differences between two arms in overall response rates (ORR), FFS and OS. (Advani et al ASH 2010 abstract 416). At a median follow up of 5.5 years 40 patients have relapsed with no difference in ABVD (n=18, 13%) versus Stanford V (n=22, 17%) (p=0.49). Central review of RT fields available in 37/40 patients found major violations with under treatment of tumor noted in 7/37 (19%). Patterns of failure are shown in Table 1. There were no differences in patterns of relapse for the two study arms. In-field relapses occurred in <10% in both study arms. Conclusion: For patients with stage I/II bulky mediastinal HL, combined modality therapy with either ABVD +RT or the Stanford V regimen results in excellent disease control. In-field relapse was uncommon. These results set a benchmark for assessing ongoing trials omitting RT in patients with stage I/II bulky mediastinal HL. Future research efforts should focus on risk stratification to identify the small subset of patients who are likely to fail standard upfront therapy. US cooperative group efforts in this subset of patients are ongoing that use interim PET-CT imaging based risk-adapted strategies. Disclosures: Horning: Genentech: Employment, Equity Ownership.

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.