ALBERT

Description: Abstract 291 Lenalidomide (L) is an immunomodulatory agent with therapeutic activity in CLL; rituximab (R), a CD20 mAb, has limited activity as monotherapy in CLL. In preclinical models, L resulted in NK cell expansion and synergized with R. Therefore, a phase II, 2-stage study was designed to evaluate this combination. Treatment-naïve patients (pts) were eligible if they had an indication for therapy, normal kidney function, and no history of deep vein thrombosis or pulmonary embolic events. Pts started L at 2.5 mg per day (D) and could escalate to 5 mg/D on D8 and again on C3D1 to a maximum of 10 mg/D if tolerated. Pts received L 21 of 35 D for cycle (C) 1, then for 21/28 D for C2-7 (7 cycles total). R was started at the end of C1 at 50 mg/m2 D29, 325 mg/m2 D31, 375 mg/m2 D33, C1, then 375 mg/m2 weekly × 4 for C2 and on D1 for C3-7. Pts received allopurinol 300 mg daily, and following a protocol amendment, aspirin at 81 mg daily. The study has closed to accrual with 69 pts enrolled at four CRC clinical sites. 40 pts enrolled into arm A (age under 65). 29 in arm B (age 65 or older). 57 now have final response data. The median age on arm A was 57 years (range 45–64) and arm B 70 years (range 65–80). Advanced Rai stage (III-IV) was present at baseline more frequently in arm B pts (48%) compared to arm A pts (23%) (p= 0.04). 73% of pts on arm A had an excellent performance status (ECOG 0/5) compared to only 54% of pts on arm B. Arm A pts frequently had aggressive leukemia features including unmutated IgVH genes and/or elevated CLL expression of ZAP-70 in 70%, these features were present in 52% of those on arm B. 4 pts on arm A and 2 on arm B had del(17p) by FISH whereas 5 pts in arm A and 4 in arm B had del(11q). A significantly lower proportion of pts on arm B (16/27) were able to complete the 7 cycles of therapy compared to (35/39) of eligible pts on arm A (p=0.013) mainly due to toxicity. Similarly, older patients were limited in dose escalation or maintenance of the maximum L dose (10 mg). 27/39 pts on arm A achieved a median L dose of 10 mg while only 13/27 pts on arm B tolerated the 10 mg L dose. The most frequent and severe adverse events (AEs) are summarized in Table 1. Infusion and tumor flare reactions (TFR) were observed more frequently during cycle 1 than in subsequent cycles. Neutropenia was frequently grade (G) 3/4 in severity. Severe (G3/4) AEs were reported in 72% of arm A pts and 82% of pts on arm B (p =.55), with non-heme G3/4 toxicities reported in 37% of arm A and 52% of arm B (p =.31).Table 1Frequent and Severe AEsArm AArm BGradeI/IIIII/IVI/IIIII/IVTFR32–161Neutropenia1119115Anemia153141Thrombocytopenia211131Fatigue25–142AST/ALT elevation183113Hypophosphatemia19271Hypocalcemia21–15–Infusion Reaction20–53Respiratory Infection17–5–Pneumonia–123Rash142121Neutropenic Fever–2–2PE/DVT–––2 Responses are summarized in Table 2. The overall response rate (ORR) to therapy for arm A was 94%, 90% CI (83%, 99%) with 20% (10%, 34%) achieving a complete remission (CR) and 17% a nodular PR (nPR). The ORR for arm B was 77% with 90% CI (58%, 91%) with 9% (2%, 26%) achieving a CR. Arm A patients had median follow-up of 17 months (from D 1 of treatment) with an estimated median progression free survival of 19 months. Arm B had a median follow-up of 7 months, with an estimated 85% remaining progression free at 7 months.Table 2ResponsesArm A (Age 〈 65) N = 35Arm B (Age 〉= 65) N = 22NCR N (%)nPR N (%)PR N (%)ORR N (%)NCR N (%)PR N (%)ORR N (%)All patients357 (20)6 (17)20 (57)33 (94)222 (9)15 (68)17 (77)IgVH unmutated224 (18)2 (9)15 (68)21 (96)131 (8)10 (77)11 (85)IgVH mutated133 (23)4 (31)5 (38)12 (92)91 (11)5 (56)6 (67)Median L dose 10 mg247 (29)5 (21)12 (50)24 (100)82 (25)5 (63)7 (88)Rai stage III/IV92 (22)1 (11)5 (56)8 (89)111 (9)6 (55)7 (64)17p del3002 (67)2 (67)100011q del31 (33)02 (67)3 (100)403 (75)3 (75)TFR present285 (18)5 (18)16 (57)26 (93)14011 (79)11 (79) A defined course of seven cycles of L and R administered for the initial treatment of CLL was associated with a high response rate (ORR 88%) with 16% CRs and 11% nPRs. Older patients were more likely to have advanced Rai stage at baseline and were less likely to escalate or maintain the maximum L dose and/or complete the 7 cycles of therapy, factors that may have contributed to a lower CR, and ORR rate in arm B. An additional 11 patients will have final response assessments by October 2011. Disclosures: James: Celgene: Honoraria, Research Funding. Off Label Use: Lenalidomide for Chronic lymphoyctic leukemia. Brown:Calistoga: Consultancy; Pharmacyclics: Consultancy; Celgene: Consultancy, Research Funding; Genzyme: Research Funding. Rai:Celgene: Membership on an entity's Board of Directors or advisory committees. Neuberg:Celgene: Research Funding. Kipps:Igenica: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Abbott Industries: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; GSK: Research Funding; Gilead Sciences: Consultancy, Research Funding; Amgen: Research Funding.