Cescon, Terrence P.

Abstract BACKGROUND PCV+RT substantially prolongs survival in AO patients, but long-term CF and QOL implications are unclear. We compared CF and QOL by treatment arm in RTOG 9402 participants and evaluated the impact that baseline characteristics had on CF, QOL, and survival. METHODS CF and QOL were evaluated using the Mini Mental State Exam (MMSE) and Brain-Quality of Life (B-QOL) scale at baseline and annually. Scores were analyzed between treatment arms at each time point for patients with ≥ 10 years of follow-up data. Shared parameter models evaluated MMSE and B-QOL scores and survival for all patients. RESULTS 42/148 (28.4%) participants in PCV+RT and 20/143 (14%) in RT alone arms survived ≥ 10 years. 35/42 and 39/42 (PCV+RT) and 18/20 and 17/20 (RT) participants completed baseline B-QOL and MMSE assessments, respectively. B-QOL scores did not differ between treatment groups at any time-point. Among 16 patients (10 PCV+RT, 6 RT) who completed year 10 MMSE evaluations, mean MMSE score at 10 years was higher in the RT arm (29.83 [95% CI 22.1, 30.0] vs. 26.50 [95% CI 29.4, 30.0], P= 0.04). Change in MMSE and B-QOL scores from baseline did not differ significantly between treatment groups at any time. In shared parameter models including all patients with baseline assessments, MMSE and B-QOL scores decreased over time (MMSE P= 0.0189, B-QOL P= 0.0005), but this did not differ by treatment group (MMSE P= 0.5727, B-QOL P= 0.3592). Younger age and higher KPS predicted better scores (MMSE P < 0.0001, P = 0.0002; B-QOL P = 0.0043, P = 0.0007). PCV+RT predicted better survival in both models. CONCLUSIONS PCV+RT improves survival in AO. Shared parameter models show decrease in MMSE and B-QOL over time. However, relative to RT alone, the addition of PCV did not impact change in CF and QOL over time.

Abstract Purpose: We sought to improve upon frontline bendamustine/rituximab (BR) induction therapy followed by rituximab maintenance in untreated high-risk follicular lymphoma (FL). Patients and Methods: Patients were randomized to BR induction followed by 2-year rituximab maintenance (BR-R), BR with bortezomib and rituximab maintenance (BVR-R), or BR followed by lenalidomide (1 year) with rituximab maintenance (BR-LR). Dual primary objectives were complete remission (CR) rate and 1-year disease-free survival (DFS); 289 patients enrolled (NCT01216683). Results: For induction, 92%, 87%, and 86% of patients randomized to BR-R, BVR-R, or BR-LR received six cycles, respectively. CR rate with BR versus BVR induction was 62% versus 75%, respectively (P = 0.04). One-year DFS rates with BR-R versus BR-LR were 85% versus 67%, respectively (P = 0.0009). This was due to an imbalance in CR rates post-BR induction and discontinuation due to adverse events (AEs). The most common grade 3–4 AEs for BVR versus BR were neutropenia and sensory neuropathy (12% vs <1%); 83% of the latter occurred with intravenous bortezomib. The most common grade 3–4 AEs related to LR versus rituximab maintenance were neutropenia 66% versus 21%, respectively (P < 0.0001), and febrile neutropenia 10% versus 2%, respectively (P = 0.05). The overall treatment-related mortality was 1.4%. With 5-year median follow-up, 3-year PFS rates for BR-R, BVR-R, and BR-LR were 77%, 82%, and 76%, respectively (P = 0.36) with OS rates of 87%, 90%, and 84%, respectively (P = 0.79). For prognostication, CR rate and POD-24 were associated with survival. Conclusions: Altogether, neither bortezomib added to BR induction nor lenalidomide added to rituximab maintenance immediately post-BR induction is recommended in untreated FL.

Abstract Abstract 1856 Background: Lenalidomide has proven to be a highly effective treatment in relapsed multiple myeloma (MM), particularly when used in combination with dexamethasone. However, over 30% of patients with myeloma have renal insufficiency and as lenalidomide is renally excreted, little information is available about its use in myeloma patients with impaired kidney function. Defining a safe and effective dose of lenalidomide in this context is critical. Objective: We undertook this study to establish the maximum tolerated dose of lenalidomide in three cohorts of patients with different levels of impaired renal function: Group A - patients with creatinine clearance (CrCl) between 30 and 60 mL/min, Group B - patients with CrCl <30 mL/min not on dialysis, and Group C - patients with CrCl < 30mL/min who are on dialysis. Secondary endpoints included response rate, progression free survival and overall survival. Methods: Eligible patients had previously treated MM with renal impairment defined as creatinine clearance < 60 mL/min measured within 21 days prior to registration. Patients previously treated with lenalidomide were required to demonstrate clinical response (any duration) or stable disease with progression-free interval of > 6 months from start of that therapy. All patients received dexamethasone 40 mg orally on days 1, 8, 15 and 22 of a 28-day cycle. Prophylactic anticoagulation consisted of either 81 mg or 325 mg per day of aspirin. Patients also received lenalidomide orally every 1 or 2 days on days 1 through 21 of a 28-day cycle, as described below (Table 1). Starting doses were as in US Product Insert. Dose escalation follows a standard 3+3 design. Results: There have been 23 patients enrolled into groups and cohorts as shown in Table 1. Median age was 73 (range 49–89) and 13 (57%) were women. ISS stage was advanced in all patients, 0 in stage 1, 4 (18%) in stage 2 and 19 (82%) in stage 3. The regimen was well tolerated. Indeed, the MTD has not been reached in any of the groups, as no DLTs have occurred to date. The most commonly reported clinical adverse events (all grades, independent of attribution) across all patients included infections, hyperglycemia, constipation, dizziness, hyponatremia, hypocalcemia and tremor. Hematological toxicities (grade 3–4) occurred in 13 out of 21 pts (62%), mostly neutropenia and thrombocytopenia. Grade 3–4 events at least possibly related to the regimen occurred in 70% and included pneumonia (26%) and otitis media (9%). Response was seen in 14 patients, resulting in an overall response rate of 61%. CR was seen in 1 patient (4%), VGPR in 2 patients (9%), PR in 11 patients (43%), and SD for 9 patients. With median follow-up of 15.5 months, median progression-free survival is 9.8 months and median overall survival is 22 months. Conclusion: Lenalidomide and dexamethasone is a safe and effective regimen in patients with multiple myeloma and renal insufficiency. It is also very well tolerated, although cytopenias are common but manageable. MTD has yet to be reached in each group, allowing for higher doses to be given than previously thought, including 25mg daily (for 21/28 days) in patients with CrCl 30–60 mL/min, 25 mg every other day (for 21/28 days) in patients with CrCl < 30 mL/min not on dialysis, and 10mg daily (for 21/28 days) in patients with CrCl < 30 mL/min on dialysis. These results will provide needed, clinically relevant dosing for lenalidomide in MM patients with renal insufficiency. Disclosures: Kaufman: Millenium: Consultancy; Onyx: Consultancy; Celgene: Consultancy; Novartis: Consultancy.