WHOLE‐EXOME‐SEQUENCING OF NODAL MARGINAL ZONE LYMPHOMAS IDENTIFIES RECURRENT MOLECULAR LESIONS IN GENES INVOLVED IN CHROMATIN REMODELLING AND NOTCH SIGNALLING

Abstract

Background: Hodgkin lymphoma (HL) in the elderly is a difficult therapeutic challenge as standard ABVD outcome in this patient subset proved unsatisfactory compared to adults. Bendamustine (Be) and brentuximab vedotin (BV) are well-tolerated and effective drugs in relapsing HL, but scarce and preliminary data exist on first-line treatment of elderly HL with this drug combination. Patients and Methods: A prospective multicenter open-label phase I/II study was launched in 2015 aimed at assessing the safety and efficacy of Be-BV combination in elderly HL patients (HALO study). BV: 1.2 mg/kg D1 and Be 90 mg/m2/day were administered in days 1 and 2, every 3 weeks for 6 cycles, in advanced-stage (IIB-IVB) patients aged 60 to 80 years (NCT identifier, 02467946). A nondecisional FDGPET after the second cycle: (PET-2) was planned and images centrally reviewed using the Lugano criteria and Deauville 5 point scale (DS). Patients with progressive disease at any time or not in CR after 4 cycles were addressed to salvage therapy. The study was split in 2 phases: a phase 1 (12 patients) aimed to assess the feasibility and phase 2 (48 patients) to assess the efficacy (CR rate) of Be-BV combination. Secondary endpoints were the efficacy of Be-BV combination (3-Y PFS and OS) and the prediction of treatment outcome by PET-2. Results: So far, 22 patients have been enrolled. The mean age was 69,6 (62-79) and M/F ratio 14/8. Histology breakdown was HL, classic NOS, 6; classic, nodular sclerosis 9, classic mixed cellularity 7, and lymphocyte rich 0. Mean hemoglobin value was 12.82 gr/dl, WBC 9.09 × 103/$μ$l, Albumin 2.4 gr/l, LDH 452 U/l. The Ann-Arbor stage was IIB in 4, III in 9, and IV in 9 patients. B-symptoms were present in 14/22. IPS was 0 to 1 in none, 2 to 3 in 15, >3 in 7. The median Medical Outcome Study (MOS) physical function score was 52.5% (20-90) and 70% had a time to “up and go” score of >13.5 seconds. Twentyone severe (grade 3-4) WHO toxicities were recorded neutropenia (9), thrombocytopenia (3), CMV reactivation (1) rash maculo-papular (1), drug hypersensitivity (1), liver toxicity (2), pulmonary embolism (1), stomatitis (2), pyrexia (1). No treatment-related deaths have been recorded, and the nonrelapse mortality is 0. Fifteen patients concluded the entire course of treatment: 13 (87%) achieved CR while 2 showed disease progression after 2 and 6 cycles. All 15 underwent PET-2: 12 were in complete metabolic response (DS score, 1-3); 1 patients had score 4 and achieved CR at the end of treatment. Two had score 5: both showed disease progression after 2 and 6 cycles. After a mean follow-up of 271 (135-445) days 10/15 (67%) are still in continuous CR: 2 showed disease progression during or immediately after treatment and 3/15 showed disease relapse, +303 days, +378 days, +488 days after registration. Conclusion: Although preliminary, these data suggest that (1) the Be-BV combination is feasible and safe with a manageable hematological toxicity; (2) the drug combination is highly effective in elderly HL patients.