IgVH Mutational Status Does Not Affect Complete Remission Rate but Is Associated with Reduced Remission Duration in CLL Patients Treated with Fludarabine, Cyclophosphamide and Rituximab (FCR)-Based Therapy.
Authors: Lin Katherine I. , Tam Constantine S. , Abruzzo Lynne V. , Wierda William , Barron Lynn , O’Brien Susan , Kipps Thomas , Rassenti Laura , Lerner Susan , Kantarjian Hagop , Keating Michael J. 
Published: October 2019

IgVH mutational status is associated with inferior survival in studies of patients with heterogenous genetic background and treatment status. Its significance in patients receiving modern fludarabine- and rituximab- containing chemoimmunotherapy is currently unknown. In order to prospectively evaluate its significance in such patients, we examined the relationship between pre-treatment IGVH mutation status and clinical outcome in patients followed in two independent cohorts at the MD Anderson Cancer Center. Cohort 1 contains 95 uniformly treated patients from the phase II study of FCR as initial therapy for CLL (Keating JCO23:4079), treated between 1999 to 2004, with unknown FISH status. Cohort 2 contains 95 patients from the Low Risk FISH study (LRF), a prospectively collected set of untreated patients with low risk (not 11q or 17p) FISH findings followed between 2004 to 2007, who started therapy with a FCR-like regimen: FCR as standard treatment (n=30, complete remission (CR) 73%); FCR with thrice weekly rituximab in the first week (n=25, 72% CR); FCR & mitoxantrone (n=19, 84% CR); CFAR (FCR & alemtuzumab, n=9, 78% CR); FCR & GMCSF (n=6, 3 CR); and fludarabine & rituximab (n=2, 2 CR). Mutational status were determined from pre-therapy peripheral blood specimens in all patients from cohort 2, and from 77 patients from cohort 1. Eighteen patients from cohort one without pre-FCR blood samples had mutational status determined from pre-treatment formalin-fixed parafin embedded bone marrow blood clot. Mutational status had no significant impact on the CR/p (complete remission with or without cytopenia) rate of FCR in patients treated in cohort one. Similarly, patients in cohort two who received FCR-like therapy had comparable CR/p rates (Table). The median follow-up for patients in cohort one was sixty-seven months. In this cohort, patients in CR (n=75) with mutated IGVH gene showed a significantly longer time to progression (TTP) compared with unmutated patients: at 5 year follw up, 93% mutated patients (n=29) remained in remission, compared with 46% in unmutated patients (n=46) (p= 0.0006). Amongst those patients in flow cytometry negative CR, 100% mutated patients (n=20) remained progression free at five years, compared with 67% for unmutated patients (n=36) (p=0.006). Despite being associated with shorter remissions, IGVH mutational status has not yet impacted on long-term survival, with 5 year survival rates of 83% and 77% for mutated and unmutated patients in cohort one respectively (p=0.34). The median follow-up was too short in cohort two for evaluation of TTP or survival. This analysis of prospectively collected patients with uniform treatment (cohort one) or similar genetic status (cohort two) showed that IGVH remained an important prognostic factor in the era of highly potent chemoimmunotherapy, with the main impact being reduction in remission duration. Most patients in CR with mutated IGVH remain in remission at five years.

N CR/p(%) P-Value Cohort 1, MUT 33 29 (88%) 0.19 Cohort 1, UNMUT 62 46 (74%) Cohort 2, MUT 34 25 (74%) 0.84 Cohort 2, UNMUT 61 46 (75%)