Early Achievement of MRD-Negativity in IGHV-Mutated (IGHV-M) Patients Portends Highly Favorable Outcomes after First-Line Treatment of CLL with Fludarabine, Cyclophosphamide and Rituximab (FCR). Serial Monitoring for Minimal Residual Disease (MRD) in Blood after Achieving MRD-Negativity Predicts Sub

Introduction Achieving MRD-negative remission after FCR therapy is an important predictor of longer progression-free (PFS) and overall survival (OS); however, with long-term follow-up, many MRD-negative patients subsequently relapse. The time course and predictive factors for relapse in initially MRD-negative patients have not been extensively characterized. Methods We prospectively analyzed 289 patients treated first-line with FCR for CLL at M.D. Anderson Cancer Center from 2008-15, to determine pre-treatment characteristics associated with post-treatment MRD negativity and the time course of relapse in MRD-negative patients. MRD analysis was performed in BM after course 3 (n=239) and at end of therapy (EOT) (n=231) using standardized 4-color flow cytometry (FLC). Ninety-five MRD-negative patients had 12-monthly serial MRD monitoring on blood. Results Pretreatment characteristics are shown below (N=289). For the total cohort, the only pre-treatment characteristic significantly associated with PFS was IGHV-unmutated (IGHV-UM) (HR 3.0 [1.6-5.5], p Overall response rate was 96%. 46/239 patients (19%) after 3 courses and 120/231 (51%) at EOT achieved MRD negativity in BM. The following pre-treatment characteristics were significantly associated in univariableanalysis with achieving MRD-negativity at EOT in all patients: negative FISH (OR 3.1 [1.3-7.0], p=0.01), trisomy 12 (OR 2.7 [1.1-6.3], p=0.03, IGHV-M [OR 3.2 (1.8-5.9), p Re-emergence of MRD in blood was detected in 45/95 MRD negative patients, at a median of 49 months post- treatment; this appeared less frequent in IGHV-M patients (Figure C). Re-emergence of MRD preceded clinical relapse by a median of 25 months. There were no significant differences in time-to-subsequent clinical relapse after re-emergence of MRD according to mutation status (Figure D). Among IGHV-M patients who were MRD-negative after 3 cycles, 4/22 had subsequent re-emergence of MRD. Conclusions Among patients with CLL receiving first-line FCR, the best pre-treatment predictor of achieving MRD-negativity and subsequent longer PFS was IGHV-M. Post-treatment MRD-negativity correlated with subsequent PFS; patients with IGHV-M who achieved MRD-negativity after 3 courses had a particularly favorable outcome, even after abbreviation of therapy. However, despite achieving MRD-negativity, many patients subsequently relapse; serial MRD monitoring in peripheral blood can herald relapse with a lead-time of approximately 2 years and potentially direct monitoring and/or early intervention strategies. Disclosures Thompson:Pharmacyclics: Consultancy, Honoraria. O9Brien:Janssen: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding. Jain:Incyte: Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding; Servier: Consultancy, Honoraria; Abbvie: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Infinity: Research Funding; Novimmune: Consultancy, Honoraria; BMS: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Genentech: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding. Kadia:Novartis: Honoraria; BMS: Research Funding. DiNardo:Novartis: Research Funding; Daiichi Sankyo: Research Funding; Agios: Research Funding; Abbvie: Research Funding; Celgene: Research Funding. Wierda:GSK/Novartis: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Emergent: Consultancy, Research Funding; Sanofi: Consultancy; Celgene: Consultancy; Genzyme: Consultancy; Merck: Consultancy; Karyopharm: Research Funding; Acerta: Research Funding; Janssen: Research Funding; Juno Therapeutics: Research Funding; KITE Pharma: Research Funding.