On 3–6 December 2016 in San Diego, CA, the 58 thAnnual Meeting & Expositionof the American Society of Hematology(ASH) took place. On Saturday 3 rdDecember, an oral abstract session was held between 4:00pm and 5:30pm in the “CLL: Therapy, Excluding Transplantation Program” category. This session was moderated by Tait D. Shanafelt, MD, of the Mayo Clinic, and John F. Seymour, MB, BS, PhD, FRACP, of the Peter MacCallum Cancer Centreand Royal Melbourne Hospital.
Abstract #232was presented during this session, titled “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 Subsequent Clinical Relapse” by Philip A. Thompson, MB, BS, of the Department of leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, and colleagues.
Two-hundred and eighty-nine patients with CLL, who between 2008 and 2015 were treated first-line with FCR at the MD Anderson Cancer Center, were prospectively analyzed to determine pre-treatment characteristics associated with post-treatment Minimal Residual Disease (MRD) negativity and the time to relapse in MRD-negative patients. Standardized Four-Color Flow Cytometry (FLC) was used to analyze bone marrow for MRD after course 3 (n=239) and at End of Therapy (EOT, n=231).
- For the total patient cohort, the sole pre-treatment characteristic significantly associated with PFS was IGHV-unmutated ( IGHV-UM )(HR 3.0 [1.6–5.5], p<0.001)
- In IGHV-M patients, only ZAP70 positivity (38/92 [41%]) by immunohistochemistry was significantly associated with shorter PFS (HR 3.2 [1.3–8.2], p=0.01)
- In IGHV-UM patients, only β 2M ≥4.0mg/L (64/146 [44%]) was significantly associated with shorter PFS (HR 1.9 [1.2–3.0], p=0.005)
- ORR = 96%
- Nineteen percent (46/239) of patients after 3 courses and 51% (120/231) at EOT achieved MRD-negativity in the bone marrow
- Multivariable analysis revealed that only IGHV-M was significantly associated with MRD-negativity (OR 3.7 [1.7–8.2], p=0.001)
- MRD-negativity at EOT correlated with PFS in both IGHV-M and IGHV-UM patients
- IGHV-M patients who were MRD-negative at EOT tended to have superior PFS if MRD-negativity was achieved after 3 courses of FCR, even though 11/22 MRD-negative patients after 3 courses received no further therapy and 3/22 received 6 courses
- MRD re-emergence in blood was reported in 45/95 MRD-negative patients, at a median time of 49 months after treatment; this was less frequent in IGHV-M patients
- MRD re-emergence preceded clinical relapse by a median of 25 months
- In IGHV-M patients who were MRD-negative after 3 treatment cycles, 4/22 had MRD re-emergence
This presentation concluded by stating that in patients receiving FCR as first-line therapy, the best pre-treatment predictor of obtaining MRD-negativity and longer PFS was IGHV-M. IGHV-M patients who achieved MRD negative disease after 3 courses of FCR had particularly favorable outcomes, even after abbreviation of therapy. Despite achieving MRD-negative disease, many patients relapsed. It was recommended that serial MRD monitoring of peripheral blood can detect relapse with a lead-time of approximately 2 years and therefore direct early intervention strategies.
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<0.001). Analyzed separately, among IGHV-mutated (IGHV-M) patients, only ZAP70 positivity (38/92 [41%]) by immunohistochemistry was significantly associated with shorter PFS (HR 3.2 [1.3-8.2], p=0.01); among IGHV-UM patients only B2M ≥4.0mg/L (64/146 [44%]) was significantly associated with shorter PFS (HR 1.9 [1.2-3.0], p=0.005). 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 univariable analysis 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<0.001], β 2-microglobulin <4.0mg/L [OR 1.85 (1.1-3.1), p=0.02] and ZAP70 negativity [OR 1.8 (1.03-3.2), p=0.04]. On multivariable analysis, only IGHV-M was significantly associated with MRD-negativity [OR 3.7 (1.7-8.2), p=0.001]. There were trends toward association between negative FISH [OR 5.4 (0.9-31.8), p=0.07] and trisomy 12 [OR 4.9 (0.8-29.8), p=0.08] with MRD-negativity. MRD negativity at EOT correlated with PFS, independent of IWCLL response category, and correlated with PFS in both IGHV-M and IGHV-UM patients (Figure A). In IGHV-M patients who were MRD-negative at EOT, there was a trend toward superior PFS if MRD-negativity was attained after 3 courses of FCR, even though 11/22 patients who were MRD-negative after 3 courses received no further therapy and only 3/22 received 6 courses (Figure B). 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.