Minimal Residual Disease (MRD) Re-Growth Kinetics Are An Independent Predictor for Progression Free Survival (PFS) in Chronic Lymphocytic Leukemia (CLL) and Are Related to Biologically Defined CLL-Subgroups– Results From the CLL8 Trial of the German CLL Study Group (GCLLSG)
Authors: Boettcher Sebastian , Ritgen Matthias , Fischer Kirsten , Stilgenbauer Stephan , Busch Raymonde , Fingerle-Rowson Gunter R. , Fink Anna-Maria , Buehler Andreas , Winkler Dirk , Wenger Michael K. , Mendila Myriam , Wendtner Clemens , Eichhorst Barbara , Döhner Hartmut , Hallek Michael , Kneba Michael 
Published: October 2019

Abstract
Abstract 1777
MRD single time point assessments during therapy and at the end of treatment have been identified as independent predictors of PFS and overall survival in CLL patients (pts) by our group and others. However, it is currently unknown whether MRD kinetics during follow-up (FU) also have prognostic significance and whether kinetics show associations with CLL risk features. We therefore investigated MRD during treatment-free FU within the CLL8 trial of the GCLLSG (phase III, front-line RFC vs FC, Hallek et al., Lancet 2010)
MRD kinetics were analyzed in 256 pts who had not progressed 1 year after completion of therapy and for whom at least 2 peripheral blood MRD assessments during the subsequent year were available. The slope of the common logarithm of MRD / time was calculated for 193 patients with at least 2 positive MRD measurements. Median MRD increase was 6.3fold during the observation period for the whole group (i.e. 0.80 log MRD unit increase / year). We compared groups of pts who (1) were always MRD negative (25% of all 256 pts), (2) had measurable disease with a slope below median (slow re-growth, 37% of pts), and (3) had measurable disease with a slope above median (fast re-growth, 39 %). The medians of the first measurable MRD levels during observation did not differ significantly between groups 2 (4.3 × 10−3) and 3 (1.7 × 10−3, p=.16). Pts with faster MRD re-growth kinetics (group 3) experienced a shorter median PFS (40 months) than pts with slower re-growth (group 2, 66 months), whereas median PFS has not been reached in pts who were always MRD negative (group 1, log-rank p= 3 × 10−14). Compared to group 1, group 2 and 3 pts carried increasingly higher risks of progression (HR 3.1 and 7.7, resp.). Pts showing a slow re-growth pattern (group 2) had a 2.5fold lower risk of clinical progression than pts with a greater MRD slope (group 3, p=5 × 10−6). The prognostic significance of MRD kinetics for PFS was also tested in Cox regression analysis together with clinical response, deletion 17p, IGHV mutational status, number of treatment cycles, treatment arm, thymidine kinase, beta2-microglobulin, pre-therapeutic WBC and MRD levels 1 year after completion of therapy. MRD kinetics (p=4×10−9), MRD levels (7×10−14), cycle number (8×10−5) and IGHV mutational status (1×10−3) remained independently significant for PFS in this multivariate analysis.
We next correlated MRD slopes during the second year of FU and prognostic features in 204 pts (groups 2 and 3 plus 11 pts with early clinical relapse but measurable MRD slope during second FU year). Pts who required treatment within 2 years from diagnosis experienced a faster re-growth after therapy (.92/a) than pts with a longer treatment-free interval (.68, p=.04). The slope was significantly lower in pts with Binet A disease prior to therapy (.43/a) than in Binet B (.77/a, p =.03) and Binet C (.88/a, p=.02) pts. Pts carrying a chromosomal deletion (del) 13q as single abnormality had a significantly slower MRD re-growth pattern (.58/a) than those with del(11q) (1.0/a, p=.0004) or without cytogenetic abnormalities (1.1/a, p=.001), while the difference to pts with 12q+ (.71/a) was not significant. Pts with a mutated IGHV gene progressed slower (.54/a) than those with unmutated IGHV (.96/a, p=.0002). A thymidine kinase of at least 10 U/L was associated with a steeper MRD slope (.82/a) than lower levels (.61/a, p=.03). MRD slopes were not significantly associated with gender, WBC prior to therapy, beta2-microglobuline levels, presence of B-symptoms, or treatment arm.
We demonstrate for the first time the independent prognostic significance of MRD kinetics during FU in CLL. MRD kinetics improve the prediction of PFS even when single time point MRD assessments during FU and other major risk features in CLL are additionally considered. MRD kinetics classify known CLL risk factors into two groups. IGHV, cytogenetics, thymidine kinase, stage, and time to treatment distinguish CLL subgroups with different re-growth kinetics, likely characterizing the relationship of proliferation to spontaneous apoptosis of the CLL clone itself. Other risk features did not show an association with kinetics in spite of proven significance in the CLL8 trial. Those features likely identify differences in responsiveness to therapy. We hypothesize that maintenance strategies will chance the course of the disease most effectively in patients who are responsive to therapy but relapse early due to fast CLL re-growth.

Disclosures:
Boettcher: Hoffmann La Roche: Honoraria, Research Funding, Travel Grants. Ritgen:Hoffmann La Roche: Research Funding. Fischer:Hoffmann La Roche: Travel grants. Stilgenbauer:Hoffmann La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Travel Grants. Fingerle-Rowson:Hoffmann-La Roche: Employment. Fink:F. Hoffmann La Roche: Travel grants. Wenger:Hoffmann La Roche: Employment, Equity Ownership. Mendila:Hoffmann La Roche: Employment, Equity Ownership. Wendtner:Hoffmann-La Roche: Honoraria, Research Funding. Eichhorst:Hoffmann La Roche: Honoraria, Research Funding, Travel Grants. Hallek:Hoffmann-La Roche: Honoraria, Research Funding. Kneba:Hoffmann La Roche: Honoraria, Research Funding.