Select High Risk Genetic Features Predict Earlier Progression Following Chemoimmunotherapy with Fludarabine and Rituximab in Chronic Lymphocytic Leukemia (CLL): Preliminary Justification for Risk-Adapted Therapy.
Authors: Byrd John C. , Gribben John G. , Peterson Bercedis , Grever Michael R. , Lozanski Gerard , Lucas David M. , Larson Richard A. , Caligiuri Michael A. , Heerema Nyla A. 
Published: April 2020

Abstract
Several prognostic factors in CLL including un-mutated VH mutational status, select interphase cytogenetic abnormalities [del(11q22.3), del(17p13.1)], and p53 mutations have been associated with decreased time from diagnosis to symptomatic disease requiring treatment as well as shortened progression-free survival (PFS) and overall survival (OS). To date, the impacts of these prognostic factors on treatment outcome with fludarabine and rituximab combination treatments have not been explored. The Cancer and Leukemia Group B recently reported results of a randomized phase II study (CALGB 9712) that added rituximab concurrently or sequentially to fludarabine as initial therapy for symptomatic, untreated CLL (Blood2003; 101:6). After a recently updated median follow-up of 43 months, PFS and OS are still similar in both arms. Of the 104 patients enrolled, we studied 88 patients for whom pre-treatment samples were available to examine the impact of VH mutational status (≥97% defined as un-mutated), common cytogenetic abnormalities, and p53 mutational status on outcome relative to CR (complete remission) and PFS. OS was not examined because only 13 deaths have occurred to date. A total of 46 out of 75 (61%) patients were VH un-mutated CLL. Fifteen (52%) of 29 mutated and 20 (43%) of 46 un-mutated patients achieved a CR (p= 0.49). The median PFS among the VH mutated patients was 46 months [95% CI (40, 54)] whereas for un-mutated it was 32 months [95% CI (22, 42)] (p= 0.05). Controlling for differences in age, sex, WBC, LDH, and stage resulted in an adjusted p-value of p=0.03. Only four patients had p53 mutations, preventing analysis of this biologic feature independently. Using the Dohner hierarchical classification, the frequency CR rate and PFS for each group are summarized below.
Cytogenetic Abnormality: del(17p) del(11q) del(6q) tris 12 del(13q) Normal No. (%) pts 3 (3%) 15 (17%) 1 (1%) 23 (26%) 24 (27%) 22 (25%) CR (%) 0 53 100 25 38 64 PFS (months) 18 25 42 42 45 49
Using the hierarchical classification of Dohner, there was not a difference in CR rate (p=0.25) and PFS (p=0.10). Controlling for differences in age, sex, WBC, LDH, and stage resulted in an adjusted p-value of p=0.04. The PFS for the del(17p13.1) and del(11q22.3) patients was significantly shorter than that observed for the remaining cytogenetic groups (p=0.03). We next sought to define a high-risk group of CLL patients, as having any of the following: VH un-mutated (≥97%), del(17p), del (11q), or non-silent p53 mutation. Using this classification, 35 patients were assigned to the low-risk and 53 to the high-risk groups. The CR rate in each group was 43%. However, the median PFS among the low risk patients was 45 months with 95% CI (45, NA) whereas the median PFS among the high-risk patients was 32 months with 95% CI (22, 42) (p=0.004). These data demonstrate that high risk CLL patients characterized by VH un-mutated (≥97%), del(17p), del (11q), or non-silent p53 mutation appear to have a shorter PFS with chemoimmunotherapy and define a subset of patients for whom additional novel treatment approaches should be targeted.