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Efficacy of venetoclax in relapsed chronic lymphocytic leukemia is influenced by disease and response variables

Andrew W. Roberts, Shuo Ma, Thomas J. Kipps, Steven E. Coutre, Matthew S. Davids, Barbara Eichhorst, Michael Hallek, John C. Byrd, Kathryn Humphrey, Lang Zhou, Brenda Chyla, Jacqueline Nielsen, Jalaja Potluri, Su Young Kim, Maria Verdugo, Stephan Stilgenbauer, William G. Wierda and John F. Seymour

Data supplements

Article Figures & Data

Figures

  • Figure 1.

    Time to response and MRD clearance in all patients receiving venetoclax. (A) Inverted Kaplan-Meier plot showing the cumulative percentage of patients with objective response and CR/CRi as a function of time. (B) Plot showing the cumulative percentage of patients who have documented clearance of minimal residual disease negativity (U-MRD) in peripheral blood (PB) and bone marrow (BM) over time. Analyses in A and B are intent to treat.

  • Figure 2.

    Survival and durability of benefit on venetoclax. (A) Kaplan-Meier plot showing the OS and PFS rates of all patients over time; number of patients at risk at each point is shown below the graph. (B) OS and PFS rates of patients who received 400 mg/day of venetoclax monotherapy over time; patients at risk at each point are shown below the graph. (C-D) Duration of response for all patients and for those patients who received 400 mg/day of monotherapy, respectively.

  • Figure 3.

    Progression and durability of response rates over time, according to response depth. (A) Kaplan-Meier plot showing the PFS rates of all patients over time, stratified by best objective response. (B) DoR for all patients, starting from the day of best response, stratified by best overall response. (C) Duration of response for all patients, stratified by response at the 9-month landmark. (D) Duration of response for all patients with available data, stratified by MRD status (in peripheral blood) at the 24-month landmark. Patients at risk at each point are shown beneath each graph. MRD positive, detectable MRD; nPR, nodular PR.

  • Figure 4.

    Summary of univariate analyses of pretreatment factors for association with response outcomes. This figure shows the overall response rates, CR/CRi rates, and relapse rates segregated according to different pretreatment variables, along with the associated ORs and HRs for those values in univariate analyses. (Left) Overall response rate (includes patients with CR, CRi, PR, or nPR); the corresponding OR represents the likelihood for failure to respond compared with the first listed category for each variable. (Middle) Complete response rate; the OR represents the likelihood for failure to achieve CR/CRi. (Right) The relative relapse rate; the HR for loss of response, which is also represented numerically to the right of the graph. The N column represents the number of patients with data for each category. Dotted vertical lines for response rate and CR/CRi rate represent the overall rates observed for all patients. For the relative relapse rate, the vertical dotted line represents a HR of 1.0 (no hazard) associated with the first listed category for each variable). ORs and HRs are shown with 95% CIs for each column. Variables tested but found to be nonsignificant on univariate analyses and not shown in the figure were age (≥70, <70 years) and sex. For these analyses, where data on a cytogenetic abnormality or mutation in TP53, NOTCH1, SF3B1, or IGHV was missing, the patient was included in the no category. del, deletion; mut, mutated.

Tables

  • Table 1.

    Patient demographics and pretreatment clinical and biological characteristics

    All doses (n = 436)400 mg monotherapy (n = 347)
    Age
     Median (range), y66 (28-88)66 (28-85)
     ≥70 y, n (%)152 (35)116 (33)
    Male, n (%)298 (68)236 (68)
    Diagnosis, n (%)
     Chronic lymphocytic leukemia421 (97)339 (98)
     Small lymphocytic lymphoma15 (3)8 (2)
    ECOG performance status, n (%)
     0187 (43)139 (40)
     1225 (52)184 (53)
     222 (5)22 (6)
    No. of prior therapies, median (range)3 (1-15)3 (1-15)
    No. of prior therapies, n (%)
     175 (17)61 (18)
     2 to 3172 (39)133 (38)
     >3189 (43)153 (44)
    Bulky nodes, n (%)
     <5 cm216 (51)167 (49)
     5 to <10 cm156 (36)124 (37)
     ≥10 cm56 (13)48 (14)
    Cytogenetic abnormalities by FISH*, n (%)
     17p deletion231 (53)208 (60)
     11q deletion125 (29)98 (28)
     Trisomy 1285 (20)62 (18)
     13q deletion261 (60)222 (64)
     No abnormality47 (11)37 (10)
     Other/missing23 (5)11 (3)
    TP53 mutation &/or 17p deletion, n/N (%)
     Either or both243 (71)216 (76)
     Neither101 (29)68 (24)
    NOTCH1 mutation, n/N (%)
     Mutated37 (15)26 (13)
     Unmutated217 (85)167 (87)
    SF3B1 mutation, n/N (%)
     Mutated58 (23)45 (23)
     Unmutated196 (77)148 (77)
    IGHV mutational status, n/N (%)
     Mutated57 (24)43 (24)
     Unmutated176 (76)138 (76)
    Prior BCRi therapy, n (%)
     Yes149 (34)146 (42)
      Refractory115 (26)112 (32)
      Nonrefractory34 (8)34 (10)
     No287 (66)201 (58)
    Fludarabine refractory, n (%)134 (31)107 (31)
    • Inclusion of patients with SLL were from M12-175 trial only. Data are missing for some patients for ECOG status (n = 2), node size (n = 8). For each of these variables, positive results are expressed as a percentage of whole population.

    • BCRi, B-cell receptor inhibitor; ECOG, Eastern Cooperative Oncology Group; IGHV, immunoglobulin heavy chain variable region.

    • * FISH data are reported categorically, with each locus considered independently

    • Informative data were available in N = 254 for TP53, NOTCH1, and SF3B1 mutations and N = 233 for IGHV mutational status among all patients; and N = 193 for TP53, NOTCH1, and SF3B1 mutations and N = 181 for IGHV mutation status in the 400-mg monotherapy subgroup. TP53 and/ 17pDEL FISH results were available for N = 344 among all patients and N = 284 in the 400-mg monotherapy subgroup. For these variables, positive results are expressed as a percentage of the population with available results.

  • Table 2.

    Summary of multiple regression analyses for response

    VariableOR (95% CI] for failure to respondOR (95% CI] for failure to achieve CR
    All patients (n = 428)400 mg monotherapy (n = 339)All patients (n = 428)400 mg monotherapy (n = 339)
    Max node size, cm
     ≥5 to <10NINI3.1 (1.8-5.4)3.5 (1.6-7.5)
     ≥10NINI13.5 (3.1-58.5)7.6 (1.7-34.5)
    Prior therapies
     2 to 31.5 (0.7-3.3)1.5 (0.6-3.5)2.2 (1.1-4.0)2.8 (1.3-6.0)
     >32.5 (1.2-5.3)2.7 (1.2-6.1)2.6 (1.3-5.1)3.5 (1.5-8.1)
    Fludarabine refractoryNINININI
    Prior BCRi exposure2.2 (1.4-3.5)2.4 (1.4-4.0)5.1 (2.6-10.1)3.0 (1.4-6.4)
    TP53 mutation and/or 17p deletionNI1.8 (1.0-3.1)NINI
    13q deletionNININI0.4 (0.2-0.9)
    NOTCH1 mutationNINININI
    IGHV wild typeNINININI
    Monotherapy vs combination*0.8 (0.3-1.8)0.4 (0.2-0.7)
    • All variables included in univariate analyses were tested in the multiple regressions. Covariates selected by stepwise regression are reported, and the effects of monotherapy vs combination were added as a variable of interest after model selection. Those bolded are significant, and are italicized if they are also confirmed as significant in a lesser powered sensitivity analysis that only included patients in whom all data for all genetic variables were informative (supplemental Table 4).

    • NI, not included in final model; —, not applicable

    • * After pretreatment variables of significance in multiple regression analyses were identified, the treatment variable of venetoclax monotherapy (reference) or combination with rituximab was added into the multiple logistical regression model. Significant pretreatment variables remained significant.

  • Table 3.

    Summary of multiple regression analyses for durability of response

    VariableHR (95% CI] for relapse risk
    Pretreatment variables onlyPretreatment variables plus response depth (PR vs CR) at 9 moPretreatment variables plus MRD status (pos vs U) at 24 mo
    All patients (n = 323)400 mg monotherapy (n = 250)All patients (n = 311)400 mg monotherapy (n = 242)All patients (n = 187)400 mg monotherapy (n =)159
    Max node size, cm
     ≥5 to <102.5 (1.7-3.7)2.4 (1.5-3.7)2.1 (1.4-3.3)2.1 (1.3-3.3)2.9 (1.7-5.1)2.8 (1.6-5.1)
     ≥102.8 (1.7-4.6)2.7 (1.5-4.8)2.3 (1.3-3.9)2.4 (1.4-4.3)3.6 (1.6-7.9)3.0 (1.4-6.8)
    Prior therapies
     2 to 3NINININININI
     >3NINININININI
    Fludarabine refractory disease1.5 (1.1-2.2)NI1.5 (1.1-2.2)NI1.0 (0.6-1.8)*NI
    Prior BCRi exposureNINININININI
    BCRi refractory disease2.5 (1.5-4.1)† 1.9 (1.1-3.3)2.3 (1.4-3.9)1.9 (1.1-3.2)3.0 (1.6-5.8)2.6 (1.4-5.0)
    TP53 mutation and/or 17p deletion1.8 (1.2-2.5)NI1.8 (1.3-2.7)NI1.9 (1.0-3.4)NI
    13q deletionNINININININI
    NOTCH1 mutation1.8 (1.1-3.0)NI2.0 (1.2-3.3)NI2.6 (1.1-6.2)NI
    IGHV unmutated2.1 (1.0-4.3)NININININI
    Monotherapy vs combination0.8 (0.4-1.5)
    PR/nPR vs CR/CRi at 9 mo2.1 (1.1-4.0)3.3 (1.0-10.5)
    PB MRD-pos vs U-MRD at 24 mo3.0 (1.7-5.2)3.4 (1.9-6.3)
    • All variables included in univariate analyses were tested in the multiple regressions. Covariates selected by stepwise regression are reported, and the effects of monotherapy vs combination, PR/nPR vs CR/CRi at 9 mo, and PB MRD-pos vs U-MRD at 24 mo were added as a variable of interest after model selection, separately. Those bolded are significant; and italicized if confirmed as significant in a sensitivity analysis that only included patients in whom all data for all variables were informative (supplemental Table 6).

    • NI, not included in final model; U-MRD, minimal residual disease not detected by flow cytometry at 10−4 leukemic cell cutoff; MRD-pos, detectable MRD; —, not tested/not applicable; PB, peripheral blood.

    • * Significant pretreatment variable that is not statistically significant when a posttreatment response variable is included in the model.

    • In these 3 instances, prior BCRi exposure had higher priority in the model outputs of the sensitivity analyses than BCRi-refractoriness, and was statistically significant.

    • After pretreatment variables of significance in multiple regression analyses were identified, the treatment variable of venetoclax monotherapy or combination with rituximab was added into the Cox regression model.

    • After pretreatment variables of significance in multiple regression analyses were identified, the posttreatment response variable of either PR or CR at 9 months or MRD-pos or U-MRD status at 24 months was added into the Cox regression model.