PURPOSE
The CLL14 study has established one-year fixed-duration treatment of venetoclax and obinutuzumab (Ven-Obi) for patients with previously untreated chronic lymphocytic leukemia. With all patients off treatment for at least three years, we report a detailed analysis of minimal residual disease (MRD) kinetics and long-term outcome of patients treated in the CLL14 study.
PATIENTS AND METHODS
Patients were randomly assigned to receive six cycles of obinutuzumab with 12 cycles of venetoclax or 12 cycles of chlorambucil (Clb-Obi). Progression-free survival (PFS) was the primary end point. Key secondary end points included rates of undetectable MRD and overall survival. To analyze MRD kinetics, a population-based growth model with nonlinear mixed effects approach was developed.
RESULTS
Of 432 patients, 216 were assigned to Ven-Obi and 216 to Clb-Obi. Three months after treatment completion, 40% of patients in the Ven-Obi arm (7% in the Clb-Obi arm) had undetectable MRD levels < 10−6 by next-generation sequencing in peripheral blood. Median MRD doubling time was longer after Ven-Obi than Clb-Obi therapy (median 80 v 69 days). At a median follow-up of 52.4 months, a sustained significant PFS improvement was observed in the Ven-Obi arm compared with Clb-Obi (median not reached v 36.4 months; hazard ratio 0.33; 95% CI, 0.25 to 0.45; P < .0001). The estimated 4-year PFS rate was 74.0% in the Ven-Obi and 35.4% in the Clb-Obi arm. No difference in overall survival was observed (hazard ratio 0.85; 95% CI, 0.54 to 1.35; P = .49). No new safety signals occurred.
CONCLUSION
Appearance of MRD after Ven-Obi is significantly slower than that after Clb-Obi with more effective MRD reduction. These findings translate into a superior long-term efficacy with the majority of Ven-Obi–treated patients remaining in remission.
INTRODUCTION
Measurement of minimal residual disease (MRD) of chronic lymphocytic leukemia (CLL) is particularly relevant for fixed-duration combination therapies, as the level of MRD at the end of treatment (EoT) has been shown to be prognostic for progression-free survival (PFS).1,2 However, EoT-MRD is only one snapshot in the highly dynamic process of this heterogeneous disease. Some patients might eventually show increasing MRD levels over time that can be difficult to identify clinically, as standard blood counts or flow cytometry requires more sensitivity to detect CLL cells below 10−4.3 Therefore, capturing MRD dynamics by regular and more sensitive MRD measurements during and after treatment might yield valuable information on disease-specific kinetics.4 Previously, the CLL14 study demonstrated that the combination of the BCL2 inhibitor venetoclax with the CD20 antibody obinutuzumab (venetoclax and obinutuzumab [Ven-Obi]) induces deep remissions after a fixed-treatment duration of 12 cycles in patients with previously untreated CLL with coexisting conditions.5,6 In addition to the high rates of undetectable MRD (uMRD), a significantly longer PFS was observed with Ven-Obi compared with chlorambucil-obinutuzumab (Clb-Obi). On the basis of these findings, one year fixed-duration treatment with Ven-Obi was approved by the US Food and Drug Administration and the European Medicines Agency for treatment of patients with previously untreated CLL. With all patients now being off treatment for at least 3 years, we present here a detailed analysis of patients' long-term outcomes after Ven-Obi and Clb-Obi treatment with a particular focus on serial MRD levels and MRD dynamics.
CONTEXT
Key Objective
This analysis of the phase III CLL14 study investigated long-term minimal residual disease (MRD) dynamics and clinical outcomes of patients with previously untreated chronic lymphocytic leukemia treated with fixed-duration venetoclax-obinutuzumab (Ven-Obi) versus chlorambucil-obinutuzumab (Clb-Obi).
Knowledge Generated
Appearance of detectable MRD after end of treatment is significantly slower after Ven-Obi than Clb-Obi therapy. At a median follow-up of 52 months, progression-free survival and undetectable MRD rates remained superior with Ven-Obi.
Relevance
These data demonstrate a sustained long-term benefit of 12 cycles of Ven-Obi in frontline chronic lymphocytic leukemia across all clinically relevant risk groups. The MRD analyses indicate a deep clearance of residual disease across compartments by Ven-Obi compared with Clb-Obi. Longer follow-up and further randomized studies are warranted to compare this regimen with other frontline treatment strategies.
PATIENTS AND METHODS
Study Design and Participants
The CLL14 study is an ongoing phase III, open-label, randomized study of Ven-Obi compared with Clb-Obi in patients with previously untreated CLL and coexisting conditions. Details on the study design and eligibility criteria were outlined previously.5,6 The Protocol (online only) was registered at US and EU clinical trial registries (NCT, NCT02242942; EudraCT 2014-001810-24) and approved by ethical review boards responsible for each participating center. The study was performed according to the principles of the Declaration of Helsinki. All patients provided written informed consent to participate. The data cutoff date was September 11, 2020.
Procedures
Previously untreated patients in need of therapy and with coexisting medical conditions (assessed by the Cumulative Illness Rating Scale with a threshold of > 6 and/or creatinine clearance < 70 mL/min) were randomly assigned 1:1 to receive either Clb-Obi or Ven-Obi. Treatment in both groups was administered for 12 cycles, each lasting 28 days. Dosing, prophylactic measures, and monitoring were described previously.5,6
Assessments
The primary end point was investigator-assessed PFS, defined as the time from random assignment to the first occurrence of progression, relapse, or death from any cause. Key secondary end points included rate of uMRD (cutoff 10−4) in peripheral blood (PB) and bone marrow (BM), by an allele-specific oligonucleotide polymerase chain reaction (ASO-PCR), overall and complete response rates by iwCLL criteria7 (assessed 2 months after treatment completion, ie, follow-up [FU] month 3), and overall survival (OS). Exploratory end points included uMRD rates with the cutoff of 10−4, 10−5, and 10−6, by next-generation sequencing (NGS). MRD in PB and BM was analyzed centrally according to international guidelines,8-10 by means of ASO-PCR; additionally, Adaptive's clonoSEQ Assay for NGS was used for MRD measurements in PB samples.4 MRD in BM was assessed in patients with treatment response at cycle 9 and 2 months after completion of treatment (EoT). MRD in PB was assessed at baseline, cycles 7, 9, and 12, and every 3 months after treatment completion until FU month 18, and then every 6 months until 9 years from last patient enrollment. Reporting of adverse events was required until a next line of therapy or progression of disease (PD) occurred. Only study drug––related serious adverse events and second primary malignancies (SPMs) were reported throughout FU.
Statistical Analyses
Statistical analyses were performed on an intention-to-treat (ITT) basis including all patients with available information for the corresponding analyses. All randomly assigned patients were included in the ITT population. All randomly assigned patients who received at least one dose of study medication were included in the safety analyses (safety population).
Model of MRD dynamics.
For the longitudinal analyses of MRD dynamics, patients in the ITT population with at least two measurable MRD samples by NGS on and after FU month 3 were included. Data below the lower limit of quantification were considered using a likelihood-based approach.11 A population-based logistic growth model with the nonlinear mixed effects approach was developed to estimate the growth parameters at population and patient levels, to assess the interindividual variability around the parameters, and to identify covariates with a significant impact on the appearance of detectable MRD.12 Prognostic and predictive markers at FU month 3 were screened as covariates for their impact on the key model parameters on the basis of statistical (with –2-log-likelihood as the objective function) and graphical assessment. Statistical inference on time from FU month 3 MRD assessment to MRD doubling and time to reach the MRD level of 10−2 was derived for the stratified subgroups. A detailed outline of the model setup is provided in the Data Supplement (online only).
Clinical outcomes.
Kaplan-Meier estimates were used to analyze time-to-event data. The log-rank test and Cox proportional hazards regression model—stratified by Binet stage and geographic region—were used to compare PFS, time to next treatment, and OS from random assignment across arms. Landmark analyses from last treatment exposure were performed for PFS and OS as post hoc with regard to the MRD level at EoT by ASO-PCR in BM (for PFS) and by NGS in PB (for OS). For patients with the uMRD level < 10−4 by NGS at EoT, time to MRD conversion by NGS from MRD assessment date at EoT was analyzed using the Kaplan-Meier method and was compared using a nonstratified Cox proportional hazards regression model across arms. Apart from redetection of MRD level ≥ 10−4 in two consecutive visits, patients with PD or death of PD also counted toward total MRD conversion events (Data Supplement). Independent prognostic factors for PFS, OS, and MRD conversion were identified by multivariate analyses using Cox proportional hazards regression modeling with stepwise forward and backward selection procedures. Treatment arm and baseline characteristics that were independently associated with PFS, OS, and MRD conversion in univariate analyses (test level at 5%) were considered as candidates for the multivariate modeling. MRD rates at FU month 30 by treatment group were compared using the Cochran-Mantel-Haenszel test stratified by the Binet stage and geographical region. All P values reported were exploratory without adjustments for multiple testing (test level at 5%). Clinical outcome analyses were performed using SPSS (version 25.0).
RESULTS
Patients
Between August 2015 and August 2016, 432 patients were included defining the ITT population. Overall, 216 patients were randomly assigned to Ven-Obi and 216 to Clb-Obi (Data Supplement). Patient characteristics were previously reported.6 The median observation time from random assignment was 52.4 months. All patients have been off study treatment for at least 3 years.
MRD Dynamics
At FU month 3, 86 (39.8%) patients in the Ven-Obi arm had uMRD levels < 10−6, 57 (26.4%) ≥ 10−6 and < 10−5, 18 (8.3%) ≥ 10−5 and < 10−4, 11 (5.1%) ≥ 10−4 and < 10−2, and 7 (3.2%) ≥ 10−2. Thirty-seven (17.1%) had missing MRD results (22 because of missing MRD samples, five because of PD or death, and 10 because of withdrawal from the study, by NGS on the basis of ITT population, Fig 1). For patients in the Clb-Obi arm, uMRD levels < 10−6 were found in 14 (6.5%) patients, levels ≥ 10−6 and < 10−5 in 27 (12.5%), 30 (13.9%) had levels ≥ 10−5 and < 10−4, 46 (21.3%) had levels ≥ 10−4 and < 10−2, and 57 (26.4%) ≥ 10−2. Forty-two (19.4%) had missing MRD results (24 because of missing MRD samples, 14 because of PD or death, and four because of withdrawal from study).
FIG 1.
Follow-up month 3 (ie, 2 months after treatment completion) minimal residual disease status by next-generation sequencing on the basis of intention-to-treat population. Clb-Obi, chlorambucil-obinutuzumab; MRD, minimal residual disease; NE, not evaluable; PD, progressive disease; Ven-Obi, venetoclax-obinutuzumab.
In the Ven-Obi arm, most of the 86 patients (55.8%) who had uMRD levels < 10−6 at FU month 3 already had uMRD levels < 10−6 at cycle 7, that is, after completing combination therapy with Ven-Obi. In 55 (25.5%) of the patients in the Ven-Obi arm, MRD response deepened after continuing with six cycles of venetoclax monotherapy (Fig 2A).
FIG 2.
(A) Sankey plot for MRD levels by NGS between cycle 7 and FUm3 (ie, 2 months after treatment completion) in the Ven-Obi arm (patients during Ven-Obi treatment). (B) Waterfall plot for the 14 patients with detectable MRD (≥ 10−4) at FUm3 in the Ven-Obi arm and available MRD assessment at cycle 7 by NGS, with each bar representing absolute log changes from cycle 7 to FUm3 per patient. FUm3, follow-up month 3; H-MRD, high minimal residual disease; L-MRD, low minimal residual disease; MRD, minimal residual disease; NGS, next-generation sequencing; PD, progressive disease; Ven-Obi, venetoclax-obinutuzumab.
Of the 14 patients in the Ven-Obi arm with detectable MRD (≥ 10−4) at FU month 3 and available MRD assessment at cycle 7, 7 (50%) had decreasing MRD values from cycle 7 to FU month 3 and 7 (50%) had increasing MRD values until EoT (Fig 2B).
On the basis of the inclusion criteria for the population-based MRD analysis, 154 patients from the Clb-Obi arm and 153 patients from the Ven-Obi arm were included for the MRD model (Data Supplement). The model was overall well calibrated with high concordance between observed and predicted MRD values (Fig 3A). On the basis of a covariate screening of 32 biologic and clinical characteristics, a significant impact on the appearance of detectable MRD was observed by Ven-Obi treatment, MRD levels at the start of treatment, CLL-IPI, 11q deletion, disease burden (definition in the Data Supplement), response to treatment, immunoglobulin heavy-chain variable-region (IGHV) gene status, and complex karyotype (P < .05; Data Supplement). The median MRD doubling time was significantly longer after Ven-Obi than Clb-Obi therapy (median days 80 v 69 days, P = .0039; Fig 3B, Data Supplement). The median time from FU month 3 to the MRD level of 10−2 was also significantly longer after Ven-Obi therapy compared with Clb-Obi therapy (median 1,259 days v 233 days, P < .0001; Fig 3C). Patients with detectable MRD in BM (≥ 10−4) and uMRD in PB had a shorter MRD doubling time than patients with uMRD in both PB and BM (60 days v 80 days in the Ven-Obi arm and 42 v 52 days in the Clb-Obi arm; Data Supplement).
FIG 3.
(A) Model calibration for (left) Clb-Obi and (right) Ven-Obi arms. (B) Time to MRD doubling and (C) time to MRD 10−2 in days, predicted by the growth model. (D) Time to MRD conversion (≥ 10−4) according to the treatment arm, from EoT. (E) Time to MRD conversion (≥ 10−4) according to the treatment arm and BM MRD status, from EoT. (F) PFS according to BM MRD status, from last treatment exposure. BM, bone marrow; Clb-Obi, chlorambucil-obinutuzumab; EoT, end of treatment; H-MRD, high minimal residual disease; L-MRD, low minimal residual disease; MRD, minimal residual disease; PFS, progression-free survival; uMRD, undetectable minimal residual disease; Ven-Obi, venetoclax-obinutuzumab.
On the basis of Kaplan-Meier analysis, the median time to MRD conversion by NGS, defined as an increase in patients with MRD levels < 10−4 at EoT to MRD levels ≥ 10−4, was 21.0 months for patients in the Ven-Obi arm and 6.0 months for patients in the Clb-Obi arm (Fig 3D). In the Ven-Obi arm, 16 of 169 (9.5%) patients with uMRD at EoT showed an increase to low (L)-MRD (≥ 10−4 and < 10−2) and 75 of 169 (44.4%) patients had an increase to high (H)-MRD (≥ 10−2; Data Supplement).
The difference in MRD conversion time between Ven-Obi and Clb-Obi was also observed in patients with BM uMRD in both arms: in the Ven-Obi arm, patients with BM uMRD had a median MRD conversion time of 21.7 months, compared with 9.2 months in the Clb-Obi arm (Fig 3E). However, patients with detectable BM MRD had a similarly short MRD conversion time in both arms (6.0 months and 5.5 months). This was also reflected in PFS, where patients with detectable BM had a shorter PFS than patients with uMRD in BM (Fig 3F).
Twenty-nine months after treatment completion (ie, FU month 30), 58 (26.9%) patients in the Ven-Obi arm had uMRD levels below 10−4, 47 (21.8%) had L-MRD, and 29 (13.4%) had H-MRD (Fig 4). MRD results were missing for 82 (38.0%) patients (35 because of missing samples, 36 because of PD or death, and 11 because of study withdrawal). In the Clb-Obi arm, 7 (3.2%, P < .0001) patients had uMRD levels, 19 (8.8%, P < .001) L-MRD, and 61 (28.2%, P < .001) H-MRD, compared with the Ven-Obi arm. MRD results were missing for 129 (59.7%) patients (23 because of missing samples, 99 because of PD or death, and seven because of study withdrawal). Baseline characteristics for patients with sustained uMRD levels at FU month 30 are presented in the Data Supplement.
FIG 4.
Sankey plot showing MRD levels, measured by next-generation sequencing, from baseline to latest FU visit in the (A) Ven-Obi (n = 216) and (B) Clb-Obi (n = 216) arm. Percentages are provided in relation to the intention-to-treat population. Clb-Obi, chlorambucil-obinutuzumab; FU, follow-up; H-MRD, high minimal residual disease; L-MRD, low minimal residual disease; MRD, minimal residual disease; PD, progressive disease; Ven-Obi, venetoclax-obinutuzumab.
In multivariate analysis, independent prognostic factors for MRD conversion were treatment arm, disease burden (definition in the Data Supplement), CLL-IPI, and BM MRD status at EoT (Data Supplement).
Clinical Outcomes
At a median observation time of 52.4 months (interquartile range 49.5-56.2), patients in the Ven-Obi arm had a significantly longer PFS than patients in the Clb-Obi arm. The median PFS was not reached in the Ven-Obi arm and was 36.4 months in the Clb-Obi arm (hazard ratio [HR] 0.33; 95% CI, 0.25 to 0.45; P < .0001). Four years after random assignment, the PFS rate was 74.0% in the Ven-Obi arm and 35.4% in the Clb-Obi arm (Fig 5A).
FIG 5.
Kaplan-Meier analyses for PFS according to (A) the study arm, (B) status of TP53 aberrations and study arm, and (C) IGHV status and study arm. Clb-Obi, chlorambucil-obinutuzumab; OS, overall survival; PFS, progression-free survival; Ven-Obi, venetoclax-obinutuzumab.
The PFS benefit with Ven-Obi was observed across all clinical and biologic risk groups (Data Supplement). Patients with TP53 aberrations, that is, deletion and/or mutation, had a significantly longer PFS in the Ven-Obi arm than in the Clb-Obi arm (median 49.0 months v 20.8 months; HR 0.44; 95% CI, 0.21 to 0.91; P = .03; Fig 5B). PFS was shorter for patients with TP53 aberrations in both arms compared with patients without TP53 aberrations (Ven-Obi arm: HR 2.50; 95% CI, 1.35 to 4.63; P = .004 and Clb-Obi arm: HR 1.74; 95% CI, 1.07 to 2.83; P = .03).
For patients with both unmutated and mutated IGHV, PFS was significantly longer with Ven-Obi than with Clb-Obi. In the mutated IGHV group, the median PFS was not reached with Ven-Obi and was 54.5 months with Clb-Obi (HR 0.36; 95% CI, 0.19 to 0.68; P = .002; Fig 5C). In the unmutated IGHV group, the median PFS was 57.3 months versus 26.9 months (HR 0.25; 95% CI, 0.17 to 0.37; P < .0001). In both arms, PFS was longer for patients with mutated IGHV compared with unmutated IGHV (Ven-Obi arm: HR 0.47; 95% CI, 0.25 to 0.87; P = .02 and Clb-Obi arm: HR 0.33; 95% CI, 0.22 to 0.48; P < .0001).
Of the 61 PFS events in the Ven-Obi arm, 35 were PDs and 26 were deaths (Data Supplement). Seventeen patients received a next line of antileukemic treatment in the Ven-Obi arm and 70 in the Clb-Obi arm. Time to next treatment was significantly longer in the Ven-Obi arm compared with the Clb-Obi arm (HR 0.46; 95% CI, 0.32 to 0.65; P < .0001; Fig 6A). Most patients received Bruton tyrosine kinase (BTK) inhibitor monotherapy as second-line treatment after progressive disease in both arms (47.1% in the Ven-Obi arm and 50% in the Clb-Obi arm). For cases where investigator-assessed response was available, most patients responded to second-line BTK inhibitor therapy (Data Supplement).
FIG 6.
Kaplan-Meier analysis for (A) TTNT per study arm and (B) OS per study arm. Clb-Obi, chlorambucil-obinutuzumab; OS, overall survival; TTNT, time to next anti-leukemic treatment; Ven-Obi, venetoclax-obinutuzumab.
No difference in OS was observed. Thirty-four (15.7%) patients died in the Ven-Obi arm, and 41 (19.0%) in the Clb-Obi arm (HR 0.85; 95% CI, 0.54 to 1.35; P = .49; Fig 6B). Four years after random assignment, the Kaplan-Meier estimate of OS was 85.4% in the Ven-Obi arm and 83.1% in the Clb-Obi arm. Three years after last treatment exposure, patients with uMRD by NGS at EoT had the highest OS rate in both arms (92.2% after Ven-Obi and 94.6% after Clb-Obi), compared with patients with detectable MRD (72.7% and 82.7%; Data Supplement).
In multivariate analysis, independent prognostic factors associated with PFS were treatment arm, disease burden (high v intermediate or low), IGHV mutation, 17p deletion, and complex karyotype (Data Supplement). For OS, independent prognostic factors were age (cutoff: 75 years), serum β2-microglobulin (cutoff: 3.5 mg/L), and 17p deletion (Data Supplement). In the Ven-Obi arm, only 17p deletion and high disease burden were independent prognostic factors for PFS (Data Supplement).
Safety
For the safety population, the rates of adverse events during treatment were reported previously.6 The current analysis does not reveal new treatment-related adverse events. SPMs of any grade including nonmelanoma skin cancers were observed in 40 (18.9%) patients in the Ven-Obi arm and 30 (14.0%) in the Clb-Obi arm (Data Supplement). Overall, 47 SPM events were reported in the Ven-Obi arm and 42 in the Clb-Obi arm. Most frequent SPMs were basal cell carcinoma (8 [3.8% and 3.7%] patients in both arms, respectively) and squamous cell carcinoma of skin (7 [3.3%] v 8 [3.7%]). Three cases of Richter transformation have been reported in the Clb-Obi arm, and two in the Ven-Obi arm. Four SPMs had a fatal outcome in the Ven-Obi arm and seven in the Clb-Obi arm (Data Supplement).
DISCUSSION
The first aim of this report was to analyze longitudinal MRD assessments, to develop an MRD model, and to characterize and compare MRD kinetics in a prospective, randomized setting. The second aim of this report was to outline the long-term efficacy of first-line Ven-Obi therapy compared with Clb-Obi, once all patients were off treatment for at least 3 years. Previously, several studies have shown the close correlation of EoT MRD status with PFS and OS.5,13-17 The depth of remission should therefore be proportional to the time to disease relapse.2,18 On the basis of this understanding, different treatment strategies for fixed-duration therapy have been suggested for patients who do not reach uMRD at EoT, including continuation of treatment or treatment intensification. In this analysis, half of the 14 patients with detectable MRD at EoT showed decreasing MRD levels while on treatment, suggesting a continuous benefit from venetoclax continuation. The other half of the patients showed increasing MRD levels while on treatment and are therefore unlikely to benefit from continuation beyond 12 cycles. For this group, addition of other agents might facilitate MRD response.19 Ultimately, individualized strategies taking the potential benefit of increasing the remission depth beyond 10−4 into account need to be explored in further clinical studies.
The longitudinal MRD assessments by NGS were used to establish a population-based growth model. The higher efficacy of Ven-Obi compared with that of Clb-Obi was previously mainly attributed to the significantly higher rate of uMRD at FU month 3 (75% v 33%, by NGS-MRD < 10−4). To our knowledge, we show here for the first time that the appearance of detectable MRD after Ven-Obi is significantly slower than after Clb-Obi. This finding seems to be supported by the deeper remissions in the Ven-Obi arm not only in PB but also in BM, suggesting that sufficient compartment clearance is critical for long-term disease control after fixed-duration treatment. Furthermore, the assessment of serial MRD kinetics is particularly informative for patients with high-risk features: previous analyses showed high rates of uMRD at EoT even for patients with TP53 aberrations, unmutated IGHV status, or complex karyotype, suggesting a similar depth of remission in all subgroups after Ven-Obi treatment.5,20 Conversely, the calculation of MRD kinetics indicates that despite similar rates of uMRD after EoT, the growth dynamics of clones in patients with high-risk disease features are accelerated. Therefore, EoT uMRD status alone might yield limited information on the durability of deep remissions in these high-risk subgroups.
The differences in MRD dynamics between Ven-Obi–treated and Clb-Obi–treated patients fit with the significant differences in clinical events between both arms: With a 4-year PFS rate of 74.0%, the most Ven-Obi–treated patients remain without PD despite being off treatment for at least 3 years. Only 17 patients have so far required a next line of treatment after Ven-Obi. Similar to the Clb-Obi arm, most patients received BTK inhibitors as a second-line treatment and responded to therapy. In both arms, patients with TP53 aberrations or unmutated IGHV status had a shorter PFS than patients with unaltered TP53 or mutated IGHV status. This finding differs from previous analyses with shorter FU.5,6,21 Overall, our findings show that the outcome of this high-risk population can be improved markedly with targeted agents; however, similar to other agents such as BTK inhibitors, the adverse impacts of TP53 aberrations and unmutated IGHV status have not been entirely overcome yet.22-25
In contrast to the strong PFS differences, no differences in OS were observed between both study arms, although EoT uMRD status was associated with longer OS. The high median age and presence of coexisting conditions in all patients represent a competing risk for CLL-related OS. The number of CLL-related deaths was higher in the Clb-Obi arm (16 CLL-related deaths) than in the Ven-Obi arm (seven CLL-related deaths), indicating that the impact of the more effective CLL therapy with Ven-Obi might indeed be masked by comorbidities. No new safety signals were reported with the current extended FU. Although previous analyses had reported an increase in the frequency of SPMs in the Ven-Obi arm, this finding has mostly balanced out in the current FU with 47 SPM events in the Ven-Obi arm and 42 in the Clb-Obi arm.
Our exploratory analyses of the MRD model have a few methodologic limitations. Since CLL14 is so far the only phase III study with mature frontline Ven-Obi data, there is no appropriate external validation cohort available. Nevertheless, multiple internal validation strategies indicate a reasonable model calibration. Another caveat might be uncertainties because of imputation of missing data, although this affected < 10% of the data and was conducted using established methods.11,26 Also, some open questions need to be considered. Although different growth dynamics have been observed between Ven-Obi and Clb-Obi, the composition of clones and gene sets driving disease growth is yet to be clarified. Differences in clonal composition of residual disease, in addition to the different compartment clearance, might be contributing to differences in the appearance of detectable MRD. First analyses indicated that the frequency of acquired mutations is higher at relapse and that certain clones such as TP53 mutations or BIRC3 mutations do expand more after Clb-Obi than after Ven-Obi.27 Further analyses are part of ongoing work.
In conclusion, this analysis shows that serial MRD assessments can be used within clinical studies to assess disease dynamics after a fixed-duration treatment. Patients who received Ven-Obi had slower appearance of detectable MRD than patients after Clb-Obi treatment. This finding translated into a sustained clinical benefit for patients who received Ven-Obi as frontline treatment, with only 7.9% of patients requiring a next line of therapy over 3 years after treatment cessation. Thus, these 4-year results of the CLL14 study confirm the sustained efficacy and safety of 12-month fixed-duration Ven-Obi for patients with previously untreated CLL and coexisting conditions.
ACKNOWLEDGMENT
We thank the patients, their families, and their nurses and physicians for their participation in the trial. The authors thank Michele Porro Lurà and Juliana Biondo (Roche/Genentech) for invaluable support in the conception and conduct of the study.
Othman Al-Sawaf
Honoraria: Janssen-Cilag, Roche, Gilead Sciences, AbbVie, AstraZeneca, Adaptive Biotechnologies, BeiGene
Consulting or Advisory Role: Roche, Janssen-Cilag, Gilead Sciences, AbbVie
Research Funding: BeiGene (Inst), Roche (Inst), AbbVie (Inst), Janssen/Pharmacyclics (Inst)
Travel, Accommodations, Expenses: Roche, AbbVie, Gilead Sciences, Janssen-Cilag
Tong Lu
Employment: Genentech/Roche
Stock and Other Ownership Interests: Roche
Patents, Royalties, Other Intellectual Property: P36418-US Title: Methods and systems for placebo response modeling
Michael Z. Liao
Employment: Genentech/Roche
Stock and Other Ownership Interests: Roche, Amgen
Anesh Panchal
Employment: Genentech/Roche
Travers Ching
Employment: Adaptive Biotechnologies
Stock and Other Ownership Interests: Adaptive Biotechnologies
Maneesh Tandon
Employment: Roche (I)
Stock and Other Ownership Interests: Roche Pharma AG
Anna-Maria Fink
Research Funding: Celgene/Bristol Myers Squibb (Inst), AstraZeneca (Inst)
Travel, Accommodations, Expenses: AbbVie
Eugen Tausch
Consulting or Advisory Role: Roche, AbbVie
Speakers' Bureau: Roche, AbbVie, Janssen-Cilag
Travel, Accommodations, Expenses: AbbVie
Matthias Ritgen
Honoraria: Roche, Janssen Oncology, AstraZeneca, AbbVie, MSD
Consulting or Advisory Role: AbbVie, Roche, AstraZeneca
Research Funding: Roche (Inst), AbbVie (Inst)
Patents, Royalties, Other Intellectual Property: Partial patent holder, only intellectual property
Travel, Accommodations, Expenses: AstraZeneca, Takeda
Sebastian Böttcher
Honoraria: Roche, AbbVie, AstraZeneca, Janssen, Sanofi
Consulting or Advisory Role: AstraZeneca, Janssen
Research Funding: Janssen (Inst)
Karl-Anton Kreuzer
Honoraria: Roche, AbbVie
Consulting or Advisory Role: Roche, AbbVie
Speakers' Bureau: Roche, AbbVie
Research Funding: Roche (Inst), AbbVie (Inst)
Expert Testimony: Roche, AbbVie
Travel, Accommodations, Expenses: Roche, AbbVie
Brenda Chyla
Employment: AbbVie
Stock and Other Ownership Interests: AbbVie
Dale Miles
Employment: Genentech
Stock and Other Ownership Interests: Genentech
Travel, Accommodations, Expenses: Genentech
Clemens-Martin Wendtner
Honoraria: Roche, Janssen-Cilag, AbbVie/Genentech, AstraZeneca, Gilead Sciences
Consulting or Advisory Role: Roche, Janssen-Cilag, AbbVie/Genentech, AstraZeneca, Gilead Sciences
Research Funding: Roche, Janssen-Cilag, AbbVie/Genentech, AstraZeneca, Gilead Sciences
Travel, Accommodations, Expenses: Roche, Janssen-Cilag, AbbVie/Genentech, AstraZeneca, Gilead Sciences
Barbara Eichhorst
Honoraria: Roche, AbbVie, Gilead Sciences, Janssen, Novartis, Hexal, AstraZeneca, Adaptive Biotechnologies, Oxford Biomedica, Miltenyi Biotec
Consulting or Advisory Role: Gilead Sciences, Janssen-Cilag, Roche, AbbVie, Novartis, Celgene, AstraZeneca, ArQule
Speakers' Bureau: Roche/Genentech, Janssen-Cilag, Gilead Sciences, Celgene, AbbVie, Novartis
Research Funding: Roche, AbbVie, Gilead Sciences, Janssen, Beijing Genomics Institute
Travel, Accommodations, Expenses: Roche, AbbVie, Gilead Sciences, Janssen
Stephan Stilgenbauer
Honoraria: AbbVie, AstraZeneca, Celgene, Gilead Sciences, GlaxoSmithKline, Roche, Janssen
Consulting or Advisory Role: AbbVie, AstraZeneca, Celgene, Gilead Sciences, GlaxoSmithKline, Roche, Janssen
Speakers' Bureau: AbbVie, AstraZeneca, Celgene, Gilead Sciences, GlaxoSmithKline, Roche, Janssen
Research Funding: AbbVie, AstraZeneca, Celgene, Gilead Sciences, GlaxoSmithKline, Roche, Janssen
Travel, Accommodations, Expenses: AbbVie, AstraZeneca, Celgene, Gilead Sciences, GlaxoSmithKline, Roche, Janssen
Yanwen Jiang
Employment: Genentech
Stock and Other Ownership Interests: Genentech
Michael Hallek
Honoraria: Roche, Janssen, AbbVie, Gilead Sciences, AstraZeneca
Consulting or Advisory Role: Janssen, AbbVie, Gilead Sciences, Genentech/Roche, AstraZeneca
Speakers' Bureau: Janssen, AbbVie, Gilead Sciences, Roche/Genentech, AstraZeneca
Research Funding: Roche (Inst), AbbVie (Inst), Janssen (Inst), Gilead Sciences (Inst), AstraZeneca (Inst), Travel, Accommodations, Expenses: Roche, Janssen
Kirsten Fischer
Honoraria: AbbVie, Roche
Consulting or Advisory Role: AbbVie, Roche
Travel, Accommodations, Expenses: Roche
No other potential conflicts of interest were reported.
PRIOR PRESENTATION
Presented in part at the 63rd ASH Annual Meeting (virtual), December 5-8, 2020.
SUPPORT
Supported by F. Hoffmann-La Roche Ltd and AbbVie Inc. Also supported in part by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – Projektnummer 467697427 (O.A.-S.).
CLINICAL TRIAL INFORMATION
M.H. and K.F. contributed equally and are co-corresponding authors to this work.
DATA SHARING STATEMENT
The German CLL Study Group, Roche, and AbbVie will consider data sharing requests on a case-by-case basis. With publication, requests by academic study groups for deidentified patient data with the intent-to-achieve aims of the original proposal can be forwarded to the corresponding author and will be evaluated by the German CLL Study Group, Roche, and AbbVie.
AUTHOR CONTRIBUTIONS
Conception and design: Othman Al-Sawaf, Can Zhang, Tong Lu, Michael Z. Liao, Yanwen Jiang, Michael Hallek, Kirsten Fischer
Administrative support: Othman Al-Sawaf, Can Zhang, Kirsten Fischer
Provision of study materials or patients: Othman Al-Sawaf, Eugen Tausch, Matthias Ritgen, Karl-Anton Kreuzer, Clemens-Martin Wendtner, Barbara Eichhorst, Stephan Stilgenabuer, Michael Hallek, Kirsten Fischer
Collection and assembly of data: Othman Al-Sawaf, Tong Lu, Michael Z. Liao, Travers Ching, Anna-Maria Fink, Eugen Tausch, Christof Schneider, Matthias Ritgen, Karl-Anton Kreuzer, Clemens-Martin Wendtner, Stephan Stilgenbauer, Yanwen Jiang, Michael Hallek, Kirsten Fischer
Data analysis and interpretation: Othman Al-Sawaf, Can Zhang, Tong Lu, Michael Z. Liao, Anesh Panchal, Sandra Robrecht, Maneesh Tandon, Anna-Maria Fink, Eugen Tausch, Matthias Ritgen, Sebastian Böttcher, Karl-Anton Kreuzer, Brenda Chyla, Dale Miles, Clemens-Martin Wendtner, Barbara Eichhorst, Stephan Stilgenbauer, Yanwen Jiang, Michael Hallek, Kirsten Fischer
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Minimal Residual Disease Dynamics After Venetoclax-Obinutuzumab Treatment: Extended Off-Treatment Follow-up From the Randomized CLL14 Study
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).
Othman Al-Sawaf
Honoraria: Janssen-Cilag, Roche, Gilead Sciences, AbbVie, AstraZeneca, Adaptive Biotechnologies, BeiGene
Consulting or Advisory Role: Roche, Janssen-Cilag, Gilead Sciences, AbbVie
Research Funding: BeiGene (Inst), Roche (Inst), AbbVie (Inst), Janssen/Pharmacyclics (Inst)
Travel, Accommodations, Expenses: Roche, AbbVie, Gilead Sciences, Janssen-Cilag
Tong Lu
Employment: Genentech/Roche
Stock and Other Ownership Interests: Roche
Patents, Royalties, Other Intellectual Property: P36418-US Title: Methods and systems for placebo response modeling
Michael Z. Liao
Employment: Genentech/Roche
Stock and Other Ownership Interests: Roche, Amgen
Anesh Panchal
Employment: Genentech/Roche
Travers Ching
Employment: Adaptive Biotechnologies
Stock and Other Ownership Interests: Adaptive Biotechnologies
Maneesh Tandon
Employment: Roche (I)
Stock and Other Ownership Interests: Roche Pharma AG
Anna-Maria Fink
Research Funding: Celgene/Bristol Myers Squibb (Inst), AstraZeneca (Inst)
Travel, Accommodations, Expenses: AbbVie
Eugen Tausch
Consulting or Advisory Role: Roche, AbbVie
Speakers' Bureau: Roche, AbbVie, Janssen-Cilag
Travel, Accommodations, Expenses: AbbVie
Matthias Ritgen
Honoraria: Roche, Janssen Oncology, AstraZeneca, AbbVie, MSD
Consulting or Advisory Role: AbbVie, Roche, AstraZeneca
Research Funding: Roche (Inst), AbbVie (Inst)
Patents, Royalties, Other Intellectual Property: Partial patent holder, only intellectual property
Travel, Accommodations, Expenses: AstraZeneca, Takeda
Sebastian Böttcher
Honoraria: Roche, AbbVie, AstraZeneca, Janssen, Sanofi
Consulting or Advisory Role: AstraZeneca, Janssen
Research Funding: Janssen (Inst)
Karl-Anton Kreuzer
Honoraria: Roche, AbbVie
Consulting or Advisory Role: Roche, AbbVie
Speakers' Bureau: Roche, AbbVie
Research Funding: Roche (Inst), AbbVie (Inst)
Expert Testimony: Roche, AbbVie
Travel, Accommodations, Expenses: Roche, AbbVie
Brenda Chyla
Employment: AbbVie
Stock and Other Ownership Interests: AbbVie
Dale Miles
Employment: Genentech
Stock and Other Ownership Interests: Genentech
Travel, Accommodations, Expenses: Genentech
Clemens-Martin Wendtner
Honoraria: Roche, Janssen-Cilag, AbbVie/Genentech, AstraZeneca, Gilead Sciences
Consulting or Advisory Role: Roche, Janssen-Cilag, AbbVie/Genentech, AstraZeneca, Gilead Sciences
Research Funding: Roche, Janssen-Cilag, AbbVie/Genentech, AstraZeneca, Gilead Sciences
Travel, Accommodations, Expenses: Roche, Janssen-Cilag, AbbVie/Genentech, AstraZeneca, Gilead Sciences
Barbara Eichhorst
Honoraria: Roche, AbbVie, Gilead Sciences, Janssen, Novartis, Hexal, AstraZeneca, Adaptive Biotechnologies, Oxford Biomedica, Miltenyi Biotec
Consulting or Advisory Role: Gilead Sciences, Janssen-Cilag, Roche, AbbVie, Novartis, Celgene, AstraZeneca, ArQule
Speakers' Bureau: Roche/Genentech, Janssen-Cilag, Gilead Sciences, Celgene, AbbVie, Novartis
Research Funding: Roche, AbbVie, Gilead Sciences, Janssen, Beijing Genomics Institute
Travel, Accommodations, Expenses: Roche, AbbVie, Gilead Sciences, Janssen
Stephan Stilgenbauer
Honoraria: AbbVie, AstraZeneca, Celgene, Gilead Sciences, GlaxoSmithKline, Roche, Janssen
Consulting or Advisory Role: AbbVie, AstraZeneca, Celgene, Gilead Sciences, GlaxoSmithKline, Roche, Janssen
Speakers' Bureau: AbbVie, AstraZeneca, Celgene, Gilead Sciences, GlaxoSmithKline, Roche, Janssen
Research Funding: AbbVie, AstraZeneca, Celgene, Gilead Sciences, GlaxoSmithKline, Roche, Janssen
Travel, Accommodations, Expenses: AbbVie, AstraZeneca, Celgene, Gilead Sciences, GlaxoSmithKline, Roche, Janssen
Yanwen Jiang
Employment: Genentech
Stock and Other Ownership Interests: Genentech
Michael Hallek
Honoraria: Roche, Janssen, AbbVie, Gilead Sciences, AstraZeneca
Consulting or Advisory Role: Janssen, AbbVie, Gilead Sciences, Genentech/Roche, AstraZeneca
Speakers' Bureau: Janssen, AbbVie, Gilead Sciences, Roche/Genentech, AstraZeneca
Research Funding: Roche (Inst), AbbVie (Inst), Janssen (Inst), Gilead Sciences (Inst), AstraZeneca (Inst), Travel, Accommodations, Expenses: Roche, Janssen
Kirsten Fischer
Honoraria: AbbVie, Roche
Consulting or Advisory Role: AbbVie, Roche
Travel, Accommodations, Expenses: Roche
No other potential conflicts of interest were reported.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The German CLL Study Group, Roche, and AbbVie will consider data sharing requests on a case-by-case basis. With publication, requests by academic study groups for deidentified patient data with the intent-to-achieve aims of the original proposal can be forwarded to the corresponding author and will be evaluated by the German CLL Study Group, Roche, and AbbVie.