Outcomes in Patients with High-Risk Features after Fixed-Duration Ibrutinib plus Venetoclax: Phase II CAPTIVATE Study in First-Line Chronic Lymphocytic Leukemia

Ibrutinib, a Bruton's tyrosine kinase inhibitor, and venetoclax, a BCL-2 inhibitor, are once-daily, oral-targeted therapies that are both approved for the treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL; refs. 1, 2). Through distinct and complementary mechanisms of action, the combination of ibrutinib and venetoclax has the potential to eradicate both dividing and resting CLL cells by preferentially targeting distinct cell compartments and CLL subpopulations (3–5). Ibrutinib mobilizes CLL cells out of lymph nodes and other protective lymphoid niches into peripheral blood, where they are more susceptible to venetoclax-induced apoptosis (5, 6). Ibrutinib also enhances the dependence of CLL cells on BCL-2, thereby increasing sensitivity to venetoclax and accelerating apoptosis (3, 6, 7). Synergistic antitumor activity with the combination of ibrutinib plus venetoclax has been demonstrated in preclinical models of CLL (8). The combination of ibrutinib plus venetoclax demonstrated high rates of undetectable minimal residual disease (uMRD) in both peripheral blood and bone marrow, high rates of progression-free survival (PFS), and durable treatment-free remissions in patients with previously untreated CLL/SLL treated with fixed-duration ibrutinib plus venetoclax in the CAPTIVATE and GLOW studies (9–11).

CLL is characterized by molecular heterogeneity resulting in variability in disease course, clonal growth rates, and response to treatment (12, 13). In particular, presence of TP53 aberrations (deletion of the TP53 gene locus on chromosome 17 [del(17p)] or mutations in the TP53 gene) is strongly prognostic for disease progression and worse overall survival (OS; refs. 13, 14), and patients with TP53 aberrations experience inferior outcomes with first-line chemoimmunotherapy than patients without TP53 aberrations (15–18). Mutational status of the variable region of the immunoglobulin heavy chain (IGHV) gene has also been identified as a prognostic factor in CLL, with poor prognosis in patients with unmutated IGHV (19, 20). Unmutated IGHV predicts inferior outcomes with first-line chemoimmunotherapy, whereas patients with mutated IGHV can achieve long-term PFS with chemoimmunotherapy (16–18, 21). Ibrutinib- and venetoclax-based regimens (including the fixed-duration regimen of venetoclax plus obinutuzumab) have both demonstrated PFS benefit over chemoimmunotherapy in patients with previously untreated CLL/SLL and high-risk genomic features, including del(17p), TP53, mutation, and/or unmutated IGHV (22, 23). In addition, combined ibrutinib plus venetoclax demonstrated promising efficacy in a phase II study in patients with previously untreated CLL with at least 1 high-risk feature [del(17p), TP53 mutation, del(11q), or unmutated IGHV, or age ≥65 years; ref. 24].

The phase II CAPTIVATE study demonstrated deep and durable responses with ibrutinib plus venetoclax in first-line treatment of CLL/SLL (9, 10). Here, we report efficacy and safety of fixed-duration ibrutinib plus venetoclax in patients with high-risk genomic features [del(17p), TP53 mutation, and/or unmutated IGHV] in the CAPTIVATE study.

Design of this trial was also summarized elsewhere (9, 10, 25). CAPTIVATE is a multicenter, international, phase II study comprising 2 sequentially enrolled cohorts: the MRD cohort (9) and the FD cohort (10). In both cohorts, patients received single-agent oral ibrutinib (420 mg once daily) lead-in for three 28-day cycles followed by 12 cycles of ibrutinib in combination with oral venetoclax [target dose 400 mg once daily after standard 5-week ramp-up, with tumor lysis syndrome (TLS) prophylaxis and monitoring per venetoclax prescribing information; ref. 2]. Subsequently, patients in the FD cohort received no further treatment regardless of MRD status at the end of treatment (10). Patients in the MRD cohort were randomly assigned to subsequent treatment according to MRD status after 12 cycles of ibrutinib plus venetoclax; the placebo arm comprised patients who achieved confirmed uMRD (defined as having uMRD <10^–4 by 8-color flow cytometry serially over at least three cycles, and undetectable MRD in both peripheral blood and bone marrow) and were randomly assigned to receive placebo in a double-blind manner (9).

Eligible patients were adults aged ≥18 to <70 years (MRD cohort) or ≤70 years (FD cohort) with previously untreated CLL/SLL requiring treatment per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria (26), measurable nodal disease by computed tomography, Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 2, and adequate hepatic, renal, and hematologic function. Patients with known allergy to xanthine oxidase inhibitors and/or rasburicase were excluded due to the requirement for TLS prophylaxis per venetoclax prescribing information (2).

The study was conducted in accordance with International Conference on Harmonisation guidelines for Good Clinical Practice and principles of the Declaration of Helsinki. The protocol was approved by the institutional review boards or independent ethics committees of all participating institutions. All patients provided written informed consent. This study is registered with ClinicalTrials.gov (NCT02910583).

In this exploratory post hoc analysis, data from the FD cohort and MRD cohort placebo arm were pooled for patients with known status for high-risk features [del(17p), TP53 mutation, or unmutated IGHV] treated with fixed-duration ibrutinib plus venetoclax. Patients with unknown/missing status were excluded. Clinical outcomes of interest were overall response rate, defined as the proportion of patients with a best response of partial response (PR) or better by investigator assessment per 2008 iwCLL criteria (26, 27); complete response (CR) rate, including CR with incomplete bone marrow recovery (CRi); uMRD rates in peripheral blood and bone marrow (<10^–4 by 8-color flow cytometry); PFS by investigator assessment; OS; and safety. Adverse events (AE) were monitored during the treatment-emergent AE reporting period (from first dose until 30 days after the last dose of fixed-duration study treatment). Only serious AEs considered related to study treatment and secondary malignancies continued to be collected during follow-up posttreatment. PFS and OS were estimated using the Kaplan–Meier method. Outcomes were analyzed for subgroups with versus without ≥1 high-risk feature [del(17p), TP53 mutation, and/or unmutated IGHV]. Analyses of outcomes by individual high-risk features were also performed for patients with or without del(17p)/TP53 mutation, and for patients with unmutated IGHV or mutated IGHV. To address the potential bias from inclusion of patients from the MRD cohort placebo arm, all of whom achieved uMRD with ibrutinib plus venetoclax, sensitivity analyses were performed with patients from the FD cohort only (excluding patients from the MRD cohort placebo arm who were known to have uMRD at end of treatment). Given the exploratory post hoc nature of the analysis, no formal statistical comparisons were done; results are reported descriptively.

Cytogenetics were evaluated using FISH by local laboratory or by central laboratory; central laboratory results were used where available (93% of patients). Mutational status of TP53 was assessed using next-generation sequencing by a central laboratory. The threshold for reporting TP53 mutations was a variant allele frequency of ≥10% per European Research Initiative on CLL recommendations (28). IGHV gene mutational status was assessed with somatic hypermutation assay by a central laboratory. Karyotype was evaluated using CpG-stimulated cytogenetics by a central laboratory; complex karyotype was defined as ≥3 abnormalities.

Requests for access to individual participant data from clinical studies conducted by Pharmacyclics LLC, an AbbVie Company, can be submitted through Yale Open Data Access (YODA) Project site at http://yoda.yale.edu.

A total of 323 patients were enrolled in CAPTIVATE: 164 patients in the MRD cohort and 159 patients in the FD cohort. Overall, 202 patients were treated with fixed-duration ibrutinib plus venetoclax in the FD cohort (n = 159) and MRD cohort placebo arm (n = 43); baseline characteristics by cohort are described in Supplementary Table S1. Of 195 patients with known status of risk features at baseline, 129 (66%) patients had high-risk features, including 29 patients with del(17p)/TP53 mutation and 119 patients with unmutated IGHV; 19 patients had both unmutated IGHV and del(17p)/TP53 mutation. Baseline characteristics for patients with and without high-risk features are described in Table 1. At the time of analysis, median time on study was 38.9 months (range, 0.8–56.4) for patients with high-risk features, and 38.8 months (range, 2.6–53.4) for patients without high-risk features (n = 66). Median duration of posttreatment follow-up for the total pooled population was 25.1 months (range, 0.07–41.2).

Overall response rates were >95% regardless of the presence of high-risk features (Fig. 1). CR/CRi rates were 61% [95% confidence interval (CI), 53–70] and 53% (95% CI, 41–65) in patients with and without high-risk features, respectively (Fig. 1A). Of patients who achieved CR/CRi, duration of CR/CRi lasting ≥12 cycles was confirmed in 92% (73/79) of patients with high-risk features and 97% (34/35) of patients without high-risk features. The 24-month landmark estimate for duration of CR/CRi was 93% (95% CI, 83–97) in patients with high-risk features and 100% (95% CI, 100–100) in those without high-risk features. In the subsets of patients with (n = 29) and without del(17p)/TP53 mutation (n = 169), CR/CRi rates were 52% (95% CI, 34–70) and 60% (95% CI, 52–67), respectively (Fig. 1B). In the subsets of patients with unmutated IGHV (n = 119) and mutated IGHV (n = 78), CR/CRi rates were 61% (95% CI, 53–70) and 54% (95% CI, 43–65), respectively (Fig. 1B). The 24-month landmark estimate for duration of CR/CRi was 86% (95% CI, 54–96) and 97% (95% CI, 90–99) in patients with and without del(17p)/TP53 mutation, respectively, and 94% (95% CI, 84–98) and 97% (95% CI, 83–100) in patients with unmutated IGHV and mutated IGHV, respectively. For patients with unmutated IGHV without del(17p)/TP53 mutation (n = 100), the CR/CRi rate was 64% (95% CI, 55–73) and the 24-month landmark estimate for duration of CR/CRi was 95% (95% CI, 84–98).

Best uMRD rates were 88% (95% CI, 83–94) and 70% (95% CI, 59–81) in peripheral blood and 72% (95% CI, 64–80) and 61% (95% CI, 49–72) in bone marrow in patients with and without high-risk features, respectively (Fig. 1C). In patients who achieved CR/CRi, best uMRD rates were 96% and 83% in peripheral blood and 78% and 77% in bone marrow in patients with and without high-risk features, respectively. While uMRD rates were relatively consistent among patients with and without high-risk features, analysis of uMRD rates by individual high-risk features showed lower bone marrow uMRD rates in patients with del(17p)/TP53 mutation. Best uMRD rates in peripheral blood were 83% (95% CI, 69–97) and 82% (95% CI, 76–88) for the subsets of patients with and without del(17p)/TP53 mutation, respectively, and 88% (95% CI, 82–94) and 72% (95% CI, 62–82) for the subsets with unmutated IGHV and mutated IGHV, respectively. Best uMRD rates in bone marrow were 45% (95% CI, 27–63) and 72% (95% CI, 65–79) for the subsets of patients with and without del(17p)/TP53 mutation, respectively, and 73% (95% CI, 65–81) and 60% (95% CI, 49–71) for those with unmutated IGHV and mutated IGHV, respectively (Fig. 1D). In patients with unmutated IGHV without del(17p)/TP53 mutation, best uMRD rates in peripheral blood and bone marrow were 90% (95% CI, 84–96) and 80% (95% CI, 72–88), respectively. In patients with CR/CRi, best uMRD rates in peripheral blood were 100% and 91% in the subsets of patients with and without del(17p)/TP53 mutation, respectively, and 96% and 86% in the subsets of patients with unmutated IGHV and mutated IGHV, respectively; corresponding uMRD rates in bone marrow were 67% and 80% in patients with and without del(17p)/TP53 mutation, respectively, and 78% and 79% in those with unmutated IGHV and mutated IGHV, respectively.

PFS rates in patients with high-risk features were similar to those observed in patients without high-risk features, with 36-month PFS rates of 88% (95% CI, 81–93) and 92% (95% CI, 82–97), respectively (Fig. 2A). Compared with the relatively consistent PFS rates among patients with and without high-risk features, analysis of PFS by individual high-risk features showed a slightly lower PFS among the small subset of patients with del(17p)/TP53 mutation. The 36-month PFS rates for the subsets of patients with and without del(17p)/TP53 mutation were 81% (95% CI, 61–92) and 91% (95% CI, 85–94), respectively, and 36-month PFS rates for those with unmutated IGHV and mutated IGHV were 88% (95% CI, 80–93) and 92% (95% CI, 83–96), respectively (Fig. 2B). The 36-month PFS rate for patients with unmutated IGHV without del(17p)/TP53 mutation was 90% (95% CI, 82–94). At 36 months, OS rates were >95% in patients with and without high-risk features (Fig. 2C) and in the subsets of patients with and without del(17p)/TP53 mutation and with unmutated IGHV and mutated IGHV (Fig. 2D). The 36-month OS rate for patients with unmutated IGHV without del(17p)/TP53 mutation was 98% (95% CI, 92–99). PFS and OS for the total pooled population (n = 202) are shown in Supplementary Fig. S1.

Sensitivity analyses were performed to address the potential bias from inclusion of patients from the MRD cohort placebo arm, all of whom had uMRD at the end of treatment. Results of these sensitivity analyses including patients from the FD cohort only (excluding patients from the MRD cohort placebo arm) demonstrated similar outcomes to those observed in the total pooled population (Supplementary Table S2). Among patients from the FD cohort only, CR/CRi rates were 64% (95% CI, 55–74) in patients with high-risk features (n = 98) and 46% (95% CI, 32–59) in those without high-risk features (n = 55). At 36 months, PFS rates were 86% (95% CI, 77–92) and 90% (95% CI, 78–96) in patients with and without high-risk features, respectively, and OS rates were 97% (95% CI, 91–99) and 100% (95% CI, 100–100), respectively.

At the time of analysis, PD had occurred in 26 of 129 (20%) patients with high-risk features and in 5 of 66 (8%) patients without high-risk features. Among the 26 patients with high-risk features who had subsequent PD, best overall response with fixed-duration ibrutinib plus venetoclax was CR/CRi in 13 patients and PR in 13 patients; best MRD response was uMRD in peripheral blood in 23 patients and uMRD in bone marrow in 15 patients. Among the 5 patients without high-risk features who had subsequent PD, best overall response with fixed-duration ibrutinib plus venetoclax was PR in all 5 patients; none of these 5 patients achieved uMRD in peripheral blood or bone marrow. No resistance-associated mutations in BTK, PLCγ2, or BCL-2 were detected at the time of PD in 26 patients with PD samples tested.

After experiencing PD, 9 patients with high-risk features and 3 patients without high-risk features have been retreated with single-agent ibrutinib. Of the 9 patients with high-risk features, 8 had unmutated IGHV, 2 had del(17p), 1 had TP53 mutation, and 4 had complex karyotype at baseline. Of the 3 patients classified as without high-risk features, 2 had complex karyotype at baseline. In the patients with high-risk features retreated with single-agent ibrutinib [duration of retreatment, median 6.1 months (range, 0.03–27.6)], 6 of 6 patients with available response data achieved a best response of PR, and 3 additional patients are pending response evaluation. In the patients without high-risk features retreated with single-agent ibrutinib [duration of retreatment, median 3.7 months (range, 3.7–7.4)], 3 of 3 achieved a best response of PR.

At the time of analysis, no patients remained on fixed-duration treatment with ibrutinib plus venetoclax. Of the 129 patients with high-risk features, 121 (94%) completed planned treatment with ibrutinib and venetoclax. Of the 66 patients without high-risk features, 62 (94%) completed planned treatment with ibrutinib and venetoclax. Median treatment duration was 13.8 months (range, 0.7–24.9 months) for ibrutinib and 11.1 months (range, 9.9–22.1 months) for venetoclax in patients with high-risk features. Median duration of treatment was 13.8 months (range, 0.5–14.9) for ibrutinib and 11.1 months (range, 1.3–12.2) for venetoclax in patients without high-risk features.

The safety profile of ibrutinib plus venetoclax in patients with high-risk features was similar to that observed in patients without high-risk features (Table 2). The most common AEs of any grade during the treatment-emergent AE reporting period (from first dose until 30 days after the last dose of fixed-duration study treatment) were diarrhea (62% and 59% of patients with and without high-risk features, respectively), neutropenia (46% and 55%), nausea (42% and 44%), and arthralgia (33% and 32%). The most common grade 3/4 treatment-emergent AEs were neutropenia (36% and 36% of patients with and without high-risk features, respectively), and hypertension (9% and 3%). Overall, serious AEs during the treatment-emergent AE reporting period were reported in 22% and 21% of patients with and without high-risk features, respectively. During the fixed-duration treatment period, AEs led to discontinuation of ibrutinib only in 2% and 3% of patients with and without high-risk features, respectively, and discontinuation of both ibrutinib and venetoclax in 1% and 3% of patients, respectively.

Results from this pooled analysis of patients treated with fixed-duration ibrutinib plus venetoclax in the CAPTIVATE study confirm that deep, durable responses and sustained PFS seen with fixed-duration ibrutinib plus venetoclax are maintained in patients with 1 or more high-risk genomic features [del(17p), TP53 mutation, or unmutated IGHV], with PFS and OS rates that are similar to patients without high-risk features. The presence of high-risk genomic features did not appear to have a discernible impact on rates of treatment-emergent AEs, with a similar safety profile to that previously reported for the overall population of the CAPTIVATE FD cohort (10).

Interestingly, CR/CRi rates and uMRD rates were slightly higher in patients with 1 or more high-risk features than in patients without high-risk features, which may be at least partially due to the contribution of patients with unmutated IGHV who comprised 78% of the patients in the subgroup with high-risk features. In the primary analysis of the CAPTIVATE FD cohort, we observed that patients with unmutated IGHV had higher CR/CRi rates (62% vs. 47%) and higher uMRD rates in both peripheral blood (84% vs. 67%) and bone marrow (64% vs. 53%) than patients with mutated IGHV, which may reflect BCR pathway inhibition by ibrutinib (10). In the current analysis, the subset of patients with unmutated IGHV demonstrated high CR/CRi rates (61%) and uMRD rates in peripheral blood (88%) and bone marrow (73%). The small subset of patients with del(17p)/TP53 mutation had similar rates of CR/CRi (52%) and uMRD in peripheral blood (83%) to those observed in patients without high-risk features (53% and 70%, respectively), whereas the rate of uMRD in bone marrow (45%) was markedly lower than that observed in patients without high-risk features (61%), albeit with a wide 95% CI.

Patients with CLL bearing TP53 aberrations [del(17p) and/or TP53 mutation] have poor outcomes on chemoimmunotherapy, with 3-year PFS and OS rates of only 18% and 38%, respectively, in those treated with first-line fludarabine, cyclophosphamide, and rituximab (FCR; ref. 16). In contrast, the 3-year PFS and OS rates were 81% and 96%, respectively, in patients with del(17p)/TP53 mutation treated with fixed-duration ibrutinib plus venetoclax in the current study. These rates are consistent with those observed in patients with TP53 aberrations with first-line continuous BTK inhibitor-based therapy while providing the advantage of fixed-duration therapy (29–31). While cross-trial comparisons should be interpreted with caution given differences in study designs and patient populations, when looking at other novel fixed-duration combinations, the 3-year PFS rate in this subgroup was 81% in the current analysis compared with the 3-year PFS rate of 60% achieved with fixed-duration venetoclax plus obinutuzumab in patients with del(17p)/TP53 mutation in the CLL14 study (32). Similarly, patients with unmutated IGHV have worse outcomes on chemoimmunotherapy than patients with mutated IGHV, with 3-year PFS and OS rates of 55% and 86%, respectively, in patients with unmutated IGHV treated with first-line FCR (16). In the subset of patients with unmutated IGHV treated with fixed-duration ibrutinib plus venetoclax in the current study, 3-year PFS and OS rates were 88% and 98%, respectively. The 3-year PFS rate in patients with unmutated IGHV treated with fixed-duration venetoclax plus obinutuzumab in CLL14 was 81% (32), and 3-year PFS rates in patients with unmutated IGHV treated with time-limited venetoclax plus obinutuzumab and venetoclax plus obinutuzumab plus ibrutinib in the CLL13 study were 83% and 87%, respectively (33).

Our study has some limitations given the exploratory nature of these analyses. Inclusion of patients from the placebo arm of the MRD cohort had the potential to introduce bias because, by definition, all of these patients had confirmed uMRD after 12 cycles of ibrutinib plus venetoclax; however, sensitivity analyses excluding these patients demonstrated similar outcomes to those in the total pooled population. Although PFS appeared to be slightly worse in patients with del(17p)/TP53 mutation in the current study, no meaningful statistical comparisons are possible given the relatively small number of patients with del(17p)/TP53 mutation. Complex karyotype was not included in the definition of high-risk genomic features in the current analysis given the lack of consensus in the definition for complex karyotype (e.g., ≥3 or ≥5 abnormalities) and lack of clear guidance on how complex karyotype should inform decision making in the clinic (34). In addition, data on complex karyotype was missing in many patients (particularly in the FD cohort) and exclusion of these patients with missing data would have further reduced the numbers of patients in already small subgroups, whereas del(17p), TP53 mutation, and IGHV mutation status were known for nearly all patients.

In conclusion, fixed-duration treatment with ibrutinib plus venetoclax demonstrated deep, durable responses in patients with 1 or more high-risk genomic features [del(17p), TP53 mutation, or unmutated IGHV]. Patients with high-risk features had high PFS and OS rates that were similar to those observed in patients without high-risk features, although a slightly lower PFS rate was seen in the small subset of patients with TP53 aberrations. Ibrutinib plus venetoclax had a manageable safety profile in patients with high-risk features, with 94% of these patients completing all planned treatment with ibrutinib plus venetoclax. These results support first-line treatment with ibrutinib plus venetoclax as an all-oral, once-daily, chemotherapy-free, fixed-duration regimen that provides clinically meaningful PFS and treatment-free remissions in patients with CLL/SLL, including those with high-risk genomic features.

J.N. Allan reports grants from Pharmacyclics during the conduct of the study as well as personal fees from AbbVie, AstraZeneca, BeiGene, Lilly, and Pharmacyclics and grants and personal fees from Genentech, Janssen and TG Therapeutics outside the submitted work. I.W. Flinn reports other support from Pharmacyclics during the conduct of the study as well as other support from AbbVie, BeiGene, Century Therapeutics, Genentech, Genmab, Hutchison MediPharma, InnoCare Pharma, Kite Pharma, Myeloid Therapeutics, Novartis, Secura Bio, Servier Pharmaceuticals, TG Therapeutics, Vincerx Pharma, and Xencor and grants from AbbVie, Acerta Pharma, Agios, ArQule, AstraZeneca, BeiGene, Biopath, Bristol-Myers Squibb, CALIBR, CALGB, Celgene, City of Hope National Medical Center, Constellation Pharmaceuticals, Curis, CTI Biopharma, Epizyme, Fate Therapeutics, Forma Therapeutics, Forty Seven, Genentech, Gilead Sciences, InnoCare Pharma, IGM Biosciences, Incyte, Infinity Pharmaceuticals, Janssen, Kite Pharma, Loxo, Marker Therapeutics, Merck, Millennium Pharmaceuticals, Morphosys, Myeloid Therapeutics, Novartis, Nurix, Pfizer, Pharmacyclics, Portola Pharmaceuticals, Rhizen Pharmaceuticals, Roche, Seattle Genetics, Step Pharma, Tessa Therapeutics, TG Therapeutics, Trillium Therapeutics, Triphase Research & Development Corp., Unum Therapeutics, Verastem, Vincerx Pharma, and 2seventy Bio outside the submitted work. T. Siddiqi reports personal fees from Pharmacyclics, AstraZeneca, BeiGene, BMS/Celgene/Juno, and AbbVie during the conduct of the study as well as personal fees from Gilead/Kite outside the submitted work. P. Ghia reports grants and personal fees from AstraZeneca, AbbVie, and Janssen and personal fees from BeiGene, Lilly/Loxo Oncology, BMS, MSD, and Roche outside the submitted work. C.S. Tam reports other support from Janssen and Pharmacyclics during the conduct of the study as well as other support from AbbVie and BeiGene outside the submitted work. T.J. Kipps reports personal fees from Pharmacyclics/AbbVie, Dava Oncology, Genentech/Roche, Gilead, European Research Initiative on CLL, and Janssen; grants from Breast Cancer Research Foundation, California Institute for Regenerative Medicine, and NCI/NIH; and other support from Velos Bio and Oncternal Therapeutics outside the submitted work. In addition, T.J. Kipps has a patent (9,217,040) issued to University of California, San Diego; cirmtuzumab was developed by T.J. Kipps in the Thomas Kipps laboratory and licensed by the University of California to Oncternal Therapeutics, Inc., which provided stock options and research funding to the Thomas Kipps laboratory. P.M. Barr reports other support from AbbVie/Pharmacyclics during the conduct of the study as well as other support from PCYC/AbbVie, Gilead, Merck, Genentech, Celgene/BMS, TG Therapeutics, Janssen, BeiGene, Seattle Genetics, Morphosys, and AstraZeneca outside the submitted work. X.C. Badoux reports personal fees from Janssen and AbbVie outside the submitted work. R. Jacobs reports grants and personal fees from Pharmacyclics and personal fees from AbbVie, Genentech, and Janssen during the conduct of the study as well as grants and personal fees from Lilly, AstraZeneca, TG Therapeutics; grants from TeneoBio; and personal fees from Securabio and BeiGene outside the submitted work. B.J. Kuss reports that this work is part of an international clinical trial that is drug company sponsored; B.J. Kuss participated and recruited patients for the trial but did not receive funding for contributions to the writing of this manuscript. L. Trentin reports personal fees from Janssen, grants from AstraZeneca and AbbVie and grants and personal fees from Takeda outside the submitted work. C. Zhou is an employee of AbbVie, the sponsor of the published trial. A. Szoke reports other support from Pharmacyclics LLC, an AbbVie Company, outside the submitted work; in addition, A. Szoke reports employment with Pharmacyclics LLC, an AbbVie Company, and stock or other ownership with AbbVie. C. Abbazio reports other support from AbbVie and Bristol-Myers Squibb outside the submitted work. W.G. Wierda reports other support from GSK/Novartis, AbbVie, Genentech, Pharmacyclics LLC, AstraZeneca/Acerta Pharma Inc., Gilead Sciences, Juno Therapeutics, Kite Pharma, Sunesis, Miragen, Oncternal Therapeutics, Cyclacel, Loxo Oncology, Janssen, and Xencor during the conduct of the study. No disclosures were reported by the other authors.

J.N. Allan: Conceptualization, resources, investigation, methodology, writing–review and editing. I.W. Flinn: Resources, investigation, writing–review and editing. T. Siddiqi: Resources, investigation, writing–review and editing. P. Ghia: Conceptualization, resources, investigation, methodology, writing–review and editing. C.S. Tam: Conceptualization, resources, investigation, methodology, writing–review and editing. T.J. Kipps: Resources, investigation, writing–review and editing. P.M. Barr: Conceptualization, resources, investigation, methodology. A. Elinder Camburn: Resources, investigation, writing–review and editing. A. Tedeschi: Resources, investigation, writing–review and editing. X.C. Badoux: Resources, investigation, writing–review and editing. R. Jacobs: Resources, investigation, writing–review and editing. B.J. Kuss: Resources, investigation, writing–review and editing. L. Trentin: Resources, investigation, writing–review and editing. C. Zhou: Conceptualization, data curation, formal analysis, validation, visualization, methodology, writing–review and editing. A. Szoke: Conceptualization, supervision, methodology, writing–review and editing. C. Abbazio: Conceptualization, visualization, methodology, writing–original draft, writing–review and editing. W.G. Wierda: Conceptualization, resources, investigation, methodology, writing–review and editing.

We thank the patients who participated in the study and their supportive families, as well as the investigators and clinical research staff from the study centers. This study was sponsored by Pharmacyclics LLC, an AbbVie Company. Medical writing and editorial support was provided by Melanie Sweetlove, MSc, and funded by Pharmacyclics LLC, an AbbVie Company.

The publication costs of this article were defrayed in part by the payment of publication fees. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.