Leukemia & Lymphoma ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ilal20 Up to 6.5 years (median 4 years) of follow-up of first-line ibrutinib in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma and high-risk genomic features: integrated analysis of two phase 3 studies Jan A. Burger, Tadeusz Robak, Fatih Demirkan, Osnat Bairey, Carol Moreno, David Simpson, Talha Munir, Don A. Stevens, Sandra Dai, Leo W. K. Cheung, Kevin Kwei, Indu Lal, Emily Hsu, Thomas J. Kipps & Alessandra Tedeschi To cite this article: Jan A. Burger, Tadeusz Robak, Fatih Demirkan, Osnat Bairey, Carol Moreno, David Simpson, Talha Munir, Don A. Stevens, Sandra Dai, Leo W. K. Cheung, Kevin Kwei, Indu Lal, Emily Hsu, Thomas J. Kipps & Alessandra Tedeschi (2022) Up to 6.5 years (median 4 years) of follow-up of first-line ibrutinib in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma and high-risk genomic features: integrated analysis of two phase 3 studies, Leukemia & Lymphoma, 63:6, 1375-1386, DOI: 10.1080/10428194.2021.2020779 To link to this article: https://doi.org/10.1080/10428194.2021.2020779 © 2022 The Author(s). Published by Informa View supplementary material UK Limited, trading as Taylor & Francis Group Published online: 11 Jan 2022. Submit your article to this journal Article views: 2070 View related articles View Crossmark data Citing articles: 3 View citing articles Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=ilal20 LEUKEMIA & LYMPHOMA 2022, VOL. 63, NO. 6, 1375–1386 https://doi.org/10.1080/10428194.2021.2020779 ORIGINAL ARTICLE Up to 6.5 years (median 4 years) of follow-up of first-line ibrutinib in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma and high-risk genomic features: integrated analysis of two phase 3 studies Jan A. Burgera, Tadeusz Robakb , Fatih Demirkanc, Osnat Baireyd, Carol Morenoe, David Simpsonf, Talha Munirg, Don A. Stevensh, Sandra Daii, Leo W. K. Cheungi, Kevin Kweii, Indu Lali, Emily Hsui, Thomas J. Kippsj and Alessandra Tedeschik a Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA; bMedical University of Lodz, Copernicus Memorial Hospital, Lodz, Poland; cDokuz Eylul University, Izmir, Turkey; dRabin Medical Center, Petah Tikva, Israel; e Hospital de la Santa Creu I Sant Pau, Autonomous University of Barcelona, Barcelona, Spain; fBeiGene, San Mateo, CA, USA; g Department of Haematology, St. James’s Hospital, Leeds, United Kingdom; hNorton Cancer Institute, Louisville, KY, USA; i Pharmacyclics LLC, an AbbVie Company, South San Francisco, CA, USA; jUniversity of California San Diego, Moores Cancer Center, La Jolla, CA, USA; kASST Grande Ospedale Metropolitano Niguarda, Milan, Italy ABSTRACT ARTICLE HISTORY Genomic abnormalities, including del(17p)/TP53 mutation, del(11q), unmutated IGHV, and muta- Received 14 September 2021 tions in BIRC3, NOTCH1, SF3B1, and XPO1 predict poor outcomes with chemoimmunotherapy in Revised 23 November 2021 chronic lymphocytic leukemia. To better understand the impact of these high-risk genomic fea- Accepted 13 December 2021 tures on outcomes with first-line ibrutinib-based therapy, we performed pooled analysis of two KEYWORDS phase 3 studies with 498 patients randomized to receive ibrutinib- or chlorambucil-based ther- Chronic lymphocytic apy with median follow-up of 49.1 months. Ibrutinib-based therapy improved overall response leukemia; ibrutinib; rates (ORRs), complete response rates, and progression-free survival (PFS) versus chlorambucil- chlorambucil; obinutuzu- based therapy across all subgroups. In ibrutinib-randomized patients with versus without speci- mab; pooled analysis fied genomic features, ORR and PFS were comparable across subgroups. PFS hazard ratio (95% CI) for del(17p)/TP53 mutated/BIRC3 mutated: 1.05 (0.54–2.04); del(17p)/TP53 mutation, del(11q), and/or unmutated IGHV: 1.11 (0.69–1.77); unmutated IGHV: 1.79 (0.99–3.24); and NOTCH1 mutated 1.05 (0.65–1.69). This integrated analysis demonstrated efficacy of first-line ibrutinib- based treatment irrespective of cytogenetic and mutational risk features. Registered at ClinicalTrials.gov (NCT01722487 and NCT02264574). Introduction the high-risk subgroup of TP53 mutation and/or BIRC3 mutation and the intermediate-risk subgroup of Chronic lymphocytic leukemia (CLL) is a B-cell malig- NOTCH1 and/or SF3B1 mutation and/or del (11q) as nancy that is characterized by a variable clinical course independent risk factors for inferior overall survival (OS) and heterogeneous biology [1]. A variety of genomic [3]. Mutational status of the variable region of the features have been identified that are associated with immunoglobulin heavy chain (IGHV) gene has also inferior prognosis in patients with CLL [1]. Dohner et al been identified as a prognostic factor in CLL, with bet- identified a hierarchical model of chromosomal abnor- ter prognosis in patients with mutated versus unmu- malities with prognostic value in CLL, with the shortest tated IGHV [4,5]. In addition to genomic abnormalities, survival estimates observed in patients with del(17p), such as del(17p)/TP53 mutation, del(11q), and unmu- followed by those with del(11q) in the absence of tated IGHV, mutations in BIRC3, NOTCH1, SF3B1, and del(17p) [2]. Subsequently, Rossi et al developed a XPO1 have been recently associated with poor out- revised hierarchical classification integrating chromo- comes in patients treated with chemoimmunotherapy somal abnormalities with recurrent gene mutations, [6,7]. Despite the known association between inferior refining the prognostic order of relevance to implicate outcomes and chemoimmunotherapy in the presence CONTACT Jan A. Burger jaburger@mdanderson.org Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA Supplemental data for this article can be accessed here. ß 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by- nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. 1376 J. A. BURGER ET AL. of these high-risk genomic features [8–12], patients randomized 1:1 to receive single-agent oral ibrutinib with CLL are frequently treated with such therapies (420 mg once daily) until progressive disease or regardless of genomic status [13]. unacceptable toxicity, or up to 12 cycles of chlorambucil Ibrutinib, a once-daily Bruton’s tyrosine kinase (0.5 mg/kg, increased up to 0.8 mg/kg as tolerated, on inhibitor, is the only targeted therapy to demonstrate days 1 and 15 of each 28-day cycle). In iLLUMINATE significant progression-free survival (PFS) benefit and (PCYC-1130), patients with previously untreated CLL/SLL OS benefit in multiple randomized phase 3 studies in aged 65 years or <65 years with either coexisting both previously untreated and relapsed/refractory CLL/ conditions or del(17p)/TP53 mutation were randomized small lymphocytic lymphoma (SLL) [14–19]. Of note, 1:1 to receive ibrutinib (420 mg once daily) until pro- patients with and without high-risk genomic features gressive disease or unacceptable toxicity plus six cycles known to confer inferior outcomes with chemoimmu- of obinutuzumab (100 mg on day 1, 900 mg on day 2, notherapy have shown consistently enhanced PFS and 1,000 mg on days 8 and 15 in cycle 1, then with single-agent ibrutinib or ibrutinib-based combin- 1,000 mg on day 1 of each 28-day cycle) or six cycles of ation therapy, including combinations with anti-CD20 chlorambucil (0.5 mg/kg on days 1 and 15 of each 28- antibodies, compared to those treated with estab- day cycle) plus obinutuzumab (as described for the ibru- lished therapies [14–16,19,20]. In the RESONATE-2 tinib plus obinutuzumab arm). Both studies were study, first-line ibrutinib was associated with superior approved by institutional review boards at each partici- PFS and OS compared with chlorambucil, with PFS pating institution and were conducted in accordance benefit for ibrutinib observed across all patient sub- with the Declaration of Helsinki. All patients provided groups, including those with TP53 mutation, del(11q), written informed consent. RESONATE-2 and iLLUMINATE and/or unmutated IGHV [14]. In the iLLUMINATE study, were registered at ClinicalTrials.gov (numbers first-line ibrutinib plus obinutuzumab was associated NCT01722487 and NCT02264574, respectively). with superior PFS compared with chlorambucil plus Data were pooled for patients randomized to obinutuzumab [16]. Significant PFS benefit with ibruti- receive ibrutinib-based therapy (single-agent ibrutinib nib-obinutuzumab over chlorambucil-obinutuzumab or ibrutinib-obinutuzumab) and for those randomized was observed in patients with del(17p), TP53 muta- to receive chlorambucil-based therapy (single-agent tions, del(11q), and/or unmutated IGHV [16]. chlorambucil or chlorambucil-obinutuzumab). High-risk Previously, in the phase 3 RESONATE study, muta- genomic features were evaluated by central laboratory tions in BIRC3, NOTCH1, SF3B1, or XPO1 had no signifi- testing. Cytogenetics (del(17p) and del(11q)) were cant impact on the PFS benefit conferred by ibrutinib assessed using fluorescence in situ hybridization in patients with relapsed/refractory CLL/SLL treated (FISH). IGHV mutational status was assessed by with ibrutinib or ofatumumab [21,22]. However, lim- somatic hypermutation assay (LymphoTrack Dx IGHV; ited evidence is available regarding the efficacy of Invivoscribe, Inc., San Diego, CA, USA). TP53, BIRC3, ibrutinib in patients with these single-gene mutations SF3B1, NOTCH1, and XPO1 mutations were assessed by in the first-line setting. To better understand outcomes targeted next-generation sequencing (ACE Extended in patients with previously untreated CLL with various Cancer Panel; Personalis, Menlo Park, CA, USA). high-risk genomic features, including integrated gene Clinical outcomes of interest were PFS, OS, overall mutations and chromosomal abnormalities, we per- response rates (ORRs), complete response (CR) rate formed a pooled analysis of two large registrational including CR with incomplete bone marrow recovery phase 3 studies (RESONATE-2 and iLLUMINATE) with (CRi), and safety. Response was assessed by investiga- extended follow-up of ibrutinib-based therapy for first- tors per 2008 International Workshop on Chronic line treatment of CLL/SLL. Safety analyses were per- Lymphocytic Leukemia criteria [24]. Outcomes were formed to help inform the benefit–risk profile in analyzed for various subgroups as defined by FISH patients with high-risk genomic features. cytogenetics or single-gene mutations alone and in combination, including subgroups defined by hierarch- Materials and methods ical classification after Dohner et al. [2]; revised hier- archical classification after Rossi et al. [3]; high-risk Pooled analysis population per ibrutinib US prescribing information Detailed methods for RESONATE-2 [23] and iLLUMINATE [25] with del(17p)/TP53 mutation, del(11q), and/or [16] were previously reported. Briefly, in RESONATE-2 unmutated IGHV; IGHV mutational status; and single- (PCYC-1115/1116), patients aged 65 years with previ- gene mutations in TP53, BIRC3, SF3B1, NOTCH1, and ously untreated CLL/SLL without del(17p) were XPO1. As patients with B-cell receptor (BCR) stereotype IBRUTINIB IN GENOMIC HIGH-RISK GROUPS 1377 subset 2 (IGHV3-21/IGLV3-21) predominantly carry patients randomized to ibrutinib-based therapy, com- mutated IGHV but have similar prognosis to those pared with 50%–71% across subgroups of patients with unmutated IGHV [26], we performed a sensitivity randomized to chlorambucil-based therapy, with rate analysis that included seven additional patients with ratios of 1.28–1.84 (Figure 1). CR rates were 22%–47% BCR stereotype subset 2 in the unmutated versus 6%–20% with ibrutinib- versus chlorambucil- IGHV subgroup. based therapy across genomic risk subgroups (Figure Outcomes were compared between (1) ibrutinib- 1). With a median follow-up of 49 months (up to versus chlorambucil-based therapies and (2) ibrutinib- 79 months), ibrutinib-randomized patients had longer randomized patients with versus without specified PFS compared with chlorambucil-randomized patients, high-risk genomic features. regardless of genomic risk features. Median PFS was not reached in any subgroup in ibrutinib-randomized patients and ranged from 11.2 to 20.2 months across Statistical analysis high-risk genomic subgroups in chlorambucil-random- Efficacy analyses included all intention-to-treat ized patients (Table 1). At 42 months, PFS rates were patients from both studies; safety analyses included significantly higher across high-risk genomic sub- patients who received 1 dose of study treatment. groups in ibrutinib-randomized patients (63%–87%) PFS and OS were estimated using Kaplan-Meier meth- compared with chlorambucil-randomized patients odology; subgroups were compared using hazard (6%–34%) (Table 1). Consistent PFS benefit with ibruti- ratios (HRs) with P values based on unstratified log- nib- versus chlorambucil-based therapy was observed rank test. OS was estimated without censoring or across all high-risk genomic subgroups, with HRs rang- adjustment for crossover. ORRs were compared ing from 0.06 to 0.30 (Figure 2(A)). Kaplan-Meier between subgroups using rate ratios with P values curves for PFS in patients randomized to ibrutinib- based on the chi-square test. No multiplicity adjust- versus chlorambucil-based therapy by NOTCH1 and ments were performed. SF3B1 mutational status are shown in Supplementary Figure S1. OS results had not reached maturity at the Results time of analysis, with median OS not reached in any subgroup in either ibrutinib- or chlorambucil-random- Patients ized patients. Although no differences were observed Pooled analyses included 498 patients randomized to in OS between ibrutinib- vs chlorambucil-based ther- receive ibrutinib-based therapy (n ¼ 249) or chloram- apy (Figure 2(B)), OS analyses were confounded by the bucil-based therapy (n ¼ 249). One patient randomized high rate of crossover after progression; in total, 123 to ibrutinib-based therapy and two patients random- of 249 patients (49%) initially assigned to chlorambu- ized to chlorambucil-based therapy did not receive cil-based therapy crossed over to receive ibrutinib- the assigned study treatment; thus, pooled safety pop- based therapy. ulations included 248 ibrutinib-treated patients and 247 chlorambucil-treated patients. Within each study, Outcomes with ibrutinib-based therapy in patients baseline characteristics were balanced across treat- with versus without specified genomic ment arms [16,23]. Genomic risk subgroups are risk features described in Supplementary Table S1. In patients randomized to receive ibrutinib-based therapy, base- In patients randomized to ibrutinib-based therapy, line characteristics were generally similar across gen- ORR and CR rates were generally comparable between omic risk subgroups (Supplementary Table S2). At the patients with versus without specified high-risk gen- time of analysis, median follow-up for all patients in omic features (Figure 3), with rate ratios for ORR of the pooled analysis was 49.1 months (range, 0.1–78.7). 0.90–1.10. Similarly, PFS was generally comparable between patients with versus without specified high- risk genomic features (Figure 4(A)), including those Outcomes with ibrutinib- versus chlorambucil- with the highest risk classification of del(17p)/TP53 based therapy by specified genomic risk features mutated/BIRC3 mutated per Rossi et al. (HR, 1.05; 95% Ibrutinib-based therapy improved ORR and CR rates CI, 0.54–2.04; p ¼ 0.8962); the high-risk population compared with chlorambucil-based therapy across with del(17p)/TP53 mutation, del(11q), and/or unmu- patients with different genomic risk features. ORRs tated IGHV per ibrutinib US prescribing information were 83%–97% across genomic risk subgroups in (HR, 1.11; 95% CI, 0.69–1.77; p ¼ 0.6729); those with 1378 J. A. BURGER ET AL. ORR With Ibrutinib- vs CR/CRi Rates With Ibrutinib- vs Chlorambucil-Based Therapy Chlorambucil-Based Therapy Hierarchical classification Rate ratio for ORR (after Dohner) (95% CI)c P value 90 24 Del(17p)/TP53 mutation 52 1.73 (1.18–2.54) 0.0018 7 Del(11q) 56 97 1.75 (1.30–2.36) <0.0001 6 37 91 38 All othersa 65 1.39 (1.22–1.59) <0.0001 15 Revised hierarchical classification (after Rossi) 86 22 Del(17p)/TP53 mutation/BIRC3 mutation 53 1.61 (1.20–2.16) 0.0006 7 Del(11q)/SF3B1 mutation/NOTCH1 mutation 96 1.44 (1.26–1.65) <0.0001 47 67 14 87 26 All othersb 58 1.51 (1.15–1.97) 0.0006 16 Del(17p)/TP53 mutation, del(11q), and/or unmutated IGHV 92 38 Yes 53 1.75 (1.49–2.06) <0.0001 7 89 35 No 64 1.40 (1.19–1.64) <0.0001 16 IGHV 92 39 Unmutated 51 1.79 (1.49–2.16) <0.0001 6 93 38 Mutated 70 1.33 (1.15–1.54) 0.0001 20 BIRC3 83 25 Mutated 64 1.31 (0.91–1.88) 0.1286 5 92 38 Not mutated 61 1.50 (1.33–1.69) <0.0001 13 SF3B1 93 41 Mutated 57 1.64 (1.28–2.10) <0.0001 12 91 35 Not mutated 63 1.44 (1.26–1.63) <0.0001 12 NOTCH1 91 42 Mutated 71 1.28 (1.13–1.46) 0.0001 15 92 31 Not mutated 50 1.84 (1.49–2.28) <0.0001 8 XPO1 96 38 Mutated 52 1.83 (1.21–2.77) 0.0007 10 91 37 Not mutated 63 1.45 (1.29–1.63) <0.0001 12 0 20 40 60 80 100 0 20 40 60 80 100 ORR, % CR/CRi rate, % Ibrutinib-based therapy Chlorambucil-based therapy Figure 1. Response with ibrutinib- versus chlorambucil-based therapy by specified genomic risk features. CI: confidence interval; CR/CRi: complete response/complete response with incomplete bone marrow recovery; ORR: overall response rate. aNeither del(17p)/TP53 mutation nor del(11q). bNeither del(17p)/TP53 mutation/BIRC3 mutation nor del(11q)/SF3B1 mutation/NOTCH1 muta- tion. cRate ratio for ORR with ibrutinib-based therapy versus chlorambucil-based therapy. unmutated IGHV (HR, 1.79; 95% CI, 0.99–3.24; with del(17p)/TP53 mutation randomized to ibrutinib- p ¼ 0.0512); and those with NOTCH1 mutations based therapy (Table 1). Median OS was not reached (HR, 1.05; 95% CI, 0.65–1.69; p ¼ 0.8555). A sensitivity in any subgroup and OS was generally similar analysis including patients with BCR stereotype subset between ibrutinib-randomized patients with versus 2 provided similar results to the overall comparison of without specified genomic high-risk features unmutated versus mutated IGHV, with a slight shift in (Figure 4(B)). the HR for PFS in favor of the mutated IGHV subgroup in patients randomized to ibrutinib-based therapy (HR, Safety of ibrutinib-based therapy 1.85; 95% CI, 0.99–3.45; p ¼ 0.0489). Kaplan-Meier curves for PFS in patients randomized to ibrutinib- The median duration of ibrutinib-based treatment was based therapy according to subgroups defined by 40.8 months (range, 0.1–74.0) and ranged from 35.7 to hierarchical classification after Dohner et al (del(17p) 43.8 months across genomic risk subgroups versus del(11q) versus all others), by revised hierarch- (Supplementary Table S3). In the overall population of ical classification after Rossi et al (del(17p)/TP53 muta- patients treated with ibrutinib-based therapy, preva- tion/BIRC3 mutation versus del(11q)/SF3B1 mutation/ lence of adverse events (AEs) of clinical interest NOTCH1 mutation versus all others) are shown in (hypertension, atrial fibrillation, neutropenia, anemia, Supplementary Figure S2. Of note, a sustained PFS infection, and bleeding) of any grade (Figure 5(A)) or rate of 79% was observed at 42 months in patients grade 3 (Figure 5(B)) demonstrated some variability IBRUTINIB IN GENOMIC HIGH-RISK GROUPS 1379 Table 1. Progression-free survival in patients randomized to ibrutinib- versus chlorambucil-based therapy by specified genomic risk features. 42-month PFS rate, % (95% CI) Median PFS, months (95% CI) Ibrutinib Chlorambucil Ibrutinib Chlorambucil Hierarchical classification (after Dohner) Del(17p)/TP53 mutation 79 (58–90) All PD or not in follow-up NR (60.0–NE) 11.2 (9.7–20.2) Del(11q) 82 (65–92) 6 (1–18) NR (63.3–NE) 15.2 (9.3–21.9) All othersa 75 (67–81) 36 (28–45) NR (NE–NE) 22.9 (18.6–27.0) Revised hierarchical classification (after Rossi) Del(17p)/TP53 mutation/BIRC3 mutation 72 (56–82) 16 (6–28) NR (52.0–NE) 14.5 (10.8–22.6) Del(11q)/SF3B1 mutation/NOTCH1 mutation 80 (71–86) 28 (20–37) NR (NE–NE) 20.2 (15.8–24.0) All othersb 73 (60–82) 38 (23–52) NR (67.8–NE) 24.9 (17.7–42.7) Del(17p)/TP53 mutation, del(11q) and/or unmutated IGHV Yes 76 (68–82) 10 (6–16) NR (71.0–NE) 14.5 (11.1–18.0) No 78 (68–85) 50 (39–59) NR (71.0–NE) 39.4 (24.4–52.3) IGHV Unmutated 72 (63–80) 9 (5–16) NR (64.3–NE) 14.5 (10.7–18.0) Mutated 87 (77–93) 48 (37–58) NR (NE–NE) 27.7 (22.1–53.5) BIRC3 Mutated 63 (40–80) 18 (6–36) NR (23.9–NE) 19.6 (9.9–29.9) Not mutated 78 (72–83) 29 (23–36) NR (NE–NE) 20.2 (18.3–22.9) SF3B1 Mutated 82 (69–90) 23 (12–36) NR (NE–NE) 18.9 (14.2–24.0) Not mutated 75 (68–81) 30 (22–37) NR (71.0–NE) 21.0 (17.4–24.6) NOTCH1 Mutated 76 (66–83) 27 (19–35) NR (56.0–NE) 19.4 (15.2–22.4) Not mutated 77 (69–84) 30 (20–40) NR (71.0–NE) 21.9 (17.7–25.9) XPO1 Mutated 78 (54–90) 34 (14–55) NR (46.2–NE) 18.9 (11.1–43.3) Not mutated 77 (70–82) 27 (21–34) NR (NE–NE) 20.3 (18.0–22.6) CI: confidence interval; NE: not estimable; NR: not reached; PD: progressive disease; PFS: progression-free survival. a Neither del(17p)/TP53 mutation nor del(11q). b Neither del(17p)/TP53 mutation/BIRC3 mutation nor del(11q)/SF3B1 mutation/NOTCH1 mutation. but generally decreased over time, with the exception and XPO1 [6,7]. While PFS data have been previously of hypertension. Bleeding events of any grade published separately for the RESONATE-2 and declined from 40% during the first year to 27% after iLLUMINATE studies according to FISH cytogenetics, year 6; no grade 3 bleeding events occurred after IGHV status, and TP53 mutation status [14,16], we year 3. No clinically meaningful differences in the rates report here for the first time a pooled cross-trial of these grade 3 AEs were observed across high-risk analysis on the single-gene mutations of BIRC3, genomic subgroups compared to the overall popula- NOTCH1, SF3B1, and XPO1 and introduce novel data tion (Supplementary Table S3). Similarly, no clinically according to the revised Rossi hierarchical classifica- meaningful differences were seen in any grade AEs tion. The presence of high-risk genomic features did compared to the overall population (Supplementary not appear to have a discernible impact on rates of Table S3). treatment-emergent AEs. Patients with CLL bearing TP53 aberrations (del (17p) and/or TP53 mutations) have poor outcomes Discussion on chemoimmunotherapy, with 3-year PFS and OS Overall, this integrated analysis of patients undergoing rates of only 18% and 38%, respectively, in those first-line ibrutinib-based treatment, with median fol- treated with first-line fludarabine, cyclophosphamide, low-up of 49 months (up to 79 months), confirmed and rituximab [11]. In contrast, the 42-month PFS rate significant PFS and ORR benefits with ibrutinib (with for patients with TP53 aberrations randomized to first- or without obinutuzumab) versus chlorambucil (with line ibrutinib-based therapy was 79% in the current or without obinutuzumab) irrespective of high-risk pooled analysis. These findings are consistent with genomic features. Additionally, the analyses generally those from a pooled analysis of patients with TP53 demonstrated relatively similar PFS and ORR for ibruti- aberrations with median follow-up of 4 years (up to nib-randomized patients with or without high-risk 8 years) across four clinical trials of first-line ibrutinib- genomic features associated with inferior outcomes based therapy, including the two trials in this current with chemoimmunotherapy, including del(17p), analysis (RESONATE-2 and iLLUMINATE) as well as two del(11q), TP53 mutation, or unmutated IGHV [8–12] trials sponsored by the National Institutes of Health and single-gene mutations in BIRC3, NOTCH1, SF3B1, (PCYC-1122e and ECOG-1912), that demonstrated 1380 J. A. BURGER ET AL. A PFS With Ibrutinib- vs Chlorambucil-Based Therapy Hazard ratio Favors ibrutinib-based therapy Favors comparator N (95% CI)c All patients 498 0.19 (0.14–0.25) Hierarchical classification (after Dohner) Del(17p)/TP53 mutation 56 0.11 (0.04–0.29) Del(11q) 74 0.06 (0.02–0.15) All othersa 310 0.26 (0.18–0.36) Revised hierarchical classification (after Rossi) Del(17p)/TP53 mutation/BIRC3 mutation 94 0.19 (0.10–0.36) Del(11q)/SF3B1 mutation/NOTCH1 mutation 239 0.15 (0.10–0.23) All othersb 107 0.29 (0.16–0.52) Del(17p)/TP53 mutation, del(11q), and/or unmutated IGHV Yes 290 0.12 (0.08–0.17) No 208 0.30 (0.19–0.47) IGHV Unmutated 241 0.13 (0.09–0.19) Mutated 173 0.20 (0.11–0.36) BIRC3 Mutated 46 0.28 (0.12–0.63) Not mutated 406 0.17 (0.13–0.24) SF3B1 Mutated 109 0.12 (0.06–0.24) Not mutated 343 0.21 (0.15–0.29) NOTCH1 Mutated 235 0.19 (0.13–0.30) Not mutated 217 0.18 (0.12–0.28) XPO1 Mutated 45 0.18 (0.06–0.50) Not mutated 407 0.19 (0.14–0.25) 0 0.5 1.0 1.5 2.0 Hazard ratio B OS With Ibrutinib- vs Chlorambucil-Based Therapy Hazard ratio Favors ibrutinib-based therapy Favors comparator N (95% CI)c All patients 498 0.70 (0.48–1.02) Hierarchical classification (after Dohner) Del(17p)/TP53 mutation 56 0.55 (0.15–1.93) Del(11q) 74 0.69 (0.27–1.77) All othersa 310 0.84 (0.51–1.37) Revised hierarchical classification (after Rossi) Del(17p)/TP53 mutation/BIRC3 mutation 94 1.04 (0.43–2.52) Del(11q)/SF3B1 mutation/NOTCH1 mutation 239 0.75 (0.43–1.30) All othersb 107 0.65 (0.28–1.51) Del(17p)/TP53 mutation, del(11q), and/or unmutated IGHV Yes 290 0.67 (0.41–1.08) No 208 0.74 (0.41–1.35) IGHV Unmutated 241 0.77 (0.45–1.30) Mutated 173 0.51 (0.24–1.08) BIRC3 Mutated 46 1.09 (0.36–3.25) Not mutated 406 0.79 (0.51–1.23) SF3B1 Mutated 109 0.75 (0.33–1.74) Not mutated 343 0.84 (0.53–1.34) NOTCH1 Mutated 235 0.87 (0.50–1.52) Not mutated 217 0.81 (0.44–1.48) XPO1 Mutated 45 0.86 (0.12–6.09) Not mutated 407 0.82 (0.54–1.24) 0 0.5 1.0 1.5 2.0 Hazard ratio Figure 2. Forest plots of (A) progression-free survival and (B) overall survival with ibrutinib- versus chlorambucil-based therapy by specified genomic risk features. OS: overall survival; PFS: progression-free survival. aNeither del(17p)/TP53 mutation nor del(11q). b Neither del(17p)/TP53 mutation/BIRC3 mutation nor del(11q)/SF3B1 mutation/NOTCH1 mutation. cHazard ratio for PFS or OS with ibrutinib-based therapy versus chlorambucil-based therapy. IBRUTINIB IN GENOMIC HIGH-RISK GROUPS 1381 ORR for Patients With CR/CRi Rate for Patients With High-Risk Feature vs High-Risk Feature vs Without High-Risk Feature Without High-Risk Feature Hierarchical classification Rate ratio for ORR (after Dohner) (95% CI)c P value Del(17p)/TP53 mutation 90 0.99 (0.87–1.13) 0.8591 24 Del(11q) 97 1.07 (1.00–1.15) 0.1724 37 All othersa 91 NA 38 Revised hierarchical classification (after Rossi) Del(17p)/TP53 mutation/BIRC3 mutation 86 0.98 (0.85–1.14) 0.8324 22 Del(11q)/SF3B1 mutation/NOTCH1 mutation 96 1.10 (0.996–1.22) 0.0213 47 All othersb 87 NA 26 Del(17p)/TP53 mutation, del(11q), and/or unmutated IGHV Yes 92 1.04 (0.95–1.12) 0.3891 38 No 89 NA 35 IGHV Unmutated 92 0.99 (0.92–1.08) 0.8639 39 Mutated 93 NA 38 BIRC3 Mutated 83 0.90 (0.75–1.09) 0.1405 25 Not mutated 92 NA 38 SF3B1 Mutated 93 1.03 (0.94–1.12) 0.5877 41 Not mutated 91 NA 35 NOTCH1 Mutated 91 0.98 (0.91–1.06) 0.6557 42 Not mutated 92 NA 31 XPO1 Mutated 96 1.06 (0.96–1.16) 0.4111 38 Not mutated 91 NA 37 0 20 40 60 80 100 0 20 40 60 80 100 ORR, % CR/CRi rate, % With high-risk feature Without high-risk feature Figure 3. Response rates with ibrutinib-based therapy in patients with versus without specified high-risk genomic features. CI: confidence interval; CR/CRi: complete response/complete response with incomplete bone marrow recovery; NA: not applicable; ORR: overall response rate. aWithout high-risk feature ¼ all others (neither del(17p)/TP53 mutation nor del(11q)). bWithout high- risk feature ¼ all others (neither del(17p)/TP53 mutation/BIRC3 mutation nor del(11q)/SF3B1 mutation/NOTCH1 mutation). cRate ratio for ORR with versus without high-risk features. 4-year PFS and OS rates of 79% and 88%, respectively should be noted that the proportion of patients with [27]. With a median follow-up of 6.5 years, the PCYC- TP53 aberrations is small in these first-line studies rela- 1122e study demonstrated 6-year PFS and OS rates of tive to the relapsed/refractory setting in which the 61% and 79%, respectively, in patients with TP53 aber- prevalence of TP53 aberrations is increased as a result rations treated with first-line ibrutinib [28]. of expansion of refractory TP53-aberrant subclones Additionally, the 2-year PFS rate in the CLL14 study under selective pressure of chemoimmunother- was 74% for patients with TP53 aberrations receiving apy [30,31]. first-line treatment with venetoclax plus obinutuzumab Unmutated IGHV predicts inferior outcomes with [29]. While previous findings in patients receiving sin- first-line chemoimmunotherapy in patients with CLL, gle-agent ibrutinib in the relapsed/refractory setting whereas patients with mutated IGHV can achieve suggested that patients with del(17p) and/or TP53 long-term PFS with chemoimmunotherapy [9–12]. mutations tended to have shorter PFS than patients Consistent with previous findings [14–16,20,32], we without TP53 aberrations [15,22], the current pooled found that PFS benefit with ibrutinib-based therapy analyses demonstrated comparable PFS between versus comparators was similar between patients with patients with and without TP53 aberrations receiving and without unmutated IGHV and ibrutinib-based ibrutinib-based therapy in the first-line setting. It therapy substantially abrogated the negative 1382 J. A. BURGER ET AL. A PFS for Patients With High-Risk Feature vs Without High-Risk Feature With high- Without high- Hazard ratio risk feature risk feature N (95% CI)c P value Hierarchical classification (after Dohner) Del(17p)/TP53 mutationa 201 0.83 (0.37–1.82) 0.6352 Del(11q)a 210 0.85 (0.44–1.63) 0.6205 Revised hierarchical classification (after Rossi) Del(17p)/TP53 mutation/BIRC3 mutationb 111 1.05 (0.54–2.04) 0.8962 Del(11q)/SF3B1 mutation/NOTCH1 mutationb 190 0.82 (0.48–1.43) 0.4887 Del(17p)/TP53 mutation, del(11q), and/or unmutated IGHV 249 1.11 (0.69–1.77) 0.6729 Unmutated IGHV 205 1.79 (0.99–3.24) 0.0512 BIRC3 mutated 243 1.60 (0.79–3.22) 0.1852 SF3B1 mutated 243 0.75 (0.42–1.35) 0.3402 NOTCH1 mutated 243 1.05 (0.65–1.69) 0.8555 XPO1 mutated 243 0.95 (0.41–2.19) 0.8949 0 0.5 1.0 1.5 2.0 Hazard ratio B OS for Patients With High-Risk Feature vs Without High-Risk Feature With high- Without high- Hazard ratio risk feature risk feature N (95% CI)c P value Hierarchical classification (after Dohner) Del(17p)/TP53 mutationa 201 0.70 (0.25–1.97) 0.4963 Del(11q)a 210 1.08 (0.52–2.25) 0.8427 Revised hierarchical classification (after Rossi) Del(17p)/TP53 mutation/BIRC3 mutationb 111 1.49 (0.64–3.45) 0.3497 Del(11q)/SF3B1 mutation/NOTCH1 mutationb 190 1.28 (0.63–2.60) 0.5038 Del(17p)/TP53 mutation, del(11q), and/or unmutated IGHV 249 1.12 (0.63–1.99) 0.6960 Unmutated IGHV 205 1.76 (0.85–3.64) 0.1250 BIRC3 mutated 243 1.84 (0.83–4.11) 0.1298 SF3B1 mutated 243 0.96 (0.49–1.88) 0.9009 NOTCH1 mutated 243 1.39 (0.78–2.48) 0.2590 XPO1 mutated 243 0.41 (0.10–1.68) 0.1993 0 0.5 1.0 1.5 2.0 Hazard ratio Figure 4. Forest plots of (A) progression-free survival and (B) overall survival with ibrutinib-based therapy in patients with versus without specified high-risk genomic features. CI: confidence interval; OS: overall survival; PFS: progression-free survival. aWithout high-risk feature ¼ all others (neither del(17p)/TP53 mutation nor del(11q)). bWithout high-risk feature ¼ all others (neither del(17p)/TP53 mutation/BIRC3 mutation nor del(11q)/SF3B1 mutation/NOTCH1 mutation). cHazard ratio for PFS or OS with versus without high-risk features. prognostic impact of unmutated IGHV status. Because NOTCH1 and/or TP53 mutations [7]. Consistent with the BCR stereotype subset 2 is enriched in the mutated previous analyses in patients treated with ibrutinib in IGHV population but carries a prognosis similar to that the relapsed/refractory setting [21,22], we found no conferred by unmutated IGHV [26], we performed a significant differences in PFS or OS in patients sensitivity analysis that included patients with BCR randomized to first-line ibrutinib-based therapy stereotype subset 2 in the unmutated IGHV subgroup. according to the presence or absence of mutations in Although patient numbers were small, inclusion of NOTCH1, SF3B1, BIRC3, or XPO1. However, it should be these seven additional subset 2 patients in the unmu- noted that these analyses are limited by the small tated IGHV subgroup resulted in a slight shift in the HR numbers of patients in some of these subgroups, with for PFS in favor of the mutated IGHV subgroup. only 24 patients each in the BIRC3-mutated and XPO1- More novel mutations in BIRC3, NOTCH1, SF3B1, and mutated subgroups. Conversely, the prevalence of XPO1 have also been associated with poor outcomes NOTCH1 mutations was relatively high in our study with chemoimmunotherapy in patients with CLL [6,7]. population, likely due to enrollment for other high-risk BIRC3 and SF3B1 appear to be associated with refrac- features, including TP53 mutation and unmutated toriness to chemotherapy [7], whereas NOTCH1 muta- IGHV, both of which are known to correlate frequently tions appear to be associated with refractoriness to with NOTCH1 mutation [35]. anti-CD20 antibodies [9,33,34]. The role of XPO1 muta- Integration of cytogenetic and mutational features tions is less clear as these frequently co-occur with using the revised hierarchical classification after Rossi IBRUTINIB IN GENOMIC HIGH-RISK GROUPS 1383 A Prevalence of AEs of Any Grade B Prevalence of AEs of Grade ≥3 With Ibrutinb-Based Therapy With Ibrutinb-Based Therapy 29/248 8/248 >0–1 year (n = 248) 20/221 5/221 27/195 3/195 >1–2 years (n = 221) Hypertension 26/174 Hypertension 5/174 >2–3 years (n = 195) 18/107 5/107 17/79 6/30 3/79 0/30 >3–4 years (n = 174) >4–5 years (n = 107) 19/248 14/221 7/248 2/221 >5–6 years (n = 79) Atrial 16/195 Atrial 4/195 >6 years (n = 30) 14/174 2/174 fibrillation 6/107 fibrillation 0/107 6/79 1/79 1/30 0/30 64/248 49/248 26/221 16/221 9/195 4/195 Neutropenia 1/174 Neutropenia 1/174 1/107 0/107 1/79 1/79 0/30 0/30 38/248 12/248 17/221 1/221 12/195 1/195 Anemia 11/174 Anemia 0/174 6/107 0/107 5/79 1/79 1/30 0/30 138/248 38/248 108/221 17/221 a 80/195 a 15/195 Infection 69/174 Infection 16/174 52/107 12/107 39/79 7/79 14/30 1/30 98/248 5/248 64/221 4/221 a 51/195 a 4/195 Bleeding 37/174 Bleeding 0/174 20/107 0/107 19/79 0/79 8/30 0/30 0 20 40 60 80 100 0 20 40 60 80 100 Patients, % Patients, % Figure 5. Prevalence of (A) any-grade AEs of clinical interest and (B) grade 3 AEs of clinical interest by yearly intervals in ibruti- nib-treated patients. AEs: adverse events. aCombined terms. Infection was identified using the MedDRA System Organ Class term for Infections and infestations. Bleeding was identified using the Standardized MedDRA Query for Hemorrhage, excluding labora- tory terms. et al. affords a more nuanced approach to CLL prog- that these high-risk genomic features have less prog- nostication compared to analyses based on FISH cyto- nostic significance with first-line ibrutinib-based ther- genetics alone [3]. In this integrated model, patients apy. Additionally, numerous studies of patients with with del(17p)/TP53 mutation and/or BIRC3 mutations CLL/SLL receiving single-agent ibrutinib or ibrutinib- comprise the highest risk group with the least favorable based combination therapies in the real-world setting survival outcomes on chemotherapy or chemoimmuno- have shown that clinical outcomes are generally con- therapy [3]. Patients with del(11q) and/or SF3B1 and/or sistent with efficacy observed in clinical studies, includ- NOTCH1 mutations have intermediate risk, whereas ing in patients with high-risk disease features, such as patients without any of these cytogenetic or mutational del(17p), del (11q), TP53 mutations, and/or unmutated lesions have lower risk [3]. In the current analysis, effi- IGHV [32,36–40]. cacy outcomes in patients randomized to first-line ibru- This analysis pooling two registrational phase 3 tinib-based therapy were generally comparable across studies demonstrated the efficacy of first-line ibruti- subgroups defined by the revised hierarchical classifica- nib-based treatment irrespective of cytogenetic and tion, including those in the highest risk subgroup. mutational risk features, including those with unmu- Despite the robust efficacy of novel targeted ther- tated IGHV, with NOTCH1 mutation, and with the high- apy, an interim analysis from the prospective, observa- est risk classification of del(17p)/TP53 mutation/BIRC3 tional informCLL registry (N ¼ 840) showed that mutation. Evidence to date indicates that ibrutinib- chemotherapy and chemoimmunotherapy were com- based therapy achieves consistent efficacy across monly used as first-line treatment in patients with multiple patient subgroups defined by clinical charac- high-risk prognostic factors, including those with teristics [14–17] and high-risk genomic features, which del (17p) (34%), TP53 mutation (36%), or unmutated may help inform treatment decisions for patients with IGHV (57%) [13]. Data from the current analysis confirm previously untreated CLL/SLL. 1384 J. A. BURGER ET AL. Acknowledgments employed with Pharmacyclics LLC, an AbbVie Company; spouse employment with The Permanente Medical Group; The authors thank all the patients who participated in the and stock or other ownership with AbbVie, Clovis, Gilead RESONATE-2 and iLLUMINATE studies and their families. We Sciences, Infinity, Reviva Pharmaceuticals, and The also thank Jennifer Lin, MA, MS, for biometrics support and Permanente Medical Group. EH: employment with Melanie Sweetlove, MSc, for medical writing support, funded Pharmacyclics LLC, an AbbVie Company; and stock or other by Pharmacyclics LLC, an AbbVie Company. ownership with AbbVie. TJK: employment with Moores Cancer Center; stock or other ownership with Oncternal; hon- oraria from AbbVie, Celgene, DAVA Oncology, Genentech, Author contributions Gilead, Janssen, Roche, and Pharmacyclics LLC, an AbbVie JAB, TJK, and AT designed the analyses in collaboration with Company; consulting/advisory role with AbbVie, Celgene, representatives of the sponsor; JAB, TR, FD, OB, CM, DSi, TM, DAVA Oncology, Genentech-Roche, Gilead, Janssen, and DAS, TJK, and AT contributed to data collection; SD, LWKC, Pharmacyclics LLC, an AbbVie Company; research funding and KK performed the data analyses; SD, LWKC, KK, IL, and from Celgene, CIRM, MD Anderson Cancer Center, Oncternal, EH confirmed the accuracy of the data and compiled it for Velos, and Pharmacyclics LLC, an AbbVie Company; speakers analysis; all authors had access to the data and were bureau for AbbVie, DAVA Pharmaceuticals, Genentech, Gilead, involved in the interpretation of data, contributed to the Janssen, Verastem, and Pharmacyclics LLC, an AbbVie manuscript review and revisions, and approved the final ver- Company; patents/royalties/other intellectual property for sion for submission. development of cirmtuzumab, which is licensed by Oncternal from the University of California; and travel/accommodations/ expenses from AbbVie, Bionest Partners, Celgene, DAVA Disclosure statement Oncology, G-Therapeutics Genentech, Gilead, Indy JAB: honoraria from and consulting/advisory role for Hematology Review, Janssen, OncLive, Roche, Verastem, and Janssen; research funding from AstraZeneca, BeiGene, and Pharmacyclics LLC, an AbbVie Company. AT: consulting/advis- Pharmacyclics LLC, an AbbVie Company; and speakers ory role and speakers bureau for AbbVie, AstraZeneca, bureau for and travel/accommodations/expenses from Gilead, BeiGene, and Janssen. Janssen, Novartis, TG Therapeutics, and Pharmacyclics LLC, an AbbVie Company. TR: honoraria from AstraZeneca and Janssen; and consulting/advisory role for and research fund- Funding ing from Acerta, AstraZeneca, and Janssen. FD: consulting/ The RESONATE-2 and iLLUMINATE studies were sponsored advisory role for AbbVie, Amgen, AstraZeneca, and Roche; by Pharmacyclics LLC, an AbbVie Company. research funding from AbbVie, AstraZeneca, Janssen, and Pharmacyclics LLC, an AbbVie Company; speakers bureau for AbbVie, Amgen, and Janssen; and travel/accommodations/ expenses from AbbVie, Amgen, Janssen, and Pfizer. OB: con- ORCID sulting/advisory role for AbbVie, AstraZeneca, and Janssen; and research funding from Janssen. CM: consulting/advisory Tadeusz Robak http://orcid.org/0000-0002-3411-6357 role for AbbVie, AstraZeneca, BeiGene, and Janssen; research funding from AbbVie and Janssen; and speakers bureau for Janssen. DSi: employment and stock or other ownership with Data availability statement BeiGene; honoraria and travel/accommodations/expenses Requests for access to individual participant data from clin- from AbbVie and Janssen; research funding from AbbVie, ical studies conducted by Pharmacyclics LLC, an AbbVie Acerta, Amgen, BeiGene, Celgene, GlaxoSmithKline, Janssen, Company, can be submitted through Yale Open Data Access Merck Sharp & Dohme, Roche, Sanofi, and Pharmacyclics LLC, (YODA) Project site at http://yoda.yale.edu an AbbVie Company. TM: honoraria from AbbVie, AstraZeneca, Gilead, Janssen, and Novartis; consulting/advis- ory role for MorphoSys and Sunesis; and travel/accommoda- References tions/expenses from AbbVie, Gilead, and Janssen. DAS: consulting/advisory role for Amgen and MorphoSys. SD: cur- [1] Burger JA. Treatment of chronic lymphocytic leuke- rent employment with Horizon Therapeutics and previously mia. N Engl J Med. 2020;383(5):460–473. employed with Pharmacyclics LLC, an AbbVie Company; and [2] Dohner H, Stilgenbauer S, Benner A, et al. Genomic stock or other ownership with AbbVie, Bristol Myers Squibb, aberrations and survival in chronic lymphocytic leuke- Exelixis, Gilead, GlaxoSmithKline, Horizon Therapeutics, mia. N Engl J Med. 2000;343(26):1910–1916. Myovant Sciences, and Revance Therapeutics. LWKC: employ- [3] Rossi D, Rasi S, Spina V, et al. Integrated mutational ment with Pharmacyclics LLC, an AbbVie Company; stock or and cytogenetic analysis identifies new prognostic other ownership with AbbVie; and other relationships with subgroups in chronic lymphocytic leukemia. Blood. Pfizer and Tizona Therapeutics. KK: current employment with 2013;121(8):1403–1412. BioSplice Therapeutics and previously employed with [4] Damle RN, Wasil T, Fais F, et al. Ig V gene mutation Pharmacyclics LLC, an AbbVie Company; and stock or other status and CD38 expression as novel prognostic indi- ownership with AbbVie, BioSplice Therapeutics, and Gilead. IL: cators in chronic lymphocytic leukemia. Blood. 1999; current employment with Gilead Sciences and previously 94(6):1840–1847. IBRUTINIB IN GENOMIC HIGH-RISK GROUPS 1385 [5] Hamblin TJ, Davis Z, Gardiner A, et al. Unmutated Ig [18] Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib V(H) genes are associated with a more aggressive regimens versus chemoimmunotherapy in older form of chronic lymphocytic leukemia. Blood. 1999; patients with untreated CLL. N Engl J Med. 2018; 94(6):1848–1854. 379(26):2517–2528. [6] Foa R, Del Giudice I, Guarini A, et al. Clinical implica- [19] Fraser G, Cramer P, Demirkan F, et al. Updated results tions of the molecular genetics of chronic lympho- from the phase 3 HELIOS study of ibrutinib, benda- cytic leukemia. Haematologica. 2013;98(5):675–685. mustine, and rituximab in relapsed chronic lympho- [7] Jain P, Kanagal-Shamanna R, Wierda W, et al. Clinical cytic leukemia/small lymphocytic lymphoma. and molecular characteristics of XPO1 mutations in Leukemia. 2019;33(4):969–980. patients with chronic lymphocytic leukemia. Am J [20] Kipps TJ, Fraser G, Coutre SE, et al. Long-term studies Hematol. 2016;91(11):E478–E479. assessing outcomes of ibrutinib therapy in patients [8] Byrd JC, Gribben JG, Peterson BL, et al. Select high- with del(11q) chronic lymphocytic leukemia. Clin risk genetic features predict earlier progression fol- Lymphoma Myeloma Leuk. 2019;19(11):715–722.e716. lowing chemoimmunotherapy with fludarabine and [21] Byrd JC, Hillmen P, O’Brien S, et al. Long-term follow- rituximab in chronic lymphocytic leukemia: justifica- up of the RESONATE phase 3 trial of ibrutinib vs ofa- tion for risk-adapted therapy. J Clin Oncol. 2006;24(3): tumumab. Blood. 2019;133(19):2031–2042. 437–443. [22] Brown JR, Hillmen P, O’Brien S, et al. Extended follow- [9] Stilgenbauer S, Schnaiter A, Paschka P, et al. Gene up and impact of high-risk prognostic factors from mutations and treatment outcome in chronic lympho- the phase 3 RESONATE study in patients with previ- cytic leukemia: results from the CLL8 trial. Blood. ously treated CLL/SLL. Leukemia. 2018;32(1):83–91. 2014;123(21):3247–3254. [23] Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as [10] Thompson PA, Tam CS, O’Brien SM, et al. Fludarabine, initial therapy for patients with chronic lymphocytic cyclophosphamide, and rituximab treatment achieves leukemia. N Engl J Med. 2015;373(25):2425–2437. long-term disease-free survival in IGHV-mutated [24] Hallek M, Cheson BD, Catovsky D, et al. Guidelines for chronic lymphocytic leukemia. Blood. 2016;127(3): the diagnosis and treatment of chronic lymphocytic 303–309. leukemia: a report from the international workshop [11] Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition on chronic lymphocytic leukemia updating the of rituximab to fludarabine and cyclophosphamide in national cancer institute-working group 1996 guide- patients with chronic lymphocytic leukaemia: a rando- lines. Blood. 2008;111(12):5446–5456. mised, open-label, phase 3 trial. Lancet. 2010; [25] IMBRUVICA (ibrutinib) [prescribing information]. 376(9747):1164–1174. Sunnyvale, CA: Pharmacyclics LLC; 2020. [12] Eichhorst B, Fink AM, Bahlo J, et al. First-line chemo- [26] Baliakas P, Agathangelidis A, Hadzidimitriou A, et al. immunotherapy with bendamustine and rituximab Not all IGHV3-21 chronic lymphocytic leukemias are versus fludarabine, cyclophosphamide, and rituximab equal: prognostic considerations. Blood. 2015;125(5): in patients with advanced chronic lymphocytic leu- 856–859. kaemia (CLL10): an international, open-label, rando- [27] Allan JN, Shanafelt T, Wiestner A, et al. Long-term effi- mised, phase 3, non-inferiority trial. Lancet Oncol. cacy of first-line ibrutinib treatment for chronic 2016;17(7):928–942. lymphocytic leukemia (CLL) with 4 years of follow-up [13] Mato AR, Barrientos JC, Ghosh N, et al. Prognostic in patients with TP53 aberrations (del(17p) or TP53 testing and treatment patterns in chronic lymphocytic mutation): a pooled analysis from 4 clinical trials. leukemia in the era of novel targeted therapies: Poster presented at: 62nd ASH Annual Meeting and results from the inform CLL registry. Clin Lymphoma Exposition; December 5-8, 2020; Virtual Meeting. Myeloma Leuk. 2020;20(3):174–183.e173. [28] Ahn IE, Tian X, Wiestner A. Ibrutinib for chronic [14] Burger JA, Barr PM, Robak T, et al. Long-term efficacy lymphocytic leukemia with TP53 alterations. N Engl J and safety of first-line ibrutinib treatment for patients Med. 2020;383(5):498–500. with CLL/SLL: 5 years of follow-up from the phase 3 [29] Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and RESONATE-2 study. Leukemia. 2020;34(3):787–798. obinutuzumab in patients with CLL and coexisting [15] Munir T, Brown JR, O’Brien S, et al. Final analysis from conditions. N Engl J Med. 2019;380(23):2225–2236. RESONATE: up to six years of follow-up on ibrutinib [30] Landau DA, Tausch E, Taylor-Weiner AN, et al. in patients with previously treated chronic lympho- Mutations driving CLL and their evolution in progres- cytic leukemia or small lymphocytic lymphoma. Am J sion and relapse. Nature. 2015;526(7574):525–530. Hematol. 2019;94(12):1353–1363. [31] Rossi D, Khiabanian H, Spina V, et al. Clinical impact [16] Moreno C, Greil R, Demirkan F, et al. Ibrutinib plus of small TP53 mutated subclones in chronic lympho- obinutuzumab versus chlorambucil plus obinutuzu- cytic leukemia. Blood. 2014;123(14):2139–2147. mab in first-line treatment of chronic lymphocytic leu- [32] Mato AR, Roeker LE, Allan JN, et al. Outcomes of kaemia (iLLUMINATE): a multicentre, randomised, front-line ibrutinib treated CLL patients excluded open-label, phase 3 trial. Lancet Oncol. 2019;20(1): from landmark clinical trial. Am J Hematol. 2018; 43–56. 93(11):1394–1401. [17] Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib-rituxi- [33] Dal Bo M, Del Principe MI, Pozzo F, et al. NOTCH1 mab or chemoimmunotherapy for chronic lympho- mutations identify a chronic lymphocytic leukemia cytic leukemia. N Engl J Med. 2019;381(5):432–443. patient subset with worse prognosis in the setting of 1386 J. A. BURGER ET AL. a rituximab-based induction and consolidation treat- presented at: 61st ASH Annual Meeting & Exposition; ment. Ann Hematol. 2014;93(10):1765–1774. December 7-10, 2019; Orlando, FL. [34] Tausch E, Beck P, Schlenk RF, et al. NOTCH1 mutation [38] UK CLL Forum. Ibrutinib for relapsed/refractory and treatment outcome in CLL patients treated with chronic lymphocytic leukemia: a UK and Ireland chlorambucil (chl) or ofatumumab-Chl (O-Chl): results analysis of outcomes in 315 patients. Haematologica. from the phase III study complement 1 (OMB110911). 2016;101:1563–1572. Poster presented at: American Society of Hematology [39] Olszewski AJ, Davids MS, Yakirevich I, et al. Early 55th Annual Meeting; December 7-10, 2013; New adoption and outcomes of ibrutinib as treatment for Orleans, LA. older patients with chronic lymphocytic leukemia [35] Rosati E, Baldoni S, De Falco F, et al. NOTCH1 aberra- (CLL): a population-based study. Poster presented at: tions in chronic lymphocytic leukemia. Front Oncol. 61st ASH Annual Meeting & Exposition; December 7- 2018;8:229. [36] Mato AR, Nabhan C, Thompson MC, et al. Toxicities 10, 2019; Orlando, FL. and outcomes of 616 ibrutinib-treated patients in the [40] Costa A, Loscertales J, Terol MJ, et al. Retrospective United States: a real-world analysis. Haematologica. observational study of the treatment of chronic 2018;103(5):874–879. lymphocytic leukemia (CLL) with ibrutinib in routine [37] Aarup K, Enggaard L, Pedersen RS, et al. Real-world clinical practice in Spain. Poster presented at: 25th outcomes for 205 Danish patients with chronic Congress of the European Hematology Association; lymphocytic leukemia treated with ibrutinib. Poster June 11-21, 2020; Virtual Congress.