Clinical trials that led to ibrutinib's approval for the treatment of chronic lymphocytic leukemia showed that its side effects differ from those of traditional chemotherapy. Reasons for ...discontinuation in clinical practice have not been adequately studied. We conducted a retrospective analysis of chronic lymphocytic leukemia patients treated with ibrutinib either commercially or on clinical trials. We aimed to compare the type and frequency of toxicities reported in either setting, assess discontinuation rates, and evaluate outcomes. This multicenter, retrospective analysis included ibrutinib-treated chronic lymphocytic leukemia patients at nine United States cancer centers or from the Connect® Chronic Lymphocytic Leukemia Registry. We examined demographics, dosing, discontinuation rates and reasons, toxicities, and outcomes. The primary endpoint was progression-free survival. Six hundred sixteen ibrutinib-treated patients were identified. A total of 546 (88%) patients were treated with the commercial drug. Clinical trial patients were younger (mean age 58
61 years,
=0.01) and had a similar time from diagnosis to treatment with ibrutinib (mean 85
87 months,
=0.8). With a median follow-up of 17 months, an estimated 41% of patients discontinued ibrutinib (median time to ibrutinib discontinuation was 7 months). Notably, ibrutinib toxicity was the most common reason for discontinuation in all settings. The median progression-free survival and overall survival for the entire cohort were 35 months and not reached (median follow-up 17 months), respectively. In the largest reported series on ibrutinib- treated chronic lymphocytic leukemia patients, we show that 41% of patients discontinued ibrutinib. Intolerance as opposed to chronic lymphocytic leukemia progression was the most common reason for discontinuation. Outcomes remain excellent and were not affected by line of therapy or whether patients were treated on clinical studies or commercially. These data strongly argue in favor of finding strategies to minimize ibrutinib intolerance so that efficacy can be further maximized. Future clinical trials should consider time-limited therapy approaches, particularly in patients achieving a complete response, in order to minimize ibrutinib exposure.
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Introduction:The CLL Society, a patient-driven, physician-curated nonprofit organization focusing on the unmet needs of the CLL community, sought to explore how patients (pts) make decisions about ...their CLL treatment (tx) as little is known about factors that influence pts decision making in the modern era. We focused on three areas of interest: 1) clinical factors that drive decision-making in tx selection; 2) where pts gather information to inform their decisions and 3) the role of the patient versus physician in making tx decisions. To achieve this goal, we conducted a web-based survey.
Methods: We conducted an online survey between Mar-Apr 2016 of CLL pts registered to receive the CLL Society online quarterly newsletter The CLL Tribune as well as those registered with the online CLL specific patient forums hosted by ACOR (Association of Cancer Online Resources) and groups.IO. Data were analyzed using descriptive methods.
Results: 281 US patients completed the survey.The average age was 64 (range 38-84), 46% were male. Additionally 37% were considering front-line therapy and 32% considering tx options in the relapse setting. 40% of pts defined their disease as high-risk (del 17p, p53 mut, del 11q or IGHV unmutated) and 13% were not aware of risk status. The three most important criteria to pts in selecting a tx option included: progression free survival (67%), overall survival (66%) and response rate (62%). Immediate adverse events (AEs) were important to only 35% while long-term AEs influenced 50% in their tx decisions. Cost (30%), location of tx administration (19%) and participation in a clinical trial (20%) were of lowest importance to pts. 96% of pts would be willing to take a continuous therapy if it offered long-term control without the possibility of cure. Only 37% would be willing to take a tx that included chemotherapy if it offered a chance of cure with higher risks of death and serious life threatening complications. Similarly, 42% would be willing to consider "CAR-T" or "bone marrow transplant" if it offered a chance of cure with higher risks of death and serious life threatening complications. Websites focused on CLL (87%), healthcare providers (74%), and online blogs by physicians (72%) were the three most common educational sources for information on CLL. Only 14% let the treating physician primarily make the tx decision without patient input. 95% stated their own involvement in the tx decision: 84% depended on a CLL expert and 49%, a local hematologist.
Summary: These data provide important insight as to what drives patient CLL tx decision making in the era of modern therapies. While the data is reflective of the pts who use the Internet or of those who have family members helping them use the Internet, it does suggest that pts are increasingly engaging in their tx decisions and relying on multiple sources of information beyond their physician. Moreover, there seems to be broad acceptance of long-term non-curative tx and significant hesitancy for chemotherapy, CAR-T therapy and stem cell transplantation (even if cure is possible when risks are perceived as high). Providers need to engage in shared decision-making with pts. The survey was only available online, hence the results are influenced by the self-selection by those who use the Internet and access the sources mentioned above.
Nabhan:Celgene, Genentech, Abbvie, Infinity, Cardinal Health: Consultancy; Celgene, Genentech, Seattle Genetics, Astellas: Research Funding. Mato:Abbvie, Acerta Pharma, Gilead Sciences, ProNAi, TG Therapeutics, Theradex: Research Funding; Abbvie, Gilead Sciences, Pharmacyclics, TG Therapeutics: Consultancy.
Introduction: Ibrutinib (Ibr), idelalisib (Ide), andvenetoclax (Ven), are all now approved for treating CLL patients in the US. However, in the absence of head-to-head comparator trials, there is ...limited guidance as to the optimal sequence of these therapies and to the best choice upon failure of first selected agent. To address these gaps in current literature, 9 large US cancer centers and the Connect CLL Registry collaborated to capture the experience of 683 CLLpts treated with kinase inhibitors (KIs) - focusing on optimal sequencing and patterns of failure.
Patients and Methods: We conducted a multicenter, retrospective analysis of CLLpts treated withIbr-, Ide- orVen-based therapy. We examined demographics, discontinuation rates, reasons for discontinuation, overall response rates (ORR), survival, and post kinase inhibitor (KI) salvage strategies. Primary endpoint was progression-free survival (PFS) (time from KI treatment to progression, death, or last follow-up) as determined by the Kaplan Meier (KM) method. Comparisons were made using the log rank (LR) test and COX regression analyses.
Results: A total of 683 pts treated with KI therapy (Ibr=621/Ide=62) were identified (Table 1). Baseline characteristics were similar in theIbr and Ide-based groups. ORR toIbr as first KI was 69% complete response (CR) 11%, partial response (PR) 45%, and PR-L 13% and Ide was 81% (CR 5%, PR 71%,PR-L 5%). With a median follow-up from start of first KI of 17 months (range 1-60), median PFS and OS for the entire cohort from first KI was 35 months (216 events) and not reached respectively (107 events). Interestingly,pts treated withIbr (vs. Ide) as first KI had a significantly better PFS in all settings; front-line (figure a, HR 2.8, CI 1.3-6.3 p=.01), relapsed-refractory (figure b, HR 2.8, CI 1.9-4.1 p<.001), clinical trials (HR 3.3, CI 1.8-5.9 p<.001), commercial use (HR 2.5, CI 1.5-4.0 p<.001), del17p (HR 2.0, CI 1.2-3.4 p=.008), or complex karyotype (HR 2.5, CI 1.2-5.2 p=.02). Moreover, at the time of initial KI failure, the use of either an alternate KI orVen was associated with superior PFS as compared tochemoimmunotherapy (CIT) combinations (figure c). When treated with an alternate KI (Ibr followed by Ide or Ide followed byIbr),pts intolerant of a KI therapy due to toxicity had a superior PFS compared with those taken off a KI therapy due to CLL progression (p=0.03, LR test). Furthermore,Ibr-failurepts had a marginally better PFS if treated withVen (ORR 79%) vs. Ide (ORR 46%) (figure d, HR .6, CI.3-1.0 p=.06).
Conclusions: In the largest experience of novel agents published to date in CLL,Ibr appears superior to Ide in all settings as first choice KI. Further, in the setting of KI failure, an alternate KI orVen therapy appear superior to CIT combinations. Alternate KI appear particularly effective in the setting of intolerance to a prior KI. The use ofVen uponIbr failure might be superior to the use of Ide. These data provide guidance for sequencing of novel agents and support the need for trials directly comparing novel agents and sequencing strategies in CLL.
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Mato:Abbvie, Gilead Sciences, Pharmacyclics, TG Therapeutics: Consultancy; Abbvie, Acerta Pharma, Gilead Sciences, ProNAi, TG Therapeutics, Theradex: Research Funding. Lamanna:Roche-Genentech: Honoraria, Research Funding; Celgene: Honoraria; Janssen: Honoraria; Pharmacyclics: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Infinity: Research Funding; Acerta: Research Funding; TGR Therapeutics: Research Funding. Barr:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Consultancy. Ujjani:Genentech: Consultancy; Abbvie: Consultancy; Gilead: Consultancy; Pharmacyclics: Consultancy. Brander:Gilead: Honoraria; TG Therapeutics: Research Funding. Cheson:Acerta: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Kiselev:Celgene: Employment, Equity Ownership. Svoboda:Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding. Schuster:Genentech: Consultancy, Honoraria; Gilead: Research Funding; Pharmacyclics: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Hoffman-LaRoche: Research Funding; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Merck: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Janssen Research & Development: Research Funding. Nabhan:Celgene Corporation: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Abbvie: Consultancy; Infinity: Consultancy; Cardinal Health: Consultancy; Seattle Genetics: Research Funding; Astellas: Research Funding.
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Introduction: Ibrutinib (Ibr) is a kinase inhibitor (KI) indicated for treating CLL. Clinical trials that led to its approval showed that its unique side effects differ from traditional ...chemotherapy toxicities. We previously reported (Mato et al, ASH 2015) that intolerance was the most common reason for discontinuation of Ibr in 123 patients treated in a real world setting. Whether reasons for discontinuation reported in clinical trials mirror those encountered in the real world is unknown and has not been studied. Therefore, we conducted a retrospective analysis of 621 CLL patients treated with Ibr either on clinical studies or commercially. We aimed to compare the type and frequency of toxicities reported in either setting, assess discontinuation rates, and evaluate outcomes.
Patients and Methods: This multicenter, retrospective analysis included Ibr-treated CLL patients at 9 US cancer centers or the Connect® CLL Registry. We examined demographics, dosing, discontinuation rates and reasons, toxicities, and outcomes. The primary endpoint was progression-free survival (PFS) (time from KI treatment to progression, death or last f/u) as determined by the Kaplan Meier method. Comparisons of outcomes data were made using the log rank (LR) test. All other comparisons were descriptive.
Results: 621 patients treated with Ibr were identified. Table 1 includes available baseline characteristics stratified by line of therapy. A total of 546 (88%) patients were treated with commercial drug. Clinical trial patients were younger (median age 57 vs. 61 years), had a longer time from diagnosis to Ibr (median 85 vs. 72 months) and were more consistently initiated at 420 mg daily (100% vs. 89%). With a median f/u of 14.5 months, the Ibr discontinuation rate was estimated to be 42% (median time to Ibr discontinuation was 7 months). Reasons for discontinuation are listed in table 2. Notably, Ibr toxicity was the most common reason for discontinuation in all settings. Ibr starting dose (420 mg daily vs. < 420 mg daily) did not impact the proportion of patients who discontinued Ibr due to toxicity (51% vs. 50%). In relapsed CLL, the 5 most common Ibr-related toxicities as a reason for discontinuation included: atrial fibrillation (12.3%), infection (10.7%), pneumonitis (9.9%), bleeding (9%), and diarrhea (6.6%). In front line CLL, the 3 most common Ibr-related toxicities as a reason for discontinuation included arthralgia (41.6%), atrial fibrillation (25%), and rash (16.7%). Median times to discontinuation by toxicity were as follows: bleeding (8 months), diarrhea (7.5 months), atrial fibrillation (7 months), infection (6 months), arthralgia (5 months), pneumonitis (4.5 months), and rash (3.5 months). Median PFS and OS for the entire cohort were 35 months and not reached (median f/u 17 months) respectively. Figure 1 describes PFS for Ibr treated patients stratified by line of therapy (A), reason for discontinuation (B), clinical trial participation (C) and depth of response (D). In a multivariable model, complex karyotype was validated as an independent predictor of PFS (HR 1.6, CI 1.1-2.5 p=.04) but not OS (HR 1.6, CI .9-3.1 p=.1).
Conclusions: In the largest reported series on Ibr-treated CLL patients, we show that 40% of patients have discontinued Ibr during this observation period. Intolerance as opposed to CLL progression or transformation was the most common reason for discontinuation. As compared to previous reports from clinical trials, the discontinuation rate appears to be higher suggesting (1) a learning curve in terms of toxicity management, (2) a higher incidence of toxicity in clinical practice, (3) or a lower threshold for discontinuation given alternative choices. Outcomes remain excellent and were not impacted by line of therapy and whether patients were treated on studies or commercially. These data strongly argue to find strategies to minimize Ibr intolerance so that efficacy can be further maximized.
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Mato:Abbvie, Acerta Pharma, Gilead Sciences, ProNAi, TG Therapeutics, Theradex: Research Funding; Abbvie, Gilead Sciences, Pharmacyclics, TG Therapeutics: Consultancy. Lamanna:Acerta: Research Funding; TGR Therapeutics: Research Funding; Janssen: Honoraria; Pharmacyclics: Honoraria, Research Funding; Roche-Genentech: Honoraria, Research Funding; Celgene: Honoraria; AbbVie: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Infinity: Research Funding; Acerta: Research Funding; TGR Therapeutics: Research Funding. Ujjani:Gilead: Consultancy; Abbvie: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy. Brander:TG Therapeutics: Research Funding; Gilead: Honoraria. Howlett:Sandoz: Honoraria; Teva: Speakers Bureau; Amgen: Honoraria; Pfizer: Honoraria; Eisai: Honoraria. Skarbnik:Gilead Sciences: Speakers Bureau; Seattle Genetics: Speakers Bureau; Genentech: Speakers Bureau; Abbvie: Consultancy; Pharmacyclics: Consultancy. Cheson:Acerta: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Kiselev:Celgene: Employment, Equity Ownership. Nasta:Millennium Pharmaceuticals: Research Funding. Schuster:Janssen Research & Development: Research Funding; Hoffman-LaRoche: Research Funding; Gilead: Research Funding; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Genentech: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Research Funding; Merck: Research Funding. Porter:Novartis: Patents & Royalties, Research Funding; Genentech: Employment. Nabhan:Seattle Genetics: Research Funding; Cardinal Health: Consultancy; Infinity: Consultancy; Abbvie: Consultancy; Genentech: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding; Astellas: Research Funding. Barr:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Consultancy.
Venetoclax is a BCL2 inhibitor approved for 17p-deleted relapsed/refractory chronic lymphocytic leukemia with activity following kinase inhibitors. We conducted a multicenter retrospective cohort ...analysis of patients with chronic lymphocytic leukemia treated with venetoclax to describe outcomes, toxicities, and treatment selection following venetoclax discontinuation. A total of 141 chronic lymphocytic leukemia patients were included (98% relapsed/refractory). Median age at venetoclax initiation was 67 years (range 37-91), median prior therapies was 3 (0-11), 81% unmutated
, 45% del(17p), and 26.8% complex karyotype (≥ 3 abnormalities). Prior to venetoclax initiation, 89% received a B-cell receptor antagonist. For tumor lysis syndrome prophylaxis, 93% received allopurinol, 92% normal saline, and 45% rasburicase. Dose escalation to the maximum recommended dose of 400 mg daily was achieved in 85% of patients. Adverse events of interest included neutropenia in 47.4%, thrombocytopenia in 36%, tumor lysis syndrome in 13.4%, neutropenic fever in 11.6%, and diarrhea in 7.3%. The overall response rate to venetoclax was 72% (19.4% complete remission). With a median follow up of 7 months, median progression free survival and overall survival for the entire cohort have not been reached. To date, 41 venetoclax treated patients have discontinued therapy and 24 have received a subsequent therapy, most commonly ibrutinib. In the largest clinical experience of venetoclax-treated chronic lymphocytic leukemia patients, the majority successfully completed and maintained a maximum recommended dose. Response rates and duration of response appear comparable to clinical trial data. Venetoclax was active in patients with mutations known to confer ibrutinib resistance. Optimal sequencing of newer chronic lymphocytic leukemia therapies requires further study.
Introduction: Venetoclax has demonstrated consistent efficacy and manageable toxicity in patients with previously untreated or relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic ...leukemia (CLL/SLL). However, evidence on venetoclax use in patients previously treated with Bruton tyrosine kinase inhibitors (BTKi) is limited. This real-world evidence (RWE) study assessed clinical outcomes of patients who received venetoclax after covalent BTKi (cBTKi) therapy, i.e., response rates, time to next treatment or death (TTNT-D), and progression-free survival (PFS), overall and stratified by line of therapy. Methods: The CLL Collaborative Study of Real-World Evidence (CORE), a retrospective, international, observational study (23 centers) provided data for this analysis. Adult patients diagnosed with CLL/SLL were included if they received a venetoclax-based regimen after discontinuation of a cBTKi-based regimen. Baseline characteristics at venetoclax initiation were summarized using descriptive statistics. Overall response rate (ORR) was calculated as the proportion of patients with complete response (CR) or partial response (PR) among patients with documented responses as recorded in the patients' medical charts based on physician assessment. TTNT-D was measured from date of venetoclax initiation to change of treatment/death (event) or end of follow-up, while PFS was measured from date of venetoclax initiation to disease progression/death (event) or end of follow-up. Outcomes were reported for the overall population and stratified by line of therapy (1L→2L and 2L→3L) and also by with and without CT/CIT exposure prior to cBTKi for 2L→3L. Results: Of the 2,020 patients included in CORE, 1,287 (63.7%) received a cBTKi-based regimen in ≥1 line of therapy; 184 patients (14.3%) discontinued cBTKi (intolerance: 83 45.1%, progression: 78 42.4%) and initiated venetoclax-based therapy (115 venetoclax monotherapy; 69 venetoclax combined with rituximab or obinutuzumab). Mean age at venetoclax initiation was 68.6 (median: 68.2) years old, 69.0% were male, and 31.0% had Medicare. Among tested patients, 41/61 (67.2%) had unmutated IGHV, and 28/109 (25.7%) had 17p deletion or TP53 mutation at venetoclax initiation. Average follow-up time from initiation of venetoclax therapy was 19.6 months (median: 16.6). Of the 127 patients (69.0%) with a documented response, the ORR was 78.0% (CR: 43.3%, PR: 34.6%). The median TTNT-D for these patients was 39.5 months (95% CI: 30.4, not reached NR) with 12- and 18-month rates of 82.3% and 72.4%, respectively. The median PFS was 43.2 months (95% CI: 31.9, NR), with 12- and 18- month PFS rates of 82.8% and 75.1%, respectively. Among patients who started venetoclax-based therapy post-cBTKi as 1L→2L (n=65), the ORR was 84.1% (CR: 54.5%, PR: 29.5%, out of 44 documented). The median TTNT-D for these patients was NR (95% CI: 31.9, NR) but the 12- and 18-month rates were 85.0% and 73.9%, respectively. The median PFS was 43.2 months (95% CI: 39.5, NR) with 12- and 18- month rates of 86.4% and 81.8%, respectively. Among patients who started venetoclax-based therapy post-cBTKi as 2L→3L (n=67), the ORR was 78.3% (CR: 41.3%, PR: 37.0%, out of 46 documented). The median TTNT-D for these patients was 44.2 months (95% CI: 37.0, NR) with 12- and 18-month rates were 83.1% and 76.5%, respectively. The median PFS for these patients was 44.1 months (95% CI: 31.8, NR) with 12- and 18- months rates were 85.2% and 80.4%, respectively. The results for ORR, TTNT-D, and PFS were also similar for those with and without CT/CIT exposure prior to cBTKi. Conclusions: In this multicenter real-world study, results demonstrate that venetoclax is effective overall and also when used either in 2L or 3L following cBTKi therapy. Additionally, even with prior CT/CIT exposure, results support that venetoclax-based therapy remains effective as a therapeutic option. Thus, this study demonstrates that venetoclax-based therapy post-cBTKi is associated with durable remission. These results are especially timely as the CLL treatment paradigm continues to evolve with multiple treatment options available, providing clinicians with valuable evidence to inform modern clinical practice. Further analysis of this study with larger cohorts and longer follow-up time will be undertaken as part of future work to grow this body of evidence.
Introduction: Ibrutinib is approved for all lines of therapy in CLL with a recommended starting dose at 420mg daily. Dose interruptions ≥ 8 days may negatively impact both progression free survival ...(PFS) and overall survival (OS) (Barr et al, Blood 2017). However, dose reduction did not appear to affect responses or survival (Timlin et al, ASCO 2015; Mato A et al, BJH 2016). We aimed to comprehensively study the impact of dose interruptions and ibrutinib starting dose (< 420 mg) on survival outcomes in front-line ibrutinib use.
Methods: We conducted a multicenter, retrospective cohort study of CLL patients treated with front-line ibrutinib. We recorded and categorized ibrutinib starting dose (reduced dose vs. 420 mg daily) and number of days required for dose interruptions (0-7 days vs. ≥ 8 days). Study endpoints included overall response rates, PFS and reasons for discontinuation. Comparisons of outcomes data were made using COX regression. All other comparisons were descriptive.
Results: We identified 391 patients treated with front-line ibrutinib. Of these, 30 (7.6%) initiated treatment at doses < 420 mg (47% 140 mg daily and 53% 280 mg daily). For the reduced dose cohort, median age was 76 years (range: 47-96) vs. 67 years (range: 36-96) in the standard dose cohort, 60% were males, and 83% Caucasians. Prognostic factors included: 27% del17p+ (vs. 30% in the standard dose cohort), 78% IGHV unmutated (vs. 66%), 21% complex karyotype (vs. 24%). In this cohort, the ORR was 85% (vs. 81% in the full dose cohort), but 12 month PFS was 71% (vs. 93% in the full dose). This inferior PFS was significant (HR 3.3, p=0.003; 95%CI: 1.57.0). Eighty-six (22%, 86/391) patients had a dose interruption of ≥ 8 days (median duration = 14 days). The 12 month PFS was not impacted with dose interruption (90% if ≥ 8 days vs. 96% if <8 days) (HR 1.48, CI .48-4.6 p=0.49). At the time of this analysis, 8 patients discontinued reduced dose ibrutinib. Reasons for discontinuation included: 4 patients for toxicity, 2 patients for CLL progression and 1 patient for Richter's transformation. Median time to discontinuation was 10.5 months for patients who initiated treatment on a reduced dose of ibrutinib. Figure 1 describes PFS stratified by dose interruptions (<8 days vs ≥8 days) and ibrutinib starting dose (<420 mg daily vs 420 mg daily).
Conclusions: While response rates appear to not be affected when ibrutinib is initiated at lower than 420 mg daily, patients starting at lower doses appear to have inferior PFS. Unlike in high-risk heavily pretreated patients, the PFS of patients receiving front-line ibrutinib was not adversely affect by dose interruptions of ≥ 8 days. To our knowledge, these data are the first to show a relationship between front-line ibrutinib dosing and outcomes. These data support dosing and dose interruption recommendations as guided by the ibrutinib FDA label.
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Barr:Gilead: Consultancy; Novartis: Consultancy; Infinity: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Celgene: Consultancy; AbbVie: Consultancy, Research Funding; Seattle Genetics: Consultancy. Ujjani:Genentech: Consultancy; Abbvie: Research Funding, Speakers Bureau; Gilead: Consultancy; Pharmacyclics: Consultancy, Research Funding. Tam:Janssen Cilag: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Lansigan:Seattle Genetics: Consultancy; Spectrum Pharmaceuticals: Consultancy, Research Funding. Brander:Teva Pharmaceuticals, Genentech, AbbVie, Pharmacyclics: Consultancy; Genentech: Consultancy; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Shadman:TG Therapeutics: Research Funding; Celgene: Research Funding; Pharmacyclics: Other: advisory board, Research Funding; Emergent: Research Funding; AbbVie: Other: advisory board; Genentech: Consultancy, Research Funding; Gilead: Research Funding; PLEXXIKON: Research Funding; Acerta Pharma: Research Funding; Merck: Research Funding. Skarbnik:Seattle Genetics: Speakers Bureau; Genentech: Speakers Bureau; Abbvie: Other: Ad board, Speakers Bureau; Gilead: Speakers Bureau; Novartis: Speakers Bureau. Pagel:Pharmacyclics: Consultancy; Gilead: Consultancy. Cheson:Acerta, Pharmacyclics, Epizyme, Gilead, Roche, AbbVi: Other: Institution receives research support ; AbbVie, Roche-Genentech, Pharmacyclics, Acerta: Consultancy. Furman:Gilead: Consultancy; Pharmacyclics: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Genentech: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy. Mato:Acerta: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; DTRM: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Research Funding; Portola: Research Funding; Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; Janssen: Consultancy; AstraZeneca: Consultancy; Kite: Consultancy.
Introduction: Venetoclax (Ven) is approved for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) as monotherapy (Ven mono) or in combination (Ven paired) with rituximab based on clinical ...trials with selected patients (pts) and limited ibrutinib exposure. Whether Ven paired is superior to Ven mono, patterns of care, and outcomes following Ven discontinuation are unknown. Further, better delineation of adverse events (AEs) when Ven is used outside of clinical trials is needed. To address these gaps, we conducted a multicenter, international study in partnership with CLL Collaborative Study of Real World Evidence (CORE) and UK CLL Study Forum examining the clinical experience of 348 Ven treated CLL pts, representing the largest series of Ven treated pts reported to date.
Methods: We conducted a retrospective cohort analysis of CLL pts treated with Ven across 24 US and 42 UK academic and community centers. We examined demographics, baseline disease characteristics, dosing, AEs, TLS risk and outcomes, response rates, outcomes (overall survival (OS) and progression free survival (PFS)), and tx sequencing. TLS events were defined by Howard criteria. PFS and OS were estimated by the Kaplan Meier method. Comparisons of outcomes used the Log Rank test. Univariate and multivariate analyses were performed with COX regression. All other comparisons were descriptive.
Results: Of these 348 CLL pts, 94% were R/R, median age 67 years (range:37-91), 69% male, 85% white, and 73% Rai stage ≥2. 19% received Ven on clinical trial. 79% had Ven mono; Ven was paired most commonly with anti-CD20 (n=51) and ibrutinib (n=10). Pts received a median of 3 tx (range 0-15) before Ven; 78% received ibrutinib, 29% received PI3Ki, 20% had ≥2 prior kinase inhibitors, and 68% had chemoimmunotherapy. Median time from most recent tx to Ven start was 1.1 months (range 0-62). Pre-Ven prognostic markers included 43% del17p, 34% TP53 mutated, 24% del11q, 38% complex karyotype (≥ 3 abnormalities), and 84% IGHV unmutated (Table 1). TLS risk was low in 38%, intermediate in 34% and high in 28%. During ramp up, TLS was observed in 10% (22 lab, 9 clinical TLS events, 3 missing data). Following dose escalation, 70% achieved a stable Ven dose of 400 mg, 33% required ≥ 1 dose interruption and 27% required ≥ 1 dose reduction. AEs included grade 3 neutropenia 39%, grade 3 thrombocytopenia 29%, infections 25%, grade ≥ 2 diarrhea 7.8%, and neutropenic fever 7.7%. AEs were similar whether treated on or off clinical trial. The ORR to Ven mono, Ven paired was 81% (34% CR), 86% (29% CR). With a median follow-up of 14.2 months, median PFS and OS were not reached (12 month PFS 74%, OS 82%). Figure 1 depicts PFS stratified by Ven mono vs. paired, clinical trial vs. clinical practice, del17p status, and complex karyotype. Pts who discontinued Ven due to AEs had better OS compared with those who discontinued due to progression or Richter Transformation (RT) (Median OS 47 vs. 15.1 vs. 8.6 months, respectively). In multivariate analyses, complex karyotype was the only independent predictor of PFS (HR 2.8, p <.0001) and OS (HR 3.0, p=.002). In the absence of complex karyotype, number of prior lines of tx (PFS HR 1.1, p=.03; OS HR 1.1 p=.032), presence of del17p (PFS HR 2.1 p=0.001; OS HR 1.7 p=0.03) and prior ibrutinib exposure (PFS HR 2.0, p=0.04; OS HR 1.4, p=0.3) remained independent predictors of PFS and/or OS. A total of 142 pts (41.5%) have discontinued Ven, most commonly due to CLL progression (37%), AEs (20%), and RT (10%). 67 have not had subsequent therapy. Of 75 pts treated following Ven discontinuation, most common tx was a kinase inhibitor (KI) (n= 21). Among these, 18 pts had received a KI prior to Ven and were retreated with KI (ORR 17%, median PFS 2 months, Figure 2). With limited follow up, ORR to ibrutinib post Ven in 6 KI naïve pts was 50%.
Conclusions: In this heavily pretreated, poor risk group, Ven showed favorable outcomes with comparable toxicity and efficacy on or off clinical trial. Similar outcomes were observed for Ven mono and Ven paired; longer follow up is needed from studies of Ven paired to understand depth and durability of response. Complex karyotype independently predicted inferior PFS and OS. Without complex karyotype, del(17p), multiple lines of prior tx, and prior ibrutinib tx were independent predictors of inferior outcomes. Outcomes of retreatment with KI in Ven-failure previously treated with KI were poor. Data on sequencing cellular therapies post Ven is forthcoming.
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Mato:AbbVie: Consultancy, Research Funding; Pharmacyclics, an AbbVie Company: Consultancy, Research Funding; Regeneron: Research Funding; AstraZeneca: Consultancy; Medscape: Honoraria; TG Therapeutics: Consultancy, Research Funding; Acerta: Research Funding; Prime Oncology: Honoraria; Portola: Research Funding; Celgene: Consultancy; Johnson & Johnson: Consultancy. Eyre:Abbvie: Consultancy, Other: travel support; Janssen: Consultancy, Other: travel support; Roche: Consultancy; Gilead: Consultancy, Other: travel support; Celgene: Other: travel support. Nabhan:Cardinal Health: Employment, Equity Ownership. Lamanna:Acerta: Research Funding; TG Therapeutics: Research Funding; Jannsen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hill:Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Brander:Pharmacyclics, an AbbVie Company: Consultancy, Honoraria, Research Funding; Acerta: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Novartis: Consultancy, Other: DSMB; TG Therapeutics: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Teva: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Genentech: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; DTRM: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; BeiGene: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding. Barr:AbbVie, Gilead: Consultancy. Cheson:AbbVie, Roche/Genentech, Pharmacyclics, Acerta, TG Therapeutics: Consultancy. Shah:Geron: Equity Ownership; Lentigen Technology: Research Funding; Exelexis: Equity Ownership; Oncosec: Equity Ownership; Miltenyi: Other: Travel funding, Research Funding; Juno Pharmaceuticals: Honoraria. Allan:AbbVie: Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy; Sunesis: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees. Kennard:AbbVie, Gilead, Verastem: Consultancy. Schuster:Gilead: Membership on an entity's Board of Directors or advisory committees; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Research Funding; Physician's Education Source, LLC: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Research Funding; Dava Oncology: Consultancy, Honoraria; OncLive: Honoraria; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Skarbnik:Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Genentech: Honoraria, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau. Coombs:AROG: Other: Travel fees; Abbvie: Consultancy; Incyte: Other: Travel fees; DAVA Oncology: Honoraria; H3 Biomedicine: Honoraria. Ujjani:AbbVie: Consultancy, Speakers Bureau. Jacobs:Genentech: Honoraria. Pagel:Pharm
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