A multicenter, retrospective study of accelerated venetoclax ramp‐up in patients with relapsed/refractory chronic lymphocytic leukemia
Authors: Matthew S. Davids, Mazyar Shadman, Sameer A. Parikh, Chaitra Ujjani, Jennifer L. Crombie, Dingfeng Jiang, Cynthia Llamas, Dai Feng, Nicole Lamanna
Journal: American Journal of Hematology (2021)

The efficacy of venetoclax in chronic lymphocytic leukemia (CLL) is well established.1-3 Venetoclax is approved with a 5-week dose ramp-up schedule to mitigate risk of tumor lysis syndrome (TLS); dosing is increased weekly according to a schedule of 20 mg, 50 mg, 100 mg, 200 mg, reaching a target dose of 400 mg daily in Week 5 per United States prescribing information. Although this standard 5-week ramp-up is appropriate for most patients with CLL, rapid disease control is needed for some patients with very aggressive disease. While many such patients respond to venetoclax treatment it remains critical, especially for those who progress on B-cell receptor pathway inhibitor (BCRi) therapies such as ibrutinib, to rapidly achieve a therapeutically-relevant dose of venetoclax.4 Thus, certain patients with CLL might benefit from expedited venetoclax ramp-up, per National Comprehensive Cancer Network Clinical Practice Guidelines. Limited data are available on strategies for more rapid escalation of venetoclax in CLL.5 We report the first multicenter study to characterize the safety and feasibility of an accelerated venetoclax ramp-up schedule in patients with rapid progression of relapsed/refractory (R/R) CLL. This retrospective chart review was conducted across four large academic medical centers in the United States from 2019 to 2020. Patients with R/R CLL who had received prior treatment and had a documented accelerated venetoclax ramp-up period (<5 weeks) were retrospectively identified from medical charts. The study period began 1 month before ramp-up initiation and continued until 1 month after ramp-up completion. The primary endpoint was the proportion of patients with Grade ≥3 adverse events (AEs) during ramp-up, chosen to capture a comprehensive safety profile of venetoclax in this setting. Further details are provided in Appendix S1. Twenty-eight patients were identified and included in the analysis (Table S1). Seven patients (25.0%) had an absolute lymphocyte count (ALC) of ≥ 100 × 109 cells/L (median 27.5; range 0.03–2160), and 7 patients (25.0%) had lymph node involvement > 5 cm. Median creatinine clearance was 84.0 mL/min (range 51.0–136.3). Patients had a median of 3 prior lines of CLL therapy (range 1–7; Table S1). Last line of therapy was discontinued before venetoclax ramp-up in 25 patients (89.3%). One patient discontinued last line of therapy during ramp-up. Two other patients (7.1%) discontinued their last line of therapy once the stable dose of venetoclax was reached. Among these three patients who did not discontinue prior therapy before venetoclax initiation, two patients (7.1%) were receiving ibrutinib and one patient (3.6%) was receiving idelalisib. Nine patients (32.1%) experienced Grade ≥ 3 AEs (primary endpoint; Table S2), including anemia (n = 5; 17.9%), neutropenia (n = 2; 7.1%), thrombocytopenia (n = 1; 3.6%), and febrile neutropenia (n = 1; 3.6%). Additional Grade ≥ 3 AEs included hyperkalemia (n = 2; 7.1%), hypocalcemia (n = 2; 7.1%), hypovolemic shock (n = 2; 7.1%), lymphopenia (n = 2; 7.1%), cardiovascular insufficiency (n = 1; 3.6%), and hypophosphatemia (n = 1; 3.6%). Three patients (10.7%) discontinued venetoclax due to AEs; two did not reach a stable dose and one patient discontinued after 12 days of ramp-up and a maximum dose of 200 mg (Table S3). The venetoclax ramp-up schedules initiated are described in Table S4. All patients received antihyperuricemic drugs during ramp-up, and all but one patient (96.4%) received intravenous hydration. The majority of the patients (n = 15, 53.6%) had a ramp-up period of between 3 and < 5 weeks (Table S5). Twenty-six patients (92.9%) reached a stable dose of venetoclax; of these, 20 patients (71.4%) reached the target dose of 400 mg. The median time to reach any stable dose of venetoclax was 21 days (range 11–25) and was also 21 days (range 18–25) for the 20 patients who reached a stable dose of 400 mg. All patients underwent accelerated ramp-up as inpatients, with median hospital stay of 11 days (range 4–28) overall (Table S4). Timing of hospital admission varied, with 18 patients (64.3%) admitted 1–5 days before ramp-up initiation; 9 (32.1%) admitted on the day of initiation, and 1 (3.6%) admitted 1 day after initiation. At least one AE of TLS was experienced by seven patients (25.0%; Table 1), including five cases of laboratory TLS (17.9%) and two cases of clinical TLS (7.1%). Two additional patients (7.1%) experienced metabolic abnormalities (hyperuricemia, hypocalcemia, and acute kidney disease) that did not meet the Howard Criteria for laboratory TLS per investigator assessment. Of the seven patients who developed TLS (at doses ranging between 20 and 200 mg), six had event onset within the first week of ramp-up; one had onset in the second week of ramp-up. Three of five patients (10.7% of all patients) who experienced a single AE of laboratory TLS did not receive any interventions because the TLS was self-limited with ongoing hydration and TLS prophylaxis. Hyperkalemia (1)cc Whole blood potassium was checked to confirm true hyperkalemia. [Pre: 4.2; Max: 6.1dd Sample was hemolyzed. ] Hyperkalemia (2)cc Whole blood potassium was checked to confirm true hyperkalemia. ,ee Significant pseudohyperkalemia was observed prior to dosing, and although potassium measurements increased following dosing, pseudohyperkalemia may still have been present. [Pre: 5.1; Max: 8.5] Hypocalcemia (4) [Pre: 1.07; Max: 1.17] Hyperphosphatemia (2) [Pre: 3.8; Max: 5.6] Hyperphosphatemia (1) [Pre: 4.2; Max:7.2] Hyperphosphatemia (1) [Pre:3.8; Max:5.3] Acute kidney injury (4) [Pre: 1.2; Max: 1.57] Hyperphosphatemia (4) [Pre: 3.3; Max: 6.4] Hyperkalemia (4) [Pre: 3.9; Max: 6.0cc Whole blood potassium was checked to confirm true hyperkalemia. ] Calcium gluconate Polyethylene glycol Hyperphosphatemia (4) [Pre: 5.7; Max: 11.2] Hypocalcemia (4) [Pre: 8.8; Max: 7.3] Hyperkalemia (4) [Pre: 4.0; Max: 6.1cc Whole blood potassium was checked to confirm true hyperkalemia. ] Calcium gluconate Calcium chloride Dialysis Hypovolemic shock (4) Hyperuricemia (4) [Pre: 3.9; Max: 5.5] Allopurinol Rasburicase Acute kidney injury (4) [Pre: 1.3; Max: 1.55] Of the two patients (7.1%; Table 1) who developed clinical TLS, one was assessed as being at high risk of TLS at baseline, and experienced increased creatinine levels following venetoclax initiation (20 mg dose); the patient received aggressive hydration and close laboratory monitoring, with creatinine returning to baseline within 24 h. Venetoclax was escalated to 50 mg, and the patient then experienced grade 4 acute kidney injury, hyperphosphatemia, and hyperkalemia. The other patient, assessed as being at medium risk of TLS at baseline, experienced hyperphosphatemia, hypocalcemia, and hyperkalemia, 1 day after initiation of venetoclax monotherapy; hyperuricemia 2 days after initiation; and acute kidney injury 3 days after the single initial dose of 20 mg. Both patients required interventions (Table 1) administered in an intensive care unit but did not require hemodialysis. All AEs of TLS (including clinical events) resolved without long-term clinical sequelae. Between-group comparisons of patients who developed TLS (n = 7, 25.0%) versus patients who did not (n = 21, 75.0%) reveal that none of the baseline patient characteristics analyzed (including ALC and lymph node size) were significantly associated with subsequent risk of TLS. None of the genetic features analyzed, number of prior lines of therapy (≤3 or >3), type of prior line of therapy (BCRis, chemoimmunotherapy, or other), or timing of discontinuation of prior therapy (during/after ramp-up or prior to venetoclax initiation) were found to be associated with the development of TLS. In this multicenter, retrospective chart review study, 32.1% of patients with R/R CLL treated with accelerated venetoclax ramp-up experienced an AE of Grade ≥3 (primary endpoint), and 10.7% of patients discontinued venetoclax during the treatment period due to AEs. Rates of discontinuation due to AEs were similar to those observed in an integrated safety analysis of three phase 1/2 studies of venetoclax monotherapy (10.0%), although the study period here was shorter.6 The median time to reach the approved dose of venetoclax 400 mg was substantially shorter at 21 days than the 35 days per the standard ramp-up schedule. While TLS was observed in one-quarter of patients, all TLS events were manageable and recovered without clinical sequelae. This high rate of observed TLS could be explained in part by the patient selection, which was enriched for high risk of TLS. These confirmatory findings will help to inform future changes in dose ramp-up for patients that require more urgent treatment. Our data indicate that patients with R/R CLL requiring rapid disease control could receive a more rapid dose acceleration if they receive appropriate inpatient monitoring and administration of adequate prophylactic hydration and antihyperuricemics to reduce risk of TLS. Clinical decision-making should balance the possible increased risk of TLS with the risk of rapid progression of CLL. The rates of laboratory and clinical TLS noted in our cohort were higher than those associated with the approved 5-week ramp-up schedule (range 0%–2.6% laboratory TLS and 0%–0.5% clinical TLS) but lower than rates reported from other studies of accelerated ramp-up schedules (range up to 52% laboratory TLS and up to 15% clinical TLS).1-3, 5 Our report describes a select group of patients who were assessed to be at higher risk of rapid disease progression following discontinuation of BCRi therapy; therefore, patient selection may have affected the results. Additional limitations include the heterogeneity of the venetoclax ramp-up schedule used in our patients due to the real-world nature of the study, the challenge of comparing to other studies that did not use Howard Criteria for TLS, and our relatively small sample size. Overall, with close inpatient monitoring, accelerated venetoclax ramp-up was feasible in a population of patients with aggressive R/R CLL. Although TLS was observed in a higher proportion of patients than is commonly reported with standard ramp-up, all cases were manageable and did not result in long-term clinical sequelae. Thus, accelerated venetoclax ramp-up may benefit patients with aggressive CLL, particularly those progressing on/after BCRi therapy, or patients who would find a shorter ramp-up schedule performed in the inpatient setting more convenient than the standard 5-week ramp-up in the outpatient setting. As all of the patients in our study were treated at experienced academic centers with close inpatient monitoring, we do not believe that our data can be extrapolated outside of this setting. A prospective clinical trial of accelerated venetoclax ramp-up in CLL is now underway (NCT04843904) to validate the findings of our retrospective study. Medical writing support was provided by Hayley Ellis, PhD, of Fishawack Communications Ltd, part of Fishawack Health, and funded by AbbVie. Matthew S. Davids is a Scholar in Clinical Research from the Leukemia & Lymphoma Society. Jennifer L. Crombie is supported by a K12 (K12CA087723). Venetoclax (ABT-199/GDC-0199) is being developed in collaboration between AbbVie, Inc., and Genentech. AbbVie, Inc. sponsored the study, contributed to the analysis, and interpretation of the data, and participated in the writing, review, and approval of the manuscript. All authors had access to all relevant data. No honoraria or payments were made for authorship. Matthew S. Davids: Institutional research grants—Ascentage Pharma, AstraZeneca, BMS, Genentech, MEI Pharma, Novartis, Pharmacyclics, Surface Oncology, TG Therapeutics, Verastem. Consulting fees—AbbVie, Adaptive Biotechnologies, Ascentage Pharma, AstraZeneca, BeiGene, BMS, Celgene, Eli Lilly, Genentech, Janssen, MEI Pharma, Merck, Takeda, TG Therapeutics, Verastem. Mazyar Shadman: Consulting, advisory boards, steering committees or data safety monitoring committees—AbbVie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Verastem, ADC Therapeutics, BeiGene, Cellectar, Bristol-Myers Squibb, Morphosys, Merck, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, and Atara Biotherapeutics. Research funding—Mustang Bio, Celgene, Bristol-Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, BeiGene, AstraZeneca, Sunesis. Sameer A. Parikh: Research funding (provided to institution) from Pharmacyclics, Janssen, AstraZeneca, TG Therapeutics, Merck, AbbVie, and Ascentage Pharma for clinical studies in which Sameer A. Parikh is a principal investigator. Advisory board meetings—Pharmacyclics, AstraZeneca, Genentech, GlaxoSmithKline, Innate Pharma, Adaptive Biotechnologies, and AbbVie (he was not personally compensated for his participation). Chaitra Ujjani: Research—AbbVie, AstraZeneca, Gilead/Kite, Loxo/Eli Lilly, PYC. Consulting—AbbVie, AstraZeneca, Atara, Beigene, Epizyme, Genentech, Gilead/Kite, Incyte, Jannsen, MorphoSys, PYC, TG Therapeutics, Verastem. Jennifer Crombie: Research funding (provided to institution)—AbbVie, Bayer, Merck, Roche. Consulting—Incyte, Karyopharm. Dingfeng Jiang, Cynthia Llamas, Dai Feng: Employees—AbbVie, may hold stock or options. Nicole Lamanna: Consulting and advisory boards—AbbVie, AstraZeneca, BeiGene, Celgene, Genentech, Gilead, Janssen, Pharmacyclics. Research funding (to institution)—AbbVie, AstraZeneca, BeiGene, Genentech, Juno, MingSight, Oncternal, TG Therapeutics, Verastem. All authors had access to relevant data, and participated in the writing, review, and approval of the manuscript. Matthew S. Davids, Mazyar Shadman, Sameer A. Parikh, Chaitra Ujjani, Jennifer L. Crombie, Dingfeng Jiang, Cynthia Llamas, Dai Feng, Nicole Lamanna—study concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; statistical analysis; obtained funding; administrative, technical, or material support; study supervision. AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual, and trial-level data (analysis data sets), as well as other information (eg, protocols and Clinical Study Reports), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications. This clinical trial data can be requested by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). Data requests can be submitted at any time and the data will be accessible for 12 months, with possible extensions considered. For more information on the process, or to submit a request, visit the following link: https://www.abbvie.com/our-science/clinical-trials/clinical-trials-data-and-information-sharing/data-and-information-sharing-with-qualified-researchers.html. Appendix S1: Supporting information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.