A multicenter, retrospective study of accelerated venetoclax ramp‐up in patients with relapsed/refractory chronic lymphocytic leukemia

Le résumé fourni par la source

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

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.