Reduction of Tumor Lysis Syndrome Risk after Debulking with Obinutuzumab in Patients Treated with Venetoclax–Obinutuzumab in the Randomized Phase 3 CRISTALLO Trial

Background: Severe events of tumor lysis syndrome (TLS) were observed in early studies of Venetoclax (Ven) in chronic lymphocytic leukemia (CLL), leading to the implementation of a 5-week ramp-up period to mitigate TLS. When combined with obinutuzumab (O) in the front-line setting, Ven ramp-up is initiated after 3 doses of O, potentially debulking CLL. The rate of TLS events associated with Ven alone is 2%. However, occurrences of TLS associated with Ven after 3 doses of O are extremely rare in clinical trials. Baseline TLS risk stratification and prophylactic measures are also used to mitigate TLS, and patients (pts) are monitored during Ven treatment (tx) to identify TLS early. Pts at high-risk for TLS should be hospitalized for the initial Ven dose and at the first dose increase during Ven ramp-up. This analysis assessed TLS risk reduction in high-risk pts prior to Ven initiation and incidence of TLS in pts receiving VenO in the CRISTALLO phase III trial (NCT04285567).

Methods: CRISTALLO is an open-label, randomized trial, comparing VenO vs fludarabine, cyclophosphamide, and rituximab (FCR)/bendamustine–rituximab (BR) in pts with previously untreated CLL, cumulative illness rating scale score ≤6, creatinine clearance ≥70 mL/min, and without del(17p) or TP53 mutations. Pts were randomized 1:1 to receive VenO (6 cycles of VenO plus 6 cycles of Ven) or FCR/BR (6 cycles). Intravenous O was administered for 6 cycles on Day (D) 1/2 (split dose), 8, and 15 of Cycle (C) 1, and on D1 of the remaining cycles. Oral Ven was administered once-daily for a 5-week ramp-up period, starting on C1D22 at 20 mg for 7 days, increasing to 50 mg and up to 400 mg during C2, continuing at 400 mg from C3D1 onwards. Primary endpoint was undetectable minimal residual disease (uMRD) rate in peripheral blood (PB) at Month 15. Secondary endpoints included progression-free survival, uMRD rates in PB and bone marrow at end of tx, and TLS risk reduction in the VenO arm. Pts were stratified into risk categories based on tumor burden (assessed by computed tomography [CT] scan and blood count): low (all lymph nodes [LN] <5 cm and absolute lymphocyte count [ALC] <25x10⁹/L); medium (any LN 5–10 cm or ALC ≥25x10⁹/L); and high (any LN ≥10 cm or any LN ≥5 cm and ALC ≥25x10⁹/L). TLS risk was reassessed after 3 doses of O debulking (prior to Ven initiation); high-risk pts at baseline with any LN ≥10 cm had a repeat CT scan. Risk reduction was defined as reduced risk at reassessment compared with baseline. TLS incidence was assessed using the Howard criteria (laboratory [lab] TLS: 2 post-dosing metabolic abnormalities within 24 hours; clinical TLS: lab TLS with clinical symptoms within 24 hours).

Results: At data cutoff (March 19, 2024), 80 pts received VenO and 86 pts received FCR/BR. At baseline, 11 (13.8%), 50 (62.5%), and 19 (23.8%) pts in the VenO arm were low-, medium-, and high-risk for TLS, respectively. Following O debulking, 51 (63.8%), 22 (27.5%), and 0 (0%) pts were low-, medium-, and high-risk, respectively, with 7 (8.8%) pts not undergoing risk reassessment. Risk reduction was achieved in 57 (71.3%) pts after 3 doses of O, prior to Ven initiation. Of the 19 high-risk pts at baseline, 2 (10.5%) withdrew from the study prior to Ven initiation; the remaining 17 (89.5%) pts had reduced TLS risk (16 were reduced to medium-risk, 1 was reduced to low-risk) before initiating Ven. Of the 17 high-risk pts who were reassessed for TLS risk and initiated Ven, the number of potential mandatory hospitalizations for TLS monitoring during Ven ramp-up was reduced from 34 to 0.

Of the 162 safety-evaluable pts, 77 received VenO. Lab TLS occurred in 8 (10.4%) pts in the VenO arm; none experienced clinical TLS. All TLS events occurred within the first week of O and none during Ven ramp-up. Of the 8 pts with TLS in the VenO arm, 6 were medium-risk and 2 were high-risk at baseline. Five pts in the VenO arm received tx for TLS, 2 pts had dose modification/interruption, and no pts withdrew from tx due to TLS. No events were fatal and all resolved (median time to resolution: 2 days [range: 1–4]).

Conclusions: O debulking led to TLS risk reduction in the majority of pts in the VenO arm, and no pts were high-risk at Ven initiation, allowing pts to be easily managed during Ven tx. Lab TLS occurred in 10% of pts which was comparable to previous reports. O debulking appeared to be a safe and effective strategy for reducing TLS risk in previously untreated pts with CLL; however, physicians should remain vigilant when prescribing VenO.