Venetoclax + chemo disappoints in double-hit lymphoma trial

In patients with double-hit lymphoma (DHL), the addition of the BCL2 inhibitor venetoclax to a chemoimmunotherapeutic regimen comprising DA-EPOCH-R* led to excess treatment-related mortality compared with DA-EPOCH-R alone, according to the initial results of the phase II/III Alliance A051701 trial.

“[Our results] prompted early discontinuation of accrual and venetoclax treatment … Based on [our] data, we recommend against combining venetoclax with DA-EPOCH-R in DHL,” said Dr Jeremy Abramson from the Massachusetts General Hospital Cancer Center, Boston, Massachusetts, US, at ASH 2021.

“[DHLs, which are] high-grade B-cell lymphomas with rearrangements of MYC and BCL2 and/or BCL6, … are highly aggressive B-cell non-Hodgkin lymphomas associated with historically poor outcomes using R-CHOP**. DA-EPOCH-R has been widely adopted as initial treatment for this disease, largely based on favourable results in retrospective analyses,” continued Abramson.

Seventy-three patients (median age 66 years, 55 percent male) with newly diagnosed DHL were randomized 1:1 to receive DA-EPOCH-R with (arm 1) or without venetoclax (arm 2). Venetoclax was dosed at 600 mg daily on days 4–8 of cycle 1 and on days 1–5 of subsequent cycles, for up to six 21-day cycles. [ASH 2021, abstract 523]

Half of the arm 1 cohort ceased treatment as opposed to only 30 percent in arm 2. Compared with participants in arm 2, those in arm 1 were less likely to escalate their DA-EPOCH-R dose levels (22 percent vs 70 percent) and more likely to require dose de-escalations (36 percent vs 17 percent [–1 dose level] and 14 percent vs 7 percent [–2 dose levels]).

Arms 1 and 2 had similar rates of neutrophil count reduction (77 percent in each arm), lymphocyte count reduction (49 percent vs 50 percent), and febrile neutropenia (40 percent vs 37 percent). The number of deaths due to adverse events were greater in arm 1 vs 2 (n=6 vs 1), with sepsis being the most common cause (n=5 and 1). Other infection-related deaths in arm 1 were a case of lung infection and another case of COVID-19.

“It is important to note that … the DA-EPOCH-R regimen is literally designed to induce neutropenia,” Abramson pointed out. “The excess infection-related mortality says there is something probably at work here other than just achieving neutropenia … [As such,] DA-EPOCH-R alone warrants further investigation.”

End of treatment response by intention-to-treat showed a lower overall response rate (ORR) in arm 1 vs 2 (58 percent and 73 percent), as well as complete response rate (CRR; 50 percent and 66 percent). When limiting the analysis to response-evaluable patients only at end of treatment, ORR was higher in arm 1 vs 2 (88 percent and 79 percent), while CRRs were similar (75 percent vs 72 percent).

Progression-free survival favoured arm 2 over arm 1 at a median follow-up of 7.4 months (median, not reached [NR] vs 6.7 months; p_two-sided=0.13). Overall survival was significantly better in arm 2 vs arm 1 (median, NR vs 8.5 months; p_two-sided=0.004), with most patients remaining alive at a median follow-up of 9.2 months.

“[W]hat we observed is a cautionary tale of combining novel agents with CT … I think our study right now is really hampered by the fact that due to the excess toxicity observed, there were so many dose reductions with both venetoclax [and] the standard chemotherapeutics. [U]ltimately, patients likely received suboptimal [treatment],” explained Abramson.

“But I wouldn’t say that we can conclude that venetoclax does not have a role in DHL. Unfortunately, I think we showed that, with this design and dosing schedule and strategy, we were not able to see that due to excess toxicity,” he continued.

“Despite this, we did demonstrate that prospective trials of DHL are achievable in the cooperative group setting and this high-risk population does warrant further study. We also demonstrated that DA-EPOCH-R performed well as control arm in a prospective study and can serve as a benchmark for future trials in DHL,” said Abramson.