A Phase I/II Study of Mini-Hyper-CVD, Venetoclax and Navitoclax in Patients with Relapsed/Refractory Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia

Background: While the outcomes of patients (pts) with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) have improved in the past decade, there are still few effective options for pts treated in later salvage. Both Bcl-2 and Bcl-xL dependence have been reported in ALL, with Bcl-xL upregulation being a recognized driver of resistance to venetoclax-based regimens. Retrospective and prospective studies have shown encouraging clinical activity with low-intensity chemotherapy + venetoclax in R/R ALL, although the durability of these responses is modest. Navitoclax is a dual Bcl-2/Bcl-xL inhibitor that may overcome Bcl-xL-mediated resistance in ALL.

Methods: In this phase I/II study, pts ≥18 years of age with R/R Ph- ALL or lymphoblastic lymphoma (LBL) after any number of prior therapies were eligible. Pts received the mini-hyper-CVD regimen for up to 8 cycles. In cycle 1, pts received venetoclax 200 mg or 400 mg (determined by the dose level in phase I) and navitoclax 50 mg on days 1-21. A bone marrow was performed on day 14 and both drugs were held if blasts <5% or aplastic. In cycles 2 to 8, pts received venetoclax at the assigned dose and navitoclax 50 mg on days 1-7 once in remission (or for up to 21 days if not yet in remission). Pts with CD20+ ALL also received up to 8 doses of rituximab. Pts with T-cell ALL also received additional cycles of nelarabine and PEG-asparaginase, given in cycles 4N and 5N (intercalated after cycle 4 and cycle 5). Nelarabine 650 mg/m2 IV was given on days 1 to 5, and PEG-asparaginase (1500 IU/m2 [capped at 3750 IU] in pts <60 years and 1000 IU/m2 [capped at 2000 IU] in pts ≥60 years) was given on day 5.

Results: Between 10/2021 to 11/2023, 22 pts were treated with the mini-hyper-CVD + venetoclax + navitoclax regimen. The median age was 36 (range, 18-70 years), and 7 pts (32%) were female. 12 pts (55%) had B-cell ALL and 10 (45%) had T-cell ALL/LBL, 3 of whom had ETP ALL. 8 pts (36%) were treated in first salvage, 3 (14%) in second salvage, and 11 (50%) in third salvage or later. Among the 12 pts with B-cell ALL, all had received prior blinatumomab and 9 (75%) had received prior inotuzumab ozogamicin; among the 10 pts with T-cell ALL/LBL, 5 (50%) had received prior nelarabine. 6 pts (27%) had prior allogeneic stem cell transplant (ASCT) and 10 (45%) had prior CAR T-cell therapy.

The CR/CRi rate was 50% (CR in 45%; CRi in 5%); an additional 1 pt (5%) achieved PR. The CR/CRi rate in B-cell ALL and T-cell ALL/LBL were 4/12 (33%) and 7/10 (70%), respectively, and for salvage 1 and salvage 2+ were 4/8 (50%) and 7/14 (50%), respectively. All 3 pts with ETP ALL responded (all CR). Among the 11 responses, 6 (55%) were after cycle 1, 4 (36%) after cycle 2, and 1 (9%) after cycle 3. Among evaluable pts, 2/10 (20%) achieved MRD negativity by flow cytometry after cycle 1, and 5/11 (45%) at any time.

The median duration of follow-up is 17.9 months. At last follow-up, 5 pts (23% overall; 45% of responders) underwent ASCT, 3 pts (14%) relapsed in the absence of ASCT, 1 (5%) died in remission (unknown causes), and 2 (9%) are in ongoing remission without ASCT. The median OS is 8.5 months, and the 1-year OS is 34%; the median RFS is 8.3 months, and the 1-year RFS is 31%. Pts treated in first salvage had better outcomes than those treated in salvage 2+ (median OS: 10.3 vs. 7.5 months; 1-year OS 47% vs. 26%, respectively; P=0.11).

No DLTs were observed with either the 200mg or 400mg doses of venetoclax, and venetoclax 400mg daily was chosen as the RP2D. No pts discontinued venetoclax or navitoclax due to related adverse events. The most common grade 3+ adverse events were infections and febrile neutropenia, observed in 13 (59%) and 7 (32%) pts, respectively. There were 3 on-study deaths (2 from infection in pts with refractory ALL and 1 due to unknown causes). The 30-day and 60-day mortality rates were 0% and 9%, respectively. The 2 early deaths occurred in pts in salvage 4 and 6, respectively.

Conclusion: Mini-hyper-CVD + venetoclax + navitoclax could be delivered safely and achieved a CR/CRi rate of 50% and median OS of 8.5 months in pts with heavily pretreated R/R Ph- ALL (50% in salvage 3+). Notably, all 3 pts with R/R ETP ALL achieved CR. While response rate and survival appear better than historical expectations with chemotherapy alone in this population, these outcomes appear similar to those achieved with mini-hyper-CVD + venetoclax in a similar cohort of pts with R/R Ph- ALL (Short NJ et al Blood Adv 2023), questioning the benefit of adding a Bcl-xL inhibitor to this regimen.