Venetoclax and navitoclax for R/R ALL and lymphoblastic lymphoma

Despite the development of novel therapeutic and chemotherapeutic agents, a great percentage of patients with relapsed or refractory (R/R) acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL) respond badly to treatment and have poor prognosis.¹ Effective anti-leukemic activity in ALL xenografts seems to be achieved when venetoclax, a highly selective B-cell lymphoma-2 (BCL-2) inhibitor, is combined with the anti-BCL-2 and anti-BCL-extra-large (BCL-X_L) inhibitor, navitoclax.² These findings indicate that a dual BCL-2 and BCL-X_L inhibition might provide a new treatment combination for patients with R/R ALL or LL.

During the 2020 European Hematology Association (EHA) Annual Congress, our ALL Hub Steering Committee member, Elias Jabbour, presented results from a phase I trial (NCT03181126) investigating the combination of venetoclax and navitoclax for pediatric and adult R/R ALL and LL. We hereby provide a summary of these results.

Study design

• Multicenter, open-label, dose-escalation, phase I clinical trial
• Eligible patients ≥ 4 years old with measurable R/R ALL or radiographically confirmed R/R LL
  • Refractoriness was defined as persistent disease after at least two courses of chemotherapy
• The study design and dosing schedules are depicted below in Figure 1. Briefly, patients received 400 mg of venetoclax or a weight-adjusted equivalent (200 mg) once daily, and oral navitoclax daily at three dose levels (25, 50, 100 mg) for patients ≥ 45kg or two dose levels (25, 50 mg) for patients < 45 kg
  • Patients could receive chemotherapy with vincristine, dexamethasone, and PEG-asparaginase at the investigator’s discretion
• Primary endpoint was the safety and pharmacokinetics of venetoclax and navitoclax
• Secondary endpoints included complete response (CR) rate, progression-free survival, overall survival, and the proportion of patients proceeding to stem cell transplantation or chimeric antigen receptor (CAR) T-cell therapy

Figure 1. Study design of the phase I trial investigating venetoclax plus navitoclax in R/R ALL and LL²

Results

Patient characteristics

• Patient baseline characteristics are shown below in Table 1. In general, patients were heavily pretreated with many having failed prior cellular and immune therapies like CAR T-cell therapy, blinatumomab or inotuzumab ozogamicin (anti-CD22)

Table 1. Patient baseline characteristics²

ALL, acute lymphoblastic leukemia; BM, bone marrow; CAR T, chimeric antigen receptor T-cell therapy; ECOG PS, Eastern Cooperative Oncology Group Performance Status; LL, lymphoblastic lymphoma; SCT, stem cell transplantation
Baseline characteristic	All patients (N = 47)
Median age (range), years Pediatric (< 18 years old)	29 (6–72) 26%
Males, %	62
Type of primary cancer, % B-ALL T-ALL LL	53 40 6
ECOG PS, % 1 2	72 14
Baseline BM blasts Median (range) ALL patients with < 5%	52% (0–99) 11%
Median number of prior lines (range) Had prior blinatumomab, % Had prior inotuzumab ozogamicin, % Had prior CAR T, % Had prior SCT, %	4 (1–10) 28 15   13 28
Median time since last therapy, months (range)	2 (0.1–21)
Grade 3/4 thrombocytopenia, %	43

Safety

• Ten fatal treatment-emergent adverse events (TEAEs) were reported but only one was considered as related to the drug combination (intestinal ischemia)
• Of the 30 patients who died, 87% had a relapse
• The most common Grade 3–4 TEAEs reported with venetoclax and navitoclax are shown below in Table 2
• In total, 13% of patients discontinued the venetoclax/navitoclax combination due to treatment related toxicity
• Two patients developed tumor lysis syndrome after ≥ 1 dose of venetoclax which was managed and resolved

Table 2. Most common Grade 3–4 TEAEs²

ALT, alanine aminotransferase; TEAEs, treatment-emergent adverse events
TEAEs (N = 47)	Grade 3–4 (≥ 15% of patients), %		Possible association to venetoclax/navitoclax, %
Any	98		74
Hematological
Febrile neutropenia	47		19
Neutropenia	28		21
Anemia	17		9
Thrombocytopenia	26		21
Non-hematological
Hypokalemia		23	2
ALT increase		19	4
Sepsis		19	4
Blood bilirubin increase		15	4
Pneumonia		15	2

• With regards to dose-limiting toxicities (DLTs) induced by navitoclax, one DLT was reported in 16 patients at Dose Level 1 (25 mg), two DLTs in 11 patients at Dose Level 2 (25 mg, 50 mg), and five DLTs in 20 patients in Dose Level 3
  • Thus, the recommended phase II dose for navitoclax in combination with the 400 mg of venetoclax was established at 50 mg for patients ≥ 45 kg and at 25 mg for patients < 45kg
• Since the main DLT observed across all navitoclax dose levels was delayed count recovery, a safety expansion cohort (n = 22) is currently evaluating a 21-day dosing schedule instead of 28-day, to help with blood count recovery

Efficacy

• With regards to preliminary efficacy data, these are very promising and are shown below in Table 3
• CR rates were ≥ 50% across patient subgroups, including those R/R to:
  • Blinatumomab (62%)
  • Inotuzumab ozogamicin (57%)
  • SCT (63%)
  • CAR T-cell therapy (50%)
• Following B-ALL subtype analysis (21 patients classified into 11 subgroups), the authors reported that responses were across all subtypes in patients with B-ALL, while T-ALL subtype analysis is ongoing
• Treatment was discontinued in 46 patients: Most patients either relapsed (n = 20) or proceeded to SCT or CAR T-cell therapy (n = 13)
• ALL or LL patient cell samples were assessed for BCL-2 and BCL-X_L dependency via BH3 profiling
  • B-ALL patients at baseline had more diverse BCL-2 and BCL-X_L dependency when compared to T-ALL patients
  • In T-ALL patients, there was a time-dependent shift towards a BCL-X_L or a mix of BCL-2/ BCL-X_L dependency

Table 3. Preliminary efficacy of navitoclax plus venetoclax in R/R ALL and LL patients²

ALL, acute lymphoblastic leukemia; BM, bone marrow; CAR T, chimeric antigen receptor T-cell therapy; CR, complete response; CRi, CR with incomplete count recovery; CRp, CR with incomplete platelet recovery; DoR, duration of response; MRD, measurable residual disease; LL, lymphoblastic lymphoma; NE, not evaluable; NR, not reached; OS, overall survival; PR, partial response; SCT, stem cell transplantation
Response	B-ALL (n = 25)	T-ALL (n = 19)	LL (n = 3)	All patients (N = 47)
CR, CRi, CRp, % ALL patients with ≥ 5% BM blasts, % ALL patients with morphologic CR at baseline, %	64 65 NE	53 50 75	67 — —	60 59 75
PR, %	12	0	0	6
MRD-negative CR, CRi, CRp in ALL, %	56	60	—	58
Median DoR, (95% CI), months	9.1 (1.4–14.6)	4.2 (0.8–12.3)	NE (NE–NE)	4.2 (2.3–11.5)
Median OS (95% CI), months	9.7 (4.0–15.7)	6.6 (3.2–12.5)	NR (2.0–NE)	7.8 (4.0–12.5)
Proceeded to SCT or CAR T, %	32	16	67	28

Conclusion

The results of this phase I trial indicate that the combination of venetoclax and low-dose navitoclax is well tolerated in patients with R/R ALL or LL, at the recommended phase II dose of 400 mg of venetoclax and 25/50 mg of navitoclax (weight-dependent). Prolonged cytopenia is the most relevant safety concern with this treatment combination. The preliminary efficacy data are very promising especially due to the heavily pretreated nature of this patient population with high rates of MRD negative complete remissions. A clinical follow-up with biomarker analysis, as well as a safety expansion cohort with 21-day treatment cycles to manage the observed prolonged blood count recoveries, are currently ongoing.