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Phase I results show venetoclax and navitoclax combination is tolerable and associated with responses in pediatric patients with R/R ALL and LL

Feb 9, 2021

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The prognosis is poor for pediatric patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LL); there is an unmet need for more effective therapeutic approaches to improve outcomes.

The combination of BCL-2 and BCL-XL inhibitors have shown antileukemic activity in ALL mouse models, and the BCL-2/BCL-XL inhibitor navitoclax was investigated in patients with R/R ALL. However, standard-dose navitoclax treatment has been associated with dose-limiting toxicities (DLTs), primarily thrombocytopenia, and the aim of this previous study was related to navitoclax monotherapy only.

The combination of venetoclax, a potent, oral BCL-2 inhibitor, with navitoclax was later investigated in a phase I trial in adult and pediatric patients with ALL and LL (NCT03181126), in order to evaluate whether the addition of venetoclax to low-dose navitoclax would improve efficacy in BCL-2 inhibition without the dose-limiting thrombocytopenia. Results were presented during the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition by Jeffrey E. Rubnitz.1 We are pleased to summarize these results.

Study design

  • Phase I, multicenter, open-label, dose-escalation study (Figure 1)
  • Eligibility criteria were as follows:
  • Measurable R/R ALL or radiologically confirmed LL
  • Age ≥ 4 to < 18 years
  • Body weight ≥ 20 kg
  • Adequate organ function and performance status
  • Primary endpoints were safety, including rate of DLTs and adverse events (AEs), and pharmacokinetics
  • Secondary endpoints included complete response (CR) rate, progression-free survival (PFS), overall survival (OS), and percentage of patients undergoing stem cell transplantation (SCT) or chimeric antigen receptor (CAR) T-cell therapy
  • Exploratory endpoints were minimal residual disease (MRD) and biomarkers

Figure 1. Study design1

ALL, acute lymphoblastic leukemia; BM, bone marrow; LL, lymphoblastic lymphoma; PEG, pegylated; PET, positron emission tomography.
*Body weight ≥45kg: 25, 50, 100 mg; body weight <45 kg: 25, 50 mg.

  • Study protocol was amended to allow starting chemotherapy as early as Day 1
  • Patients with ALL underwent bone marrow evaluation on Day 8 (before starting chemotherapy) and on Day 36
  • Patients with LL underwent positron emission tomography (PET) scan on Day 36
  • A 21-day dosing schedule of 400 mg venetoclax followed by a 7-day off period, plus navitoclax 50 mg (weight 45kg) or 25 mg (weight < 45 kg), was evaluated in a safety expansion cohort


  • The number patients included was 18 (dose escalation, n = 12; safety expansion, n = 6) with a median age of 10 years (range, 6–16)
  • More than half of patients (55%) had a Larnsky or Karnofsky performance status of ≥ 90
  • Most patients (72%) had B-cell ALL (Table 1)

Table 1. Pediatric patient characteristics1


N = 18

ALL, acute lymphoblastic leukemia; B-ALL, B-cell ALL; BM, bone marrow; CAR, chimeric antigen receptor; CI, confidence interval; LL, lymphoblastic lymphoma; SCT, stem cell transplantation; T-ALL, T-cell ALL; T-LL, T-cell LL.

Male sex, n (%)

10 (56)

Primary diagnosis, n (%)
              LL (T-LL)

13 (72)
3 (17)
2 (11)

Median baseline BM blasts, % (range)

69.5 (2.0–97.0)

Prior therapies, n
              Median (range)
              CAR T-cell therapy, n
              SCT, n

2 (1–6)

Median time since last therapy, months (range)

1.6 (0–174)

Median time on study, months (95% CI)

10.4 (3.6–15.2)

Median duration of venetoclax exposure, months (range)

1.4 (0–4.9)

Median duration of navitoclax exposure, months (range)

1.4 (0.2–4.8)

In the dose-escalation cohort (n = 12), six patients received 25 mg, five received 50 mg, and one received 100 mg navitoclax.



All patients experienced adverse events (AEs) of any grade, and the rate of Grade 3/4 AEs was 89%. Grade 3/4 AEs related to venetoclax or navitoclax occurred in 56% of patients each. DLTs were reported in two patients, including delayed count recovery (25 mg navitoclax) and sepsis (50 mg navitoclax). Table 2 summarizes Grade 3/4 AEs reported in ≥ 15% of patients. There were no Grade 5 treatment-emergent AEs or tumor lysis syndrome reported. Eight patients died due to disease progression.

Table 2. Grade 3/4 AEs1

AE, adverse event; ALT, alanine transaminase.

AE, %

Grade 3/4 ( 15% of patients)



Hematologic AEs

Febrile neutropenia










Nonhematologic AEs



ALT increased



Efficacy outcomes and response rates amongst different cohorts are summarized in Table 3. The rate of CR/CR with incomplete recovery (CRi)/CR without platelet recovery was 56%.

Table 3. Summary of efficacy analysis1

ALL, acute lymphoblastic leukemia; B-ALL, B-cell ALL; CI, confidence interval; CR, complete response; CRi, CR with incomplete marrow recovery; CRp, CR without platelet recovery; DOR, duration of response; LL, lymphoblastic lymphoma; MRD, minimal residual disease; NE, not evaluable; NR, not reached; OS, overall survival; PR, partial response; T-ALL, T-cell ALL.

* Among those who achieved CR/CRi/CRp


(n = 13)

(n = 3)

(n = 2)

All patients
(N = 18)

CR/CRi/CRp, %





PR, %





MRD-negativity, %*





Median time to first response, months (range)

1.0 (0.2–2.1)

1.3 (1.3–1.3)

1.2 (1.2–1.2)

1.0 (2.9–NE)

Median DOR, months (95% CI)

3.5 (0.7–10.4)



3.5 (0.7–10.4)

Median OS, months (95% CI)

11.4 (3.2–NE)

2.9 (1.2–NE)

NR (2.0–NE)

11.4 (2.9–NE)

  • Eight patients (44%) proceeded to SCT or CAR T-cell therapy, and all patients achieved CR or CRp. Most of these patients were alive at the time of last follow-up
  • OS at 1 year in all patients was about 50%

BH3 profiling and genomic analysis

  • The dependency of blasts on BCL-2, BCL-XL and MCL-1 was evaluated via BH3 profiling, showing more diversity in the B-ALL patients compared to early T-cell precursor and T-ALL patients
  • Patients with BCL-2 or BCL-XL dependency achieved responses; none of the patients showed MCL-1 dependency
  • Preliminary genomic analysis demonstrated that there was a variation of low- and high-risk subtypes among patients, and responses were observed in both risk groups
  • Amongst BCL2, BCL2L1, and MCL1, baseline gene expression was highest with MCL1, however there was no dependency on MCL1. Although small, BCL2 and BCL2L1 gene expression was slightly higher in responders versus non-responders


The study population included heavily pre-treated pediatric patients with R/R ALL or LL. The combination of venetoclax and navitoclax plus chemotherapy was well tolerated, however, delayed count recovery was still an important safety concern. Response rates were promising amongst patients. BH3 profiling and genomic analysis are currently ongoing. Biomarker results suggests the venetoclax and navitoclax combination may be a valid option to target BCL-2 and BCL-XL.

The recommended phase II dose is 400 mg venetoclax with 25 mg navitoclax for patients weighing < 45 kg, or 50 mg navitoclax for patients weighing ≥ 45 kg, and preparations for this trial are currently ongoing.

  1. Rubnitz JE, Alexander TB, Laetsch TW, et al. Venetoclax and navitoclax in pediatric patients with acute lymphoblastic leukemia and lymphoblastic lymphoma. Oral abstract #466. 62nd ASH Annual Meeting and Exposition; Dec 6, 2020; Virtual.


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