Introduction: Inotuzumab ozogamicin (INO), an anti-CD22 antibody-drug conjugate, can induce a complete remission (CR) in >80% of R/R ALL patients (pts), but remissions are not durable. BCL-2 inhibitors, such as venetoclax (VEN), induce apoptosis in malignant lymphoblasts (Del Gaizo Moore et al. Blood 2007) and are synergistic with INO (Kirchhoff et al. Blood 2021). Due to distinct mechanisms of action and non-overlapping toxicities, we hypothesized that adding VEN to INO would be safe and effective.

Methods: This investigator-sponsored phase I study (NCT05016947) enrolled pts ≥18 years with CD22+ (≥20% of blasts) R/R ALL (≥5% bone marrow [BM] blasts) or lymphoblastic lymphoma (LBL, BM <5% blasts). Philadelphia chromosome-negative (Ph-) pts had received ≥1 line of therapy; Ph+ pts were ponatinib (PON)-refractory or ineligible. Key exclusions included symptomatic central nervous system (CNS) disease, prior receipt of INO or VEN, and history of sinusoidal obstructive syndrome (SOS) or other liver disease.

VEN was escalated in a 3+3 design with 2 dose levels (DL): 200 mg (DL1) and 400 mg (DL2). Dose-limiting toxicity (DLT) criteria during Induction Cycle 1 (C1) included any grade SOS or liver toxicity, failure of hematologic recovery (ANC ≤500 or plt ≤25 K/mL) by day 42 in responding pts, or any treatment-related non-hematologic grade ≥3 toxicity. Secondary outcomes included depth of response, disease-free survival (DFS), and overall survival (OS).

Pts had peripheral blood blast count ≤25 K/μL before treatment initiation. VEN Lead-in was 3 days (DL1: 100/200/200 mg, DL2: 100/200/400 mg). Induction consisted of one or two 28-day cycles of VEN (D1-21) added to INO. Pts who achieved CR proceeded to Consolidation with VEN (D1-21) and INO for up to 6 total cycles. Dexamethasone (10 mg/m2) was given during Lead-In and D1-4 of C1 Induction. Pts were recommended to receive CNS prophylaxis with intrathecal chemotherapy. Pts proceeded to stem cell transplant (SCT), or other consolidation, per treating provider.

Results: We enrolled 23 pts: 3 at DL1, 6 at DL2, and with no recorded DLTs during dose escalation (Luskin Blood 2023;142:1509), 14 additional pts were treated at the RP2D (DL2: VEN 400 mg x 21 days). The median age was 39 years (range 24-74). Pts were 47.8% (n=11) female, 60.9% (n=14) non-Hispanic White, 26.1% (n=6) Hispanic, 8.7% (n=2) non-Hispanic Black, and 4.3% (n=1) Asian. Four pts (17.4%) were Ph+ (3 PON-refractory, 1 PON-intolerant) and 34.8% (n=8) had LBL (7 Ph-, 1 Ph+). Pts had received 1 (n=11, 47.8%), 2 (n=10, 43.5%), or 3 (n=2, 8.7%) prior treatment lines; 5 (21.7%) had a prior SCT.

Pts received 1 (17.4%, n=4), 2 (65.2%, n=15), or ≥3 (17.4%, n=4) cycles of VEN plus INO (median n=2, range 1 – 5). The median time to hematologic recovery after C1D1 and C2D1 was 26 (range 19 – 46) and 21 (range 20 – 35) days, respectively. There was no early mortality. Grade ≥3 adverse events at least possibly related to treatment were neutropenia (n=5, 21.7%), thrombocytopenia (n=5, 21.7%), anemia (n=2, 8.7%), febrile neutropenia (n=2, 8.7%), hepatobiliary disorder (n=1, 4.3%), leukocytosis (n=1, 4.3%), and failure to thrive (n=1, 4.3%). There were 4 cases of SOS after protocol treatment (3 after SCT, of which 1 case was fatal).

One LBL pt was retrospectively deemed to have enrolled without active disease and was not analyzed for response. The CR rate was 95.5% (21/22), most after C1 (19/22, 86.4%). CR was achieved in 100% (15/15) of ALL patients and 85.7% (6/7) of LBL pts; the LBL pt who did not remit had mixed B/T LBL. Measurable residual disease (MRD) negativity was achieved by flow cytometry (≤10-4) and by Clonoseq (≤10-6) in 88.9% (16/18; 15 after C1) and 73.7% (14/19; 13 by C2) of pts, respectively. BH3 profiling showed that pts MRD- by C2 had lower pre-treatment mitochondrial apoptotic priming.

Of the 21 CR patients, 1 pt (KMT2Ar) progressed during C2, and the remaining 20 pts (95.2%) were consolidated with blinatumomab (n=9, 42.9%), SCT (n=14, 66.7%, 6 after blinatumomab), DLI (n=1), XRT (n=1), or POMP (n=1). Median follow-up time was 19.6 months (95% CI: 11.2-25.0). To date, 33.3% (n=7) have relapsed (median DFS 36.1 months, 95% CI 10.3-NA), and 23.8% (n=5) have died (n=4 from ALL, n=1 from SOS; median OS not reached).

Conclusion: VEN can be safely added to INO in pts with R/R CD22+ ALL/LBL including Ph+ ALL, with a very high and durable rate of MRD- CR. VEN plus INO is thus a promising regimen, including in those with LBL.

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2025
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