A Phase I Study to Evaluate the Safety and Tolerability of Gemtuzumab Ozogamicin and Midostaurin When Used in Combination with Standard Cytarabine and Daunorubicin Induction for Newly Diagnosed FLT3-Mutated Acute Myeloid Leukemia

Introduction: Approximately 25-30% of acute myeloid leukemia (AML) have FLT3 mutations, including internal tandem duplication (ITD) and tyrosine kinase domain mutations (TKD). Standard treatment for newly diagnosed (ND) FLT3 AML includes induction therapy with cytarabine and anthracycline and a FLT3 inhibitor such as midostaurin or quizartinib, followed by consolidation therapy +/- allogenic stem cell transplant (HSCT).

FLT3 AML cells have significantly higher CD33 expression at diagnosis compared to non-FLT3 AML. Gemtuzumab ozogamicin (GO) is a humanized anti-CD33 antibody conjugated to calicheamicin, a DNA damaging agent; currently approved for ND and relapsed/refractory CD33+ AML. Several studies have illustrated a benefit to adding GO to induction therapy, in patients with good and intermediate risk cytogenetics. Given the increased level of CD33 expression on blasts in FLT3 positive AML, we conducted an investigator-initiated study to assess safety and efficacy of addition of GO to induction therapy in ND FLT3 AML in combination with induction therapy with FLT3 inhibitor.

Methods: In this phase I, open-label study (NCT03900949), eligible patients were 18 years or older with ND, CD33+, FLT3 AML (ITD or TKD). ECOG performance status 2 or less with adequate organ function was required. Patients with APL, isolated myeloid sarcoma, or CNS involvement were not eligible. Prior hydroxyurea was allowed; other systemic anti-AML therapies were prohibited. Four dose levels (DL) were assessed. Intravenous (IV) cytarabine (100mg/m2, days 1-7) and oral midostaurin (50mg bid, days 8-21) were the same across all DL. Daunorubicin (60mg/m2, days 1-3) was administered at DL1-3 , 90mg/m2, days 1-3 at DL4. GO was dosed at 3mg/m2 IV with increasing frequency as follows DL1: day 1; DL2: days 1 and 4; and DL3 and DL4: days 1, 4, and 7. Individual GO doses were limited to one 4.5 mg vial. Bayesian toxicity probability interval design “keyboard design” was used to guide dose escalations. Three patients were treated on DL1, 9 on DL 2, 6 on DL3, and 3 patients on DL4. Toxicities were summarized as the percent of patients who experienced the specific adverse event at the maximum grade. Overall survival (OS) was calculated from the start of treatment to death, censoring those alive at the last contact and analyzed using the Kaplan-Meier method.

The study completed accrual in July 2024. The primary outcome was presence of dose-limiting toxicity (DLTs) during induction therapy. All patients were included in the efficacy and safety population for study analyses. Patients will be followed for up to two years after ending study treatment. Exploratory objectives included CD33 SNP and expression as it correlates to response and clinical outcomes.

Results: Twenty-one patients with ND AML were enrolled. Median age was 51 years (range 20-73). Following induction therapy, 16 (76%) patients achieved a composite CR (CR+CRi), 2 (9.5%) had stable disease, 2 (9.5%) did not undergo disease assessments, and 1 patient has completed induction pending count recovery marrow .

There were no DLTs observed on DL1 or DL4. One patient on DL2 experienced a hematologic DLT (inadequate count recovery by day 42 in the absence of disease). Two of 6 patients on DL3 experienced DLTs of GI toxicity resulting in less than 50% of the planned midostaurin administered. The most frequent toxicities overall were nausea (79%) and diarrhea (74%); the most frequent grade 3+ toxicities were white blood cell decreased (58%), and platelet count decreased (53%). DLT review of the final cohort will be available at time of presentation.

Eleven patients received HSCT (52%), 7 (33%) have not, and 3 (14%) are being considered for transplant. Ten patients remain either on treatment or in study follow-up. Eleven patients have either completed study follow-up or died. OS was 79% at 6 months, 65% at 1 year, 52% at 1.5 years, and 39% at 2 years. Median survival follow-up was 367 days.

Conclusions: The addition of CD33+ directed therapy, Gemtuzumab ozogamicin, to a standard of care cytarabine, anthracycline, and midostaurin induction regimen was found to be well-tolerated in ND, CD33+, FLT3-mutated AML patients, with toxicities similar to standard intensive induction therapy. The use of GO was tolerable as all DLTs were related to midostaurin and similar to those seen in standard of care treatment. The exploratory analyses are ongoing and will be reported at the main meeting.