First-in-human phase I trial combining radiopharmaceutical therapy (RPT) using a 90y-anti-CD25 monoclonal antibody (Mab) with total marrow and lymphoid irradiation (TMLI) in relapsed or refractory (R/R) acute leukemia Free

Purpose: Patients with R/R acute leukemia who undergo allogeneic hematopoietic cell transplantation (alloHCT) have a dismal prognosis. A phase 2 randomized trial in AML demonstrated that a higher total body irradiation (TBI) dose decreased relapse rates, but increased toxicities and non-relapse mortality (NRM) rate, resulting in no change in overall survival [Clift et al. Blood 1998]. To improve outcomes, innovative conditioning using organ sparing targeted radiotherapy, such as radiolabeled Mab and TMLI, are needed to dose escalate with acceptable toxicities, including in older patients who cannot tolerate myeloablative TBI. In older patients with R/R acute leukemia, conditioning with TMLI 12 Gy, fludarabine (flu), and melphalan (mel) resulted in a 5-year overall survival (OS) and event-free survival (EFS) of 42% and 41%, respectively [Jensen et al. BBMT 2018]. In this trial (NCT05139004) we evaluated adding anti-CD25 Mab radiolabeled with ⁹⁰Y (a β-emitting therapy radionuclide) to TMLI 12 Gy, flu and mel in this same population.

Methods: The primary objective of this 3+3 design phase I trial was to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of ⁹⁰Y-anti-CD25 Mab (Basiliximab) (Day -15) combined with 12 Gy TMLI (1.5 Gy twice daily, days -8 to -5), flu (30 mg/m²/d days -5 to -2), and mel (100 mg/m², day -2) in patients > 60 years old (or in younger patients with a HCT-comorbidity index > 2) with R/R acute leukemia scheduled for alloHCT with a matched donor. Planned dose levels of ⁹⁰Y-anti-CD25 Mab were 0.3, 0.4, and 0.5 mCi/kg (10 mg Mab). ¹¹¹In-anti-CD25 Mab was co-infused followed by serial nuclear scans to assess dosimetry and pharmacokinetics using a 2-compartment model. Tacrolimus and sirolimus were started on day -1 and tapered at day 90 in the absence of GVHD.

Results: 7 patients with R/R AML were treated at the dose levels of 0.3 mCi/kg (n=3) and 0.4 mCi/kg (n=4). Median age was 60 years old (31-74). Median number of prior regimens were 3 (range 1-5). Per ELN 2022 criteria, 2 patients were intermediate risk and 5 adverse risk, including 2 TP53. All patients had detectable bone marrow (BM) blasts (10-36%) and 5 patients had detectable circulating blasts (0.1-1.8 K/uL; 9-91%). ¹¹¹In-anti-CD25 Mab scans demonstrated uptake in bone marrow and spleen out to 144 hours. Blood clearance kinetics demonstrated a T1/2α = 0.9 +/- 0.8 hours; T1/2β = 49.1 h +/- 31.2 hours (mean +/- SD). All patients completed TMLI 12 Gy, flu and mel. Mean doses from combined RPT and TMLI to lungs were 6.6 Gy, kidneys 8.5 Gy, liver 10.8 Gy and lower GI 6.6 Gy.

All patients achieved complete remission (CR n=5/ CRi n=2) on day +30 bone marrow biopsies. All 7 patients reached ANC > 500/uL (median of 13 days, range 12-20) and 6 of 7 patients achieved platelets > 20 K/uL (median of 27 days, range 20-37). Regimen-related toxicities were grade 3 nausea (n=1), grade 3 diarrhea (n=2), and grade 3 anorexia (n=3). Grade 3-4 acute GVHD was observed in 3 of 7 patients and moderate to severe chronic GVHD was in 2 of 3 evaluable patients. At 0.3 mCi/kg, one patient remained in CR for 923 days but died from complications of thrombotic microangiopathy. One remained in CR for 442 days but died of an unrelated cerebral vascular accident and one died from disease at 10 months. At 0.4 mCi/kg, two patients expired from GVHD at 54 and 177 days; and two expired from infection at 64 and 110 days. Although no dose-limiting toxicities (DLT) were observed, there was no further dose escalation due to non-relapse mortality (NRM) developing in all 4 patients within 6 months at the 0.4 mCi/kg dose level.

Conclusion:⁹⁰Y-anti-CD25 Mab at 0.3 mCi/kg combined with 12 Gy TMLI / flu / mel appears feasible with no DLTs observed. All patients achieved CR/CRi. Scans demonstrated that ⁹⁰Y-anti-CD25 Mab targeted radiation dose to bone marrow and spleen. Combined radiation doses from ⁹⁰Y-anti-CD25 Mab and TMLI to critical organs were less compared to conventional 12 Gy TBI. Combining RPT and TMLI warrants further evaluation as a way to intensify dose to R/R acute leukemia. A successor trial evaluating ²²⁵Ac-anti-CD38 combined with TMLI/ flu/ mel in R/R AML and ALL in patients undergoing alloHCT has been initiated (NCT06287944). CD38 is more frequently expressed in AML and ALL than CD25. ²²⁵Ac is a more potent, densely ionizing, high linear energy transfer α-emitter which could help to increase leukemia radiation response and reduce toxicities.