First-in-Human Phase I Trial Combining Biologically Guided Radioimmunotherapy (RIT) Using a 90Y-Anti-CD25 Monoclonal Antibody (Mab) with CT-guided Total Marrow and Lymphoid Irradiation (TMLI) in Relapsed and Refractory (R/R) Acute Leukemia

Abstract

Patients with R/R acute leukemia after allogeneic hematopoietic cell transplant (alloHCT) have a dismal prognosis with 3-year survival rates of < 20%. To improve outcomes, innovative targeted forms of organ sparing radiotherapy, such as tumor-specific RIT and TMLI, are needed to dose escalate with acceptable toxicities, especially in patients ≥ age 60 years who cannot tolerate total body irradiation (TBI) / myeloablative regimens and who have a poor prognosis. CD25 is an ideal RIT target given its expression in acute leukemias, association with poor prognosis, and expression by leukemia stem cells. In this phase I trial (NCT05139004) we hypothesized that combining dose escalated 90Y-anti-CD25 RIT with fixed dose TMLI 12 Gy, fludarabine (flu), and melphalan (mel) in patients with R/R disease is safe and associated with acceptable toxicities. The primary objective of this trial is to determine the maximum tolerated dose and recommended phase 2 dose of 90Y-anti-CD25 Mab (Day -15) with 12 Gy TMLI (1.5 Gy twice a day, 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 with a HCT-comorbidity index ≥ 2 and with R/R AML, ALL or myelodysplastic syndrome (MDS) scheduled to undergo alloHCT from a matched donor. TMLI mean organ dose constraints for kidney, lung and liver were 4 Gy. Planned dose levels of 90Y-anti-CD25 were 0.3, 0.4, and 0.5 mCi/kg. 111In-anti-CD25 (5 mCi) was co-infused followed by serial nuclear scans to assess dosimetry and biodistribution. To date 5 patients (ages 31-74) with R/R AML have been treated. Marrow and circulating blasts ranged from 10-36% and 9-44%, respectively. For the 3 patients at 0.3 mCi/kg, follow-up ranged from 89-191+ days. 90Y/111In-anti-CD25 nuclear scans demonstrated persistent uptake in bone out to 144 hours, which was associated with a decline in circulating blasts. After combined RIT and TMLI, mean doses (Gy) to lungs ranged from 5.7-6.5, to kidneys from 7.5-8.2 and to liver from 7.2-11.6. No dose-limiting toxicities (DLT) were observed. All 3 patients achieved CR on day +30 bone marrow biopsies and 2 remained in CR on day +90 biopsies. Two patients have recently been treated at the 0.4 mCi/kg dose level. The results of patients treated at the higher dose levels will be provided. Dose escalation by adding 90Y-anti-CD25 RIT at 0.3 mCi/kg to 12 Gy TMLI was safe, including in older patients, with no dose-limiting toxicities, mean critical organ doses lower than conventional myeloablative TBI, and encouraging response rates. The toxicity profile and dose estimates at 0.3 mCi/kg predict that the planned higher dose levels will also be feasible with acceptable toxicities. RIT and TMLI are complementary and when combined address the limitations of each modality. Combining these targeted therapies may be a superior strategy to intensify dose to leukemia compared to dose escalation of either modality alone.