209 - a and ß Emitting Radiopharmaceutical Therapy (RPT) and Total Marrow and Lymphoid Irradiation (TMLI) Conditioning in Relapsed / Refractory (R/R) AML / ALL Undergoing Allogeneic Transplant (alloHCT)
Presenter(s)
J. Y. C. Wong1, S. V. Dandapani1, M. Al Malki2, D. Yang3, B. Ball2, N. Rashid2, A. Salhotra2, V. Adhikarla4, C. Han1, D. M. Yamauchi5, E. Poku5, P. Yazaki6, J. E. Shively6, A. Wu6, S. K. Hui1, E. Smith2, G. Marcucci2, S. J. Forman2, R. Nakamura2, and A. Stein2; 1Department of Radiation Oncology, City of Hope National Medical Center, Duarte, CA, 2Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA, 3Department of Biostatistics, City of Hope National Medical Center, Duarte, CA, 4Division of Mathematical Oncology, City of Hope National Medical Center, Duarte, CA, 5Department of Diagnostic Radiology, City of Hope National Medical Center, Duarte, CA, 6Department of Immunology and Theranostics, Beckman Research Institute, City of Hope, Duarte, CA
Purpose/Objective(s):
Patients with R/R acute leukemia have limited treatment options and a dismal prognosis. Innovative conditioning using organ sparing targeted radiotherapy prior to alloHCT is needed to dose escalate with acceptable toxicities, including older patients who cannot tolerate TBI. In R/R acute leukemia patients undergoing alloHCT, TMLI 12 Gy, fludarabine (F), and melphalan (M) resulted in a promising 5-year overall survival of 42%. We evaluated through two 3+3 design phase I trials adding a or ß emitting RPT to TMLI / F / M in this population.Materials/Methods:
Trial 1 NCT05139004: Beta-emitting 90Y-anti-CD25 Basiliximab (Day -15) followed 1 week later by 12 Gy TMI (1.5 Gy twice daily, days -8 to -5), F (30 mg/m2/d days -5 to -2), and M (100 mg/m2, day -2) in patients with R/R AML scheduled for alloHCT with a matched donor. Dose levels were 0.3 and 0.4 mCi/kg. Trial 2 NCT06287944: Same study design except alpha-emitting 225Ac-anti-CD38 Daratumumab was used. Planned dose levels 20, 40 and 60 kBq/kg. For both trials TMLI target structures were bone, lymph node chains and spleen. The primary objective was to determine feasibility, toxicities, and the maximum tolerated dose (MTD).Results:
Trial 1: 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). All patients had detectable bone marrow (BM) blasts (10-36%) and 5 had detectable circulating blasts (0.1-1.8 K/uL; 9-91%). In 4 patients, RPT decreased circulating blast count to undetectable levels prior to TMLI. 111In-anti-CD25 Mab scans demonstrated uptake in bone marrow and spleen out to 144 hours. All patients completed TMLI 12 Gy, F/M. Mean doses (Gy) from combined RPT and TMLI to lungs were 6.6, kidneys 8.5, liver 10.8 and lower GI 6.6. All patients achieved CR on day +30 bone marrow biopsies (BM). At 0.3 mCi/kg, one patient remained in CR for 923 days but died from thrombotic microangiopathy. One remained in CR for 442 days but died of an unrelated CVA 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. Trial 2 (ongoing): Two patients were treated at the 20 kBq/kg level. No DLTs or GVHD were observed. Both remain without signs of recurrence at day 194 and day 62. Updated results will be presented.Conclusion:
Combining a or ß emitting RPT with 12 Gy TMLI /F/M appears feasible with no DLTs observed to date. Combined radiation doses to organs from RPT and TMLI were lower compared to 12 Gy TBI. Using RPT in a combined modality approach, in a radiosensitive disease and in a potentially curative setting warrants further evaluation.