253 - Phase II Trial of TMLI 20 Gy in Combination with Cyclophosphamide and Etoposide in Patients with Poor-Risk Acute Leukemia

J. Y. C. Wong¹, A. M. Monzr², A. Salhotra², S. V. Dandapani¹, Y. Wang³, J. Palmer³, C. Han¹, A. Liu¹, E. H. Radany¹, I. Aldoss², H. Ali², L. Farol², F. Sahebi², R. Spielberger², G. Marcucci², R. Nakamura², E. Smith², S. K. Hui¹, S. J. Forman², 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, ³Division of Biostatistics, City of Hope National Medical Center, Duarte, CA

Purpose/Objective(s): Patients with relapsed or refractory (R/R) acute leukemia have a poor prognosis with current hematopoietic cell transplant (HCT) options. Total marrow and lymphoid irradiation (TMLI), which delivers escalated targeted radiation doses to bone marrow (BM) while reducing doses to multiple organs at risk (OARs), was developed to address this unmet need. We report results of a phase II study (NCT02446964) which combined TMLI (20 Gy to BM/ lymph nodes/ spleen; 12 Gy to liver/brain) with cyclophosphamide (Cy) and etoposide (VP16) as a conditioning regimen in patients with R/R acute leukemia undergoing allogeneic HCT. Materials/

Methods: TMLI was administered 2 Gy twice a day on days -9 to day -5, VP16 60mg/kg on day -4, and Cy 100mg/kg on day -2. Graft versus host disease (GVHD) prophylaxis was tacrolimus and sirolimus. The primary endpoint was progression free survival (PFS), and secondary endpoints included overall survival (OS), non-relapse mortality (NRM), and toxicity.
Results: 74 patients (AML n=56, ALL n=18) were treated from 5/2014-9/2020. Median age was 40.1 (16.5 - 59.3) years. 51 (69%) patients were induction failures. 72 (97%) patients had detectable marrow blasts and 36 (49%) detectable circulating blasts just prior to TMLI. The day+30 BM biopsy CR rate was 92%. Engraftment occurred for all subjects. Mean organ doses (Gy) were lung 8.8, kidneys 7.3, heart 7.5, thyroid 8.0, lens 2.5 and lower GI 10.2. Grade =2 Bearman scale toxicities were stomatitis (Gr2 n=17, Gr3 n=5), gastrointestinal (Gr2 n=10, Gr3 n=4), renal (Gr2 n=1, Gr3 n=5), hepatic (Gr2 n=3, Gr3 n=2), central nervous system (Gr2 n=3, Gr3 n=1), bladder (Gr2 n=4), pulmonary (Gr2 n=1), and cardiac (Gr2 n=1). Median follow-up was 1.8 years (range: 0.1-5.9) and for surviving patients 4.2 years (range: 2.0-5.9). The 2-year PFS and 2-year OS were 31.1% (95%CI: 21%-42%) and 45.9% (95%CI: 34%-57%). The cumulative incidence of NRM at day+100, year 1, and year 2 were 4.1% (95%CI: 1-10%), 8.1% (95%CI: 3-16%), and 12% (95%CI: 6-21%), respectively. Peripheral blasts = 20% prior to TMLI was associated with higher risk of disease relapse/progression or death.
Conclusion: To our knowledge this is the largest prospective experience using TMLI 20 Gy. TMLI results in significant dose reduction to OARs allowing for target doses of 20 Gy to be safely delivered in combination with VP16 and Cy in patients < 60 years of age. This regimen provides an effective HCT option for patients with R/R acute leukemia, with PFS, OS and NRM rates that compare favorably to historical results. Given these results, TMLI 20 Gy followed by post-transplant Cy is currently being evaluated as a potential replacement for standard TBI conditioning in patients with AML in complete remission (NCT03467386).