Total Marrow and Lymphoid Irradiation to 20 Gy Combined With Post-Transplant Cyclophosphamide Graft vs. Host Disease (GvHD) Prophylaxis is Associated With Low Non-Relapse Mortality Rates and Favorable GvHD-Free/Relapse-Free Survival in AML

Abstract

<h3>Purpose/Objective(s)</h3> Allogeneic hematopoietic cell transplantation (alloHCT) offers the highest curative rate for AML with intermediate or high-risk cytogenetics in remission. GvHD is a main cause of alloHCT mortality and morbidity. This trial evaluated the feasibility of a novel conditioning regimen of total marrow and lymphoid irradiation (TMLI) at 20 Gy combined with post-transplant cyclophosphamide (PTCy), which was designed to reduce the chronic GvHD risks using PTCy and reduce relapse rates with TMLI, thereby improving GRFS rates compared to standard myeloablative conditioning regimens. <h3>Materials/Methods</h3> Eighteen patients with AML in first or second complete remission were treated with TMLI 20 Gy (2 Gy twice daily) to bone, lymph nodes and spleen (liver and brain 12 Gy) on days -4 to 0; stem cell infusion on day 0; PTCy 50 mg/kg/day on days +3 and +4; and tacrolimus 1 mg continuous infusion on days +5 to +90. Endpoints included toxicity, GRFS at 1 year, engraftment, overall survival (OS), and non-relapse mortality (NRM). GRFS was defined as grade 3-4 acute GvHD (aGvHD), chronic GvHD (cGvHD) requiring systemic treatment, relapse, or death (from any cause). <h3>Results</h3> The median age was 40 (range 19-56). Seventeen of 18 patients had intermediate to high-risk cytogenetics. The average (range) Dmean organ doses (Gy) were lungs 8.1 (7.5-9.5), kidneys 7.5 (6.3-9.2), heart 7.3 (6.6-8.3), oral cavity 4.4 (3.0–6.7), esophagus 6.4 (4.7-7.6), upper GI 9.1 (7.3-12.0), lower GI 10.2 (8.9-12.1), and bladder 10.0 (6.8-14.6). Median follow-up was 12.5 months (range 5.9 to 25.4) for surviving patients (n = 17). All patients engrafted. Bearman toxicity data were available for all patients. Grade 2 toxicities were bladder (n = 3) and stomatitis (n = 1). No grade 3-4 toxicities or toxicity-related deaths were observed. aGvHD developed in 2 patients with grade III-IV in only 1 patient (100-day Grade III-IV aGvHD: 5.6%, 95% CI: 0.3-23.1). Five patients developed chronic GvHD with one patient developing moderate to severe cGVHD (1-year cGvHD rate: 28.6%, 95% CI: 7.5%-54.7%). The GRFS rate at 1 year was 60.6% (95% CI: 34.6-79.0). One-year estimates of OS and relapse-free survival were 100% and 83.3% (95% CI: 62.8-96.1), respectively. Disease relapse at 1 year was 16.7% (95% CI: 3.9-37.2). The estimates of NRM at 100 days and 1 year were both 0%. Relapsed disease after transplant occurred in 3 patients (16.7%). One patient died after relapse. <h3>Conclusion</h3> This TMLI 20 Gy only conditioning regimen, together with PTCy and tacrolimus, is associated with low toxicity and NRM. All patients achieved engraftment. Participants with ≥ 1-year follow-up have discontinued immunosuppressive therapy. The results suggest an improved GRFS rate compared to traditional myeloablative regimens reported. A larger phase II trial is planned.