Total Body Irradiation (TBI) Dose Escalation Decreases Risk of Progression and Graft Rejection after Hematopoietic Cell Transplantation with Nonmyeloablative Conditioning for Myelodysplastic Syndrome (MDS) or Myeloproliferative Neoplasms (MPN)

Abstract

PurposeA nonmyeloablative (NMA) regimen of fludarabine and 200cGy TBI combined with post-grafting immunosuppression with mycophenolate mofetil (MMF) and a calcineurin inhibitor allows for allogeneic hematopoietic cell transplantation (HCT) from HLA-matched related or unrelated donors in older patients and those with comorbidities affected by myelodysplastic syndrome (MDS) or myeloproliferative neoplasms (MPN). Results of phase I/II studies in patients with chronic myelomonocytic leukemia (CMML) or MDS/MPN have been disappointing, however, due to high incidences of relapse or graft failure (together termed HCT-failure). We hypothesized that escalating the TBI dose may decrease relapse and ensure engraftment. We performed a phase I/II TBI dose-escalation trial and compared the rates of HCT-failure.MethodsThis was a study conducted at three transplant centers. Patients ages 50-75 or <50 (median age 66) years with high risk comorbidities (Table 1) received NMA conditioning followed by HCT, with TBI dose escalation: •Arm A - patients with MPN or low-risk MDS (RA-RARS-RCMD) or PNH•Arm B - patients with high-risk MDS (RAEB-1) or CMMLPatients with MDS/MPN could not have received myelosuppressive chemotherapy; patients with CMML who had progressed could have received myelosuppressive chemotherapy before HCT to reduce marrow blasts to less than 5%.Patients were enrolled in groups of 6; dose escalation rules were imposed for HCT failure >20% before day 200 on Arms A and B. Stopping rules were imposed for nonrelapse mortality (NRM) at day 200 of >25% in Arm A and >35% in Arm B.The TBI dose levels were: 1.Level 1: 300cGy2.Level 2: 400cGy3.Level 3: 450cGyAll patients received fludarabine 30/m2/day IV x3 days on days -4 to -2. TBI was administered on day 0 followed by infusion of G-CSF mobilized PBSC from HLA-matched related (n=30) or unrelated (n=47) donors. Post-grafting immunosuppression with MMF and cyclosporine was administered.The primary endpoint was a decrease in the incidence of day200 HCT-failure to <20%; secondary endpoints included overall survival (OS), progression-free survival (PFS), relapse incidence (RI) and NRM.ResultsThe study enrolled 77 patients with 36 patients in Arm A and 41 patients in Arm B. Median follow-up is 56.3 months among surviving patients.The primary endpoint (Figure 1) was reached on Arm A at dose level 1 (300cGy TBI) with a cumulative incidence of day200 HCT-failure of 11%.The primary endpoint was not reached in Arm B at dose levels 1 and 2, with dose escalation being triggered at 12 and 5 patients respectively. The endpoint was reached on dose level 3 (450cGy) with a cumulative incidence of day200 HCT-failure of 9%.See Table 2 and Figures 2-5 for OS, PFS, RI and NRM.Cumulative incidence of grades III-IV acute graft-versus-host (aGvHD) by day100 was 17% in Arm A, 12% in Arm B for dose levels 1-2, and 9% in Arm B for dose level 3. Chronic graft-versus-host (cGvHD) cumulative incidence at 1year was 44% in Arm A, 35% in Arm B for dose levels 1-2 and 29% in Arm B for dose level 3.Regarding chimerism analysis, no statistically significant differences were seen among the different arms (Figure 6).Summary and ConclusionsIn Group A (MPN / low-risk MDS), increasing the TBI dose from 200cGy to 300cGy reduced the day200 HCT-failure rate from 31% in previous trials to 11%. As a result, the OS and PFS was 61% and 58%, respectively, at 2 years. Similarly, for Group B (high-risk MDS / CMML), the day200 HCT-failure rate was reduced from 58% in previous trials to 9% when 450cGy was used. This resulted in an OS and PFS of 37% and 33%, respectively, at 2 years. TBI doses of 300cGy and 400cGy were insufficient to reduce HCT-failure in this high risk group.In conclusion, increasing the TBI dose can lead to a higher success rate in this setting of nonmyeloablative conditioning by reducing both relapse and rejection. Further studies are necessary to decrease nonrelapse mortality, especially among patients affected by high-risk disease. Current trials using targeted radioimmunotherapy are currently being investigated towards this end. [Display omitted] DisclosuresFlowers:Pharmacyclics: Consultancy. Maloney:Kite Pharmaceuticals: Other: Advisory board; Celgene: Other: Advisory board; Juno Theraapeutics: Other: Advisory board, Patents & Royalties, Research Funding; Roche/Genetech: Other: Advisory board.