Radiation Sparing Reduced Intensity Conditioning for Allogeneic Cell Transplantation in Patients with Dyskeratosis Congenita Comparable to Standard of Care: A Phase III Single Institution Trial

Introduction

Dyskeratosis congenita (DKC) is a rare form of inherited multiorgan disease caused by mutations affecting telomere maintenance. Complications include bone marrow failure (BMF), pulmonary and liver fibrosis, and predisposition to malignancy. Allogeneic hematopoietic cell therapy (alloHCT) can rescue affected individuals from hematologic complications. However, toxicity from alkylator and radiation exposure can be lethal or potentially expedite DKC-specific organ complications. In this single institution phase III clinical trial, we aimed to demonstrate non-inferior short-term alloHCT outcomes with a radiation sparing reduced intensity conditioning (RIC) regimen while monitoring for long-term reductions in systemic toxicity.

Methods

We compared two consecutive cohort of patients with DKC requiring alloHCT for BMF or myelodysplastic syndrome (MDS). Both received RIC with fludarabine 200 mg/m², cyclophosphamide 50 mg/kg, and alemtuzumab 1 mg/kg. The earlier cohort (4/2006-8/2012) additionally received 200 cGy total body irradiation ("TBI"), while the latter (11/2015-2/2021) "Non-TBI" cohort did not. We restricted our analysis to bone marrow (BM) and peripheral blood stem cell (PBSC) recipients. AlloHCT milestones including neutrophil engraftment, graft failure, disease progression, acute and chronic graft-versus host disease (GvHD), serious infections, and overall survival were prospectively recorded. The cumulative incidence of time-dependent events was compared between cohorts using the Fine-Gray test with death as a competing risk. Infection density over the first 100 days after alloHCT was calculated using the Mantel-Haenszel chi-square test for incidence density. Estimates of overall survival were calculated by Kaplan-Meier curves.

Results

The TBI cohort included 12 patients aged 2.2-52.2 years (median 20.5), 11 with SAA and 1 with MDS. Stem cell sources were unrelated donor BM in 8, sibling donor PBSCs in 2, and sibling BM in 1, with a median follow-up of 1531 days (range 83-3960). The comparable Non-TBI group included 10 patients aged 1.7-65.9 years (median 9.8), 8 with SAA and 2 with MDS/RAEB. Stem cell donor sources were unrelated donor BM in 8 and sibling BM in 2, with a median follow-up of 870 days (range 303-2420). Neutrophil engraftment occurred at a median of 13 days in the TBI cohort and 8.5 days in the Non-TBI cohort (p<0.001; Fig 1a). Cumulative incidence of acute GvHD by day 100 for the TBI cohort was 0.08 (95% CI <0.01, 0.32) compared to 0.1 (95% CI <0.01, 0.37) for the Non-TBI cohort (p=0.74). Cumulative incidence of chronic GvHD by 3 years for the TBI cohort was 0.17 (95% CI 0.02, 0.43) compared to 0.1 (95% CI <0.01, 0.37) for the Non-TBI cohort (p=0.7). With regard to serious infections the first 100 days after alloHCT, there were no fungal infections in either group and infection density of viral infections, bacteremia, and pneumonia episodes was equivalent between cohorts. In the TBI cohort, one case was recorded as a late graft failure at day +1371, however upon retrospective review, this patient maintained 10% BM cellularity with 100% donor chimerism and experienced cytopenias and death likely resulting from Epstein-Barr viremia and possible post-transplant lymphoproliferative disease. In the Non-TBI cohort, one patient experienced non-neutropenic graft failure/rejection at day +28. A second Non-TBI patient demonstrated graft failure in the form of MDS recurrence at day +359. There was no statistically significant difference in overall survival between the two groups (p=0.4; Fig 1b, Table 1), with the 5.5 years median survival of the TBI cohort and the median survival not achieved for the Non-TBI cohort.

Conclusions

A successful alloHCT conditioning regimen for DKC must provide myeloablation to allow for sustained donor engraftment and immunosuppression to decrease GvHD risk, while limiting an unfavorable toxicity profile to which DKC patients are more susceptible. Elimination of TBI from the RIC regimen demonstrated equivalent overall survival, acute and chronic GvHD incidence, and day +100 infection density with an expedited neutrophil engraftment and no increase in graft failure risk. While there appears to be a trend toward less lethal DKC late effects like pulmonary failure and secondary malignancy, definitive assessment of such outcomes requires further longitudinal follow-up of both cohorts.

Vercellotti:Omeros: Research Funding; Mitobridge-Astellas: Research Funding; CSL-Behring: Research Funding. Holtan:Vitrac Therapeutics: Research Funding; Incyte: Research Funding; Ossium: Consultancy; Generon: Consultancy; CSL Behring: Other: Clinical trial adjudication. Tolar:Rheacell: Consultancy; Richard M. Schulze Family Foundation: Other: scientific advisor; Marketa Dimitrov: Other: she is his daughter.