Safe & Effective Reduced Intensity Conditioning Regimen in Patients with Dyskeratosis Congenita
Authors: Ramgopal Archana , Carella Beth , Szabolcs Paul , Allen Steven William , Barnum Jessie L. 
Published: February 2021

Background:
Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome, caused by telomerase dysfunction leading to shortened telomeres.1 Recent literature shows only a 23% estimated 10-year survival, secondary to death from pulmonary complications.2 Currently, hematopoietic cell transplantation (HCT) is the only curative therapy for marrow failure but has been limited by mortality related to infection, sinusoidal obstructive syndrome (SOS), graft-versus-host disease (GVHD) and respiratory failure.3,4 The ideal conditioning regimen that optimizes engraftment while maximizing long-term survival is yet to be determined.
Methods:
We describe three consecutive patients with DC who underwent matched unrelated donor (MUD) allogeneic HCT following a reduced-intensity conditioning regimen similar to protocol NCT03330795 that uses a reduced intensity conditioning (RIC) while maximizing the benefits of shielding vulnerable organs in this populations. These three patients received a RIC regimen of rituximab, alemtuzumab, hydroxyurea, thiotepa, fludarabine, and 250 cGy total body irradiation; patients 1 and 2 received 85% lung shielding and 50% liver shielding.
Results:
Patient 1 is a 17-year-old male with reduced diffusing capacity of the lungs for carbon monoxide (DLCO), splenomegaly, splenic varices and nodular regenerative hyperplasia (NRH) who presented with pancytopenia. Testing revealed telomeres below the 1st percentile in all WBC subtypes, a PARN c.1257dup heterozygous mutation and a TERC c.17_31 mutation. He underwent a 12/12 MUD HCT and engrafted on Day +18. His course was complicated by poor adherence to medications and visits, and development of skin and GI GVHD, which responded to steroids. He was weaned off of immunosuppression by 11 months post-transplant. Twenty-eight months post-transplant, he remains 100% donor engrafted with no chronic GVHD or organ toxicity, including stable pulmonary function tests (PFT). See figure 1 and 2.
Patient 2 is a 16-year-old male with reduced DLCO, splenomegaly and NRH who was diagnosed after his brother (Patient 1). He was found to have very short telomeres in all testable WBC subtypes and the same mutations as his brother. After marrow failure, he underwent a 12/12 MUD HCT, with neutrophil engraftment on Day +16. His course was complicated by sudden noncompliance with tacrolimus at day +100, after which he suffered GI GVHD which responded to steroids. He then developed disseminated adenovirus infection which responded to an adenovirus-specific T-cell infusion. He is now Day +356 after transplant and has been off all immunosuppression for 4 months. He remains &gt;98% donor-engrafted without evidence of GVHD or organ toxicity, and his PFTs have remained stable.
Patient 3 is a 16-year-old male with a history of antibody-negative autoimmune hepatitis who later developed pancytopenia. Telomere testing revealed very short telomeres in 4 of the 5 evaluable WBC subtypes. His genetic testing did not uncover a mutation yet identified as pathogenic in DC. He received a 12/12 MUD HCT and engrafted on Day +12. He had skin GVHD which responded to ruxolitinib. He remains 100% donor-engrafted, most recently at 9 months post-transplant without organ toxicity.
Conclusions:
All patients had timely neutrophil engraftment without SOS or other organ toxicity, despite being at increased risk for organ morbidity due to preexisting liver and lung disease. GVHD was noted, although two of the cases were related to poor adherence, and all responded to treatment. There is sustained donor-engraftment at a median of 637 days (range 356-1186 days) post-transplant.
References
1. Dietz AC, Orchard PJ, Baker KS, et al. Disease-specific hematopoietic cell transplantation: nonmyeloablative conditioning regimen for dyskeratosis congenita. Bone Marrow Transplant. 2011;46(1):98-104.
2. Elmahadi S, Muramatsu H, Kojima S. Allogeneic hematopoietic stem cell transplantation for dyskeratosis congenita. Curr Opin Hematol. 2016;23(6):501-507.
3. Nelson AS, Marsh RA, Myers KC, et al. A Reduced-Intensity Conditioning Regimen for Patients with Dyskeratosis Congenita Undergoing Hematopoietic Stem Cell Transplantation. Biol. Blood Marrow Transplant. 2016;22(5):884-888.
4. Fioredda F, Iacobelli S, Korthof ET, et al. Outcome of haematopoietic stem cell transplantation in dyskeratosis congenita. Br. J. Haematol. 2018;183(1):110-118.

Disclosures
No relevant conflicts of interest to declare.