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Reduced intensity conditioning regimen with fludarabine, cyclophosphamide, low dose TBI and alemtuzumab leading to successful unrelated umbilical cord stem cell engraftment and survival in two children with dyskeratosis congenita

Bone Marrow Transplantation volume 51, pages 744–746 (2016)Cite this article

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Dyskeratosis congenita (DC) is a rare genetic disorder characterized by a classic triad of physical findings consisting of nail dystrophy of the hands and/or feet, mucosal leukoplakia and reticular pigmentation of the skin, most commonly on the head, neck and trunk.1 Bone marrow failure along with pulmonary complications and malignancies are all common causes of premature death in patients with DC as well as a myriad of other abnormalities.2, 3 Hematopoietic stem cell transplantation (HSCT) with fully myeloablative regimens has historically been the only curative treatment.2, 3 Attempts at reducing morbidity and mortality post HSCT with reduced intensity conditioning regimens instead of myeloablative regimens have been reported, and over the past decade, experience treating DC associated marrow failure with reduced intensity HSCT has increased.4 Here we report the HSCT course of two patients with successful restoration of hematopoiesis following reduced intensity conditioning and unrelated cord blood transplant (see Table 1 for patient descriptions).

Table 1 Description of patient 1 and patient 2
Full size table

Patient 1 is a 9-year-old white male with a history of macrocephaly. He was diagnosed with severe aplastic anemia at the age of 5 years. Approximately 1.5 years before this diagnosis, he had an event where the tip of his tongue became white, jagged and painful. He presented to his primary care physician where it was treated as a viral infection. Concomitantly, circular flat scalp lesions appeared on his head followed by hair loss and crusted patches. He also had a history of easy bruising for 18 months and dysplastic nails. He was hospitalized multiple times for immunosuppressant therapy with cyclosporine and anti-thymocyte globulin (ATG) over the previous year. A bone marrow biopsy was obtained and showed markedly hypocellular marrow with cellularity <10% on average and tri-lineage hypoplasia with no evidence of malignancy. Telomere length testing was done and shown to be less than the first percentile in all lymphocyte subset and granulocytes, supporting a diagnosis of DC. Genetic testing revealed heterozygosity for R282H mutation in the TINF2 gene. He was referred for allogeneic stem cell transplantation. He did not have a fully matched sibling and an extensive unrelated donor search did not reveal a fully matched unrelated donor nor a good size, well matched umbilical cord. He received 2 partially matched unrelated umbilical cords; 4/6 with a total neutrophil count (TNC) 9.2 x 107 and 5/6 with a TNC of 2.2 x 107/kg. The preparative regimen consisted of cyclophosphamide 50 mg/kg x 1, fludarabine 40 mg/m2 x 5, low dose TBI at 200cGy, and alemtuzumab 0.2 mg/kg x 5. GvHD prophylaxis consisted of tacrolimus and mycophenolate mofetil. The patient engrafted his WBC with an ANC >500 x 3 days on day +30 post transplant. He was discharged from the hospital on day +34 with no significant toxicity and was transfusion independent. On day +45 after transplant, chimerism evaluation showed 100% donor. The patient was weaned off immunosuppressant by 6 months post transplant. He continues to have normal blood counts over 43 months post transplant with full donor chimerism. He never developed acute or chronic GvHD (cGvHD) or other transplant-related toxicities.

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References

  1. Vuong LG, Hemmati PG, Neuburger S, Terwey TH, Vulliamy T, Dokal I et al. Reduced-intensity conditioning using fludarabine and antithymocyte globulin alone allows stable engraftment in a patient with dyskeratosiscongenita. Acta Haematol 2010; 124: 200–203.

    Article  CAS  Google Scholar 

  2. De la Fuente J, Dokal I . Dyskeratosis congenital: Advances in the understanding of the telomerase defect and the role of stem cell transplantation. Pediatr Transplant 2007; 11: 584–594.

    Article  CAS  Google Scholar 

  3. Gadalla SM, Sales-Bonfirm C, Carreras J, Alter BP, Antin JH, Ayas M et al. Outcomes of allogeneic hematopoietic cell transplant in patients with dyskeratosis congenital. Biol Blood Marrow Transplant 2013; 19: 1238–1243.

    Article  Google Scholar 

  4. Dietz AC, Orchard PJ, Baker KS, Giller RH, Savage SA, Alter BP et al. Disease- specific hematopoietic cell transplantation: nonmyeloablative conditioning regimen for dyskeratosis congenital. Bone Marrow Transplant 2011; 46: 98–104.

    Article  CAS  Google Scholar 

  5. Ballew BJ, Yeager M, Jacobs K, Giri N, Boland J, Burdett L . Germline mutations of regulator telomere elongation helicase 1, RTEL1, in Dyskeratosis Congenita. Hum Genet 2013; 132: 473–480.

    Article  CAS  Google Scholar 

  6. Colado RT, Young NS . Telomere disease. N Engl J Med 2009; 361: 2353–2365.

    Article  Google Scholar 

  7. Knight S, Vullimay T, Copplestone A, Gluckman E, Mason P, Dokal I . DyskeratosisCongenita (DC) Registry: identification of new features of DC. Br J Haematol. 1998; 103: 990–996.

    Article  CAS  Google Scholar 

  8. Bizzetto R, Bonfim C, Rocha V, Socie G, Locatelli F, Chan K et al. Outcomes after related and unrelated umbilical cord blood transplantation for hereditary bone marrow failure syndromes other than Fanconi anemia. Haematologica 2011; 96: 134–141.

    Article  Google Scholar 

  9. Shaw PH, Haut PR, Olszewski M, Kletza M . Hematopoietic stem-cell transplantation using unrelated cord-blood versus matched sibling marrow in pediatric bone marrow failure syndrome: One center’s experience. Pediatr Transplant 1999; 3: 315–321.

    Article  CAS  Google Scholar 

  10. Nishio N, Takahashi Y, Ohashi H, Doisaki S, Muramatsu H, Hama A et al. Reduced- intensity conditioning for alternative donor hematopoietic stem cell transplantation in patients with dyskeratosis congenital. Pediatr Transplant 2011; 15: 161–166.

    CAS  PubMed  Google Scholar 

  11. Algeri M, Comoli P, Strocchio L, Perotti C, Franco C, Del Fante C et al. Successful T-cell-depleted haploidentical hematopoietic stem cell transplantation in a child with dyskeratosis congenita after a fludarabine-based conditioning regimen. J Pediatr Hematol Oncol 2015; 37: 322–326.

    Article  Google Scholar 

  12. Ayas M, Nassar A, Kharfam-Dabaja M, Othman TB, Elhaddad A, Seraihy A et al. Reduced Intensity Conditioning is effective for Hamatopoietic SCT in Dyskeratosis Congenita-related BM failure. Bone Marrow Transplant 2013; 48: 1168–1172.

    Article  CAS  Google Scholar 

  13. Kharfan-Dabaja MA, Otrock ZK, Bacigalupo A, Mahfouz RA, Bazarbachi A . A reduced intensity conditioning regimen of fludarabine, cyclophosphamide, antithymocyte globulin, plus 2 Gy TBI facilitates successful hematopoietic cell engraftment in an adute with dyskertosis congenital. Bone Marrow Transplant 2012; 47: 1254–1255.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pediatrics, University of Missouri Kansas City-School of Medicine, Kansas City, MO, USA

    M Brown

  2. Department of Pediatrics, Children’s Mercy Hospital, Kansas City, MO, USA

    D Myers, N Shreve, R Rahmetullah & M Radhi

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Brown, M., Myers, D., Shreve, N. et al. Reduced intensity conditioning regimen with fludarabine, cyclophosphamide, low dose TBI and alemtuzumab leading to successful unrelated umbilical cord stem cell engraftment and survival in two children with dyskeratosis congenita. Bone Marrow Transplant 51, 744–746 (2016). https://doi.org/10.1038/bmt.2015.333

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