Results of allogeneic hematopoietic stem cell transplantation in patients with chronic granulomatous disease at the Russian Children’s Clinical Hospital

Relevance. Chronic granulomatous disease (CGD) belongs to the group of primary immunodeficiencies. Patients with CGD have an impaired quality of life, severe infections and inflammatory organ damage. Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective treatment method for CGD. The authors of the article presented the experience of HSCT in patients with CGD in the Russian Children’s Clinical Hospital.

Materials and methods. 20 (19 primary and 1 repeated) HSCT during the period from 2009 to 2020 were performed in nineteen patients with CGD. All patients had a long history of infections, three or more foci of chronic infection, 9 patients had a generalized BCG infection. Bone marrow (ВМ) from a related HLA-identical donor was the source of hematopoietic stem cells (HSC) for 4 (21 %) patients, peripheral blood stem cells (PBSC) for 2 (10.5 %). ВМ from a unrelated fully HLA-identical donor was performed in 9 (47.4 %) patients, PBSC – 2 (10.5 %). ВМ from a unrelated 9/10 HLA-compatible donor was performed in one (5.3 %) patient. In one case (5.3 %) the HSC source became PBSC from a unrelated 9/10 HLA-compatible donor after TcRαβ/CD19+ depletion. In 68.5 % (n = 13) cases the conditioning regimen included threosulfan, fludarabine, melphalan, and antithymocyte globulin. In 2 (10.5 %) patients, melphalan was excluded from the conditioning regimen; in 4 (21 %), it was replaced by thiotepa.

Results. The overall survival (OS) was 88.9 ± 10.5 %, the event-free survival (EFS) was 88.1 ± 7.9 %, and there was no transplant mortality. Transplant rejections were observed in two patients who received HSC from a unrelated 9/10 HLA-compatible donor with a previous conditioning regimen that included only one alkylating agent. In 4 patients (21 %) there was a prolonged persistence of mixed chimerism after HSCT without clinical and laboratory signs of CGD. After successful transplantation all patients were cured of the infectious and inflammatory diseases characteristic of CGD.

Conclusion. Results of HSCT in patients with CGD can be considered satisfactory, the OS and EFS are high. Failure of HSCT is associated with transplant rejection, which is most likely due to the donor and patient mismatch, as well as the use of conditioning modes with reduced intensity.

1. Kang E.M., Marciano B.E., DeRavin S., Zarember K.A., Holland S.M., Malech H.L. Chronic granulomatous disease: overview and hematopoietic stem cell transplantation. J. Allergy Clin. Immunol 2011;127(6):1319–26. doi: 10.1016/j.jaci.2011.03.028.

2. Mouy R., Veber F., Blanche S., Donadieu J., Brauner R., Levron J.C., Griscelli C., Fischer A. Long-term itraconazole prophylaxis against Aspergillus infections in thirty-two patients with chronic granulomatous disease. J Pediatr 1994;125(6 Pt 1):998–1003. doi: 10.1016/s0022-3476(05)82023-2.

3. Finn A., Hadzić N., Morgan G., Strobel S., Levinsky R.J. Prognosis of chronic granulomatous disease. Arch Dis Child 1990;65(9):942–5. doi: 10.1136/adc.65.9.942.

4. Liese J., Kloos S., Jendrossek V., Petropoulou T., Wintergerst U., Notheis G., Gahr M., Belohradsky B.H. Long-term follow-up and outcome of 39 patients with chronic granulomatous disease. J Pediatr 2000;137(5):687–93. doi: 10.1067/mpd.2000.109112.

5. Jones L.B., McGrogan P., Flood T.J., Gennery A.R., Morton L., Thrasher A., Goldblatt D., Parker L., Cant A.J. Chronic Granulomatous Disease in the UK and Ireland – A comprehensive national patient based registry. Clin Exp Immunol 2008;152(2):211–8. doi: 10.1111/j.1365-2249.2008.03644.x.

6. Martire B., Rondelli R., Soresina A., Pignata C., Broccoletti T., Finocchi A., Rossi P., Gattorno M., Rabusin M., Azzari C., Dellepiane R.M., Pietrogrande M.C., Trizzino A., Di Bartolomeo P., Martino S., Carpino L., Cossu F., Locatelli F., Maccario R., Pierani P., Putti M.C., Stabile A., Notarangelo L.D., Ugazio A.G., Plebani A., De Mattia D.; IPINET (Italian Network for Primary Immunodefi ciencies). Clinical features, long-term follow-up and outcome of a large cohortof patients with Chronic Granulomatous Disease: an Italian multicenter study. Clin. Immunol 2008;126(2):155–64. doi: 10.1016/j.clim.2007.09.008.

7. Schäppi M.G., Smith V.V., Goldblatt D., Lindley K.J., Milla P.J. Colitis in chronic granulomatous disease. Arch Dis Child 2001;84(2):147–51. doi: 10.1136/adc.84.2.147.

8. Walther M.M., Malech H., Berman A., Choyke P., Venzon D.J., Linehan W.M., Gallin J.I. The urological manifestations of chronic granulomatous disease. J Urol 1992;147(5):1314–8. doi: 10.1016/s0022-5347(17)37552-3.

9. van den Berg J.M., van Koppen E., Ahlin A., Belohradsky B.H., Bernatowska E., Corbeel L., Español T., Fischer A., Kurenko-Deptuch M., Mouy R., Petropoulou T., Roesler J., Seger R., Stasia M.J., Valerius N.H., Weening R.S., Wolach B., Roos D., Kuijpers T.W. Chronic granulomatous disease: the European experience. PLoS One 2009;4(4):e5234. doi: 10.1371/journal.pone.0005234.

10. Winkelstein J.A., Marino M.C., Johnston R.B. Jr., Boyle J., Curnutte J., Gallin J.I., Malech H.L., Holland S.M., Ochs H., Quie P., Buckley R.H., Foster C.B., Chanock S.J., Dickler H. Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine (Baltimore) 2000;79(3):155–69. doi: 10.1097/00005792-200005000-00003.

11. Martinez C.A., Shah S., Shearer W.T., Rosenblatt H.M., Paul M.E., Chinen J., Leung K.S., Kennedy-Nasser A., Brenner M.K., Heslop H.E., Liu H., Wu M.F., Hanson I.C., Krance R.A. Excellent survival after sibling or unrelated donor stem cell transplantation for chronic granulomatous disease. J Allergy Clin Immunol 2012;129(1):176–83. doi: 10.1016/j.jaci.2011.10.005.

12. Soncini E., Slatter M.A., Jones L.B., Hughes S., Hodges S., Flood T.J., Barge D., Spickett G.P., Jackson G.H., Collin M.P., Abinun M., Cant A.J., Gennery A.R. Unrelated donor and HLA-identical sibling haematopoietic stem cell transplantation cure chronic granulomatous disease with goodlong-term outcomeand growth. Br J Haematol 2009;145(1):73–83. doi: 10.1111/j.1365-2141.2009.07614.x.

13. Connelly J.A., Marsh R., Parikh S., Talano J.A. Allogeneic hematopoietic cell transplantation for chronic granulomatous disease: controversies and state of the art. J Pediatric Infect Dis Soc 2018;7(suppl 1):S31–9. doi: 10.1093/jpids/piy015.

14. Marciano B.E., Zerbe C.S., Falcone E.L., Ding L., DeRavin S.S., Daub J., Kreuzburg S., Yockey L., Hunsberger S., Foruraghi L., Barnhart L.A., Matharu K., Anderson V., Darnell D.N., Frein C., Fink D.L., Lau K.P., Long Priel D.A., Gallin J.I., Malech H.L., Uzel G., Freeman A.F., Kuhns D.B., Rosenzweig S.D., Holland S.M. X-linked carriers of chronic granulomatous disease: Illness, lyonization, and stability. J Allergy Clin Immunol 2018;141(1):365–71. doi: 10.1016/j.jaci.2017.04.035.

15. Parta M., Kelly C., Kwatemaa N., Theobald N., Hilligoss D., Qin J., Kuhns D.B., Zerbe C., Holland S.M., Malech H., Kang E.M. Allogeneic reduced-intensity hematopoietic stem cell transplantation for chronic granulomatous disease: a single-center prospective trial. J Clin Immunol 2017;37(6):548–58. doi: 10.1007/s10875-017-0422-6.