Treatment of refractory chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation with low-dose interleukin-2

Refractory chronic graft-versus-host disease (cGVHD) is the complication of allogeneic hematopoietic stem cell transplantation (HCT) that signi ficantly impacts quality of life, may be associated with morbidity and mortality and has limited treatment options. 16 adult pts (median age 22, range 16 - 51 y.o.) with refractory cGVHD were enrolled. 6 pts were on steroids upon inclusion. 11 patients had severe (NIH) cGVHD, 6 - moderate, and have received 1-3 anti-cGVHD treatments before IL-2. Pts received IL-2 sc injections 1 MIU 3 times a week. Median duration of treatment was 2.5 moths (range 1 - 8 months). Partial clinical response was observed in 5 pts, complete response in 2 pts with overall response of 44 %. There was an improvement of Karnofsky in 25 % of pts, reduction in NIH severity scores in 37.5 % of and any objective response also in 44 % of pts. With median follow-up of 14 months overall survival was 62.5 %, non-relapse mortality was 12.5 % (2 pts), 25 % of patients had a relapse of underlying disease.

аллогенная ТГСК, хроническая реакция «трансплантат против хозяина», облитерирующий бронхиолит, интерелейкин-2, allogeneic HSCT, chronic graft-versus-host disease, bronchiolitis obliterans, interleukin-2

1. Ahmed S.S., Wang X.N., Norden J. et al. Identification and validation of biomarkers associated with acute and chronic graft versus host disease // Bone Marrow Transplant. - 2015. - № 14. doi: 10.1038/bmt.2015.191. [Epub ahead of print].

2. Allen J.L., Fore M.S., Wooten J. et al. B cells from patients with chronic GVHD are activated and primed for survival via BAFF-mediated pathways // Blood. - 2012. - Vol. 20. - № 120 (12). - Р. 2529-2536.

3. Ayuk F., Veit R., Zabelina T. et al. Prognostic factors for survival of patients with newly diagnosed chronic GVHD according to NIH criteria // Ann. Hematol. - 2015. - № 94 (10). - Р. 1727-1732.

4. Bensinger W.I., Martin P.J., Storer B. et al. Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers // N. Engl. J. Med. - 2001. - № 18. - № 344 (3). - Р. 175-181.

5. Brkic S., Tsoi M.S., Mori T. et al. Cellular interactions in marrow-grafted patients. III. Normal interleukin 1 and defective interleukin 2 production in short-term patients and in those with chronic graft-versus-host disease // Transplantation. - 1985. -№ 39 (1). - Р. 30-35.

6. Eapen M., Logan B.R., Confer D.L. et al. Peripheral blood grafts from unrelated donors are associated with increased acute and chronic graft-versus-host disease without improved survival // Biol. Blood Marrow. Transplant. - 2007. - № 13 (12). -Р. 1461- 1468.

7. Filipovich A.H., Weisdorf D., Pavletic S. et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report // Biol. Blood Marrow Transplant. - 2005. - № 11 (12). - Р. 952-956.

8. Fiuza-Luces C., Simpson R.J., Ramirez M. et al. Physical function and quality of life in patients with chronic GvHD: a summary of preclinical and clinical studies and a call for exercise intervention trials in patients // Bone Marrow. Transplant. - 2015. - Sep 14. doi: 10. 1038/bmt. 2015. 195. [Epub ahead of print].

9. Koreth J., Matsuoka K., Kim H.T. et al. Interleukin-2 and regulatory T cells in graft-versus-host disease // N. Engl. J. Med. - 2011. - Vol. 1. - № 365 (22). - Р. 2055-2066.

10. Lee S.J., Wolff D., Kitko C. et al. Measuring therapeutic response in chronic graft-versus-host disease. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: IV. The 2014 Response Criteria Working Group report // Biol. Blood Marrow. Transplant. -2015. - № 21 (6). - Р. 984-999.

11. Matsuoka K., Koreth J., Kim H.T. et al. Low-dose interleukin-2 therapy restores regulatory T cell homeostasis in patients with chronic graft-versus-host disease // Sci. Transl. Med. - 2013. - Vol. 3. - № 5 (179). - Р. 179ra43.

12. Miroux C., Morales O., Ouaguia L. et al. Corticosteroids do not reverse the inhibitory effect of cyclosporine on regulatory T-cell activity in contrast to mycophenolate mofetil // Transplant. Proc. - 2012. - № 44 (9). - Р. 2834-2839.

13. Ruutu T., Gratwohl A., de Witte T. et al. Prophylaxis and treatment of GVHD: EBMT-ELN working group recommendations for a standardized practice // Bone Marrow Transplant. - 2014. - № 49 (2). - Р. 168-173.

14. Vigorito A.C., Campregher P.V., Storer B.E. et al. Evaluation of NIH consensus criteria for classification of late acute and chronic GVHD // Blood. - 2009. - Vol. 16. - № 114 (3). -Р. 702-708.

15. Vogtenhuber C., Bucher C., Highfill S.L. et al. Constitutively active Stat5b in CD4+ T cells inhibits graft-versus-host disease lethality associated with increased regulatory T-cell potency and decreased T effector cell responses // Blood. - 2010. - Vol. 22. - № 116 (3). - Р. 466-474.

16. Zhang P., Tey S.K., Koyama M. et al. Induced regulatory T cells promote tolerance when stabilized by rapamycin and IL-2 in vivo // J. Immunol. - 2013. - Vol. 15. - № 191 (10). - Р. 5291-303.