CHIMERISM AS A PROGNOSTIC FACTOR OF RELAPSE AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION IN HEMATOLOGICAL MALIGNANCIES

Relapse remains one of the main causes of treatment failure and mortality after allogeneic hematopoietic stem cell transplantation (alloHSCT) in patients with hematological malignancies. Chimerism monitoring provides information on engraftment and risk of relapse. The results of 104 alloHSCT performed in patients with hematological malignancies during 2009–2016 were included. Increasing mixed chimerism (MC) was an unfavorable prognostic factor for the event-free survival (EFS) (HR = 6.9, p < 0.0001) and was associated with a high risk of relapse after alloHSCT (HR = 12.2, p < 0.0001). EFS in patients with full donor chimerism (FDC), decreasing MC, increasing MC was 68.1 ± 6.4; 60.0 ± 21.9 and 0 % (p < 0.0001), the cumulative incidence of relapse was 10.8 ± 4.6; 0 and 81.3 ± 10.8 % (p < 0.0001), respectively. Increasing MC was detected in 2–435 (median 23.5) days before relapse in 10 (62.5 %) of 16 cases. Increasing MC appeared in bone marrow earlier and more often than in peripheral blood (p = 0.06). During hematologic relapse, FDC in peripheral blood can be observed. A graft-versushost disease was observed more often in patients with full donor chimerism than with MC (p = 0.0004).

chimerism, allogeneic hematopoietic stem cell transplantation, relapse, graft-versus-host disease, prognosis, children

1. Barrett A. J., Battiwalla M. Relapse after allogeneic stem cell transplantation. Expert Review of Hematology, 2010, vol. 3, no. 4, pp. 429-441. https://doi.org/10.1586/ehm.10.32.

2. A. D’Souza, X. Zhu. Current Uses and Outcomes of Hematopoietic Cell Transplantation (HCT): CIBMTR Summary Slides, 2016. Available at: http://www.cibmtr.org. (Accessed 05.04.2017).

3. Porter D. L., Alyea E. P., Antin J. H., DeLima M., Estey E., Falkenburg J. H., Hardy N., Kroeger N., Leis J., Levine J., Maloney D. G., Peggs K., Rowe J. M., Wayne A. S., Giralt S., Bishop M. R., van Besien K. NCI First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation: Report from the Committee on Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation. Biology of Blood and Marrow Transplantation, 2010, vol. 16, no. 11, pp. 1467-1503. https://doi.org/10.1016/j.bbmt.2010.08.001.

4. LaBelle J. L., Cunningham J. M. Stem cell transplant as an immunomodulatory tool for children with hematologic malignancies. American Society of Clinical Oncology Educational Book, 2013, pp. 347-352. https://doi.org/10.1200/EdBook_AM.2013.33.e347.

5. Thanarajasingam G., Kim H. T., Cutler C., Ho V. T., Koreth J., Alyea E. P., Antin J. H., Soiffer R. J., Armand P. Outcome and prognostic factors for patients who relapse after allogeneic hematopoietic stem cell transplantation. Biology of Blood and Marrow Transplantation, 2013, vol. 19, no. 12, pp. 1713-1718. https://doi.org/10.1016/j.bbmt.2013.09.011.

6. Ge L., Ye F., Mao X., Chen J., Sun A., Zhu X., Qiu H., Jin Z., Miao M., Fu C., Ma X., Chen F., Xue S., Ruan C., Wu D., Tang X. Extramedullary relapse of acute leukemia after allogeneichematopoietic stem cell transplantation: different characteristics between acute myelogenous leukemia and acute lymphoblasticleukemia. Biology of Blood and Marrow Transplantation, 2014, vol. 20, no. 7, pp. 1040-1047. https://doi.org/10.1016/j.bbmt.2014.03.030.

7. Savani B. N., Mielke S., Reddy N., Goodman S., Jagasia M., Rezvani K. Management of relapse after allo-SCT for AML and the role of second transplantation. Bone Marrow Transplantation, 2009, vol. 44, no. 12, pp. 769-777. https://doi.org/10.1038/bmt.2009.300.

8. Mielcarek M., Storer B. E., Flowers M. E., Storb R., Sandmaier B. M., Martin P. J. Outcomes among patients with recurrent high-risk hematologic malignancies after allogeneic hematopoietic cell transplantation. Biology of Blood and Marrow Transplantation, 2007, vol. 13, no. 10, pp. 1160-1168. https://doi.org/10.1016/j.bbmt.2007.06.007.

9. Kröger N., Miyamura K., Bishop M. R. Minimal residual disease following allogeneic hematopoietic stem cell transplantation. Biology of Blood and Marrow Transplantation, 2011, vol. 20, no. 1, pp. S94-S100. https://doi.org/10.1016/j.bbmt.2010.10.031.

10. Athale U. H., Gibson P. J., Bradley N. M., Malkin D. M., Hitzler J., POGO MRD Working Group. Minimal Residual Disease and Childhood Leukemia: Standard of Care Recommendations From the Pediatric Oncology Group of Ontario MRD Working Group. Pediatric Blood & Cancer, 2016, vol. 63, no. 6, pp. 973-982. https://doi.org/10.1002/pbc.25939.

11. Bacher U., Haferlach T., Fehse B., Schnittger S., Kröger N. Minimal residual disease diagnostics and chimerism in the post-transplant period in acute myeloid leukemia. Scientific World Journal, 2011, vol. 11, pp. 310-319. https://doi.org/10.1100/tsw.2011.16.

12. Antin J. H., Childs R., Filipovich A. H., Giralt S., Mackinnon S., Spitzer T., Weisdorf D. Establishment of complete and mixed donor chimerism afterallogeneic lymphohematopoietic transplantation: recommendations from a workshop at the 2001 tandem meetings of the International bone marrow transplant registry and the american society of blood and marrow transplantation. Biology of Blood and Marrow Transplantation, 2001, vol. 7, no. 9, pp. 473-485. https://doi.org/10.1053/bbmt.2001.v7.pm11669214.

13. Terwey T. H., Hemmati P. G., Nagy M., Pfeifer H., Gökbuget N., Brüggemann M., Le Duc TM., le Coutre P., Dörken B., Arnold R. Comparison of chimerism and minimal residual disease monitoring for relapse prediction after allogeneic stem cell transplantation for adult acute lymphoblastic leukemia. Biology of Blood and Marrow Transplantation, 2014, vol. 20, no. 10, pp. 1522-1529. https://doi.org/10.1016/j.bbmt.2014.05.026.

14. Bader P., Niethammer D., Willasch A., Kreyenberg H., Klingebiel T. How and when should we monitor chimerism after allogeneic stem cell transplantation? Bone Marrow Transplantation, 2005, vol. 35, no. 2, pp. 107-119. https://doi.org/10.1038/sj.bmt.1704715.

15. Bader P., Kreyenberg H., Hoelle W., Dueckers G., Kremens B., Dilloo D., Sykora K. W., Niemeyer C., Reinhardt D., Vormoor J., Gruhn B., Lang P., Greil J., Handgretinger R., Niethammer D., Klingebiel T., Beck J. F. Increasing mixed chime-rism defines a high-risk group of childhoodacute myelogenous leukemia patients after allogeneic stem cell transplantation where pre-emptive immunotherapy may be effective. Bone Marrow Transplantation, 2004, vol. 33, no. 8, pp. 815-821. https://doi.org/10.1038/sj.bmt.1704444.

16. Bader P., Kreyenberg H., Hoelle W., Dueckers G., Handgretinger R., Lang P., Kremens B., Dilloo D., Sykora K. W., Schrappe M., Niemeyer C., Von Stackelberg A., Gruhn B., Henze G., Greil J., Niethammer D., Dietz K., Beck J. F., Klingebiel T. Increasing mixed chimerism is an important prognostic factor for unfavorable outcome in children with acute lymphoblastic leukemia after allogeneic stem-cell transplantation: possible role for pre-emptive immunotherapy? Journal of Clinical Oncology, 2004, vol. 22, no. 9, pp. 1696-1705. https://doi.org/10.1200/JCO.2004.05.198.

17. Rettinger E., Willasch A. M., Kreyenberg H., Borkhardt A., Holter W., Kremens B., Strahm B., Woessmann W., Mauz-Koerholz C., Gruhn B., Burdach S., Albert M. H., Schlegel P. G., Klingebiel T., Bader P. Preemptive immunotherapy in childhood acute myeloid leukemia for patients showing evidence of mixed chimerism after allogeneic stem cell transplantation. Blood, 2011, vol. 118, no. 20, pp. 5681-5688. https://doi.org/10.1182/blood-2011-04-348805.

18. Zeiser R., Spyridonidis A., Wäsch R., Ihorst G., Grüllich C., Bertz H., Finke J. Evaluation of immunomodulatory treatment based on conventional and lineage-specific chimerism analysis in patients with myeloid malignancies after myeloablative allogeneic hematopoietic cell transplantation. Leukemia, 2005, vol. 19, no. 5, pp. 814-821. https://doi.org/10.1038/sj.leu.2403719.

19. Koldehoff M., Steckel N. K., Hlinka M., Beelen D. W., Elmaagacli A. H. Quantitative analysis of chimerism after allo- geneic stem cell transplantation by real-time polymerase chain reaction with single nucleotide polymorphisms, standard tandem repeats, and Y-chromosome-specific sequences. American Journal of Hematology, 2006, vol. 81, no. 10, pp. 735-746. https://doi.org/10.1002/ajh.20693.

20. Elkaim E., Picard C., Galambrun C., Barlogis V., Loundou A., Curtillet C., Oudin C., Thuret I., Chambost H., Michel G. Peripheral blood cells chimerism after unrelated cord blood transplantation in children: kinetics, predictive factors and impact on post-transplant outcome. British Journal of Haematology, 2014, vol. 166, no. 4, pp. 557-565. https://doi.org/10.1111/bjh.12918.

21. Nikolousis E., Robinson S., Nagra S., Brookes C., Kinsella F., Tauro S., Jeffries S., Griffiths M., Mahendra P., Cook M., Paneesha S., Lovell R., Kishore B., Chaganti S., Malladi R., Raghavan M., Moss P., Milligan D., Craddock C. Post-transplant T cell chimerism predicts graft versus host disease but not disease relapse in patients undergoing an alemtuzumab based reduced intensity conditioned allogeneic transplant. Leukemia Research, 2013, vol. 37, no. 5, pp. 561-565. https://doi.org/10.1016/j.leukres.2013.01.010.

22. Van Leeuwen J. E., van Tol M. J., Joosten A. M., Wijnen J. T., Khan P. M., Vossen J. M. Mixed T-lymphoid chimerism after allogeneic bone marrow transplantation for hematologic malignancies of children is not correlated with relapse. Blood, 1993, vol. 82, no. 6, pp. 1921-1928.

23. Alizadeh M., Bernard M., Danic B., Dauriac C., Birebent B., Lapart C., Lamy T., Le Prisé P. Y., Beauplet A., Bories D., Semana G., Quelvennec E. Quantitative assessment of hematopoietic chimerism after bone marrow transplantation by real-time quantitative polymerase chain reaction. Blood, 2002, vol. 99, no. 12, pp. 4618-4625.

24. Lavrinenko V. A., Savitskaya T. V., Volochnik Ye. V., Mareiko Yu. E., Aleynikova O. V. Quantitative analysis of chime-rism after allogeneic hematopoietic stem cell transplantation with molecular genetic methods. Oncohematology, 2014, no. 2, pp. 29-36. (in Russian).

25. Kaplan E., Meier P. Nonparametric estimation from incomplete observations. Journal of the American Statistical Association, 1958, vol. 53, no. 282, pp. 457-481.

26. Gooley T. A., Leisenring W., Crowley J., Storer B. E. Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Statistics in Medicine, 1999, vol. 18, no. 6, pp. 695-706.

27. Gray R. A class of K-sample tests for comparing the cumulative incidence of a competing rick. The Annals of Statistics, 1988, vol. 16, no. 3, pp. 1140-1154.

28. Imahashi N., Ohashi H., Terakura S., Miyao K., Sakemura R., Kato T., Sawa M., Yokohata E., Kurahashi S., Ozawa Y., Nishida T., Kiyoi H., Watamoto K., Kohno A., Kasai M., Kato C., Iida H., Naoe T., Miyamura K., Murata M. Nagoya Blood and Marrow Transplantation Group. Chimerism status after unrelated donor bone marrow transplantation with fludarabinemelphalan conditioning is affected by the melphalandose and is predictive of relapse. Annals of Hematology, 2015, vol. 94, no. 7, pp. 1139-1148. https://doi.org/10.1007/s00277-015-2312-4.

29. Saito B., Fukuda T., Yokoyama H., Kurosawa S., Takahashi T., Fuji S., Takahashi N., Tajima K., Kim S. W., Mori S., Tanosaki R., Takaue Y., Heike Y. Impact of T cell chimerism on clinical outcome in 117 patients who underwent allogeneic stem cell transplantation with a busulfan-containing reduced-intensity conditioning regimen. Biology of Blood and Marrow Transplantation, 2008, vol. 14, no. 10, pp. 1148-1155. https://doi.org/10.1016/j.bbmt.2008.07.013.

30. Koreth J., Kim H. T., Nikiforow S., Milford E. L., Armand P., Cutler C., Glotzbecker B., Ho V. T., Antin J. H., Soiffer R. J., Ritz J., Alyea E. P. Donor chimerism early after reduced-intensity conditioning hematopoietic stem cell transplantation predicts relapse and survival. Biology of Blood and Marrow Transplantation, 2014, vol. 20, no. 10, pp. 1516-1521. https://doi.org/10.1016/j.bbmt.2014.05.025.

31. Peterlin P., Delaunay J., Guillaume T., Gastinne T., Mahé B., Dubruille V., Blin N., Le Bourgeois A., Brissot E., Lodé L., Le Gouill S., Moreau P., Mohty M., Chevallier P. Complete donor T cell chimerism predicts lower relapse incidence after standard double umbilical cord blood reduced-intensity conditioning regimen allogeneic transplantation in adults. Biology of Blood and Marrow Transplantation, 2015, vol. 21, no. 1, pp. 180-184. https://doi.org/10.1016/j.bbmt.2014.08.018.

32. Huisman C., de Weger R. A., de Vries L., Tilanus M. G., Verdonck L. F. Chimerism analysis within 6 months of allogeneic stem cell transplantation predicts relapse in acute myeloid leukemia. Bone Marrow Transplantation, 2007, vol. 39, no. 5, pp. 285-291. https://doi.org/10.1038/sj.bmt.1705582.

33. Wiedemann B., Klyuchnikov E., Kröger N., Zabelina T., Stahl T., Zeschke S., Badbaran A., Ayuk F., Alchalby H., Wolschke C., Bokemeyer C., Fehse B., Zander A. R., Bacher U. Chimerism studies with quantitative real-time PCR in stem cell recipients with acute myeloid leukemia. Experimental Hematology, 2010, vol. 38, no. 12, pp. 1261-1271. https://doi.org/10.1016/j.exphem.2010.08.006.

34. Jiménez-Velasco A., Barrios M., Román-Gómez J., Navarro G., Buño I., Castillejo J. A., Rodríguez A. I., García-Gemar G., Torres A., Heiniger A. I. Reliable quantification of hematopoietic chimerism after allogeneic transplantation for acute leukemia using amplification by real-timePCR of null alleles and insertion/deletion polymorphisms. Leukemia, 2005, vol. 19, no. 3, pp. 336-343. https://doi.org/10.1038/sj.leu.2403622.

35. Horky O., Mayer J., Kablaskova L., Razga F., Krejci M., Kissova J., Borsky M., Jeziskova I., Dvorakova D. Increasing hematopoietic microchimerism is a reliable indicator of incipient AML relapse. International Journal of Laboratory Hematology, 2011, vol. 33, no. 1, pp. 57-66. https://doi.org/10.1111/j.1751-553X.2010.01249.x.

36. Willasch A. M., Kreyenberg H., Shayegi N., Rettinger E., Meyer V., Zabel M., Lang P., Kremens B., Meisel R., Strahm B., Rossig C., Gruhn B., Klingebiel T., Niemeyer C. M., Bader P. Monitoring of hematopoietic chimerism after transplantation for pediatric myelodysplastic syndrome: real-time or conventional short tandem repeat PCR in peri- pheral blood or bone marrow? Biology of Blood and Marrow Transplantation, 2014 , vol. 20, no. 12, pp. 1918-1925. https://doi.org/10.1016/j.bbmt.2014.07.030.

37. Qin X. Y., Li G. X., Qin Y. Z., Wang Y., Wang F. R., Liu D. H., Xu L. P., Chen H., Han W., Wang J. Z., Zhang X. H., Li J. L., Li L. D., Liu K. Y., Huang X. J. Quantitative chimerism: an independent acute leukemia prognosis indicator following allogeneic hematopoietic SCT. Bone Marrow Transplantation, 2014, vol. 49, no. 10, pp. 1269-1277. https://doi.org/10.1038/bmt.2014.158.

38. Barrios M., Jiménez-Velasco A., Román-Gómez J., Madrigal M. E., Castillejo J. A., Torres A., Heiniger A. Chimerism status is a useful predictor of relapse after allogeneic stem cell transplantation for acute leukemia. Haematologica, 2003, vol. 88, no. 7, pp. 801-810.

39. Mo X. D., Kong J., Zhao T., Xu L. P., Zhang X. H., Liu D. H., Wang Y., Chen H., Yan C. H., Chen Y. H., Han W., Wang F. R., Wang J. Z., Liu K. Y., Huang X. J. Extramedullary relapse of acute leukemia after haploidentical hematopoietic stem cell transplantation: incidence, risk factors, treatment, and clinical outcomes. Biology of Blood and Marrow Transplantation, 2014, vol. 20, no. 12, pp. 2023-2028. https://doi.org/10.1016/j.bbmt.2014.08.023.

40. Mattsson J., Uzunel M., Tammik L., Aschan J., Ringdén O. Leukemia lineage-specific chimerism analysis is a sensitive predictor of relapse in patients with acute myeloid leukemia and myelodysplastic syndrome after allogeneic stem cell transplantation. Leukemia, 2001, vol. 15, no. 12, pp. 1976-1985.