poor graft function

Severe Hypofunction of Allogeneic Hematopoietic Stem Cell Transplant in Patients with Oncohematological Diseases: Incidence, Risk Factors, and Outcomes

BONE MARROW TRANSPLANTATION ,

TA Rudakova, AD Kulagin, OU Klimova, IK Golubovskaya, EI Darskaya, TA Bykova, AG Smirnova, EV Morozova, SN Bondarenko, IS Moiseev, AV Beinarovich, DE Pevtsov, AL Alyanskii, EV Babenko, IM Barkhatov, BV Afanas’ev

RM Gorbacheva Scientific Research Institute of Pediatric Oncology, Hematology and Transplantation; IP Pavlov First Saint Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

For correspondence: Tat’yana Aleksandrovna Rudakova, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022; e-mail: t_a_rudakova@mail.ru

For citation: Rudakova TA, Kulagin AD, Klimova OU, et al. Severe Hypofunction of Allogeneic Hematopoietic Stem Cell Transplant in Patients with Oncohematological Diseases: Incidence, Risk Factors, and Outcomes. Clinical oncohematology. 2019;12(3):309–18 (In Russ).

doi: 10.21320/2500-2139-2019-12-3-309-318

ABSTRACT

Aim. Based on strict criteria, to assess incidence, pretransplantation risk factors, and outcomes of severe hypofunction of graft, i.e. poor graft function (sPGF), following allogeneic hematopoietic stem cell transplantation (allo-HSCT) in adults.

Materials & Methods. The trial included 710 adult patients (median age was 31 years, range 18–70 years; 55 % male and 45 % female patients) with different hematological diseases and documented transplant engraftment after allo-HSCT from matched sibling (20 %), unrelated (67 %) and haploidentical (13 %) donors in the period from 2008 to 2016. Myeloablative and reduced-intensity conditioning regimens were administered in 30 % and 70 % of patients, respectively. The analysis was based on the following sPGF criteria: 2 or more lines of cytopenia (thrombocytes < 20 × 109/L, absolute neutrophil count < 0.5 × 109/L, and hemoglobin < 70 g/L at any time after documented engraftment), complete or stable mixed donor chimerism > 90 %, and absence of relapse signs, rejection, and severe acute graft-versus-host reaction. The following factors were analyzed: age, sex, diagnosis, presence/absence of remission in acute leukemias, ferritin level, type of donor, HLA-match, blood group and sex match, transplant origin, number of transplanted CD34+ cells, and conditioning regimen. Multivariate analysis included parameters of univariate analysis with p < 0.05.

Results. After allo-HSCT sPGF was identified in 103 patients with 2-year cumulative incidence of 15 % (95% confidence interval [95% CI] 12–18 %). In most cases sPGF developed during the 1st year after allo-HSCT (median 50 days). Bi- and trilineage cytopenia was found in 59 % and 41 % of cases, respectively. In multivariate analysis sPGF risk was associated with myelodysplastic syndrome, myeloproliferative disorders (hazard ratio [HR] 3.403; 95% CI 1.972–5.606; p < 0.0001), and haploidentical donors (HR 3.830; 95% CI 1.545–8.828; p = 0.001). The absence of remission at the time of allo-HSCT in acute leukemias and blood group incompatibility were of borderline significance. In 50 % of cases sPGF determined poor outcome, including death from cytopenia-related complications, further relapses, and graft rejection. Prognosis of bilineage sPGF was slightly more favorable than that of trilineage sPGF.

Conclusion. The present large cohort trial yielded the incidence and analyzed the structure of sPGF in adult patients with oncohematological diseases. In addition, the key pretransplantation sPGF risk factors were identified. The results of the trial can serve to optimize the choice of therapy after allo-HSCT.

Keywords: allogeneic hematopoietic stem cell transplantation, poor graft function.

Received: March 6, 2018

Accepted: June 20, 2019

Read in PDF 

REFERENCES

  1. Sureda A, Bader P, Cesaro S, et al. Indications for allo- and auto-SCT for haematological diseases, solid tumours and immune disorders: current practice in Europe, 2015. Bone Marrow Transplant. 2015;50(8):1037–56. doi: 10.1038/bmt.2015.6.

  2. Афанасьев Б.В., Зубаровская Л.С., Семенова Е.В. и др. Опыт применения неродственной аллогенной трансплантации стволовых гемопоэтических клеток в клинике трансплантации костного мозга СПБГМУ им. акад. И.П. Павлова. Терапевтический архив. 2007;79(7):36–43.

    [Afanas’ev BV, Zubarovskaya LS, Semenova EV, et al. Experience of non-related allogeneic transplantation of stem hematopoietic cells in the Clinic of Bone Marrow Transplantation at I.P. Pavlov St. Petersburg Medical University. Terapevticheskii arkhiv. 2007;79(7):36–43. (In Russ)]

  3. Афанасьев Б.В., Зубаровская Л.С., Моисеев И.С. Аллогенная трансплантация гемопоэтических стволовых клеток у детей: настоящее, проблемы, перспективы. Российский журнал детской гематологии и онкологии. 2015;2(2):28–42. doi: 10.17650/2311-1267-2015-2-2-28-42.

    [Afanasiev BV, Zubarovskaya LS, Moiseev IS. Allogeneic hematopoietic stem cell transplantation in children: now, problems and prospects. Russian Journal of Children Hematology and Oncology. 2015;2(2):28–42. doi: 10.17650/2311-1267-2015-2-2-28-42. (In Russ)]

  4. Румянцев А.Г., Масчан А.А. Трансплантация гемопоэтических стволовых клеток у детей. М.: МИА, 2003. 912 с.

    [Rumyantsev AG, Maschan AA. Transplantatsiya gemopoeticheskikh stvolovykh kletok u detei. (Hematopoietic stem cell transplantation in children.) Moscow: MIA Publ.; 2003. 912 p. (In Russ)]

  5. Савченко В.Г., Любимова Л.С., Паровичникова Е.Н. и др. Трансплантация аллогенных и аутологичных гемопоэтических стволовых клеток при острых лейкозах (итоги 20-летнего опыта). Терапевтический архив. 2007;79(7):30–5.

    [Savchenko VG, Lyubimova LS, Parovichnikova EN, et al. Transplantation of allogeneic and autologous hematopoietic stem cells in acute leukemias (summary of 20-year experience). Terapevticheskii arkhiv. 2007;79(7):30–5. (In Russ)]

  6. Olsson R, Remberger M, Schaffer M, et al. Graft failure in the modern era of allogeneic hematopoietic SCT. Bone Marrow Transplant. 2013;48(4):537–43. doi: 10.1038/bmt.2012.239.

  7. Locatelli F, Lucarelli B, Merli P. Current and future approaches to treat graft failure after allogeneic hematopoietic stem cell transplantation. Expert Opin Pharmacother. 2014;15(1):23–36. doi: 10.1517/14656566.2014.852537.

  8. Kong Y, Chang Y-J, Wang Y-Z, et al. Association of an impaired bone marrow microenviroment with secondary poor graft function after allogenic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2013;19(10):1465–73. doi: 10.1016/j.bbmt.2013.07.014.

  9. Stasia A, Ghiso A, Galaverna F, et al. CD34 selected cells for the treatment of poor graft function following allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2014;20(9):1440–3. doi: 10.1016/j.bbmt.2014.05.016.

  10. Лисуков И.А., Успенская О.С., Кулагин А.Д. и др. Использование ромиплостима в терапии тромбоцитопений после аллогенной трансплантации костного мозга. Онкогематология. 2012;7(1):29–34. doi: 17650/1818-8346-2012-7-1-29-34.

    [Lisukov IA, Uspenskaya OS, Kulagin AD, et al. Romiplostim in thrombocytopenia treatment after allogeneic bone marrow transplantation. Oncohematology. 2012;7(1):29–34. doi: 10.17650/1818-8346-2012-7-1-29-34. (In Russ)]

  11. Алянский А.Л., Макаренко О.А., Иванова Н.Е. и др. Развитие регистра неродственных доноров костного мозга в Российской Федерации: опыт НИИ детской онкологии, гематологии и трансплантологии им. Р.М. Горбачeвой. Российский журнал детской гематологии и онкологии. 2016;3(2):68–74. doi: 10.17650/2311-1267-2016-3-2-68-74.

    [Alyanskiy AL, Makarenko OA, Ivanova NE, et al. Development of donor bone marrow registry in Russian Federation: experience of Raisa Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation. Russian Journal of Children Hematology and Oncology. 2016;3(2):68–74. doi: 10.17650/2311-1267-2016-3-2-68-74. (In Russ)]

  12. Serov YA, Barkhatov IM, Klimov AS, Berkos AS. Current methods and opportunities of next-generation sequencing (NGS) for HLA-typing. Cellular Therapy and Transplantation. 2016;5(4):63–70. doi: 10.18620/ctt-1866-8836-2016-5-4-63-70.

  13. Бархатов И.М., Шакирова А.И., Евдокимов А.В. и др. InDel-полиморфизм в количественной оценке посттрансплантационного химеризма. Ученые записки СПбГМУ им. акад. И.П. Павлова. 2016;23(4):40–5. doi: 10.24884/1607-4181-2016-23-4-40-45.

    [Barkhatov IM, Shakirova AI, Evdokimov AV, et al. InDel polymorphisms in quantitative posttransplant chimerism evaluation. The Scientific Notes of the I.P. Pavlov St. Petersburg State Medical University. 2016;23(4):40–5. doi: 10.24884/1607-4181-2016-23-4-40-45. (In Russ)]

  14. Valcarcel D, Sureda A. Graft Failure. In: E Carreras, C Dufour, M Mohty, N Kroger, eds. The EBMT Handbook. Hematopoietic Stem Cell Transplantation and Cellular Therapies. Springer, Cham; 2019. pp. 314. doi: 10.1007/978-3-030-02278-5.

  15. Davies SM, Weisdorf DJ, Haake RJ, et al. Second infusion of bone marrow for treatment of graft failure after allogeneic bone marrow transplantation. Bone Marrow Transplant. 1994;14:73–7.

  16. Dominietto A, Raiola AM, van Lint MT, et al. Factors influencing haematological recovery after allogeneic haemopoietic stem cell transplants: graft-versus-host disease, donor type, cytomegalovirus infections and cell dose. Br J Haematol. 2001;112(1):219–27. doi: 10.1046/j.1365-2141.2001.02468.x.

  17. Rondon G, Saliba RM, Khouri I, et al. Long Term Follow Up Of Patients Who Experienced Graft failure Post Allogeneic Progenitor Cell Transplantation. Results of a Single Institution Analysis. Biol Blood Marrow Transplant. 2008;14(8):859–66. doi: 10.1016/j.bbmt.2008.05.005.

  18. Tamari R, Ramnath Sh, Kuk D, et al. Poor graft function in recipients of T-cell depleted (TCD) allogeneic hematopoietic cell transplants (HSCT) is mostly related to viral infections and anti-viral therapy. Blood. 2012;120:3147.

  19. Xiao Y, Song J, Jiang Z, et al. Risk-Factor Analysis of Poor Graft Function after Allogeneic Hematopoietic Stem Cell Transplantation. Int J Med Sci. 2014;11(6):652–7. doi: 10.7150/ijms.6337.

  20. Askaa B, Fischer-Nielsen A, Vindelov L, et al. Treatment of poor graft function after allogeneic hematopoietic cell transplantation with a booster of CD34-selected cells infused without conditioning. Bone Marrow Transplant. 2014;49(5):720–1. doi: 10.1038/bmt.2014.5.

  21. Tang C, Chen F, Rong D, et al. Successful treatment of secondary poor graft function post allogeneic hematopoietic stem cell transplantation with eltrombopag. J Hematol Oncol. 2018;11(1):103. doi: 10.1186/s13045-018-0649-6.

  22. Rudakova TA, Eismont YuA, Moiseev IS, et al. Role of polyomavirus in emerging secondary hypofunction of marrow graft following allogeneic bone marrow transplantation in adults. Cellular Therapy and Transplantation. 2016;5(3):79–82. doi: 10.18620/ctt-1866-8836-2016-5-3-79-82.

  23. Alchalby H, Yunus D-R, Zabelina T, et al. Incidence and risk factors of poor graft function after allogeneic stem cell transplantation for myelofibrosis. Bone Marrow Transplant. 2016;51(9):1223–7. doi: 10.1038/bmt.2016.98.

  24. Klyuchnikov E, El-Cheikh J,Sputtek A, et al. CD34(+)-selected stem cell boost without further conditioning for poor graft function after allogeneic stem cell transplantation in patients with hematological malignancies. Biol Blood Marrow Transplant. 2014;20(3):382–6. doi: 10.1016/j.bbmt.2013.11.034.

  25. Kroger N, Holler E, Kobbe G, et al. Allogeneic stem cell transplantation after reduced-intensity conditioning in patients with myelofibrosis: a prospective, multicenter study of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Blood. 2009;114(26):5264–70. doi: 10.1182/blood-2009-07-234880.

  26. Bacigalupo A, Soraru M, Dominietto A, et al. Allogeneic hemopoietic SCT for patients with primary myelofibrosis: a predictive transplant score based on transfusion requirement, spleen size and donor type. Bone Marrow Transplant. 2010;45(3):458–63. doi: 10.1038/bmt.2009.188.

  27. Akpek G, Pasquini MC, Logan B, et al. Effects of spleen status on early outcomes after hematopoietic cell transplantation. Bone Marrow Transplant. 2013;48(6):825–31. doi: 10.1038/bmt.2012.249.

  28. Champlin RE, Horowitz MM, van Bekkum DW, et al. Graft failure following bone marrow transplantation for severe aplastic anemia: risk factors and treatment results. Blood. 1989;73:606–13.

  29. Shi M-M, Kong Y, Song Y, et al. Atorvastatin enhances endothelial cell function in posttransplant poor graft function. Blood. 2016;128(25):2988–99. doi: 10.1182/blood-2016-03-702803.

  30. Armand P, Kim HT, Cutler CS, et al. Prognostic impact of elevated pretransplantation serum ferritin in patients undergoing myeloablative stem-cell transplantation. Blood. 2007;109(10):4586–8. doi: 1182/blood-2006-10-054924.

  31. Shaheen M, Ivanova MO, Moiseev IS, et al. Impact of initial serum ferritin on early post-HSCT complications: a single-center study. Cellular Therapy and Transplantation. 2016;5(2):40–9. doi: 10.18620/1866-8836-2016-5-2-40-49.

  32. Chang Y-J, Zhao X-Y, Xu L-P, et al. Donor-specific anti-human leukocyte antigen antibodies were associated with primary graft failure after unmanipulated haploidentical blood and marrow transplantation: a prospective study with randomly assigned training and validation sets. J Hematol Oncol. 2015;8(1):84. doi: 10.1186/s13045-015-0182-9.

  33. Lee K-H, Lee J-H, Choi S-J et al. Failure of trilineage blood cell reconstitution after initial neutrophil engraftment in patients undergoing allogeneic hematopoietic cell transplantation – frequency and outcomes. Bone Marrow Transplant. 2004;33(7):729–34. doi: 10.1038/sj.bmt.1704428.

  34. Larocca A, Piaggio G, Podesta M, et al. Boost of CD34+-selected peripheral blood cells without further conditioning in patients with poor graft function following allogeneic stem cell transplantation. Haematologica. 2006;91:935–40.