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Original article

The frequency of poor engraftment after allogeneic hematopoietic stem cell transplantation

Nikola Peulić1, Milena Todorović-Balint1, Nikola Lemajić1

ABSTRACT

Introduction: Poor engraftment represents one of the possible complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). It presents as pancytopenia or bicytopenia, with or without complete donor chimerism. There are three entities of poor engraftment: poor graft function (PGF), graft failure (GF), and graft rejection (GR).

Aim: This study aims to show the frequency of poor engraftment, as well as the frequency of all of its entities individually, among the patients of the Clinic of Hematology of the University Clinical Center of Serbia (UCCS), who underwent allo-HSCT between December 20, 2017 and December 25, 2020, for the purpose of achieving improved management and understanding of this serious complication.

Materials and methods: This retrospective cohort study included 58 patients. Diagnosis of poor engraftment was confirmed by pancytopenia (cut off values: hemoglobin < 70g/L; platelet count < 20 x 109 /L; absolute neutrophil count (ANC) < 0.5 x 109 /L), for three consecutive days, as of day D+28, with the exclusion of severe graft versus host disease (GvHD) and relapse, with complete donor chimerism in PGF and with incomplete donor chimerism in GF. GR presented as acute rejection of the graft by the recipient with bone marrow aplasia or pancytopenia.

Results: Poor engraftment was confirmed in 13 of 58 patients (22.4%). Patients with PGF were the majority, with 12.1% (seven patients), while patients with GF and those with GR had the same incidence of 5.2% (three patients). Overall survival for patients with poor engraftment after allo-HSCT was five months, which is significantly less than the overall survival of the patients who had good engraftment after allo-HSCT (57 months).

Conclusion: The three types of poor engraftment must be precisely discriminated and diagnosed in relation to donor chimerism in order to decrease morbidity and mortality in patients, post allo-HSCT.


INTRODUCTION

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the replacement and repopulation of the hematopoietic tissue of the recipient with the hematopoietic tissue of another person, who may be related to the recipient or is found through a search in the donor registry. It is a method of treating high-risk hematological diseases, such as the following: acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), myelodysplastic/myeloproliferative syndrome (MDS/ MPN), severe aplastic anemia (SAA), Hodgkin’s lymphoma (HL), and Non-Hodgkin’s lymphoma (NHL).

Upon successful allogeneic transplantation, in addition to relapse, complications, such as graft versus host disease (GvHD) or different forms of poor engraftment, may occur.

Poor engraftment manifests as pancytopenia with complete donor chimerism (poor graft function (PGF)), pancytopenia with incomplete donor chimerism (graft failure (GF)), or graft rejection (GR) can occur, which manifests as bone marrow aplasia and/or pancytopenia [1],[2],[3].

PGF is a life-threatening complication, characterized by cell loss in two or three blood cell lineages with bone marrow hypoplasia and the occurrence of complete donor chimerism. With the rapid development of allogeneic HSCT, especially haploidentical-HSCT, PGF has become an important ongoing problem. The most common risk factors for the development of PGF are as follows: low dose of donor CD34+ cells, donor specific antibodies (DSA), cytomegalovirus (CMV) infection, graft versus host disease (GvHD), excess iron saturation, splenomegaly, and other factors [1],[2],[3],[4],[5],[6],[7].

GF is defined as the lack of donor cells upon engraftment in allo-HSCT. It may be primary or secondary.

Primary GF is defined as incomplete engraftment and recovery of donor cells in the patient within the first month following allo-HSCT, without the occurrence of relapse. Secondary GF relates to the loss of a previously functional graft, resulting in cytopenia, in at least two cell lineages. Primary GF is more frequently linked to severe clinical presentation and a poorer prognosis than secondary GF [8].

As a medical term, GR relates to the immune-mediated reaction of residual host cells to donor cells, which is why it is linked only to allo-HSCT. In international literature, it is often noted along with GF, as its subentity [8],[9].

Review of available literature shows that poor engraftment and its incidence have been one of the leading topics regarding allogeneic transplantation, in the previous ten years. A study by Zhao et al., carried out in the period between 2014 and 2018, shows that the presence of PGF was confirmed in 43 out of 830 patients who had undergone allo-HSCT [1]. The incidence of GF varies depending on the transplantation modality, as well as on the different studies and reports [8]. Analysis of 23,272 patients from the Center for International Blood and Marrow Transplant Research (CIBMTR) database demonstrated a GF incidence of 5.5 %, in 2015, while a year later, in a large retrospective cohort study, which included 4,684 unrelated allogeneic transplantations (2006 - 2012), an GF incidence of 3.8% was confirmed [9].

Bearing in mind the results from previous studies, the aim of this paper is to demonstrate the incidence of poor engraftment in patients who underwent allo-HSCT in the period between December 20, 2017 and December 25, 2020, at the Clinic of Hematology of the University Clinical Center of Serbia (UCCS), as well as to demonstrate the incidence of each type of poor engraftment individually, for the purpose of understanding this ongoing problem more thoroughly and improving the way that it is resolved.

MATERIALS AND METHODS

This retrospective cohort study involved 58 patients treated at the Clinic of Hematology of the UCCS, of whom 33 male and 25 female subjects, of a median age of 38 years (range: 19 – 59 years). Of the 58 patients, five died before engraftment. The patients were diagnosed with the following diseases: Hodgkin’s lymphoma (HL), Non-Hodgkin’s lymphoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and myelodysplastic/myeloproliferative syndrome (MDS/MPN).

According to protocol, the day when the neutrophil count was 1 x 109 and the platelet count was above 20 x 109 , for the third consecutive day, without previous thrombocyte transfusion, was taken as the day of engraftment. The conditioning regimens represent the application of chemotherapeutic agents and/or radiation therapy prior to allogeneic HSCT, and according to their intensity they can be categorized as myeloablative conditioning (MAC) regimens, which lead to complete bone marrow ablation, and reduced-intensity conditioning (RIC) regimens, which use lower doses of radiation and chemotherapeutic agents.

For infection prophylaxis in allo-HSCT, the following protocol was observed:

  1. Antibacterial prophylaxis (the quinolone levofloxacin, 500 mg per os (p.o.))
  2. Trimethoprim-sulfamethoxazole, 2 x 400 mg p.o., until D+90 (against: Toxoplasma gondii and Pneumocystis jirovecii)
  3. Antiviral prophylaxis: acyclovir, 3 x 400 mg p.o.
  4. Antifungal prophylaxis: micafungin, 50 mg IV, for two weeks, as of D0 until engraftment, then posaconazole, 3 x 200 mg p.o. (sol.) until D+90

In keeping with the standard protocol, prevention of GvHD was carried out through the implementation of immunosuppressive therapy (IST), within the conditioning regimen with antithymocyte globulin (ATG), (dose for unrelated transplantation: 20 mg/kg BM; dose for unrelated transplantation: 10 mg/kg BM, D–3 to D–1), with cyclosporine, at a dose of 3 mg/kg BM, from D-1 to D+180, with the application of the Seattle protocol for related allogeneic transplantations, namely: methotrexate, at a dose of 15 mg/m2 , D+1, and at a dose of 10 mg/ m2 , D+3 and D+6, while in unrelated transplantation, it was administered on D+11, at a dose of 10 mg/m2.

In keeping with the standard protocol, in case of the development of GvHD, antifungal prophylaxis was continued with posaconazole, along with IST: cyclosporine A (CSA), which was administered at a dose of 3 mg/kg BM until D+180, upon which the dose was gradually reduced. Also, according to protocol, IST medication can subsequently, in case of cyclosporin A toxicity, be replaced with prolonged-release tacrolimus.

According to the current standards, for the purpose of diagnosing poor engraftment in patients, the existence of pancytopenia was determined (hemoglobin level below 70 g/l; absolute neutrophil count (ANC) below 0.5 x 109 /L; platelet count below 20 x 109 /L), for three consecutive days, from D+28, with the exclusion of GvHD and relapse, with complete donor chimerism in PGF and incomplete donor chimerism in GF. GR was diagnosed in acute graft rejection by the recipient, with bone marrow aplasia and pancytopenia.

STATISTICAL ANALYSIS

Initially, a database was formed by grouping and tabulating results according to the patient characteristics being investigated. Descriptive statistical parameters were expressed as the median, mode, and relative frequency distribution. The overall patient survival covered the period from the moment of diagnosis until the lethal outcome, or until December 25, 2020, in living patients. Patient survival, in relation to whether the patients had poor engraftment or not, was analyzed with the Kaplan-Meier method and compared with the use of the log-rank method. The SPSS 23.0 software for Microsoft Windows was used for statistical data processing.

RESULTS

This study involved 58 patients, of whom 33 (56.9%) male and 25 (43.1%) female subjects, of a median age of 38 years (range: 19 – 59 years), (Appendices I and II).

Table 1. Age of patients treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT)

0501

Table 2. Distribution of patients treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT), by sex

0502

Most patients had AML, a total of 26 (44.8%); followed by 18 (31%) ALL patients; next, there were eight HL (13.8%) patients; followed by three (5.1%) NHL patients; as well as also three (5.1%) MDS/MPN patients (Appendix III).

Table 3. Distribution of patients treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT), by their diagnoses

0503

After allo-HSCT, the expected survival was 57 months (Appendix IV). On D+30, complete donor chimerism was achieved by 45 patients (77.6%). The conditioning regimens were RIC and MAC, with a dominance of MAC as compared to RIC – MAC: 74.1% (43 of 58 patients); RIC: 25.9% (15 of 58 patients), (Appendix V).

0504

Figure 1. Overall survival after allogeneic hematopoietic stem cell transplantation (allo-HSCT)

Table 4. Distribution of patients by type of conditioning regimen (MAC vs RIC) and by achievement of donor chimerism on D+30

0505

Poor engraftment was found in 13 (22.5%) patients of all those included in the study, while PGF was present in seven patients (12.1% of 58 patients; 53.8% of 13 patients). GF was present in three (5.2% of 58 patients; 23.1% of 13 patients), while GR was also found in three patients (5.2% of 58 patients; 23.1% of 13 patients), (Appendix VI). The expected survival of patients without poor engraftment was 57 months, while patients with poor engraftment had a survival of five months, which is statistically significantly less (p = 0.002), (Appendix VII).

0506

Figure 2 and 3. Distribution of patients in relation to poor engraftment and in relation to each type of poor engraftment, after allogeneic hematopoietic stem cell transplantation (allo-HSCT)

0507

Figure 4. Overall survival after allogeneic hematopoietic stem cell transplantation (allo-HSCT), in relation to poor engraftment (patients who had poor engraftment (1); patients who did not have poor engraftment (0))

DISCUSSION

Based on the obtained results, the incidence of poor engraftment in our study was 22.4%, while available literature lacks data on the overall incidence of poor engraftment, as previous studies focus on each type of poor engraftment individually.

The incidence of PGF differed from other studies and was 12.1%, which is higher than the studies carried out by Zhao et al. (5.18%) and Sun et al. (5.6%) [1],[4]. The incidence reported in studies varies between 5% and 27%, since there are no exact cut-off values for hemoglobin, thrombocytes, and leukocytes, in pancytopenia diagnosis, which, along with complete chimerism, defines this type of poor engraftment [2]. The most common cause of PGF is CMV infection, which directly (through the infection of bone marrow cells) or indirectly (through the infection of stromal cells) inhibits hematopoiesis, which is substantiated by the fact that every patient with PGF in our study had a CMV infection [7],[10]. Some clinical studies have shown that even antiviral therapy aimed at CMV, especially ganciclovir, may cause myelosuppression after allo-HSCT [11]. Shimomura et al. [5] showed that significant splenomegaly (≥ 340 cm3 ) participates in poor engraftment of thrombocytes and neutrophils after transplantation, in patients diagnosed with AML and MDS. Also, the development of acute GvHD grade II or higher, statistically significantly correlates with PGF (p = 0.001), which is also true of iron overload, which increases the accumulation of reactive oxygen species (ROS), leading to hematopoiesis inhibition and increasing the risk of infection (it serves as food for bacteria and fungi) [12],[13],[14].

Bearing in mind the increasing number of haploidentical allogeneic HSCTs, the matter of the impact of donor specific HLA antibodies (DSA) on the occurrence of PGF has also become an issue for consideration. To that effect, Sun et al. reported a significant connection (PGF incidence of 34% in DSA positive patients vs. 3.2% in DSA negative patients), while Bramanti et al. showed a statistically significant link (two out of 26 patients with PGF had DSA) [3],[4].

On the other hand, the incidence of GF varies between 3.8% and 5.6 %, depending on the different types of transplantation [8]. Our study showed an incidence which was within this interval – it was 5.2%. As opposed to PGF, the main reason for the occurrence of this type of poor engraftment was the immune response of the resident recipient cells, which remained after the implementation of a certain type of conditioning regimen, to the immuno-hematopoietic donor cells. It was demonstrated that donor cytotoxic T cells also have a facilitating effect on engraftment and that their absence significantly effects increased GF incidence [15],[16],[17]. Certain studies have shown that, in non-myeloablative conditioning regimens, i.e., RIC regimens, the probability of poor engraftment or of the occurrence of GF is much higher, while in our study, all three patients diagnosed with GF were on the MAC regimen [18],[19]. A low dose of hematopoietic stem cells during transplantation (values < 2.5 x 109 ), as well as major incompatibility in the ABO system, significantly affect the increase in the risk of GF, both in related and in unrelated transplantation [18],[20]. Since in all our patients, the average dose of hematopoietic stem cells in transplantation was 7 x 109 , and since there was no major incompatibility in any of the three patients, it is probable that the cause of poor engraftment lay in some of the comorbidities that the patients had.

GR is identified as the third type of poor engraftment. Its incidence was the same as in patients with GF, i.e., 5.2%. The incidence cannot be compared to other studies, due to the fact that GR is identified as a subentity of GF, since the immunological reaction of resident immune host cells is at the core of its development. This type of poor engraftment may occur in totally HLAmatched allogeneic transplantations, due to the fact that incompatible T cells originating from the host recognize minor histocompatible antigens (MiHA) on the donor cell membranes and cause a strong immune response [21]. In allogeneic HSCT, regulatory T cells (T-reg), whether originating from the donor or the recipient, play an important part in engraftment. Host T-reg cells produce Il-10 and thereby facilitate the development of a new bone marrow niche [22]. The lack of these cells leads to GR mediated by natural killer cells [23],[24].

In addition to incidence, survival calculated with the Kaplan-Meier curve represents overall cumulative survival for all types of poor engraftment after allogeneic HSCT and shows that the expected survival for patients with poor engraftment was five months, which was statistically significantly shorter (p = 0.002) as compared to patients without poor engraftment (57 months). This poor engraftment can be compared with poor overall survival in each type individually. Sun et al. [4] demonstrated in their study that the overall survival in patients who developed PGF was significantly shorter than in patients with a good graft function (overall survival: 34.6% vs. 82.7%; p < 0.001). In a study investigating five-year survival in patients with primary GF, secondary GF post allo-HSCT, as well as GR post allo-HSCT, the survival was approximately the same: 18%, 11%, and 13% [22].

CONCLUSION

Poor engraftment can result in serious morbidity and mortality after allogeneic HSCT, which is why all three types of poor engraftment must be clearly differentially diagnosed in relation to chimerism, since the defining of the exact type of poor engraftment can significantly influence the therapeutic approach applied to the patient and the final outcome. Viral infections, the presence of GvHD, the iron level (serum ferritin as marker), and splenomegaly, must be evaluated before the diagnosis of poor engraftment is established. Also, the level of DSA needs to be determined prior to allo-HSCT, especially in haploidentical transplantation, in order to avoid poor engraftment and achieve successful engraftment, with the aid of the appropriate conditioning regimen. A higher incidence of poor engraftment speaks in favor of identifying the appropriate therapy for preventing this ongoing problem and improving its outcome.

LIST OF ABBREVIATIONS AND ACRONYMS

allo-HSCT – allogeneic hematopoietic stem cell transplantation
GvHD – graft versus host disease
PGF – poor graft function
GF – graft failure
GR – graft rejection
CMV – cytomegalovirus
ALL – acute lymphoblastic leukemia
AML – acute myeloid leukemia
HLL – chronic lymphocytic leukemia
HL – Hodgkin’s lymphoma
NHL – Non-Hodgkin’s lymphoma
SAA – severe aplastic anemia
MDS/MPN – myelodysplastic/myeloproliferative syndrome
MAC – myeloablative conditioning
RIC – reduced intensity conditioning
DSA – donor specific antibodies
MiHA – minor histocompatibility antigens
ROS – reactive oxygen species
IST – immunosuppressive therapy
CSA – cyclosporin A
ATG – anti-thymocyte globulin
T-reg – regulatory T cells
p. o. – per os
IV – intravenous
BM – body mass

  • Conflict of interest:
    None declared.

Informations

Volume 3 No 3

Volume 3 No 3

September 2022

Pages 323-333
  • Keywords:
    poor graft function, graft failure, graft rejection, allo-HSCT
  • Received:
    13 August 2022
  • Revised:
    04 September 2022
  • Accepted:
    09 September 2022
  • Online first:
    25 September 2022
  • DOI:
Corresponding author

Nikola Peulić
Clinic of Hematology, University Clinical Center of Serbia
2 Dr Koste Todorovića Street, Vračar, 11 000 Belgrade, Serbia
E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.


  • 1. Zhao Y, Gao F, Shi J, Luo Y, Tan Y, Lai X, et al. Incidence, Risk Factors, and Outcomes of Primary Poor Graft Function after Allogeneic Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2019 Sep;25(9):1898-1907. doi: 10.1016/j.bbmt.2019.05.036. [CROSSREF]

    2. Chen J, Wang H, Zhou J, Feng S. Advances in the understanding of poor graft function following allogeneic hematopoietic stem-cell transplantation. Ther Adv Hematol. 2020 Aug 17;11:2040620720948743. doi: 10.1177/2040620720948743. [CROSSREF]

    3. Bramanti S, Calafiore V, Longhi E, Mariotti J, Crespiatico L, Sarina B, et al. Donor-Specific Anti-HLA Antibodies in Haploidentical Stem Cell Transplantation with Post-Transplantation Cyclophosphamide: Risk of Graft Failure, Poor Graft Function, and Impact on Outcomes. Biol Blood Marrow Transplant. 2019 Jul;25(7):1395-1406. doi: 10.1016/j. bbmt.2019.02.020. [CROSSREF]

    4. Sun YQ, He GL, Chang YJ, Xu LP, Zhang XH, Han W, et al. The incidence, risk factors, and outcomes of primary poor graft function after unmanipulated haploidentical stem cell transplantation. Ann Hematol. 2015 Oct;94(10):1699-705. doi: 10.1007/s00277-015-2440-x. [CROSSREF]

    5. Shimomura Y, Hara M, Katoh D, Hashimoto H, Ishikawa T. Enlarged spleen is associated with low neutrophil and platelet engraftment rates and poor survival after allogeneic stem cell transplantation in patients with acute myeloid leukemia and myelodysplastic syndrome. Ann Hematol. 2018 Jun;97(6):1049-1056. doi: 10.1007/s00277-018- 3278-9. [CROSSREF]

    6. Akpek G, Pasquini MC, Logan B, Agovi MA, Lazarus HM, Marks DI, et al. Effects of spleen status on early outcomes after hematopoietic cell transplantation. Bone Marrow Transplant. 2013 Jun;48(6):825-31. doi: 10.1038/bmt.2012.249. [CROSSREF]

    7. Cho SY, Lee DG, Kim HJ. Cytomegalovirus Infections after Hematopoietic Stem Cell Transplantation: Current Status and Future Immunotherapy. Int J Mol Sci. 2019 May 30;20(11):2666. doi: 10.3390/ ijms20112666. [CROSSREF]

    8. Ozdemir ZN, Civriz Bozdağ S. Graft failure after allogeneic hematopoietic stem cell transplantation. Transfus Apher Sci. 2018 Apr;57(2):163- 167. doi: 10.1016/j.transci.2018.04.014. [CROSSREF]

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    10. Torok-Storb B, Boeckh M, Hoy C, Leisenring W, Myerson D, Gooley T. Association of specific cytomegalovirus genotypes with death from myelosuppression after marrow transplantation. Blood. 1997 Sep 1;90(5):2097-102. [CROSSREF]

    11. Shmueli E, Or R, Shapira MY, Resnick IB, Caplan O, Bdolah-Abram T, et al. High rate of cytomegalovirus drug resistance among patients receiving preemptive antiviral treatment after haploidentical stem cell transplantation. J Infect Dis. 2014 Feb 15;209(4):557-61. doi: 10.1093/ infdis/jit475. [CROSSREF]

    12. Peralvo J, Bacigalupo A, Pittaluga PA, Occhini D, Van Lint MT, Frassoni F, et al. Poor graft function associated with graft-versus-host disease after allogeneic marrow transplantation. Bone Marrow Transplant. 1987 Oct;2(3):279-85.

    13. Isidori A, Borin L, Elli E, Latagliata R, Martino B, Palumbo G, et al. Iron toxicity - Its effect on the bone marrow. Blood Rev. 2018 Nov;32(6):473- 479. doi: 10.1016/j.blre.2018.04.004. [CROSSREF]

    14. Ohmoto A, Fuji S, Miyagi-Maeshima A, Kim SW, Tajima K, Tanaka T, et al. Association between pretransplant iron overload determined by bone marrow pathological analysis and bacterial infection. Bone Marrow Transplant. 2017 Aug;52(8):1201-1203. doi: 10.1038/bmt.2017.93. [CROSSREF]

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REFERENCES

1. Zhao Y, Gao F, Shi J, Luo Y, Tan Y, Lai X, et al. Incidence, Risk Factors, and Outcomes of Primary Poor Graft Function after Allogeneic Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2019 Sep;25(9):1898-1907. doi: 10.1016/j.bbmt.2019.05.036. [CROSSREF]

2. Chen J, Wang H, Zhou J, Feng S. Advances in the understanding of poor graft function following allogeneic hematopoietic stem-cell transplantation. Ther Adv Hematol. 2020 Aug 17;11:2040620720948743. doi: 10.1177/2040620720948743. [CROSSREF]

3. Bramanti S, Calafiore V, Longhi E, Mariotti J, Crespiatico L, Sarina B, et al. Donor-Specific Anti-HLA Antibodies in Haploidentical Stem Cell Transplantation with Post-Transplantation Cyclophosphamide: Risk of Graft Failure, Poor Graft Function, and Impact on Outcomes. Biol Blood Marrow Transplant. 2019 Jul;25(7):1395-1406. doi: 10.1016/j. bbmt.2019.02.020. [CROSSREF]

4. Sun YQ, He GL, Chang YJ, Xu LP, Zhang XH, Han W, et al. The incidence, risk factors, and outcomes of primary poor graft function after unmanipulated haploidentical stem cell transplantation. Ann Hematol. 2015 Oct;94(10):1699-705. doi: 10.1007/s00277-015-2440-x. [CROSSREF]

5. Shimomura Y, Hara M, Katoh D, Hashimoto H, Ishikawa T. Enlarged spleen is associated with low neutrophil and platelet engraftment rates and poor survival after allogeneic stem cell transplantation in patients with acute myeloid leukemia and myelodysplastic syndrome. Ann Hematol. 2018 Jun;97(6):1049-1056. doi: 10.1007/s00277-018- 3278-9. [CROSSREF]

6. Akpek G, Pasquini MC, Logan B, Agovi MA, Lazarus HM, Marks DI, et al. Effects of spleen status on early outcomes after hematopoietic cell transplantation. Bone Marrow Transplant. 2013 Jun;48(6):825-31. doi: 10.1038/bmt.2012.249. [CROSSREF]

7. Cho SY, Lee DG, Kim HJ. Cytomegalovirus Infections after Hematopoietic Stem Cell Transplantation: Current Status and Future Immunotherapy. Int J Mol Sci. 2019 May 30;20(11):2666. doi: 10.3390/ ijms20112666. [CROSSREF]

8. Ozdemir ZN, Civriz Bozdağ S. Graft failure after allogeneic hematopoietic stem cell transplantation. Transfus Apher Sci. 2018 Apr;57(2):163- 167. doi: 10.1016/j.transci.2018.04.014. [CROSSREF]

9. Hutt D. Engraftment, Graft Failure, and Rejection. 2017 Nov 22. In: Kenyon M, Babic A, editors. The European Blood and Marrow Transplantation Textbook for Nurses: Under the Auspices of EBMT [Internet]. Cham (CH): Springer; 2018. Chapter 13.

10. Torok-Storb B, Boeckh M, Hoy C, Leisenring W, Myerson D, Gooley T. Association of specific cytomegalovirus genotypes with death from myelosuppression after marrow transplantation. Blood. 1997 Sep 1;90(5):2097-102. [CROSSREF]

11. Shmueli E, Or R, Shapira MY, Resnick IB, Caplan O, Bdolah-Abram T, et al. High rate of cytomegalovirus drug resistance among patients receiving preemptive antiviral treatment after haploidentical stem cell transplantation. J Infect Dis. 2014 Feb 15;209(4):557-61. doi: 10.1093/ infdis/jit475. [CROSSREF]

12. Peralvo J, Bacigalupo A, Pittaluga PA, Occhini D, Van Lint MT, Frassoni F, et al. Poor graft function associated with graft-versus-host disease after allogeneic marrow transplantation. Bone Marrow Transplant. 1987 Oct;2(3):279-85.

13. Isidori A, Borin L, Elli E, Latagliata R, Martino B, Palumbo G, et al. Iron toxicity - Its effect on the bone marrow. Blood Rev. 2018 Nov;32(6):473- 479. doi: 10.1016/j.blre.2018.04.004. [CROSSREF]

14. Ohmoto A, Fuji S, Miyagi-Maeshima A, Kim SW, Tajima K, Tanaka T, et al. Association between pretransplant iron overload determined by bone marrow pathological analysis and bacterial infection. Bone Marrow Transplant. 2017 Aug;52(8):1201-1203. doi: 10.1038/bmt.2017.93. [CROSSREF]

15. Lapidot T, Faktorowich Y, Lubin I, Reisner Y. Enhancement of T-cell-depleted bone marrow allografts in the absence of graft-versus-host disease is mediated by CD8+ CD4- and not by CD8- CD4+ thymocytes. Blood. 1992 Nov 1;80(9):2406-11. [CROSSREF]

16. Martin PJ. Donor CD8 cells prevent allogeneic marrow graft rejection in mice: potential implications for marrow transplantation in humans. J Exp Med. 1993 Aug 1;178(2):703-12. doi: 10.1084/jem.178.2.703. [CROSSREF]

17. Gandy KL, Domen J, Aguila H, Weissman IL. CD8+TCR+ and CD8+TCR- cells in whole bone marrow facilitate the engraftment of hematopoietic stem cells across allogeneic barriers. Immunity. 1999 Nov;11(5):579-90. doi: 10.1016/s1074-7613(00)80133-8. [CROSSREF]

18. Mattsson J, Ringdén O, Storb R. Graft failure after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2008 Jan;14(1 Suppl 1):165-70. doi: 10.1016/j.bbmt.2007.10.025. Erratum in: Biol Blood Marrow Transplant. 2008 Nov;14(11):1317-8. [CROSSREF]

19. Olsson RF, Logan BR, Chaudhury S, Zhu X, Akpek G, Bolwell BJ, et al. Primary graft failure after myeloablative allogeneic hematopoietic cell transplantation for hematologic malignancies. Leukemia. 2015 Aug;29(8):1754-62. doi: 10.1038/leu.2015.75. [CROSSREF]

20. Olsson R, Remberger M, Schaffer M, Berggren DM, Svahn BM, Mattsson J, et al. Graft failure in the modern era of allogeneic hematopoietic SCT. Bone Marrow Transplant. 2013 Apr;48(4):537-43. doi: 10.1038/ bmt.2012.239. [CROSSREF]

21. Vogt MH, de Paus RA, Voogt PJ, Willemze R, Falkenburg JH. DFFRY codes for a new human male-specific minor transplantation antigen involved in bone marrow graft rejection. Blood. 2000 Feb 1;95(3):1100-5. [CROSSREF]

22. Masouridi-Levrat S, Simonetta F, Chalandon Y. Immunological Basis of Bone Marrow Failure after Allogeneic Hematopoietic Stem Cell Transplantation. Front Immunol. 2016 Sep 16;7:362. doi: 10.3389/fimmu.2016.00362. [CROSSREF]

23. Barao I, Hanash AM, Hallett W, Welniak LA, Sun K, Redelman D, et al. Suppression of natural killer cell-mediated bone marrow cell rejection by CD4+CD25+ regulatory T cells. Proc Natl Acad Sci U S A. 2006 Apr 4;103(14):5460-5. doi: 10.1073/pnas.0509249103. [CROSSREF]

24. Rondón G, Saliba RM, Khouri I, Giralt S, Chan K, Jabbour E, et al. Longterm follow-up of patients who experienced graft failure postallogeneic progenitor cell transplantation. Results of a single institution analysis. Biol Blood Marrow Transplant. 2008 Aug;14(8):859-66. doi: 10.1016/j.bbmt.2008.05.005. [CROSSREF]

1. Zhao Y, Gao F, Shi J, Luo Y, Tan Y, Lai X, et al. Incidence, Risk Factors, and Outcomes of Primary Poor Graft Function after Allogeneic Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2019 Sep;25(9):1898-1907. doi: 10.1016/j.bbmt.2019.05.036. [CROSSREF]

2. Chen J, Wang H, Zhou J, Feng S. Advances in the understanding of poor graft function following allogeneic hematopoietic stem-cell transplantation. Ther Adv Hematol. 2020 Aug 17;11:2040620720948743. doi: 10.1177/2040620720948743. [CROSSREF]

3. Bramanti S, Calafiore V, Longhi E, Mariotti J, Crespiatico L, Sarina B, et al. Donor-Specific Anti-HLA Antibodies in Haploidentical Stem Cell Transplantation with Post-Transplantation Cyclophosphamide: Risk of Graft Failure, Poor Graft Function, and Impact on Outcomes. Biol Blood Marrow Transplant. 2019 Jul;25(7):1395-1406. doi: 10.1016/j. bbmt.2019.02.020. [CROSSREF]

4. Sun YQ, He GL, Chang YJ, Xu LP, Zhang XH, Han W, et al. The incidence, risk factors, and outcomes of primary poor graft function after unmanipulated haploidentical stem cell transplantation. Ann Hematol. 2015 Oct;94(10):1699-705. doi: 10.1007/s00277-015-2440-x. [CROSSREF]

5. Shimomura Y, Hara M, Katoh D, Hashimoto H, Ishikawa T. Enlarged spleen is associated with low neutrophil and platelet engraftment rates and poor survival after allogeneic stem cell transplantation in patients with acute myeloid leukemia and myelodysplastic syndrome. Ann Hematol. 2018 Jun;97(6):1049-1056. doi: 10.1007/s00277-018- 3278-9. [CROSSREF]

6. Akpek G, Pasquini MC, Logan B, Agovi MA, Lazarus HM, Marks DI, et al. Effects of spleen status on early outcomes after hematopoietic cell transplantation. Bone Marrow Transplant. 2013 Jun;48(6):825-31. doi: 10.1038/bmt.2012.249. [CROSSREF]

7. Cho SY, Lee DG, Kim HJ. Cytomegalovirus Infections after Hematopoietic Stem Cell Transplantation: Current Status and Future Immunotherapy. Int J Mol Sci. 2019 May 30;20(11):2666. doi: 10.3390/ ijms20112666. [CROSSREF]

8. Ozdemir ZN, Civriz Bozdağ S. Graft failure after allogeneic hematopoietic stem cell transplantation. Transfus Apher Sci. 2018 Apr;57(2):163- 167. doi: 10.1016/j.transci.2018.04.014. [CROSSREF]

9. Hutt D. Engraftment, Graft Failure, and Rejection. 2017 Nov 22. In: Kenyon M, Babic A, editors. The European Blood and Marrow Transplantation Textbook for Nurses: Under the Auspices of EBMT [Internet]. Cham (CH): Springer; 2018. Chapter 13.

10. Torok-Storb B, Boeckh M, Hoy C, Leisenring W, Myerson D, Gooley T. Association of specific cytomegalovirus genotypes with death from myelosuppression after marrow transplantation. Blood. 1997 Sep 1;90(5):2097-102. [CROSSREF]

11. Shmueli E, Or R, Shapira MY, Resnick IB, Caplan O, Bdolah-Abram T, et al. High rate of cytomegalovirus drug resistance among patients receiving preemptive antiviral treatment after haploidentical stem cell transplantation. J Infect Dis. 2014 Feb 15;209(4):557-61. doi: 10.1093/ infdis/jit475. [CROSSREF]

12. Peralvo J, Bacigalupo A, Pittaluga PA, Occhini D, Van Lint MT, Frassoni F, et al. Poor graft function associated with graft-versus-host disease after allogeneic marrow transplantation. Bone Marrow Transplant. 1987 Oct;2(3):279-85.

13. Isidori A, Borin L, Elli E, Latagliata R, Martino B, Palumbo G, et al. Iron toxicity - Its effect on the bone marrow. Blood Rev. 2018 Nov;32(6):473- 479. doi: 10.1016/j.blre.2018.04.004. [CROSSREF]

14. Ohmoto A, Fuji S, Miyagi-Maeshima A, Kim SW, Tajima K, Tanaka T, et al. Association between pretransplant iron overload determined by bone marrow pathological analysis and bacterial infection. Bone Marrow Transplant. 2017 Aug;52(8):1201-1203. doi: 10.1038/bmt.2017.93. [CROSSREF]

15. Lapidot T, Faktorowich Y, Lubin I, Reisner Y. Enhancement of T-cell-depleted bone marrow allografts in the absence of graft-versus-host disease is mediated by CD8+ CD4- and not by CD8- CD4+ thymocytes. Blood. 1992 Nov 1;80(9):2406-11. [CROSSREF]

16. Martin PJ. Donor CD8 cells prevent allogeneic marrow graft rejection in mice: potential implications for marrow transplantation in humans. J Exp Med. 1993 Aug 1;178(2):703-12. doi: 10.1084/jem.178.2.703. [CROSSREF]

17. Gandy KL, Domen J, Aguila H, Weissman IL. CD8+TCR+ and CD8+TCR- cells in whole bone marrow facilitate the engraftment of hematopoietic stem cells across allogeneic barriers. Immunity. 1999 Nov;11(5):579-90. doi: 10.1016/s1074-7613(00)80133-8. [CROSSREF]

18. Mattsson J, Ringdén O, Storb R. Graft failure after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2008 Jan;14(1 Suppl 1):165-70. doi: 10.1016/j.bbmt.2007.10.025. Erratum in: Biol Blood Marrow Transplant. 2008 Nov;14(11):1317-8. [CROSSREF]

19. Olsson RF, Logan BR, Chaudhury S, Zhu X, Akpek G, Bolwell BJ, et al. Primary graft failure after myeloablative allogeneic hematopoietic cell transplantation for hematologic malignancies. Leukemia. 2015 Aug;29(8):1754-62. doi: 10.1038/leu.2015.75. [CROSSREF]

20. Olsson R, Remberger M, Schaffer M, Berggren DM, Svahn BM, Mattsson J, et al. Graft failure in the modern era of allogeneic hematopoietic SCT. Bone Marrow Transplant. 2013 Apr;48(4):537-43. doi: 10.1038/ bmt.2012.239. [CROSSREF]

21. Vogt MH, de Paus RA, Voogt PJ, Willemze R, Falkenburg JH. DFFRY codes for a new human male-specific minor transplantation antigen involved in bone marrow graft rejection. Blood. 2000 Feb 1;95(3):1100-5. [CROSSREF]

22. Masouridi-Levrat S, Simonetta F, Chalandon Y. Immunological Basis of Bone Marrow Failure after Allogeneic Hematopoietic Stem Cell Transplantation. Front Immunol. 2016 Sep 16;7:362. doi: 10.3389/fimmu.2016.00362. [CROSSREF]

23. Barao I, Hanash AM, Hallett W, Welniak LA, Sun K, Redelman D, et al. Suppression of natural killer cell-mediated bone marrow cell rejection by CD4+CD25+ regulatory T cells. Proc Natl Acad Sci U S A. 2006 Apr 4;103(14):5460-5. doi: 10.1073/pnas.0509249103. [CROSSREF]

24. Rondón G, Saliba RM, Khouri I, Giralt S, Chan K, Jabbour E, et al. Longterm follow-up of patients who experienced graft failure postallogeneic progenitor cell transplantation. Results of a single institution analysis. Biol Blood Marrow Transplant. 2008 Aug;14(8):859-66. doi: 10.1016/j.bbmt.2008.05.005. [CROSSREF]


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