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Original article

Incidence and therapy of relapse after allogenic hematopoietic stem cell transplantation

Nikola Lemajić1, Milena Todorović Balint1, Nikola Peulić1

ABSTRACT

Introduction/Aim: Disease relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is one of the most common and most severe post transplantation complications and represents the leading cause of treatment failure and patient death. The aim of this study is to assess the frequency and types of relapse, in relation to the time of occurrence; analyze the influence of conditioning regimens on relapse occurrence; review the therapeutic options after the occurrence of relapse; assess the prognosis in patients with relapse.

Methods: This retrospective cohort study included 58 patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). Pre-transplantation therapy was performed with a reduced-intensity conditioning regimen (RIC) or a myeloablative regimen (MAC). The diagnosis of relapse was made through myelogram analysis, analysis of cytogenetics, analysis of minimal residual disease (MRD), analysis of cellular chimerism, and analysis of immunohematological chimerism of blood group antigens. A database was formed in relation to the examined patient characteristics. Patient survival was analyzed using the Kaplan-Meier method and the log-rang test.

Results: MAC (43 patients) was used more frequently than RIC (15 patients), as a conditioning regimen. After transplantation, 18 (34%) out of 53 patients had a relapse. The choice of regimen did not affect the occurrence of relapse, but patients on the RIC regimen lived longer (38.5 ± 7 months) as compared to patients on the MAC regimen (27.8 ± 3.5 months). However, the difference in survival was without statistical significance (p = 0.318). The median survival time of patients who relapsed was 26 ± 5 months, while patients without disease relapse had a median survival time of 41 ± 4 months.

Conclusion: Patients who received reduced-intensity regimens (RIC) had a longer survival time, without an increase in the relapse rate. In future, consideration should be given to the inclusion of patients older than 60 years, as candidates for transplantation, as well as to the possible use of prophylactic therapy aimed at preventing relapse in high-risk patients.


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. Allogeneic transplantation aims at being a curative method of treating hematological malignancies and it is used in patients in whom the chance of controlling their disease with less invasive treatment methods is small. Transplantation is usually the last therapeutic option.

Possible complications upon transplantation are as follows: rejection of the graft, graft versus host disease (GvHD), graft failure, as well as relapse of the underlying disease.

Relapse is the recurrence of the underlying disease, which the patient had suffered from prior to transplantation, after complete remission of the disease had been achieved with therapy. Data indicates that relapse may be expected in 40 – 45% of recipients of HLA (human leukocyte antigen) identical stem cells, as well as in approximately 35% of stem cells originating from unrelated donors. Relapse can be diagnosed with PCR (polymerase chain reaction) analysis, use of flow cytometry, or bone marrow aspirate evaluation [1],[2].

Relapse can occur early after transplantation, if the initial conditioning regimen was insufficient, if the immune system weakens, or if the disease undergoes immune escape through clonal selection of immune-resistant progenitors. Less frequently, de novo leukemia may develop in the donor cells, which presents as relapse in the form of donor derived leukemia [1].

Relapses most frequently occur in patients with acute leukemia or myelodysplastic syndrome, and it can be expected that half of all relapses will occur within the first six months. Depending on the time when relapse occurs, it can be categorized as early (within the first 100 days), intermediate (within the first 200 days) and late (after 200 days). For certain prognoses, relapse within the first six months is linked to a median survival of six months, with only 5% of cases surviving for more than a year [1].

Therapy of relapse is a great challenge and entails the application of different forms of chemotherapy, as well as targeted biological therapy, radiation therapy, donor lymphocyte infusion, and secondary transplantation.

Donor lymphocyte infusion (DLI) is a form of adaptive immunotherapy which is used after hematopoietic stem cell transplantation, in order to modulate the graft versus tumor effect (GvT), as well as to increase the probability of achieving the engraftment of donor cells. The effect of graft versus tumor cells, i.e., graft versus leukemia (GvL) is of special significance in patients in whom relapse of the underlying disease occurs [3],[4],[5].

The purpose of this study is to use the data from the medical records of the Clinic for Hematology of the University Clinical Center of Serbia (UCCS) in order to: assess the incidence and type of relapse of the underlying disease; analyze the effect of conditioning regimens on the incidence of relapse; analyze the different treatment options and their effect; as well as analyze patient prognosis, all for the purpose of possible prophylactic application of therapy that would prevent relapse after allogeneic hematopoietic stem cell transplantation.

MATERIALS AND METHODS

A total of 58 patients from the Clinic for Hematology of the UCCS, who had undergone allo-HSCT, were included in this cohort study. The patients with the following diagnoses were included: Hodgkin’s lymphoma (HL), Non-Hodgkin’s lymphoma (NHL), acute lymphoblastic leukemia (ALL), acute myeloblastic leukemia (AML), and myelodysplastic/myeloproliferative syndrome (MDS/MPN), which were all established in keeping with the Classification of Tumors of Hematopoietic and Lymphoid Tissues of the World Health Organization (WHO), from 2016 [6].

As conditioning regimens, only those based on chemotherapeutic drugs were used, without the application of radiation therapy prior to allogeneic hematopoietic stem cell transplantation. The conditioning regimens can be categorized, according to their intensity as: myeloablative conditioning (MAC) regimens, which lead to the complete ablation of the bone marrow, and reduced intensity regimens (reduced intensity conditioning – RIC), which do not cause bone marrow ablation in the patient.

GvHD prevention was carried out through the application of immunosuppressive therapy within the conditioning regimen with anti-T lymphocyte globulin and cyclosporine A, at the dose of 3 mg/kg BM, from d-1 to d+180, with the application of the Seattle protocol for related allogeneic transplantations, which entails the use of the following: methotrexate, at the dose of 15 mg/m2 on d+1, and 10mg/m2 on d+3 and d+6, while in unrelated transplantations, it requires to be also used on d+11, at the dose of 10mg/m2.

For the prevention of bacterial infections, the therapy consisted of quinolones, at a dose of 500 mg per os, and trimethoprim-sulfamethoxazole, at a dose of 2 x 400 mg per os, until d+90, as protection against T. Gondi and P. Jirovecii. Antiviral prevention consisted of acyclovir, at a dose of 3 x 400 mg per os. Protection against fungal infections was carried out with micafungin, at a dose of 50 mg IV, for two weeks, from d-0 until engraftment, and after that with posaconazole, until d+90.

The day when the neutrophil count was above 1 x 109 /l and the platelet count was 20 x 109 /l for the third consecutive day, without platelet transfusion, was considered to be the day of engraftment. Patients were tested for cellular chimerism on the following days: d+30, d+90, d+180, and d+360, with the PCR method.

Diagnosis of relapse was established with myelogram analysis, with the analysis of minimal residual disease (MRD), on the basis of the findings of flow cytometry of the bone marrow cells and peripheral blood cells, with PCR analysis of cellular chimerism, as well as with the analysis of immunohematological chimerism of blood group antigens.

STATISTICAL ANALYSIS

Initially, a database was formed by grouping and tabulating results according to the patient characteristics being investigated. Descriptive statistical parameters are 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 the end of December 2020, in living patients. Patient survival, in relation to treatment, was analyzed with the Kaplan-Meier method and compared with the use of the log-rank (Mantel–Cox) test. The SPSS 23.0 for Windows software (IBM Chicago, Illinois, USA) was used for statistical data processing.

RESULTS

The demographic and clinical characteristics of our patients are presented in Table 1.

Table 1. Patient demographic and clinical characteristics

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The greatest number of the donors were patients’ family members, 27 related (46.5%) and 8 haploidentical (13.8%) donors, while 23 (39.6%) patients received stem cells from unrelated donors, found through the search of the registry.

Of the 58 patients included in the study, transplantation was performed in 53 patients, while five patients died in the early induction period. MAC was the most commonly applied induction regimen – in 43 (74.1%) patients, while the RIC regimen was administered to five (25.8%) patients. Chimerism on d+30 was achieved in 45 patients, while it was not achieved in eight patients. Complete remission of the disease was achieved in 47 patients. Relapse upon transplantation occurred in 18 (34%) patients out of 53 (Table 2).

Table 2. Use of the conditioning regimen, chimerism after allogenic hematopoietic stem cell transplantation (allo-HSCT), distribution in relation to the achievement of complete remission and in relation to the relapse of the underlying disease

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The average time elapsing before the occurrence of relapse was 275 days. The greatest number – nine (50%) patients, had late relapse, four (22.2%) patients had intermediate relapse, while five (27.7%) patients had early relapse (Figure 1). A total of 25 patients died, from the beginning of patient monitoring until the end of December 2020.

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Figure 1. Time to relapse

The average time of survival, from the moment when diagnosis was established, was 96.8 ± 16.4 months, while the average time of survival, from the moment of transplantation, was 34 ± 3.6 months. Median survival, from the moment of diagnosis, was 20 months, and from the moment of transplantation, it was nine months.

Female patients, who were followed-up from the moment of diagnosis, lived longer on average (111 ± 26 months), in relation to male patients (58 ± 9 months). Average posttransplantation survival was better in women (40 ± 5 months) than in men (25 ± 4 months). The choice of conditioning regimen had no influence on the length of patient survival – RIC: 38.5 ± 7 months, and MAC: 27.8 ± 3.5 months. Although longer survival was present in patients who received RIC and not MAC, the data obtained were not statistically significant (p = 0.318), (Figure 2).

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Figure 2. Survival after allogenic hematopoietic stem cell transplantation (allo- -HSCT), depending on the conditioning regimen applied

The patients who achieved complete remission after the first transplantation lived longer than the patients who did not (39 ± 4 months, as compared to 4 ± 6 months), however, the noted difference was not statistically significant (p = 0.055), (Figure 3). The average time of the survival of patients who had relapse was 26 ± 5 months, while in patients without relapse it was 41 ± 4 months. The median survival of patients who had relapse was 14 months, and it was 57 months in patients who did not experience relapse (p = 0.180), (Figure 4).

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Figure 3. Survival after allogenic hematopoietic stem cell transplantation (allo- -HSCT), with and without the achievement of complete remission

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Figure 4. Survival after allogenic hematopoietic stem cell transplantation (allo- -HSCT), with and without relapse of the disease

DISCUSSION

Due to the development of new therapeutic modalities, the improvement of biological therapies, the application of new generation medications, as well as the application of new technologies, such as CAR-T (chimeric antigen receptor T-cell) therapy, survival and prognosis of hematological patients has shown a constant improvement trend. A drastic increase in hematological malignancies, the increase in the incidence of leukemias by 26% and NHL by 45% (in 2016 as compared to 2006), as well as the development of better conditioning and immunosuppressive regimens, have led to a significant increase in the number of allogeneic

transplantations. The European Group for Blood and Marrow Transplantation (EBMT) states that the number of allogeneic hematopoietic stem cell transplantations performed annually has risen by 360% in the past 20 years [5],[7],[8].

Our study included 58 adult patients who had received allo-HSCT. Acute leukemias (AML and ALL) were the most frequent diagnoses in patients who had allo-HSCT (75%), while, according to the EBMT, acute leukemias are the cause of 54.5% of all allogeneic hematopoietic stem cell transplantations. The second highest was the incidence of HL, with 13.8%. NHL made up 5.1%, while EBMT states a percentage of 9.1% for NHL. In our study, MDS/MPN were present with 5.1%, while EBMT reports a percentage of 15.6%. None of the patients diagnosed with a disease outside the group of malignant hemopathies received allogeneic hematopoietic stem cell transplantation [6],[8].

With the development of less intensive conditioning regimens, allo-HSCT has become a therapeutic option for many patients who would earlier have been excluded from consideration, due to their age (>50) and their comorbidities. In USA, this led to the rise in the percentage of patients older than 60 being treated with transplantation, from 4% to 25%, in the period between 2000 and 2015. In our study, the patient age ranged from 18 to 58 years, while the average age was 38 years [9].

Most (74%) of our patients received the myeloablative conditioning regimen (MAC), while 26% of patients received RIC. The predominant proportion of the MAC regimen is in keeping with the trends of selecting the conditioning regimens, as stated by D’Souza and Gyurkocza [9],[10].

The occurrence of relapse greatly depends on the diagnosis and the selection of the conditioning regimen. Relapse occurred most frequently in patients with ALL, wherein out of 18 patients, 8 had relapse. This makes up 44,4% of all relapses in our study. Patients with AML followed after patients with ALL; of 26 patients, seven had a relapse, and they made up 38.8% of all relapses. Acute leukemias jointly made up 75% of all diagnoses in our study and 82.8% of all relapses.

One third of the patients on the RIC regimen, i.e., five out of 15 patients, had a relapse, while in the group of patients on the MAC regimen, relapse occurred in 13 (30.2%) out of 43 patients. As expected, a higher probability of relapse was noted in patients who were on the RIC regimen. This difference can be explained with the characteristics of the regimens themselves. Also, the age of the patients, as well as their HCT-CI (hematopoietic cell transplantation-specific comorbidity index), EBMT, and ECOG PS (Eastern Cooperative Oncology Group Performance Status Scale) scores affect the outcome of transplantation. The data obtained is consistent with the data reported by Martino et al. (23% for MAC and 39% for RIC), and Ringdén et al. (42% ± 3% for RIC and 29% ± 3% for MAC), while Luger et al. reported a relative relapse risk after RIC of 1.32 in relation to MAC [11],[12],[13],[14],[15].

Patients on the RIC regimen had a longer survival, in relation to patients who were on the MAC regimen, however, the difference in survival in our study was not statistically significant – RIC: 38.5 ± 7 months; MAC: 27.8 ± 3.5 months (p = 0.318). During the follow-up period of 18 months, Scott et al. did not determine statistically significant differences in the overall survival (OS) between the MAC and the RIC regimen. Similar data, which was also in accordance with our results, were obtained over a longer follow-up period – the study by Çiftçiler et al. covered a period of three years, while the study by Martin et al. covered a period of seven years, which more closely matches our study. These studies also did not report statistically significant differences in the overall survival between patents on the MAC and those on the RIC regimen [13],[16],[17].

Time of relapse occurrence has significant impact on the outcome of the transplantation itself, as well as on patient survival. There are different opinions on how relapses should be classified by the time of their occurrence. Some authors set six months as the cutoff point for early relapse, categorizing everything after that as late relapse. The Seattle group categorizes three types of relapse: early relapse – in the first 100 days, intermediate relapse – between day 100 and day 200, and late relapse – after day 200. Since we used the Seattle protocol for preventing GvHD, we categorized patients with relapse according to the criteria defined by this group of authors. In their study, the Seattle group reports that out of 1,111 patients, 307 (27.6%) patients had a relapse, of whom 111 (36.1%) had a relapse within the first 100 dana, intermediate relapse was experienced by 73 (23.7%) patients, while late relapse occurred in 123 (40%) patients. In our study, 18 (34%) patients had a relapse. Five (27.7%) patients had an early relapse, i.e., relapse within the first 100 days, intermediate, i.e., relapse between day 100 and day 200 occurred in four (22.2%) patients, while late relapse, after 200 days, occurred in nine (50%) patients. Our data are similar to the data obtained in the Seattle group study, even though our sample size was small [1],[18].

Relapse treatment is a great problem, especially in patients suffering from AML and MDS, where probability of relapse is high, and relapse itself occurs early after transplantation and is connected to a poor prognosis. This complex problem requires the application of a wide spectrum of drugs and different procedures. The drugs most frequently used are different cytostatic drugs, immunosuppressants, and immunomodulators, and lately, targeted biological therapy is becoming more and more significant. After relapse, some patients need to be given DLI, CD34+ stem cell boost, or may even need to receive secondary allogeneic hematopoietic stem cell transplantation.

Based on data related to 2,815 patients, obtained from the EBMT database, Schmid et al. reported that only moderate chemotherapy was used most frequently in treatment (33.5%); intensive chemotherapy was used in 17.9% of cases; chemotherapy followed by DLI was applied in 18.3% of patients; chemotherapy followed by secondary allogeneic hematopoietic stem cell transplantation was applied in 7.6% of patients; DLI without chemotherapy was given to 15.2% of patients, while secondary allo-HSCT without previous chemotherapy was applied in 7.6% cases. In our study, only chemotherapy as the sole method of relapse treatment was administered to seven (38.8%) out of 18 patients, with one of these patients also receiving biological therapy (nivolumab). DLI preceded by chemotherapy was given to four (22.2%) patients, of whom one patient was treated with a combination of COP protocol and biological therapy (blinatumomab). Secondary allo-HSCT with previous chemotherapy was administered to five (27.7%) patients, of whom one patient received only biological therapy (blinatumomab) prior to the transplantation. Two (11.1%) patients were treated with secondary transplantation without previous chemotherapy, with one of the patients receiving antithymocyte globulin therapy as well. Of the seven secondary transplantations in total, in four patients, additional therapy in the form of DLI was needed, and in one patient, DLI and boost therapy were needed.

Out of the 18 patients with relapse, nine (50%) of them received DLI. This significantly differs from the study by Schmid et al., where 33.5% patients received DLI, as well as the study by Ciurea et al., where only 13.7% of patients were reported to have received DLI. The differences in therapeutic modalities and their prevalence can be attributed to the patient structure, as well as to the total number of patients included in the study. Both Schmid and Ciurea analyzed only patients with AML, while our study covered a broader spectrum of diagnoses [19],[20].

CONCLUSION

The data from our study, which relate to trends in the choice of the conditioning regimen, the relapse rate upon transplantation, the overall survival upon relapse, as well as to the application of therapy upon relapse, are in keeping with data from different centers in the world. Patients who received reduced intensity conditioning regimens had a better length of survival, however without statistical significance, as well without an increase in the relapse rate. As yet, our center has not introduced a significant ratio of patients above the age of 60 years in transplantation procedures. In the future, inclusion of older patients should be initiated, and efforts should be made to further reduce relapse rates, especially in patients with acute leukemias. Targeted prophylactic application of therapy should be considered in patients with ALL and AML, for the purpose of preventing relapse.

LIST OF ABBREVIATIONS AND ACRONYMS

allo-HSCT – allogeneic hematopoietic stem cell transplantation
MAC – myeloablative conditioning
RIC – reduced intensity conditioning
MRD –minimal residual disease
GvHD – graft versus host disease
HLA – human leukocyte antigen
PCR – polymerase chain reaction
DLI – donor lymphocyte infusion
GvT – graft versus tumor effect
GvL – graft versus leukemia effect
ALL – acute lymphoblastic leukemia
AML – acute myeloblastic leukemia
HL – Hodgkin’s lymphoma
NHL – Non-Hodgkin’s lymphoma
MDS – myelodysplastic syndrome
MPN – myeloproliferative syndrome
d – day of transplantation
WHO – World Health Organization
IV – intravenous
USA – United States of America
CAR-T – chimeric antigen receptor T-cell
EBMT – European Group for Blood and Marrow Transplantation
OS – overall survival
HCT-CI – hematopoietic cell transplantation-specific comorbidity index
ECOG PS – Eastern Cooperative Oncology Group Performance Status Scale

  • Conflict of interest:
    None declared.

Informations

Volume 3 No 3

Volume 3 No 3

September 2022

Pages 334-345
  • Keywords:
    reduced intensity conditioning, myeloablative conditioning, survival
  • Received:
    13 August 2022
  • Revised:
    29 August 2022
  • Accepted:
    03 September 2022
  • Online first:
    25 September 2022
  • DOI:
Corresponding author

Nikola Lemajić
Clinic for Hematology, University Clinical Center of Serbia
2 Dr Koste Todorovića Street, 1100 Belgrade, Serbia
E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.


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    14. Ringdén O, Labopin M, Ehninger G, Niederwieser D, Olsson R, Basara N, et al. Reduced intensity conditioning compared with myeloablative conditioning using unrelated donor transplants in patients with acute myeloid leukemia. J Clin Oncol. 2009 Sep 20;27(27):4570-7. doi: 10.1200/JCO.2008.20.9692. [CROSSREF]

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REFERENCES

1. Barrett AJ, Battiwalla M. Relapse after allogeneic stem cell transplantation. Expert Rev Hematol. 2010 Aug;3(4):429-41. doi: 10.1586/ehm.10.32. [CROSSREF]

2. Bacher U, Talano JA, Bishop MR. Monitoring and prevention of relapse after allogeneic hematopoietic cell transplantation for myeloid malignancies. Biol Blood Marrow Transplant. 2012 Jan;18(1 Suppl):S62-73. doi: 10.1016/j. bbmt.2011.10.028. [CROSSREF]

3. Loren AW, Porter DL. Donor leukocyte infusions after unrelated donor hematopoietic stem cell transplantation. Curr Opin Oncol. 2006 Mar;18(2):107-14. doi: 10.1097/01.cco.0000208781.61452.d3. [CROSSREF]

4. Porter D, Levine JE. Graft-versus-host disease and graft-versus-leukemia after donor leukocyte infusion. Semin Hematol. 2006 Jan;43(1):53-61. doi: 10.1053/j.seminhematol.2005.09.005. [CROSSREF]

5. van den Brink MR, Porter DL, Giralt S, Lu SX, Jenq RR, Hanash A, et al. Relapse after allogeneic hematopoietic cell therapy. Biol Blood Marrow Transplant. 2010 Jan;16(1 Suppl):S138-45. doi: 10.1016/j.bbmt.2009.10.023. [CROSSREF]

6. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al., editors. WHO Classification of Tumours of Haematopoetic and Lymphoid Tissues. 4th edition. Lyon: IARC Press 2017. [HTTP]

7. Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Akinyemiju TF, Al Lami FH, Alam T, Alizadeh-Navaei R, Allen C, et al. Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-Years for 29 Cancer Groups, 1990 to 2016: A Systematic Analysis for the Global Burden of Disease Study. JAMA Oncol. 2018 Nov 1;4(11):1553-68. doi: 10.1001/jamaoncol.2018.2706. [CROSSREF]

8. Passweg JR, Baldomero H, Basak GW, Chabannon C, Corbacioglu S, Duarte R, et al; European Society for Blood and Marrow Transplantation (EBMT). The EBMT activity survey report 2017: a focus on allogeneic HCT for nonmalignant indications and on the use of non-HCT cell therapies. Bone Marrow Transplant. 2019 Oct;54(10):1575-85. doi: 10.1038/s41409-019-0465-9. [CROSSREF]

9. D’Souza A, Lee S, Zhu X, Pasquini M. Current Use and Trends in Hematopoietic Cell Transplantation in the United States. Biol Blood Marrow Transplant. 2017 Sep;23(9):1417-21. doi: 10.1016/j.bbmt.2017.05.035. [CROSSREF]

10. Gyurkocza B, Sandmaier BM. Conditioning regimens for hematopoietic cell transplantation: one size does not fit all. Blood. 2014 Jul 17;124(3):344-53. doi: 10.1182/blood-2014-02-514778. [CROSSREF]

11. Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG, et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood. 2005 Oct 15;106(8):2912-9. doi: 10.1182/blood-2005-05-2004. [CROSSREF]

12. Gratwohl A. The EBMT risk score. Bone Marrow Transplant. 2012 Jun;47(6):749- 56. doi: 10.1038/bmt.2011.110. [CROSSREF]

13. Martino R, de Wreede L, Fiocco M, van Biezen A, von dem Borne PA, Hamladji RM, et al.; Acute Leukemia Working Party the subcommittee for Myelodysplastic Syndromes of the Chronic Malignancies Working Party of the European group for Blood Marrow Transplantation Group (EBMT). Comparison of conditioning regimens of various intensities for allogeneic hematopoietic SCT using HLA-identical sibling donors in AML and MDS with <10% BM blasts: a report from EBMT. Bone Marrow Transplant. 2013 Jun;48(6):761-70. doi: 10.1038/bmt.2012.236. [CROSSREF]

14. Ringdén O, Labopin M, Ehninger G, Niederwieser D, Olsson R, Basara N, et al. Reduced intensity conditioning compared with myeloablative conditioning using unrelated donor transplants in patients with acute myeloid leukemia. J Clin Oncol. 2009 Sep 20;27(27):4570-7. doi: 10.1200/JCO.2008.20.9692. [CROSSREF]

15. Luger SM, Ringdén O, Zhang MJ, Pérez WS, Bishop MR, Bornhauser M, et al. Similar outcomes using myeloablative vs reduced-intensity allogeneic transplant preparative regimens for AML or MDS. Bone Marrow Transplant. 2012 Feb;47(2):203-11. doi: 10.1038/bmt.2011.69. [CROSSREF]

16. Çiftçiler R, Göker H, Demiroğlu H, Aladağ E, Aksu S, Haznedaroğlu İC, et al. Comparison of Myeloablative Versus Reduced-Intensity Conditioning Regimens for Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemia: A Cohort Study. Turk J Haematol. 2019 May 3;36(2):88-96. doi: 10.4274/tjh.galenos.2019.2018.0220. [CROSSREF]

17. Scott BL, Pasquini MC, Logan BR, Wu J, Devine SM, Porter DL, et al. Myeloablative Versus Reduced-Intensity Hematopoietic Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndromes. J Clin Oncol. 2017 Apr 10;35(11):1154-61. doi: 10.1200/JCO.2016.70.7091. [CROSSREF]

18. Mielcarek M, Storer BE, Flowers ME, Storb R, Sandmaier BM, Martin PJ. Outcomes among patients with recurrent high-risk hematologic malignancies after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2007 Oct;13(10):1160-8. doi: 10.1016/j.bbmt.2007.06.007. [CROSSREF]

19. Schmid C, Labopin M, Nagler A, Niederwieser D, Castagna L, Tabrizi R, et al.; Acute Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Treatment, risk factors, and outcome of adults with relapsed AML after reduced intensity conditioning for allogeneic stem cell transplantation. Blood. 2012 Feb 9;119(6):1599-606. doi: 10.1182/ blood-2011-08-375840. [CROSSREF]

20. Ciurea SO, Labopin M, Socie G, Volin L, Passweg J, Chevallier P, et al. Relapse and survival after transplantation for complex karyotype acute myeloid leukemia: A report from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation and the University of Texas MD Anderson Cancer Center. Cancer. 2018 May 15;124(10):2134-41. doi: 10.1002/ cncr.31311. [CROSSREF]

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8. Passweg JR, Baldomero H, Basak GW, Chabannon C, Corbacioglu S, Duarte R, et al; European Society for Blood and Marrow Transplantation (EBMT). The EBMT activity survey report 2017: a focus on allogeneic HCT for nonmalignant indications and on the use of non-HCT cell therapies. Bone Marrow Transplant. 2019 Oct;54(10):1575-85. doi: 10.1038/s41409-019-0465-9. [CROSSREF]

9. D’Souza A, Lee S, Zhu X, Pasquini M. Current Use and Trends in Hematopoietic Cell Transplantation in the United States. Biol Blood Marrow Transplant. 2017 Sep;23(9):1417-21. doi: 10.1016/j.bbmt.2017.05.035. [CROSSREF]

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11. Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG, et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood. 2005 Oct 15;106(8):2912-9. doi: 10.1182/blood-2005-05-2004. [CROSSREF]

12. Gratwohl A. The EBMT risk score. Bone Marrow Transplant. 2012 Jun;47(6):749- 56. doi: 10.1038/bmt.2011.110. [CROSSREF]

13. Martino R, de Wreede L, Fiocco M, van Biezen A, von dem Borne PA, Hamladji RM, et al.; Acute Leukemia Working Party the subcommittee for Myelodysplastic Syndromes of the Chronic Malignancies Working Party of the European group for Blood Marrow Transplantation Group (EBMT). Comparison of conditioning regimens of various intensities for allogeneic hematopoietic SCT using HLA-identical sibling donors in AML and MDS with <10% BM blasts: a report from EBMT. Bone Marrow Transplant. 2013 Jun;48(6):761-70. doi: 10.1038/bmt.2012.236. [CROSSREF]

14. Ringdén O, Labopin M, Ehninger G, Niederwieser D, Olsson R, Basara N, et al. Reduced intensity conditioning compared with myeloablative conditioning using unrelated donor transplants in patients with acute myeloid leukemia. J Clin Oncol. 2009 Sep 20;27(27):4570-7. doi: 10.1200/JCO.2008.20.9692. [CROSSREF]

15. Luger SM, Ringdén O, Zhang MJ, Pérez WS, Bishop MR, Bornhauser M, et al. Similar outcomes using myeloablative vs reduced-intensity allogeneic transplant preparative regimens for AML or MDS. Bone Marrow Transplant. 2012 Feb;47(2):203-11. doi: 10.1038/bmt.2011.69. [CROSSREF]

16. Çiftçiler R, Göker H, Demiroğlu H, Aladağ E, Aksu S, Haznedaroğlu İC, et al. Comparison of Myeloablative Versus Reduced-Intensity Conditioning Regimens for Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemia: A Cohort Study. Turk J Haematol. 2019 May 3;36(2):88-96. doi: 10.4274/tjh.galenos.2019.2018.0220. [CROSSREF]

17. Scott BL, Pasquini MC, Logan BR, Wu J, Devine SM, Porter DL, et al. Myeloablative Versus Reduced-Intensity Hematopoietic Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndromes. J Clin Oncol. 2017 Apr 10;35(11):1154-61. doi: 10.1200/JCO.2016.70.7091. [CROSSREF]

18. Mielcarek M, Storer BE, Flowers ME, Storb R, Sandmaier BM, Martin PJ. Outcomes among patients with recurrent high-risk hematologic malignancies after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2007 Oct;13(10):1160-8. doi: 10.1016/j.bbmt.2007.06.007. [CROSSREF]

19. Schmid C, Labopin M, Nagler A, Niederwieser D, Castagna L, Tabrizi R, et al.; Acute Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Treatment, risk factors, and outcome of adults with relapsed AML after reduced intensity conditioning for allogeneic stem cell transplantation. Blood. 2012 Feb 9;119(6):1599-606. doi: 10.1182/ blood-2011-08-375840. [CROSSREF]

20. Ciurea SO, Labopin M, Socie G, Volin L, Passweg J, Chevallier P, et al. Relapse and survival after transplantation for complex karyotype acute myeloid leukemia: A report from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation and the University of Texas MD Anderson Cancer Center. Cancer. 2018 May 15;124(10):2134-41. doi: 10.1002/ cncr.31311. [CROSSREF]


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