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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 9  |  Issue : 4  |  Page : 120-125

Hematopoietic stem cell transplantation in children with hemoglobinopathies: A single-center experience


1 Department of Oncology, King Faisal Specialist Hospital and Research Centre, Jeddah, Saudi Arabia
2 King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia
3 Ibn Sina National College, Jeddah, Saudi Arabia

Date of Web Publication4-Feb-2019

Correspondence Address:
Dr. Muhammad Matloob Alam
Department of Oncology, King Faisal Specialist Hospital and Research Centre, P. O. Box 40047, Jeddah 21499
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/joah.joah_32_18

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  Abstract 


INTRODUCTION: Hematopoietic stem cell transplantation (HSCT) is a curative treatment for children with serious hematological disorders including thalassemia major (TM) and sickle cell disease (SCD). This study aimed to determine the frequencies of transplant-related morbidity and outcome in our tertiary health-care facility.
MATERIALS AND METHODS: We retrospectively analyzed the clinical, laboratory, and outcome data of 32 cases of hemoglobinopathies (TM = 19 and SCD = 13) who underwent bone marrow (BM) transplantation between 2005 and 2016. SPSS was used for statistical analysis, and Kaplan–Meier curve was constructed for overall survival (OS) and event-free survival.
RESULTS: The median age of the study population at the time of transplant was 7.8 (range 2–14 years). Male-to-female ratio was 1:1. All patients were received allogeneic full matched related donor transplantation. Conditioning regimen was Bu/Cy/antithymocyte globulin (ATG) for SCD and Flu/Bu/Cy/ATG for TM. Source of stem cell in all patients was bone marrow and median stem cell dose CD 34+ was 5.26 (range 2.9–9.9) × 106/kg. All patients were received cyclosporin and methotrexate for graft versus host disease (GVHD) prophylaxis. Acute and chronic GVHD were observed in 10 (31.25%) and 2 (6.3%) cases, respectively. The median time to absolute neutrophil count (ANC) engraftment was 22 days (range: 12–27), and the median time to platelet engraftment was 32 days (range: 18–45) in 28 patients and the remaining four patients had delayed platelet engraftment (62–90 days). Cytomegalovirus (CMV) reactivation was observed in 18 (56.3%) cases; majority were asymptomatic (n = 17/18; 94.4%). Three-year event-free survival (EFS) and OS were 90.6% and 93.7%, respectively, with median duration of follow-up 33.72 (± 25.3) months.
CONCLUSION: The results of the pediatric HSCT for hemoglobinopathies at our institution are excellent and are comparable to published reports from international collaborative groups.

Keywords: Cytomegalovirus, engraftment, graft versus host disease, hematopoietic stem cell transplantation, hemoglobinopathies, mortality relapse, survival


How to cite this article:
Alam MM, Bayoumy MS, Abosoudah IF, Zabani R, Al-Trabolsi HA. Hematopoietic stem cell transplantation in children with hemoglobinopathies: A single-center experience. J Appl Hematol 2018;9:120-5

How to cite this URL:
Alam MM, Bayoumy MS, Abosoudah IF, Zabani R, Al-Trabolsi HA. Hematopoietic stem cell transplantation in children with hemoglobinopathies: A single-center experience. J Appl Hematol [serial online] 2018 [cited 2019 Jun 18];9:120-5. Available from: http://www.jahjournal.org/text.asp?2018/9/4/120/251484


  Introduction Top


Although improvements in supportive treatment have significantly improved the prognosis in thalassemia major (TM) and sickle cell disease (SCD) in developed nations,[1],[2] hematopoietic stem cell transplantation (HSCT) remains the only proven curative treatment of these disorders.[3],[4],[5]

Since the first successful transplant performed in a child with TM by Thomas et al. in Seattle,[4] more than 1000 patients with TM or SCD have been cured by HSCT, in most cases performed using a human leukocyte antigen (HLA)-identical sibling donor with bone marrow (BM) as the stem cell source.[6] More recently, BM transplantation (BMT) from an unrelated volunteer, selected by high-resolution molecular typing of Class I and II HLA loci and stringent criteria of compatibility, also proved to be a possible alternative for selected patients with TM who lack a compatible family donor.[5],[6] In the last two decades, cord blood from an HLA-identical sibling increasingly is being used as an alternative source of hematopoietic cells for transplanting patients.[7] All of these advances have resulted in both improved outcomes and greater use of HSCT in clinical practice.[8]

Specific studies regarding BMT indications in children with hemoglobinopathies, their complications, outcome, and survival are deficient from this region, and the majority of data are derived from studies performed on adults or in combination and only few local data[9] have been available especially from this region. Thus, we are planning to conduct this study to determine the frequencies of transplant-related morbidity and mortality and to report the prognosis and outcome of these pediatric post-HSCT cases at in our BMT unit.


  Materials and Methods Top


Study design and setting

This study is a retrospective analysis of clinical and laboratory data of post-HSCT pediatric patients. We included all pediatric patients with hemoglobinopathies consecutively underwent HSCT at pediatric BMT unit, King Faisal Specialist Hospital and Research Centre (KFSH and RC)-Jeddah, Saudi Arabia, over a period of 10 years from 2005 to 2016.

KFSH and RC-Jeddah is a tertiary health-care facility and is accredited by the international arm of the Joint Commission International Accreditation Survey. There is a 20-bed, pediatric hematology/oncology ward along with a 5-bed HSCT unit within the hematology/oncology ward. A total of 110 pediatric patients underwent HSCT in the last 10-year duration and average HSCT was 11 per year, of them 1/4 were patients with a diagnosis of hemoglobinopathies.

Patient population and definition

All cases under 14 years of age with a diagnosis of hemoglobinopathies, who were admitted to the pediatric HSCT unit for transplantation from 2005 to 2016, were included in this study, including two patents who received second transplantation due to engraftment failure. For the definition of GVHD, veno-occlusive disease (VOD), CMV reactivation, viremia/infection, and engraftment failure, the Center of International Blood and Bone Marrow Transplantation Research manual definitions forms 2450 Manual[10] and the American Society for Blood and Marrow Transplantation (2009) guidelines were accepted.[11]

Data collection

All cases with a diagnosis of hemoglobinopathies, who received BMT, and who were under 14 years of age were identified by internal BMT registry and were included in the analysis. For those patients who had more than one BMT, each BMT was counted and analyzed as separate case. The basic demographic feature was collected for both recipients and donors. Primary diagnosis, indication of HSCT, and co-morbidities were also noted. Data about type of different BMT procedures, conditioning regimen, and GVHD prophylaxis were also collected. Pretransplant CMV status of all recipients and donors along with post-HSCT assessment, investigations, and prophylaxis and management of CMV was also recorded. The overall survival (OS) was defined as the time interval between the date of transplantation and the date of death or the date of last follow-up visit. The EFS was taken as the period between the date of transplantation and the date of relapse, engraftment failure, or date of death from any cause.

Statistical analysis

All the clinical data were analyzed retrospectively using SPSS package software version 20.0 (IBM, Chicago, IL, USA). Summary statistics was used to describe the cohort. The frequency of CMV antigenemia was measured during the posttransplantation period of 100 days. Frequencies were computed for qualitative variables, and the mean and standard deviation was computed for quantitative variables. Kaplan–Meier curve was constructed for OS and EFS.

Ethical approval/considerations

The study was started after approval from the Institutional Review Board of KFSH and RC-Jeddah.


  Results Top


The total number of transplantation in hemoglobinopathy patients during this study period was 32, and two TM patients received second transplantation due to engraftment failure. Of 32 transplantation cases, 19 (59.4%) were TM and the remaining 13 (40.6%) were SCD patients [Table 1]. The median age of the study population at the time of transplant was 7.8 (range 2–14 years). Male-to-female ratio was 1:1. All patients were received allogeneic full matched related donor transplantation, out of 32 donors 14 each were brother and sister, 3 were mother and 1 was father. Conditioning regimen for SCA was busulfan, cyclophosphamide, and thymoglobulin rabbit antithymocyte globulin (ATG) (Bu/Cy/ATG) and for TM was fludarabine, busulfan, cyclophosphamide, and thymoglobulin rabbit ATG (Flu/Bu/Cy/ATG) [Table 2]. The source of stem cell in all patients was BM. The median stem cell dose CD 34+ was 5.26 (range, 2.9–9.9) × 106/kg. All patients received cyclosporine and methotrexate for GVHD prophylaxis.
Table 1: Basic Characteristic of study population (N = 32)

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Table 2: Conditioning regimen

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Acute GVHD was observed in 10 (31.25%) cases, of them skin was involved in 5 (15.6%), gut (n = 2, 6.3%), liver (n = 2, 6.3%), and both skin and gut (n = 1, 3.1%). Grades I, II, III, and IV GVHD were observed in 1 (3.1%), 4 (12.5%), 4 (12.5%), and 1 (3.1%) patient, respectively. Chronic GVHD was noticed in 2 (6.3%) patients and both had skin Grade I–II GVHD.

The median time to ANC engraftment was 22 (range: 12–27) days in most patients except two. One patient had delayed ANC engraftment at day 57 secondary to infection, and another patient was expired before day 28 posttransplantation. The median time to platelet engraftment was 28 (range: 18–90) days, of them four patients had delayed platelet engraftment (62–90 days).

CMV reactivation was observed in 18 (56.3%) cases within 100 days of post-BMT. Of them, majority were asymptomatic (n = 17; 53.1%). Only one patient (n = 1; 3.2%) had clinical CMV infection and manifestation of organ involvement (pneumonia and skin manifestation) and was expired on day + 75 posttransplantation due to acute respiratory distress syndrome. Most of CMV cases were resolved (n = 17; 53.1%). In most cases (16/18; 88.8%), the level of antigenemia declined within 2 weeks as a result of the continuation of GCV therapy.

Three-year EFS and OS were 90.6% and 93.7%, respectively, with median duration of follow-up of 33.72 (±25.3) months [Figure 1] and [Figure 2]. In subgroup analysis, SCA patients had EFS and OS of 100%; however, TM patients had EFS and OS of 83.3% and 88.9%, respectively. Two beta-TM patients lost engraftment at 6-month and 9-month posttransplantation, both belonged to Class III thalassemia and received second transplantation. Thalassemia-free survival was 88.9%. Both patients who expired had a diagnosis of TM, one expired at day +16 posttransplantation with pulmonary hemorrhage and massive ICH and another had CMV infection and was expired at day + 75 posttransplantation with ARDS.
Figure 1: Kaplan–Meier curve of overall survival

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Figure 2: Kaplan–Meier curve of event-free survival

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  Discussion Top


Transplantation outcomes today are much improved compared with the 1980s and 1990s, with more than 90% of patients surviving transplantation and more than 80% of them being disease free.[12] Our OS and EFS of 93.75% and 90.6%, respectively, with median duration of follow-up of 34 months in our study, were very much comparable with other international published data for similar patient's categories. In a large EBMT survey of 1061 cases of MSD-transplantation performed in the last decade, OS and disease-free survival (DFS) were 91% and 83%, respectively. Moreover, in this report, there was a significant age threshold of 14 years for optimal results (96% vs. 82% and 86% vs. 74% for OS and DFS, respectively).[13] A large study recently published the outcome data of more than 200 patients with SCA who underwent HSCT from an HLA-matched sibling and reported that OS was found to be around 95%.[14],[15] Bernaudin et al. reported 121 patients transplanted in France after 2000 with a DFS of 95% at 3 years.[16] A small patient series using mainly fludarabine-based regimens have shown promising results with an OS of 100% and a DFS of 95%.[17],[18]

The outcome of transplantation is dependent on multiple clinical factors and development of GVHD, CMV infection and engraftment are few of those important factors responsible for success.[19] The following observations were made in relation to these specific conditions and complications in our study.

Acute GVHD is one of the major complications of BMT.[20] In our study, acute GVHD was observed in 10 (31%) cases, overall rate of GVHD was 19.8%, and as high as 28.3% was observed in allogeneic transplant patients, which is substantially lower than reports recently published by other centers. However, another center of our region reported the GVHD rate of 35%, which was similar to what has been described in several international studies.[9],[21] Many variables can impact the likelihood and severity of GVHD; however, the most important factor reported is HLA disparity.[22] A meta-analysis suggested that acute GVHD is slightly increased and chronic GVHD is increased when comparing PBSC and BM transplants.[23]

The incidence of CMV reactivation in our study population was 56.3%, of them majority were asymptomatic (n = 17; 53.1%). Nichols et al. reported the incidence of 39%, which was slightly higher than our observation, but substantially higher than the 13% of cases observed in another study.[24],[25] However, the incidence of CMV disease in our patients was 5.5%, which was substantially lower than that reported recently by Yanada et al. (7.5%) and other results of preemptive therapy for other groups.[24],[25],[26] Pneumonia and gastrointestinal involvement are the most frequently described clinical pictures caused by CMV after BMT followed by hepatitis, retinitis, and encephalitis.[27],[28] There is a significant association between development of CMV antigenemia and disease and acute GVHD, indicating an urgent need for the establishment of an optimum preemptive strategy based on the severity of acute GVHD.[29],[30],[31],[32],[33]

Notably, 31.6% (12/38) of patients developed rising antigenemia in our study had acute GVHD and 12/26 (46.2%) patients with acute GVHD had a history of CMV reactivation, suggesting significant associations between two and that the immunological status of the host may be of importance.

Despite recent outstanding progresses in preventing transplantation complications, the occurrence and fatality rates of GVHD and engraftment failure after allo-HSCT remain high and may be limiting factors in the clinical application of allo-HSCT.[34],[35],[36] Stable engraftment of donor hematopoiesis in which donor cells are integrated into the recipient's cell population is essential for a successful outcome of BMT.[37],[38] Reduced donor chimerism is closely related to graft rejection and primary disease reoccurrence and should, therefore, be measured dynamically after transplantation.

The frequency and timing of engraftment in our study is comparable with other published data. Previous reports have shown incidences of engraftment failure after allo-HSCT of 5%–27%, suggesting that it represents a severe posttransplant complication. Patients who experienced engraftment failure showed continuous bilineage or trilineage dysplasia for at least 30 days.[38],[39] Previous reports have focused on two factors: first repopulation problems caused by inadequate infusion of hematopoietic stem cells or conditioning-induced hematopoietic stromal cell damage, BM fibrosis or BM suppression during transplantation. Secondly posttransplatation GVHD, VOD and virus infection, which may destroy blood cells and cause engraftment failure.[40]

Unfortunately, the clinical group studied is small in number, homogeneous, single center, and retrospective; therefore, the results should be generalized with caution.


  Conclusion Top


The results of the pediatric HSCT for thalassemia and sickle cell anemia at our institution are excellent and are comparable to published reports from international collaborative groups. However, the duration of follow-up is short, and the long-term outcome is yet to be determined.

Acknowledgments

The authors thank all transplantation team of the KFSH and RC–Jeddah, especially our BM coordinators Ms. Bayanah and clinical pharmacist Dr. Marwa for their contributions, and all the patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

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