Stem Cell Transplantation in children: A single-center experience in Saudi Arabia

Muhammad Matloob Alam; Ibraheem Abosoudah; Shara Al Harbi; Marwa Elhadidy; Mohamed Bayoumy

doi:10.4103/1658-5127.186324

ORIGINAL ARTICLE

Year : 2016 | Volume : 7 | Issue : 2 | Page : 54-62

Stem Cell Transplantation in children: A single-center experience in Saudi Arabia

Muhammad Matloob Alam¹, Ibraheem Abosoudah¹, Shara Al Harbi¹, Marwa Elhadidy², Mohamed Bayoumy¹
¹ Department of Oncology, Section of Pediatric Hematology, Oncology and Blood and Marrow Transplantation, King Faisal Specialist Hospital and Research Centre, Jeddah, Saudi Arabia
² Department of Pharmaceutical Care, Section of Pediatric Hematology, Oncology and Blood and Marrow Transplantation, King Faisal Specialist Hospital and Research Centre, Jeddah, Saudi Arabia

Date of Web Publication

14-Jul-2016

Correspondence Address:
Muhammad Matloob Alam
Department of Oncology, Section of Pediatric Hematology, Oncology and Blood and Marrow Transplantation, King Faisal Specialist Hospital and Research Centre, P.O. Box 40047, Jeddah 21499
Saudi Arabia

Source of Support: None, Conflict of Interest: None

Check

DOI: 10.4103/1658-5127.186324

Abstract

Introduction: Bone marrow transplantation (BMT) has frequently considered as a curative treatment for children with serious hematological and malignant disorders. The aim of this study was to determine the indication, frequencies of transplant-related morbidity, and outcome at our tertiary health care facility. Materials and Methods: We retrospectively analyzed the clinical, laboratory, and outcome data of all 131 pediatric patients consecutively underwent BMT between 2005 and 2014. SPSS package software version 20.0 (IBM, Chicago, IL, USA) was used for statistical analysis and Kaplan-Meier curve were constructed for overall survival (OS) and event free survival (EFS), and compared according to type of BMT, impact of graft-versus-host disease (GVHD), and cytomegalovirus (CMV) reactivation on survival function were evaluated. Results: The mean age of the study population at the time of transplant was 6.5 ± 4 years. Eighty-five (64.9%) were males and 46 (35.1%) were females. Majority of patients had nonmalignant hematological disorder (n = 51, 38.2%) followed by hematological malignancy (n = 50; 38.2%) and solid tumors (n = 30; 22.8%). Most of the patients received allogeneic transplant (n = 92; 70.2%) and remaining received autologous transplant (n = 39; 29.8%). Acute and chronic GVHD was observed in 26 (19.8%) and (6.9%) cases, respectively. Most of the patients were engrafted (n = 109; 83.2%). CMV reactivation was observed in 38 patients (29%); out of them majority were asymptomatic (n = 35/38; 92.1%) and in most of cases CMV were resolved (n = 35/38; 92.1%) with antigenemia-guided preemptive therapy with ganciclovir. OS and EFS rate were 69.5% and 59.6%, respectively. OS time was 35.5 months and EFS time was 31.6 months with median duration of follow-up of 72 months. Conclusions: The results of the pediatric BMT program at our institution have been comparable to those reported in the literature as far as transplant-related morbidity and mortality is concerned.

Keywords: Allogeneic/autologous transplant, bone marrow transplantation, cytomegalovirus, engraftment, graft-versus-host disease, mortality, relapse, survival

How to cite this article:
Alam MM, Abosoudah I, Al Harbi S, Elhadidy M, Bayoumy M. Stem Cell Transplantation in children: A single-center experience in Saudi Arabia. J Appl Hematol 2016;7:54-62

How to cite this URL:
Alam MM, Abosoudah I, Al Harbi S, Elhadidy M, Bayoumy M. Stem Cell Transplantation in children: A single-center experience in Saudi Arabia. J Appl Hematol [serial online] 2016 [cited 2023 Mar 24];7:54-62. Available from: https://www.jahjournal.org/text.asp?2016/7/2/54/186324

Introduction

Bone marrow transplantation (BMT) has become an accepted therapeutic modality for a wide variety of diseases and is increasingly utilized for the treatment of malignant and nonmalignant disorders and frequently considered as a curative treatment for children with serious hematological disorders. ^[1],[2]

The most common type of stem cell transplantation (SCT) to treat hematological malignancies and nonmalignant disorder is allogeneic, using a human leukocyte antigen (HLA)-matched histocompatible donor, usually a sibling. ^[3],[4] Solid tumors have been treated with high-dose chemotherapy followed by autologous peripheral blood SCT or BMT (purged or unpurged depending on whether the bone marrow is actually or potentially invaded with malignant cells) with concomitant use of hematopoietic growth factors, such as, granulocyte colony-stimulating factor (G-CSF), or granulocytic-macrophage-CSF, to reduce the effects of neutropenia caused by escalating doses of chemotherapy. ^[5],[6],[7]] Patients with solid tumors have <30% chance of long-term survival with conventional chemotherapy alone, thus they could be considered for autologous or allogeneic SCT if bone marrow is invaded. ^[1] New applications for BMT are currently being explored to provide adoptive immunotherapy against neoplastic diseases, to reverse immune deficits in autoimmune diseases, and to repair organ and tissue damage in regenerative medicine. ^[7] All these advances have resulted in both improved outcomes and greater use of BMT in clinical practice.

Specific studies on children regarding BMT indications, complications, outcome, and survival are lacking, and the majority of data are derived from studies performed on adults and only few local data ^[8] have been available especially from this region. Thus, we conducted this study to determine the indication of BMT, frequencies of transplant-related morbidity and mortality in post-BMT pediatric patients at our tertiary health care facility.

Materials and methods

Study Design and Setting

This study was a retrospective analysis of clinical and laboratory data of post-BMT pediatric patients. We include all pediatric patients consecutively underwent BMT in pediatric BMT unit, at King Faisal Specialist Hospital and Research Centre (KFSH and RC), Jeddah, Saudi Arabia, over a period of 10 years from 2005 to 2014.

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 BMT unit within the hematology/oncology ward. Total of 131 pediatric patients underwent BMT in the last 10 years duration and average BMT was 30 per year for the last 3 years.

Patient Population and Definition

Patients from 1 month to 15 years of age, who were admitted to the pediatric BMT unit for transplantation from 2005 to 2014, were included in this study. For infection-related issues such as definition of cytomegalovirus (CMV) reactivation and viremia or infection, investigations and management in this study American Society for Blood and Marrow Transplantation (2009) guidelines for preventing infectious complications among hematopoietic cell transplantation recipients will be accepted. ^[9]

For definition of engraftment, graft failure Center of International Blood and Bone Marrow Transplant Research (CIBMTR Forms 2450 Manual) ^[10] and American Society for Blood and Marrow Transplantation (2009) guidelines for preventing infectious complications among hematopoietic cell transplantation recipients will be accepted. ^[10]

Transplantation Procedure

Conditioning regimen

The conditioning regimens used different diseases as preparative regimens were described in [Table 1].

Table 1: Preparative regimens used for different diseases

Click here to view

Prophylaxis and treatment of graft-versus-host disease

The graft-versus-host disease (GVHD) prevention regimen was for all indications was performed as follows cyclosporine A (CsA) and short-term methotrexate (MTX) on day 1 after transplantation, 15 mg/m ² MTX was injected intravenously (IV), followed by 10 mg/m ² MTX IV on day +3, and day +6. Except for Fanconi anemia patients, the regimen is CsA and methylprednisolone (2 mg/kg/day, day 0 to day +19 with a 25% taper every other day; off by day +24 if no evidence of GVHD) and HLH cases received only CsA.

Supportive Care and Infection Prophylaxis

All patients were in a laminar-flow ward. Supportive care was provided after hematopoietic SCT (HSCT) to sustain normal organ functions (liver, heart, and gastrointestinal mucosa).

Bacterial infection prophylaxis

From 2005 to 2012, all pediatric HCT recipients were given IVIG, 400 mg/kg/dose every 2 weeks starting on day 0 till day + 90, from 2012 only recipients with severe hypogammaglobulinemia (i.e., serum IgG level <400 mg/dL) were given IVIG, 400 mg/kg/dose. IgG level was checked every 2 weeks.

Cytomegalovirus infection prophylaxis

In our center, preemptive therapy (<100 days post-HCT) is adopted: All allogeneic recipients screened for the presence of CMV in blood samples once weekly from 7 days to at least 100 days after HCT.

All BMT recipients with evidence of CMV infection in blood by antigenemia (before 2012), and polymerase, polymerase chain reaction (PCR) >500 copies/ml for CMV DNA or detection of CMV mRNA
Administer ganciclovir, 5 mg/kg/dose, IV induction: Twice daily for 7-14 days till CMV PCR titer is negative for two consecutive readings then start maintenance with valganciclovir once daily dose (mg) = 7 × body surface area × creatinine clearance for another 7-14 days
For patients who are showing persistent CMV PCR titer after 2 weeks of ganciclovir treatment, they are shifted to Foscarnet 60 mg/kg IV q8 h till achieving two consecutive negative readings, then start maintenance by Foscarnet 90 mg/kg IV Q24 h for 14-21 days
Note: Continue screening for CMV reactivation weekly and retreat if screening tests become positive after discontinuation of therapy.

Herpes simplex virus and herpes zoster virus infection prevention

From 2005 to 2012, all allogeneic recipients received IV acyclovir starting on day -3 for 28 days
After 2012, only herpes simplex virus seropositive recipients either auto- or allo- received IV aciclovir 250 mg/m ² q8 h starting on day -3 and continued till stable engraftment and mucositis resolved. For herpes zoster virus seropositive recipients received IV aciclovir 250 mg/m ² /dose q8 h then changed to oral aciclovir when oral administration is possible for 1 year posttransplant.

Pneumocystis jiroveci pneumonia infection prophylaxis

PO trimethoprim-sulfamethoxazole (5 mg/kg/day) as TMP in two divided doses for around 1 week before stem cell infusion to be stopped on day-2 and resume when absolute neutrophil count (ANC) >1000 by same dose twice weekly every Saturday and Monday for total of 6 months posttransplant.

Antifungal prophylaxis

From 2005to 2012, fluconazole was used in a dose of 3-6 mg/kg/dose once daily starting on day 1 and continue tell stable engraftment
Due to high incidence of invasive fungal infection in our patients, from 2012 voriconazole was used for recipients >2 years at a dose of 9 mg/kg/dose (max 350 mg) q12 h start on day-1 as loading then maintenance 8 mg/kg/dose (max 350 mg) q12 h until stable engraftment (ANC >1000 for 3 days) and no GVHD
Caspofungin was used at a dose of 70 mg/m ² /dose loading then 50 mg/m ² /dose once daily as maintenance in some cases who developed any signs or were at high risk for sinusoidal obstructive disease instead of voriconazole.

Sinusoidal obstruction syndrome prophylaxis and management

Ursodeoxycholic acid PO 7.5-15 mg/kg/dose, (max: 600 mg) q12 h was used starting with the conditioning for all recipients who are at high risk for sinusoidal obstruction syndrome (SOS), (i.e., conditioning regimens that contain busulfan or high dose cyclophosphamide) for a total of 90 days
Defibrotide IV at a dose of 6.25 mg/kg/dose q6 h was used when available for cases with severe SOS plus the supportive care measures such as sodium and fluid restriction and stopping any hepatotoxic medications.

Filgrastim (granulocyte colony-stimulating factor)

G-CSF SC or IV (5 μg/kg/day) administered only to auto-SCT recipients starting on day +5 till stable engraftment, i.e., ANC >2 × 10 ⁹ /L.

General supportive care measures during conditioning

Antiemetics were used as per antiemetic guidelines risk stratifications (reference) for prevention of antineoplastic induced nausea and vomiting
Mesna was used as 100% of cyclophosphamide dose in concurrence with hydration at a rate of 125 ml/m ² /h tell 24 h post cyclophosphamide for prevention of hemorrhagic cystitis with frequent urine analysis
Clonazepam administered to all patients who are getting busulfan during conditioning at a dose of 0.025-0.1 mg/kg/day in three divided doses to start before 1 ^st dose of busulfan and continue tell 24 h post last dose
Cryotherapy protocol was used since 2012 to all patients receiving melphalan in their conditioning starting oral cavity cooling by either ice chips or ice cream during melphalan infusion and for 2 h post end of infusion
Leucovorin was administered to all allogenic patient who received MTX in their GVHD prophylaxis regimen as 15 mg/m ² /dose for 4 doses on day +2, 12 h post first dose of MTX, 10 mg/m ² /dose for 6 doses 24 h post second dose of MTX and 10 mg/m ² /dose for 8 doses 24 h postlast dose of MTX.

MTX dose modifications were decided according to the grade of mucositis Grades 2-3 (25% to 50%) reduction, if Grade 4 mucositis omit the dose.

Data Collection

All patients who have diagnosis codes for both neoplastic disease (International Classification of Diseases, 9 ^th revision, clinical modification code 140-239), nonmalignant disease and BMT, and 15 years or younger was identified by using health information management system and internal BMT registry, which records all the MBT patients will included in the analysis.

The primary outcome of this analysis was to identify the risk factors and outcomes (GVHD, survival rate and mortality). Relevant covariates data were collected including demographic features, age, gender, primary diagnosis, phase of chemotherapy (if applicable), clinical features at presentation, duration of symptoms, initial laboratory work up including CMV status and radiological finding (if applicable) and microbiological data, management, and outcomes. Underlying disease (acute leukemia, solid tumors, and nonmalignant diseases), type of donors, transplant type (myeloablative/nonmyeloablative), conditioning regimen, etc., Pretransplant CMV status of all recipients and donors along with post-BMT assessment, investigations and prophylaxis, and management of CMV were also be recorded. All patients were treated as inpatients following the American Society for Blood and Marrow Transplantation (2009) guidelines for preventing infectious complications among hematopoietic cell transplantation. ^[9]

The overall survival (OS) was defined as the time interval between the date of diagnosis and date of death or date of last follow-up visit. The event free survival (EFS) was taken as the period between the date of diagnosis 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) was used. Summary statistics was used to describe the cohort. The frequency of CMV antigenemia was measured during the posttransplantation period of 100 days. Frequencies will be computed for qualitative variables, and mean and standard deviation were computed for quantitative variables. Kaplan-Meier curve were constructed for OS and EFS, and compared according to type of BMT, impact of GVHD and CMV reactivation on survival function were evaluated. A P = 0.05 will be considered statistically significant at the univariate level.

Ethical Approval/Considerations

The study was started after getting approval from the Institutional Review Board.

Results

All 131 pediatric patients who consecutively admitted for BMT during this study period were included in final analysis. The mean age of the study population at the time of transplant was 6.5 ± 4 years. Eighty-five (64.9%) were males and 46 (35.1%) were females [Table 2].

Table 2: Summary of patient's demographics

Click here to view

Majority of patients have nonmalignant hematological disorder (n = 51, 38.2%) including beta-thalassemia (n = 13; 9.9%), Sickle cell anemia (n = 8; 6.1%), aplastic anemia (n = 8; 6.1%), Fanconi anemia (n = 4; 3.1%), followed by hematological malignancy (n = 50; 38.2%); out of them ALL (n = 11; 8.4%), AML (n = 20; 15.3%), lymphoma (n = 8; 6.1%), then solid tumors (n = 30;22.8%) including neuroblastoma (n = 26; 19.8%) and medulloblastoma (n = 3; 2.3%) [Figure 1].

Figure 1: Distribution of cases according to diagnosis

Click here to view

Most of the patients received allogeneic transplant (n = 92; 70.2%) and remaining (n = 39; 29.8%) received autologous transplant. Source of donor in all allogeneic cases was full matched-related donor. Source of stem cell in (n = 51; 38.9%) patients was bone marrow and in remaining (n = 43; 32.9%) was peripheral stem cell. Mean stem cell dose CD 34 was 7.2 (±0.25) × 10 ⁶ /kg. Pretransplantation CMV serology was positive for all recipients and donors except one donor have negative CMV serology. [Table 1] provides a summary of patient's demographics.

Acute GVHD was observed in 26 patients (19.8% in all and 28.3% in allogeneic transplant patients). Out of them Grades 1-4 GVHD were observed in nine, ten, five, and two patients, respectively. Sixteen patients have only skin, three only gut, one only liver involvement and five with both skin and gut and one with both skin and liver. Chronic GVHD was observed in nine (6.9%) cases; out of them, seven had skin and one each had gut and liver involvement. Most of patients were engrafted (n = 109; 83.2%) with median duration of ANC engraftment is 20.9 (range: 9-48) days and median platelet engraftment days of 28 (range: 7-200) days. Remaining 22 (16.8%) patients had delayed engraftment.

CMV reactivation was observed in 38 patients (29%) cases within 100 days of post-BMT. Out of them majority were asymptomatic (n = 35/38; 92.1%) and remaining (n = 3/38; 7.9%) had clinical manifestation/organ involvement (retinitis/pneumonia/colitis/hepatitis and skin manifestation). Most of CMV cases were resolved (n = 35/38; 92.1%). Antigenemia-guided preemptive treatment strategy with GCV was used for all patients. In most case (35/38; 92.1%), the level of antigenemia declined within 2 weeks as a result of the continuation of GCV therapy, but only three out of 38 patients subsequently developed CMV disease. There is no difference in engraftment failure in patients who had CMV reactivation and no CMV reactivation (18.5% vs. 16%); however, patients who had CMV reactivation had significantly higher rate of GVHD as compared to patients without CMV reactivation (12/38 = 31.6% vs. 14/93 = 15.1%) (P = 0.031).

OS and relapse free survival (EFS) rate were 69.5% and 59.6%, respectively. OS time was 35.5 (±2.8) months, and EFS time is 31.6 (±2.6) months with median duration of follow-up 72 months [Figure 2] and [Figure 3]. Cause of death in majority of patients (31/40) was either progressive disease and/or relapse; however, in other 9 (9/40 = 6.9%) patients who died in remission, the possible causes of death were as follows: 5 sepsis, 3 GVHD and/or VOD, 1 secondary pulmonary fibrosis.

Figure 2: Kaplan-Meier curve of event free survival: (a) Event free survival of all postbone marrow transplantation patients. (b) Event free survival according to type of transplantation (auto/allo). (c) Event free survival according to presence and absence of graft-versus-host disease. (d) Event free survival according to cytomegalovirus reactivation status

Click here to view

Figure 3:Kaplan-Meier curve of overall survival: (a) Overall survival of all postbone marrow transplantation patients. (b) Overall survival according to type of transplantation (auto/allo). (c) Overall survival according to presence and absence of graft-versus-host disease. (d) Overall survival according to cytomegalovirus reactivation status

Click here to view

Discussion

Our OS and EFS of 69.5% and 59.6%, respectively, with median duration of follow-up 72 months is relatively comparable with other international published data for similar patient's categories. The outcome of transplantation is dependent on multiple clinical factors that can be manipulated depending on the clinical purpose and development of GVHD, CMV infection, and engraftment are few of those important factors responsible for success. ^[11] 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. ^[12] In our study, acute GVHD was observed in 26 patients, 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 others 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. ^[13] Out of 26 patients in our study, Grade 1-2 and 3-4 GVHD were observed in 19 and 7 patients, respectively. Twenty-one patients had involvement of skin and seven of them had gut GVHD and one only had liver involvement. Of interest is that when the occurrence of GVHD was analyzed in patients with malignant disorders, only 7.1% (2/28) of the patients who had relapse and 19.3% (10/52) of those in remission, developed GVHD. This finding is consistent with the observation of other workers that GVHD provides graft versus leukemia effect which has a role in preventing relapse. ^[13],[14]

Many variables including stem cell source, age of donor and recipient, preparative regimen, and prophylaxis can impact the likelihood and severity of GVHD. The most important factor for the development of GVHD is HLA disparity. ^[14] Among siblings, patients receiving matched grafts have lower rates of GVHD than those receiving HLA-mismatched grafts. ^[15] In a large registry-based study of allogeneic matched-sibling BMTs (630 children with leukemia), the incidences of Grades 2-4 and Grades 3-4 acute GVHD were 28 and 11%, respectively. ^[16] There is increasing use of peripheral blood stem cells (PBSCs) as a way of collecting cells from related or unrelated donors. No randomized study has been completed to determine if PBSC transplants change GVHD incidence or the eventual outcome. However, there is a suggestion from a meta-analysis that acute GVHD is slightly increased (relative risk 1.16, P = 0.006) and chronic GVHD is increased (relative risk 1.53, P < 0.001) when comparing PBSC and BMTs. ^[17] There are few reports of acute GVHD following PBSC transplants in pediatrics.

The incidence of CMV reactivation in our study population was overall 29% and in allogeneic transplantation it was 34.8%. Nichols et al. reported a high incidence of rising antigenemia, whereas patients were receiving preemptive therapy, which was caused by the immunosuppressed status of the host, not by resistance to antiviral agents. ^[18] The incidence reported by them (39%) was slightly higher than our observation but substantially higher than the 13% of cases with rising antigenemia observed among the patients in another study. However, the incidence of CMV disease in our patients was 2.3%, which was substantially lower than report recently published by Yanada et al. (7.5%) and other results of preemptive therapy for other groups. ^{[18],[19],[20],[21]}

Pneumonia and gastrointestinal involvement are the most frequently described clinical pictures caused by CMV after BMT. Other documented conditions include hepatitis, retinitis, encephalitis, hemorrhagic cystitis, unexplained fever, endothelial damage, and thrombotic microangiopathy. ^[22],[23] Frequency of CMV disease (2.3%), CMV pneumonia (0.8%), Colitis (0.8%), and hepatitis (0.8%) was low in our study. Several risk factors have been identified for CMV reactivation and disease after HSCT, including pretransplant serostatus, GVHD, transplant from an unrelated or HLA mismatched donor, the use of total body irradiation or antithymocyte globulin in the conditioning regimen, T-cell-depleted transplant, and advanced age. ^{[24],[25],[26],[27],[28],[29],[30],[31]} The development of GVHD after transplant is another important risk factor for CMV reactivation or disease. In a time-dependent multivariate analysis, acute ^[25] and chronic ^[32] GVHD significantly increased the risk of CMV infection and patients with CMV infection show an increased risk of acute and chronic GVHD. ^[33]

Notably, 31.6% (12/38) patients developed rising antigenemia in our study had acute GVHD and 12/26 (46.2%) patient with acute GVHD had history of CMV reactivation suggesting significant associations between two and that the immunological status of the host may be of importance. It has been shown ^[32] that the cumulative probability of first positivization or recurrence of antigenemia increased during the first year after allogeneic BMT from 45.4% on day 100, 64.8% on day 180, and to 71.2% on day 365, especially in the presence of chronic GVHD. Presence of GVHD and administration of preemptive therapy has also been demonstrated to be major risk factors for late CMV reactivation, ^[34] but administration of antiviral prophylaxis during the first 3 months after transplantation also has a significant impact on frequency, timing, and outcome of CMV infection that occur later than in patients receiving preemptive therapy. ^[35] There is 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.

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. ^{[36],[37],[38]} Engraftment is the result of a dynamic cellular process of stem cell homing and differentiation in a recipient of HSCT. ^[38] 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. ^[39] 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 are 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. ^[39],[40] Long-term decreases in bilineage or trilineage cells would lead to hemorrhage and elevated infection rates, thus adversely affecting posttransplantation survival. However, the mechanisms responsible for Primary graft failure (PGF) after allo-HSCT remain unclear, and multiple factors may be involved in the occurrence of PGF. Previous reports have focused on two factors: Repopulation problems caused by inadequate infusion of hematopoietic stem cells or conditioning-induced hematopoietic stromal cell damage, bone marrow fibrosis or bone marrow suppression during transplantation; and posttransplantation GVHD, VOD and virus infection, which may destroy blood cells and cause engraftment failure. ^[41] Another study demonstrated that engraftment failure was a common complication after allo-HSCT, with an incidence of 12.1%, and could thus be considered as a potentially major lethal factor in patients undergoing allo-HSCT. Elderly patients or those with incompatible donor-recipient blood matches and/or at high-risk of CMV infection should receive early medical intervention.

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

Conclusions

Recent development in better understanding of GVHD, process of engraftment, and advances in the field of infection control after BMT have had a great impact on the improvement in transplant outcomes. The results of the pediatric BMT program at our institution have been comparable to those reported in the literature as far as transplant-related morbidity and mortality is concerned. 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 bone marrow coordinators Ms. Bayanah and Ms. Areej for their contributions, and all the patients.

Financial Support and Sponsorship

Nil.

Conflicts of Interest

There are no conflicts of interest.

References

1.	Philip Lanzkowsky D. Hematopoietic Stem Cell Transplantation: Manual of Pediatric Hematology and Oncology. 5 ^th ed. Elsevier Inc; 2011.
2.	Yumura-Yagi K, Inoue M, Sakata N, Okamura T, Yasui M, Sawada A, et al. Unrelated donor bone marrow transplantation for 100 pediatric patients: A single institute′s experience. Bone Marrow Transplant 2005;36:307-13.
3.	Al-Kasim FA, Thornley I, Rolland M, Lau W, Tsang R, Freedman MH, et al. Single-centre experience with allogeneic bone marrow transplantation for acute lymphoblastic leukaemia in childhood: Similar survival after matched-related and matched-unrelated donor transplants. Br J Haematol 2002;116:483-90.
4.	Finke J, Bethge WA, Schmoor C, Ottinger HD, Stelljes M, Zander AR, et al. Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: A randomised, open-label, multicentre phase 3 trial. Lancet Oncol 2009;10:855-64.
5.	Antin JH. Stem cell transplantation-harnessing of graft-versus-malignancy. Curr Opin Hematol 2003;10:440-4.
6.	Coppell JA, Richardson PG, Soiffer R, Martin PL, Kernan NA, Chen A, et al. Hepatic veno-occlusive disease following stem cell transplantation: Incidence, clinical course, and outcome. Biol Blood Marrow Transplant 2010;16:157-68.
7.	Wingard JR. Hematopoietic Stem Cell Transplantation: A Handbook for Clinicians. Bethesda, Maryland: American Academy of Blood & Bone Marrow Transplantation; 2009.
8.	El Solh H, Al-Nasser A, Al-Sudairy R. Bone marrow transplantation in children: The King Faisal Specialist Hospital experience. Saudi J Kidney Dis Transpl 1996;7:194-8.
9.	Tomblyn M, Chiller T, Einsele H, Gress R, Sepkowitz K, Storek J, et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: A global perspective. Biol Blood Marrow Transplant 2009;15:1143-238.
10.	O′Donnell PV. Hematopoietic Stem Cell Transplantation: A Handbook for Clinicians. Bethesda, Maryland: AABB; 2009. p. 163-78.
11.	Fries BC, Riddell SR, Kim HW, Corey L, Dahlgren C, Woolfrey A, et al. Cytomegalovirus disease before hematopoietic cell transplantation as a risk for complications after transplantation. Biol Blood Marrow Transplant 2005;11:136-48.
12.	Jacobsohn DA. Acute graft-versus-host disease in children. Bone Marrow Transplant 2008;41:215-21.
13.	Ferrara JL, Deeg HJ. Graft-versus-host disease. N Engl J Med 1991;324:667-74.
14.	Ringdén O, Shrestha S, da Silva GT, Zhang MJ, Dispenzieri A, Remberger M, et al. Effect of acute and chronic GVHD on relapse and survival after reduced-intensity conditioning allogeneic transplantation for myeloma. Bone Marrow Transplant 2012;47:831-7.
15.	Sullivan KM, Weiden PL, Storb R, Witherspoon RP, Fefer A, Fisher L, et al. Influence of acute and chronic graft-versus-host disease on relapse and survival after bone marrow transplantation from HLA-identical siblings as treatment of acute and chronic leukemia. Blood 1989;73:1720-8.
16.	Eapen M, Horowitz MM, Klein JP, Champlin RE, Loberiza FR Jr., Ringdén O, et al. Higher mortality after allogeneic peripheral-blood transplantation compared with bone marrow in children and adolescents: The Histocompatibility and Alternate Stem Cell Source Working Committee of the International Bone Marrow Transplant Registry. J Clin Oncol 2004;22:4872-80.
17.	Cutler C, Giri S, Jeyapalan S, Paniagua D, Viswanathan A, Antin JH. Acute and chronic graft-versus-host disease after allogeneic peripheral-blood stem-cell and bone marrow transplantation: A meta-analysis. J Clin Oncol 2001;19:3685-91.
18.	Nichols WG, Corey L, Gooley T, Drew WL, Miner R, Huang M, et al. Rising pp65 antigenemia during preemptive anticytomegalovirus therapy after allogeneic hematopoietic stem cell transplantation: Risk factors, correlation with DNA load, and outcomes. Blood 2001;97:867-74.
19.	Yanada M, Yamamoto K, Emi N, Naoe T, Suzuki R, Taji H, et al. Cytomegalovirus antigenemia and outcome of patients treated with pre-emptive ganciclovir: Retrospective analysis of 241 consecutive patients undergoing allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2003;32:801-7.
20.	Boeckh M, Gooley TA, Myerson D, Cunningham T, Schoch G, Bowden RA. Cytomegalovirus pp65 antigenemia-guided early treatment with ganciclovir versus ganciclovir at engraftment after allogeneic marrow transplantation: A randomized double-blind study. Blood 1996;88:4063-71.
21.	Ljungman P, Loré K, Aschan J, Klaesson S, Lewensohn-Fuchs I, Lönnqvist B, et al. Use of a semi-quantitative PCR for cytomegalovirus DNA as a basis for pre-emptive antiviral therapy in allogeneic bone marrow transplant patients. Bone Marrow Transplant 1996;17:583-7.
22.	Ljungman P, Griffiths P, Paya C. Definitions of cytomegalovirus infection and disease in transplant recipients. Clin Infect Dis 2002;34:1094-7.
23.	Takatsuka H, Wakae T, Mori A, Okada M, Fujimori Y, Takemoto Y, et al. Endothelial damage caused by cytomegalovirus and human herpesvirus-6. Bone Marrow Transplant 2003;31:475-9.
24.	Ljungman P, Hakki M, Boeckh M. Cytomegalovirus in hematopoietic stem cell transplant recipients. Hematol Oncol Clin North Am 2011;25:151-69.
25.	Meyers JD, Flournoy N, Thomas ED. Risk factors for cytomegalovirus infection after human marrow transplantation. J Infect Dis 1986;153:478-88.
26.	Enright H, Haake R, Weisdorf D, Ramsay N, McGlave P, Kersey J, et al. Cytomegalovirus pneumonia after bone marrow transplantation. Risk factors and response to therapy. Transplantation 1993;55:1339-46.
27.	Forman SJ, Zaia JA. Treatment and prevention of cytomegalovirus pneumonia after bone marrow transplantation: Where do we stand? Blood 1994;83:2392-8.
28.	Bacigalupo A, Tedone E, Isaza A, Soracco M, Van Lint MT, Sanna A, et al. CMV-antigenemia after allogeneic bone marrow transplantation: Correlation of CMV-antigen positive cell numbers with transplant-related mortality. Bone Marrow Transplant 1995;16:155-61.
29.	Takenaka K, Gondo H, Tanimoto K, Nagafuji K, Fujisaki T, Mizuno S, et al. Increased incidence of cytomegalovirus (CMV) infection and CMV-associated disease after allogeneic bone marrow transplantation from unrelated donors. The Fukuoka Bone Marrow Transplantation Group. Bone Marrow Transplant 1997;19:241-8.
30.	Ljungman P, Aschan J, Lewensohn-Fuchs I, Carlens S, Larsson K, Lönnqvist B, et al. Results of different strategies for reducing cytomegalovirus-associated mortality in allogeneic stem cell transplant recipients. Transplantation 1998;66:1330-4.
31.	Osarogiagbon RU, Defor TE, Weisdorf MA, Erice A, Weisdorf DJ. CMV antigenemia following bone marrow transplantation: Risk factors and outcomes. Biol Blood Marrow Transplant 2000;6:280-8.
32.	Machado CM, Menezes RX, Macedo MC, Mendes AV, Boas LS, Castelli JB, et al. Extended antigenemia surveillance and late cytomegalovirus infection after allogeneic BMT. Bone Marrow Transplant 2001;28:1053-9.
33.	Matthes-Martin S, Aberle SW, Peters C, Holter W, Popow-Kraupp T, Pötschger U, et al. CMV-viraemia during allogenic bone marrow transplantation in paediatric patients: Association with survival and graft-versus-host disease. Bone Marrow Transplant 1998;21 Suppl 2:S53-6.
34.	Einsele H, Hebart H, Kauffmann-Schneider C, Sinzger C, Jahn G, Bader P, et al. Risk factors for treatment failures in patients receiving PCR-based preemptive therapy for CMV infection. Bone Marrow Transplant 2000;25:757-63.
35.	Nguyen Q, Champlin R, Giralt S, Rolston K, Raad I, Jacobson K, et al. Late cytomegalovirus pneumonia in adult allogeneic blood and marrow transplant recipients. Clin Infect Dis 1999;28:618-23.
36.	Deeg HJ, Antin JH. The clinical spectrum of acute graft-versus-host disease. Semin Hematol 2006;43:24-31.
37.	Bittencourt H, Rocha V, Filion A, Ionescu I, Herr AL, Garnier F, et al. Granulocyte colony-stimulating factor for poor graft function after allogeneic stem cell transplantation: 3 days of G-CSF identifies long-term responders. Bone Marrow Transplant 2005;36:431-5.
38.	Davies SM, Kollman C, Anasetti C, Antin JH, Gajewski J, Casper JT, et al. Engraftment and survival after unrelated-donor bone marrow transplantation: A report from the national marrow donor program. Blood 2000;96:4096-102.
39.	Xiao Y, Song J, Jiang Z, Li Y, Gao Y, Xu W, et al. Risk-factor analysis of poor graft function after allogeneic hematopoietic stem cell transplantation. Int J Med Sci 2014;11:652-7.
40.	Larocca A, Piaggio G, Podestà M, Pitto A, Bruno B, Di Grazia C, 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.
41.	Dominietto A, Raiola AM, van Lint MT, Lamparelli T, Gualandi F, Berisso G, 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;112:219-27.