This study presents the pediatric hematopoietic SCT (HSCT) activity in Iran between 1991 and 2012. Overall, 1105 fifteen-year-old or younger patients have undergone HSCT (975 allogeneic and 130 autologous). Annual HSCTs have been increasing steadily since 2007. HLA-matched siblings and other related donors were the main source of HSCs, although since 2008 a national HLA registry has been established to fill the gap for patients lacking a related donor. Inherited abnormalities of RBCs (45.88%), leukemias (27.6%) and BM failure syndromes (11.94%) constituted the majority of HSCTs during this period. Two-year overall survival and disease-free survival rates for all patients were 74.2% (95% confidence interval (CI): 71.6–77) and 66.3% (95% CI: 63.5–69.3), respectively. Leading cause of death in allogeneic group was TRM (165 deaths) and relapse caused the majority of deaths in the autologous group (39 deaths). All HSCTs from the beginning have been performed exclusively with TBI-free-conditioning regimens, which provides unique data for comparison with activities of other centers. Encouraging survival rates provide a basis for future studies on the extensive applicability of TBI-free-conditioning regimens in pediatric HSCT.
The introduction and evolution of hematopoietic SCT (HSCT) can be traced back to 1950s,1, 2, 3 to the studies on interactions among irradiation, shielding the spleen and BM from it and injection of BM cells. Today, HSCT is considered a well-established, effective and promising therapy for various malignant and nonmalignant medical conditions, both in children and adult patients,4, 5, 6, 7, 8, 9 and it is no longer restricted by limited sources of HSCs, donor pools or explicit need for matched family members.7 With the availability of unrelated cord blood and safer use of HLA-matched unrelated donors, allogeneic HSCT has become available to virtually all patients.10 Also in developing countries, HSCT programs have started over the last decades, including in Iran.
Although various studies on combined adult and pediatric populations11 and studies dedicated to pediatric HSCT have been conducted in developed countries,8, 12, 13 similar reports on pediatric patients in developing countries, including the ones in the Eastern Mediterranean region, are infrequent. The Hematology-Oncology and Stem Cell Transplantation Research Center (HORCSCT) is performing the highest number of HSCTs per annum (>400) in both pediatric and adult patients in the Middle East and Eastern Mediterranean. Our center has a long-standing experience in pediatric HSCT field with numerous corresponding cases and was the exclusive center performing pediatric HSCT in Iran until 2012.
TBI has been used in conditioning from the beginnings of HSCT.2 Trends in recent years are moving away from TBI. For most HSCT indications (in pediatric patients) TBI-free-containing regimens are used frequently, except for ALL.14
This study presents the results of a very active pediatric wing of an HSCT center in a developing country, in the Middle East, that has been using TBI-free-conditioning regimens for all indications of HSCT (including ALL) since the beginning of its activity. Our results are comparable with those of similar studies and they could interest researchers, clinicians and authorities who intent to expand pediatric HSCT using TBI-free-conditioning regimens.
As well as relevance to individual patient-counseling, surveys on trends of HSCT and activities of corresponding centers could be useful in the development of new techniques, channeling financial resources9, 12, 15, 16, 17, 18 and promoting regional cooperation.4, 19
Materials and methods
HORCSCT is the pioneering center of its type in Iran; pediatric HSCT has been performed since 1991, initially in a mixed setting, wherein pediatric and adult recipients were admitted to and taken care of in a single ward. After the separation of pediatric and adult HSCT units in 2007, 15-year-old or younger individuals have been admitted to the pediatric wing of HORCSCT.
The Data Management Office in our center has been responsible for data gathering, storage and management from the beginning.
Patients who were 15-years old or younger at the time of transplantation were considered pediatric HSCT candidates and included in the study. Transplantation activity up to 31 December 2012 was assessed, to allow for 1 year of follow-up.
Myeloid engraftment was defined as at least three consecutive daily ANC of 500 or more per microliter (/μL), without G-CSF administration and seven consecutive daily platelet counts of 20 000 or more/μL without transfusion.20
Primary end points
On the basis of recommendation of Statistical Guidelines for European Group for Bone Marrow Transplantation, OS was defined as the probability of survival regardless of disease status and was expressed as the time between HSCT and death. Disease-free survival (DFS) was defined as the probability of survival without evidence of disease at any time and was expressed as the time after HSCT when the patient has no evidence of disease, with relapse, graft failure or death as events, whichever comes first.
Secondary end points
Acute and chronic GVHD were defined according to consensus criteria.21 TRM was defined as death from causes other than relapse or progression of the underlying medical condition. TRM was assessed at 100-day and 1-year intervals after HSCT.
All patients were hospitalized under strict isolation. The same supportive care was provided for all patients, and nutritional supplementation was introduced by hyperalimentation. Phenytoin was administered in all patients who received BU as a prophylaxis for BU-mediated seizure. Patients were screened for CMV infection by looking for CMV DNA and CMV PP65 antigen. Antimicrobial prophylaxis with acyclovir, itraconazole, fluconazole and sulfamethoxazole/trimethoprime was given against viral, fungal and Pneumocystis jiroveci infections.
Conditioning regimens and GVHD prophylaxis
BU and CY were the most common regimen used and none of those regimens included TBI as a component. In majority of our patients, CsA has been the mainstay of GVHD prophylaxis, with or without a short course of MTX. Conditioning regimens and GVHD prophylaxis in patients have been presented in detail in Table 1.
OS and DFS curves were estimated using the Kaplan–Meier method, and their 95% confidence intervals (CI) were calculated through log-transformed method. Cumulative incidence functions for relapse and TRM were computed in a competing risk setting. Cumulative incidence of TRM was compared among groups through Gray's test. P-values ⩽0.05 were considered as statistically significant.
Between March 1991 and December 2012, nearly 4000 HSCTs were performed in our center; 1105 of these were performed on patients of 15 years or less (Figure 1).
Overall, 657 (59.46%) boys and 448 (40.54%) girls have undergone treatment in our center. The median age of transplant recipients in our center was 8 years of age (4 months to 15 years). Further details about gender and age of patients based on type of their HSCTs are presented in Table 2. Allogeneic HSCT accounts for 88.2% (975 patients) of the transplants and it has gradually increased over the years, particularly since 2007.
Only in 34 (3.49%) cases of allogeneic HSCTs, was the donor not a relative of the patient, whereas patients’ HLA-matched siblings accounted for up to 82.87% of the total performed allogeneic HSCTs (Table 2). At the beginning, HSCTs were limited to those with a sibling donor; following the establishment of pediatric wing of our center in 2007, HSCs from other related and unrelated donors have been increasingly used. Proportionally, HLA-matched other related donors group has been the fastest expanding group of its kind.
PB was the most common source of HSCs (62.62%) for all patients; it constituted a greater percentage of stem cell sources in the autologous group (80.77%) compared with the allogeneic group (60.2%). Although cord blood had been used as a source for stem cells before 2007, not only the annual figures have risen markedly since then, but also we have moved from related donors to unrelated cord blood donors.
Indications for HSCT
Overall, inherited RBC abnormalities and leukemias constitute the majority of HSCT recipients in our center, accounting for 45.8% and 27.6% of total HSCTs, respectively. It is noteworthy to mention that the patients with thalassemia constitute the majority (98.81%) of HSCT candidates with RBC abnormalities. They are followed by BM failures (BMF), primary immunodeficiency diseases (PID), solid tumors, inborn errors of metabolism (IEM) and lymphomas. The numbers of HSCTs for IEM and BMF patients have been continuously increasing since 2007; PID cases have increased markedly, too.
OS and DFS
Two-year OS and DFS rates for all patients were 74.2% (95% CI: 71.6–77) and 66.3% (95% CI: 63.5–69.3), respectively. Two-year OS rates in allogeneic and autologous groups were 75.8% (95% CI: 73.1–78.6) and 60.1% (95% CI: 52.3–71.7), respectively, whereas 2-year DFS rates in those groups were 67.5% (95% CI: 64.6–70.6) and 55.7% (95% CI: 47.7–66.7).
Survival rates were assessed for each disease category and patients with RBC abnormalities, PIDs and BMF syndromes had 2-year DFS over 70% (Table 3). Patients with SAA, a subgroup in BMF group, had the best outcomes and their 2-year OS and DFS were 84.4% (s.e.: 5.4%) and 80% (s.e.: 6.0%), respectively. OS and DFS survival curves for different malignant and nonmalignant conditions requiring allogeneic and autologous HSCT are illustrated in Figure 2. Two-year OS and DFS rates for various indications are presented in Table 3.
Mortality, relapse and TRM
In autologous HSCT patients, relapse accounts for 85% of all deaths (39 deaths). In the allogeneic group, TRM accounted for the rest; GVHD (59 deaths, 23.5%) and infections (46 deaths, 18.3%) were the main causes of TRM in the allogeneic group. Mortality associated with relapse constituted 34% (86 deaths) of all deaths in the allogeneic group.
Two-year relapse rates among allogeneic and autologous groups were 16.4% (95% CI: 14.1–18.9) and 38.8% (95% CI: 28.7–47.2), respectively, whereas 2-year probability of TRM for allogeneic and autologous groups were 16.1% (95% CI: 13.8–18.5) and 5.5% (95% CI: 2.5–10.6), respectively.
One-year TRM probabilities for different indications of autologous HSCT are as the following: 10% for lymphomas (95% CI: 2–27), 6% for leukemias (95% CI: 2–14) and 3% for solid tumors (95% CI: 0–14). One-year TRM probability for allogeneic indications of HSCT are as the following: 31% for IEM (95% CI: 16–46), 22% for PID (95% CI: 12–34), 19% for BMF (95% CI: 12–26), 15% for RBC abnormalities (95% CI: 12–18) and 11% for leukemias and lymphomas.7, 8, 9, 10, 11, 12, 13, 14, 15
This report is the first comprehensive activity survey of pediatric HSCT in Iran since the beginning of HORCSCT activity in 1991; it provides data on a large cohort of HSCT patients and shows encouraging outcomes in HSCT in 15-year-old and younger patients in a developing country.
The need for greater international collaboration in pediatric HSCT has been stressed before,22 and HORCSCT has shared its data with the Center for International Blood and Marrow Transplantation Registry,6 the Asia-Pacific Blood and Marrow Transplantation Group9 and Eastern Mediterranean Blood and Marrow Transplantation group,19, 23, 24 in addition to being a non-European party to European Group for Bone Marrow Transplantation activity surveys.11, 17, 25 We have reported our experience in TBI-free HSCT for different indications of HSCT before,26, 27, 28, 29, 30, 31 yet this is our first comprehensive report dedicated to pediatric HSCT.
Several pediatric HSCT activity surveys have reported that allogeneic HSCT constitutes the majority of HSCTs7, 32, 33 or their numbers are gradually increasing;12 similarly, allogeneic group comprised the majority of our patients. Also, latest report of HORCSCT activity suggested that up to 2010, unrelated donors had a small part in HSCT in Iran,9 and our findings suggested that unrelated donors constitute a small proportion of donors in pediatric HSCT, as well. Another notable attribute of our donor composition was the rise in HLA-matched other related donors numbers, following separation of pediatric wing of HORCSCT in 2007.
Household size and consanguineous marriages in the Middle East means that many pediatric candidates of HSCT can find suitable donors among their siblings and extended family members; however, both of these contributing factors are gradually declining in the region.34 Iran has been experiencing slower population growth and smaller household sizes since 20 years ago.35 Hence, according to statements on Eastern Mediterranean Blood and Marrow Transplantation group website (http://www.embmt.org/index.php/37-misc/280-newsletter, September 2011, Volume 1(Issue 3) last accessed on 23 March 2014), Iranian Stem Cell Donor Program has started its activity in 2008 as the first HLA registry in the Eastern Mediterranean region and has joined Bone Marrow Donors Worldwide, in an effort to maximize chances of finding HLA-matched donors in countries in the Eastern Mediterranean Region and beyond. HORCSCT is committed to expand unrelated donors pool, and so far public participation has been encouraging. Nonetheless, our findings could be applicable to the societies in which consanguineous marriage is practiced.
When comparing outcomes for various HSCT indications with findings of other centers, we must take differences in methods for categorization of HSCT indications in different centers into account, which limited our ability to compare our findings with similar studies.
Overall, nonmalignant indications for HSCT constitute a greater proportion of performed HSCTs in Iran. Inherited abnormalities of RBCs and thalassemia in particular are responsible for this disparity in part.12, 32, 33 OS and DFS rates for disease categories suggest that nonmalignant indications of HSCT had more favorable outcomes, particularly in patients with SAA. Majority of patients with RBC abnormalities who have undergone HSCT in our center have had thalassemia; DFS of these patients is comparable with that in similar studies (72.1% versus 73%).36 OS in patients with PID was similar to findings of another report from the Stem Cell Transplantation for Immunodeficiencies in Europe database.37 We have not calculated OS and DFS for each category of BMF, and we should be cautious when comparing our outcomes with similar studies on BMF;38 however, our patients with SAA had 2-year DFS after HSCT of around 80%, compared with 85% in 8-year-old and younger patients in a report from SAA working party of European Group for Bone Marrow Transplantation.39 As for patients with IEM, patients in our center had 5-year OS of around 70% compared with 78% in a report from the Australian and New Zealand Children’s Haematology Oncology Group.40 OS for patients with IEM in our center was consistent with findings of other studies.41, 42
In a study of HSCT in pediatric patients with leukemia in Italian centers, probability of survival at 24-month interval for patients with matched sibling donors was between 60 and 70%.43 Even though our method of classification in calculating survival was different, majority of donors for our patients were their siblings or other relatives; OS at 24-month interval in the leukemia patients of allogeneic group was also 60–70%. More detailed comparison would be the subject of a separate study.
HSCT outcomes in our center show encouraging results, which are comparable to studies reported by others. Sticking to a TBI-free-conditioning regimen has probably impacted the outcomes as well. International collaboration is essential to ensure that our patients could be provided with best possible care and we would happily share our experience with TBI-free regimens and HSCT in HLA-matched siblings, especially with centers operating in populations with demographic features similar to ours.
Limitations and perspectives for the future
One of the limitations of our study was that during early years of HORCSCT activity, pediatric patients underwent HSCT in the same ward where adult patients were admitted. Furthermore, as stated before, prior to 2012 our center was the only active pediatric HSCT center in Iran, subsequently creating a long waiting list; many families had to forgo treatment because of financial strains or because they resided far from Tehran. Also, some patients presented to our center late in the course of their conditions, which greatly reduced their chances of survival or cure. Even though the majority of donors are HLA-matched siblings of our patients, there were those who couldn’t receive treatment because they didn’t have a matched or partially matched donor. Finally, we have never had access to irradiation devices, therefore we had to rely on TBI-free-conditioning regimens for all HSCT indications, even in patients with ALL; we have been trying to turn this challenge into an opportunity.
After the Iranian Stem Cell Donor Program, was launched our sources for HSCT have been undergoing a transformation; theoretically, an HLA-matched unrelated donor could be found for every Iranian pediatric HSCT candidate. We hope in the near future that half of annual HSCTs could be performed using HLA-matched unrelated donors. We plan to equip our center’s laboratory wing for extensive research projects, particularly collaborative international projects. We seek to help other countries in the region without pediatric HSCT centers with establishing centers of their own. Also, we have programs for training of other pediatric HSCT teams, in Iran and throughout the region, so that new centers could be launched.
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We wish to acknowledge the contributions of all physicians, nursing staff, patients and their families and all who have made it possible to continue HSCT through many years.
The authors declare no conflict of interests.