Abstract
Objectives
Allogeneic hematopoietic cell transplantation (Allo-HCT) is a curative option for children with various malignant and non-malignant diseases. Most reports studied all age groups amongst children. Herein we analyzed our data in children transplanted at or less than 2-years of age.
Patients and methods
We reviewed medical charts of 618 patients who underwent 666 transplantation at our center between 1993 and 2015. There were 340 boys and 278 girls. Median age was 0.7 years (range 0.04–2). Stem cell source was bone marrow (BM) in 492 (73.9%), unrelated umbilical cord blood (UCB) in 161 (24.2%) followed by peripheral blood stem cell (PBSC) in 13 (2%) patients. Matched siblings were the most common donors (n = 356, 53.5%), followed by unrelated (n = 161, 24.2%) with haploidentical family member donors in 29 (4.4%) transplants. Disease groups were categorized as benign hematology (Thalassemia, Fanconi, Aplastic anemia etc.), benign neoplasm (Langerhans cell histiocytosis, Hemophagocytic Lymphohistiocytosis etc.), non-neoplasms (metabolic disorders, immunodeficiency disorders etc.) and Leukemia/lymphomas (myeloid and lymphoid malignancies etc.)
Results
Cumulative incidence of acute GvHD (I-IV) was 31.5% (n = 210) and grade III-IV GvHD was 8.7% (n = 58). At median follow-up of 115.1 months, the cumulative probability of overall survival (OS) at 5 years was 70.0% ± 1.9%. Our mortality rate was 31.2% (n = 193). The five-year OS was significantly better in patients transplanted for benign hematological disorders (P = .001). Patients transplanted using BM/PBSC as source of stem cells fared significantly better compared to those in which CB was used (P<.001). Post-transplant graft failure remains the leading cause requiring further transplants in this age group. In conclusion, the cumulative probability of OS at 5 years was about 70.0% for all with an OS of 61% in our haploidentical recipients.
Conclusion
Analyzing our institutional data over time has enabled us to develop tentative strategies to minimize transplant related toxicities in very young children who are candidates for allo-HCT.
Keywords: Hematopoietic cell transplantation outcomes, Very young children
1. Introduction
Allogeneic hematopoietic cell transplant (Allo-HCT) is an established and widely performed curative therapy for a various malignant and nonmalignant disorders in children. These include but are not limited to hematologic malignancies, inherited bone marrow failures syndromes (IBMFS), primary immune deficiencies (PID) and some inborn errors of metabolism (IEM) [[1], [2], [3], [4], [5], [6]]. Indications for various diagnoses, comorbidities, conditioning regimens and graft source are different from adults and have also varied between pediatric groups [6].
Our clinical practice has evolved over the past decades giving us better insight into various aspects such as decreasing cytoreductive toxicity, optimizing graft source, adjusting graft versus host disease (GvHD) medications and improving supportive management of patients [7,8]. Establishing and studying trends in transplant activities is crucial for enhanced patient care. Such studies have helped us recognize effective clinical practices, disparities between disease outcomes and conditions that need more focused research.
Children in the first few years of life are at a higher risk of therapy related acute and chronic complications affecting their survival and outcomes [9,10]. There are few studies on survival and transplant related morbidity in children who are less than 3 years of age [[11], [12], [13]]. We conducted a retrospective study of the pediatric Allo-HCT activity in our center over two decades in children who were younger than or equal to two years of age at the time of transplant.
2. Patients and method
2.1. Study design
This is a descriptive account of all patient who were given an allo-HCT at our institution between January 1993 to December 2015 and were younger than or equal to two years of age at transplant. Clinical, laboratory and transplant related data was collected prospectively at an institutional database. All patients' guardians signed consent before transplant. International Classification of Diseases for Oncology (ICD-O, Version 3.0), International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9CM) and Online Mendelian Inheritance in Man (OMIM) were used to record the primary diagnoses for relevant diagnostic related groups.
2.2. Patients
Six hundred and eighteen (618) patients underwent 666 blood and marrow transplantation at our center. Patients' demographics and related data is shown in Table 1. For most patients the primary indication for transplant were non-neoplastic diseases (primary immunodeficiency and metabolic disorders), followed by ‘benign neoplasms except benign hematological disorders’ (histiocytic disorders), benign hematological disorders, and leukemias and lymphomas, combined.
Table 1.
Patient and transplant related parameters (618 patients with 666 transplants).
| Female | Male | Total | P Value | |
|---|---|---|---|---|
| Number of patients transplanted | 278 (45%) | 340 (55%) | 618 | – |
| Total transplant episodes | 300 (45%) | 366 (55%) | 666 | – |
| Single transplant | 258 (45.1%) | 314 (54.9%) | 572 (85.9%) | |
| Multiple transplants | 42 (44.7%) | 52 (55.3%) | 94 (14.1%) | |
| First transplant | 278 | 340 | 618 | |
| Second transplant | 20 | 26 | 46 | |
| Third transplant | 2 | 0 | 2 | |
| Age at first transplant, years, median (range) | 0.7 (0.04–2.0) | 0.7 (0.05–2.0) | 0.7 (0.04–2.0) | .250 |
| Primary DRG (all patients, n = 618) | .005 | |||
| Benign Hematological Disorders | 23 (31.9% | 49 (68.1%) | 72 (11.7%) | |
| Benign Neoplasmsa | 29 (34.9%) | 54 (65.1%) | 83 (13.4%) | |
| Leukemias and Lymphomas | 24 (40.7%) | 35 (59.3%) | 59 (9.5%) | |
| Non-Neoplasms | 202 (50.0%) | 202 (50.0%) | 404 (65.4%) | |
| Source of stem cells (all transplants, n = 666) | .637 | |||
| Cord blood | 67 (41.6%) | 94 (58.4%) | 161 (24.2%) | |
| PBSC | 6 (46.2%) | 7 (53.8%) | 13 (2.0%) | |
| Bone marrow | 227 (46.1%) | 265 (53.9%) | 492 (73.9%) | |
| Donor HLA Type for all transplants (n = 666) | – | |||
| Matched sibling donor | – | – | 356 (53.5%) | |
| Matched related donor | – | – | 120 (18.0%) | |
| Haploidentical family member | – | – | 29 (4.4%) | |
| Unrelated | – | – | 161 (24.2%) | |
| Use of TBI in conditioning regimen | 1.0 | |||
| TBI (−) | 293 (45.1%) | 357 (54.9%) | 650 (97.6%) | |
| TBI (+) | 7 (43.8%) | 9 (56.2%) | 16 (2.4%) | |
| Era of first transplant (n = 618) | .326 | |||
| 1993–2004 | 86 (48.3%) | 92 (51.7%) | 178 (28.8%) | |
| 2005–2015 | 192 (43.6%) | 248 (56.4%) | 440 (71.2%) | |
Except benign and pre-malignant hematological disorders.
2.3. Graft and donor source
Bone marrow (BM) was the major source of stem cells in 492 (73.9%) transplants. . Matched siblings were the most commonly used donors (n = 356, 53.5%) whereas in 29 (4.4%) transplants we used a haplotype identical family member for donor as well. Median CD34+ cell dose was 8.1 × 106/kg of recipient's weight (range, 0.03–124.0) for BM/PBSC and 0.3 × 106/kg of recipient's weight (range, 0.03–14.9) for UCB transplants. Majority of the patients (n = 576, 86.5%) received GvHD prophylaxis as per institutional guidelines.
2.4. Transplant procedure
All patients were admitted to private rooms and received disease specific cytoreductive regimen followed by an infusion of graft cells. Every patient remained hospitalized till hematopoietic count recovery with no ongoing clinical concerns. Total body irradiation (TBI) combined with cyclophosphamide (Cy) was frequently used in patients undergoing allo-HCT for Acute Lymphoblastic Leukemia (ALL). Busulfan combined with cyclophosphamide was the most regularly used conditioning regimen for Acute Myeloid Leukemia (AML). A regimen was considered ‘reduced intensity’ if the dose of busulfan was ≤8 mg/kg orally or ≤6.4 mg/kg intravenously, dose of melphalan was 150 mg/m2, and if the TBI dose was between 200 and 400 cGy. GvHD prophylaxis was mostly cyclosporine. Cyclosporine was either used alone or with methotrexate, mycophenolate mofetil (MMF) and or methylprednisone., All blood products were, irradiated and leukoreduced. Acyclovir, trimethoprim-sulfamethazole and an antifungal agent (usually fluconazole) was used as prophylaxis. In patients with neutropenia, empiric broad-spectrum antibiotics were started for a body temperature 38 °C and/or clinical signs of infection.
2.5. End point definition
Time to neutrophil recovery was defined as the first of three consecutive days of absolute neutrophil count (ANC) ≥0.5 × 109/L. Primary graft failure was labeled when there was failure to achieve ANC of 0.5 × 109/L by day 28 for BM or PBSC and day 42 for UCB. Patients who have already achieved an ANC of ≥0.5 × 109/L followed by a decline in counts with no recovery or 0% donor chimerism by PCR were categorized as secondary graft failure. Platelet engraftment was defined as the first of three consecutive days on which platelet count is > 20 × 109/L without transfusions for seven days.. We defined survival as time from transplant to death from any cause.
2.6. Statistical consideration
Continuous data is presented as median with minimum and maximum points and mean (±SD) wherever appropriate, while discrete data is provided as n(%). Kaplan-Meier curves are used for survival analysis Breslow (Generalized Wilcoxon) test was used to test for the significance of the difference between the groups. Independent sample Mann-Whitney U test was used to test for the significance of difference between two groups of non-normal continuous variables. Chi-square test or Fisher's exact test has been used for testing the significance of independence between categorical variables.
3. Results
3.1. Engraftment
ANC engraftment by clinical definition was seen in 494 (74.2%) transplants at a median time to recovery of 15 days (range, 8–93). In 409 (61.4%) transplants we saw platelet transfusion independence at a median of 33 days (range, 3–171). ANC engraftment and platelets recovery were found to be significantly associated with source of stem cells and primary diagnostic related groups (DRG) with those transplanted for non-neoplasms having the highest failure rate (P < .001, Table 2).
Table 2.
Transplants outcome (618 patients with 666 transplants).
| DRG |
P value | Source |
P-value | |||||
|---|---|---|---|---|---|---|---|---|
| A (73 in 72 pts) | B (89 in 83 pts) | C (62 in 59 pts) | D (442 in 404 pts) | CB (161 in 151 pts) | BM/PBSC (505 in 467 pts) | |||
| ANC engraftment | <.001 | .006 | ||||||
| No engraftment | 1 (1.4%) | 8 (9.0%) | 4 (6.5%) | 159 (36.0%) | 28 (17.4%) | 144 (28.5%) | ||
| Engrafted within timea | 70 (95.9%) | 78 (87.6%) | 52 (83.9%) | 268 (60.0%) | 123 (76.4%) | 345 (68.3%) | ||
| Engrafted beyond time | 2 (2.7%) | 3 (3.4%) | 6 (9.7%) | 15 (3.4%) | 10 (6.2%) | 16 (3.2%) | ||
| Platelets recovery | <.001 | <.001 | ||||||
| Never Recovered | 8 (11.0%) | 25 (28.1%) | 11 (17.7%) | 213 (48.2%) | 60 (37.3%) | 197 (39.0%) | ||
| Recovered within 40 days | 43 (58.9%) | 47 (52.8%) | 38 (61.3%) | 141 (31.9%) | 49 (30.4%) | 220 (43.6%) | ||
| Recovered 41–60 days | 15 (20.5%) | 9 (10.1%) | 9 (14.5%) | 55 (12.4%) | 29 (18.0%) | 59 (11.7%) | ||
| Recovered 61–100 days | 4 (5.5%) | 6 (6.7%) | 4 (6.5%) | 29 (6.6%) | 19 (11.8%) | 24 (4.8%) | ||
| Recovered >100 days | 3 (4.1%) | 2 (2.2%) | 0 (0.0%) | 4 (0.9%) | 4 (2.5%) | 5 (1.0%) | ||
| D+100 Engraftment (n = 616 evaluable)b | .169 | <.001 | ||||||
| Engrafted | 66 (94.3%) | 66 (80.5%) | 53 (93.0%) | 349 (85.7%) | 109 (79.0%) | 425 (88.9%) | ||
| Primary Graft Failure | 2 (2.9%) | 9 (11.0%) | 1 (1.8%) | 30 (7.4%) | 21 (15.2%) | 21 (4.4%) | ||
| Secondary Graft Failure | 2 (2.9%) | 7 (8.5%) | 3 (5.3%) | 28 (6.9%) | 8 (5.8%) | 32 (6.7%) | ||
| Cumulative incidence of GvHD | ||||||||
| aGvHD (all grade, n = 210) | 24 (32.9%) | 23 (25.8%) | 22 (35.5%) | 141 (32.0%) | .591 | 62 (38.5%) | 148 (29.4%) | .032 |
| aGvHD (grade III-IV, n = 58) | 9 (12.3%) | 8 (9.0%) | 3 (4.8%) | 38 (8.6%) | .510 | 21 (13.0%) | 37 (7.3%) | .036 |
| cGvHD (72 of 562 evaluable) | 8 (11.8%) | 9 (13.0%) | 7 (13.0%) | 48 (12.9%) | .996 | 25 (21.9%) | 47 (10.5%) | .002 |
| SOS/VOD (∼day+100, n = 51) | 8 (11.0%) | 15 (16.9%) | 4 (6.5%) | 24 (5.4%) | .003 | 11 (6.8%) | 40 (7.9%) | .736 |
|
| ||||||||
| DRG | P value | Source | P value | |||||
| A (73 in 72) |
B (89 in 83) |
C (62 in 59) |
D (442 in 404) |
CB (161 in 151) |
BM/PBSC (505 in 467) |
|||
| Infections (∼day+100) | ||||||||
| Bacterial (n = 173) | 18 (24.7%) | 31 (34.8%) | 10 (16.1%) | 114 (25.8%) | .078 | 63 (39.1%) | 110 (21.8%) | <.001 |
| Viral (n = 87) | 10 (13.7%) | 13 (14.6%) | 6 (9.7%) | 58 (13.1%) | .842 | 32 (19.9%) | 55 (10.9%) | .005 |
| Fungal (n = 35) | 3 (4.1%) | 5 (5.6%) | 3 (4.8%) | 24 (5.4%) | .980 | 13 (8.1%) | 22 (4.4%) | .071 |
| 5-year OS (n = 618) | 83.2% (4.4%) | 56.3% (5.5%) | 56.8% (6.5%) | 72.3% (2.2%) | .001 | 53.6%(4.1) | 75.2%(2.0%) | <.001 |
| Mortality (expired = 193) | 12/72 (16.7%) | 37/83 (44.6%) | 25/59 (42.4%) | 119/404 (29.5%) | <.001 | 70/151 (46.4%) | 123/467 (26.3%) | <.001 |
| Era 1993–2004 (n = 178) | 27/72 | 14/83 | 21/59 | 116/404 | – | – | ||
| 5-year OS | 88.7%(6.1%) | 50.0%(13.4%) | 47.6% (10.9%) | 75.7% (4.0%) | .007 | – | – | |
| Mortality (expired = 54) | 3 (11.1%) | 8 (57.1%) | 11 (52.4%) | 32 (27.6%) | – | – | ||
| Era 1993–2004 (n = 440) | 45/72 | 69/83 | 38/59 | 288/404 | .056 | – | – | |
| 5-year OS | 80.0%(6.0%) | 57.6% (6.0%) | 62.3% (8.0) | 71.0% (2.7%) | – | – | ||
| Mortality (expired = 139) | 9 (20.0%) | 29 (42.0%) | 14 (36.8%) | 87 (30.2%) | – | – | ||
Recovery within day +28 for BM and within day +42 for CB.
Based on chimeric studies. Early deaths were 49, and STR values were not available for 1 transplant, A, Benign Hematological Disorders, B, Benign Neoplasms except Benign and Pre-Malignant Hematological Disorders, C, Leukemia and Lymphoma, D, Non-Neoplasms. Values are provided as n (%) and cumulative proportion of subjects surviving at the specified time with ±standard error.
3.2. GvHD
Cumulative incidence of all grades acute GvHD was 31.5% (n = 210) with grade III-IV GvHD at 8.7% (n = 58). Incidence of severe acute GvHD (grade ≥ III) was significantly higher in patients transplanted with UCB compared to BM (13.0% vs. 7.3%, P = .036) and was not associated with the primary DRG. For 562 evaluable transplants, chronic GvHD was seen in 72 (12.8%) transplants; significantly higher in patients transplanted with UCB (21.9%, n = 25, P = .002, Table 2).
3.3. Graft failure, transplant related toxicity and survival
Of 666 transplants 49 could not be followed for evaluation due to early death and for one patient graft assessment by short tandem repeat analysis was not available. Thus out of the 616 evaluable transplants at day +100 primary graft failure was recorded in 42 (6.8%) and secondary graft failure occurred in 40 (6.5%). Engraftment rate was significantly better for patients transplanted with BM/PBSC (88.9%) than those transplanted with UCB (79%, P<.001), and was not associated with primary DRG (Table 2). Though, infectious toxicity recorded during the first day +100 was not associated with primary indication for transplants, episodes of bacterial and viral infections were noted to be significantly higher in patients transplanted using UCB (P < .001 and .003 respectively). Incidence of veno-occlusive disease (VOD) measured at day +100 was 7.7% (n = 51 transplants).
At a median follow-up of 115.1 months (95% CI, 111.2–118.8, range, 1.4–314.9 months), cumulative probability of OS at 5 years was 70.0% (1.9%). Our mortality rate was 31.2% (n = 193). Five-year OS was significantly better in patients transplanted for benign hematological disorders (P = .001, Fig. 1, Table 2). Patients transplanted using BM/PBSC as source of stem cells fared significantly better compared to those in which UCB was used (P < .001, Fig. 2, Table 2).
Fig. 1.
OS by primary DRG.
Fig. 2.
OS by source of stem cells.
Upon dividing our data set according to the chronology of first transplant into two era; 1993–2004 and 2005–2015, there was more than two folds increase in the number of transplants (Table 1). The cumulative probability of OS at 5 years was 72.2% ± 3.4% for early recipients compared to 69.1% (2.2%) (P = .370). The same was also not statistically significantly different when analyzed separately for malignant (50.0% [10.7%], n = 22, events = 11 vs. 62.3% [8.0%], n = 38, events = 14, P = .678) and for non-malignant disorders (75.4% [3.5%], n = 156, events = 43 vs. 69.7% [2.3%], n = 402, events = 125, P = .201).
3.4. New malignancy
Overall, new malignancy developed in three patients (0.005%) out of the 616 observed. There were two children with familial hemophagocytic lymphohistiocytosis (HLH). One developed AML that was refractory to treatment and expired after receiving 2nd line chemotherapy. The second child was diagnosed with Hodgkin's lymphoma about a year post-HCT. His lymphoma was resistant to therapy and succumbed to disease after two-lines of chemotherapy. The third child had SCID and developed non-metastatic rhabdomyosarcoma a few years after HCT. He responded to therapy and is currently disease free as per his last clinic visit.
3.5. Recipients transplanted using haploidentical family donor
In 29 transplants haploidentical family donor was used for 24 patients. Severe combined immune deficiency (SCID) was the primary indication of transplant in 13 (54.2%), Omenn Syndrome in 10 (41.7%) and Osteopetrosis in the remaining one case. Overall mortality rate was 37.5% (9 out of 24) with a median follow-up of 150.9 months (range, 0.7–252.5, 95% confidence interval, 106.4–195.4 months). Cumulative probability of ten year overall survival for this subgroup of patients was 61.1% ± 10.2%. Six (46.2%) patients transplanted for SCID and three (30%) patients transplanted for Omenn Syndrome died from this sub-group of recipients transplanted from haploidentical family donors. Details on nine patients who underwent multiple transplants where haploidentical family donor was used in first, second or the both, are presented in Table 3.
Table 3.
Details on patients transplanted from Haplo-type identical donors.
| Primary disease | 1st Transplant |
2nd Transplant |
Survival status | Causes of death | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age (months) | Cell Source | Donor | HLA type | CD34+ cells (10 [6]) | Acute GvHD | Graft Failure | Cell Source | Donor | HLA type | CD34+ cells (10 [6]) | Acute GvHD | Graft status | |||
| Omenn Synd. | 6.5 | BM | Mother | Haplo | 8.15 | -ve | SGF | BM | Mother | Haplo | 5.71 | -ve | Engrafted | Alive | – |
| Omenn Synd. | 2.8 | BM | Mother | Haplo | 7.73 | -ve | SGF | BM | Mother | Haplo | 5.3 | -ve | SGF | Alive | – |
| Omenn Synd. | 1.9 | BM | Sister | Haplo | 14.78 | -ve | PGF | BM | Sister | Haplo | 10.67 | -ve | PGF | NS | Multi-organ failure secondary to MDR sepsis |
| SCID | 3.5 | BM | Sister | Haplo | 8.73 | -ve | SGF | BM | Sister | Haplo | 10.7 | -ve | Engrafted | Alive | – |
| SCID | 6.4 | PBSC | Mother | Haplo | 15.12 | -ve | PGF | PBSC | Mother | Haplo | 6.05 | -ve | SGF | NS | Sepsis with ARDS |
| Omenn Synd. | 8.4 | UCB | Unrel | 2-AGm | 0.56 | -ve | SGF | BM | Mother | Haplo | 14.44 | -ve | SGF | LTFU | – |
| Osteopetrosis | 9.7 | UCB | Unrel | 1-AGm | 0.19 | -ve | PGF | BM | Father | Haplo | 5.84 | Skin, II | Engrafted | Alive | – |
| Omenn Synd. | 2.0 | BM | Mother | Haplo | 14.00 | -ve | SGF | BM | Aunt | HLA Id | 13.40 | -ve | Engrafted | LTFU | – |
| Omenn Synd. | 2.3 | PBSC | Father | Haplo | 13.91 | -ve | SGF | UCB | Unrel | 2-AG | 1.10 | -ve | Engrafted | Alive | – |
BM, Bone marrow; PGF, Primary Graft Failure; SGF, Secondary Graft Failure; NS, Non-survivor; MDR, Multi-drug resistant; ARDS, Acute respiratory distress syndrome.
4. Discussion
HCT is an essential therapeutic modality in infants as well as young children with both malignant and non-malignant diseases. This study is a large single center analysis of allo-HCT outcomes in 618 children who were less than 2-years of age at transplant. Here we see that the number of allogeneic transplants increased over the time studied between the two era's. Reasons for this can be the availability of varied graft sources, establishment and access to donor registries as well as improvement in modalities for treating GvHD when using unrelated donors as resources improved [14,15].
The median age for these young children transplanted in the first era (1993–2004) was about 9-months (range, 0.7–24 months) which was higher than those transplanted in the second era (2005–2015) with a median of 8-months (range, 0.5–24 months). With our continuing understanding, experience of transplant in younger children along with managing comorbidities during transplant course, led us to lay down more defined criteria for disease categories going forward. With the given improvement in transplant related approaches the tendency for upfront transplant in younger children gained momentum in our practice.
Among our cohort the most common indication for an allo-HCT were non-neoplastic disorders, primarily comprising of immunodeficiencies and inborn errors of metabolism. Despite continued monitoring of infectious parameters, prophylaxis and treatment of invasive infections and interval checks for organ toxicities we did not see an increase in OS across all disease categories. The reason might be the inherent nature of the underlying diseases in such young children. Though, an improved trend in five year OS was observed in two DRG's (Table 2). There can be multiple reasons for this improvement including but not limited to the advancement in supportive care, development of care pathways, awareness amongst families and early referrals over time [16]. Over the years, number of patients getting allogeneic HCT for hematologic malignancies increased despite improvement in chemotherapeutic regimens. We did not see good outcomes with infantile acute lymphoblastic leukemias as expected [[17], [18], [19]].
In our cohort, cumulative incidence of grade III-IV acute GvHD was higher in the second era (8.9%, 42 of 474 evaluable transplants) as compared to the first (8.6%, 16 of 185 evaluable transplants), unlike other reports [20,21]. A major reason for this was increased usage of CB grafts in the second era. Despite the improvement in supportive care strategies for infections in children with delayed immune reconstitution the above mentioned patient groups did not do well overall [22].
Sinusoidal obstruction syndrome/Hepatic veno-occlusive disease (SOS/VOD) is a potentially life-threatening complication of HCT conditioning chemotherapy. Lee et al. reported the overall incidence of VOD at 21.1% for children less than 2-years of age [23]. While the overall mean incidence of SOS/VOD has been reported to be 14% in a pooled analysis of 135 studies [24]. Looking at SOS/VOD toxicity in our patients, the highest incidence was seen in children with hemoglobinopathies and histiocytic disorders (14%) followed by those with metabolic disorders (5.4%) [25]. Across all DRGs our incidence was about 10%. It is the lowest amongst those reported in literature to our knowledge. These very young patients likely did better than older children due to the immature and adaptability of their hepatic function despite the myeloablative (MAC) conditioning given in the background of transfusion needs.
Patients undergoing allo-HCT have a higher risk of presenting with severe infections. These can be due to commensal and/or opportunistic microorganisms. In our young patients, the overall rates of bacterial infection (25.4%) are lower than that reported in published literature. Perez et al. in their retrospective review found an overall bacteremia incidence of 41% during the initial 100-days of allo-HCT for all indications in children less than 18-years of age [26]. Others have also reported bacterial infection rates around 20–39% [27]. The lower rates are possibly due to their limited mobility and caution observed while handling these very young children.
In conclusion survival in very young children with malignant diseases improved over the period analyzed. Our outcomes of transplanting children with benign hematological entities are better among other indications for transplant. SOS/VOD as well as infectious complications are lower in very young children thus it is safe to transplant sooner than later for established indications. More graft failure and infection related complications are expected with UCB transplants. Analyzing our institutional trends has enabled us to develop further strategies to minimize transplant related toxicities in these very young children needing allo-HCT.
Ethical statement
This clinical research study was approved by the Institutional Review Board (IRB) the hospitals via approval numbers 2141033, which was to be conducted under the international guidelines for the enrollment of human subjects. The data from patients' medical records were collected and maintained at the Department of Pediatric Hematology/Oncology, in accordance with institutional policy on data confidentiality, security, and safety. As the study was designed as a retrospective review, no consent/assent was taken from patients/parents. A waiver of informed consent/assent was sought from the IRB and was duly granted.
Author statement
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1.
Saadiya Khan: Conceptualization; Investigation; Methodology; Project administration; Resources; Supervision; Validation; Writing - original draft; Writing - review & editing.
-
2.
Khawar Siddiqui: Conceptualization; Methodology; Data processing; Formal analysis; Validation; Writing Results; Writing - review & editing.
-
3.
Hasan ElSolh: Writing - review & editing.
-
4.
Abdullah AlJefri: Writing - review & editing.
-
5.
Ali AlAhmari: Writing - review & editing.
-
6.
Ibrahim Ghemlas: Writing - REVIEW & editing.
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7.
Hawazen AlSaedi: Writing - review & editing.
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8.
Awatif AlAnazi: Writing - review & editing.
-
9.
Amal AlSeraihy: Writing - review & editing.
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10.
Mouhab Ayas: Project administration; Resources; Supervision; Writing - original draft; Writing - review & editing.
Ethical approval
This study was submitted to the Institutional Review Board of King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia, before initiation and was approved by the Research Advisory Committee through established procedures with Approval Number 2141033.
Funding
This work did not receive any financial support in any form from any funding agency.
Submission declaration and verification
The work described in this article has not been published previously (except in the form of an abstract, a published lecture or academic thesis), and is not under consideration for publication elsewhere. Its publication is approved by all authors and is explicitly approved by the responsible authorities where the work was carried out. If the work gets accepted in IJPAM, it will not be published elsewhere in the same form, in English or in any other language, including electronically without the written consent of the copyright-holder.
Data statement
The data used in this work cannot be shared publicly in its raw format due to institutional restrictions.
Declaration of competing interest
None of the authors have any conflicts of interest to declare.
Footnotes
Peer review under responsibility of King Faisal Specialist Hospital & Research Centre (General Organization), Saudi Arabia.
References
- 1.Copelan E.A. Hematopoietic stem-cell transplantation. N Engl J Med. 2006;354(17):1813–1826. doi: 10.1056/NEJMra052638. [DOI] [PubMed] [Google Scholar]
- 2.Lucarelli G., Andreani M., Angelucci E. The cure of thalassemia by bone marrow transplantation. Blood Rev. 2002;16(2):81–85. doi: 10.1054/blre.2002.0192. [DOI] [PubMed] [Google Scholar]
- 3.Niederwieser D., Baldomero H., Szer J., Gratwohl M., Aljurf M., Atsuta Y., et al. Hematopoietic stem cell transplantation activity worldwide in 2012 and a SWOT analysis of the Worldwide Network for Blood and Marrow Transplantation Group including the global survey. Bone Marrow Transplant. 2016;51(6):778–785. doi: 10.1038/bmt.2016.18. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Sureda A., Bader P., Cesaro S., Dreger P., Duarte R.F., Dufour C., et al. Indications for allo- and auto-SCT for haematological diseases, solid tumours and immune disorders: current practice in Europe, 2015. Bone Marrow Transplant. 2015;50(8):1037–1056. doi: 10.1038/bmt.2015.6. [DOI] [PubMed] [Google Scholar]
- 5.Gennery A.R., Slatter M.A., Grandin L., Taupin P., Cant A.J., Veys P., et al. Transplantation of hematopoietic stem cells and long-term survival for primary immunodeficiencies in Europe: entering a new century, do we do better? J Allergy Clin Immunol. 2010;126(3):602–610. doi: 10.1016/j.jaci.2010.06.015. e1-11. [DOI] [PubMed] [Google Scholar]
- 6.Kurosawa S., Yakushijin K., Yamaguchi T., et al. Changes in incidence and causes of non-relapse mortality after allogeneic hematopoietic cell transplantation in patients with acute leukemia/myelodysplastic syndrome: an analysis of the Japan Transplant Outcome Registry. Bone Marrow Transplant. 2013;48(4):529–536. doi: 10.1038/bmt.2012.172. [DOI] [PubMed] [Google Scholar]
- 7.Passweg J.R., Baldomero H., Peters C., Gaspar H.B., Cesaro S., Dreger P., et al. Hematopoietic SCT in Europe: data and trends in 2012 with special consideration of pediatric transplantation. Bone Marrow Transplant. 2014;49(6):744–750. doi: 10.1038/bmt.2014.55. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Balduzzi A., Conter V., Uderzo C., Valsecchi M.G. Transplantation in childhood very high risk acute lymphoblastic leukemia in first complete remission: where are we now? J Clin Oncol. 2007;25(18):2625–2626. doi: 10.1200/JCO.2007.11.5014. author reply 7-8. [DOI] [PubMed] [Google Scholar]
- 9.Chow E.J., Anderson L., Baker K.S., Bhatia S., Guilcher G.M., Huang J.T., et al. Late effects surveillance recommendations among survivors of childhood hematopoietic cell transplantation: a children's oncology group report. Biol Blood Marrow Transplant. 2016;22(5):782–795. doi: 10.1016/j.bbmt.2016.01.023. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Yesilipek M.A. Hematopoetic stem cell transplantation in children. Turk Pediatri Ars. 2014;49(2):91–98. doi: 10.5152/tpa.2014.2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Davies S.M., Ramsay N.K., Klein J.P., Weisdorf D.J., Bolwell B., Cahn J.Y., et al. Comparison of preparative regimens in transplants for children with acute lymphoblastic leukemia. J Clin Oncol. 2000;18(2):340–347. doi: 10.1200/JCO.2000.18.2.340. [DOI] [PubMed] [Google Scholar]
- 12.Mulcahy Levy J.M., Tello T., Giller R., Wilkening G., Quinones R., Keating A.K., et al. Late effects of total body irradiation and hematopoietic stem cell transplant in children under 3 years of age. Pediatr Blood Cancer. 2013;60(4):700–704. doi: 10.1002/pbc.24252. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Allewelt H., El-Khorazaty J., Mendizabal A., Taskindoust M., Martin P.L., Prasad V., et al. Late effects after umbilical cord blood transplantation in very young children after busulfan-based, myeloablative conditioning. Biol Blood Marrow Transplant. 2016;22(9):1627–1635. doi: 10.1016/j.bbmt.2016.05.024. [DOI] [PubMed] [Google Scholar]
- 14.Kurtzberg J., Prasad V.K., Carter S.L., Wagner J.E., Baxter-Lowe L.A., Wall D., et al. Results of the Cord Blood Transplantation Study (COBLT): clinical outcomes of unrelated donor umbilical cord blood transplantation in pediatric patients with hematologic malignancies. Blood. 2008;112(10):4318–4327. doi: 10.1182/blood-2007-06-098020. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.MacMillan M.L., Davies S.M., Nelson G.O., Chitphakdithai P., Confer D.L., King R.J., et al. Twenty years of unrelated donor bone marrow transplantation for pediatric acute leukemia facilitated by the National Marrow Donor Program. Biol Blood Marrow Transplant. 2008;14(9 Suppl):16–22. doi: 10.1016/j.bbmt.2008.05.019. [DOI] [PubMed] [Google Scholar]
- 16.Spees L.P., Martin P.L., Kurtzberg J., Stokhuyzen A., McGill L., Prasad V.K., et al. Reduction in mortality after umbilical cord blood transplantation in children over a 20-year period (1995-2014) Biol Blood Marrow Transplant. 2019;25(4):756–763. doi: 10.1016/j.bbmt.2018.11.018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Brown P. Treatment of infant leukemias: challenge and promise. Hematology Am Soc Hematol Educ Program. 2013;2013:596–600. doi: 10.1182/asheducation-2013.1.596. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Tomizawa D., Kato M., Takahashi H., Fujimura J., Inukai T., Fukushima T., et al. Favorable outcome in non-infant children with MLL-AF4-positive acute lymphoblastic leukemia: a report from the Tokyo Children's Cancer Study Group. Int J Hematol. 2015;102(5):602–610. doi: 10.1007/s12185-015-1869-y. [DOI] [PubMed] [Google Scholar]
- 19.Dreyer Z.E., Dinndorf P.A., Camitta B., Sather H., La M.K., Devidas M., et al. Analysis of the role of hematopoietic stem-cell transplantation in infants with acute lymphoblastic leukemia in first remission and MLL gene rearrangements: a report from the Children's Oncology Group. J Clin Oncol. 2011;29(2):214–222. doi: 10.1200/JCO.2009.26.8938. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Brissot E., Rialland F., Cahu X., Strullu M., Corradini N., Thomas C., et al. Improvement of overall survival after allogeneic hematopoietic stem cell transplantation for children and adolescents: a three-decade experience of a single institution. Bone Marrow Transplant. 2016;51(2):267–272. doi: 10.1038/bmt.2015.250. [DOI] [PubMed] [Google Scholar]
- 21.Khandelwal P., Millard H.R., Thiel E., Abdel-Azim H., Abraham A.A., Auletta J.J., et al. Hematopoietic stem cell transplantation activity in pediatric cancer between 2008 and 2014 in the United States: a center for international blood and marrow transplant research report. Biol Blood Marrow Transplant. 2017;23(8):1342–1349. doi: 10.1016/j.bbmt.2017.04.018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Dvorak C.C., Fisher B.T., Sung L., Steinbach W.J., Nieder M., Alexander S., et al. Antifungal prophylaxis in pediatric hematology/oncology: new choices & new data. Pediatr Blood Cancer. 2012;59(1):21–26. doi: 10.1002/pbc.23415. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Lee S.H., Yoo K.H., Sung K.W., Koo H.H., Kwon Y.J., Kwon M.M., et al. Hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation: incidence, risk factors, and outcome. Bone Marrow Transplant. 2010;45(8):1287–1293. doi: 10.1038/bmt.2009.349. [DOI] [PubMed] [Google Scholar]
- 24.Coppell J.A., Richardson P.G., Soiffer R., Martin P.L., Kernan N.A., Chen A., et al. Hepatic veno-occlusive disease following stem cell transplantation: incidence, clinical course, and outcome. Biol Blood Marrow Transplant. 2010;16(2):157–168. doi: 10.1016/j.bbmt.2009.08.024. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Orchard P.J., Fasth A.L., Le Rademacher J., He W., Boelens J.J., Horwitz E.M., et al. Hematopoietic stem cell transplantation for infantile osteopetrosis. Blood. 2015;126(2):270–276. doi: 10.1182/blood-2015-01-625541. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Perez P., Patino J., Estacio M., Pino J., Manzi E., Medina D. Bacteremia in pediatric patients with hematopoietic stem cell transplantation. Hematol Transfus Cell Ther. 2020;42(1):5–11. doi: 10.1016/j.htct.2019.05.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Mikulska M., Del Bono V., Bruzzi P., Raiola A.M., Gualandi F., Van Lint M.T., et al. Mortality after bloodstream infections in allogeneic haematopoietic stem cell transplant (HSCT) recipients. Infection. 2012;40(3):271–278. doi: 10.1007/s15010-011-0229-y. [DOI] [PubMed] [Google Scholar]