Pulmonary Hemorrhage in Pediatric Hematopoietic Stem Cell Transplant Recipients: A Single-Center Retrospective Study.

OBJECTIVES: Pulmonary hemorrhage (PH) is a serious complication posthematopoietic stem cell transplant (HSCT). In view of limited available pediatric data, we performed a retrospective study to describe epidemiology, management, and outcomes of PH post-HSCT in children in our national center. DESIGN: Retrospective study. SETTING: Academic children's hospital (2000-2015). SUBJECTS: Children (< 18 yr) with PH and requiring PICU care post-HSCT. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The historical prevalence of PH in our center was 2.7% (31/1,148). Twenty patients had a concomitant infection, 15 had bacterial infection, 8 had viral infection, and 3 patients had a fungal infection. With a median follow-up time of 60 months, 7 of 31 patients were alive. Early PH (< 40 d post-HSCT) was associated with improved survival (6/15 vs 1/16, p = 0.035). Patients who received high-dose pulsed corticosteroid had improved survival when compared with those who did not (7/22 vs 0/9, p = 0.0012); this also applied to the subgroup of patients with a concomitant infection (5/15 vs 0, p = 0.001). None of the patients who survived had measurable respiratory sequelae. CONCLUSIONS: PH is a rare but serious complication after HSCT. Corticosteroids were associated with improved survival even in patients with a concomitant infection.

Outcomes of pediatric patients with therapy-related myeloid neoplasms.

Long-term outcomes after allogeneic hematopoietic cell transplantation (HCT) for therapy-related myeloid neoplasms (tMNs) are dismal. There are few multicenter studies defining prognostic factors in pediatric patients with tMNs. We have accumulated the largest cohort of pediatric patients who have undergone HCT for a tMN to perform a multivariate analysis defining factors predictive of long-term survival. Sixty-eight percent of the 401 patients underwent HCT using a myeloablative conditioning (MAC) regimen, but there were no statistically significant differences in the overall survival (OS), event-free survival (EFS), or cumulative incidence of relapse and non-relapse mortality based on the conditioning intensity. Among the recipients of MAC regimens, 38.4% of deaths were from treatment-related causes, especially acute graft versus host disease (GVHD) and end-organ failure, as compared to only 20.9% of deaths in the reduced-intensity conditioning (RIC) cohort. Exposure to total body irradiation (TBI) during conditioning and experiencing grade III/IV acute GVHD was associated with worse OS. In addition, a diagnosis of therapy-related myelodysplastic syndrome and having a structurally complex karyotype at tMN diagnosis were associated with worse EFS. Reduced-toxicity (but not reduced-intensity) regimens might help to decrease relapse while limiting mortality associated with TBI-based HCT conditioning in pediatric patients with tMNs.

Effect of different conditioning regimens on survival and engraftment for children with hemophagocytic lymphohistiocytosis undergoing allogeneic hematopoeitic stem cell transplantation: A single institution experience.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH), a rare hyperinflammatory immuneregulatory disorder, is a challenge in hematopoietic stem cell transplantation (HSCT) because of the high rate of mixed chimerism, relapse, and graft failure (GF) unless intensive myeloablative regimens are used. However, historically conventional myeloablative regimens (conv MA) are associated with high toxicity and mortality. PROCEDURE: We retrospectively compared transplant outcomes between three preparative regimens of varying intensities: Conv MA (n = 15), reduced-intensity conditioning (RIC, n = 12), and a treosulfan-based reduced-toxicity conditioning (RTC, n = 9). RESULTS: Patients in the RIC cohort had a higher incidence of mixed donor chimerism and five patients (42%) developed secondary GF (P = .002) compared to the other two regimens. There was a higher incidence of veno-occlusive disease and intensive care unit (ICU) admissions in the Conv MA cohort. With the RTC regimen, there was a similar 2-year overall survival (89, 73, and 83%; P = .87), but improved compound EFS (lack of relapse, GF, second transplant or additional donor cell infusions, or death; 89, 73, and 42%, P = .041) in RTC, Conv MA, and RIC regimen, respectively. CONCLUSIONS: The intensity of the preparative regimen has a significant impact on outcome of HSCT for HLH. The newly described treosulfan-based RTC provides for a stable graft with a reasonable toxicity profile.

Relationship between cyclosporine area-under-the curve and acute graft versus host disease in pediatric patients undergoing hematopoietic stem cell transplant: A prospective, multicenter study.

Traditionally in hematopoietic stem cell transplant (HSCT), cyclosporine doses are individualized using cyclosporine trough concentrations (C0) while area under the concentration vs time curve (AUC) is used in solid organ transplant. AUC potentially has an important relationship with the development of acute graft-versus-host-disease (aGVHD). We conducted a prospective study to describe the relationship between severe (grade III-IV) aGVHD and cyclosporine AUC in pediatric HSCT recipients. Pediatric patients who underwent allogeneic myeloablative HSCT and scheduled to receive cyclosporine for aGVHD prophylaxis participated in this multicenter study. Cyclosporine doses were adjusted based on C0 according to each center's standard of care. Cyclosporine AUC was determined weekly until neutrophil engraftment or Day +42, whichever was later. Associations between severe aGVHD and cyclosporine AUC and other patient and treatment-related factors were evaluated. Of the 110 children enrolled, 97 were evaluable. Thirty-seven (38%) children developed aGVHD; 13 (13.4%) had severe aGVHD. On univariate analysis, there was no association between severe aGVHD and cyclosporine AUC at any time point before engraftment. Future research should focus on refinement of C0 targets for cyclosporine therapeutic drug monitoring in HSCT.

High transplant-related mortality associated with haematopoietic stem cell transplantation for paediatric therapy-related acute myeloid leukaemia (t-AML). A study on behalf of the United Kingdom Paediatric Blood and Bone Marrow Transplant Group.

Paediatric therapy-related acute myeloid leukaemia (t-AML) is rare and the outcome is poor. While allogeneic haematopoietic stem cell transplantation (HSCT) is generally the accepted modality of treatment, data regarding salvage chemotherapy, remission induction, conditioning regimens, transplant-related mortality and outcome is scarce. Between 2000 and2016, 36 children with t-AML were treated in seven UK paediatric HSCT centres. The most common salvage protocol for remission induction was FLAG with or without idarubicin and 28 patients were in complete morphological remission prior to BMT. Only 12 patients survived (33%). Transplant-related mortality (TRM) was the leading cause of death.

Eltrombopag for secondary failure of platelet recovery post-allogeneic hematopoietic stem cell transplant in children.

Secondary failure of platelet engraftment occurs in 20% of patients undergoing allogeneic HSCT and is associated with poor outcome. Currently, there are no guidelines for treatment of late thrombocytopenia and platelet transfusion is the mainstay of treatment. Here, we describe the use of Eltrombopag to treat secondary failure of platelet recovery following HSCT in a child with severe aplastic anemia. Eltrombopag resulted in recovery of platelet count with no need for platelet transfusion support with no reported side effects. Eltrombopag may be used successfully in children with secondary failure of platelet recovery post-HSCT for SAA.

Brincidofovir is highly efficacious in controlling adenoviremia in pediatric recipients of hematopoietic cell transplant.

Cidofovir is preemptively used for controlling adenoviremia and preventing disseminated viral disease in hematopoietic cell transplant (HCT) recipients but does not lead to resolution of viremia without T-cell immune-reconstitution. The lipid-conjugated prodrug of cidofovir, brincidofovir, has improved oral bioavailability and achieves higher intracellular concentrations of active drug. We present retrospective multicenter data comparing the kinetics of viremia and toxicities following preemptive treatment with and brincidofovir in children and adolescents diagnosed with HCT-related adenoviremia. Forty-one episodes (18 = brincidofovir; 23 = cidofovir) of antiviral therapy were observed in 27 patients. The 2 groups had comparable immune-reconstitution and viral burden. Major (≥2 log-reduction in 2 weeks; n = 13) and minor (≥1 to ≤2 log-reduction in 2 weeks; n = 2) virological responses were observed in 15 (83%) brincidofovir episodes compared to only 2 (9%) major virological responses with cidofovir (P < .0001). Brincidofovir mediated major responses in 9 of 11 cidofovir-unresponsive patients and resulted in complete responses (CR) despite significant lymphopenia (Brincidofovir vs cidofovir; CR = 13 (80%) vs 8 (35%); median lymphocyte count = 320/µl vs 910/µl; P < .05). One patient experienced abdominal cramps and diarrhea necessitating interruption of brincidofovir and none developed nephrotoxicity with brincidofovir. Thus, brincidofovir is well-tolerated and highly efficacious in controlling adenoviremia during the lymphopenic phase of HCT.

Comparison of two apheresis systems for autologous stem cell collections in pediatric oncology patients.

BACKGROUND: Peripheral stem cell collections can be challenging in the pediatric population and respective experience is limited. Since February 2015 our institution is utilizing the new Spectra Optia (Optia) apheresis device, which has replaced the former COBE Spectra (COBE) device. As a quality initiative we collected and compared collection efficiency (CE2) and other collection variables between the two devices. STUDY DESIGN AND METHODS: In this retrospective study we collected and compared clinical, laboratory, and technical collection data from stem cell collection procedures done with the Optia and COBE devices. The collected data included patient demographics, precollection peripheral CD34+ cell counts, total CD34+ cells collected, complete blood count, electrolytes before and after collection, side effects attributed to the collection, total blood volumes processed (TBVs), collection times, and calculated CE2 and collection ratios. RESULTS: Forty-one collection procedures performed on 29 pediatric patients with the Optia device were compared to 41 collections performed on 27 patients with the COBE device. The TBVs through the Optia device were significantly smaller than the COBE (3.9 ± 0.2 × TBV vs. 5.5 ± 0.1 × TBV, respectively; p < 0.001), requiring significantly less anticoagulant and providing similar amounts of stem cells while collection times were significantly shorter (mean, 238 ± 9 min vs. 264 ± 9 min, respectively; p < 0.05). Collections on the Optia caused significantly smaller reductions of plasma calcium and magnesium. No significant side effects attributed to the procedure were noted. CONCLUSION: Stem cell apheresis with the Optia device in children is safe and feasible with smaller blood volumes with shorter collection times.

Safety and Role of Gastrointestinal Endoscopy in the Management of Gastrointestinal Acute GVHD in Children After Hematopoietic Stem Cell Transplantation.

Gastrointestinal (GI) endoscopy and biopsy is a common procedure to confirm the diagnosis of acute graft-versus-host disease (aGVHD) in children after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Its safety and benefits in aGVHD management is unclear. We aimed to review the safety and benefits of GI endoscopy and biopsy for GI-aGVHD management. From January 2000 to December 2009, 450 Children received allo-HSCT at SickKids. Seventy-nine (17.5%) patients underwent GI endoscopy and biopsy for suspicion of GI-aGVHD. GI-aGVHD grading was I (n=5), II (n=39), III (n=23), and IV (n=12). GI biopsy confirmed aGVHD in 49 (62%) patients and results were negative in 30 (38%). Thirty-two (40%) patients started treatment based on clinical criteria before procedure. Twenty-four out of 79 patients had a change in therapy because of biopsy results. Treatment change was significantly more common in patients who had a positive biopsy results compared with those with negative results (24/49 vs. 4/30, P=0.02). Comparing patients who started therapy before the biopsy results (n=32) and the remaining patients (n=47) who were not started on therapy, the biopsy results had more impact in altering/starting therapy in these patients (24/47 vs. 0/32, P<0.00001). For the 32 patients who started therapy before the procedure, the biopsy confirmed aGVHD diagnosis in 20 of them (63%). Only 1 patient (1.25%) had duodenal hematoma and needed prolong GI rest and ultimately recovered. GI endoscopy and biopsy was safe and useful in guiding therapy for GI-aGVHD.

Infections and neutrophils in the pathogenesis of bronchiolitis obliterans syndrome in children after allogeneic stem cell transplantation.

It is plausible that infections post-hematopoietic SCT play a role in the pathogenesis of BOS. A prospective study for children with history, questionnaire, examination, PFTs, and blood counts at one, three, six, nine, 12, 18, and 24 months post-SCT was conducted. Between September 2009 and September 2011 (n = 39), six developed BOS at 200 days (range 94-282), three patients had probable clinical respiratory infection, and all six had higher neutrophil count compared to non-BOS patients (4.7 vs. 2.4 at three months and 6.3 vs. 2.9 at six months ×10(9) /L, p = 0.03). Contribution of clinical and subclinical infection needs to be considered in the pathogenesis of BOS.

A Feasibility Pilot Trial of Individualized Homeopathic Treatment of Fatigue in Children Receiving Chemotherapy.

BACKGROUND: Fatigue is a major problem in children with cancer. The objective was to examine the feasibility of performing a clinical trial of homeopathic treatment for fatigue in children receiving chemotherapy. MATERIALS: This was a single-institution, open-label, pilot study. Children 2 to 18 years old, diagnosed with cancer, and receiving chemotherapy were eligible. Participants were given individualized homeopathic treatment for a maximum of 14 days. In-home or clinic assessments were conducted up to 3 times weekly. Feasibility was defined as the ability to recruit and administer homeopathy to 10 participants within 1 year. Fatigue was measured using the Symptom Distress Scale daily and the PedsQL Multidimensional Fatigue Module weekly. RESULTS: Between April 2012 and April 2014, 155 potential participants were identified. There were 45 eligible and contacted patients; 36 declined participation, 30 because they were not interested; 9 agreed to participate, but 1 participant withdrew prior to treatment initiation. Median length of homeopathic treatment was 10.5 (range = 6 to 14) days. All parents found homeopathic treatment to be easy or very easy to follow. CONCLUSIONS: Trials of individualized homeopathy for fatigue reduction in pediatric cancer are not feasible in this context; lack of interest was a primary reason. Alternative approaches to evaluating homeopathy efficacy are needed.

Successful Allogeneic Hematopoietic Stem Cell Transplantation in XIAP Deficiency Using Reduced-Intensity Conditioning.

Hematopoietic stem cell transplantation (HSCT) is currently the only available curative therapy for X-linked inhibitor of apoptosis (XIAP) deficiency. Myeloablative conditioning regimens are associated with high mortality rates. Reduced-intensity conditioning (RIC) is recommended in order to decrease treatment-related toxicities, but RIC regimens increase the risk for mixed donor-recipient chimerism that may progress to graft loss. We report our experience with a patient with XIAP deficiency who was successfully treated with allogeneic HSCT using a RIC protocol. Post-transplant chimerism was vigilantly monitored and maintained with donor lymphocyte infusions and a stem cell boost to a level that prevented hemophagocytic lymphohistiocytosis recurrence.

Humanized Chronic Graft-versus-Host Disease in NOD-SCID il2rγ-/- (NSG) Mice with G-CSF-Mobilized Peripheral Blood Mononuclear Cells following Cyclophosphamide and Total Body Irradiation.

Chronic graft-versus-host disease (cGvHD) is the major source of late phase morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Humanized acute GvHD (aGvHD) in vivo models using NOD-SCID il2rγ-/- (NSG) mice are well described and are important tools for investigating pathogenicity of human cells in vivo. However, there have been only few reported humanized cGvHD mouse models. We evaluated if prolonged inflammation driven by low dose G-CSF-mobilized human PBMCs (G-hPBMCs) would lead to cGvHD following cyclophosphamide (CTX) administration and total body irradiation (TBI) in NSG mice. Engraftment was assessed in peripheral blood (PB) and in specific target organs by either flow cytometry or immunohistochemistry (IHC). Tissue samples were harvested 56 days post transplantation and were evaluated by a pathologist. Some mice were kept for up to 84 days to evaluate the degree of fibrosis. Mice that received CTX at 20mg/kg did not show aGvHD with stable expansion of human CD45+ CD3+ T-cells in PB (mean; 5.8 to 23.2%). The pathology and fibrosis scores in the lung and the liver were significantly increased with aggregation of T-cells and hCD68+ macrophages. There was a correlation between liver pathology score and the percentage of hCD68+ cells, suggesting the role of macrophage in fibrogenesis in NSG mice. In order to study long-term survival, 6/9 mice who survived more than 56 days showed increased fibrosis in the lung and liver at the endpoint, which suggests the infiltrating hCD68+ macrophages may be pathogenic. It was shown that the combination of CTX and TBI with a low number of G-hPBMCs (1x106) leads to chronic lung and liver inflammation driven by a high infiltration of human macrophage and mature human T cells from the graft, resulting in fibrosis of lung and liver in NSG mice. In conclusion this model may serve as an important pre-clinical model to further current understanding of the roles of human macrophages in cGvHD.

The yield of monitoring for HSV and VZV viremia in pediatric hematopoietic stem cell transplant patients.

Reactivation of HSV and VZV is common following HSCT. Consensus guidelines do not support the use of routine screening for viremia following HSCT in adults, but no such clear guidelines exist in pediatrics. In our center, routine practice was to screen patients weekly for HSV and VZV viremia until engraftment in autologous transplant patients and up to day +100 in allogeneic transplant patients. We conducted a retrospective study of over 500 patients to establish whether this screening identified any patients with HSV or VZV viremia who would not have been identified by clinical signs or symptoms. Over a 4.5-yr period, routine screening identified three cases of HSV viremia and one case of VZV viremia. Two patients had persistent, unexplained fever and two patients had skin or mucosal lesions suggestive of HSV/VZV. We conclude that routine screening for HSV and VZV viremia in pediatric HSCT patients has a very low yield and that viremia can be reliably identified by targeted testing in patients with vesicular skin lesions, oral or genital ulceration, unexplained fever, neurological symptoms, or unexplained abnormal liver transaminases.

Significant Transplantation-Related Mortality from Respiratory Virus Infections within the First One Hundred Days in Children after Hematopoietic Stem Cell Transplantation.

Respiratory viral infections (RVI) are important in hematopoietic stem cell transplantations (HSCT) and knowledge regarding incidence, morbidity, mortality, and long-term pulmonary complications is limited. We report a study to evaluate incidence and outcomes, both short and long-term, of RVI in children receiving HSCT. Between January 2000 and December 2012, 844 patients underwent hematopoietic stem cell transplantation (HSCT) at the Hospital for Sick Children: 491 were allogeneic and 353 were autologous. When screening for causes of death in the first year after HSCT in the 844 patients, we found that RVI as a cause of death was only evident in the first 100 days after HSCT. Fifty-four (6.5%) patients were found to have an RVI within the first 100 days after HSCT (allogeneic = 32, autologous = 22). Upper and lower respiratory tract infections were documented in 31 (57%) and 23 (43%) patients, respectively. Viruses were parainfluenza (35%), respiratory syncytial virus (28%), influenza (22%), adenovirus (7%), human metapneumovirus (4%), coronavirus (2%), and rhinovirus (2%). Three patients relapsed with their primary disease before day 100 and were excluded. The overall mortality for the remaining 51 patients was 10% (allogeneic = 4, autologous = 1). All 5 deaths were directly attributable to RVI and all 5 deaths occurred in patients with a lower respiratory tract infection. The remaining patients were followed for a median of 4.3 years (range, 1.4 to 11.8) and no chronic pulmonary complications were observed. A clear seasonal pattern for contracting RVI was evident with 65% of total RVI occurring between October and March (35 of 427 versus 19 of 417, P = .03). Given the significant mortality from RVI and the challenges in preventing them, choosing the time to start HSCT, whenever possible, may help prevent RVI and improve outcomes.

Serum Krebs Von Den Lungen-6 as a Biomarker for Early Detection of Bronchiolitis Obliterans Syndrome in Children Undergoing Allogeneic Stem Cell Transplantation.

Bronchiolitis obliterans syndrome (BOS) is a devastating complication after allogeneic stem cell transplantation (allo-SCT). Early identification of high-risk patients is pivotal for success. Lung proteins, KL-6, CCSP, SP-A, and SP-D, measured in the serum may identify high-risk patients for BOS earlier than pulmonary function tests (PFTs) can identify changes or clinical symptoms. Lung proteins were measured in patients' serum at baseline and at 1, 3, 6, 9, 12, 18, and 24 months after transplantation along with history, clinical examination, and PFTs. Serum levels of lung proteins were also measured in healthy control subjects. The primary endpoint was the development of BOS confirmed by pathological biopsy or National Institutes of Health criteria. Between September 2009 and September 2011, 39 patients were enrolled. Six children developed BOS at a median time of 200 days (range, 94 to 282). KL-6 levels were low in control subjects, at a median of .1 U/mL (range, .1 to 1.5). Pre-SCT and 1-month KL-6 levels were significantly higher in surviving patients who developed BOS (n = 6) versus those who did not (n = 18) (pre-SCT: mean, 32.6 U/mL [IQR, 9.7 to 89.3] versus 5.8 U/mL [IQR, 2.1 to 12.6], P = .03; at 1 month: mean, 52.5 U/mL [IQR, 20.2 to 121.3] versus 11.4 U/mL [IQR, 5.7 to 36.0], P = .04). Three- and 6-month KL-6 levels continued to be higher in BOS group but were not statistically significant. CCSP, SP-A, and SP-D were not predictive. KL-6 measured in the serum of children receiving allo-SCT may identify patients at high risk for the development of BOS. These patients will benefit from intensive surveillance protocol and early therapy before irreversible lung damage.

Performance of Busulfan Dosing Guidelines for Pediatric Hematopoietic Stem Cell Transplant Conditioning.

Achievement of a busulfan area-under-the-concentration versus time curve (AUC) of 900 to 1500 µM·min is associated with improved hematopoietic stem cell transplant (HSCT) outcomes. Multiple pediatric busulfan dosing guidelines aim to achieve this target. The authors' objective was to describe the AUCs achieved after simulated dosing using available pediatric i.v. busulfan dosing guidelines. The health records of children who received i.v. busulfan for HSCT conditioning at The Hospital for Sick Children were reviewed. Busulfan AUCs were calculated for each patient based on plasma busulfan concentrations using either a 1-compartment model or a validated limited-sampling strategy. Published pediatric busulfan dosing guidelines were identified. Initial busulfan doses were determined for all patients using each dosing guideline and total body weight (TBW). For overweight patients (TBW-to-ideal body weight [IBW] ≥ 1.25), initial busulfan doses were also determined using IBW and adjusted IBW (IBWadj). The resulting AUCs were simulated. The proportion of subjects (TBW/IBW < 1.25, TBW/IBW ≥ 1.25, and infants) with an AUC within target (900 to 1500 µM·min) after dosing simulation with each guideline was compared. One hundred eleven children (mean age, 6.2 years [SD, ±5.2]) who received i.v. busulfan were included. When dosing with each of the 12 i.v. busulfan dosing guidelines identified was simulated using TBW in 97 non-overweight patients, the proportion of patients with an AUC within the target range varied from 51% to 74% and from 45% to 64% in infants. Use of IBW or IBWadj to calculate initial busulfan doses in overweight children improved the performance of most guidelines. Current busulfan dosing guidelines vary in their ability to achieve AUCs within the target range. For children who are not overweight, we recommend 1 of 3 high-performing guidelines that allow individualization of the target busulfan AUC. Use of either IBW or IBWadj in overweight children improves the performance of most guidelines. Regardless of the guideline used, therapeutic drug monitoring is essential to verify achievement of the target AUC.

Unrelated donor hematopoietic stem cell transplantation for infantile enteropathy due to IL-10/IL-10 receptor defect.

Recent advances in genetic diagnosis have identified mutations in gene encoding interleukin-10 (IL-10) and IL-10 receptor (IL-10R) proteins as a cause for early-onset enterocolitis leading to hyperinflammatory immune response. Allogeneic HSCT offers a potential cure; however, it was only performed in a few infants and mainly from family-related donors. We report a case of a girl who presented very early in life with severe infantile enterocolitis. Gene sequencing confirmed IL-10R defect. Her older sister died at 13 months of age from severe undiagnosed enterocolitis. There was no family donor. An unrelated search identified a potential 10/10 high-resolution HLA-matched donor. There was some delay in donor activation because IL-10R defect was not on the standard list of indications for unrelated HSCT. Our patient received the unrelated HSCT at seven months of age, and she is currently nine months after transplant and doing very well. Because HSCT is the curative option of choice for this disorder, we encourage adding IL-10 and IL-10R protein defects to the list of HSCT indications for unrelated donor procurement.

The outcome of allogeneic hematopoietic cell transplantation for children with FMS-like tyrosine kinase 3 internal tandem duplication-positive acute myelogenous leukemia.

FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) is a somatic mutation associated with poor outcome when treated with chemotherapy alone. In children, hematopoietic stem cell transplantation (HSCT) is recommended, but very limited data on outcome are reported. We determined the outcome of 29 children with FLT3/ITD-positive acute myelogenous leukemia (AML) who underwent allogeneic HSCT in 4 pediatric centers. Eleven patients (38%) received matched related donor hematopoietic stem cells and 18 (62%) received alternative donors. Eighteen patients (62%) received total body irradiation (TBI)-based regimens. No patients experienced transplantation-related mortality. Eleven patients (38%) experienced relapsed disease. The cumulative incidence of relapse at 2 years was 34.7% (95% confidence interval [CI], 20.4% to 54.9%). Two-year disease-free survival (DFS) and overall survival (OS) were 65.3% (95% CI, 45.1% to 79.6%) and 82.2% (95% CI, 58.5% to 91.3%), respectively. There was no difference in the DFS of patients who received transplants from related donors versus the DFS of those who received transplants from alternative donors (hazard ratio [HR], 2.64; 95% CI, .79 to 8.76; P = .10), using univariate analysis. Patients with higher FLT3/ITD ratio at diagnosis had significantly worse DFS (HR, 1.42; 95% CI, 1.04 to 1.93; P = .03). The use of TBI in the preparative regimen was associated with superior DFS (HR, .29; 95% CI, .08 to .99; P = .04) and OS (HR, .07; 95% CI, .01 to .62; P = .002). We conclude that allogeneic HSCT improves DFS and OS in children with FLT3/ITD-positive AML compared with what has been reported in those treated with chemotherapy alone.

Hematopoietic stem cell transplantation in infants.

BACKGROUND: It is rare for infants, who are less than 365 days old, to receive hematopoietic stem cell transplantation (HSCT). Our objective was to review the indications, survival, and late effects of infants who received HSCT. PROCEDURE: Between April 1992 and March 2010, a total of 1,363 children underwent HSCT (775 allogeneic [allo]; 588 autologous [auto]) in the Hospital for Sick Children, Toronto. Of these, 51 (3.7%) were infants. RESULTS: Seventeen infants received allo HSCT for a genetic metabolic disorder. The median age at HSCT was 211 days (29-334 days). After median follow-up of 8.9 years (2.9-20.2 years), 12 patients remained alive, representing an overall survival rate of 70%. Infants with non-metabolic disorders (n = 34); 10 (three neuroblastoma [NBL], three brain tumor, two acute meylogenous leukemia [AML], one rhabdomyosarcoma, and one retinoblastoma) received auto HSCT, and 24 (eight hemophagocytic lymphohistiocytosis [HLH], four juvenile meylomonocytic leukemia [JMML], four Wiscott-Aldrych Syndrome [WAS], three acute lymphoblastic leukemia [ALL], two AML, one severe aplastic anemia [SAA], one chronic granulomatous disease [CGD], and one amegakaryocytic thrombocytopenia) received allo HSCT. Their median age at HSCT was 255 days (142-365 days). At median follow-up of 8.7 years (2.5-17.6 years), 26 infants remained alive, representing an overall survival rate of 76%. In the auto HSCT category, eight of 10 infants are long-term survivors. Late effects such as organ dysfunction, endocrinopathy, and secondary tumors were within accepted range. CONCLUSION: The survival rate of infants who receive HSCT is encouraging.