Hematopoietic Cell Transplantation Trends and Outcomes in Canada: A Registry-Based Cohort Study.

Background: Hematopoietic cell transplantation (HCT) is an established therapy for hematologic malignancies and serious non-malignant blood disorders. Despite its curative potential, HCT is associated with substantial toxicity and health resource utilization. Effective delivery of HCT requires complex hospital-based care, which limits the number of HCT centres in Canada. In Canada, the quantity, indications, temporal trends, and outcomes of patients receiving HCT are not known. Methods: A retrospective cohort study of first transplants reported to the Cell Therapy Transplant Canada (CTTC) registry between 2000 and 2019. We determined overall survival (OS) and non-relapse mortality (NRM), categorizing the cohort into early (2000-2009) and later (2010-2019) eras to investigate temporal changes. Results: Of 18,046 transplants, 7571 were allogeneic and 10,475 were autologous. Comparing the two eras, allogeneic transplants increased in number by 22.3%, with greater use of matched unrelated donors in the later era. Autologous transplants increased by 10.9%. Temporal improvements in NRM were observed in children and adults. OS improved in pediatric patients and in adults receiving autologous HCT. In adults receiving allogeneic HCT, OS was stable despite the substantially older age of patients in the later era. Interpretation: HCT is an increasingly frequent procedure in Canada which has expanded to serve older adults. Noted improvements in NRM and OS reflect progress in patient and donor selection, preparation for transplant, and post-transplant supportive care. In allogeneic HCT, unrelated donors have become the most frequent donor source, highlighting the importance of the continued growth of volunteer donor registries. These results serve as a baseline measure for quality improvement and health services planning in Canada.

Alberta Childhood Cancer Survivorship Research Program.

Adverse outcomes after childhood cancer have been assessed in a range of settings, but most existing studies are historical and ascertain outcomes only after 5-year survival. Here, we describe the Alberta Childhood Cancer Survivorship Research Program and its foundational retrospective, population-based cohort of Albertan residents diagnosed with a first primary neoplasm between the ages of 0 and 17 years from 1 January 2001 to 31 December 2018. The cohort was established in collaboration with the Alberta Cancer Registry and Cancer in Young People in Canada program and has been linked to existing administrative health databases and patient-reported outcome questionnaires. The cohort comprised 2580 survivors of childhood cancer, 1379 (53.4%) of whom were 5-year survivors. Approximately 48% of the cohort was female, 47% of the cohort was diagnosed between 0 and 4 years of age, and the most frequent diagnoses were leukemias (25.4%), central nervous system tumors (24.0%), and lymphomas (14.9%). Detailed treatment information was available for 1741 survivors (67.5%), with manual abstraction ongoing for those with missing data. By the study exit date, the median time since diagnosis was 5.5 years overall and 10.4 years for 5-year survivors. During the follow-up time, 82 subsequent primary cancers were diagnosed, 20,355 inpatient and 555,425 ambulatory/outpatient events occurred, 606,773 claims were reported, and 437 survivors died. The results from this research program seek to inform and improve clinical care and reduce cancer-related sequelae via tertiary prevention strategies.

Impact of Public Reporting of Center-Specific Survival Analysis Scores on Patient Volumes at Hematopoietic Cell Transplant Centers.

The Center for International Blood and Marrow Transplant Research reports the outcomes of allogeneic hematopoietic cell transplantation (alloHCT) at United States transplantation centers (TC) annually through its Center-Specific Survival Analysis (CSA). The CSA compares the actual 1-year overall survival (OS) and predicted 1-year OS rate after alloHCT at each TC, which is then reported as 0 (OS as expected), -1 (OS worse than expected), or 1 (OS better than expected). We evaluated the impact of public reporting of TC performance on their alloHCT patient volumes. Ninety-one TCs that serve adult or combined adult and pediatric populations and had CSA scores reported for 2012-2018 were included. We analyzed prior-calendar-year TC volume, prior-calendar-year CSA score, whether the CSA score had changed in the prior year from two years earlier, calendar year, TC type (adult only vs. combined adult and pediatric), and years of alloHCT experience for their impact on patient volumes. A CSA score of -1, as compared with 0 or 1, was associated with an 8% to 9% reduction in the mean TC volume (P < 0.001) in the subsequent year, adjusting for the prior year center volume. Additionally, being a TC neighboring an index TC with a -1 CSA score, was associated with a 3.5% increase in mean TC volume (P = 0.04). Our data show that public reporting of CSA scores is associated with changes in alloHCT volumes at TCs. Additional investigation into the causes of this shift in patient volume and the impact on outcomes is ongoing.

A population-based analysis of the presentation and outcomes of pediatric patients with osteosarcoma in Canada: a report from CYP-C.

BACKGROUND: Frequently occurring in adolescents, osteosarcoma is the most common primary malignant bone disease, with a reported 15% of patients who present with metastasis. With advances in imaging and improvements in surgical care, an updated analysis is warranted on the outcomes of pediatric patients with osteosarcoma. METHODS: We completed a retrospective review of pediatric patients who presented with osteosarcoma between 2001 and 2017, using The Cancer in Young People in Canada (CYP-C) national database. Data on 304 patients aged younger than 15 years were analyzed. RESULTS: The proportion of patients who presented with metastasis was 23.0%. The overall 5-year survival (OS) for patients who presented with metastasis was 37.4%. Overall survival and event-free survival (EFS) were lower in these patients than in patients with localized disease (hazard ratio [HR] 4.3, p < 0.0001 and HR 3.1, p < 0.0001). For patients who presented with metastatic disease, the OS for those undergoing an operative intervention was 44.1% compared with 17.6% for those who did not undergo resection (p < 0.0001). CONCLUSION: The proportion of patients who presented with metastatic osteosarcoma in our population is higher than previously reported. Overall outcomes of patients with metastatic disease have not changed. Our data reaffirm a role for surgical resection in patients with metastasis with a need to explore new treatment strategies to improve the overall prognosis of these patients.

Neuropsychological, behavioral, and quality-of-life outcomes in children and adolescents with sickle cell disease treated with nonmyeloablative matched sibling donor hematopoietic cell transplantation: A case series.

BACKGROUND/OBJECTIVES: Despite advances in the treatment of sickle cell disease (SCD), cerebrovascular and cognitive insults can have lifelong consequences. Hematopoietic cell transplantation (HCT) is an established curative therapy, and recent studies have demonstrated efficacy with reduced toxicity nonmyeloablative (NMA) regimens, but little is known about neuropsychological outcomes. The objective of this study was to describe neuropsychological, behavioral, and quality-of-life outcomes with medical correlates in children with SCD who received an NMA matched sibling donor (MSD) HCT. DESIGN/METHODS: Retrospective cohort analysis of nine recipients with hemoglobin SS SCD who underwent MSD HCT using the National Institutes of Health (NIH) NMA protocol. RESULTS: Mean full-scale intellectual functioning (FSIQ) was average pre-HCT (FSIQ = 92.1, SD 9.0; n = 8) and 2 years post-HCT (mean FSIQ = 96.6; SD 11.1; N = 9). Neuropsychological functioning was largely average across all cognitive domains, and no pre/post-HCT differences were found to be statistically significant given the small sample size. However, effect sizes revealed moderate improvements in processing speed (Cohen's d = .72) and verbal memory (Cohen's d = .60) post-HCT, and declines in measures of attention (Cohen's d = -.54) and fine motor speed and dexterity (Cohen's d = -.94). Parents endorsed better quality of life (Cohen's d = .91), less impact of SCD on their family, and less worry about their child's future (Cohen's d = 1.44). CONCLUSION: Neuropsychological functioning in a sample of children and adolescents treated uniformly with NMA MSD HCT remained stable or improved in most cognitive domains, and improvements in quality of life and family functioning were observed.

ADaPTS "(AD)olescents (P)ath through (T)ransplant (S)ickle cell disease".

BACKGROUND: Sickle cell disease is an inherited chronic hematological disorder with an average lifespan of fifty years. The human cost of sickle cell disease includes missed school days, occupational opportunities, social isolation, stigmatization, and psychological sequelae. Hematopoietic cell transplantation (HCT) is the only curative therapy available but comes with potential morbidity and mortality. Our study explores how quality of life (QoL) is affected from the perspective of an adolescent who has undergone a nonmyeloablative matched sibling donor HCT. METHODS: We employed multiple case study methodology with purposeful sampling by selecting information-rich cases. DATA SOURCES: 1) QoL inventories 2) patient interviews 3) parent interview 4) vital support interview 5) medical record analysis. DATA ANALYSIS: Intra-case analysis by assembling evidence within a single case and then analyzing the differences within cases to create a rich case description. Next, a time series analysis was completed to track changes in patients' QoL. We used multiple sources of data to compose a timeline and changes across time. Then, we employed pattern matching as an analytical technique allowing for examination of patterns across cases. Finally, we used cross case synthesis to review results of each case. RESULTS: Quality of life was reported across the physical, social and psychological domains for 5 participants. All had sickle cell HgSS genotype, 80% were male and 80% were born outside of Canada. Physical domain: pre-transplant, 100% of patients experienced pain, and the majority suffered from fatigue, insomnia, and fevers resulting in hospitalizations. Afterwards, participants reported improved physical wellbeing. Social domain: pre-transplant, QoL was poor characterized by stigma, social isolation, and parental absenteeism. Post-HSCT adolescents gained social acceptance in areas that had stigmatized and excluded them. They were able to participate freely in activities with peers and their social life vastly improved. Psychological pre-transplant life experiences were overshadowed by psychological stress. The majority commented that their future was bleak and may lead to premature death. Afterwards adolescents described a crisis free life with positive psychological outcomes. CONCLUSIONS: Adolescents with sickle cell disease who undertook HCT demonstrated improved QoL one year post transplant with regard to physical, social and psychological well-being.

Evaluation of COVID-19 vaccine response in patients with cancer: An interim analysis.

BACKGROUND: Efficacy and safety data of COVID-19 vaccines among cancer populations have been limited; however, preliminary data from recent studies have emerged regarding their immunogenicity and safety in this population. In this review, we examined current peer-reviewed publications containing serological and safety data after COVID-19 vaccination of patients with cancer. METHODS: This analysis examined 21 studies with a total of 5012 patients with cancer, of which 2676 (53%) had haematological malignancies, 2309 (46%) had solid cancers and 739 were healthy controls. Serological responses by anti-SARS-CoV-2 spike protein S1/S2 immunoglobulin G antibody levels and post-vaccination patient questionnaires regarding vaccine-related side-effects after the first and second dose were collected and analysed. RESULTS: In general, a single dose of the COVID-19 vaccine yields weaker and heterogeneous serological responses in both patients with haematological and solid malignancies. On receiving a second dose, serological response rates indicate a substantial increase in seropositivity to the SARS-CoV-2 spike protein in all cancer cohorts, but antibody titres remain reduced in comparison with healthy controls. Furthermore, seroconversion in patients with haematological malignancies was significantly lower than that in patients with solid tumours. COVID-19 vaccines are safe and well-tolerated in patients with cancer based on current data of local and systemic effects. CONCLUSION: Together, these data support the prioritisation of patients with cancer to receive their first and second doses to minimise the risk of COVID-19 infection and severe complications in this vulnerable population. Additional prophylactic measures must be considered for high-risk patients where current vaccination programs may not mount sufficient protection against SARS-CoV-2 infection.

Minimal Residual Disease Prior to and After Haematopoietic Stem Cell Transplantation in Children and Adolescents With Acute Lymphoblastic Leukaemia: What Level of Negativity Is Relevant?

Minimal residual disease (MRD) assessment plays a central role in risk stratification and treatment guidance in paediatric patients with acute lymphoblastic leukaemia (ALL). As such, MRD prior to haematopoietic stem cell transplantation (HSCT) is a major factor that is independently correlated with outcome. High burden of MRD is negatively correlated with post-transplant survival, as both the risk of leukaemia recurrence and non-relapse mortality increase with greater levels of MRD. Despite growing evidence supporting these findings, controversies still exist. In particular, it is still not clear whether multiparameter flow cytometry and real-time quantitative polymerase chain reaction, which is used to recognise immunoglobulin and T-cell receptor gene rearrangements, can be employed interchangeably. Moreover, the higher sensitivity in MRD quantification offered by next-generation sequencing techniques may further refine the ability to stratify transplant-associated risks. While MRD quantification from bone marrow prior to HSCT remains the state of the art, heavily pre-treated patients may benefit from additional staging, such as using 18F-fluorodeoxyglucose positron emission tomography/computed tomography to detect focal residues of disease. Additionally, the timing of MRD detection (i.e., immediately before administration of the conditioning regimen or weeks before) is a matter of debate. Pre-transplant MRD negativity has previously been associated with superior outcomes; however, in the recent For Omitting Radiation Under Majority age (FORUM) study, pre-HSCT MRD positivity was associated with neither relapse risk nor survival. In this review, we discuss the level of MRD that may require pre-transplant therapy intensification, risking time delay and complications (as well as losing the window for HSCT if disease progression occurs), as opposed to an adapted post-transplant strategy to achieve long-term remission. Indeed, MRD monitoring may be a valuable tool to guide individualised treatment decisions, including tapering of immunosuppression, cellular therapies (such as donor lymphocyte infusions) or additional immunotherapy (such as bispecific T-cell engagers or chimeric antigen receptor T-cell therapy).

Chemotherapy readiness in pediatric oncology: Assessing an automated method to measure urine specific gravity.

As part of the evaluation for chemotherapy readiness, urine specific gravity is measured to assess the patient's overall hydration status. Depending on the accuracy of the methods used, patients may be adversely affected by having their chemotherapy delayed or prematurely started. To evaluate the diagnostic accuracy of a new automated urine dipstick readout device (Clinitek), we tested 196 consecutive urine samples for urine specific gravity and compared them with the practical gold standard, a urine refractometer. We found a high correlation between both tools among clean urine samples, but a poor correlation among the pathological urine samples.

Total Body Irradiation or Chemotherapy Conditioning in Childhood ALL: A Multinational, Randomized, Noninferiority Phase III Study.

PURPOSE: Total body irradiation (TBI) before allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients with acute lymphoblastic leukemia (ALL) is efficacious, but long-term side effects are concerning. We investigated whether preparative combination chemotherapy could replace TBI in such patients. PATIENTS AND METHODS: FORUM is a randomized, controlled, open-label, international, multicenter, phase III, noninferiority study. Patients ≤ 18 years at diagnosis, 4-21 years at HSCT, in complete remission pre-HSCT, and with an HLA-compatible related or unrelated donor were randomly assigned to myeloablative conditioning with fractionated 12 Gy TBI and etoposide versus fludarabine, thiotepa, and either busulfan or treosulfan. The noninferiority margin was 8%. With 1,000 patients randomly assigned in 5 years, 2-year minimum follow-up, and one-sided alpha of 5%, 80% power was calculated. A futility stopping rule would halt random assignment if chemoconditioning was significantly inferior to TBI (EudraCT: 2012-003032-22; ClinicalTrials.gov: NCT01949129). RESULTS: Between April 2013 and December 2018, 543 patients were screened, 417 were randomly assigned, 212 received TBI, and 201 received chemoconditioning. The stopping rule was applied on March 31, 2019. The median follow-up was 2.1 years. In the intention-to-treat population, 2-year overall survival (OS) was significantly higher following TBI (0.91; 95% CI, 0.86 to 0.95; P < .0001) versus chemoconditioning (0.75; 95% CI, 0.67 to 0.81). Two-year cumulative incidence of relapse and treatment-related mortality were 0.12 (95% CI, 0.08 to 0.17; P < .0001) and 0.02 (95% CI, < 0.01 to 0.05; P = .0269) following TBI and 0.33 (95% CI, 0.25 to 0.40) and 0.09 (95% CI, 0.05 to 0.14) following chemoconditioning, respectively. CONCLUSION: Improved OS and lower relapse risk were observed following TBI plus etoposide compared with chemoconditioning. We therefore recommend TBI plus etoposide for patients > 4 years old with high-risk ALL undergoing allogeneic HSCT.

Allogeneic Hematopoietic Stem Cell Transplantation for Children With Acute Lymphoblastic Leukemia: Shifting Indications in the Era of Immunotherapy.

Pediatric acute lymphoblastic leukemia generally carries a good prognosis, and most children will be cured and become long-term survivors. However, a portion of children will harbor high-risk features at the time of diagnosis, have a poor response to upfront therapy, or suffer relapse necessitating more intensive therapy, which may include allogeneic hematopoietic stem cell transplant (HSCT). Recent advances in risk stratification, improved detection and incorporation of minimal residual disease (MRD), and intensification of upfront treatment have changed the indications for HSCT over time. For children in first complete remission, HSCT is generally reserved for those with the highest risk of relapse. These include patients with unfavorable features/cytogenetics who also have a poor response to induction and consolidation chemotherapy, usually reflected by residual blasts after prednisone or by detectable MRD at pre-defined time points. In the relapsed setting, children with first relapse of B-cell ALL are further stratified for HSCT depending on the time and site of relapse, while all patients with T-cell ALL are generally consolidated with HSCT. Alternatives to HSCT have also emerged over the last decade including immunotherapy and chimeric antigen receptor (CAR) T-cell therapy. These novel agents may spare toxicity while attempting to achieve MRD-negative remission in the most refractory cases and serve as a bridge to HSCT. In some situations, these emerging therapies can indeed be curative for some children with relapsed or resistant disease, thus, obviating the need for HSCT. In this review, we seek to summarize the role of HSCT in the current era of immunotherapy.

Fludarabine, Campath, and Low-Dose Cyclophosphamide (FCClow) with or without TBI Conditioning Results in Excellent Transplant Outcomes in Children with Severe Aplastic Anemia.

Various reduced-intensity conditioning regimens are in use for allogeneic hematopoietic cell transplant (HSCT) in patients with idiopathic severe aplastic anemia (SAA). We describe the use of fludarabine, Campath, and low-dose cyclophosphamide (FCClow) conditioning in 15 children undergoing related or unrelated donor transplants. Total body irradiation (TBI) of 2 Gy was added for unrelated donor HSCT. At a median follow-up of 2.3 years, the failure-free survival was 100%, with low rates of infection and toxicity. There was no occurrence of grade III to IV acute graft-versus-host disease (GVHD). All patients had full donor myeloid chimerism post-HSCT, even with mixed chimerism in the T cell lineage. The absence of chronic GVHD and long-term stable mixed donor T cell chimerism confirms immune tolerance following FCClow (± TBI) conditioned transplantation in children with SAA.

Regional differences in access to hematopoietic stem cell transplantation among pediatric patients with acute myeloid leukemia.

INTRODUCTION: Indications for hematopoietic stem cell transplantation (HSCT) in pediatric acute myeloid leukemia (AML) are primarily dependent on risk stratification at diagnosis and relapse status. We sought to determine whether access to HSCT is influenced by regional and socioeconomic factors. METHODS: Children with newly diagnosed AML aged < 15 years between 2001 and 2015 were identified using the Cancer in Young People in Canada national population-based registry. Factors potentially associated with the receipt of HSCT were studied using univariate and multivariable logistic regression models. RESULTS: Overall, 568 children with newly diagnosed AML were included and 262 (46%) received HSCT. A greater proportion of patients, 103/157 (65.6%), underwent HSCT after first or subsequent relapse compared to 159/411 (38.7%) patients who underwent transplant before relapse. Among patients for whom HSCT would be considered before relapse, factors associated with higher odds of HSCT in a multivariable analysis were: poor versus good-risk cytogenetics (Odds ratio [OR]: 30.0, 95% confidence interval [CI]: 7.7-117.0), diagnosis during 2012-2015 versus 2001-2006 (OR: 3.2, 95% CI: 1.6-6.3), diagnosis in eastern Canada versus central Canada (OR: 3.7, 95% CI: 1.9-7.3), and age 10-14 years versus age < 1 year (OR: 5.4, 95% CI: 2.3-12.8). Among patients for whom HSCT would be considered after first relapse, higher odds of HSCT was associated with diagnosis at a HSCT center (OR: 2.1, 95% CI: 1.1-4.1). CONCLUSION: Patients diagnosed at a HSCT performing center and patients from eastern Canada had higher odds of receiving HSCT. This may suggest preferential access to HSCT for certain patients.

Predictive factors for successful peripheral blood stem cell mobilization and collection in children.

Factors affecting the success of peripheral blood stem cell collection (SCC) in children are not well characterized. We reviewed 218 stem cell collections among 199 pediatric donors, of which 35 were from healthy sibling donors and 164 were for autologous collections. Successful SCC, defined as a CD34+ cell count of ≥2 × 106 /kg of recipient weight per intended transplant, occurred in 188 of 199 donors (94%). Ideal SCC defined ≥5 × 106 CD34+ cells/kg of recipient per intended transplant, occurred in 147 (74%) patients. Failure of collection occurred in 11 (6%) patients and was significantly associated with an autologous collection for a brain tumor diagnosis (P = .003) and a pre-apheresis peripheral blood (PB) CD34+ count <20 × 106 cells/L (P = .002). Ideal SCC was significantly associated with age < 10 years (P = .01) and pre-apheresis PB-CD34+ count ≥20 × 106 cells/L (P < .0001). Factors associated with failure of SCC may be identified in advance of the collection procedure allowing appropriate counselling of patients as well as anticipatory guidance for multiple collections or justify the preemptive use of stem cell mobilizing agents.

Access to Hematopoietic Stem Cell Transplantation among Pediatric Patients with Acute Lymphoblastic Leukemia: A Population-Based Analysis.

Access to hematopoietic stem cell transplantation (HSCT) in pediatric acute lymphoblastic leukemia (ALL) primarily depends on disease-related factors but may be influenced by social and economic determinants. We included all children aged < 15 years with newly diagnosed ALL in Canada between 2001 and 2018 using the Cancer in Young People in Canada national registry. We examined factors potentially associated with the likelihood of receiving HSCT using univariate and multivariable logistic regression models. A total of 3992 patients with newly diagnosed ALL were included. Three hundred twenty-five (8.1%) received an HSCT and formed the transplant cohort. In multivariable analysis factors independently associated with an increased odds of receiving HSCT were male sex (odds ratio [OR], 1.42; 95% confidence interval [CI], 1.05 to 1.93), initial WBC ≥ 50,000 × 109/L (OR, 1.58; 95% CI, 1.09 to 2.28), mixed phenotype acute leukemia relative to B-precursor ALL (OR, 34.32; 95% CI, 16.64 to 70.79), T cell relative to B-precursor ALL (OR, 1.77; 95% CI, 1.07 to 2.91), unfavorable relative to standard cytogenetics (OR, 3.96; 95% CI, 2.56 to 6.12), and relapse before HSCT (OR, 32.77; 95%, 23.89 to 44.96). No association was found between race, neighborhood income quintile or region at diagnosis, and receipt of HSCT. Diagnosis at an HSCT treating center (OR, 1.51; 95% CI, 1.09 to 2.09) and residential distance from the ALL treating center (OR, 1.84 for ≥300 km compared with <100 km; 95% CI, 1.17 to 2.91) were associated with higher odds of receiving HSCT. In a publically funded healthcare system, children with ALL had equitable access to HSCT, which was largely governed by biologic disease-related factors. Patients diagnosed at an HSCT performing center and patients who live farthest away from their treatment center had higher odds of receiving HSCT, although the effect was small, possibly suggesting preferential referral to HSCT for some patients.

Targeted Polo-like Kinase Inhibition Combined With Aurora Kinase Inhibition in Pediatric Acute Leukemia Cells.

BACKGROUND: Recent studies have shown that cell cycle events are tightly controlled by complex and shared activities of a select group of kinases. Among these, polo-like kinases (Plks) are regulatory mitotic proteins that are overexpressed in several types of cancer and are associated with poor prognosis. MATERIALS AND METHODS: We have evaluated, in preclinical in vitro studies, the activity of a panel of Plk inhibitors against cell lines derived from refractory pediatric leukemia, as well as primary leukemia cells, in culture. Through in vitro growth inhibition studies, Western blot analysis for the expression and activation of key regulators of cell growth and survival and gene silencing studies, we specifically examined the ability of these agents to induce cytotoxicity through the activation of apoptosis and their capacity to interact and modulate the expression and phosphorylation of Aurora kinases. RESULTS: Our findings show that the various Plk-1 inhibitors in development show potential utility for the treatment of pediatric leukemia and exhibit a wide range of phosphorylation and target modulatory capabilities. Finally, we provide evidence for a complex interregulatory relationship between Plk-1 and Aurora kinases enabling the identification of synergy and biologic correlates of drug combinations targeting the 2 distinct enzyme systems. DISCUSSION: This information provide the rationale for the evaluation of Plk-1 as an effective target for therapeutics in refractory pediatric leukemia and indicate compensatory activities between Plk-1 and Aurora kinases, providing insight into some of the complex mechanisms involved in the process of cell division.

Nonmyeloablative Matched Sibling Donor Hematopoietic Cell Transplantation in Children and Adolescents with Sickle Cell Disease.

Sickle cell disease is a potentially debilitating hemoglobinopathy associated with early mortality. The only established curative therapy is hematopoietic cell transplantation (HCT) with a matched sibling donor. The National Institutes of Health nonmyeloablative regimen of alemtuzumab/300 cGy total body irradiation and prolonged sirolimus exposure for graft-versus-host disease (GVHD) prophylaxis was administered to 16 children and adolescents. Infused products were unmanipulated granulocyte colony stimulating factor mobilized peripheral blood stem cells. All patients achieved mixed donor-recipient engraftment with no cases of secondary graft failure to date. Two patients have donor myeloid chimerism in the range of 30% to 40%. No sickling crises post-HCT have been observed. Event-free and overall survival rates are 100% with median follow-up of 19.5 months. No cases of GVHD have been observed. Sirolimus weaning was possible in all but one eligible patient to date. Ongoing follow-up and a larger prospective clinical trial are required to determine the long-term safety and efficacy of this regimen in children.

Enrollment on clinical trials does not improve survival for children with acute myeloid leukemia: A population-based study.

BACKGROUND: It is questionable whether enrollment on clinical trials offers any survival advantage at the population level over standard-of-care treatment. The objectives of this study were to describe the impact of trial enrollment on event-free survival and overall survival in pediatric acute myeloid leukemia (AML) using the Cancer in Young People in Canada (CYP-C) database. METHODS: Children were included if they had had AML newly diagnosed between ages birth and 14 years from 2001 to 2012. CYP-C is a national pediatric cancer population-based database that includes all cases of pediatric cancer diagnosed and treated at 1 of the 17 tertiary pediatric oncology centers in Canada. Univariate and Cox proportional hazards models were used to evaluate the impact of initial trial enrollment on survival. RESULTS: In total, 397 eligible children with AML were included in the analysis, of whom 94 (23.7%) were enrolled on a clinical trial at initial diagnosis. The most common reason for non-enrollment was that no trial was available. The event-free survival rate at 5 years was 57.8% ± 5.2% for those enrolled versus 54.8% ± 2.9% for those not enrolled (P = .75). The overall survival rate at 5 years was 70.1% ± 4.9% for those enrolled versus 66.3% ± 2.8% for those not enrolled (P = .58). Enrollment on a trial was not associated with improved event-free or overall survival in multiple regression analyses. CONCLUSIONS: Enrollment on a clinical trial was not associated with improved survival for children with AML in a population-based cohort. Rationale for trial enrollment should not include the likelihood of benefit compared with non-enrollment.