Gregory M.T. Guilcher

Late Effects Surveillance Recommendations among Survivors of Childhood Hematopoietic Cell Transplantation: A Children's Oncology Group Report.

Hematopoietic cell transplantation (HCT) is an important curative treatment for children with high-risk hematologic malignancies, solid tumors, and, increasingly, nonmalignant diseases. Given improvements in care, there are a growing number of long-term survivors of pediatric HCT. Compared with childhood cancer survivors who did not undergo transplantation, HCT survivors have a substantially increased burden of serious chronic conditions and impairments involving virtually every organ system and overall quality of life. This likely reflects the joint contributions of pretransplantation treatment exposures and organ dysfunction, the transplantation conditioning regimen, and any post-transplantation graft-versus-host disease (GVHD). In response, the Childrens Oncology Group (COG) has created long-term follow-up guidelines (www.survivorshipguidelines.org) for survivors of childhood, adolescent, and young adult cancer, including those who were treated with HCT. Guideline task forces, consisting of HCT specialists, other pediatric oncologists, radiation oncologists, organ-specific subspecialists, nurses, social workers, other health care professionals, and patient advocates systematically reviewed the literature with regards to late effects after childhood cancer and HCT since 2002, with the most recent review completed in 2013. For the most recent review cycle, over 800 articles from the medical literature relevant to childhood cancer and HCT survivorship were reviewed, including 586 original research articles. Provided herein is an organ system-based overview that emphasizes the most relevant COG recommendations (with accompanying evidence grade) for the long-term follow-up care of childhood HCT survivors (regardless of current age) based on a rigorous review of the available evidence. These recommendations cover both autologous and allogeneic HCT survivors, those who underwent transplantation for nonmalignant diseases, and those with a history of chronic GVHD.

The feasibility and benefits of a 12-week yoga intervention for pediatric cancer out-patients.

Increasing rates of survival present a new set of psychosocial and physical challenges for children undergoing treatment for cancer. Physical activity (PA) has been shown to be a safe and effective strategy to mitigate the significant burden of cancer and its treatments, with yoga increasingly gaining recognition as a gentle alternative. The purpose of this study was to determine the feasibility and benefits of a 12‐week community‐based yoga intervention on health‐related quality of life (HRQL), select physical fitness outcomes and PA levels (PAL).

Are hybrid umbilical cord blood banks really the best of both worlds

Since the first use of umbilical cord blood (UCB) as a medical therapy, the number of UCB banks worldwide has grown. Public UCB banks offer the option of altruistic donation, whereas private banks allow a product to be stored for the exclusive use of the paying client. With many more UCB products banked privately than publicly in countries such as the USA, hybrid models blending aspects of public and private banking have been proposed. One such bank is in operation in the UK. In this paper we review the hybrid UCB model and conclude that it offers limited benefit to the general public. Furthermore, compared with private banking, this model provides few advantages and potential disadvantages to private clients.

Relationship between Mixed Donor–Recipient Chimerism and Disease Recurrence after Hematopoietic Cell Transplantation for Sickle Cell Disease

Mixed donor chimerism after hematopoietic cell transplantation for sickle cell disease (SCD) can result in resolution of disease symptoms, but symptoms recur when donor chimerism is critically low. The relationship between chimerism, hemoglobin S (HbS) level, and symptomatic disease was correlated retrospectively in 95 patients who had chimerism reports available at day 100 and at 1 and 2 years after transplantation. Recurrent disease was defined as recurrence of vaso-occlusive crises, acute chest syndrome, stroke, and/or HbS levels > 50%. Thirty-five patients maintained full donor chimerism (myeloid or whole blood) through 2 years. Donor chimerism was less than 10% (defined as graft failure) in 13 patients during this period. Mixed chimerism was reported in the remaining 47 patients (range, 10% to 94%). The lowest documented donor chimerism without symptomatic disease was 26%. Of 12 surviving patients with recurrent disease, 2 had recurrence of symptoms before documented graft failure (donor chimerism of 11% and 17%, respectively). Three patients underwent second transplantation for graft failure. None received donor leukocyte infusion to maintain mixed chimerism or prevent graft failure. We conclude stable donor chimerism greater than 25% is associated with resolution of SCD-related symptoms, and HbS levels in transplant recipients should be interpreted in context of the sickle trait status of the donors.

Adverse reactions during stem cell infusion in children treated with autologous and allogeneic stem cell transplantation

Adverse reactions (ARs) during the infusion of cellular therapy products (CTPs) are common in patients undergoing hematopoietic stem cell transplantation (HSCT). We retrospectively studied pediatric patients undergoing autologous and allogeneic HSCT to determine the incidence and grade of ARs during stem cell infusion and their predictors. We analyzed data from 213 patients (120 allogeneic and 93 autologous) who received at least 1 CTP, totaling 361 infusion episodes. Serious ARs, defined as grade 2 and 3, occurred in 25 and 11% of infusions, respectively. No grade 4 or 5 ARs were noted. Independent risk factors for developing a serious AR included stem cell source (PBSC vs marrow (odds ratio (OR) 1.8, 95% confidence interval (CI): 0.4–9); cord vs marrow (OR 7.3, 95% CI: 1.3-40), overall P=0.0001) but manipulated CTPs were protective (OR 0.4, 95% CI: 0.2-0.7, P=0.004). Unlike previous adult studies, WBC and granulocyte content were not found to be risk factors in this pediatric population. These data suggest that children tolerate higher WBC content during infusion of CTPs and support the use of manipulated CTP, as indicated, to reduce the risk of adverse infusion reactions.

Transplant Outcomes for Children with T Cell Acute Lymphoblastic Leukemia in Second Remission: A Report from the Center for International Blood and Marrow Transplant Research

Survival for children with relapsed T cell acute lymphoblastic leukemia (T-ALL) is poor when treated with chemotherapy alone, and outcomes after allogeneic hematopoietic cell transplantation (HCT) is not well described. Two hundred twenty-nine children with T-ALL in second complete remission (CR2) received an HCT after myeloablative conditioning between 2000 and 2011 and were reported to the Center for International Blood and Marrow Transplant Research. Median age was 10 years (range, 2 to 18). Donor source was umbilical cord blood (26%), matched sibling bone marrow (38%), or unrelated bone marrow/peripheral blood (36%). Acute (grades II to IV) and chronic graft-versus-host disease occurred in, respectively, 35% (95% confidence interval [CI], 27% to 45%) and 26% (95% CI, 20% to 33%) of patients. Transplant-related mortality at day 100 and 3-year relapse rates were 13% (95% CI, 9% to 18%) and 30% (95% CI, 24% to 37%), respectively. Three-year overall survival and disease-free survival rates were 48% (95% CI, 41% to 55%) and 46% (95% CI, 39% to 52%), respectively. In multivariate analysis, patients with bone marrow relapse, with or without concurrent extramedullary relapse before HCT, were most likely to relapse (hazard ratio, 3.94; P = .005) as compared with isolated extramedullary disease. In conclusion, HCT for pediatric T-ALL in CR2 demonstrates reasonable and durable outcomes, and consideration for HCT is warranted.

Personalized Prognostic Risk Score for Long-Term Survival for Children with Acute Leukemia after Allogeneic Transplantation

We studied leukemia-free (LFS) and overall survival (OS) in children with acute myeloid (AML, n = 790) and acute lymphoblastic leukemia (ALL, n = 1096) who underwent transplantation between 2000 and 2010 and who survived for at least 1 year in remission after related or unrelated donor transplantation. Analysis of patient-, disease-, and transplantation characteristics and acute and chronic graft-versus-host disease (GVHD) was performed to identify factors with adverse effects on LFS and OS. These data were used to develop risk scores for survival. We did not identify any prognostic factors beyond 4 years after transplantation for AML and beyond 3 years for ALL. Risk score for survival for AML includes age, disease status at transplantation, cytogenetic risk group, and chronic GVHD. For ALL, the risk score includes age at transplantation and chronic GVHD. The 10-year probabilities of OS for AML with good (score 0, 1, or 2), intermediate (score 3), and poor risk (score 4, 5, 6, or 7) were 94%, 87%, and 68%, respectively. The 10-year probabilities of OS for ALL were 89% and 80% for good (score 0 or 1) and poor risk (score 2), respectively. Identifying children at risk for late mortality with early intervention may mitigate some excess late mortality.

EXERCISE in pediatric autologous stem cell transplant patients: a randomized controlled trial protocol

BackgroundHematopoietic stem cell transplantation is an intensive therapy used to improve survivorship and cure various oncologic diseases. However, this therapy is associated with high mortality rates and numerous negative side-effects. The recovery of the immune system is a special concern and plays a key role in the success of this treatment. In healthy populations it is known that exercise plays an important role in immune system regulation, but little is known about the role of exercise in the hematological and immunological recovery of children undergoing hematopoietic stem cell transplant. The primary objective of this randomized-controlled trial (RCT) is to study the effect of an exercise program (in- and outpatient) on immune cell recovery in patients undergoing an autologous stem cell transplantation. The secondary objective is to determine if an exercise intervention diminishes the usual deterioration in quality of life, physical fitness, and the acquisition of a sedentary lifestyle.MethodsThis RCT has received approval from The Conjoint Health Research Ethics Board (CHREB) of the University of Calgary (Ethics ID # E-24476). Twenty-four participants treated for a malignancy with autologous stem cell transplant (5 to 18 years) in the Alberta Children’s Hospital will be randomly assigned to an exercise or control group. The exercise group will participate in a two-phase exercise intervention (in- and outpatient) from hospitalization until 10 weeks after discharge. The exercise program includes strength, flexibility and aerobic exercise. During the inpatient phase this program will be performed 5 times/week and will be supervised. The outpatient phase will combine a supervised session with two home-based exercise sessions with the use of the Wii device. The control group will follow the standard protocol without any specific exercise program. A range of outcomes, including quantitative and functional recovery of immune system, cytokine levels in serum, natural killer (NK) cells and their subset recovery and function, and gene expression of activating and inhibitory NK cell receptors, body composition, nutrition, quality of life, fatigue, health-related fitness assessment and physical activity levels will be examined, providing the most comprehensive assessment to date.DiscussionWe expect to find improvements in immunological recovery and quality of life, and decreased acquisition of sedentary behavior and fitness deconditioning. The comprehensive outcomes generated in this RCT will provide preliminary data to conduct a multisite study that will generate stronger outcomes.Trial registrationGov identification # NCT01666015

Single-agent high-dose melphalan followed by auto-SCT for relapsed and refractory Hodgkin lymphoma in children and adolescents

Hodgkin lymphoma (HL) is cured in the majority of children and adolescents. However, there remains a group of patients with primary refractory or relapsed disease for whom cure is more difficult to achieve. Most of these patients receive high-dose chemotherapy followed by auto-SCT, with expected cure rates ranging from 40 to 60%. Conditioning regimens often consist of multiple non-cross-resistant agents, with well-described risks of morbidity and mortality. The use of single-agent high-dose melphalan (HDM) as conditioning, before autologous rescue, has been described in adult patients at our center, with comparable efficacy and less morbidity. We present a series of eight pediatric patients conditioned with single-agent HDM before autologous stem cell rescue for relapsed and primary refractory HL. All patients engrafted with a median of 12 days to neutrophil engraftment. Two patients subsequently relapsed. Seven patients are currently alive, and seven of eight patients have no evidence of disease (one in CR3). Toxicities included grade 4 hematologic in 8/8, grade 3 mucositis in 3/8, grade 3 infectious in 2/8 and grade 4 infectious in 1/8. Our analysis suggests that this regimen is feasible in pediatric patients with acceptable engraftment and toxicity.

Hematopoietic Stem Cell Transplantation in Children and Adolescents.

1. Gregory M.T. Guilcher, MD* 1. *Section of Pediatric Oncology/BMT, Alberta Children’s Hospital; Departments of Oncology and Pediatrics, University of Calgary, Calgary, Alberta, Canada. Hematopoietic stem cell transplantation (HSCT) indications and practices have changed significantly over the last 20 years. Evolving hematopoietic stem cell sources, less toxic conditioning regimens, and improving graft-versus-host disease prophylaxis and therapy have broadened the application of HSCT from malignant conditions to increasing numbers of nonmalignant diseases. After completing this article, the reader should be able to: 1. Understand general principles of allogeneic and autologous hematopoietic stem cell transplantation (HSCT), including the variety of hematopoietic stem cell sources. 2. Discuss the variability in intensity of current conditioning approaches, which influences the risks and applicability of HSCT. 3. Recognize that HSCT involves acute and chronic complications and the importance of general clinicians and subspecialists in their management. 4. Review the pathophysiology of graft-versus-host disease, its presentation, and its prevention and management. 5. Identify the increasing number of nonmalignant indications for HSCT in children such that children who might benefit from this procedure are considered for timely referral as appropriate. A 1-year-old child is referred to your office for a developmental assessment due to delayed speech and gross motor skills. You notice coarse facial features and on physical examination document corneal clouding, hepatosplenomegaly, and numerous skeletal deformities. You suspect a metabolic disorder and request an urgent referral to a metabolic specialist. The specialist clinically diagnoses Hurler syndrome (mucopolysaccharidosis IH) and confirms α-L-iduronidase deficiency with urinary glycosaminoglycan testing and subsequently by enzyme deficiency in fibroblasts. While genetic testing results are pending, you discuss the case with the metabolic specialist and agree that an urgent referral to a pediatric hematopoietic stem cell transplantation (HSCT) specialist is warranted before genetic testing results are available. The best neurologic outcomes are seen when HSCT is …