Ami J. Shah

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.

Progressive declines in neurocognitive function among survivors of hematopoietic stem cell transplantation for pediatric hematologic malignancies.

Neurocognitive function of pediatric patients is of great concern after hematopoietic stem cell transplantation (HSCT). We evaluated the neurocognitive function of pediatric patients pre-HSCT, 1, 3, and 5 years post-HSCT. All patients had a hematologic malignancy and received therapy to their central nervous system. Healthy siblings were tested as a comparison group. Pediatric patients with a hematologic malignancy did not have a significant decrease in their cognitive function before HSCT compared with their siblings except in areas of academic achievement. Our study population had significant declines in visual motor skills and memory test scores within the first year post-HSCT. By 3 years post-HSCT, there was an improvement in the visual motor development scores and memory scores, but there were new deficits in verbal skills. By 5 years post-HSCT, there were progressive declines in verbal skills (P=0.005), performance skills (0.04), and new deficits seen in long-term verbal memory scores (0.04). On the basis of the raw scores, most of these tests showed that patients had an inability to acquire new skills at a rate comparable to their age-matched healthy peers. However, long-term memory scores showed definite declines. The greatest decline in neurocognitive function occurred in those patients who received cranial irradiation either as part of their initial therapy or as part of their HSCT conditioning. Pediatric patients who received HSCT for hematologic malignancies have neurocognitive deficiencies that are both acute and chronic. Although some patients have acute deficits that appear and improve over time, other patients have progressive declines in neurocognitive function that are chronic.

Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy

BACKGROUND In X‐linked adrenoleukodystrophy, mutations in ABCD1 lead to loss of function of the ALD protein. Cerebral adrenoleukodystrophy is characterized by demyelination and neurodegeneration. Disease progression, which leads to loss of neurologic function and death, can be halted only with allogeneic hematopoietic stem‐cell transplantation. METHODS We enrolled boys with cerebral adrenoleukodystrophy in a single‐group, open‐label, phase 2–3 safety and efficacy study. Patients were required to have early‐stage disease and gadolinium enhancement on magnetic resonance imaging (MRI) at screening. The investigational therapy involved infusion of autologous CD34+ cells transduced with the elivaldogene tavalentivec (Lenti‐D) lentiviral vector. In this interim analysis, patients were assessed for the occurrence of graft‐versus‐host disease, death, and major functional disabilities, as well as changes in neurologic function and in the extent of lesions on MRI. The primary end point was being alive and having no major functional disability at 24 months after infusion. RESULTS A total of 17 boys received Lenti‐D gene therapy. At the time of the interim analysis, the median follow‐up was 29.4 months (range, 21.6 to 42.0). All the patients had gene‐marked cells after engraftment, with no evidence of preferential integration near known oncogenes or clonal outgrowth. Measurable ALD protein was observed in all the patients. No treatment‐related death or graft‐versus‐host disease had been reported; 15 of the 17 patients (88%) were alive and free of major functional disability, with minimal clinical symptoms. One patient, who had had rapid neurologic deterioration, had died from disease progression. Another patient, who had had evidence of disease progression on MRI, had withdrawn from the study to undergo allogeneic stem‐cell transplantation and later died from transplantation‐related complications. CONCLUSIONS Early results of this study suggest that Lenti‐D gene therapy may be a safe and effective alternative to allogeneic stem‐cell transplantation in boys with early‐stage cerebral adrenoleukodystrophy. Additional follow‐up is needed to fully assess the duration of response and long‐term safety. (Funded by Bluebird Bio and others; STARBEAM ClinicalTrials.gov number, NCT01896102; ClinicalTrialsRegister.eu number, 2011‐001953‐10.)

Successful Hematopoietic Stem Cell Transplantation for Niemann-Pick Disease Type B

Histocompatible hematopoietic stem cell transplantation (HSCT) was conducted on a 4.5-year-old girl with Niemann-Pick disease type B. The donor was her unaffected brother. At the time of transplantation, she had severe pulmonary disease. After her first HSCT, she developed graft failure. Five years after her second HSCT, her sphingomyelinase levels are within normal levels, she has no pulmonary symptoms, and aside from persistent graft versus host disease, she is doing well.

Vascular occlusion associated with incontinentia pigmenti

A 4 1/2-year-old girl with incontinentia pigmenti developed acute-onset hemiparesis. Magnetic resonance angiography revealed occlusion of the left middle cerebral artery. Many neurocutaneous syndromes have been linked to ischemic stroke syndromes. Incontinentia pigmenti has not been associated with stroke syndromes in the past; however, this report illustrates that the patient and her mother, who also has incontinentia pigmenti, may have had similar ischemic stroke events.

Hepato-Biliary Late Effects in Survivors of Childhood and Adolescent Cancer: A Report from the Children’s Oncology Group

Curative therapy for childhood and adolescent cancer translates to 1 in 640 young adults being a survivor of cancer. Although acute hepato‐biliary toxicity occurs commonly during pediatric cancer therapy, the impact of antineoplastic therapy on long‐term liver health in childhood/adolescent cancer survivors is unknown. This article reviews the medical literature on late liver dysfunction following treatment for childhood/adolescent cancer. We also outline the Childrens Oncology Group (COG) guidelines for screening and follow‐up of hepato‐biliary sequelae. As the population of survivors grow and age, vigilance for risks to hepatic health needs to continue based on specific exposures during curative cancer therapy. Pediatr Blood Cancer 2010;54:663–669.

Busulfan and cyclophosphamide as a conditioning regimen for pediatric acute lymphoblastic leukemia patients undergoing bone marrow transplantation.

Bone marrow transplantation (BMT) has become the standard therapy for children with relapsed acute lymphoblastic leukemia. The authors report their experience with histocompatible BMT for 52 children with acute lymphoblastic leukemia conditioned with a non-total body irradiation (TBI) regimen using busulfan and cyclophosphamide (Bu/Cy). The efficacy and long-term toxicity of the Bu/Cy regimen were determined. Overall survival was 35%. One-year, 3-year, and 7-year event-free survival rates were 54%, 33%, and 23%, respectively. Of the 52 BMT recipients, 26 relapsed. Thirteen of the relapsed patients received a second BMT and three were surviving as of this writing. The most frequent cause of death was leukemia relapse. An initial remission duration of less than 18 months was a factor in decreasing the event-free survival. The Bu/Cy regimen was well tolerated, with minimal transplant-related mortality. Neurocognitive function was tested before BMT and 1 year after BMT. When 1-year posttransplant neurocognitive test scores were compared with pretransplant scores, there was no decrease. However, there was a significant decrease in the pretransplant neurocognitive test scores in BMT recipients compared with their normal siblings. The use of Bu/Cy as a conditioning regimen for BMT does not appear to affect posttransplant neurocognitive function. Other long-term side effects, such as endocrinopathies and secondary malignancies, were also minimal. These data show that the Bu/Cy regimen is well tolerated, but the overall survival rate remains low.

Clinical and genetic heterogeneity in Omenn syndrome and severe combined immune deficiency.

Abstract:  OS has been described as a clinical phenotype in infants characterized by SCID, diffuse erythroderma, and other distinct features. The pathogenesis is secondary to autologous, auto‐reactive T cells produced as rare escapees from the SCID blockade. Mutations in either the RAG1 or RAG2 gene that lead to partial recombinase activity are responsible for many of the patients with these clinical features. We report on two patients, one with an atypical phenotype of OS (absence of rash but presence of other typical features) who harbored a previously undescribed mutation in RAG1, and a second who had many of the classic features of OS but was found to have a mutation in the common gamma chain (γc) cytokine receptor gene. These cases highlight the clinical and genetic heterogeneity of OS.

Tacrolimus versus Cyclosporine after Hematopoietic Cell Transplantation for Acquired Aplastic Anemia

Combinations of cyclosporine (CSP) with methotrexate (MTX) have been widely used for immunosuppression after allogeneic transplantation for acquired aplastic anemia. We compared outcomes with tacrolimus (TAC)+MTX versus CSP+MTX after transplantation from HLA-identical siblings (SIB) or unrelated donors (URD) in a retrospective cohort of 949 patients with severe aplastic anemia. Study endpoints included hematopoietic recovery, graft failure, acute graft-versus-host disease (GVHD), chronic GVHD, and mortality. TAC+MTX was used more frequently in older patients and, in recent years, in both SIB and URD groups. In multivariate analysis, TAC+MTX was associated with a lower risk of mortality in URD recipients and with slightly earlier absolute neutrophil count recovery in SIB recipients. Other outcomes did not differ statistically between the 2 regimens. No firm conclusions were reached regarding the relative merits of TAC+MTX versus CSP+MTX after hematopoietic cell transplantation for acquired aplastic anemia. Prospective studies would be needed to determine whether the use of TAC+MTX is associated with lower risk of mortality in URD recipients with acquired aplastic anemia.

Human Lymphoid Development in the Absence of Common γ-Chain Receptor Signaling

Despite the power of model systems to reveal basic immunologic mechanisms, critical differences exist between species that necessitate the direct study of human cells. Illustrating this point is the difference in phenotype between patients with SCID caused by mutations affecting the common γ-chain (γc) cytokine signaling pathway and mice with similar mutations. Although in both species, null mutations in either IL-2RG (which encodes γc), or its direct downstream signaling partner JAK3, result in T and NK cell deficiency, an associated B cell deficiency is seen in mice but not in humans with these genetic defects. In this study, we applied recent data that have revised our understanding of the earliest stages of lymphoid commitment in human bone marrow (BM) to determine the requirement for signaling through IL-2RG and JAK3 in normal development of human lymphoid progenitors. BM samples from SCID patients with IL-2RG (n = 3) or JAK3 deficiency (n = 2), which produce similar “T-NK-B+” clinical phenotypes, were compared with normal BM and umbilical cord blood as well as BM from children on enzyme treatment for adenosine deaminase–deficient SCID (n = 2). In both IL-2RG– and JAK3-SCID patients, the early stages of lymphoid commitment from hematopoietic stem cells were present with development of lymphoid-primed multipotent progenitors, common lymphoid progenitors and B cell progenitors, normal expression patterns of IL-7RA and TLSPR, and the DNA recombination genes DNTT and RAG1. Thus, in humans, signaling through the γc pathway is not required for prethymic lymphoid commitment or for DNA rearrangement.