Andrew C. Dietz

Disease-specific hematopoietic cell transplantation: nonmyeloablative conditioning regimen for dyskeratosis congenita

Dyskeratosis congenita (DC) is characterized by reticular skin pigmentation, oral leukoplakia and abnormal nails. Patients with DC have very short telomeres and approximately one-half have mutations in telomere biology genes. A majority of patients with DC develop BM failure (BMF). Hematopoietic cell transplantation (HCT) represents the only known cure for BMF in DC, but poses significant toxicities. We report six patients who underwent allogeneic HCT with a novel nonmyeloablative conditioning regimen specifically designed for DC patients. Graft sources included related PBSCs (1), unrelated BM (2) and unrelated double umbilical cord blood (3). Complete donor engraftment was achieved in five of six patients. One patient had initial autologous hematopoietic recovery, which was followed by a second transplant that resulted in 88% donor chimerism. With a median follow-up of 26.5 months, four patients are alive, three of whom were recipients of unrelated grafts. We conclude with this small study that encouraging short-term survival can be achieved with HCT in patients with DC using a preparative regimen designed to promote donor engraftment and minimize life-threatening disease-specific complications such as pulmonary fibrosis. Long-term follow-up will be crucial with respect to individualized patient care with each of the transplanted individuals.

Cardiovascular risk and insulin resistance in childhood cancer survivors

OBJECTIVE Increased cardiovascular (CV) risk has been reported in adults who are childhood cancer survivors (CCS). We sought to determine the emergence of CV risk factors in CCS while still children. STUDY DESIGN CCS in remission ≥5 years from cancer diagnosis (n=319, age=14.5 years) and their siblings (control subjects, n=208, age=13.6 years) participated in this cross-sectional study of CV risk, which included physiologic assessment of insulin sensitivity/resistance (hyperinsulinemic euglycemic clamp). Adjusted comparisons between CCS major diagnoses (leukemia [n=110], central nervous system tumors [n=82], solid tumors [n=127]) and control subjects were performed with linear regression for CV risk factors and insulin sensitivity. RESULTS Despite no significant differences in weight and body mass index, CCS had greater adiposity (waist [73.1 versus 71.1 cm, P=.02]; percent fat [28.1 versus 25.9%, P=.007]), lower lean body mass (38.4 versus 39.9 kg, P=.01) than control subjects. After adjustment for adiposity, CCS had higher total cholesterol level (154.7 versus 148.3 mg/dL, P=.004), low-density lipoprotein cholesterol level (89.4 versus 83.7 mg/dL, P=.002), and triglyceride level (91.8 versus 84 mg/dL, P=.03) and were less insulin sensitive (insulin stimulated glucose uptake, measure of insulin resistance, adjusted for lean body mass 12.1 versus 13.4 mg/kg/min, P=.002) than control subjects. CONCLUSIONS CCS have greater CV risk than healthy children. Because CV risk factors track from childhood to adulthood, early development of altered body composition and decreased insulin sensitivity in CCS may contribute significantly to their risk of early CV morbidity and mortality.

Modifiable risk factors associated with bone deficits in childhood cancer survivors.

BackgroundTo determine the prevalence and severity of bone deficits in a cohort of childhood cancer survivors (CCS) compared to a healthy sibling control group, and the modifiable factors associated with bone deficits in CCS.MethodsCross-sectional study of bone health in 319 CCS and 208 healthy sibling controls. Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). Generalized estimating equations were used to compare measures between CCS and controls. Among CCS, multivariable logistic regression was used to evaluate odds ratios for BMD Z-score ≤ -1.ResultsAll subjects were younger than 18 years of age. Average time since treatment was 10.1 years (range 4.3 - 17.8 years). CCS were 3.3 times more likely to have whole body BMD Z-score ≤ -1 than controls (95% CI: 1.4-7.8; p = 0.007) and 1.7 times more likely to have lumbar spine BMD Z-score ≤ -1 than controls (95% CI: 1.0-2.7; p = 0.03). Among CCS, hypogonadism, lower lean body mass, higher daily television/computer screen time, lower physical activity, and higher inflammatory marker IL-6, increased the odds of having a BMD Z-score ≤ -1.ConclusionsCCS, less than 18 years of age, have bone deficits compared to a healthy control group. Sedentary lifestyle and inflammation may play a role in bone deficits in CCS. Counseling CCS and their caretakers on decreasing television/computer screen time and increasing activity may improve bone health.

Risk and impact of pulmonary complications in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study

Pulmonary complications after cancer therapy are varied. This study describes pulmonary outcomes among childhood cancer survivors and evaluates their impact on daily activities.

Life beyond the disease: relationships, parenting, and quality of life among survivors of childhood cancer

Advances in cancer therapies and supportive care have contributed to significant increases in survival rates for children diagnosed with a malignancy. As overall survival rates approach 80%, research has focused on the long-term effects and adverse health outcomes these individuals experience later

Impact of Treatment Exposures on Cardiovascular Risk and Insulin Resistance in Childhood Cancer Survivors

Background: Childhood cancer survivors (CCS) are more insulin resistant and have higher levels of several cardiovascular risk factors even while still children. This study examines specific treatment exposures associated with cardiovascular risk factors and insulin resistance. Methods: CCS of ages 9 to 18 years at study entry and in remission 5 years or more from diagnosis (n = 319) and 208 sibling controls were recruited into this cross-sectional study that included physiologic assessment of insulin resistance (hyperinsulinemic euglycemic clamp) and assessment of cardiovascular risk factors. Regression and recursive tree modeling were used to ascertain treatment combinations associated with insulin resistance and cardiovascular risk. Results: Mean current age of CCS was 14.5 years and 54% were male (siblings 13.6 years, 54% male). Diagnoses included leukemia (35%), brain tumors (36%), solid tumors (33%), or lymphoma (6%). Among CCS, analysis of individual chemotherapy agents failed to find associations with cardiovascular risk factors or insulin resistance. Compared with siblings, insulin resistance was significantly higher in CCS who received platinum plus cranial radiotherapy (CRT, 92% brain tumors) and in those who received steroids but no platinum (majority leukemia). Insulin resistance did not differ between CCS who received surgery alone versus siblings. Within survivor comparisons failed to elucidate treatment combinations that increased insulin resistance compared with those who received surgery only. Conclusions: Exposure to platinum, CRT, or steroids is associated with insulin resistance and cardiovascular risk factors and should be taken into consideration in the development of screening recommendations for cardiovascular risk. Impact: Earlier identification of CCS who may benefit from targeted prevention efforts may reduce their future risk of cardiovascular disease. Cancer Epidemiol Biomarkers Prev; 22(11); 1954–63. ©2013 AACR.

Current Knowledge and Priorities for Future Research in Late Effects after Hematopoietic Stem Cell Transplantation (HCT) for Severe Combined Immunodeficiency Patients: A Consensus Statement from the Second Pediatric Blood and Marrow Transplant Consortium International Conference on Late Effects after Pediatric HCT

Severe combined immunodeficiency (SCID) is 1 of the most common indications for pediatric hematopoietic cell transplantation (HCT) in patients with primary immunodeficiency. Historically, SCID was diagnosed in infants who presented with opportunistic infections within the first year of life. With newborn screening (NBS) for SCID in most of the United States, the majority of infants with SCID are now diagnosed and treated in the first 3.5 months of life; however, in the rest of the world, the lack of NBS means that most infants with SCID still present with infections. The average survival for SCID patients who have undergone transplantation currently is >70% at 3 years after transplantation, although this can vary significantly based on multiple factors, including age and infection status at the time of transplantation, type of donor source utilized, manipulation of graft before transplantation, graft-versus-host disease prophylaxis, type of conditioning (if any) utilized, and underlying genotype of SCID. In at least 1 study of SCID patients who received no conditioning, long-term survival was 77% at 8.7 years (range out to 26 years) after transplantation. Although a majority of patients with SCID will engraft T cells without any conditioning therapy, depending on genotype, donor source, HLA match, and presence of circulating maternal cells, a sizable percentage of these will fail to achieve full immune reconstitution. Without conditioning, T cell reconstitution typically occurs, although not always fully, whereas B cell engraftment does not, leaving some molecular types of SCID patients with intrinsically defective B cells, in most cases, dependent on regular infusions of immunoglobulin. Because of this, many centers have used conditioning with alkylating agents including busulfan or melphalan known to open marrow niches in attempts to achieve B cell reconstitution. Thus, it is imperative that we understand the potential late effects of these agents in this patient population. There are also nonimmunologic risks associated with HCT for SCID that appear to be dependent upon the genotype of the patient. In this report, we have evaluated the published data on late effects and attempted to summarize the known risks associated with conditioning and alternative donor sources. These data, while informative, are also a clear demonstration that there is still much to be learned from the SCID population in terms of their post-HCT outcomes. This paper will summarize current findings and recommend further research in areas considered high priority. Specific guidelines regarding a recommended approach to long-term follow-up, including laboratory and clinical monitoring, will be forthcoming in a subsequent paper.

Pulmonary Outcomes in Survivors of Childhood Central Nervous System Malignancies: A Report from the Childhood Cancer Survivor Study

Adult survivors of childhood central nervous system (CNS) tumors may be at risk for pulmonary dysfunction. This study enumerates the incidence of pulmonary dysfunction and explores associations between craniospinal irradiation (CSI) and pulmonary dysfunction among survivors of childhood CNS tumors.

Donor-derived myelodysplastic syndrome and acute leukaemia after allogeneic haematopoietic stem cell transplantation: incidence, natural history and treatment response.

Donor‐derived myelodysplastic syndrome/acute leukaemia (DD‐MDS/AL) is a rare life‐threatening complication of allogeneic haematopoietic stem cell (HSC) transplantation. However, it is unknown whether the risk differs by HSC source. Therefore, we evaluated the incidence of DD‐MDS/AL in 2390 engrafted patients. With a median follow‐up of 7·1 years (1–20·8), the incidence of DD‐MDS/AL was 0·53% (95% confidence interval (CI), 0·01–1·41%], 0·56% (95%CI, 0·01–1·36%) and 0·56% (95%CI, 0·01–1·10%) in recipients of bone marrow (n = 1117), peripheral blood (n = 489) and umbilical cord blood (UCB, n = 784), respectively. While follow‐up is shorter in recipients of UCB and peripheral blood, incidence of DD‐MDS/AL is, thus far, similar between HSC sources.

Recommendations for Screening and Management of Late Effects in Patients with Severe Combined Immunodeficiency after Allogenic Hematopoietic Cell Transplantation: A Consensus Statement from the Second Pediatric Blood and Marrow Transplant Consortium International Conference on Late Effects after Pediatric HCT

Severe combined immunodeficiency (SCID) is effectively treated with hematopoietic cell transplantation (HCT), with overall survival approaching 90% in contemporary reports. However, survivors are at risk for developing late complications because of the variable durability of high-quality immune function, underlying genotype of SCID, comorbidities due to infections in the pretransplantation and post-transplantation periods, and use of conditioning before transplantation. An international group of transplantation experts was convened in 2016 to review the current knowledge of late effects seen in SCID patients after HCT and to develop recommendations for screening and monitoring for late effects. This report provides recommendations for screening and management of pediatric and adult SCID patients treated with HCT.