Osteonecrosis (ON) is a debilitating long-term complication of allogenic bone marrow transplantation (alloBMT) but may begin before alloBMT in some children because of their primary disease treatment. Therefore, to estimate the prevalence and associated risk factors for ON before alloBMT, we conducted a retrospective analysis of magnetic resonance (MR) studies of 118 children who underwent first alloBMT at our institution between December 2000 and September 2007. Of the 118 consecutive patients, 107 (90.7%) underwent prospective MR studies irrespective of symptoms (69 males; median age at alloBMT 12.9 years), and 11 underwent MR studies for symptoms. Amongst the 107 who had prospective imaging, 23 (21.5%) had ON; nearly 50% had at least 30% epiphyseal involvement. Knees were more frequently involved than were hips; severity of ON was greater in hips. ON prevalence before alloBMT was 23.72% when all 118 patients were included in the denominator. Risk factor analysis, limited to MR studies performed irrespective of symptoms, revealed female gender (P = 0.049) and age ≥10 years at the time of MR study (P = 0.03) as significant risk factors and primary diagnosis of lymphoid malignancies and aplastic anemia trended towards significance. ON prior to alloBMT is a common occurrence in children.
Osteonecrosis; allogenic bone marrow transplantation; children; females; lymphoid malignancies; aplastic anemia
Allogeneic blood and marrow transplantation (alloBMT) remains the only curative treatment for patients with myelodysplastic syndromes (MDS), but its application has been limited by the older age range of patients with this disease. T cell depletion decreases transplant-related toxicity related to graft-versus-host disease (GVHD), but does not improve overall survival because of increased risk for relapse and graft failure. Myeloid growth factors have been used to speed engraftment following alloBMT, but data suggest that they may also have anti-tumor properties. We treated 43 patients (median age 56) with MDS/AML with high risk features using a myeloablative T cell depleted alloBMT followed by prolonged systemic GM-CSF. The current event-free survival at 1 and 3 years was 47% and 34% respectively with a median follow-up of 22.8 months in surviving patients. The toxicities compared favorably with those seen using reduced intensity conditioning regimens and included grade III/IV GVHD (10%), graft failure (9%), and cumulative treatment related mortality (28%). The cumulative incidence of relapse remained high at 38%; however, 3/10 patients receiving donor lymphocyte infusions achieved durable complete remissions. These results suggest that it is possible to maintain treatment intensity while minimizing toxicity in older, high-risk MDS patients.
allogeneic bone marrow transplantation; t cell depletion; myelodysplastic syndrome; acute myeloid leukemia; GM-CSF
The prognosis for childhood acute lymphoblastic leukemia (ALL) has improved dramatically over the past quarter of a century. Despite improvements in the treatment of childhood ALL, relapse still occurs in 20 to 30% of patients. While many of these relapses occur in the “standard-risk” patients, approximately 10% of these patients present at diagnosis with clinical and biological features that identify them as very high risk of relapse. Children (2 months-21 years) with at least one ultra-high-risk feature (UHRF) of ALL in first remission treated on a frontline Children’s Cancer Group (CCG) ALL study with a matched family allogeneic donor were eligible for study entry onto CCG-1921 and an allogeneic bone marrow transplant (AlloBMT). Each patient received fractionated total body irradiation (1200 cGy) and cyclophosphamide (120 mg/kg) conditioning therapy followed by unmobilized bone marrow from a matched family donor. Graft-versus-host disease (GVHD) prophylaxis consisted of methotrexate and cyclosporin. Twenty-nine patients with median age of 8.7 years with UHRF ALL in first complete remission (CR1) received an AlloBMT from a family member. The incidence of grade II–IV acute GVHD was 20.7% and the incidence of chronic GVHD was 3.7%. AlloBMT conditioning regimen was well tolerated and only one patient (3%) had treatment-related mortality. Ten patients (35%) died due to progressive disease. The 5-year event free survival (EFS) for all patients was 58.6% and patients without cytogenetic abnormalities had a 5-year EFS of 77.8%. The 5-year EFS for infants and non-infants was 20.0% and 66.7% (log Rank p=0.01), respectively. Patients with Philadelphia chromosome positive ALL had a 5-year EFS of 66.7%. The children with UHRF of ALL may benefit from AlloBMT in CR1, especially patients with primary induction failure and Philadelphia chromosome positive ALL. Randomized prospective cooperative group studies are required to establish the role of allogeneic hematopoietic stem cell transplantation vs intensive chemotherapy in children with UHRF ALL in CR1.
childhood acute lympoblastic leukemia; stem cell transplant; Philadelphia chromosome positive ALL; infantile ALL; induction failure
Allogeneic bone marrow transplantation (BMT) may offer the only chance of cure for children with acute myeloid leukemia (AML) in second complete remission (CR2) or with relapsed disease, but the outcome of these patients has not been clearly defined. We conducted a retrospective study of 58 children, median age 7.4 years (range 0.8–17.3), who received matched related or unrelated BMT at our institution for AML in CR2 (n = 12), in untreated first relapse (n = 11) or with refractory disease (n = 35), to identify risk factors associated with disease-free survival (DFS). Life threatening to fatal regimen-related toxicity was observed in 22% of patients. Estimates of DFS at 5 years (95% confidence interval) for patients in CR2, with untreated first relapse and refractory disease were 58% (27–80%), 36% (11–63%) and 9% (2–21%), respectively. Non-relapse mortality estimates were 0%, 27% (0–54%) and 17% (5–30%), and relapse estimates were 42% (14–70%), 36% (8–65%) and 74% (60–89%), respectively. Advanced disease phase and cytogenetic abnormalities at the time of transplantation were each associated with decreased DFS and increased relapse in multivariable regression models. Survival for children transplanted in CR2 or untreated first relapse is higher than that previously reported, but relapse remains the major cause of treatment failure regardless of disease stage.
acute myeloid leukemia; childhood leukemia
We describe the
response of imatinib as lifesaving treatment of
chronic myeloid leukemia (CML) relapse in seven
patients who underwent allogeneic bone marrow
transplantation (alloBMT) at our institution
over a period of 4 years. Retrospective analysis
of their medical records revealed that a mean age at
transplant was 45.2 years. The median time to
diagnosis was 7.4 years after transplant. At
relapse, four, two, and one patients were
classified as having hematologic, major
molecular, and cytogenetic relapse, respectively.
At imatinib initiation, five had CML in a
chronic phase, while one patient was
diagnosed as having accelerated phase and blast
crisis. All these patients could be evaluated
for the therapeutic efficacy. At a mean of
follow-up of 1.9 years of therapy, all evaluable
patients achieved major molecular response
without compromising safety. Consistent with
available data, our results indicate that
imatinib is safe and effective treatment option
for patients with relapse after
There is considerable variation in the use of HLA-matched related bone marrow transplantation (BMT) for the treatment of pediatric patients with newly diagnosed acute myeloid leukemia (AML). Some oncologists have argued that BMT should be offered to most patients in first complete remission (CR). Others have maintained that transplantation in first remission should be reserved for patients with high-risk disease. We performed this study to determine how disease risk influences the efficacy of BMT.
We combined data from four cooperative group clinical trials: Pediatric Oncology Group 8821, Children's Cancer Group (CCG) 2891, CCG 2961, and Medical Research Council 10. Using cytogenetics and the percentage of marrow blasts after the first course of chemotherapy, patients were stratified into favorable, intermediate, and poor-risk disease groups. Patients who could not be risk classified were analyzed separately. Outcomes for patients assigned to BMT and for patients assigned to chemotherapy alone were compared.
The data set included 1,373 pediatric patients with AML in first CR. In the intermediate-risk group, the estimated disease-free survival at 8 years for patients who did not undergo transplantation was 39% ± 5% (2 SE), whereas it was 58% ± 7% for BMT patients. The estimated overall survival for patients who did not undergo transplantation was 51% ± 5%, whereas it was 62% ± 7% for BMT patients. Both differences were significant (P < .01). There were no significant differences for survival in the other two risk groups or in the non–risk-stratified patients.
Our study indicates that HLA-matched related BMT is an effective treatment for pediatric patients with intermediate-risk AML in first CR.
In a retrospective study, we evaluated the cost and cost-effectiveness of allogeneic peripheral blood stem cell transplantation (PBSCT) (n=30) compared with bone marrow transplantation (BMT) (n=110) in children with acute leukemia at 1 year of follow up. Treatment success was defined as disease free survival at one year post transplant. For standard risk disease patients the treatment success rate was 57.1% for PBSCT patients and 80.3% for recipients of BMT (P=NS). The average total cost per treatment success at 1 year in the standard risk disease group was $512,294 for the PBSCT group and $352,885 for the BMT group (P=NS). For patients with high risk disease, the treatment success rate was 18.8% for PBSCT patients and 23.5% for BMT (P=NS). The cumulative average cost for patients in the BMT group was $457,078 compared to $377,316 for PBSCT (P=NS). Point estimates of the incremental cost-effectiveness ratio (ICER) indicate that allogeneic transplantation of bone marrow grafts is dominant over PBSCT for its lower costs and higher effectiveness in patients with standard risk disease (ICER = −$687,108; 95% CI = $2.4 million to dominated). For patients with high risk disease, BMT was more effective and more costly and the ICER was $1.69 million (95% CI = $29.7 million to dominated) per additional treatment success. The comparative economic evaluation provides support for BMT for standard risk patients, but a great degree of uncertainty limits the clear advantage for either treatment option in patients with high risk disease. Further research using larger and randomized controlled trials will be required to confirm the long term cost-effectiveness of each procedure.
children; acute leukemia; allogeneic stem cell transplantation
Graft-versus-host-disease (GVHD) is a severe and frequent complication of allogeneic bone marrow transplantation (BMT) that involves the gastrointestinal tract and lungs. The pathobiology of GVHD is complex and involves immune cell recognition of host antigens as foreign. We hypothesize a central role for the collectin surfactant protein A (SP-A) in regulating the development of GVHD after allogeneic BMT.
C57BL/6 (H2b; WT) and SP-A deficient mice on C57BL/6 background (H2b; SP-A−/−) mice underwent allogeneic (Allo) or syngeneic (Syn) BMT with cells from either C3HeB/FeJ (H2k; SP-A−/−alloBMT or WTalloBMT) or C57Bl/6 (H2b; SP-A−/−synBMT or WTsynBMT) mice. 5 weeks post BMT, mice were necropsied and lung and gastrointestinal (GI) tissue were analyzed.
SP-A−/−alloBMT or WTalloBMT had no significant differences in lung pathology however, SP-A−/−alloBMT mice developed marked features of GI GVHD including decreased body weight, increased tissue inflammation and lymphocytic infiltration. SP-A−/−alloBMT mice also had increased colon expression of IL-1β, IL-6, TNF-α, and IFN-γ and as well as increased Th17 cells, and diminished regulatory T (Treg) cells.
Our results demonstrate the first evidence of a critical role for SP-A in modulating GI GVHD. In these studies, we demonstrate that mice deficient in SP-A that have undergone an alloBMT have a greater incidence of GI GVHD that is associated with increased Th17 cells and decreased Tregs. The results of these studies demonstrate that SP-A protects against the development of GI GVHD and establishes a role for SP-A in regulating the immune response in the GI tract.
Graft-versus-host disease; Surfactant Protein A; Th17; Regulatory T cells
Questionnaires assessing a range of quality of life (QOL) outcomes were completed by 200 adult bone marrow transplant (BMT) recipients from five BMT treatment centres. Respondents had undergone allogeneic (46%) or autologous BMT (54%) for a haematological malignancy and were disease free and at least 12 months post BMT (mean 43 months). Variability in post-BMT QOL was reported with deficits in physical, sexual and occupational functioning particularly likely. Allogeneic recipients reported poorer QOL than autologous recipients. Greater age at BMT, lower level of education and more advanced disease at BMT were consistent risk factors for poorer QOL. Contrary to previous research, evidence for improved functional status with the passage of time post BMT was obtained. Factors generally not associated with post-BMT QOL included disease diagnosis, dose of total body irradiation, presence of chronic graft-versus-host disease (GVHD), type of GVHD prophylaxis and extent of marrow graft match. In conclusion, while many BMT recipients reported normal QOL, the majority indicated that their QOL was compromised relative to premorbid status. Prospective, longitudinal research will be necessary to further identify risk factors for poor post-BMT QOL and identify the temporal trajectory of post-BMT QOL.
Osteonecrosis (ON) is a critical complication in the treatment of childhood leukemia and lymphoma. It
particularly affects survivors of acute lymphoblastic leukemia and non-Hodgkin lymphoma reflecting the
cumulative exposure to glucocorticosteroid therapy. ON is often multiarticular and bilateral, specially
affecting weight-bearing joints. A conventional approach suggests a surgical intervention even if
pharmacological options have also recently been investigated. We reported two cases of long time steroid-treated patients who underwent Bone Marrow Transplantation (BMT) for hematological disease. Both
patients developed femoral head osteonecrosis (ON) that was diagnosed by magnetic resonance imaging
(MRI) and the ON was also accompanied with pain and a limp. Despite of the conventional strategies of
therapy, we successfully started a short-term treatment with bisphosphonates in order to decrease the pain
and the risk of fracture.
The optimal treatment of acute myeloid leukemia (AML) in first complete remission (CR1) is uncertain. Current consensus, based on cytogenetic risk, recommends myeloablative allogeneic stem cell transplantation (alloSCT) for poor-risk but not for good-risk AML. AlloSCT, autologous transplant and consolidation chemotherapy are considered of equivalent benefit for intermediate-risk AML. We undertook a systematic review and meta-analysis of prospective trials evaluating alloSCT versus non-alloSCT therapies for AML-CR1.
To quantify relapse-free survival (RFS) and overall survival (OS) benefit of alloSCT for AML in CR1. In subgroup analyses, RFS and OS benefit of alloSCT was determined for good-, intermediate- and poor-risk AML.
Combining the search terms: ‘allogeneic’; ‘acut*’ and ‘leukem*/leukaem*/leucem*/leucaem*/aml’; ‘myelo*’ or ‘nonlympho*’, we searched the PubMed, Embase and Cochrane Registry of Controlled Trials databases in March 2009. 1712 articles were accessed.
Prospective trials assigning adult AML-CR1 patients to alloSCT versus non-alloSCT treatment(s) based on donor availability, and reporting RFS and/or OS outcomes on intent-to-treat, donor versus no-donor basis were identified.
Two reviewers independently extracted study characteristics, interventions, and outcomes. Hazard ratios (HR) (with 95% CI) were determined.
24 trials and 6,007 patients were analyzed. Inter-study heterogeneity was not significant. Fixed effects meta-analysis was performed. HR of relapse or death with alloSCT for AML-CR1 was 0.80 (0.74–0.86). Significant RFS benefit of alloSCT was documented for poor-risk (HR 0.69 (0.57–0.84)) and intermediate-risk AML (HR 0.76 (0.68–0.85)); but not for good-risk AML (HR 1.06 (0.80–1.42)). HR of death with alloSCT for AML-CR1 was 0.90 (0.82–0.97). Significant OS benefit of alloSCT was documented for poor-risk (HR 0.73 (0.59–0.90)) and intermediate-risk AML (HR 0.83 (0.74–0.93)); but not for good-risk AML (HR 1.07 (0.83–1.38)).
AlloSCT has significant RFS and OS benefit for intermediate- and for poor-risk AML, but not for good-risk AML in CR1.
acute myeloid leukemia; allogeneic transplantation; meta-analysis
Refractory anemia with ringed sideroblasts (RARS) is an extremely rare type of myelodysplastic syndrome in children. We describe a 10-year-old boy with RARS presented with pancytopenia. He remained relatively stable with only a few transfusions until age of 20 years, when he underwent an allogeneic bone marrow transplantation (BMT) because of increased transfusion requirements. He remains in complete chimeric state at 20 months posttransplant with normal hematologic parameters. To our knowledge, this is the first description of successful BMT in a patient with childhood-onset RARS. The indication of BMT for this rare disorder in children is discussed.
The Children's Oncology Group Long-Term Follow-Up (COG-LTFU) Guidelines use consensus-based recommendations for exposure-driven, risk-based screening for early detection of long-term complications in childhood cancer survivors. However, the yield from these recommendations is not known.
Survivors underwent COG-LTFU Guideline–directed screening. Yield was classified as negligible/negative (< 1%), intermediate (≥ 1% to < 10%), or high (≥ 10%). For long-term complications with high yield, logistic regression was used to identify subgroups more likely to screen positive.
Over the course of 1,188 clinic visits, 370 childhood cancer survivors (53% male; 47% Hispanic; 69% leukemia/lymphoma survivors; median age at diagnosis, 11.1 years [range, 0.3 to 21.9 years]; time from diagnosis, 10.5 years [range, 5 to 55.8 years]) underwent 4,992 screening tests. High-yield tests included thyroid function (hypothyroidism, 10.1%), audiometry (hearing loss, 22.6%), dual-energy x-ray absorptiometry scans (low bone mineral density [BMD], 23.2%), serum ferritin (iron overload, 24.0%), and pulmonary function testing/chest x-ray (pulmonary dysfunction, 84.1%). Regression analysis failed to identify subgroups more likely to result in high screening yield, with the exception of low BMD (2.5-fold increased risk for males [P = .04]; 3.3-fold increased risk for nonobese survivors [P = .01]). Screening tests with negligible/negative (< 1%) yield included complete blood counts (therapy-related leukemia), dipstick urinalysis for proteinuria and serum blood urea nitrogen/creatinine (glomerular defects), microscopic urinalysis for hematuria (hemorrhagic cystitis, bladder cancer), ECG (anthracycline-related conduction disorder), and hepatitis B and HIV serology.
Screening tests with a high yield are appropriate for risk groups targeted for screening by the COG-LTFU Guidelines. Elimination of screening tests with negligible/negative yield should be given consideration.
Allogeneic bone marrow transplantation (BMT) has been associated with a graft-vs.-leukemia (GVL) reactivity. Since T cell depletion of the bone marrow graft has decreased the risk of graft-vs.-host disease (GVHD), but has been associated with higher rates of leukemia relapse, GVL reactivity is probably caused by donor-derived T lymphocytes. Previously, we demonstrated that minor histocompatibility (mH) antigen- specific cytotoxic T lymphocyte (CTL) clones, generated from patients after BMT, are capable of major histocompatibility complex-(MHC) restricted lysis of (clonogenic) myeloid leukemic cells. Here, we investigated whether donor-derived leukemia-specific CTL clones can be generated in vitro, before BMT, using irradiated leukemic cells from a patient with acute myeloid leukemia as stimulator cells, and peripheral blood or bone marrow from the HLA genotypically identical sibling donor as responder cells. Several CTL lines were generated that showed specific lysis (> 50%) of the recipient leukemic cells in a 51Cr- release assay. Two of these CTL lines were cloned by limiting dilution in the presence of the irradiated recipient cells. Multiple leukemia- reactive, HLA class I and II-restricted clones with various specificities could be established. These alloreactive, antileukemic CTL clones may cause GVL reactivity after BMT, and may be used as adjuvant immunotherapy in the treatment of leukemia.
The combination of allogeneic bone marrow transplantation (allo-BMT) and donor lymphocyte infusion (DLI) is a useful method for establishing donor chimerism and preventing a relapse of leukemia/lymphoma. However, there is a risk of inducing uncontrollable fatal graft-versus-host disease (GVHD). In fact, allo-BMT plus intravenous (IV)-DLI using donor splenocytes induces fatal GVHD in recipient mice. In this study, we examined the effects of the combination of intra-bone marrow (IBM)-BMT and the subcutaneous injection of donor splenocytes (SC-DLI) on the allo-BMT system. Recipient BALB/c mice were conditioned by sublethal irradiation (5 Gy), followed by IBM-BMT plus IV-DLI or SC-DLI in C57BL/6 mice. The IV-DLI group showed better engraftment of donor hemopoietic cells than the control group (without DLI) but showed fatal GVHD. The SC-DLI group, however, showed good reconstitution and mild GVHD. These results suggest that the combination of SC-DLI and IBM-BMT promotes the reconstitution of hemopoiesis and helps reduce the risk of GVHD.
Pneumothorax is very rare after early phase of hematopoietic stem cell transplantation (HSCT) and usually accompanied with pulmonary chronic graft-versus-host disease (GVHD), such as bronchiolitis obliterans and bronchiolitis obliterans organizing pneumonia. The present study describes the case of a seventeen-year-old male diagnosed with acute myeloid leukemia who underwent allogeneic bone marrow transplantation (BMT). Pneumothorax occurred at day 43 after BMT. Pneumothorax occurred in early phase of HSCT is extremely rare. The early onset of acute GVHD and the entity of cytomegalovirus might worsen the pulmonary tissue damages for the onset of pneumothorax, indicating that we should be aware of the possibility to occur pneumothorax even in the early period after allogeneic HSCT.
pneumothorax; air-leak syndrome; allogeneic hematopoietic stem cell transplantation
Unrelated donor (URD) BMT is an effective treatment for leukemia in children, but success is limited by graft versus host disease (GVHD) and relapse. In this study we describe the incidence and risk factors for GVHD over time in children receiving URD BMT. We analyzed outcomes of 638 myeloablative URD BMT performed between 1990 and 2003 for treatment of AML, ALL, CML or MDS, using the Center for International Blood & Marrow Transplant Research (CIBMTR) database. Recipients were <18 years of age, and had available high resolution HLA typing for HLA A, B, C and DRB1. Overall, 27% of recipients developed aGVHD grades III-IV and risk was significantly higher in recipients of T-replete compared with T-depleted grafts (OR 3.12, 95%CI 2.02-4.83; p< 0.0001). Acute GVHD significantly reduced risk of relapse in children with ALL (OR 0.34 95% CI 0.13-0.86, p=0.0052) but not AML (OR 0.58, 95% CI 0.22-2.98; p=0.26). Risk of aGVHD was higher in children transplanted in earlier years (1990-1998, n=365) compared to 1999-2003 (OR 1.93 95%CI 1.27-2.91; p=0.002). We conclude that outcomes have changed significantly over time, with reduced risk of aGVHD in more recent transplants.
Purpose of review
Administration of high-dose cyclophosphamide (Cy) after transplantation inhibits both graft rejection and graft-versus-host-disease (GvHD) in mouse models of allogeneic blood or marrow transplantation (alloBMT). This strategy has recently been adapted to human transplantation.
The safety and efficacy of high-dose post-transplantation Cy, when given in combination with tacrolimus and mycophenolate mofetil, was first demonstrated after nonmyeloablative conditioning and allografting using HLA-mismatched related donors. Further analysis shows that increasing HLA disparity does not worsen overall outcome. High-dose post-transplantation Cy was also found to be effective as sole prophylaxis of acute and chronic GvHD after HLA-matched alloBMT.
Taking advantage of the differential susceptibility of proliferating, alloreactive T cells over non-proliferating, non-alloreactive T cells to high dose Cy, and owing to the drug’s stem cell sparing effects, this novel strategy provides a unique opportunity to optimize GvHD prophylaxis after HLA-matched alloBMT and increase the use of HLA-mismatched related donors. Safe and effective mismatched related alloBMT provides access to essentially everyone, such as patients with sickle cell anemia, in need of the procedure.
graft-versus-host disease; allogeneic blood or marrow transplantation; posttransplantation cyclophosphamide; transplantation tolerance
Children with acute lymphoblastic leukemia (ALL) are often cured, but the therapies they receive may be neurotoxic. Little is known about the incidence and severity of late-occurring neurologic sequelae in ALL survivors. Data were analyzed to determine the incidence of adverse long-term neurologic outcomes and treatment-related risk factors.
Patients and Methods
We analyzed adverse neurologic outcomes that occurred after diagnosis in 4,151 adult survivors of childhood ALL who participated in the Childhood Cancer Survivor Study (CCSS), a retrospective cohort of 5-year survivors of childhood cancer diagnosed between 1970 and 1986. A randomly selected cohort of the survivors' siblings served as a comparison group. Self-reported auditory-vestibular-visual sensory deficits, focal neurologic dysfunction, seizures, and serious headaches were assessed.
The median age at outcome assessment was 20.2 years for survivors. The median follow-up time to death or last survey since ALL diagnosis was 14.1 years. Of the survivors, 64.5% received cranial radiation and 94% received intrathecal chemotherapy. Compared with the sibling cohort, survivors were at elevated risk for late-onset auditory-vestibular-visual sensory deficits (rate ratio [RR], 1.8; 95% CI, 1.5 to 2.2), coordination problems (RR, 4.1; 95% CI, 3.1 to 5.3), motor problems (RR, 5.0; 95% CI, 3.8 to 6.7), seizures (RR, 4.6; 95% CI, 3.4 to 6.2), and headaches (RR, 1.6; 95% CI, 1.4 to 1.7). In multivariable analysis, relapse was the most influential factor that increased risk of late neurologic complications.
Children treated with regimens that include cranial radiation for ALL and those who suffer a relapse are at increased risk for late-onset neurologic sequelae.
Purpose: Cancer in childhood may disrupt normal developmental processes and cause psychosocial problems in adolescent survivors of childhood cancers (ACCSs). Previous studies report inconsistent findings. Study aims were to assess subjective well-being (SWB), psychological distress, and school contentment in survivors of three dissimilar childhood cancers. Patients and methods: Nordic patients treated for acute myeloid leukemia (AML), infratentorial astrocytoma (IA), and Wilms tumor (WT) in childhood from 1985 to 2001, aged ≥1 year at diagnosis, and aged 13–18 years at the time of study were eligible for this questionnaire-based survey that included items on SWB, psychological distress, school contentment, self-esteem, and personality traits; 65% (151/231) responded. An age-equivalent group from a Norwegian health survey (n=7910) served as controls. Results: The median age of ACCSs was 16 years; 52% were males. ACCSs reported better SWB (p=0.004) and self-esteem (p<0.001). They had fewer social problems in school (p=0.004) and their school contentment tended to be higher than controls. SWB and school contentment were positively influenced by self-esteem. However, ACCSs reported higher levels of psychological distress (p=0.002), mostly attributable to general worrying. No significant differences in outcomes were found across diagnoses, and time since diagnosis did not significantly affect the results. Conclusion: The overall emotional functioning of ACCSs was good, possibly due to changes in their perception of well-being after having survived a life-threatening disease. However, they seemed more worried than their peers. This may cause an additional strain at a vulnerable period in life.
We examined substance use onset and associations with pregnancy by age 15 years. Participants were girls ages 15 years or younger (weighted n = 8319) from the 1999–2003 Youth Risk Behavior Surveillance System (YRBS). Multivariable logistic regression examined pregnancy as a function of substance use onset (i.e., age 10 years or younger, 11–12, 13–14, and age 15 years) for alcohol, cigarettes and marijuana, controlling for race/ethnicity and metropolitan location. Of girls pregnant by age 15 years (3% of the sample, weighted n = 243), 16% had smoked marijuana by age 10 years and over 20% had smoked cigarettes and initiated alcohol use by age 10 years. In the multivariable analysis, marijuana use by age 14 years and/or cigarette smoking by age 12 years clearly distinguished girls who became pregnant by age 15 years and is perhaps due to a common underlying risk factor.
Teenage pregnancy; Adolescent risk behaviors; Sexual intercourse; Substance use
Leukemia is the most common childhood cancer. With the exception of Down syndrome, prenatal radiation exposure, and higher birth weight, particularly for acute lymphoid leukemia (ALL), few risk factors have been firmly established. Translocations present in neonatal blood spots and the young age peak of diagnosis suggest that early-life factors are involved in childhood leukemia etiology.
We investigated the association between birth characteristics and childhood leukemia through linkage of the Minnesota birth and cancer registries using a case-cohort study design. Cases included 560 children with ALL and 87 with acute myeloid leukemia (AML) diagnoses from 28 days to 14 years. The comparison group was comprised of 8,750 individuals selected through random sampling of the birth cohort from 1976–2004. Cox proportional hazards regression specific for case-cohort studies was used to compute hazard ratios (HR) and 95% confidence intervals (CIs).
Male sex (HR = 1.41, 95% CI 1.16–1.70), white race (HR = 2.32, 95% CI 1.13–4.76), and maternal birth interval ≥ 3 years (HR = 1.31, 95% CI 1.01–1.70) increased ALL risk, while maternal age increased AML risk (HR = 1.21/5 year age increase, 95% CI 1.0–1.47). Higher birth weights (>3798 grams) (HRALL = 1.46, 1.08–1.98; HRAML = 1.97, 95% CI 1.07–3.65), and one minute Apgar scores ≤ 7 (HRALL = 1.30, 95% CI 1.05–1.61; HRAML = 1.62, 95% CI 1.01–2.60) increased risk for both types of leukemia. Sex was not a significant modifier of the association between ALL and other covariates, with the exception of maternal education.
We confirmed known risk factors for ALL: male sex, high birth weight, and white race. We have also provided data that supports an increased risk for AML following higher birth weights, and demonstrated an association with low Apgar scores.
Veno-occlusive disease (VOD) of the liver is a clinical syndrome characterized by hyperbilirubinemia, painful hepatomegaly, and fluid retention. In the bone marrow transplantation (BMT) setting, VOD is caused by dose-intensive chemotherapy and/or radiotherapy used to prepare patients for transplant. VOD occurs in up to 50% of the patients who undergo BMT and is usually associated with a high mortality rate. Until recently, there was no proven effective medical therapy for this condition once it was clinically apparent. We report here on the frequency and treatment result of VOD with rt-PA in our allogeneic BMT patients. Eight patients (median age 28.5 years) underwent allogeneic BMT from December, 1993 to June, 1995 in Asan Medical Center. Six leukemia patients were prepared for BMT with busulfan and cyclophosphmide, while two aplastic anemia patients received cyclophosphamide and antithymocyte globulin. VOD was defined as having two of the following features before day 20 posttransplant: jaundice (bilirubin > or = 2 mg/dL), tender hepatomegaly and/or right upper quadrant pain, ascites and/or unexplained weight gain (> 2% from baseline). All patients who were diagnosed with VOD received rt-PA (10-20 mg/day) and heparin (10,000 U/day). Three (37.5%) of the eight patients developed VOD that occurred between 6 and 10 days posttransplant. All three patients developed jaundice, weight gain, and tender hepatomegaly. Ascites and renal insufficiency occurred in two patients and pleural effusion in one patient. rt-PA and heparin were begun 6 to 26 days posttransplant and rt-PA was administered for 7 to 14 days. All three patients responded to the therapy; bilirubin levels began to decrease at 4 to 13 days from the start of therapy. They are all alive at day 111, 316, and 548 days posttransplant. None of the patients had significant hemorrhagic complications after rt-PA treatment. Prolonged administration of rt-PA was feasible without bleeding episode and it seems that rt-PA may alter the natural course of VOD.
To determine risk factors associated with reduced adult height in survivors of childhood acute lymphoblastic leukemia (ALL).
Cross-sectional study. Attained adult height was determined among 2,434 ALL survivors participating in the Childhood Cancer Survivor Study, a cohort of five-year survivors of common pediatric cancers diagnosed from 1970–1986, and compared with 3,009 siblings.
All survivor treatment exposure groups (chemotherapy alone, chemotherapy with cranial or craniospinal radiotherapy) had decreased adult heights and an increased risk of adult short stature (height standard deviation score < −2) compared with siblings (p<0.001). Compared with siblings, the risk of short stature for survivors treated with chemotherapy alone was elevated (OR 3.4, 95% CI 1.9, 6.0). Among survivors, significant risk factors for short stature included diagnosis of ALL prior to puberty, higher dose cranial radiotherapy (≥20 Gy versus <20 Gy), any radiotherapy to the spine, and female sex.
Survivors of childhood ALL are at increased risk of adult short stature, including those treated with chemotherapy alone. Risk is highest for those treated with cranial and craniospinal radiotherapy at a young age.
chemotherapy; epidemiology; growth deficiency; late effects; radiation; survivorship
To determine the risk of thyroid dysfunction and subsequent thyroid cancer among childhood acute lymphoblastic leukemia (ALL) survivors.
Rates of self-reported thyroid dysfunction and thyroid cancer were determined among 3,579 ALL survivors participating in the Childhood Cancer Survivor Study, a cohort of 5-year survivors of pediatric cancers diagnosed from 1970–1986, and compared with 3,846 siblings and population rates, respectively.
The cumulative incidence of hypo- and hyperthyroidism among survivors 15 years following leukemia diagnosis was 1.6% (95% CI 1.1, 2.1) and 0.6% (95% CI 0.3, 1.1), respectively, both significantly increased compared with siblings. In multivariate analysis, survivors who received ≥20 Gy cranial radiotherapy plus any spinal radiotherapy had the highest risk of subsequent hypothyroidism (HR 8.3, 95% CI 3.3, 20.5) compared with those treated with chemotherapy alone. Craniospinal radiotherapy also was associated with an increased risk of subsequent hyperthyroidism (HR 6.1, 95% CI 1.1, 34.2) compared with chemotherapy alone, as well as an increased risk of subsequent thyroid cancers (SIR 30.3, 95% CI 14.5, 55.7) compared with population rates. In radiation dosimetry analysis, pituitary doses ≥20 Gy combined with thyroid doses ≥10 Gy were associated with hypothyroidism, whereas pituitary doses ≥20 Gy combined with thyroid doses ≥15 Gy were associated with hyperthyroidism.
The risk of thyroid dysfunction and thyroid cancer was increased among childhood ALL survivors treated with craniospinal radiotherapy. In these individuals, long-term surveillance is warranted as no obvious plateau in risk was seen, even after 25 years of follow-up.
late effects; leukemia; radiation; hypothyroidism; hyperthyroidism; thyroid cancer