Solid organ transplantation after treatment for childhood cancer: a retrospective cohort analysis from the Childhood Cancer Survivor Study.

BACKGROUND: Serious chronic medical conditions occur in childhood cancer survivors. We aimed to investigate incidence of and risk factors for end-organ damage resulting in registration on a waiting list for or receiving a solid organ transplantation and 5-year survival following these procedures. METHODS: The Childhood Cancer Survivor Study (CCSS) is a retrospective cohort of individuals who survived at least 5 years after childhood cancer diagnosed at younger than 21 years of age, between Jan 1, 1970, and Dec 31, 1986, at one of 25 institutions in the USA. We linked data from CCSS participants treated in the USA diagnosed between Jan 1, 1970, and Dec 31, 1986 (without solid organ transplantation before cohort entry) to the Organ Procurement and Transplantation Network-a database of all US organ transplants. Eligible participants had been diagnosed with leukaemia, lymphoma, malignant CNS tumours, neuroblastoma, Wilms' tumours, and bone and soft tissue sarcomas. The two primary endpoints for each type of organ transplant were date of first registration of a transplant candidate on the waiting list for an organ and the date of the first transplant received. We also calculated the cumulative incidence of being placed on a waiting list or receiving a solid organ transplantation, hazard ratios (HRs) for identified risk factors, and 5-year survival following transplantation. FINDINGS: Of 13 318 eligible survivors, 100 had 103 solid organ transplantations (50 kidney, 37 heart, nine liver, seven lung) and 67 were registered on a waiting list without receiving a transplant (21 kidney, 25 heart, 15 liver, six lung). At 35 years after cancer diagnosis, the cumulative incidence of transplantation or being on a waiting list was 0·54% (95% CI 0·40-0·67) for kidney transplantation, 0·49% (0·36-0·62) for heart, 0·19% (0·10-0·27) for liver, and 0·10% (0·04-0·16) for lung. Risk factors for kidney transplantation were unilateral nephrectomy (HR 4·2, 95% CI 2·3-7·7), ifosfamide (24·9, 7·4-83·5), total body irradiation (6·9, 2·3-21·1), and mean kidney radiation of greater than 15 Gy (>15-20 Gy, 3·6 [1·5-8·5]; >20 Gy 4·6 [1·1-19·6]); for heart transplantation, anthracycline and mean heart radiation of greater than 20 Gy (dose-dependent, both p<0·0001); for liver transplantation, dactinomycin (3·8, 1·3-11·3) and methotrexate (3·3, 1·0-10·2); for lung transplantation, carmustine (12·3, 3·1-48·9) and mean lung radiation of greater than 10 Gy (15·6, 2·6-92·7). 5-year overall survival after solid organ transplantation was 93·5% (95% CI 81·0-97·9) for kidney transplantation, 80·6% (63·6-90·3) for heart, 27·8% (4·4-59·1) for liver, and 34·3% (4·8-68·6) for lung. INTERPRETATION: Solid organ transplantation is uncommon in ageing childhood cancer survivors. Organ-specific exposures were associated with increased solid organ transplantation incidence. Survival outcomes showed that solid organ transplantation should be considered for 5-year childhood cancer survivors with severe end-organ failure. FUNDING: US National Institute of Health, American Lebanese Syrian Associated Charities, US Health Resources and Services Administration.

Advances in cellular and humoral immunotherapy - implications for the treatment of poor risk childhood, adolescent, and young adult B-cell non-Hodgkin lymphoma.

Patients with relapsed, refractory or advanced stage B non-Hodgkin lymphoma (NHL) continue to have a dismal prognosis. This review summarises current and novel cellular and immunotherapy for these high-risk populations, including haematopoietic stem cell transplant, bispecific antibodies, viral-derived cytotoxic T cells, chimeric antigen receptor (CAR) T cells, and natural killer (NK) cell therapy, as discussed at the 6th International Symposium on Childhood, Adolescent and Young Adult Non-Hodgkin Lymphoma on September 26th-29th 2018 in Rotterdam, the Netherlands, and explores the future of NK/CAR NK therapies.

Comparison of self-report and electronic monitoring of 6MP intake in childhood ALL: a Children's Oncology Group study.

Adequate exposure to oral 6-mercaptopurine (6MP) during maintenance therapy for childhood acute lymphoblastic leukemia (ALL) is critical for sustaining durable remissions; accuracy of self-reported 6MP intake is unknown. We aimed to directly compare self-report to electronic monitoring (Medication Event Monitoring System [MEMS]) and identify predictors of overreporting in a cohort of 416 children with ALL in first remission over 4 study months (1344 patient-months for the cohort) during maintenance therapy. Patients were classified as "perfect reporters" (self-report agreed with MEMS), "overreporters" (self-report was higher than MEMS by ≥5 days/month for ≥50% of study months), and "others" (not meeting criteria for perfect reporter or overreporter). Multivariable logistic regression examined sociodemographic and clinical characteristics, 6MP dose intensity, TPMT genotype, thioguanine nucleotide levels, and 6MP nonadherence (MEMS-based adherence <95%) associated with the overreporter phenotype; generalized estimating equations compared 6MP intake by self-report and MEMS. Self-reported 6MP intake exceeded MEMS at least some of the time in 84% of patients. Fifty patients (12%) were classified as perfect reporters, 98 (23.6%) as overreporters, 2 (0.5%) as underreporters, and 266 (63.9%) as others. In multivariable analysis, the following variables were associated with the overreporter phenotype: non-white race: Hispanic, odds ratio (OR), 2.4, P = .02; Asian, OR, 3.1, P = .02; African American, P < .001; paternal education less than college (OR, 1.4, P = .05); and 6MP nonadherence (OR, 9.4, P < .001). Self-report of 6MP intake in childhood ALL overestimates true intake, particularly in nonadherent patients, and should be used with caution.

Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure.

Hepatic veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). Untreated hepatic VOD/SOS with multi-organ failure (MOF) is associated with >80% mortality. Defibrotide has shown promising efficacy treating hepatic VOD/SOS with MOF in phase 2 studies. This phase 3 study investigated safety and efficacy of defibrotide in patients with established hepatic VOD/SOS and advanced MOF. Patients (n = 102) given defibrotide 25 mg/kg per day were compared with 32 historical controls identified out of 6867 medical charts of HSCT patients by blinded independent reviewers. Baseline characteristics between groups were well balanced. The primary endpoint was survival at day +100 post-HSCT; observed rates equaled 38.2% in the defibrotide group and 25% in the controls (23% estimated difference; 95.1% confidence interval [CI], 5.2-40.8;P= .0109, using a propensity-adjusted analysis). Observed day +100 complete response (CR) rates equaled 25.5% for defibrotide and 12.5% for controls (19% difference using similar methodology; 95.1% CI, 3.5-34.6;P= .0160). Defibrotide was generally well tolerated with manageable toxicity. Related adverse events (AEs) included hemorrhage or hypotension; incidence of common hemorrhagic AEs (including pulmonary alveolar [11.8% and 15.6%] and gastrointestinal bleeding [7.8% and 9.4%]) was similar between the defibrotide and control groups, respectively. Defibrotide was associated with significant improvement in day +100 survival and CR rate. The historical-control methodology offers a novel, meaningful approach for phase 3 evaluation of orphan diseases associated with high mortality. This trial was registered at www.clinicaltrials.gov as #.

Genomic characterization of pediatric B-lymphoblastic lymphoma and B-lymphoblastic leukemia using formalin-fixed tissues.

BACKGROUND: Recurrent genomic changes in B-lymphoblastic leukemia (B-ALL) identified by genome-wide single-nucleotide polymorphism (SNP) microarray analysis provide important prognostic information, but gene copy number analysis of its rare lymphoma counterpart, B-lymphoblastic lymphoma (B-LBL), is limited by the low incidence and lack of fresh tissue for genomic testing. PROCEDURE: We used molecular inversion probe (MIP) technology to analyze and compare copy number alterations (CNAs) in archival formalin-fixed paraffin-embedded pediatric B-LBL (n = 23) and B-ALL (n = 55). RESULTS: Similar to B-ALL, CDKN2A/B deletions were the most common alteration identified in 6/23 (26%) B-LBL cases. Eleven of 23 (48%) B-LBL patients were hyperdiploid, but none showed triple trisomies (chromosomes 4, 10, and 17) characteristic of B-ALL. IKZF1 and PAX5 deletions were observed in 13 and 17% of B-LBL, respectively, which was similar to the reported frequency in B-ALL. Immunoglobulin light chain lambda (IGL) locus deletions consistent with normal light chain rearrangement were observed in 5/23 (22%) B-LBL cases, compared with only 1% in B-ALL samples. None of the B-LBL cases showed abnormal, isolated VPREB1 deletion adjacent to IGL locus, which we identified in 25% of B-ALL. CONCLUSIONS: Our study demonstrates that the copy number profile of B-LBL is distinct from B-ALL, suggesting possible differences in pathogenesis between these closely related diseases.

Natural killer/T-cell lymphomas in pediatric and adolescent patients.

Natural killer/T-cell (NK/T-cell) lymphomas are rare in children and adolescents and consist predominantly of nasal-type extranodal NK/T-cell lymphomas. More than half of pediatric/adolescent patients with NK/T-cell lymphomas present with localized nasal/sinus involvement, but the disease may involve many organs. NK/T-cell lymphoma cells are cytotoxic and associated with necrosis and angioinvasion; they express CD56, CD2, cytoplasmic CD3 epsilon, and to a variable degree CD30. The cells contain Epstein-Barr virus (EBV)-encoded RNA. Loss of chromosome 6q is frequent, and multiple other genetic changes may occur. The Janus kinase/signal transducers and activators of transcription (JAK/STAT) and other pathways are activated in NK/T-cell lymphoma. Adults with stage I/II disease receive radiation with or without chemotherapy, whereas adults with advanced disease receive multiagent chemotherapy, including asparaginase and drugs not affected by P-glycoprotein-mediated resistance. Outcomes data for pediatric patients come from retrospective reviews and retrospective case series. The overall survival of pediatric patients is 77% for those with stage I/II disease and 36% to 59% for those with advanced disease. Bone marrow transplant (BMT) is used in children, but with little evidence regarding the indications and rationale for type of transplant. BMT achieves better outcomes for adult patients in remission, but with high levels of morbidity and mortality. Improved understanding of the biology of this disease will allow the development of targeted approaches, including JAK/STAT inhibitors, checkpoint inhibitors, anti-CD30 agents, epigenetic modifiers, and reduced-intensity conditioning for BMT, to improve outcomes in pediatric patients.

Rare Pediatric Non-Hodgkin Lymphomas: A Report From Children's Oncology Group Study ANHL 04B1.

BACKGROUND: Non-Hodgkin lymphoma (NHL) is a relatively common malignancy in pediatric patients; however, a small subgroup have unusual lymphoma subtypes for the pediatric population. PROCEDURE: The Children's Oncology Group Rare and Cutaneous NHL registry's (protocol ANHL 04B1) main objectives were to determine the pathologic, biologic, and clinical features of rare and cutaneous pediatric NHL and establish a bank of centrally reviewed tissue specimens. We report the clinical data, treatment data, and outcome for rare pediatric NHL. RESULTS: In 101 lymphomas, there is a 97.8% concordance between the reviewing study pathologists and an 87.6% concordance between the central and institutional pathology review. Samples in the specimen bank include primary tumor tissue that is snap frozen, in paraffin blocks, or H&E-stained and unstained paraffin slides as well as blood, serum, and bone marrow. This descriptive analysis shows that children with pediatric follicular lymphoma, mucosa-associated lymphoid tissue, nodal marginal zone lymphoma, primary cutaneous, primary central nervous system lymphoma, and subcutaneous panniculitis-like T-cell lymphomas have 100% survival at a median of 2 years from enrollment. There are early deaths, mostly from progressive disease, in subjects with peripheral T-cell (not otherwise specified), NKT, and hepatosplenic T-cell lymphomas. CONCLUSIONS: This registry provides high-quality biologic specimens with clinical data to investigators working on the biology of these unusual pediatric diseases.

The importance of assessing priorities of reproductive health concerns among adolescent and young adult patients with cancer.

Visions for the future are a normal developmental process for adolescents and young adults (AYAs) with and without cancer, and these visions often include expectations of sexual and romantic relationships. AYA cancer survivors indicate reproductive health is an issue of great importance and more attention is needed in the health care setting throughout the cancer experience, beginning at diagnosis. Various practice guidelines are predominately focused on fertility; are intended to influence survivorship care plans; and do not encompass the broad scope of reproductive health that includes romantic partnering, friendships, body image, sexuality, sexual identity, fertility, contraception, and more. Although interventions to reduce reproductive health-related sequelae from treatment are best approached as an evolving process, practitioners are not certain of the priorities of these various reproductive health content areas. Strategies incongruent with the reproductive health priorities of AYAs will likely thwart adequate follow-up care and foster feelings of isolation from the treatment team. Research is needed to identify these priorities and ensure discussions of diverse content areas. This review explored various domains of reproductive health and emphasized how understanding the priorities of the AYA cancer cohort will guide future models of care.

Disseminated lymphoblastic lymphoma in children and adolescents: results of the COG A5971 trial: a report from the Children's Oncology Group.

The Children's Oncology Group's A5971 trial examined central nervous system (CNS) prophylaxis and early intensification in paediatric patients diagnosed with CNS-negative Stage III and IV lymphoblastic lymphoma. Using a 2 × 2 factorial design, the study randomized patients to Children's Cancer Group (CCG) modified Berlin-Frankfurt-Muenster (BFM) acute lymphoblastic leukaemia (ALL) regimen with intensified intrathecal (IT) methotrexate (MTX) (Arm A1) or an adapted non-Hodgkin lymphoma/BFM-95 therapy with high dose MTX in interim maintenance but no IT-MTX in maintenance (Arm B1). Each cohort was randomized ± intensification (cyclophosphamide/anthracycline) (Arms A2/B2). For the 254 randomized patients, there was no difference in 5-year event-free survival (EFS) for the four arms: Arm A1, 80% [95% confidence interval (CI) 67-89%] and Arm A2, 81% (95% CI 69-89%); Arm B1, 80% (95% CI 68-88%) and Arm B2, 84% (95% CI 72-91%). The cumulative incidence of CNS relapse was 1·2%. Age <10 years and institutional imaging response at 2 weeks was associated with improved outcomes (P < 0·001 and P = 0·014 for overall survival). CNS positive patients (n = 12) did poorly [5-year EFS of 63% (95% CI 29-85%)]. For CNS-negative patients, there was no difference in outcome based on CNS prophylaxis (IT-MTX versus HD-MTX) or with intensification.

Late Health Outcomes Among Survivors of Wilms Tumor Diagnosed Over Three Decades: A Report From the Childhood Cancer Survivor Study.

PURPOSE: To evaluate long-term morbidity and mortality among unilateral, nonsyndromic Wilms tumor (WT) survivors according to conventional treatment regimens. METHODS: Cumulative incidence of late mortality (≥ 5 years from diagnosis) and chronic health conditions (CHCs) were evaluated in WT survivors from the Childhood Cancer Survivor Study. Outcomes were evaluated by treatment, including nephrectomy combined with vincristine and actinomycin D (VA), VA + doxorubicin + abdominal radiotherapy (VAD + ART), VAD + ART + whole lung radiotherapy, or receipt of ≥ 4 chemotherapy agents. RESULTS: Among 2,008 unilateral WT survivors, 142 deaths occurred (standardized mortality ratio, 2.9, 95% CI, 2.5 to 3.5; 35-year cumulative incidence of death, 7.8%, 95% CI, 6.3 to 9.2). The 35-year cumulative incidence of any grade 3-5 CHC was 34.1% (95% CI, 30.7 to 37.5; rate ratio [RR] compared with siblings 3.0, 95% CI, 2.6 to 3.5). Survivors treated with VA alone had comparable risk for all-cause late mortality relative to the general population (standardized mortality ratio, 1.0; 95% CI, 0.5 to 1.7) and modestly increased risk for grade 3-5 CHCs compared with siblings (RR, 1.5; 95% CI, 1.1 to 2.0), but remained at increased risk for intestinal obstruction (RR, 9.4; 95% CI, 3.9 to 22.2) and kidney failure (RR, 11.9; 95% CI, 4.2 to 33.6). Magnitudes of risk for grade 3-5 CHCs, including intestinal obstruction, kidney failure, premature ovarian insufficiency, and heart failure, increased by treatment group intensity. CONCLUSION: With approximately 40% of patients with newly diagnosed WT currently treated with VA alone, the burden of late mortality/morbidity in future decades is projected to be lower than that for survivors from earlier eras. Nevertheless, the risk of late effects such as intestinal obstruction and kidney failure was elevated across all treatment groups, and there was a dose-dependent increase in risk for all grade 3-5 CHCs by treatment group intensity.

Levetiracetam for busulfan-induced seizure prophylaxis in children undergoing hematopoietic stem cell transplantation.

Anti-seizure prophylaxis is routinely utilized during busulfan administration for HSCT. We evaluated the feasibility and efficacy of levetiracetam in children undergoing HSCT. A total of 28 children and young adults received levetiracetam during HSCT and the outcomes and costs were compared to a historical, but similar cohort of 25 patients who had received fosphenytoin. Levetiracetam was well tolerated and was efficacious in preventing seizures. Cost of drug, administration, and monitoring were also similar among the two groups. Due to non-induction of the hepatic cytochrome P450 enzymes, levetiracetam may lead to better dose assurance of busulfan in targeted dose regimens for HSCT.

Outcome of newly diagnosed children and adolescents with localized lymphoblastic lymphoma treated on Children's Oncology Group trial A5971: a report from the Children's Oncology Group.

BACKGROUND: Localized lymphoblastic lymphoma (LL) is rare in pediatric patients. We report the 5-year event-free survival (EFS) and overall survival (OS) for children and adolescents with localized LL treated on a uniform regimen based on Children's Cancer Group (CCG) leukemia therapy (COG A5971). PROCEDURE: From June 2000 to October 2005, the study enrolled 60 patients >12 months old with Murphy stages I or II LL. Central review confirmed 56 eligible patients. Treatment consisted of 24 months of CCG BFM without day 28 intrathecal methotrexate in maintenance therapy or prophylactic cranial radiation. RESULTS: Most patients had pre-B immunophenotype (75%). At a median follow-up of 5.9 years (range 1.4-9.3 years), the 5-year EFS was 90% [95% confidence interval (CI), 78-96%] and the 5-year OS was 96% (95% CI, 84-99%). Stage (I vs. II), immunophenotype, elevated LDH > institutional normal, or primary site did not impact outcome. Five relapses occurred-none in the CNS and none in patients with pre-T lymphoblastic disease. Patients tolerated treatment well with no toxic deaths. CONCLUSION: Outcomes of pediatric patients with localized LL treated with 2 years of intensive acute lymphoblastic leukemia (ALL)-type therapy was excellent and is similar to the outcome for standard risk ALL treated less intensively. CNS prophylaxis was adequate with limited intrathecal methotrexate and no radiation. Future studies should identify biologic prognostic factors or biomarkers for pediatric patients with LL, explore less intensive treatment for patients with localized disease, and explore novel immunophenotype directed therapies.

Gender Distribution of Authors of Evaluation Letters for Promotion at One Medical School.

PURPOSE: Women remain underrepresented in key leadership positions and advanced ranks in academic medicine. This study examines the numbers of men and women letter writers for promotion candidates during a 5-year period across departments, tracks, ranks, and candidate gender. METHOD: A descriptive study characterized the gender of evaluation letter writers for candidates for promotion to associate or full professor at the University of Minnesota Medical School between 2015 and 2020. Letter writer and candidate gender were characterized by self-identified pronouns in the faculty biography or dossier. Letter writer gender was described by candidate department, promotion track, rank, terminal degree, and gender. RESULTS: Among 299 candidates for promotion, 172 (58%) were men and 127 (42%) were women; dossiers included 3,995 evaluation letters. Across all years, men wrote more letters than women (external letters, range, 69% in 2019-2020 to 75% in 2015-2016; internal letters, range, 67% in 2018-2019 to 77% in 2015-2016). Candidates in the family medicine and pediatrics departments had the highest percentages of letters written by women (44% and 40%, respectively). No differences were found in the number of women letter writers by candidate promotion track; however, differences were found by candidate rank (associate professor, 30%; full professor, 23%) and terminal degree (MD/DO, 25%; PhD, 33%; MD-PhD, 20%). Regardless of candidate gender, most evaluation letters were written by men. Women candidates had 15% to 20% more letters authored by women than men candidates (34%-40% vs 18%-23%). CONCLUSIONS: The gender pattern of letter writers may reflect implicit biases regarding gender and perceived leadership status, expertise, and success. Adopting policies that promote or require gender diversity among letter writers for promotion candidates may provide an opportunity to encourage faculty to seek diverse networks and recognize the achievements of women faculty.

Autologous peripheral blood stem cell transplantation in children with refractory or relapsed lymphoma: results of Children's Oncology Group study A5962.

This prospective study was designed to determine the safety and efficacy of cyclophosphamide, BCNU, and etoposide (CBV) conditioning and autologous peripheral blood stem cell transplant (PBSCT) in children with relapsed or refractory Hodgkin and non-Hodgkin lymphoma (HL and NHL). Patients achieving complete remission (CR) or partial remission (PR) after 2 to 4 courses of reinduction underwent a granulocyte-colony stimulating factor (G-CSF) mobilized PBSC apheresis with a target collection dose of 5 × 106 CD34(+)/kg. Those eligible to proceed received autologous PBSCT after CBV (7200 mg/m², 450-300 mg/m², 2400 mg/m²). Forty-three of 69 patients (30/39 HL, 13/30 NHL) achieved a CR/PR after reinduction. Thirty-eight patients (28 HL, 10 NHL) underwent PBSCT. All initial 6 patients who received BCNU at 450 mg/m² experienced grade III or IV pulmonary toxicity compared to none of the subsequent 32 receiving 300 mg/m² (P < .0001). The probability of overall survival (OS) at 3 years for all patients is 51% and for transplanted patients is 64%. The 3-year event-free survival (EFS) is 38% (45% for HL; 30% NHL). The 3-year EFS in transplanted patients is 66% (65% HL; 70% NHL). Initial duration of remission of ≥12 versus <12 months was associated with a significant increase in OS (3 years OS 70% versus 34%) (P = .003). BCNU at 300 mg/m(2) in a CBV regimen prior to PBSCT is well tolerated in relapsed or refractory pediatric lymphoma patients. A short duration (<12 months) of initial remission is associated with a poorer prognosis. Last, a high percentage of patients achieving a CR/PR after reinduction therapy can be salvaged with CBV and autologlous PBSCT.

Venous thromboembolism and adolescent and young adult oncology inpatients in US children's hospitals, 2001 to 2008.

OBJECTIVES: To determine the frequency of venous thromboembolism (VTE) in the adolescent and young adult oncology population and the effects of age and cancer type on VTE, and to characterize adolescent and young adult oncology admissions at US children's hospitals. STUDY DESIGN: We extracted data on oncology patients 15 to 24 years of age who were discharged from 35 hospitals in the Pediatric Hospital Information System (PHIS) between 2001 and 2008. RESULTS: Of 9721 unique patients, VTE occurred in 511 (5.3%). An elevated OR of VTE occurred in patients 18 to 20 and 21 to 24 years of age (OR, 1.65; 95% CI, 1.36-2.00 and OR, 1.67; 95% CI, 1.21-2.32, respectively) compared with that in patients 15 to 17 years old. Patients with leukemia (OR, 5.53; 95% CI, 3.63-8.42) and bone/soft tissue sarcomas (OR, 4.32; 95% CI, 2.80-6.69) had a higher risk of VTE compared with patients with brain tumors. The number of adolescent and young adult oncology admissions to pediatric hospitals increased 31.9%, from 5409 admissions in 2001 to 7134 admissions in 2008. CONCLUSIONS: Adolescent and young adult oncology patients, a growing population at pediatric hospitals, experience VTE as a common complication. Pediatricians should implement adolescent and young adult-specific studies to develop a standardized approach to preventing this adverse event.

Twenty-five year follow-up of childhood Wilms tumor: a report from the Childhood Cancer Survivor Study.

BACKGROUND: Treatment cures over 90% of children with Wilms tumor (WT) who subsequently risk late morbidity and mortality. This study describes the 25-year outcomes of 5-year WT survivors in the Childhood Cancer Survivor Study (CCSS). PROCEDURE: The CCSS, a multi-institutional retrospective cohort study, assessed WT survivors (N = 1,256), diagnosed 1970-1986, for chronic health conditions, health status, health care utilization, socioeconomic status, subsequent malignant neoplasms (SMNs), and mortality compared to the US population and a sibling cohort (N = 4,023). RESULTS: The cumulative incidence of all and severe chronic health conditions was 65.4% and 24.2% at 25 years. Hazard ratios (HR) were 2.0, 95% confidence interval (CI) 1.8-2.3 for grades 1-4 and 4.7, 95%CI 3.6-6.1 for grades 3 and 4, compared to sibling group. WT survivors reported more adverse general health status than the sibling group (prevalence ratio [PR] 1.7; 95%CI 1.2-2.4), but mental health status, socioeconomic outcome, and health care utilization were similar. The cumulative incidence of SMN was 3.0% (95%CI 1.9-4.0%) and of mortality was 6.1% (95%CI 4.7-7.4%). Radiation exposure increased the likelihood of congestive heart failure (CHF) (no doxorubicin-HR 6.6; 95%CI 1.6-28.3; doxorubicin ≤ 250 mg/m(2) -HR 13.0; 95%CI 1.9-89.7; doxorubicin >250 mg/m(2) -HR 18.3; 95%CI 3.8-88.2), SMN (standardized incidence ratio [SIR] 9.0; 95%CI 3.9-17.7 with and 4.9; 95%CI 1.8-10.6 without doxorubicin) and death. CONCLUSION: Long-term survivors of WT treated from 1970 to 1986 are at increased risk of treatment related morbidity and mortality 25 years from diagnosis.

Disseminated Rhizomucor pusillus causing early multiorgan failure during hematopoietic stem cell transplantation for severe aplastic anemia.

Matched sibling donor hematopoietic stem cell transplantation is the standard of care for severe aplastic anemia, with an overall survival of 80% to 90%. Only 60% to 70% of patients respond to treatment with immunosuppressive therapy. The main life threatening complications are infections, graft failure, and graft versus host disease. A 10-year-old patient with severe aplastic anemia underwent matched sibling donor hematopoietic stem cell transplantation, but developed sudden onset of fatal multiorgan failure on day +12. The cause of death was found only after autopsy.

Hematopoietic stem cell transplantation for refractory or recurrent non-Hodgkin lymphoma in children and adolescents.

We examined the role of hematopoietic stem cell transplantation (HSCT) for patients aged< or =18 years with refractory or recurrent Burkitt (n=41), lymphoblastic (n=53), diffuse large B cell (DLBCL; n=52), and anaplastic large cell lymphoma (n=36), receiving autologous (n=90) or allogeneic (n=92; 43 matched sibling and 49 unrelated donor) HSCT in 1990-2005. Risk factors affecting event-free survival (EFS) were evaluated using stratified Cox regression. Characteristics of allogeneic and autologous HSCT recipients were similar. Allogeneic donor HSCT was more likely to use irradiation-containing conditioning regimens, bone marrow (BM) stem cells, be performed in more recent years, and for lymphoblastic lymphoma. EFS rates were lower for patients not in complete remission at HSCT, regardless of donor type. After adjusting for disease status, 5-year EFS were similar after allogeneic and autologous HSCT for DLBCL (50% vs 52%), Burkitt (31% vs 27%), and anaplastic large cell lymphoma (46% vs 35%). However, EFS was higher for lymphoblastic lymphoma, after allogeneic HSCT (40% vs 4%; P < .01). Predictors of EFS for progressive or recurrent disease after HSCT included disease status at HSCT and use of allogeneic donor for lymphoblastic lymphoma. These data were unable to demonstrate a difference in outcome by donor type for the other histological subtypes.

Lymphoma in adolescents and young adults.

Non-Hodgkin (NHL) and Hodgkin (HL) lymphomas are represented prominently in the adolescent and young adult (AYA) population. These diseases represent 11% of total cancer diagnoses in children, 4% in those 40 years of age and older, and 13% in AYA (aged 15-39 years). Although age-adjusted incidence rates of NHL increase with age, the more aggressive lymphomas are seen more commonly in the younger population with a transition to low-grade, indolent subtypes as the population ages. Burkitt lymphoma, diffuse large B-cell lymphoma, lymphoblastic lymphoma, and anaplastic large cell lymphoma make up the most common subtypes in the AYA population, although within the subgroup age 30-39 years, follicular lymphoma becomes more prominent. As a result, much of the armamentarium in the treatment of aggressive NHL and HL in adults is based on data from pediatric clinical trials. There are obvious limitations to this approach. It is vital that we gain a more thorough understanding of the biology and therapeutic responsiveness of NHL and HL in the AYA population. Thus, we must leverage the large prospective and retrospective trials that have been completed to date and redirect our approaches to cancer care in this unique population. We review the epidemiological data on NHL and HL from the Surveillance, Epidemiology and End Results registries as a cornerstone for a comparative analysis of therapeutic outcomes available in this population.

Mobilization of PML-RARA negative blood stem cells and salvage with autologous peripheral blood stem cell transplantation in children with relapsed acute promyelocytic leukemia.

BACKGROUND: Relapsed acute promyleocytic leukemia (APL) is treated with re-induction chemotherapy, commonly arsenic trioxide, and stem cell transplantation (SCT). The effect of arsenic trioxide on autologous peripheral blood stem cell collection is unknown. PROCEDURE: Five pediatric patients with relapsed APL had PML-RARA negative peripheral blood stem cells mobilized (four after arsenic trioxide) and underwent autologous SCT after cyclophosphamide (60 mg/kg x 2) and total body irradiation (TBI-fractionated 1,200 cGy) conditioning. RESULTS: All five patients remain in molecular remission a median of 20 months post-transplant. CONCLUSION: Autologous SCT performed during molecular remission is a treatment option for pediatric patients with relapsed APL and may provide durable leukemia-free survival without the complications of allogeneic transplantation.