Development Of Subsequent Malignant Neoplasms Research Articles

Long-Term Risk of Subsequent Neoplasms in 5-Year Survivors of Childhood Neuroblastoma: A Dutch Childhood Cancer Survivor Study-LATER 3 Study.

Neuroblastoma survivors have an increased risk of developing subsequent malignant neoplasms (SMNs), but the risk of subsequent nonmalignant neoplasms (SNMNs) and risk factors are largely unknown. We analyzed the long-term risks and associated risk factors for developing SMNs and SNMNs in a well-characterized cohort of 5-year neuroblastoma survivors. We included 563 5-year neuroblastoma survivors from the Dutch Childhood Cancer Survivor Study (DCCSS)-LATER cohort, diagnosed during 1963-2014. Subsequent neoplasms were ascertained by linkages with the Netherlands Cancer Registry and the Dutch Nationwide Pathology Databank (Palga) and medical chart review. We calculated standardized incidence ratios (SIRs), absolute excess risk (AER), and cumulative incidences. Multivariable competing risk regression analysis was used to evaluate risk factors. In total, 23 survivors developed an SMN and 60 an SNMN. After a median follow-up of 23.7 (range, 5.0-56.3) years, the risk of SMN was elevated compared with the general population (SIR, 4.0; 95% CI, 2.5 to 5.9; AER per 10,000 person-years, 15.1). The 30-year cumulative incidence was 3.4% (95% CI, 1.9 to 6.0) for SMNs and 10.4% (95% CI, 7.3 to 14.8) for SNMNs. Six survivors developed an SMN after iodine-metaiodobenzylguanidine (131IMIBG) treatment. Survivors treated with 131IMIBG had a higher risk of developing SMNs (subdistribution hazard ratio [SHR], 5.7; 95% CI, 1.8 to 17.8) and SNMNs (SHR, 2.6; 95% CI, 1.2 to 5.6) compared with survivors treated without 131IMIBG; results for SMNs were attenuated in high-risk patients only (SMNs SHR, 3.6; 95% CI, 0.9 to 15.3; SNMNs SHR, 1.5; 95% CI, 0.7 to 3.6). Our results demonstrate that neuroblastoma survivors have an elevated risk of developing SMNs and a high risk of SNMNs. 131IMIBG may be a treatment-related risk factor for the development of SMN and SNMN, which needs further validation. Our results emphasize the need for awareness of subsequent neoplasms and the importance of follow-up care.

Five-Year Follow-Up of Standard-of-Care Axicabtagene Ciloleucel for Large B-Cell Lymphoma: Results From the US Lymphoma CAR T Consortium.

Axicabtagene ciloleucel (axi-cel) is an autologous CD19 chimeric antigen receptor (CAR) T-cell therapy that is approved for the treatment of relapsed or refractory large B-cell lymphoma. Little is known about the long-term survivorship after CAR T-cell therapy. We previously reported the results of 298 patients who were leukapheresed with the intent to receive standard-of-care axi-cel (n = 275 infused) after two or more previous lines of therapy at a median follow-up of 12.9 months. Here, we report extended follow-up of this cohort to a median of 58 months, with a focus on late survivorship events. Among axi-cel-infused patients, progression-free survival at 5 years was 29% and overall survival (OS) at 5 years was 40%. The 5-year lymphoma-specific survival was 53% with infrequent late relapses. However, the 5-year nonrelapse mortality (NRM) was 16.2%, with over half of NRM events occurring beyond 2 years. Patients who were 60 years and older had a lower risk of relapse (P = .02), but a higher risk of NRM compared with patients younger than 60 years (NRM odds ratio, 4.5 [95% CI, 2.1 to 10.8]; P < .001). Late NRM was mainly due to infections and subsequent malignant neoplasms (SMNs). In total, SMNs occurred in 24 patients (9%), including therapy-related myeloid neoplasms (n = 15), solid tumors (n = 7), and unrelated lymphoid malignancies (n = 2). In the standard-of-care setting, axi-cel exhibits outcomes consistent with those reported in clinical trials, with sustained, durable responses observed at the 5-year time point. However, late infections and the development of SMN are key survivorship issues that reduce long-term survival after CAR T-cell therapy, particularly in the elderly.

Non-RB1 germline cancer predisposing variants found in retinoblastoma patients

PurposeIt is well known that individuals with hereditary retinoblastoma are at lifelong high risk for developing subsequent malignant neoplasms (SMN). However, the role that non-RB1 germline variants play in tumorigenesis and SMN risk has not yet been studied. The purpose of this study is to report the frequency and spectrum of non-RB1 germline cancer predisposing variants in individuals with retinoblastoma (RB). MethodsRetrospective data collection from institutional electronic medical records of 94 individuals seen at our institution with personal history of retinoblastoma, who had undergone next-generation sequencing germline analysis. ResultsThe prevalence of individuals with cancer predisposition was 57% (54/94). Of these individuals, 76% (41/54) had a pathogenic/likely pathogenic (P/LP) variant only in the RB1 gene, 9% (5/54) harbored a P/LP variant only in a non-RB1 gene, and 11% (6/54) had both. No difference was found between patients with and without non-RB1 variants when comparing demographic and clinical characteristics, including time to SMN. Variants were found in 7 different genes, with only 1 variant repeating 3 times. ConclusionIn this small cohort of patients with retinoblastoma, non-RB1 variants did not appear to augment tumorigenesis or disease progression. Larger studies are required to determine associations between specific variants and development of SMN.

Mortality and the burden of subsequent malignant neoplasms in survivors of childhood cancer beyond age 50: A report from the Childhood Cancer Survivor Study (CCSS).

10052 Background: The first generation of survivors of childhood cancer is now older than 50 years (y) of age. There is a paucity of information on the risk for late mortality and the evolving burden of subsequent malignant neoplasms (SMNs) in these aging survivors. Methods: We assessed cause-specific mortality (National Death Index) and self-reported SMNs (excluding nonmelanoma skin cancers) among CCSS participants diagnosed between 1970-1999, conditional on having survived to 50y by 12/31/2017. There were 4,772 survivors alive at 50y eligible for mortality analyses. Of the 3,355 who completed a baseline CCSS questionnaire, 2,273 also completed a follow-up questionnaire at ≥50y and were included in the SMN analyses. Cumulative mortality, standardized mortality ratios (SMRs), and, for SMNs, cumulative burden, standardized incidence ratios (SIRs), and relative rate (RR) with 95% confidence intervals (CIs) were calculated, compared with the general US population and by survivor subgroups. Piecewise-exponential multivariable regression was used to identify risk factors associated with the development of SMNs after 50y. Results: Mean age at diagnosis was 14y (standard deviation 4.2y). Mortality: Among survivors who attained 50y of age, the subsequent 5y, 10y, and 15y incidences of all-cause mortality were 9%, 19%, and 35%, respectively, (overall SMR 3.7 [95% CI 3.4-4.1]). SMRs were highest for SMN (SMR 5.1 [95% CI 4.4-5.9]), pulmonary (SMR 4.7 [95% CI 3.3-6.5]) and cardiovascular (SMR 3.9 [95% CI 3.2-4.8]) causes of death. The highest SMR (SMR 9.2 [95% CI 7.7-10.8]) was seen in female survivors of Hodgkin lymphoma. SMN: By age 50y, 14% of CCSS participants reported &gt;1 SMN. History of SMN &lt;50y was independently associated with the rate of developing another SMN at &gt;50y (RR 1.6 [95% CI 1.1-2.3]). The most frequent SMNs ≥50y were breast (41%) in females and prostate (21%) in males, followed by gastrointestinal cancers in both (14% [females], 19% [males]). The cumulative burden of SMNs in survivors treated with radiation therapy (RT) increased sharply with age and exceeded 50 per 100 survivors by 65y (SIR 3.3 95%CI 2.0-5.2]). Survivors who did not receive RT had a SMN rate comparable to the general population (Table). Conclusions: This sentinel population of survivors of childhood cancer is at high risk for poor outcomes as they enter older adulthood. RT exposure and history of SMN &lt;50y are associated with increased risk for developing SMNs after 50y. The evolving burden of late morbidity attributed to SMNs may be lower for contemporary survivors projected to have less RT exposure. [Table: see text]

KMT2A Rearrangements Are Associated with Lineage Switch Following CD19 Targeting CAR T-Cell Therapy

KMT2A Rearrangements Are Associated with Lineage Switch Following CD19 Targeting CAR T-Cell Therapy

Possible Mechanisms of Subsequent Neoplasia Development in Childhood Cancer Survivors: A Review.

Simple SummaryDue to improvements in the treatment of childhood cancer, around 80% of children are cured. However, childhood cancer survivors are at risk of developing late effects, including subsequent malignant neoplasm; these are defined as histologically different cancers, which appear after treatment for primary cancer. The risk of subsequent malignant neoplasm formation is influenced mainly by previous anticancer therapy (chemotherapy, radiotherapy, immunotherapy, and targeted therapy), genetic factors, and the length of survival. For these reasons, at present, for the treatment of tumors with a good prognosis, it is important to consider the possible risk of late side effects e.g. use of radiotherapy in Hodgkin’s lymphoma only if chemotherapy does not induce complete remission or in nephroblastoma only in locally advanced stages. Therefore, we study risk factors for the development of subsequent malignant neoplasm. In the review, we present possible risk factors for the development of subsequent neoplasm. Advances in medicine have improved outcomes in children diagnosed with cancer, with overall 5-year survival rates for these children now exceeding 80%. Two-thirds of childhood cancer survivors have at least one late effect of cancer therapy, with one-third having serious or even life-threatening effects. One of the most serious late effects is a development of subsequent malignant neoplasms (histologically different cancers, which appear after the treatment for primary cancer), which occur in about 3–10% of survivors and are associated with high mortality. In cancers with a very good prognosis, subsequent malignant neoplasms significantly affect long-term survival. Therefore, there is an effort to reduce particularly hazardous treatments. This review discusses the importance of individual factors (gender, genetic factors, cytostatic drugs, radiotherapy) in the development of subsequent malignant neoplasms and the possibilities of their prediction and prevention in the future.

Utility of a Cancer Predisposition Screening Tool for Predicting Subsequent Malignant Neoplasms in Childhood Cancer Survivors.

Childhood cancer survivors (CCS) are at risk of developing subsequent malignant neoplasms (SMNs) resulting from exposure to prior therapies. CCS with underlying cancer predisposition syndromes are at additional genetic risk of SMN development. The McGill Interactive Pediatric OncoGenetic Guidelines (MIPOGG) tool identifies children with cancer at increased likelihood of having a cancer predisposition syndrome, guiding clinicians through a series of Yes or No questions that generate a recommendation for or against genetic evaluation. We evaluated MIPOGG's ability to predict SMN development in CCS. Using the provincial cancer registry (Ontario, Canada), and adopting a nested case-control approach, we identified CCS diagnosed and/or treated for a primary malignancy before age 18 years (1986-2015). CCS who developed an SMN (cases) were matched, by primary cancer and year of diagnosis, with CCS who did not develop an SMN (controls) over the same period (1:5 ratio). Potential predictors for SMN development (chemotherapy, radiation, and MIPOGG output) were applied retrospectively using clinical data pertaining to the first malignancy. Conditional logistic regression models estimated hazard ratios and 95% CIs associated with each covariate, alone and in combination, for SMN development. Of 13,367 children with a primary cancer, 317 (2.4%) developed an SMN and were matched to 1,569 controls. A MIPOGG output recommending evaluation was significantly associated with SMN development (hazard ratio 1.53; 95% CI, 1.06 to 2.19) in a multivariable model that included primary cancer therapy exposures. MIPOGG was predictive of SMN development, showing value in nonhematologic malignancies and in CCS not exposed to radiation. MIPOGG has additional value for SMN prediction beyond treatment exposures and may be beneficial in decision making for enhanced individualized SMN surveillance strategies for CCS.

Subsequent Malignant Neoplasms in Retinoblastoma Survivors.

Simple SummaryCurrently survival from retinoblastoma exceeds 95% in high-income/resource countries. Life expectancy within the heritable retinoblastoma population is mainly threatened by trilateral retinoblastoma in early childhood and subsequent malignant neoplasms throughout life. In this review the risks of specific subsequent malignant neoplasms and trilateral Rb, age at onset and influence of therapy are examined. Furthermore, long-term surveillance guidelines in the heritable retinoblastoma survivors are discussed.Retinoblastoma (Rb) is a pediatric malignant eye tumor. Subsequent malignant neoplasms (SMNs) and trilateral Rb (TRb) are the leading cause of death in heritable Rb patients in developed countries. The high rate of SMNs in heritable Rb patients is attributed to the presence of a mutation in the RB1 tumor suppressor gene. In addition, Rb therapy choices also influence SMN incidence in this patient group. The incidence rates and age of occurrence for the most frequent SMNs and TRb will be discussed. In addition, the impact of genetic predisposition and Rb treatments on the development of SMNs will be evaluated. Furthermore, screening and other prevention methods will be reviewed.

Genetic basis of subsequent malignant neoplasms

Subsequent malignant neoplasms (SMNs) are one of the most serious late complications in pediatric patients with cancer, with more than 10% of long-term cancer survivors developing SMNs. Germline mutations in cancer predisposition genes have been recently highlighted as a risk factor. For example, germline mutations in the TP53 gene were reported to be a risk factor for SMNs. A comprehensive genomic analysis for a large cohort of long-term survivors of childhood cancer showed that variants in cancer predisposition genes were correlated with the higher cumulative incidence of SMNs. As another genetic risk, previous reports suggested that polymorphisms in genes regulating thiopurine pathway such as TPMT gene might contribute to SMN development after acute lymphoblastic leukemia treatment. Considering improved survival probability, attention should be paid for late complications. Thus, therapeutic strategy should be optimized based on a risk for SMNs of each individual.

NUDT15 Variants Confer High Incidence of Secondary Malignancies of ALL in Children

Background: Secondary or subsequent malignant neoplasms (SMNs) are one of the most serious late complications in children and adolescents after treatment for acute lymphoblastic leukemia (ALL). Several studies have reported that excess dosing of 6-mercaptopurine (6-MP) therapy and polymorphisms of 6-MP metabolizing enzyme coding gene might influence the risk of SMNs. Recently, nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) variants have been identified as a cause of high sensitivity to 6-MP, which reflects a high sensitivity to 6MP in East Asians. Therefore, we investigated an association between NUDT15 genotype and incidence of SMNs in pediatric ALL. Methods: Germline samples including bone marrow samples, peripheral blood samples and buccal swab samples during remission were obtained from 13 cases who suffered from SMN after childhood ALL. The prevalence of major NUDT15 non-functional alleles (*2 and *3), which is categorized intermediate or poor metabolizer of 6-MP in Clinical Pharmacogenetics Implementation Consortium Guideline (Relling M et al. Clin Pharmacol Ther 2019), was evaluated by using Sanger sequencing and/or whole exome sequencing. The NUDT15 variants prevalence in SMN patients with primary ALL was compared to those without SMN, who were registered in the TCCSG L04-16 study, which was conducted by the Tokyo Children's Cancer Study Group (TCCSG). Results: Patients' profiles and NUDT15 genotypes were summarized in table 1. Median ages at diagnoses of ALL and SMNs were 4 (1-15) and 13 (5-44) years, respectively. Median duration between ALL and SMNs was 8 (1-30) years. SMNs included acute myeloblastic leukemia (AML) / myelodysplastic syndrome (MDS) (n = 8), brain tumor (n = 1), basal cell carcinoma (n = 1), bladder cancer (n = 1), Ewing sarcoma (n = 1) and osteosarcoma (n = 1). Among the 13 SMN cases, six patients (46.2%) possessed NUDT15 non-functional alleles. The SMNs of these cases included AML / MDS (n = 4), bladder cancer (n = 1) and osteosarcoma (n = 1). Among them, 3 patients, whose SMNs were AML, bladder cancer and osteosarcoma, were treated with radiation therapy against primary ALL. All NUDT15 genotypes were heterozygous variants (3 were *1/*2 and 3 were *1/*3) and seemed to be intermediate metabolizers. In patients without known SMNs in TCCSG ALL L04-16 cohort study, 73 of 437 (16.7%) possessed NUDT15 non-functional alleles. Three of them had bi-allelic variants (2 cases were *3/*3, 1 case was *2/*3), and the others were all heterozygous. The prevalence of NUDT15 non-functional alleles was significantly higher in SMNs compared to that of non-SMN cases (P = 0.012). Conclusion: Our study indicated the NUDT15 hypomorphic variant alleles could be a risk of SMNs after ALL treatment with 6-MP. NUDT15 heterozygotic variants carriers are generally tolerable of 6-MP, and are usually treated with normal or slightly low-dose of 6-MP. However, our results suggested that standard adjustment of 6-MP in maintenance therapy might cause potential overdose of 6-MP for cases with NUDT15 variants, leading to increased risk of SMNs. To certify it, a higher number of study samples and somatic samples analysis of 6-MP induced SMNs are required. To obtain the best long-term event-free survival probability, it might be necessary to reduce the risk of SMNs development without compromising therapeutic effect by further optimal adjustment of 6-MP dose (or alternative agents). Disclosures No relevant conflicts of interest to declare.

Subsequent malignancies after long-term follow-up of paediatric hematopoietic stem cell transplantation

IntroductionSurvival after hematopoietic stem cell transplantation has improved dramatically in recent years. Unfortunately, there is an increased risk of subsequent malignant neoplasms (SMN) in this population and this represents a significant cause of late mortality. Patients and methodsIn this study, we analysed the incidence of SMN and the associated risk factors in patients referred at a paediatric age for hematopoietic stem cell transplantation (allogeneic or autologous) in our centre. ResultsWe observed 19 cases of SMN in a cohort of 371 patients, with a cumulative incidence of 6, 12, and 36% at 15, 20, and 30 years of follow-up, respectively. The solid tumours were the most prevalent malignancies. The risk was significantly higher than expected in the general population for each tumour type and in the different age ranges (P<.0001). Radiotherapy and chronic GvHD were the main risk factors for the development of SMN in our series. ConclusionsWe observed a high incidence of SMN among hematopoietic stem cell transplantation survivors highlighting the need for life-long surveillance.

Correlation between RB1germline mutations and second primary malignancies in hereditary retinoblastoma patients treated with external beam radiotherapy

Retinoblastoma (Rb) results from biallelic inactivation of the RB1 gene. Hereditary Rb patients i. e germline carriers of a RB1 mutation also have a risk of developing subsequent malignant neoplasms (SMN) such as osteosarcomas. This SMN risk is maximized by external beam radiotherapy treatments (EBRT), which is why these treatments are now avoided. Nevertheless, EBRT is still a matter of great concern, as EBRT-treated patients are in their adulthood and SMNs remain the major cause of death for patients.To decipher the relationship between RB1 genotype and SMN development in EBRT treated patients, we conducted a retrospective study in a cohort of 160 irradiated hereditary Rbs with fully resolved RB1 mutational status. Median follow-up was 22 years [1-51] and median age of patients was 27 years old [7-53]. Among these 160 Rb patients, 120 did not develop any SMN (75%) and 40 developed SMNs (25%). The age at which EBRT is given (i.e. before or after the age of 12 months) was not correlated to SMN development (p = 0.6). We didn't find any difference in RB1 mutation type between patients with or without SMN, neither could we detect any linkage between mutation type and SMN location, SMN type and age at diagnosis. Interestingly, among 13 carriers of a RB1 low penetrance mutation, 3 of them developed sarcomas, a rare tumor that cannot be attributed to the general population.Our study cannot explain why a RB1 mutation leads or not to a SMN but demonstrated that EBRT patients with a low penetrance mutation remain at risk of SMN and should be cautiously monitored.

Subsequent Malignant Neoplasms in a Population-Based Cohort of Pediatric Cancer Patients: A Focus on the First 5 Years.

The purpose was to describe the development of subsequent malignant neoplasms (SMN) among a population-based cohort of pediatric cancer patients, with a focus on SMNs that occurred within the first 5 years from diagnosis. The cohort was identified from POGONIS, an active provincial registry. Cohort members were Ontario residents ages 0 to 14.9 years at primary diagnosis between January 1985 and December 2008. SMNs that developed <18 years were captured by POGONIS, whereas SMNs diagnosed later were identified through linkage. Cumulative incidence and standardized incidence ratios (SIR) were calculated, and proportional hazards models were estimated to examine factors associated with SMN development. A total of 7,920 patients were eligible. 2.4% (188/7,920) developed 197 SMNs. Mean follow-up time was 10.7 years (SD = 7.6 years; range, 0.0-26.4 years) with mean time to SMN of 8.5 years (SD = 6.3 years; range, 0.0-24.9 years). The SIR for the development of a SMN was 9.9 [95% confidence interval (CI), 8.6-11.4]. 40.6% of SMNs (80/197) developed within 5 years. Early SMNs were more likely to be leukemia and lymphoma. Factors associated with early SMN were primary diagnosis of a bone tumor (OR, 4.88; 95% CI, 1.52-15.60), exposure to radiotherapy (OR, 1.82; 95% CI, 1.02-3.22), and the highest dose of epipodophyllotoxin (OR, 3.74; 95% CI, 1.88-7.42). Over 40% of SMNs diagnosed in childhood cancer patients occurred in the first 5 years after diagnosis, suggesting a need for early and ongoing surveillance. The early development of certain SMNs reinforces the need for early and continued surveillance at all stages for pediatric cancer patients.

Genetic variation as a modifier of association between therapeutic exposure and subsequent malignant neoplasms in cancer survivors.

Subsequent malignant neoplasms (SMNs) are associated with significant morbidity and are a major cause of premature mortality among cancer survivors. Several large studies have demonstrated a strong association between the radiation and/or chemotherapy used to treat primary cancer and the risk of developing SMNs. However, for any given therapeutic exposure, the risk of developing an SMN varies between individuals. Genomic variation can potentially modify the association between therapeutic exposures and SMN risk and may explain the observed interindividual variability. In this review, the author provides a brief overview of the current knowledge regarding the role of genomic variation in the development of therapy-related SMNs and discusses the methodological challenges in undertaking an endeavor to develop a deeper understanding of the molecular underpinnings of therapy-related SMNs, such as an appropriate study design, the identification of an adequately sized study population together with a reliable plan for collecting and maintaining high-quality DNA, clinical validation of the phenotype, and the selection of an appropriate approach or platform for genotyping. Understanding the factors that can modify the risk of treatment-related SMNs is critical to developing targeted intervention strategies and optimizing risk-based health care for cancer survivors.

Subsequent Malignant Neoplasms after Hematopoietic Cell Transplantation

Subsequent malignant neoplasms (SMNs) developing after hematopoietic cell transplantation (HCT) are a well-described complication (1–6). The magnitude of risk of SMNs after HCT ranges from 4-fold to 11-fold that of the general population. The estimated actuarial incidence is reported to be 3.5% at 10 years, increasing to 12.8% at 15 years among recipients of allogeneic HCT. The differing clinicopathologic characteristics of SMNs preclude assessment of risk factors in aggregate. It has become conventional practice to classify SMNs into three distinct groups (7): (i) myelodysplasia (t-MDS)/acute myeloid leukemia (t-AML); (ii) lymphoma, including lymphoproliferative disorders; and (iii) solid tumors. While t-MDS/AML and lymphoma develop relatively early in the post-transplantation period, secondary solid tumors have a longer latency. The magnitude of risk and associated risk factors for the development of SMNs are summarized in Table 1, and detailed in the sections below. Table 1 Magnitude of Risk and Populations at Increased Risk of Subsequent Malignant Neoplasms after Hematopoietic cell Transplantation Magnitude of Risk of Subsequent Malignant Neoplasm Therapy-related myelodysplasia/ acute myeloid leukemia The cumulative probability of developing t-MDS/t-AML ranges from 1.1% to 24.3% at 20 to 43 months after autologous HCT. In patients treated with alkylating agents, t-MDS/t-AML usually appears 4 to 7 years after exposure. The majority of patients present with multilineage dysplasia and peripheral cytopenias. There is a high prevalence of abnormalities involving chromosomes 5 (−5/del[5q]) and 7 (−7/del[7q]). AML secondary to topoisomerase II inhibitors presents as overt leukemia. The latency ranges from 6 months to 5 years, and is associated with balanced translocations involving chromosome bands 11q23 or 21q22. The common and nonspecific nature of cytopenias after autologous HCT has necessitated the creation of criteria for diagnosing t-MDS/t-AML after HCT. These include (i) significant marrow dysplasia in at least two cell lines, (ii) peripheral cytopenias without alternative explanations, and (iii) blasts in the marrow defined by French-American-British classification (8). Because many patients may not have an increase in blasts, presence of a clonal cytogenetic abnormality in addition to morphologic criteria of dysplasia may aid in making this diagnosis. An increased risk of t-MDS/t-AML is associated with older age at HCT (1), pretransplantation therapy with alkylating agents, topoisomerase II inhibitors, and radiation therapy (3), use of peripheral blood hematopoietic cells, stem cell mobilization with etoposide, difficult stem cell harvests, conditioning with TBI, number of CD34+ cells infused, and a history of multiple transplants (1, 3, 9–11). The diagnosis of t-MDS/t-AML after autologous HCT confers a poor prognosis, with a median survival of 6 months in patients treated with conventional chemotherapy. In fact, t-MDS/t-AML is a major cause of nonrelapse mortality in patients undergoing autologous HCT (3, 12). Allogeneic HCT has been attempted with actuarial survival ranging from 0% to 24% at 3 years (13). Among t-MDS/t-AML patients with balanced aberrations, 11q23 translocations are an independent adverse risk factor (14). Treatment-related mortality (TRM) and relapse were reported to be 41% and 27% at 1 year and 48% and 31% at 5 years, respectively in large cohort of patients undergoing allogeneic HCT (15). Disease-free (DFS) and overall survival (OS) were 32% and 37% at 1 year and 21% and 22% at 5 years, respectively. Age older than 35 years; poor-risk cytogenetics; t-AML not in remission or advanced t-MDS; and donor other than an HLA-identical sibling or a partially or well-matched unrelated donor had adverse impacts on DFS and OS. Because the poor outcomes of allogeneic transplant for t-MDS/t-AML are related in part to the high risk of TRM, it is important to evaluate the role of reduced intensity conditioning approaches in this setting. Preliminary reports suggest that allogeneic HCT using reduced-intensity conditioning is feasible and may result in improved outcomes.

Long-Term Effects of Radiation Exposure among Adult Survivors of Childhood Cancer: Results from the Childhood Cancer Survivor Study

In the last four decades, advances in therapies for primary cancers have improved overall survival for childhood cancer. Currently, almost 80% of children will survive beyond 5 years from diagnosis of their primary malignancy. These improved outcomes have resulted in a growing population of childhood cancer survivors. Radiation therapy, while an essential component of primary treatment for many childhood malignancies, has been associated with risk of long-term adverse outcomes. The Childhood Cancer Survivor Study (CCSS), a retrospective cohort of over 14,000 survivors of childhood cancer diagnosed between 1970 and 1986, has been an important resource to quantify associations between radiation therapy and risk of long-term adverse health and quality of life outcomes. Radiation therapy has been associated with increased risk for late mortality, development of second neoplasms, obesity, and pulmonary, cardiac and thyroid dysfunction as well as an increased overall risk for chronic health conditions. Importantly, the CCSS has provided more precise estimates for a number of dose-response relationships, including those for radiation therapy and development of subsequent malignant neoplasms of the central nervous system, thyroid and breast. Ongoing study of childhood cancer survivors is needed to establish long-term risks and to evaluate the impact of newer techniques such as conformal radiation therapy or proton-beam therapy.

Gastrointestinal malignancies as a subsequent malignant neoplasm in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.

9520 Background: There is emerging evidence that childhood cancer survivors (CCS) develop gastrointestinal (GI) malignancies more frequently and earlier than the general population. We determined the risk of GI subsequent malignant neoplasms (SMN) and described factors associated with their development to inform surveillance recommendations. Methods: We assessed the risk of GI SMN in a cohort of 14,372 5-year CCS and compared that to population-based data from the Surveillance, Epidemiology and End Results (SEER) program. Multivariate Cox regression models identified associations between key risk factors and GI SMN development. Results: 45 CCS developed GI SMN at a median age of 33.5 years (range: 9.7-44.8) and a median of 22.8 years (range: 5.5-30.2) from their original diagnoses. The 30-year cumulative incidence of a GI SMN was 0.64% (95% confidence interval [CI]: 0.43-0.86). The most frequent SMN locations were colorectal (n=24; 53%), stomach (n=7; 16%), and hepatobiliary system (n=4, 9%). CCS with a GI SMN were more likely to be deceased than those without (51.1 vs. 13.8%, p<0.05). 60.9% of deceased died of their GI SMN. The risk of GI SMN was almost 5-fold higher in CCS than the general population (standardized incidence ratio [SIR]=4.6, 95% CI: 3.5-6.1) with absolute excess risk (AER) of 14 per 100,000 person-years (py). Colorectal SMN SIR was 4.19 (95% CI: 2.78-6.30), EAR was 7/100,000 py. Survivors of Wilms' tumor, Hodgkin's lymphoma and bone tumors were at highest risk. The multivariate model revealed abdominal radiation (RR=5.32, 95% CI: 2.74-10.32), alkylating agents (RR=2.60, 95% CI: 1.06-6.37) and platinum drugs (RR=4.73, 95% CI: 1.49-15.14) increased the risk of GI SMN. Conclusions: While the overall incidence is low, CCS are at increased risk for developing a GI SMN with an associated elevated risk of mortality. Surveillance in at-risk survivors should commence at a younger age than is recommended for the general population. No significant financial relationships to disclose.