Cumulative Incidence Of Second Malignant Neoplasms Research Articles

The Impact of Radiation Therapy on the Incidence of Second Malignant Neoplasm among Adolescent and Young Adult Cancer Survivors

<h3>Purpose/Objective(s)</h3> The risks of second malignancy, including radiation-associated malignancies, are well described in adult populations as well as among pediatric patients. Adolescents and young adults (AYA) are a vulnerable population in which the risks of late effects may be increased relative to older adult patients but are not fully characterized. We sought to investigate the incidence second malignant neoplasm among AYA patients and hypothesize that receiving radiation therapy is associated with increased risk of secondary cancers in this population. <h3>Materials/Methods</h3> The Surveillance, Epidemiology, and End Results (SEER) Research Plus database was queried for patients age 15-39 who survived at least 5 years after diagnosis of a solid-tumor primary malignancy between 1975-2017. Descriptive statistics were obtained and univariate comparisons were performed using ANOVA and chi-square test. The 15-year cumulative incidence of second malignant neoplasm (SMN) was calculated among AYA patients overall, among those who did vs did not receive radiation therapy, and across other significant variables. A multivariable model was created to assess the effect of receiving radiation therapy on the risk of SMN when adjusting for age, sex, decade of diagnosis, and disease. <h3>Results</h3> A total of 159,829 AYA patients with ≥5-year survival were included, 31.1% of whom received radiation therapy. Median follow up among the entire cohort was 17 years (range, 5-43 years). The cumulative incidence of SMN among all AYA patients at 15 years was 5.6%. The cumulative incidence of SMN at 15 years was significantly increased among AYA patients who received radiation therapy as part of their definitive treatment (6.6% with radiation therapy versus 5.1% without, p<0.001). Cumulative incidence of SMN was also affected by sex, age, decade of initial diagnosis, and AYA primary cancer diagnosis (see Table 1). On multivariable analysis, patients who received radiation therapy remained more likely to develop a second malignancy than those who did not (HR 1.4, p<0.001). <h3>Conclusion</h3> This study uses national data to report the incidence of second malignancy among adolescents and young adults diagnosed with cancer. Receiving radiation therapy was associated with an increase in SMN at 15 years, with an absolute increase of 1.5% and HR of 1.4 compared to those who did not receive radiation. These results provide an important reference for counseling patients regarding risks of treatment and should guide further efforts to improve treatment delivery and outcomes among this vulnerable population.

Long-term outcomes in patients with localized Ewing sarcoma treated with interval-compressed chemotherapy: A long-term follow-up report from Children’s Oncology Group study AEWS0031.

11505 Background: Children’s Oncology Group study AEWS0031 demonstrated superior 5-year event-free survival (EFS) in patients with localized Ewing sarcoma (ES) receiving interval-compressed (IC) chemotherapy (every 2 weeks) compared to standard timing (ST) chemotherapy (every 3 weeks). We assessed the long-term outcome of patients treated on AEWS0031 to determine whether the survival advantage of IC chemotherapy was maintained at 10 years. Methods: AEWS0031 enrolled 568 eligible patients with localized ES. Patients were stratified into four groups by age (&lt;18 years and ≥ 18 years) and primary site (pelvic and non-pelvic), and randomized to receive 14 cycles of alternating vincristine-doxorubicin-cyclophosphamide and ifosfamide-etoposide given every 3 weeks (ST; Regimen A) vs. every 2 weeks (IC; Regimen B). For this updated report, one patient was excluded due to uncertainty of original diagnosis giving a total of 567 patients in this analysis. Data for tumor measurements and histologic response were collected retrospectively from institutional reports. EFS and overall survival (OS) were estimated using the Kaplan-Meier method and compared using the log-rank test and Gray’s test for cumulative incidence (CI). Results: The 10-year EFS for patients treated with IC chemo was 70% compared to 61% for ST chemo (p = 0.03), and the OS was 76% with IC chemo compared to 69% for ST chemo (p = 0.03). The 10-year CI of second malignant neoplasms (SMNs) for ST chemo was 4.2% [95% confidence interval: 2.4-7.5] compared to 3.2% (95% confidence interval: 1.6-6.3) for IC chemo (p = 0.5). There was a trend towards improved 10-year EFS in those receiving IC chemo both with non-pelvic (N = 477; 71% vs. 64%) and pelvic (N = 90; 67% vs. 43%) primary tumors. Similarly, the 10-year EFS was superior for patients treated with IC chemo in both the &lt; 18 years (N = 500; 73% vs. 64%) and ≥ 18 years (N = 67; 53% vs. 37%) age groups. Among the 184 patients with available histologic response data, the 10-year EFS from the time of local control was 76% for those with &lt; 10% viable tumor and 56% for those with ≥ 10% viable tumor (p = 0.01). Additional analysis comparing patients with any viable tumor vs. no viable tumor (NVT) by treatment regimen demonstrated that patients with NVT who received IC chemo had 10-year EFS and OS from local control of 91% and 97%, respectively. In the 210 patients for whom tumor volume calculations were possible, there was no difference in the 10-year EFS for patients with tumors &lt; 200 mL vs. ≥ 200 mL. Conclusions: With longer term follow-up, IC chemotherapy for localized ES is associated with superior EFS and OS without an increase in SMNs. This study suggests patients ≥ 18 years with poor necrosis or pelvic primary tumors remain at high risk for relapse despite IC chemo, emphasizing the need for alternative treatment strategies to improve their outcomes. Clinical trial information: NCT00006734.

Second Malignant Neoplasms (SMN) in Myeloma Patients Post Stem Cell Transplant (SCT)

Introduction: Recent developments in management of patients with myeloma have resulted in longer survival. Availability of newer class of agents for treatment has prolonged survival, improved quality of life and achieved better disease control. Use of SCT, either autologous (AutoSCT) and to a lesser extent allogeneic (AlloSCT) still forms an important aspect of myeloma treatment pathway. Improved survivorship mandates evaluation of long term consequences and risk of SMN is one of the most important long-term consequences affecting overall outcome.Aim: Estimate the risk of SMN post SCT in patients with Myeloma.Methods and Materials: Analysis includes 779 patients who received SCT for myeloma from January 2002 to December 2019. Data was collected using case records, electronic patient records, transplant database and information from referring hospitals. Follow-up was updated to June 2020.Results: Analysis includes 779 patients with myeloma (M: 488, F:291; median age:59yr, range: 26-75) receiving AutoSCT (n=716) or AlloSCT (n=63). Conditioning for AutoSCT was high dose melphalan in majority (n=714, 99.7%). AlloSCT conditioning was RIC (n=40/63, 63.5%) or MAC (n=23/63, 36.5%). TBI was part of conditioning in 51/779 (6.5%). There was no difference in demographics between two groups.Results: Median follow-up was 46 mo (range: 0.2-220). Second malignancy was identified in 48 of 779 cases (6.0%). SMN developed in 6/63 (10%) AlloSCT and 42/716 (6%) AutoSCT patents (p=0.25). SMN types were haematological (n=21), lymphoma (n=6) and solid tumours (n=21). MDS was the only haematological SMN in this series. Secondary MDS developed in 20/21 of AutoSCT as compared to 1/63 in AlloSCT (p=0.01). Non-haematological SMN were breast (n=3), upper GI (n=3), lower GI (n=2), hepato-billiary (n=2), prostate (n=3), skin (n=5), and unknown primary (n=1). SMN incidence was higher with increasing follow-up (2002-2014, 8%; 2015-2017, 2.8%, 2018-2019, 0%, p=0.002). There was no association with development of SMN and gender, age at transplant, type of stem cell source or transplant conditioning. Incidence of SMN was significantly higher for all sites as compared to general population. Cumulative incidence of SMN was 5% at 5 yr, and 15% at 10 yr for AutoSCT patients.Conclusion: Myeloma patients are at increased risk of SMN and need monitoring for long term side effects. Development of MDS post AutoSCT is the commonest SMN post AutoSCT but there is increased incidence of solid tumours as well. Impact of new modalities of treatment needs long term monitoring. DisclosuresBloor: Novartis: Honoraria; Kite, a Gilead Company: Honoraria.

NUDT15 variants confer high incidence of second malignancies in children with acute lymphoblastic leukemia

AbstractThe effect of genetic variation on second malignant neoplasms (SMNs) remains unclear. First, we identified the pathogenic germline variants in cancer-predisposing genes among 15 children with SMNs after childhood leukemia/lymphoma using whole-exome sequencing. Because the prevalence was low, we focused on the association between SMNs and NUDT15 in primary acute lymphoblastic leukemia (ALL) cases. NUDT15 is one of the 6-mercaptopurine (6-MP) metabolic genes, and its variants are common in East Asian individuals. The prevalence of NUDT15 hypomorphic variants was higher in patients with SMNs (n = 14; 42.9%) than in the general population in the gnomAD database (19.7%; P = .042). In the validation study with a cohort of 438 unselected patients with ALL, the cumulative incidence of SMNs was significantly higher among those with (3.0%; 95% confidence interval [CI], 0.6% to 9.4%) than among those without NUDT15 variants (0.3%; 95% CI, 0.0% to 1.5%; P = .045). The 6-MP dose administered to patients with ALL with a NUDT15 variant was higher than that given to those without SMNs (P = .045). The 6-MP–related mutational signature was observed in SMN specimens after 6-MP exposure. In cells exposed to 6-MP, a higher level of 6-MP induced DNA damage in NUDT15-knockdown induced pluripotent stem cells. Our study indicates that NUDT15 variants may confer a risk of SMNs after treatment with 6-MP in patients with ALL.

Second malignant neoplasms after childhood non-central nervous system embryonal tumours in North America: A population-based study

BackgroundFew studies in North America have quantified the risks of second malignant neoplasms (SMNs) among survivors of childhood non-central nervous system (non-CNS) embryonal tumours due to their rarity. We aimed to investigate these risks by combining population-based data from the United States of America and Canada. MethodsWe evaluated patients with childhood non-CNS embryonal tumours reported to the Surveillance Epidemiology and End Results program and eight Canadian cancer registries from 1969 to 2010. Standardised incidence ratio (SIR) and cumulative incidence of SMNs were calculated. Subgroup analyses were conducted by the type of first primary cancer, age at first primary diagnosis and follow-up duration. FindingsOf the 13,107 survivors, 190 SMNs were reported over 134,548 person-years of follow-up. The SIR for all SMNs combined was 6.4 (95% confidence interval [CI]: 5.5–7.4). Most site-specific SIRs were significantly increased, ranging from 36 (95% CI: 26–49) for bone and joint cancer to 3.1 (95% CI: 1.5–5.2) for brain tumour. The risk for second malignancies declined as the time elapsed from the first primary diagnosis and was less prominent for patients first diagnosed at age 1–4 years. Notably, rhabdomyosarcoma survivors had a higher risk for SMNs than those with other first primaries. The overall cumulative incidence of SMNs was 1.0% at 10 years, increasing to 2.2% at 20 years and 4.1% at 30 years. InterpretationSurvivors with childhood non-CNS embryonal tumours faced an increased risk for SMNs compared to the general population. The risk variations observed in different patient categories may help target prevention strategies in high-risk subgroups.

Second malignancies in patients with neuroblastoma: the effects of risk-based therapy.

To investigate the incidence of second malignant neoplasms (SMN) for patients with neuroblastoma, we analyzed patients from the SEER database according to three treatment eras (Era 1: 1973-1989, Era 2: 1990-1996, and Era 3: 1997-2006) corresponding to the introduction of multi-agent chemotherapy, risk-based treatment, and stem cell transplant. The SEER database was mined for all patients with neuroblastoma or ganglioneuroblastoma. Cumulative incidence of SMN was calculated with death as a competing risk. A poisson regression model was used to estimate incidence rate ratios and 95% confidence intervals to compare the rates of SMN between patients in different Eras. The analytic cohort included 2,801 patients. Thirty-four patients developed a SMN, accounting for 1.2% of all patients. Of the patients who developed a SMN, 47.1% received radiation for their primary neuroblastoma. Fourteen of the SMN were carcinomas, and 10 were hematologic malignancies, with six cases of acute myelogenous leukemia. There was no difference in the incidence of SMN in Era 1 compared to Era 3 (P = 0.48). The cumulative incidence of SMN at 30 years for high-risk patients was 10.44% (95% CI 3.98-20.52%) compared to 3.57% (95% CI 1.87-6.12%) for non-high-risk patients (P < 0.001). This study showed no increase in the incidence of SMNs for children treated in the most recent treatment era as compared to earlier Eras. However, as the risk for developing SMN does not plateau, the number of SMNs will likely continue to rise in the cohort of patients treated after 1996. Comprehensive follow-up care for these survivors will be important.

Second malignant neoplasms following chemoreduction with carboplatin, etoposide, and vincristine in 245 patients with intraocular retinoblastoma

To evaluate the occurrence of second malignant neoplasms (SMN) following chemoreduction (CRD) with carboplatin, vincristine, and etoposide (CEV) as frontline therapy in patients with retinoblastoma (RB). PRODECURE: We conducted a two-institution retrospective chart review of 245 patients with intraocular RB treated with six cycles of vincristine, carboplatin, and etoposide for treatment of intraocular retinoblastoma. Cumulative incidence of SMN was calculated with adjustment for the competing risk of death. There were 187 patients with germline retinoblastoma and 58 with non-germline disease. External beam radiotherapy was subsequently utilized in 46 (24%) of germline cases and six (10%) of non-germline cases. Mean follow-up of germline and non-germline patients was 80 and 70 months, respectively. Seven subsequent cancers were found in six patients for an overall incidence of 3% at a mean of 11 years. For germline cases, following CEV alone (n = 156), SMN were found in 4% following the RB diagnosis. We found no SMN in patients with non-germline RB. One patient developed pineoblastoma. SMN included osteosarcoma (n = 3), rhabdomyosarcoma (n = 1), orbital and conjunctival melanoma (n = 1), low-grade glioma (n = 1), and acute promyeloctic leukemia (n = 1). Five of the six patients with a second malignancy survive at mean of 46 months (range 15-71 months). At a mean of 11 years, 4% of children with germline RB treated with CEV as frontline therapy developed SMN's. No SMN was found in non-germline patients. Concerns regarding CEV-induced second cancers should not deter clinicians from using life and vision preserving therapy in patients with retinoblastoma.

Twenty years of follow-up of survivors of childhood osteosarcoma: a report from the Childhood Cancer Survivor Study.

Osteosarcoma survivors have received significant chemotherapy and have undergone substantial surgeries. Their very long-term outcomes (20 year) are reported here. The authors assessed the long-term outcomes of 733 5-year survivors of childhood osteosarcoma diagnosed from 1970 to 1986 to provide a comprehensive evaluation of medical and psychosocial outcomes for survivors enrolled in the Childhood Cancer Survivor Study (CCSS). Outcomes evaluated included overall survival, second malignant neoplasms (SMNs), recurrent osteosarcoma, chronic health conditions, health status (general and mental health and functional limitations), and psychosocial factors. Outcomes of osteosarcoma survivors were compared with general-population statistics, other CCSS survivors, and CCSS siblings. Survivors had a mean follow-up of 21.6 years. The overall survival of children diagnosed with osteosarcoma who survived 5 years at 20 years from original diagnosis was 88.6% (95% confidence interval [CI], 86.6%-90.5%). The cumulative incidence of SMNs at 25 years was 5.4%, with a standardized incidence ratio of 4.79 (95% CI, 3.54-6.33; P<.01). Overall, 86.9% of osteosarcoma survivors experienced at least 1 chronic medical condition, and >50% experienced ≥2 conditions. Compared with survivors of other cancers, osteosarcoma survivors did not differ in their reported general health status (odds ratio [OR], 0.9; 95% CI, 0.7-1.2), but were more likely to report an adverse health status in at least 1 domain (OR, 1.9; 95% CI, 1.6-2.2), with activity limitations (29.1%) being the most common. Childhood osteosarcoma survivors in this cohort did relatively well, considering their extensive treatment, but are at risk of experiencing chronic medical conditions and adverse health status. Survivors warrant life-long follow-up.

Long-term outcomes among survivors of childhood central nervous system tumors: A report from the childhood cancer survivor study

10015 Background: To improve survival in childhood CNS tumors aggressive surgical intervention, radiotherapy, and chemotherapy have been employed. Long-term survivors are at risk for a broad array of late-effects secondary to tumor location and/or therapeutic interventions. Methods: Analysis included 1,538 5-yr survivors of childhood CNS tumors (including 1,035 with Astrocytoma [AST], 306 Medulloblastoma/PNET [M/PNET], 115 Ependymoma [EP], and 82 Others). Patients, diagnosed 1970–86, had a median follow-up of 22.1 yrs (range16.1–34.6). Outcomes of mortality, second malignant neoplasm (SMN), health status, education, employment, insurance, and marital status were assessed to determine risk associated with tumor type and treatment modality including region-specific cumulative radiation (RT) dose to the CNS. Results: 307 deaths >5 yrs after diagnosis resulted in a cumulative late mortality rate of 18.2% (95% confidence interval [CI] 16.1–20.3) at 25 yrs (EP 23.3%; M/PNET 19.0%; AST 17.3%). Standardized mortality ratios were 13.5 (95% CI 9.2–19.1) for EP; 13.1 (95% CI 10.2–16.6) for M/PNET; and 9.8 (95% CI 8.5–11.3) for AST. Late disease recurrence (n=188) and SMN (n=37) represented the most common causes of death. Cumulative incidence of SMN was 2.7% (95% CI 1.9–3.4) at 20 yrs. RT was associated with a two-fold risk of SMN (odds ratio [OR]=2.0, 95% CI 0.95–4.3). Adverse health status was reported by 57%. Treatment with RT or chemotherapy (vs Surgery only) was associated with an increased risk of severe impairment in general health (OR=2.8, p<0.001), functional status (OR=2.2, p<0.001), and activity level (OR=2.1, p<0.001). Exposure of >30Gy to any CNS region was associated with statistically significant (P<0.01) lower rates for educational attainment, marriage, employment, and personal income while exposure to <30Gy resulted in similar rates to non-irradiated patients for all outcomes. Conclusions: Survivors of childhood CNS experience substantial long-term adverse effects of therapy and are a high priority group for intervention strategies. No significant financial relationships to disclose.

Risk of second malignant neoplasms after childhood central nervous system malignant tumours: An international study

PurposeThe aim of this study was to assess the risk of second malignant neoplasms (SMNs) other than central nervous system (CNS) neoplasms after childhood CNS cancer in an international multicentre study. MethodsIndividual data on cases of CNS cancer in children (0–14 years) and on subsequent SMNs were obtained from 13 population-based cancer registries contributing data for different time periods in 1943–2000. Standardised incidence ratios (SIRs) with 95% confidence intervals (CI), absolute excess risk and cumulative incidence of SMNs were computed. ResultsWe observed 43 SMNs in 8431 CNS cancer survivors. The SIR was 10.6 (4.85–20.1) for thyroid cancer (nine cases), 2.75 (1.01–5.99) for leukaemia (six cases) and 2.47 (0.90–5.37) for lymphoma (six cases). The SIRs were highest in the first 10 years after CNS cancer diagnosis. The cumulative incidence of non-CNS SMNs was 3.30% (0.95–5.65%) within 45 years after a CNS cancer diagnosis. Within 15 years, the cumulative incidence was highest for cases diagnosed after 1980 (0.56%, 95% CI: 0.29–0.82%). ConclusionThis population-based study indicates that about one every 180 survivors of a childhood CNS cancer will develop a non-CNS SMN within the following 15 years. The excess is higher after glioma and embryonal malignant tumour than after another CNS tumour.

Secondary malignant neoplasms after intensive treatment of relapsed acute lymphoblastic leukaemia in childhood

Purpose To investigate the cumulative incidence of and the risk factors for developing second malignant neoplasms (SMN) in children and adolescents following treatment for relapse of acute lymphocytic leukaemia (ALL). Methods Patients (1376) up to 18 years of age with first relapse of non-B-cell ALL were treated and achieved a 2nd complete remission (CR). The treatment followed trial protocol in five consecutive multicentre trials of the ALL-REZ BFM Study Group between March 1983 and December 2001. The incidence of SMN was analysed, correlated with clinical and therapeutic parameters, and compared to the age-specific incidence rates of cancers as cited in German cancer registries. Results Out of the 1376 patients 21 were diagnosed with SMN including non-lymphoblastic leukaemia/myelodysplastic syndrome ( n = 6), osteo-/Ewing’s-/fibroblastic sarcoma ( n = 4), B-cell ALL/lymphoma ( n = 2), thyroid carcinoma ( n = 2), basal cell carcinoma, adeno carcinoma, squamous cell carcinoma, meningioma, malignant histiocytosis, glioblastoma and anaplastic astrocytoma ( n = 1 each). The overall cumulative risk of SMN at 15 years (median follow-up of 13.1 years) was 1.26% ± 0.38% (SE). SMN was found to be significantly associated with stem cell transplantation (SCT), and high cumulative doses of cranial irradiation, etoposide and cyclophosphamide. In multivariate analysis etoposide (VP16) and cyclophophamide (CY) were found to be independently associated with SMN ( p = 0.047 and 0.002). Compared to the incidence of neoplasm in the age-matched population, there was a 10-fold increase of neoplasia. Conclusions Despite repeated exposure to intense frontline and relapse treatment (including multiagent chemotherapy, cranial irradiation and stem cell transplantation in some patients) the cumulative incidence of SMN was unexpectedly low, though significantly higher than in the general age-matched population. The association of SMN to SCT seemed to be a secondary effect at least partially mediated by exposure to high doses of VP16 and CY given for conditioning therapy.

Secondary Neoplasms Subsequent to Berlin-Frankfurt-Muenster (BFM) Therapy of Non-Hodgkin Lymphoma of Childhood: Significantly Higher Risk for Patients with Lymphoblastic Lymphoma Compared to Other NHL-Subtypes.

We evaluated the rate and type of second malignant neoplasms (SMN) after BFM treatment of children with Non-Hodgkin lymphoma (NHL). Between January 1981 and February 2003 2451 patients (pts) <15 years (y) of age at diagnosis were enrolled into the subsequent trials NHL-BFM 81, 83, 86, 90, and 95. Pts with lymphoblastic lymphoma (LBL) (n=547) or non-anaplastic peripheral T-cell lymphoma (n=97) received acute lymphoblastic leukemia (ALL)-type therapy including cumulative doses of cyclophosphamide (max. 3g/m2), daunorubicine/doxorubicin (max. 280mg/m2), but, except few pts, no etoposide. Prophylactic cranial radiotherapy (CRT) was given in stage III/IV (omitted in NHL-BFM95). Pts with mature B-cell neoplasms (n=1597), or anaplastic large cell lymphoma (n=210) received B-type therapy, consisting of 2–8, 5-day courses including cumulative doses of cyclophosphamide (max. 7g/m2), ifosfamide (max. 8g/m2), doxorubicine max. 150mg/m2 (in trial 81 max. 200mg/m2), and etoposide (max. 1.4g/m2). CRT was omitted since trial NHL-BFM86. With a median follow-up of 6.9 (range 0.2–22.6) years the probability of survival at 15 y was 83+1%. By June 2005, 47 SMN were documented, including 16 acute myeloid leukemias/myelodysplastic syndromes (AML/MDS), 11 NHL, 2 ALL, 1 Hodgkin's lymphoma, 7 brain tumors, and 10 other SMN. All SMN occurred in first remission after a median time of 2.9 (range: 0.4–12.3) years from diagnosis of NHL. The cumulative incidence of SMN at 15 y was 4.0% (95% confidence interval [CI]: 1.9%–6.1%) for the total group. The cumulative incidence of SMN was significantly higher among pts with LBL receiving ALL-type therapy (6.3% at 15 y [95%CI: 2.4%–10.3%] (13 AML/MDS, 2 NHL, 3 brain tumors, and 3 other SMN), as compared to pts with other NHL-entities receiving B-type therapy (3.4% at 15 y [95% CI: 0.5–6.4%] (3 AML/MDS, 9 NHL, 2 ALL, 1 Hodgkin's lymphoma, 4 brain tumors, and 7 other SMN), p=0.002. There was no significant difference of cumulative incidence of SMN in pts who received CRT compared to pts not receiving CRT. However, 5 of 7 pts, who developed brain tumor, received CRT of 12–24 Gy. Also, there was no significant correlation between the incidence of SMN and the cumulative doses of drugs, except for anthracyclines. For pts receiving a cumulative dose of anthracyclines of >160mg/m2 (almost exclusively pts with LBL receiving ALL-type therapy) the cumulative risk for SMN at 15 y was 6.5% (95% CI: 1.5-11.5%), as compared to 2.0% (95% CI: 1.1–2.9%) for pts with lower doses, p=0.007. Exposure to etoposide was not a risk factor for secondary AML/MDS (11 of 16 pts with sec. AML/MDS did not receive etoposide). In a Cox regression analysis only diagnosis of LBL remained a significant risk factor for SMN (RR 2.5, 95% CI 1.4–4.4). Our analysis revealed a cumulative risk for SMN of 4% at 15 y after successful treatment of childhood NHL. The cumulative incidence of SMN was significantly higher in LBL-pts than in other pts. AML/MDS were the most frequent SMN following LBL while second lymphoid malignancies were the most frequent SMN following non-LBL.

Risk Factors for Second Malignancies after Transplantation Differ between Allogeneic and Autologous Transplantation.

Survivors of hematopoietic stem cell transplantation (HSCT) are at risk for second malignant neoplasms (SMN). We undertook this analysis to ascertain whether risk of SMN was comparable in survivors of allogeneic and autologous transplantation. Among 8662 transplant recipients treated at the Fred Hutchinson Cancer Research Center between November 1969 and April 2004, who survived at least 100 days post transplant, there were 1743 autologous and 6919 allogeneic HSCT recipients. Within this cohort, there were 56 SMNs among the autologous and 224 among the allogeneic recipients. Cumulative incidence of SMN at 10 years post-HSCT was 2.6% in the allogeneic and 4.2% in the autologous HSCT survivors. A multivariate Cox regression model adjusted for current age, TBI, gender and length of follow-up was fit and the hazard ratio (HR) for SMN for the allogeneic transplant survivors was 0.7 (95% confidence interval {CI} 0.5, 1.0) compared to the autologous transplant survivors (reference group), suggesting that the adjusted hazard of SMN is higher for autologous than for allogeneic HSCT recipients. Risk factors differed between the two groups. For survivors of autologous transplantation, in multivariate Cox regression models, only age > 18 years at transplant was associated with decreased risk of SMN (<18 years HR = 1.0; 18–39 years HR = 0.04; 40+ years HR = 0.004). Use of total body irradiation (TBI) was not significantly associated with risk among the autologous HSCT recipients. For allogeneic transplant survivors, increased risk of SMN was associated with TBI and the effect of TBI was stronger for younger (<18 years at HSCT: HR = 4.6; 95% CI 1.6, 13.5) than for older (≥18 years; HR = 1.5; 95% CI 1.0, 2.3) HSCT recipients (interaction p = 0.04) in multivariate Cox regression models. Risk was also increased after acute graft versus host disease (HR = 1.4; 95% CI 1.0, 1.9) and with ongoing follow-up time, with HRs of 1.7 (95% CI 1.1, 2.5) at 10 – 14 years, 2.2 (95% CI 1.3, 3.7) at 15–19 years and 2.6 (95% CI 1.2, 5.4) at 20+ years of follow-up. Unrelated HSCT also increased risk of SMN (HR = 1.4; 95% CI 1.0, 2.0). In adjusted analyses, risk of SMN thus appears slightly lower in allogeneic versus autologous transplant survivors, and risk factors appear different between the two groups. Attention should focus on modifiable risk factors in both groups. Particularly in autologous transplant survivors, the relative contribution of pre-transplant exposures must be established.