Introduction: Hodgkin lymphoma (HL) is one of the most treatable cancers affecting adolescent and young adult (AYA) patients (15 - 39 years), however optimal therapy for de novo disease in this population remains a subject of debate. Population-based studies in HL consistently report a survival disadvantage for AYAs when compared with younger patients. Though the etiology of these disparities is unclear, analyses of clinical trials data suggest that observed survival differences may relate to treatment, rather than to age. Because registry analyses are often limited by lack of information about clinical characteristics and therapeutic exposures, the independent effect of age on HL-outcome outside of the cooperative group setting is unknown. To address this gap in the literature, we: (1) examined initial treatment regimen and patterns of care in a population-based cohort of AYAs compared to children with de novo HL, and (2) examined the impact of sociodemographic and clinical variables on overall survival (OS) and disease-specific survival (DSS) by age, after adjusting for therapy. Methods: Data for 4,426 patients aged 0 - 39 years diagnosed with classical HL between 2007 and 2016 were obtained from the California Cancer Registry (CCR). Detailed treatment information for each patient was extracted from unstructured free-text fields in the CCR database. Chemotherapy regimens were classified based on standard treatment approaches for adult and pediatric HL (Table). Multivariable cox proportional hazards regression models were used to examine the influence of sociodemographic and clinical variables on OS and DSS, overall and by age group, and are presented as adjusted hazard ratios (aHR) with 95% confidence intervals (CI). Models were adjusted for race/ethnicity, sex, insurance, neighborhood socioeconomic status, histology, stage, B symptoms, treatment location at a NCI (National Cancer Institute)-designated cancer center, and radiation therapy (RT). Results: Of the 4,426 patients in this cohort, 33% were <21 years (y) (N= 1,479) and 67% were 22 - 39y (N= 2,947). At median follow-up of 4.4 years, 3-year OS in the full cohort was 95%. Front-line therapy for patients with HL differed significantly across age groups (Table). Approximately 42% of patients <21y received ABVD vs. 69% of older patients. Compared with older patients, a higher proportion of younger patients received ABVE-PC (younger: 8.8% vs. <1%) and modified treatment regimens (younger: 24% vs. 9.6%). Regimens were considered modified if they omitted one drug from a standard protocol but were otherwise administered according to expected dosing schedules; the most common were ABV (18%) and AVD (15%). A higher proportion of patients with private (vs. public/no) insurance received STANFORD V chemotherapy. In total, 40% of patients aged <21y received RT as part of initial therapy vs. 27% of patients 22 - 39y. In survival models, increasing age was associated with a higher risk of death. Compared with patients <14y, the hazard of death from HL was over three-fold higher in patients 22 - 29y (aHR=3.1, CI: 1.1, 9.1) and 30 - 39y (aHR=3.8, CI: 1.3, 11.2). In multivariable models stratified by age, race/ethnicity, insurance, B-symptoms and stage were each significantly associated with survival. In patients <21y, NHBs (aHR: 7.1, CI: 2.4, 20.6) and Hispanics (aHR: 2.5, CI: 1.0, 6.4) experienced worse DSS than NHWs. Having public or no insurance also conferred worse OS (aHR: 1.9, CI: 1.1, 3.5), but initial therapy did not significantly impact OS or DSS. Among those aged 22 - 39y, NHB patients had worse OS (aHR: 1.7, CI: 1.0, 2.8) as did patients with public or no insurance (aHR: 1.7, CI: 1.2, 2.3). Stage IV disease was associated with inferior OS (aHR: 2.9, CI: 1.3, 6.8) and DSS (aHR: 3.3, CI: 1.1, 9.6). Finally, modified treatment regimens (vs. ABVD) were associated with worse OS (aHR: 1.6, CI: 1.0, 2.5), but did not significantly impact DSS in AYAs. Conclusion: In this large, population-based cohort of children and AYAs with HL, we observed that initial therapy varies, but that the majority of AYAs receive ABVD. Variation in therapy was largely insufficient to explain observed survival disparities, as older age, NHB and Hispanic race/ethnicity, and public or no insurance each conferred increased risk of death, even after adjustment for chemotherapy regimen. Further analyses examining comorbidities, treatment-related toxicities, and cause of death are ongoing. Disclosures No relevant conflicts of interest to declare.

Background

Race-based survival in children and adolescents with hematologic malignancies has been a national challenge for decades. Large-scale investigations of age- and race-based survival trends over time in these patients have not previously been reported. The objective of this study was to investigate whether race- and age-related differences in pediatric and adolescent and young adult (AYA) leukemia and lymphoma survival persist and to what extent these differences have changed over time.

Methods

Using the Surveillance, Epidemiology, and End Results program, this study investigated the outcomes of black and white (1975-2012; n = 27,369) and white and Hispanic (1992-2012; n = 20,574) children (0-14 years old) and AYAs (15-39 years old) with acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and Hodgkin lymphoma (HL). Estimates of 5- and 10-year relative survival were compared over time.

Results

Trends showed a convergence of survival for white and black children with ALL but a divergence in survival for AYA patients. Hispanic children and AYAs both suffered inferior outcomes. Trends for AML revealed persistent survival differences between black and white children and suggested worsening disparities for AYAs. Survival trends in HL revealed sustained survival differences between black and white AYA patients, whereas no differences were found in Hispanic and white patient outcomes for AML or HL.

Conclusions

Although survival for children and AYAs with ALL, AML, and HL has improved over the past 4 decades, differences persist between black, white, and Hispanic children and AYAs; survival disparities between black and white children with ALL have been nearly eliminated. Strategies aimed at identifying causality and reducing disparities are warranted. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2723-2730. © 2016 American Cancer Society.

We compared secondary primary malignancy risk (SPM) in HIV-uninfected and HIV-infected Hodgkin lymphoma (HL) survivors. We used data from the California Cancer Registry on patients diagnosed with HL from 1990 to 2015 (all ages included), and standardized incidence ratios (SIRs) and multivariable competing risk models for analyses. Of 19,667 survivors, 735 were HIV-infected. Compared with the general population, the risk of SPM was increased by 2.66-fold in HIV-infected and 1.92-fold in HIV-uninfected survivors. Among HIV-infected survivors, median time to development of SPM was shorter (5.4 years) than in HIV-uninfected patients (8.1 years). Additionally, the highest risk of SPM was observed <2 years after diagnosis in HIV-infected survivors (SIR = 4.47), whereas risk was highest ≥20 years after diagnosis (SIR = 2.39) in HIV-uninfected survivors. The risk of SPMs persisted for decades and was higher among HIV-infected survivors, suggesting that these patients should benefit from long-term surveillance and cancer prevention practices.

Background

Hodgkin lymphoma (HL) is a treatable tumor affecting children, adolescents and young adults (AYAs; 15-39 years old). Population-based studies report worse survival for non-White children and AYAs but have limited data on individual therapeutic exposures. This study examined overall and HL-specific survival in a population-based cohort of patients while adjusting for sociodemographic factors and treatment.

Methods

Data for 4807 patients younger than 40 years with HL (2007-2017) were obtained from the California Cancer Registry. Individual treatment information was extracted from text fields; chemotherapy regimens were defined by standard approaches for pediatric and adult HL. Multivariable Cox models examined the influence of patient and treatment factors on survival.

Results

At a median follow-up of 4.4 years, 95% of the patients were alive. Chemotherapy differed by age, with 70% of 22- to 39-year-olds and 41% of <22-year-olds receiving doxorubicin, bleomycin, vinblastine, and dacarbazine (P < .001). In multivariable models, older patients (22-39 vs < 21 y; hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.11-2.10), Black (vs White patients); HR, 1.90; 95% CI, 1.25-2.88), and Hispanic patients (HR, 1.45; 95% CI, 1.06-1.99) experienced worse survival; among those < 21 y, Black race was associated with a 3.3-fold increased risk of death (HR, 3.26; 95% CI, 1.43-7.42).

Conclusions

In children and AYAs with HL, older age and non-White race/ethnicity predicted worse survival after adjustments for treatment data. Further work is needed to identify the biological and nonbiological factors driving disparities in these at-risk populations.

Introduction Second primary malignancy (SPM) is one of the most devastating late complications following Hodgkin lymphoma (HL) treatment. Historically, the most common SPMs in patients treated for HL are solid tumors, which are largely related to radiation exposure during initial therapy. For the last three decades, efforts to address the risk of SPM after HL therapy have focused on reducing exposure to radiation, as well as refining the approach for patients where radiation is indicated. To date, few population-based studies in the United States have quantified the burden of SPMs and evaluated the potential effect of changes in therapeutic management over time. Additionally, to our knowledge, no study has compared SPM risk between human immunodeficiency virus (HIV)-infected and HIV-uninfected HL survivors. Methods We used data from the California Cancer Registry on 21,043 patients diagnosed with primary HL between 1988 and 2015 with follow-up through 2017. We calculated standardized incidence ratios (SIRs) with corresponding 95% confidence intervals (CIs) and absolute excess risks (AERs) to compare SPM incidence in our HL cohort with the expected number of first primary cancer incidence in the general California population, based on patient's age at diagnosis (5-year categories), sex, calendar year (3-year intervals), cancer site, and race/ethnicity. SIRs are presented by HIV status, SPM latency, treatment era, and cancer type. P-values for trends were used to examine whether SPM risk changed over time. Findings Among 20,303 HIV-uninfected patients (median follow-up of 14.1 years), overall SPM risk was increased 1.95-fold compared with the general population (SIR=1.95, 95% CI 1.86-2.04). In 740 HIV-infected patients (median follow-up of 11.7 years), overall risk was increased 2.68-fold compared with the general population (SIR=2.68, 95% CI 2.0-3.40), translating to an 37% higher incidence of SPM in HIV-infected vs. HIV-uninfected patients. The AER (per 10,000 person-years) of SPM was 43.1 in HIV-uninfected and 76.5 in HIV-infected patients, resulting in a 33.4 excess SPM per 10,000 person-years in HL survivors with HIV. Malignancies that contributed the most to overall AER were non-Hodgkin lymphoma (NHL), female breast and lung cancers in HIV-uninfected patients; and Kaposi sarcoma, NHL, anorectal and head & neck (HNC) cancers in HIV-infected patients. Notably, among HIV-uninfected patients, the highest overall risk of SPM occurred ≥20 years after diagnosis (SIR= 2.27, 95% CI 1.99-2.58) (Figure). In contrast, the highest overall risk in HIV-infected patients was observed <2 years after diagnosis (SIR=4.42, 95% CI 2.53-7.19). Radiation used decreased from 46.9% in 1988-1996 to 29.5% in 2007-2015. Among HIV-uninfected patients, there was a trend towards decreased risk over time of overall and selected solid SPMs (lung, female breast, and gastrointestinal cancers) (Table). In an analysis restricted to HIV-uninfected patients who received radiation irrespective of chemotherapy, findings also suggested a declined risk of overall and selected solid SPMs over time: any solid (SIR=2.15 in 1988-1996 and SIR=1.30 in 2007-2015, p<0.0001), lung (SIR=3.69 in 1988-1996 and SIR=1.81 in 2007-2015, p=0.0031), and female breast (SIR=2.95 in 1988-1996 and SIR=0.63 in 2007-2015, p<0.0001). Conclusion Compared with the general population, the risk of developing a SPM following HL treatment was significantly higher among both HIV-uninfected and HIV-infected patients, with the absolute excess risk greater for those with HIV infection. There were different temporal patterns and types of SPM between HIV-uninfected and HIV-infected patients. These findings prompt the question on whether earlier and/or more intensive cancer screening should be pursued for HIV-infected survivors. The trend towards decreased risk for selected solid SPMs among HIV-uninfected patients, especially lung and female breast cancers, suggest that strategies to reduce radiation in HL survivors may be working. Despite promising trends in this group, the observation that SPM risk was highest ≥20 years after initial therapy further highlights the need for long-term surveillance and survivorship care in this at-risk population. Disclosures: Rosenberg: Takeda: Speakers Bureau; Janssen: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Wun:Glycomimetics, Inc.: Consultancy.

Abstract Background: Hodgkin lymphoma (HL) is one of the most common, and one of the most curable cancers in adolescents and young adults (AYAs) (15-39 years). Despite excellent outcomes in the majority of patients, the burden of long-term morbidity and mortality persists. Prior analyses of patients treated for HL before the year 2000 have reported mortality rates as high as 30% by 20 years. Further, this mortality risk has historically differed across different racial and ethnic groups. Over the past decade, cooperative groups have expanded the use of risk-adapted, response-based treatment in an effort to maintain high cure rates, while simultaneously reducing the burden of late effects. We examined long-term survival in AYAs with HL treated after the year 2000. Methods: We used the National Cancer Institute Surveillance, Epidemiology, and End Results registry data for 18 regions in the United States (SEER18) to examine survival in AYAs with a confirmed diagnosis of HL between 2000 and 2015. We obtained overall and cause-specific survival estimates for each year after cancer diagnosis (up to 15 years) for each racial/ethnic group with corresponding 95% confidence intervals. From these yearly survival estimates, we calculated the percentage of deaths not attributed to HL at 10- and 15-years after cancer diagnosis. Results: The final analysis included 16,868 HL patients. Racial/ethnic subgroups included: non-Hispanic white (NHW; 11,016, 65%), Hispanic (2,753, 16%), non-Hispanic black (NHB; 2,131, 13%), and Asian/Pacific Islander (API; 968, 6%) AYAs with HL. Across the full cohort, the 10-year and 15-year overall survival probabilities were 90% (95% confidence interval [95%CI]: 89 - 91) and 87% (95% CI: 86 - 88), respectively. At 10- and 15-years, overall survival was highest for NHWs (10-year: 92%: 15-year: 88%) and APIs (91%; 86%) compared to Hispanics (87%; 85%) and NHBs (82%; 78%). Overall survival, cause-specific survival, and percentage of deaths not attributed to HL by race/ethnicity are presented in the Figure. In the first year after diagnosis, 22% of deaths were due to causes other than primary disease, with the percentage of deaths not attributed to HL higher in NHWs and APIs than Hispanics and NHBs. At most time points after cancer diagnosis, a higher proportion of NHW (vs. NHB, Hispanic and API) patients died from causes other than HL. By 10 years after diagnosis, 25% of NHW patients died due to causes other than HL, vs. 20% in API, 17% in NHB, and 15% in Hispanic patients. By 15 years, 33% of all deaths were not attributed to HL. This was observed most dramatically in the NHW cohort in whom 40% of all deaths were not HL-related, compared to 24% of deaths in the NHB cohort and 26% - 27% of deaths in the Hispanic and API groups. Conclusion: In AYAs diagnosed with HL between 2000 and 2015, NHB patients had worse survival compared with NHW and API patients. The higher probability of survival in NHW patients was accompanied by a consistently higher proportion of non-cancer related death in this cohort both 10- years and 15-years after diagnosis. Studies are needed to evaluate risk factors for both short- and long-term mortality in AYAs, and to examine how these risks differ across racial/ethnic groups. Findings also suggest that despite increasing use of response-adapted therapy over the past two decades, all AYAs with HL remain at risk of death in the decades following therapy, further highlighting the need for long-term follow-up of this at-risk patient population. Figure. Figure. Disclosures Muffly: Adaptive Biotechnologies: Research Funding; Shire Pharmaceuticals: Research Funding.

Despite a remarkable increase in the genomic profiling of cancer, integration of genomic discoveries into clinical care has lagged behind. We report the feasibility of rapid identification of targetable mutations in 153 pediatric patients with relapsed/refractory or high-risk leukemias enrolled on a prospective clinical trial conducted by the LEAP Consortium. Eighteen percent of patients had a high confidence Tier 1 or 2 recommendation. We describe clinical responses in the 14% of patients with relapsed/refractory leukemia who received the matched targeted therapy. Further, in order to inform future targeted therapy for patients, we validated variants of uncertain significance, performed ex vivo drug-sensitivity testing in patient leukemia samples, and identified new combinations of targeted therapies in cell lines and patient-derived xenograft models. These data and our collaborative approach should inform the design of future precision medicine trials. SIGNIFICANCE: Patients with relapsed/refractory leukemias face limited treatment options. Systematic integration of precision medicine efforts can inform therapy. We report the feasibility of identifying targetable mutations in children with leukemia and describe correlative biology studies validating therapeutic hypotheses and novel mutations.See related commentary by Bornhauser and Bourquin, p. 1322.This article is highlighted in the In This Issue feature, p. 1307.