Age over 55 Years at Diagnosis Increases Risk of Second Malignancies after Auto-Transplantation for Hodgkin's Lymphoma Patients
Authors: Pingali Sai Ravi , Saliba Rima , Anderlini Paolo , Hosing Chitra M. , Khouri Issa F. , Alousi Amin M. , Kebriaei Partow , Nieto Yago , Qazilbash Muzaffar H. , Fanale Michelle A. , Shpall Elizabeth J. , Champlin Richard E. , Popat Uday R. 
Published: October 2019

Abstract
Introduction: Age at diagnosis is of prognostic value in Hodgkin's lymphoma (HL) patients. However, there is paucity of data on the impact of age on outcomes of autologous hematopoietic transplantation (auto-HCT) for patients with relapsed and refractory HL. We studied impact of age at diagnosis on long-term outcomes of patients with HL undergoing auto-HCT.
Patients and Methods: All consecutive patients with relapsed/refractory HL who underwent auto-HCT at our center between January 1996 and December 2010 were included. Baseline patient and disease characteristics were collected. As HL has bimodal peak incidence betweenages of 15 and 34 years and over age of 50 to 55 years, we stratified patients into 3 groups: > 55, 26 to 55 years, and ≤ 25 year age groups. We compared overall survival (OS), progression free survival (PFS), relapse rate and rates of secondary malignancies between these groups. As the outcomes were similar between ≤ 25 and 26 to 55 years groups, subsequent analysis of these two groups was done together as ≤ 55 years vs. > 55 years groups. Baseline patient and disease-related characteristics were compared using the chi-square test for categorical variables and Mann Whitney's rank-sum test for continuous variables. Actuarial OS was estimated using the Kaplan-Meier method. Prognostic factors for OS, disease progression and non-relapse mortality (NRM) were assessed on univariate and multivariate analyses using Cox proportional hazards regression analysis.
Results: 30 (9.7%) patients were > 55, 168 (54.1%) patients were between 26 to 55, and 112 (36.1%) were ≤ 25 years of age. At a median follow-up of 80 months, patients > 55 were at significantly higher risk for mortality with hazard ratio (HR) of 2.3 (95% CI, 1.3-4.2; P = 0.007) compared to patients ≤25 years of age. There was no difference in mortality when between age 26 to 55 years and ≤ 25 years group (HR 1.0; 95% CI, 0.6-1.6; P = 0.9). Risk for progression was similar between the 3 groups, with HRs of 1.3 (95% CI, 0.7-1.5; P = 0.5) and 1.2 (95% CI, 0.8-1.8; P = 0.3) for > 55 group and 26 to 55 groups, respectively compared to ≤ 25 years group (Table 1). Patients > 55 years at diagnosis had significantly higher incidence of secondary malignancies mostly MDS/AML(30% vs. 8%; P<0.001) than patients ≤ 55 years (Figures 1) leading to higher NRM. Prior radiation therapy, time from initial diagnosis to transplant and number of prior therapies did not impact risk for second malignancies.
Conclusion: Patients >55 years at diagnosis who receive auto-HCT for relapsed/refractory HL experience higher mortality from secondary malignancies.
Table 1. Outcomes of Auto-HCT at Median Follow-Up of 80 Months Outcomes Entire Cohort > 55 yearsN = 30 ≤ 55 yearsN = 280 P value OS 65% (59-71) 27% (9-49) 69% (63-74) 0.003 PFS 54% (48-60) 31% (12-53) 56% (50-62) 0.2 CI of progression 41% (26-64) 52% (36-75) 37% (32-44) 0.7 CI of NRM 8% (5-12) 33% (16-65) 5% (3-9) 0.001 CI of second malignancy 11% (7-16) 30% (16-57) 8% (5-14) < 0.001 CI of second malignancy excluding skin cancers 9% (6-13) 22% (10-49) 7% (4-12) 0.003 SHAPE P=0.001 P <0.001
Figure 1. A-CI of second malignancies & 1B-CI of NRM Figure 1. A-CI of second malignancies & 1B-CI of NRM

Disclosures
Fanale: Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Research Funding; Infinity: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Research Funding; Genentech: Research Funding; Medimmune: Research Funding; Novartis: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Molecular Templates: Research Funding; ADC Therapeutics: Research Funding; Onyx: Research Funding; Gilead: Research Funding.