Late Effects of High-Dose Chemotherapy and Autologous Hematopoietic Cell Transplantation (HDT-AHCT) in Elderly Patients with Lymphoma
Authors: Dahi Parastoo B. , Obioha Chikaodi , Kenny Sheila , Hilden Patrick , Maloy Molly , Geyer Alexander , Schaffer Wendy , Tamari Roni , Sauter Craig S. , Jakubowski Ann A. , Giralt Sergio 
Published: October 2019

Abstract
Background: High-dose chemotherapy and autologous hematopoietic cell transplantation (HDT-AHCT) is an established treatment for non-Hodgkin lymphoma (NHL). Incidence of NHL is highest in patients over 60 years of age, however, limited data is available on long-term effects of HDT-AHCT in older patients. This study is conducted to evaluate the late cardiopulmonary effects and overall outcomes of HDT-AHCT in older patients.
Methods: This is a single-center, retrospective study examining late cardiopulmonary effects, and overall outcomes of HDT-AHCT in 41 patients age 70 years and older, with NHL, between January 2000 and December 2016. Clinical data and comorbidities were correlated with outcomes. Pre- and post-transplant pulmonary function tests (PFT) and echocardiograms were compared. Overall survival (OS) and progression-free survival (PFS) were analyzed according to age, gender, disease histology, disease stage at diagnosis, number of lines of treatment, Karnofsky Performance Status (KPS), hemoglobin adjusted diffusing capacity of lungs for carbon monoxide (DLCO), left ventricular ejection fraction (LVEF), and hematopoietic cell transplantation comorbidity index (HCT-CI) at the time of HDT-AHCT.
Results: A total of 41 patients underwent HDT-AHCT for follicular or diffuse large B-cell lymphoma (FL / DLBCL n=18 44%), mantle cell lymphoma (MCL n=15 37%) and T-cell or other NHL subtypes (n=8 19%). The median age was 72 (range 70-77). Eight (19%), 6 (15%) and 27 (66%) patients had a low (0), intermediate (1-2) and high (≥3) HCT-CI score, respectively, at transplant. All patients except 1, had received anthracycline as part of initial treatment. BEAM and RR-BEAM were the most common conditioning regimens (n=38 93%). Pre-transplant LVEF was within normal range in all patients except 1 (45%). The median (range) pre- and post-transplant LVEF was 63% (45-74%) and 64% (39-71%), respectively. Of the 23 patients who had a post-transplant echocardiogram (median time between the pre- and post-transplant echocardiogram was 423 days), a mild decrease in LVEF was noted in 3. Only 1 patient had a significant decline of 19% in LVEF. Pulmonary artery pressure (PAP) was within normal range pre- and post-transplant in all. The median (range) of pre-transplant DLCO, FEV1 and FVC were 70% (48-125%), 97% (83-141%), and 98% (57-123%), respectively. Of the 10 patients who underwent post-transplant PFT (median time between the pre- and post-transplant PFT was 405 days), DLCO decline of >10% was the most common abnormality, and developed in 4 out of 10 patients. In 5 patients DLCO improvement of >10% was observed. A greater than 15% improvement in FEV1 and FVC was observed in 5 of 10 and 4 of 10 patients respectively. The median improvements in FVC, FEV1 and DLCO were 4%, 6% and 10%, respectively. With a median follow-up of 58 months (range 5-123) for survivors, PFS and OS at 3 years were 84% (95% CI, 67-92%) and 94% (95% CI, 80-99%), respectively. In a univariate analysis, age, gender, histology, disease stage, number of lines of treatment, DLCO, LVEF, and HCT-CI score did not affect OS or PFS. However, KPS ≥90 was associated with worse OS (p=0.008). The small sample size may have been a contributor to this unexpected finding. Relapse occurred in 11 patients (27%), 8 of whom died. Median time to relapse was 38 months (range 26-100). Secondary malignancies developed in 4 patients (8%) which included acute myeloid leukemia in 2, melanoma in 1, and esophageal cancer in 1, and led to death in 3.
Conclusion: In this cohort of elderly patients with NHL who underwent HDT-AHCT, the late declines in cardiopulmonary function were minimal, and none resulted in mortality. Secondary malignancy was the only cause of non-relapse mortality. This can be explained by age being the biggest single risk factor for cancer development in general, in addition to the effects of HDT. We show that the most common cause of long-term mortality after HDT-AHCT continues to be lymphoma recurrence. Our data though limited by small number of patients and its retrospective nature, suggest that age alone is not predictive of post-transplant late effects and outcomes, and therefore should not be used to preclude HDT-AHCT in elderly. While prospective studies with larger number of patients are needed to evaluate long-term effects of HDT-AHCT on different organ functions in older adults, strategies to mitigate risk of relapse remain the most important area to improve outcomes.

Disclosures
Sauter: Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Precision Biosciences: Consultancy; Kite: Consultancy.