Patterns of Clinical Presentation in Patients with Classical Hodgkin Lymphoma and Impact on Prognosis
Authors: Strelec Lauren E. , Nagle Sarah Jordan , DiAngelo Zachary , Nasta Sunita Dwivedy , Mato Anthony R. , Landsburg Daniel J. , Schuster Stephen J. , Svoboda Jakub 
Published: October 2019

Abstract
Background: Patients with classical Hodgkin lymphoma (cHL) often present with asymptomatic lymphadenopathy or generalized symptoms including fevers, night sweats, or cough. The non-specific nature of cHL presentation may contribute to long time intervals between symptom onset and diagnosis. An adverse effect on overall survival due to delays between diagnostic biopsy and treatment initiation has been suggested (Connors, Blood 2014). However, the impact on prognosis due to time interval between initial onset of lymphoma-related symptoms/signs to diagnosis is unknown.
Methods: We conducted a retrospective study of cHL patients seen at a tertiary university center between 2006 and 2015. Eligible patients were age ≥18 with biopsy-proven diagnosis of cHL who completed frontline curative-intent chemotherapy. We reviewed medical records to obtain date of patient-reported onset of cHL related symptoms/signs prior initial diagnosis, nature of initial symptoms, date of diagnostic biopsy, and date of initiation of therapy. Time to diagnosis (TTD) was defined as the interval between onset of cHL related symptoms/signs to diagnostic biopsy. Patients were divided into 2 cohorts: short TTD (0-12 weeks) and long TTD (>12 weeks). We then evaluated the impact of TTD on progression free (PFS) and overall survival (OS) measured from date of treatment initiation. Univariate and multivariate analyses were used to determine the association of TTD with variables known to affect cHL prognosis: stage (limited vs. advanced), age (<45 vs. ≥45), and sex. Descriptive and survival analyses using Kaplan-Meier methodology were performed (STATA v. 14). A log-rank test was utilized to compare OS and PFS in the two cohorts. Data are reported through 7/2016.
Results: A total 114 cHL patients were eligible for the study of which 59 (52%) were male. Median age at diagnosis was 36 years (range 18-78), and 15 (13%) were non-white. Disease stage included 13 (11%) stage I, 47 (41%) II, 21 (18%) III, 32 (28%) IV, and 2 (2%) unknown. Histologic subtypes included 80 (70%) nodular sclerosing, 16 (14%) mixed cellularity, 4 (4%) lymphocyte-rich, and 14 (12%) indeterminate. Most common initial cHL related symptom or signs included 60 (53%) patients with asymptomatic lymphadenopathy, 16 (14%) fevers, 42 (37%) night sweats, 30 (26%) weight loss, 16 (14%) cough, and 7 (6%) pruritus. Fifty-five (48%) patients had short TTD and 59 (52%) had a long TTD. At median follow-up of 36 months, median PFS and OS of the total cohort were not reached. PFS by TTD is shown in Figure 1. 22 (40%) patients with short TTD relapsed or failed to respond to therapy vs. 13 (22%) patients with long TTD (p<0.05). The mean time from pathologic diagnosis to treatment was 28 days for short TTD and 26 days for long TTD (p=0.54). Of 28 patients who had significant diagnostic delay (defined as more than 6 months between onset of symptoms to diagnosis), only 1 (4%) patient died of their disease and 5 (18%) relapsed or failed to respond to therapy. Univariate and multivariate analyses revealed that age, stage, sex, and histologic subtype were not significantly associated with TTD.
Conclusions: To our knowledge, this is the first study to examine the impact of interval from initial onset of lymphoma related symptoms/sign to diagnosis in cHL patients. In our cohort, shorter interval from symptom onset to diagnosis was associated with inferior PFS which may reflect the aggressive nature of cHL in these patients. Planned correlation of time to diagnosis with known adverse prognostic indicators may validate this hypothesis. In the meantime, patients and physicians may be reassured by our findings that support excellent outcomes even in those with significant delays from symptom onset to diagnosis.
Figure 1 Figure 1.

Disclosures
Nasta: Millennium Pharmaceuticals: Research Funding. Mato:Abbvie, Gilead Sciences, Pharmacyclics, TG Therapeutics: Consultancy; Abbvie, Acerta Pharma, Gilead Sciences, ProNAi, TG Therapeutics, Theradex: Research Funding. Schuster:Hoffman-LaRoche: Research Funding; Merck: Research Funding; Janssen Research & Development: Research Funding; Pharmacyclics: Consultancy, Research Funding; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Gilead: Research Funding. Svoboda:Seattle Genetics: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding.