Classical Hodgkin Lymphoma Patients Have an Increased Incidence of Idiopathic Acquired Aplastic Anemia
Authors: Linaburg Taylor , Davis Adam R. , Frey Noelle V. , Landsburg Daniel J. , Schuster Stephen J. , Svoboda Jakub , Li Yimei , Borovskiy Yuliya , Olson Timothy S. , Bagg Adam , Hexner Elizabeth O. , Babushok Daria V. 
Published: October 2019

Abstract
Idiopathic acquired aplastic anemia (AA) is a rare immune-mediated bone marrow aplasia of unknown etiology. Interestingly, we noted several cases of AA developing after a previous diagnosis of classical Hodgkin lymphoma (HL). Due to the rarity of both HL and AA, we hypothesized that their co-occurrence represents a non-random association that may be etiologically significant. To evaluate this potential association, we analyzed the prevalence, incidence and characteristics of patients with co-occurring AA and HL at our institution and through a systematic literature review.
Using a defined search of electronic medical records for patients seen at our institution between 2005 and 2018, we identified 4 patients with severe AA who were also diagnosed with HL. The prevalence of AA in patients with HL at our institution (0.2%; 4 of ~2040) was in agreement with the prevalence of AA in published cohorts of HL patients (e.g., 1 in 138 - 200; p 0.205). Using a conservative incidence measure of AA, we found that patients with HL have a striking, over 20-fold higher incidence of AA compared to the published incidence of AA in the general population (4 in 26,497 person-years vs 2.2 to ~7 in 1,000,000 person-years; p=0.0001). To determine the clinical and pathologic characteristics of AA in patients with a history of HL, we expanded our study by performing a systematic literature review. Using the search terms "Hodgkin lymphoma", "Hodgkin disease", "aplastic anemia" and "pancytopenia" in the PubMed database, we identified 7 cases of associated AA and HL diagnoses published between 1956 and 2007. Patients with other HL complications, such as post-chemotherapy myelosuppression, infections, myelodysplastic syndrome, acute leukemia, and hemophagocytic syndrome were excluded.
Of the 11 total cases of AA also diagnosed with HL, the median age at AA diagnosis was 31.5 years (range of 12-49 years), with 80% of patients being male (Figure 1, Table 1). Ten of the 11 patients developed AA after or concurrent with a HL diagnosis. The median interval between HL diagnosis and AA onset was 2 months, ranging from concurrent presentation in 5 patients to a maximum of 14 years after an initial HL diagnosis. Of the 10 patients initially presenting with HL, 3 were treated with ABVD, 4 with MOPP-related regimens, and 2 patients required salvage therapy. There were no unusual hematological or other toxicities due to chemotherapy. At the time of AA diagnosis, none of the patients had marrow involvement with HL, and 5 of 10 patients were in complete remission from HL. Five patients for whom cytogenetic information was available had no cytogenetic abnormalities at AA diagnosis. Among the 4 cases from our institution, 2 had a diagnosis of marginal zone lymphoma (1 treated by splenectomy, 1 by rituximab monotherapy), and 1 had a remote history of testicular carcinoma treated by orchiectomy; all 3 cases were in remission prior to HL diagnosis. There was no family history indicative of bone marrow failure or inherited cancer syndromes.
The 10 patients who developed AA concurrent with or after HL had dramatically poor outcomes, with a median survival of 14 months (range of 1 month to not reached) (Figure 1, Table 1). Of these 10 patients, 4 were treated with immunosuppression, 2 with eltrombopag, and 2 received allogeneic bone marrow transplants. Of the 4 patients who received immunosuppression, 1 evolved to MDS/AML 4 months after AA diagnosis. Five patients presented with both diagnoses concurrently: 1 was refractory to immunosuppression and achieved complete remission after receiving an allogenic bone marrow transplant, while 4 were unable to receive standard therapy for either condition. Of the historical cases, 5 of the 7 patients received supportive therapy only; the median survival for these patients was 14 months (range of 1 month to 84 months).
In conclusion, the data suggest that patients with HL have a significantly higher incidence of AA compared to the general population. The underlying reason for this association is not known; however, the development of AA after HL, a unique B-cell neoplasm associated with a marked inflammatory component, without having received prior cytotoxic therapy in half of the cases, points to secondary immune dysregulation as the possible etiologic factor for AA pathogenesis. Recognition of this syndrome and improved management algorithms are needed for the management of AA presenting in patients with HL.

Disclosures
Frey: Novartis: Consultancy; Servier Consultancy: Consultancy. Landsburg:Curis: Consultancy, Research Funding; Takeda: Consultancy. Schuster:Dava Oncology: Consultancy, Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Svoboda:Kyowa: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; KITE: Consultancy; TG Therapeutics: Research Funding; Regeneron: Research Funding; Seattle Genetics: Consultancy, Research Funding; Merck: Research Funding. Olson:Novartis: Other: participated in 2 advisory boards in 2018; Merck: Other: participated on an advisory board in 2018; BluebirdBio: Other: participated in an advisory board in 2018.