Impact of Pre-Transplant Rituximab on Efficacy of Revaccination of Lymphoma Patients after Autologous Hematopoietic Stem Cell Transplantation
Authors: Preston Elaina V. , Palazzo Meighan A. , Seier Kenneth , Devlin Sean M , Giralt Sergio , Scordo Michael , Dahi Parastoo B. , Matasar Matthew J , Moskowitz Craig H. , Sauter Craig S. , Shah Gunjan L. , Perales Miguel-Angel 
Published: October 2019

Abstract
Background: Guidelines recommend reimmunization starting 12 months after autologous hematopoietic stem cell transplant (AHCT). However, lymphoma patients routinely receive rituximab, an anti-CD20 monoclonal antibody that depletes CD20+ B-cells and may impair response to vaccination. We have shown that rituximab use may prevent on time vaccination in patients who undergo an allogeneic stem cell transplant (BBMT 2018 S427-S428). We therefore aimed to evaluate the impact of rituximab on responses to revaccination after AHCT and included patients with B-cell Non-Hodgkin Lymphoma (B-NHL) and T-cell NHL (T-NHL) and Hodgkin Lymphoma (HL), with the latter two groups not routinely receiving rituximab.
Methods: Lymphoma patients who underwent AHCT between 2012 - 2016 were identified from the institutional database and included if they had completed the primary series and had pre- and post-vaccination titers to evaluate for response. Patients were divided by histology (B-NHL vs T-NHL and HL), and chart reviewed confirmed if they had received pre- or post- AHCT rituximab. Vaccine responses were determined by comparison of pre- and post- vaccination titers. Patients were classified as responders, non-responders, immune by pre-vaccination titer, and not evaluable due to missing data (had not received vaccine or had missed pre- or post-vaccination titers) by previously described criteria (Palazzo BBMT 2017). Descriptive statistics were used to summarize results, and the Fishers exact test was used for comparisons.
Results: Of the 161 patients who met our inclusion criteria, 104 (65%) received rituximab pre-AHCT with 20% of these receiving additional rituximab post-HCT. Of the 57 patients who did not receive pre-AHCT rituximab, 2% received post-AHCT rituximab. The median age of the whole group was 53 years (range, 19-73), with patients not receiving rituximab being younger (median age 43 years (range 19-71) vs 58 years (21-73), p<0.001). While 57% of the total population was male, there was a statistically significant difference based on rituximab use (42% of those not receiving rituximab vs 65.5% of those receiving rituximab, p=0.005). The no rituximab group comprised of 67% HL and 33% NHL, while the rituximab receiving group was 83% NHL. The most common conditioning regimen was BEAM (77%, carmustine, etoposide, cytarabine, and melphalan) with 12% receiving TBC (thiotepa, busulfan, and cyclophosphamide). Time to vaccination from AHCT was not different with a median of 12.4 months (range 9.1-21.8) in the no rituximab group compared to 12.6 months (range 11.3 - 45.7) in the rituximab exposed patients (p=0.08). The median time between last pre-AHCT rituximab and first vaccination was 14.1 months (range 12 - 79.8 months).
Most patients received the completed series for each vaccine (84% Haemophilus influenzae, 99% pneumococcus, 96% polio, 66% tetanus, 76% diphtheria, 91% pertussis, 78% Hepatitis A, and 84% Hepatitis B), but vaccine responses varied by vaccine type with 48% responding to Haemophilus influenzae, 45% pneumococcus, 32% tetanus, 34% diphtheria, 52% pertussis, 31% Hepatitis A, and 37% Hepatitis B (Figure 1). Response to polio vaccine could not be calculated as 53% retained immunity and the rest of the patients were non-evaluable possibly due to a change in assay. No patients retained immunity to pneumococcus or diphtheria on the pre-vaccine titers.
Univariate analyses were performed for pertussis, diphtheria, Hepatitis A, Hepatitis B and Pneumococcal vaccines evaluating the association with age, gender, disease type, and rituximab exposure. More females than males responded to B. pertussis (90% vs 78%, p=0.045). Hepatitis A and Hepatitis B response was associated with a younger age (50.7 years vs 59.6 years, p=0.037 and 54.2 years vs 62.4 years, p=0.007, respectively), and disease type was associated with pneumococcal response (62% HL vs 39% NHL, p=0.022). Patients who did not receive rituximab were more likely to respond to pneumococcus and Hepatitis B (63% vs 35%, p=0.001, and 82% vs 56%, p=0.026, respectively, Figure 2).
Conclusions: Response to reimmunization with inactivated vaccines in lymphoma patients after AHCT is similar to previously reported populations, but prior rituximab exposure appears to impact response.

Disclosures
Matasar: Seattle Genetics: Honoraria. Moskowitz:Merck & Co: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy. Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Precision Biosciences: Consultancy; Kite: Consultancy. Shah:Amgen: Research Funding; Janssen: Research Funding. Perales:Abbvie: Other: Personal fees; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees and Clinical trial support; Takeda: Other: Personal fees; Merck: Other: Personal fees; Novartis: Other: Personal fees.