VACARME : Analysis of humoral protection at baseline and after vaccination in patients with refractory/relapsed lymphoma and myeloma treated with CD19 and BCMA CAR T-cells.

Abstract Introduction Introduction. CART-cell therapy targeting CD19 and B-cell maturation antigen (BCMA) has improved the prognosis of patients (pts) with relapsed/refractory (R/R) non-hodgkin lymphoma (NHL) and multiple myeloma (MM). Upon sustained remission, infections are major causes of morbidity and mortality, some of which are vaccine-preventable. Still, there are limited evidence on vaccine immunogenicity and seroprotection after CAR T-cell therapy. This explains that the vaccination schedule after CAR T-cell is translated from guidelines used in recipients of hematopoietic stem cell transplantation. This study aims to assess humoral vaccine-induced response after vaccination in comparison with baseline in pts with R/R NHL and MM treated with anti-CD19 or anti-BCMA CAR T-cells. Patients and Methods. Pts eligible for the study had a progression-free survival of 6 months or more after CAR T-cells. Pts who had received infusion of immunoglobulins within the past 2 months were excluded. Samples were collected at the time of lymphodepletion and at least six months after CAR T-cell infusion. The seroprotection rate was defined using pre-established cutoffs (or 4 fold increases after vaccination) of IgG-specific antibodies. Post-vaccination titers were obtained at least one month after the final dose was administered. Results From 509 pts treated by CAR T-cell therapy targeting CD19 and BCMA between 2017 and 2024 in a tertiary department of hematology, we retrospectively included 92 pts who were evaluated for seroprotection levels against diphtheria (D), tetanus (T), Haemophilus influenzae (Hib), hepatitis A (HA) and B viruses (HB), the varicella-zoster virus (VZV), and the measles virus (Mv). Median age was 66 (IQR 58-72) and 64 (54-71) year old for MM and NHL pts, respectively. In MM pts, the median number of previous lines was 3 [IQR 3-5], among whom 76% (n=19/25) had received an autologous stem cell transplantation (ASCT). In NHL pts the median number of previous lines was 2 [IQR 1-3], among whom 21% (n=15/68) had received an ASCT. Forty-five pts received a three-dose revaccination schedule with the pediatric combined D, T, acellular Pertussis (aP), HB, inactivated poliovirus (IPV), Hib conjugate vaccine (DTaP-HB-IPV-Hib) and with the pneumococcal (Pc) conjugate vaccine containing 13-valent. Upon lymphodepletion preceding CAR T-cell infusion, MM pts (n = 24) had significantly lower sero-protection rates compared to NHL pts (n=68) against D: 4/23 (17%) vs. 30/60 (50%), T: 8/24 (33%) vs. 57/62 (92%), Hib: 2/24 (8%) vs. 29/61 (48%), VZV: 7/24 (29%) vs. 57/62 (92%), and Mv: 12/24 (50%) vs. 58/62 (94%). There was a trend toward lower HB sero-protection titers in MM pts [4/24 (17%)] compared to NHL pts [23/62 (37%)] (p=0.12). Similar immunization rates were found for HA (52% for both groups). At least 6 months after CAR T-cell infusion, the seroprotection rates of pts against D, T, Hib,VZV and Mv remained similar. In vaccinated pts, the median time from CAR-T cell infusion to first vaccine administration was 7 months (IQR, 6-11). Among pts who were not protected prior to vaccination, the response rates were as follows: 82% for D (14/17), 100% for T (4/4), 26% for Hib (6/23), 52% for HB (14/27), and 12% for pneumococcus (Pc) (3/26). The geometric mean titers (GMTs) increased significantly after revaccination against D (0.08 to 0.49; p =0.001), T (0.35 to 0.61; p =0.015), Pc (8.93 to 14.35; p =0.057), and HB (5.54 to 16.12; p =0.035), but not for Hib (0.30 to 0.81; p =0.104). Among immune factors, we found that pts with detectable circulating B lymphocytes CD20+ (cut off > 64 cells/mL) exhibited significantly higher antibody titers following the D and HB vaccines compared to pts with undetectable B cells (p <0.01 and p<0.01, respectively). Conclusion Pts treated with CAR T-cells retain immunity of prior vaccines. We observed lower sero-protection in MM pts treated by BCMA CAR T-cell compared to NHL pts treated with anti CD19 CAR T-cells, due to prior treatments targeting long-lived plasma cells. Immunization against D, T, Hib, and HB is effective in CAR-T cell recipients at least six months after infusion suggesting that memory B cells can be remobilized. These findings highlight the clinical relevance of implementing early and targeted revaccination strategies to restore protective immunity and prevent severe infections in CAR T-cell recipients.