Immune Recovery Post BCMA CAR-T: Implications for Infection Prophylaxis and Vaccinations

Introduction: As BCMA targeted therapies are now coming into vogue in advanced multiple myeloma, prolonged immunosuppression is increasingly being recognized as an important adverse event leading to susceptibility to infections and impaired immune responses to vaccinations. As awareness of this important issue grows, acquisition of data to define the depth and spectrum of this problem is key to developing infection prophylactic and vaccination guidelines.

Methods: Toward this goal, we analyzed retrospective data on 82 patients who had undergone a CAR-T procedure on clinical trials at our institution from April 2017 - May 2022, especially focusing on immunologic recovery of IgA and IgM levels, absolute lymphocyte counts (ALC), and lymphocyte subsets including CD3, CD4, CD8, B and NK cell counts at various time points ie., 3 months, 6 months, 12 months, 18 months and 24 months post CAR T infusion, for patients who continued in remission. Data were also collected on vaccine antibody levels post COVID vaccination. Data collection was stopped when patients progressed or died after CAR T infusion. This study has been approved by the Mount Sinai IRB.

Results: 76 patients were in complete remission (CR) for > 3 months, 59 patients for > 6 months, 44 patients for > 12 months and 28 patients for > 24 months.

Median time to recovery of ALC for patients who were in CR for > 6 months was 9 months. Of 44 patients who were in CR for 12 months or longer, 19 had not recovered ALC to at least 1000/microL (43%) by 12 months.

As per our institutional practice, IVIG was administered to all patients for the first 6 months post CAR-T therapy, and frequently beyond that for hypogammaglobulinemia (HGG) or frequent infections. Therefore, IgA and IgM levels were analyzed as they were deemed to be more accurately reflective of recovery from HGG. Of 44 patients who were in CR for > 12 months, only 8 patients (18%) had recovered IgA level to at least 70 mg/dl by 12 months post CART infusion, and of 28 patients who were in CR for at least 24 months, 46% had recovered IgA levels by 24 months post CART infusion. At the same time points, IgM levels had recovered to at least 40 mg/dl in 32% and 64% of patients respectively (Fig 1). Median time to recovery for IgA was 30+ months, and for IgM was 24 months.

We then looked at lymphocyte subset recovery of CD3, CD4, CD8, B and NK cells. The lower limits of normal range for CD3 was 500/CU MM, for CD4 was 300/CU MM, for CD8 was 90/CU MM, for B lymphocytes was 16/CU MM and for NK cells 35/CU MM. The percentage of patients who had achieved recovery for these parameters at the 3 months, 6 months, 12 months and 24 month time points are shown in the graph in Fig 2. In the 59 patients who had CR of 6 months or more, 75%, 73%, 56%, 54% and 39% of patients had recovered NK, CD8, B cell, CD3 and CD4 subsets respectively by 6 months, and at 12 months 82%, 77%, 64%, 59% and 48% of 44 patients who were in CR had recovered these subsets (Fig 2). Median time to recovery for CD3 and B lymphocytes was 6 months, and for CD4 was 9 months.

Of note, percentages at 24 months did not show significant increase in recovered patients beyond 12 months for the various lymphocyte subsets. 21% of patients had not recovered CD3 count and 16% patients had not recovered B cell count at 1 year post CART, and at 2 years post CART 21% of patients and 17% of patients had still not recovered CD3 and B cell counts.

36 patients in CR at 3-38 months post CART had COVID vaccine antibody data post vaccination. 13/36 patients (36%) had COVID Ab levels < 100 AU/mL, all 13 of them had not recovered both IgA and IgM. 18/36 (50%) patients had COVID Ab level < 300 AU/mL, all 18 had not recovered at least 1 immunoglobulin level, either IgA or IgM.

Conclusions: Overall, more than a third of patients have not recovered IgM, CD3 and B cells at 2 years post CART, even though they are still in CR, and over half have not recovered IgA levels, thus at least partially explaining the poor response to vaccinations and susceptibility to infections in these patients. Incremental improvements in recovery of these parameters beyond 1 year seem minor. Data driven clinically significant antibody levels post COVID vaccination in immunosuppressed patients are yet to be defined. However, higher antibody levels are associated with improved protection against infection, particularly in the immunosuppressed. Further study with translational data will offer scientifically based guidance for prophylaxis of infections and for optimal timing of vaccinations.

Richard:Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria; C4 Therapeutics: Research Funding. Lancman:Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Chari:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Array Biopharma: Research Funding; Glaxo Smith Klein: Research Funding; Novartis Pharmaceuticals: Research Funding; Oncoceutics: Research Funding; Pharmacyclics: Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees. Rossi:gsk: Consultancy; sanofi: Consultancy; BMS: Consultancy; janssen: Consultancy; adaptive: Consultancy. Cho:BMS/Celgene: Other: Receive laboratory research support from the above companies. Salary value is less than $10,000 per company., Research Funding; Takeda: Other: Receive laboratory research support from the above companies. Salary value is less than $10,000 per company., Research Funding. Sanchez:Takeda: Consultancy. Richter:BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Secura Bio: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Takeda: Consultancy. Rodriguez:Janssen, BMS, Takeda, AbbVie, karyopharm, Artiva: Consultancy, Speakers Bureau. Verina:janssen: Speakers Bureau; karyopharm: Speakers Bureau; BMS: Speakers Bureau; sanofi: Speakers Bureau. Escalon:Rigel Pharmaceuticals: Speakers Bureau. Jagannath:Janssen Pharmaceuticals: Consultancy; Sanofi: Consultancy; BMS: Consultancy; Legend Biotech: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy.