ABSTRACT
These risk factors of advancing age, male gender and co-existing health conditions like cancer, cardiovascular diseases, diabetes and obesity do not fully explain why some people have no or mild symptoms whereas others have severe symptoms. Genomewide association study (GWAS) identify a 3p21.31 gene cluster as a genetic susceptibility locus in patients with COVID-19 with respiratory failure. They also found a higher risk among persons with blood group A and protective effect for blood group O than among patients with other blood groups. The particular haplotype in a region of chromosome 3 is contributed to modern humans by neandertals. Another Neanderthal haplotype on chromosome 12 is associated with a 22% reduction in relative risk of becoming severely ill with COVID-19. The ApoE e4e4 homozygous genotype was found to increase the risk of severe COVID-19. Change in angiotensin converting enzyme (ACE) 2 gene was also found to be associated with increased risk of COVID-19, cardiovascular and pulmonary conditions. Copyright © 2021, Kathmandu University. All rights reserved.
ABSTRACT
Background: Bispecific antibodies (bsAb) are a promising class of therapeutics in RRMM. While hypogammaglobinemia (HGG) is anticipated due to plasma cell depletion, there is a lack of information about the degree of secondary immunodeficiency and resultant infectious complications. We investigated the kinetics of HGG in patients with RRMM on bsAb therapy. Methods: We identified and followed 42 patients treated on early clinical trials of bsAb at our institution between 2019 and 2021. Serial immunoglobulin levels and infections were obtained from the start of therapy until last follow up or 3 months after study exit. Results: 49 treatment courses were included from 42 individual patients. All patients were triple class exposed with a median of 5 prior lines of therapy. The median age was 67 (44-85) years, with 49% females. African Americans accounted for 18% of patients. 96% of patients had at least one prior ASCT. 90% of patients received bsAb targeting BCMA including 7 patients who received more than one line of BCMA targeting therapies. At a median follow up 9.5 (0.9-28.6) months, 40.8% of patients remained on bsAb therapy. At the start of therapy, the median IgG, IgA, and IgM levels were 560 (44-9436), 15 (5-3886) and 6 (5-64) mg/dL, respectively and 50% of patients had severe HGG (≤400mg/dl). Serum IgG levels reached a nadir at 3 months while, IgA and IgM at 1 month, from the start of therapy. The median nadir levels of IgG were 159 (40-2996) mg/dL, while it was < 5 mg/dL for both IgA and IgM. IgG levels were below the detectable range (< 40 mg/dl) in 28% of patients at some point during therapy. IgA and IgM were also below the detectable range (< 5 mg/dl) in 50% and 60% of patients, respectively. At last follow-up, the median IgG levels were 444 (40-1860) mg/dL and IgA 5 (5-254) mg/dL and IgM 5 (5-44) mg/dL. Additionally, 38% of patients remained severely hypogammaglobinemic. 57% (24/42) of patients received IVIG supplements in the current series. About 71% of patients had at least one infectious event and the cumulative incidence of infections progressively increased with increasing duration of therapy with risk at 3, 6, 9 12, 15 months being 41%, 57%, 64%, 67% and 70%, respectively. Among these, 54% of infection were bacterial. Viral infection accounted for 41% of infections. A third of patients had new infectious events during the first 90 days following stopping bsAb treatment. 57% (8/14) of patients did not mount a response to the primary COVID19 immunization series. Among the five patients with repeat antibody titers after the booster dose, 50% were still not able to mount an antibody response. Conclusions: bsAb therapy in RRMM can be associated with profound and prolonged HGG. The cumulative risk of infection correlated with the degree of HGG and progressively increases with treatment and persisted months after being off therapy. Additionally, an impaired antibody response to the COVID-19 immunization series was also noted.
ABSTRACT
Introduction: B cell maturation antigen (BCMA) is a novel target for T cell immunotherapy in MM including bispecific antibody (bsAb) and chimeric antigen receptor therapy (CAR-T). BCMA is critical for survival of the long-lived plasma cell, responsible for generation of protective antibodies. Impaired immune reconstitution, cytopenias, B cell aplasia and hypogammaglobinemia can compound preexisting MM-induced immunosuppression. In the case of bsAb, potential redirection/activation of T regulatory cells can create an immunosuppressive milieu. Herein, we describe the clinically relevant infectious complications observed across different BCMA-directed therapies used across multiple clinical trials at our center. Methods: Infections confirmed by microbiologic or histopathologic evidence were captured from the D1 C1 of bsAb and D 1 of lymphodepleting chemotherapy of autologous BCMA CAR-T therapies. The NCI CTCAE v5 was used to describe the site and grade of infections. Hypogammaglobinemia and severe hypogammaglobinemia were defined as ≤700 mg/dl and ≤400 mg /dl, respectively. Standard antimicrobial prophylaxis included herpes zoster prophylaxis for all MM patients with antibacterial (levofloxacin) / antifungal (fluconazole) during periods of neutropenia and IVIG supplementation as per the treating physician's discretion. PCP prophylaxis was prescribed to CAR T recipient per institutional guidelines. Descriptive statistics and comparisons were performed using two-sample t-test for continuous variables and chi-square goodness of fit test for categorical variables. Results: We identified 62 patients who received BCMA-directed bsAb (n=36) or CAR-T (n=26) between 2019-2021(table 1). The median age was 66 (range 48-84) years with % females and 14.8% of patients belonging to Black race. The median time to bsAb and CAR-T use from diagnosis were 6.6 (range 0.83-15.5) and 2.6 (range 0.35-14.4) years, respectively. The median lines of prior therapy were 6 (range 1-11) with BCMA CAR-T recipients receiving fewer prior lines of therapy (4 vs 6, p=<0.001). The baseline lymphocyte count was higher in the CAR-T (14.71 vs 0.84;p=<0.001). Baseline severe hypogammaglobulinemia and lymphopenia were present in 30% and 26.7% of all patients, respectively. Tocilizumab was used in 40.9% (bsAb -30.8% versus CAR-T 55.6%) patients for CRS. IVIG was used in 25% of patients. The median study duration for bsAb was 4 (range 0.03- 24) months across multiple dose levels. Median follow up among CAR-T recipients was 3.9 (range 0.3 - 22.3) months. Among recipients of bsAb, 41.2% of patients experienced at least one episode of infection vs. 23.1% with CAR-T (p=0.141). The cumulative incidence of infection with bsAb and CAR-T were 22 and 8, respectively. The spectrum of infections with bsAb was predominantly bacterial (64.3% While gram negative infection (Escherichia coli and Klebsiella pneumoniae bacteremia, Proteus mirabilus and Psuedomonas aeroginosa urinary tract infections) were seen in 6 patients, skin infection including cellulitis occurred in 4 patients, with 1 case of necrotizing cellulitis. Bacteremia with rare opportunistic pathogens - Rhizobium radiobacter and recurrent Ochrobacterium anthropi were also observed . Viral infections included rhinovirus, cytomegalovirus, and parvovirus B19 reactivation, and COVID-19. About 50% of infections were ≥ grade 3 with 2 grade 5 events (Pseudomonas aeruginosa bacteremia and COVID-19). In the CAR-T group, we observed more viral infections (66.7% vs 35.7%;p=0.028) and fewer bacterial infections (33.3% vs 64.3%;p=0.028) . Common viral infections included rhinovirus, RSV, and herpes simplex virus reactivation. In this group 25% of infections were ≥grade 3. Conclusion: BCMA-targeted therapies seem to be associated with clinically significant bacterial and viral infections. Repetitive dosing with bsAb therapies could be the reason for the propensity to serious bacterial infections compared to CAR-T recipients and may need novel prophylaxis strategies. (Figure Presented).
ABSTRACT
These risk factors of advancing age, male gender and co-existing health conditions like cancer, cardiovascular diseases, diabetes and obesity do not fully explain why some people have no or mild symptoms whereas others have severe symptoms. Genomewide association study (GWAS) identify a 3p21.31 gene cluster as a genetic susceptibility locus in patients with COVID-19 with respiratory failure. They also found a higher risk among persons with blood group A and protective effect for blood group O than among patients with other blood groups. The particular haplotype in a region of chromosome 3 is contributed to modern humans by neandertals. Another Neanderthal haplotype on chromosome 12 is associated with a 22% reduction in relative risk of becoming severely ill with COVID-19. The ApoE e4e4 homozygous genotype was found to increase the risk of severe COVID-19. Change in angiotensin converting enzyme (ACE) 2 gene was also found to be associated with increased risk of COVID-19, cardiovascular and pulmonary conditions.