Combined Immune Defect in B-Cell Lymphoproliferative Disorders Is Associated with Severe Infection and Cancer Progression

This research received no external funding. K.G.-H is supported by The European Social Fund (ESF) through a Río Ortega Grant for Health Research Projects by the Carlos III Health Institute (ISCIII) (CM20/00098).B cell chronic lymphoproliferative diseases (B-CLPD) are associated with secondary antibody deficiency and other innate and adaptive immune defects, whose impact on infectious risk has not been systematically addressed. We performed an immunological analysis of a cohort of 83 B-CLPD patients with recurrent and/or severe infections to ascertain the clinical relevance of the immune deficiency expression. B-cell defects were present in all patients. Patients with combined immune defect had a 3.69-fold higher risk for severe infection (p = 0.001) than those with predominantly antibody defect. Interestingly, by Kaplan–Meier analysis, combined immune defect showed an earlier progression of cancer with a hazard ratio of 3.21, than predominantly antibody defect (p = 0.005). When B-CLPD were classified in low-degree, high-degree, and plasma cell dyscrasias, risk of severe disease and cancer progression significantly diverged in combined immune defect, compared with predominantly antibody defect (p = 0.001). Remarkably, an underlying primary immunodeficiency (PID) was suspected in 12 patients (14%), due to prior history of infections, autoimmune and granulomatous conditions, atypical or variegated course and compatible biological data. This first proposed SID classification might have relevant clinical implications, in terms of predicting severe infections and cancer progression, and might be applied to different B-CLPD entities.Depto. de Inmunología, Oftalmología y ORLFac. de MedicinaTRUEpu

Economic impact of immunoglobulin replacement therapy in secondary immunodeficiency to hematological cancer: a single center observational study

This is the first report of the health economic benefits derived from preventing infections through Immunoglobulin Replacement Therapy (IgRT) in patients with secondary immunodeficiency due to hematological malignancies. We conducted a retrospective population-based cohort study using patient medical history and pharmacy data from the Hospital Clínico San Carlos for 21 patients between 2011 and 2020. The pharmacoeconomic impact of using prophylactic IgRT was assessed by comparing characteristics of the SID patients 1 year before and after initiating IgRT measured by direct medical and tangible indirect costs. Results indicate a marked reduction in hospitalization days following IgRT initiation, decreasing from an average of 13.9 to 6.1 days per patient, with the elimination of ICU admissions. While emergency department visits decreased significantly, the number of routine consultations remained unchanged. Notably, absenteeism from work dropped substantially. The financial analysis revealed significant reductions in medication use and fewer ancillary tests, resulting in considerable cost savings. Specifically, total expenditure dropped from €405,088.18 pre-IgRT to €295,804.42 post-IgRT—including the cost of IgRT itself at €156,309.60. Overall, the annual savings amounted to €109,283.84, validating the cost-effectiveness of IgRT in managing SID in patients with hematological cancers

B‐cell haematological malignancies and SARS‐CoV‐2 infection: Could immunological interventions influence the outcome?

Abstract B cell haematological malignancies (HMs) have been described as the worst cancer type for concomitant COVID‐19 in terms of mortality, with rates up to 65%. This risk factor for COVID‐19 cannot only be explained by comorbidities and advanced age of patients, but aggravated by secondary immunodeficiency (SID). We aimed at evaluating the impact of COVID‐19 on 86 HM patients with concomitant SID from a single centre. Only 14 HM patients of 86 (16.28%) patients suffered COVID‐19, with mortality rate of 7%. When we considered patients according to B‐cell defect only or multiple immune defect overlap (B‐T‐cell/NK cells/complement), patients with immune defect overlap presented 5.30‐fold higher risk of COVID‐19 than only B cell defect (95% CI, 1.67–17.0) (p = 0.004). Seven (50%) patients were on active IgRT; while five (36%) had received prior mucosal vaccines for respiratory infections. Our results show that modelling SID in HM may contribute to better prediction of infectious risk and to prompt more targeted and timely preventive therapies

Evaluation of Polysaccharide Typhim Vi Antibody Response as a predictor of Humoral Immunodeficiency in Haematological Malignancies

An increasing healthcare challenge in the management of haematological malignancy (HM) is secondary immunodeficiency. From January 2019, the EMA included the evaluation of specific antibody (Ab) responses to better select patients for immunoglobulin replacement therapy (IgRT). We evaluated Ab responses to pneumococcal and Salmonella typhi pure polysaccharide immunization in a cohort of 42 HM patients and 24 healthy-controls. Pre-post specific Ab concentrations were measured by ELISA at 4 weeks. Globally, significantly lower Typhim Vi (TV) seroprevalence (9%) compared to 23-valent pneumococcal polysaccharide vaccine (PPV) (76%) (p <0.001) was observed. TV non responders (88%) were higher than PPV non responders (62%) (p <0.0001) and correlated better to infectious history. By ROC analysis, pre-post 5-fold TV increase was the best cut-off to discriminate HM with recurrent infections and controls (sensitivity 91%, specificity 100%). Despite the small sample cohort, our results suggest that specific anti-S typhi Ab response is a useful complementary assay in the diagnosis and management decision of SID to HM.Depto. de Inmunología, Oftalmología y ORLFac. de MedicinaTRUEpu

Therapy-Related Myeloid Neoplasms as a Concerning Complication in Acute Promyelocytic Leukemia

Acute promyelocytic leukemia (APL) has become a highly curable malignant disease after the introduction of all transretinoic acid (ATRA) to chemotherapy treatment. However, the risk to develop therapy-related myeloid neoplasms (t-MN) has become a matter of concern, as APL patients are otherwise expected to have a good prognosis. We report a patient with APL who achieved complete remission after chemotherapy induction with anthracycline and ATRA, followed by consolidation and maintenance chemotherapy. Two years later, the patient developed t-AML, with MLL rearrangements, without any evidence of relapse of the APL original clone. The increasing incidence of t-MN in oncohematological patients is partly due to the development of safer, more efficient or targeted therapies, which allow better outcomes and lengthened survival amongst treated patients. The identification of genetic factors, mechanisms or prognostic biomarkers in t-MN might open new windows for the development of personalized targeted therapy regimes in this underserved patient population

Specific Cellular and Humoral Immune Responses to the Neoantigen RBD of SARS-CoV-2 in Patients with Primary and Secondary Immunodeficiency and Healthy Donors

Subvención Fundación CRIS Contra el Cáncer: SSR.C01CRIS KGH cuenta con el apoyo del Fondo Social Europeo (FSE) a través de una Ayuda Río Hortega para Proyectos de Investigación Sanitaria del Instituto de Salud Carlos III (ISCIII) (CM20/00098).Patients with antibody deficiency disorders, such as primary immunodeficiency (PID) or secondary immunodeficiency (SID) to B-cell lymphoproliferative disorder (B-CLPD), are two groups vulnerable to developing the severe or chronic form of coronavirus disease caused by SARS-CoV-2 (COVID-19). The data on adaptive immune responses against SARS-CoV-2 are well described in healthy donors, but still limited in patients with antibody deficiency of a different cause. Herein, we analyzed spike-specific IFN-γ and anti-spike IgG antibody responses at 3 to 6 months after exposure to SARS-CoV-2 derived from vaccination and/or infection in two cohorts of immunodeficient patients (PID vs. SID) compared to healthy controls (HCs). Pre-vaccine anti-SARS-CoV-2 cellular responses before vaccine administration were measured in 10 PID patients. Baseline cellular responses were detectable in 4 out of 10 PID patients who had COVID-19 prior to vaccination, perceiving an increase in cellular responses after two-dose vaccination (p &lt; 0.001). Adequate specific cellular responses were observed in 18 out of 20 (90%) PID patients, in 14 out of 20 (70%) SID patients and in 74 out of 81 (96%) HCs after vaccination (and natural infection in some cases). Specific IFN-γ response was significantly higher in HC with respect to PID (1908.5 mUI/mL vs. 1694.1 mUI/mL; p = 0.005). Whereas all SID and HC patients mounted a specific humoral immune response, only 80% of PID patients showed positive anti-SARS-CoV-2 IgG. The titer of anti-SARS-CoV-2 IgG was significantly lower in SID compared with HC patients (p = 0.040), without significant differences between PID and HC patients (p = 0.123) and between PID and SID patients (p =0.683). High proportions of PID and SID patients showed adequate specific cellular responses to receptor binding domain (RBD) neoantigen, with a divergence between the two arms of the adaptive immune response in PID and SID patients. We also focused on the correlation of protection of positive SARS-CoV-2 cellular response to omicron exposure: 27 out of 81 (33.3%) HCs referred COVID-19 detected by PCR or antigen test, 24 with a mild course, 1 with moderate symptoms and the remaining 2 with bilateral pneumonia that were treated in an outpatient basis. Our results might support the relevance of these immunological studies to determine the correlation of protection with severe disease and for deciding the need for additional boosters on a personalized basis. Follow-up studies are required to evaluate the duration and variability in the immune response to COVID-19 vaccination or infection.Fundación CRIS contra el CáncerCaja SurDepto. de MedicinaFac. de MedicinaTRUEpu