Infusion intravenous IgG replacement therapy for hypogammaglobulinemia after anti-CD20 monoclonal antibodies at patients with non-hodgkin’s malignant lymphomas

Objective. Determining the risk of infectious complications in patients with non-hodgkin’s lymphomas (NМL) who received anti-CD20 monoclonal therapy and the effectiveness of intravenous immunoglobulin G (IgG) replacement therapy. Materials and methods. A prospective analysis of data of 37 persons with NML who were treated in the hematology clinic of the National Military Medical Clinical Center “Main Military Clinical Hospital” from January to December 2019. Statistical data processing was performed using computer programs Microsoft Office Excel (2007) and statistical processing package Statistica 6.0 using the procedure 2×2 Tables (YI/VI/Phil, McNemar, Fisher Exact) module Nonparametric Statistics, which uses the analysis of a four-cell conjugation table. Results and discussion. The mean age of patients was 56.5±1.4 years; 12 (32.43 %) were female patients. Baseline IgG levels before anti-CD20 monoclonal therapy were not determined in 17 (45.94 %) patients. Hypogammaglobulinemia was detected in 20 (54.05 %) subjects who were tested for IgG levels prior to anti-CD20 therapy. After administration of anti-CD20 monoclonal therapy, hypogammaglobulinemia worsened. There was an increase in severe infections after anti-CD20 therapy (from 9.4 to 40.7 %; p<0,001). An analysis of patient survival within 6 months of starting anti-CD20 monoclonal therapy revealed an increased mortality associated with an increase in age (hazard ratio (HR) 1.05; 95 % confidence interval (CI) 1.00-1.02; p<0.005), male (HR 1.12; 95 % CI 1.01-1.18; p<0.005), severe infectious complications (HR 5.18; 95 % CI 3.16-4,72; p<0.001). Only 10 (27.02 %) patients received IgG replacement therapy after anti-CD20 monoclonal therapy. Among these patients, a higher cumulative dose of immunoglobulin replacement therapy was associated with a reduced risk of serious infectious complications (HR 1.00; 95 % CI 0.98-1.02; p<0.005). Conclusions. Monitoring of IgG levels both before and after rituximab therapy may allow for earlier identification of risk for developing significant infection and identify patients who may benefit from IgG replacement, which may in turn help to avoid excess morbidity and mortality.

Comparison of Pneumococcal Avidity and Antibody Concentration in Children with Recurrent Infections: A Retrospective Pilot Study

Measurement of pneumococcal antibody concentration is a frequently used parameter for functional antibody response to vaccination. Antibody concentration in response to vaccination and strength of antigen-antibody (avidity) interaction are both important measurements of functional antibody response. Both antibody concentration and avidity contribute to immunity against invasive pneumococcal disease. Higher avidity is correlated with increasing bactericidal activity and opsonophagocytosis. On the other hand, patients with lower pneumococcal avidity may be more likely to develop clinically significant pneumococcal sinopulmonary infections. Nine patients with recurrent bacterial respiratory infections were identified by retrospective chart review as having adequate pneumococcal antibody concentrations, but with low avidity for multiple serotypes following immunization with pneumococcal vaccine polyvalent (PPSV23). We assessed response with IgG replacement therapy in these patients. The mean number of serotypes with a normal antibody response (>1.3 mg/ml) among 9 children following immunization with pneumococcal vaccine polyvalent was 19.1 (range 12-22) of 23 serotypes while the mean number of serotypes with a normal avidity response (≥1.0) was 4.7 (range 2-7) of 23 serotypes. Flow cytometry was performed for 8 of the 9 patients prior to starting SCIG replacement therapy. 100% of the cohort experienced a significant decrease in yearly infection rate after starting immunoglobulin replacement. This is the first study to assess the clinical response to immune globulin replacement in patients with normal pneumococcal antibody response but poor pneumococcal avidity, and suggests that patients with poor pneumococcal avidity but apparent normal response by pneumococcal antibody following PPSV23 may benefit from IgG replacement therapy.

The Usefulness of Scintigraphic Studies in the Assessment of Asymptomatic Bowel Disease in Patients with Primary Antibody Diseases

Enteropathy may be the first presentation of immunodeficiency or it may occur during the course of the disease and in association with malabsorption in patients affected by primary antibody diseases. For these patients, immunoglobulin G (IgG) replacement therapy prevents infectious and non-infectious complications. Nonetheless some patients cannot achieve optimal IgG trough levels, even when treated with high Ig doses in absence of protein-losing syndromes. We investigated seven patients affected by common variable immunodeficiencies (CVIDs) and treated with high Ig doses (600–800 mg/kg/month) showing low IgG trough level. Patients underwent abdominal scintigraphy with human polyclonal immunoglobulin G labeled with 99mTc and with white blood cells labeled by 111 Indium-oxinate to investigate asymptomatic bowel inflammation. A concentration of labeled leukocytes in abdominal segments greater than that observed with human polyclonal immunoglobulin G was evident only in one patient. In five patients a slight concentration of both radiopharmaceuticals was reported, due to mild intestinal inflammatory response. These data might be related to mild increase of capillary permeability in the absence of inflammation leukocyte mediated. This study discloses a new cause of IgG-accelerated catabolism due to inflammatory bowel conditions without diarrhea in CVID patients.

Reduction of Tumor Burden Rather Than Off-Target Effects Drives Changes in T-Cell Number and Profile during Prolonged Ibrutinib Treatment in Relapsed or Refractory Chronic Lymphocytic Leukemia Patients

In this study, we analyzed the changes occurring in the peripheral blood mononuclear cells (PBMC) during long-term treatment with the Bruton's tyrosine kinase inhibitor ibrutinib in relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) patients (pts). PBMC populations were assessed by flow-cytometry including CLL cells, Natural Killer (NK) cells, T-cell memory subsets, helper subpopulations (Ths) and regulatory T cell (Tregs) subsets. Peripheral blood samples were collected before start of treatment and at week (wk) 4, 10, 16, 22 and at 8, 12, 24 and 36 months (mo) of treatment. Eleven pts were included in the study, 8 males and 3 females, with median age 73 years. Nine age- and sex-matched healthy individuals were included as controls. Comparisons between pts and controls were done with the non-parametric Mann-Whitney U test; between follow-up time points and baseline in pts by Wilcoxon rank test for paired comparisons. Simple regression analyses and the Pearson´s rank test were used to estimate the relationship between different cell populations. Eight pts had high-risk and 3 intermediate-risk disease according to the modified Rai staging system; 8/11 had 17p deletion or TP53 mutation. Three pts had mutated IgHV genes, 3 unmutated, 2 had borderline mutational status (97-98% identity), and 3 were not assessed. Median number of previous treatments was 1 (range 1-4) and median lymphocyte count 45 x 109/L (range 3.1-109.5). At 12 mo, overall response rate was 100%. All pts achieved partial response, with 63% fulfilling all complete response criteria (Hallek M et al, Blood 2018), but for minimal residual disease negativity. Eight pts were still on treatment at 24 mo, 7 pts at 36 mo. Treatment discontinuation was due to: death (n=1), allogeneic transplantation (n=1), disease progression (n=1) and toxicity (n=1). In 3 pts, ibrutinib dose was reduced due to toxicity; the remaining pts stayed on full-dose (420 mg/day p.o.) during the whole treatment period. At study entry, eight pts had hypogammaglobulinemia but none had ongoing IgG replacement therapy. Of these, 5 started IgG replacement therapy during treatment. All 11 patients experienced G2 infections. After an initial increase in circulating CLL cells due to redistribution lymphocytosis, a gradual reduction occurred during treatment becoming significant at wk 16 (p<0.005) (Fig. 1A). As we previously reported (Palma M et al, ASH abs 4322, 2017), at study entry CD8+cells were significantly higher compared to controls (p=0.0005). CD8+cells started to decrease at wk 10 (p=0.02) and normalized (i.e. reached values not significantly different from controls) by 12 mo (Fig. 1B). On the other hand, CD4+T cells, at baseline not significantly different from controls, decreased also gradually from wk 16, reaching by 24 mo levels below normal (p=0.02) (Fig.1D). We show here that the reduction of CD8+ cells correlated with that of CLL cells (r=0.45, p< 0.0001) (Fig. 1C) and that the correlation between the number of CD4+ cells and CLL cells was even more significant (r=0.66, p< 0.0001) (Fig.1E). The expression of the immune checkpoints PD-1 and CTLA-4, at baseline aberrantly high on both CD4+ and CD8+ cells and mainly in the antigen-experienced subsets, decreased gradually during treatment. Among the helper subsets, Th1 (CCR6-/ CXCR3+) cells were at baseline higher compared to controls (p=0.0003), while Th2 (CCR6-/ CXCR3-) did not significantly differ (Fig.2A-B). As expected, this resulted in a Th1/Th2 ratio significantly higher than in controls (median 2.6 vs 0.26, p<0.0001) (Fig.2C). During treatment, both Th1 and Th2 cells decreased. Th1 normalized by 12 mo, while Th2 cells decreased below normal levels at 12 mo (p=0.006). However, Th1/Th2 ratio never normalized during 36 mo of treatment. The strongest direct correlation was between the decrease of Th1 cells and CLL cells (r=0.68, p< 0.0001). During treatment, NK cells decreased and also Tregs (CD4+/CD25+/ CCR4+/CD127low), in particular the Ag-experienced non-activated subset (CD45RO+HLA-DR-). In conclusion, the reduction of tumor burden directly correlated with the reduction of all T-cell subsets, but most significantly with those subsets involved in the antitumor immune response, i.e. CD8+cells and, among the CD4+subset, Th1 cells. Whether these changes also compromised the anti-infection immunity is difficult to assess, due to the fact that most of the pts had also underlying hypogammaglobinemia. Disclosures Palma: Takeda Pharma AB: Research Funding. Österborg:Gilead: Consultancy, Research Funding; Beigene: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Abbvie: Research Funding. Mellstedt:Kancera AB: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sandoz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Astra-Zeneca: Equity Ownership; Novo Nordisk: Equity Ownership; Global Health Sciences: Speakers Bureau.

Revelance of Gammaglobulin Levels at Diagnosis and during Disease Course in Chronic Lymphocytic Leukemia

Introduction: Hypogammaglobulinemia is commonly observed in chronic lymphocytic leukemia (CLL), likely worsens over time and with chemoimmunotherapy, and eventually leads to infections which are a major cause of death in this disease. Unfortunately, newer therapies, such as ibrutinib, may not prevent the ongoing immunosuppression in CLL as a major cause of discontinuing this drug is increased infections. Nowadays, most patients present with early stage CLL, with an increasing number having monoclonal B cell lymphocytosis (MBL) and being followed for many years. CLL treatment is typically intensive, using chemoimmunotherapy with the therapeutic goal being to minimize tumor load. For these reasons, a reassessment of Ig levels in a CLL Clinic at diagnosis and during disease course in the 'real-life' setting has been carried out, along with an assessment of the need for Ig replacement. Methods: All CLL/SLL/MBL cases referred to the CLL clinic at CancerCare Manitoba, Winnipeg, Canada from 2007 to 2011 were included in this study. Immunoglobulin (Ig) levels (G, A, and M) were measured at the time of referral/diagnosis (baseline) and annually thereafter. Ig levels were correlated with patient characteristics (age at diagnosis, gender, comorbidities), CLL prognostic indicators (Rai stage, lymphocyte doubling time, creatinine, LDH, β2- microglobulin, IGHV mutational status, ZAP-70, CD38) and time to first treatment (TTFT). A subset analysis of patients treated with replacement gammaglobulin was also conducted. Results: There were 293 patents in this cohort with median age at diagnosis of 68 years. Of these, 62.5% were male, 38% had received treatment, and 24% died during the follow up time (median follow up of 71 months). Seventy percent of patients had CLL (of those 85% were diagnosed with Rai 0/I), 15% MBL and 15% SLL. At baseline, 41% had normal Ig levels while 59% had a reduced level of one or more Ig (32% had reduced levels of one Ig type, 18% two, and 9% all three). Overall, 53% of patients had low IgM, 24% low IgG and 17% low IgA. However, no consistent correlation was found between the Ig levels at diagnosis and any of the prognostic markers outlined above. Hypogammaglobulinemia (at least two consecutive values < normal) was associated with need for CLL treatment (HR 3.45, 95% CI 1.63-7.30, p=0.0012), while hypogammaglobinemia at diagnosis predicted a shorter TTFT (p=0.0008). Baseline IgA was also predictive of TTFT as well as overall survival, with patients with normal IgA having a longer TTFT, patients with high/low IgA a shorter TTFT (p=0.0012) and those with high IgA a shorter overall survival (p=0.0032). Furthermore, there was a positive correlation between baseline IgG and number of comorbidities (r=0.17, p = 0.0057) as measured by the Cumulative Index Rating Scale (CIRS) and β2-microglobulin levels. Eighteen patients (6.14%) required Ig replacement therapy, of those 13 (72%) were male and 13 (72%) had received chemotherapy. These patents also had a shorter overall survival than those not requiring IgG replacement therapy (p=0.0006). CLL cases with high baseline IgG are seven times more likely to require IgG replacement therapy (HR 6.92, 95% CI 1.78 - 29.91, p=0.0052) while cases with low baseline IgG are 5 times more likely (HR 4.99, 95% CI 1.59 - 9.43, p=0.0254) as compared to those with normal baseline IgG. Baseline IgA and IgM were not predictive of need for IgG replacement therapy. Interestingly, over a median follow-up of 4 years, one-third of patients with normal baseline IgG developed a low IgG and this was unrelated to receiving chemotherapy (Figure 1). Summary This study demonstrates that baseline Ig levels in CLL are informative of the underlying biology of this disease, and could provide valuable information regarding disease progression, survival and need for subsequent IgG replacement therapy or CLL treatment. Importantly, Ig levels may be elevated in CLL and this is associated with increased CIRS and a high β2-microglobulin level, suggesting that the increase is related to underlying comorbidities. Further studies are required to examine the cause for the progressive decline in Ig levels over time, despite an otherwise stable disease, and to determine whether this decline can be eliminated by earlier treatment with novel new therapies. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.