Immunoglobulin replacement vs prophylactic antibiotics for hypogammaglobulinemia secondary to hematological malignancy.

ABSTRACT: Immunoglobulin replacement and prophylactic antibiotics are commonly used to prevent infections in patients with secondary hypogammaglobulinemia due to hematological malignancies but have never been directly compared. In this randomized controlled feasibility trial conducted in 7 hospitals in Australia and New Zealand, we enrolled patients with secondary hypogammaglobulinemia with either a history of recurrent/severe infection or an immunoglobulin G level <4 g/L. Participants were randomized in a 1:2 ratio to immunoglobulin (0.4 g/kg per 4 weeks IV) or daily antibiotics (trimethoprim-sulfamethoxazole 160 mg/800 mg or, if contraindicated, 100 mg doxycycline) for 12 months. Participants allocated to antibiotics were allowed to crossover after grade ≥3 infections. The primary outcome was proportion of patients alive on the assigned treatment 12 months after randomization. Between August 2017 and April 2019, 63 patients were randomized: 42 to antibiotics and 21 to immunoglobulin. Proportion of participants alive on allocated treatment at 12 months was 76% in the immunoglobulin and 71% in the antibiotic arm (Fisher exact test P=.77; odds ratio, 0.78; 95% CI, 0.22-2.52). The lower quartile for time to first major infection (median, not reached) was 11.1 months for the immunoglobulin and 9.7 months for the antibiotic arm (log-rank test, P=.65). Three participants in the immunoglobulin and 2 in the antibiotic arm had grade ≥3 treatment-related adverse events. A similar proportion of participants remained on antibiotic prophylaxis at 12 months to those on immunoglobulin, with similar rates of major infections. Our findings support the feasibility of progressing to a phase 3 trial. Trial registration #ACTRN12616001723471.

Economic evaluation: immunoglobulin vs prophylactic antibiotics in hypogammaglobulinemia and hematological malignancies.

ABSTRACT: Patients with hematological malignancies are at high risk of developing hypogammaglobulinemia (HGG) and infections. Immunoglobulin (Ig) is one recommended option to prevent these infections, but it is expensive, and its cost-effectiveness compared with other prevention strategies remains unknown. We conducted a trial-based economic evaluation from the Australian health care system perspective to estimate the 12-month cost-effectiveness of prophylactic Ig vs prophylactic antibiotics in 63 adults with HGG and hematological malignancies participating in the RATIONAL feasibility trial. Two analyses were conducted: (1) cost-utility analysis to assess the incremental cost per quality-adjusted life year (QALY) gained; and (2) cost-effectiveness analysis to assess the incremental cost per serious infection prevented (grade ≥3) and per any infection (any grade) prevented. Over 12 months, the total cost per patient was significantly higher in the Ig group than in the antibiotic group (mean difference, AU$29 140; P < .001). Most patients received IVIg, which was the main cost driver; only 2 patients in the intervention arm received subcutaneous Ig. There were nonsignificant differences in health outcomes. Results showed Ig was more costly than antibiotics and associated with fewer QALYs. The incremental cost-effectiveness ratio of Ig vs antibiotics was AU$111 262 per serious infection prevented, but Ig was more costly and associated with more infections when all infections were included. On average and for this patient population, Ig prophylaxis may not be cost-effective compared with prophylactic antibiotics. Further research is needed to confirm these findings in a larger population and considering longer-term outcomes. The trial was registered at the Australian and New Zealand Clinical Trials Registry as #ACTRN12616001723471.

Interventions to reduce infections in patients with hematological malignancies: a systematic review and meta-analysis.

Acquired hypogammaglobulinemia is common in chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), and multiple myeloma (MM). No previous systematic reviews (SRs) have compared different approaches to infection prevention. We sought to assess the efficacy and safety of prophylactic immunoglobulin, antibiotics, and vaccination in these patients. We performed an SR and meta-analysis of randomized controlled trials (RCTs) evaluating the efficacy and safety of prophylactic immunoglobulin, antibiotics, and vaccination in adult patients with hematological malignancies commonly associated with acquired hypogammaglobulinemia, specifically, CLL, NHL, and MM. We searched PubMed (MEDLINE), EMBASE, and Cochrane Registry up to 9 January 2021. Results for dichotomous data were expressed as relative risk (RR) with 95% confidence interval (CI) and pooled in a random-effects model. This review was registered with PROSPERO CRD42017070825. From 10 576 studies screened, there were 21 completed RCTs and 1 ongoing. Of these, 8 evaluated prophylactic immunoglobulin (n = 370; 7 published before 2000), 5 evaluated prophylactic antibiotics (n = 1587), 7 evaluated vaccination (n = 3996), and 1 compared immunoglobulin to antibiotics (n = 60). Prophylactic immunoglobulin reduced the risk of clinically documented infection (CDI) by 28% (n = 2 trials; RR, 0.72; 95% CI, 0.54-0.96), and vaccination reduced the risk by 63% (RR, 0.37; 95% CI, 0.30-0.45). Prophylactic antibiotics did not reduce the risk. No intervention reduced all-cause mortality. Prophylactic immunoglobulin and antibiotics increased the risk of adverse events. Findings should be interpreted with caution, given the high risk of bias in many studies. There is a clear need for high-quality contemporary trials to establish the effectiveness of different approaches to preventing infection.

Immunoglobulin replacement therapy in chronic lymphocytic leukaemia patients with hypogammaglobulinaemia and infection.

OBJECTIVES: To analyse total national utilisation of immunoglobulin (Ig) replacement therapy (IgRT) for Chronic Lymphocytic Leukaemia patients with acquired hypogammaglobulinaemia and severe and/or recurrent bacterial infections. METHODS: In 2007, the National Blood Authority first published Criteria for the clinical use of intravenous immunoglobulin in Australia. The Australian Red Cross Lifeblood assessed, approved, and recorded all supply with patient demographics, distribution data, intravenous Ig (IVIg) volumes and treatment episodes. IVIg was the sole product used in Australia from 2008-2013 inclusive. RESULTS: From 2008 to 2013 across Australia, 2734 individual CLL patients received 48,870 treatment episodes using a total 1,324,926 g of IVIg therapy. Six IVIg products were available, with domestically manufactured Intragam® P accounting for 89.7% of supply. The average age for first dose was 74 years. Males received 60.6% of the total treatment episodes representing 20% more than females. The average pre-treatment IgG level was 4.03 ± 2.03 g/L (range 0.30-10.50 g/L). A sustained average annual increased IVIg utilisation of 5.5% was observed. There was significant regional variation consistent with differences in prescriber preferences across states and territories. CONCLUSION: This study provides a globally unique insight into IgRT supply and demand in CLL patients by analysis of total national use in Australia over a 6-year period.