The first trial into prophylactic antibiotics as an alternative to immunoglobulin replacement in patients with acquired hypogammaglobulinaemia secondary to a haematological malignancy appears promising, with the same proportion of patients remaining on treatment at 12 months and a similar infection rate.
Writing in Blood Advances [link here], Monash University researchers said their Role of Antibiotic Therapy or IVIg on Infections in Haematology (RATIONAL) trial was the first to directly compare the treatments commonly used to prevent infections.
The open-label phase II randomised controlled feasibility trial involved 63 patients with hypogammaglobulinaemia secondary to haematological malignancy from seven hospitals in Australia and New Zealand.
Patients (mean age 70, 54% female) had either history of recurrent/severe infection or IgG level <4g/L and were randomised in a 1:2 ratio to immunoglobulin (0.4g/kg/4-weekly IV) or daily antibiotics (trimethoprim-sulfamethoxazole 160mg/800mg; or if contraindicated doxycycline 100mg) for 12 months.
Participants on antibiotics could cross over following grade ≥ 3 infection.
Most patients had chronic lymphocytic leukaemia (46%), followed by non-Hodgkin lymphoma (32%), multiple myeloma (19%) and then other malignancies (3%).
The median baseline IgG level was 4.1 g/L (interquartile range 3.1 to 5.2) and 94% had a history of prior infection. Regarding treatment, 27% of patients had never received systemic anti-cancer therapy, 24% were receiving systemic anti-cancer therapy at randomisation, 33% were in remission having previously received therapy and 13% had refractory or relapsed disease after having received therapy.
Results showed 76% of participants were alive on allocated treatment at 12 months in the immunoglobulin arm and 71% in the antibiotic arm (odds ratio 0.78).
The lower quartile for time to first major infection (median times not reached for either arm) was 11.1 months in the immunoglobulin and 9.7 months in the antibiotic arm. Clinically documented infections averaged 1.86 per participant in the immunoglobulin arm and 1.33 per participant in the antibiotic treatment arm.
Three participants in the immunoglobulin arm and two in the antibiotic arm had a grade ≥3 treatment-related adverse event. There were two deaths in the immunoglobulin arm, including one infection-related death. One death occurred in the prophylactic arm after 12 months, following the report of a major infection.
Overall, 27% of patients either did not commence or discontinued their allocated treatment within 12-months of study follow-up.
There was similar quality of life between the arms, said the authors, which included Melbourne haematologists Professor Zoe McQuilten and Professor Erica Wood.
“Given concerns about the global health threat of antimicrobial resistance, prophylactic antibiotic strategies should be evidence-based. Our trial supports the feasibility of progressing to a larger phase III trial comparing prophylactic antibiotics with immunoglobulin replacement, powered for a patient-centered outcome incorporating survival and major infection risk,” the authors wrote.
“The choice of antibiotics and whether to include a no-prophylaxis arm would need to be considered for future trial designs.”
They said the increasing use of B-cell and plasma-cell depleting therapies, such as anti-CD20 and anti- CD38 monoclonal antibodies, BTK and BCL2 inhibitors and cellular therapies, while improving disease-specific survival rates, was likely to result in rising prevalence of acquired hypogammaglobulinaemia.
“This will place greater demand on the supply of immunoglobulin, which is increasing globally. In Australia, the demand for immunoglobulin has increased by more than 10% per year over the last decade, and patients with haematological malignancies are the largest single group using immunoglobulin products.
“There is a pressing need to generate contemporary data regarding the comparative effectiveness and safety of immunoglobulin replacement in this patient population.”