Long-term follow-up of serum immunoglobulin levels in blinatumomab-treated patients with minimal residual disease-positive B-precursor acute lymphoblastic leukemia

Blinatumomab has shown efficacy in B-cell malignancies. Rapid clearance of peripheral B cells has been demonstrated, resulting in sustained B-cell depletion throughout the treatment period. This report describes serum immunoglobulin levels during and after blinatumomab treatment in a phase 2 study in patients with minimal residual disease (MRD) of B-precursor acute lymphoblastic leukemia (ALL). The study followed an open-label, multicenter, single-arm, phase 2 design. Study details and primary analysis data have been described previously. Briefly, patients with positive MRD status (410 detectable blast cells using quantitative PCR) at any time after induction and consolidation therapy according to German multicenter study group for adult ALL (GMALL) protocols were eligible. The primary objective was to determine the efficacy of blinatumomab in patients with MRD-positive B-precursor ALL. Patients received blinatumomab as a continuous intravenous infusion at a dose of 15 μg/m/day over 4 weeks, followed by a 2-week treatment-free period (6-week cycles). For patients with an allogeneic donor, an allogeneic hematopoietic stem cell transplantation (HSCT) was offered at any time after the first 6-week cycle. Responders could receive three additional consolidation cycles of blinatumomab treatment. Between May 2008 and November 2009, 21 patients with MRD-positive B-precursor ALL were treated. Serum immunoglobulins IgM, IgG, IgA and IgE have a central role in the humoral immune response by binding to extracellular pathogens, thereby activating the complement system along with effector cells, which ultimately leads to pathogen eradication. Whereas serum IgM antibodies are mainly produced during a primary immune response by plasma cells originating from activated naive B cells, IgG, IgA, and IgE are also secreted in large amounts during secondary immune responses by plasma cells originating from activated memory B cells. Most long-lived antibody-based immunity against invading pathogens is provided by serum IgG and mucosal IgA. Hence, therapy-induced depletion of CD19-positive B cells and plasma blasts, and associated subsequent decline of plasma cells can result in a long-term decrease of serum immunoglobulin concentrations, which recover only after regeneration of naive and memory B cells from CD19negative hematopoietic B-cell progenitors. Patients receiving B-cell–depleting therapies may therefore be susceptible to severe infections during and after treatment. In our phase 2 study, IgM, IgG, IgA and IgE levels were monitored during a follow-up time ranging from 255 to 1605 days (median, 457.5 days) in six patients with MRD-positive B-precursor ALL who did not receive HSCT after blinatumomab treatment. Four of the six patients had Philadelphia chromosome