Daratumumab (Anti-CD38) for Treatment of Disseminated Nontuberculous Mycobacteria in a Patient With Anti–Interferon-γ Autoantibodies

Abstract

Patients with autoantibodies to interferon-γ (IFN-γ) may develop severe nontuberculous mycobacterial infections. We describe the novel use of daratumumab in a patient with autoantibodies to IFN-γ who had progressive infection, resulting in clinical and radiographic improvement.

(See the Editorial Commentary by Koizumi and Mikamo on pages 2209–11.)

Patients with autoantibodies to interferon-γ (IFN-γ) develop severe and progressive infections with mycobacteria and other intracellular pathogens, despite aggressive antimicrobial treatment. Rituximab has been shown to improve symptoms, disease burden, and mycobacteremia and decrease anti–IFN-γ autoantibody titers in a prior case series of 4 patients with autoantibodies to IFN-γ [1]. Overall, in a longitudinal evaluation, patients who had lower titers did better than those who failed to decrease their titers [2]. However, patients with persistently high titers despite rituximab can develop progressive and potentially fatal disease. We describe the novel use of daratumumab (an anti-CD38 monoclonal antibody targeting plasma cells approved for the treatment of multiple myeloma [MM]) in a patient with autoantibodies to IFN-γ who had progressive mycobacterial infection despite multiple cycles of rituximab, resulting in clinical and radiographic improvement.

CASE CLINICAL NARRATIVE

A 31-year-old Filipino-born woman presented with recurrent fevers, headache, and multiple soft tissue lesions in the calvarium. Initial radiological evaluation showed extensive soft tissue fluid collections and lytic bone lesions involving the calvarium, ribs, bilateral arm soft tissue, paraspinal muscles, bilateral glutei, left inferior pubic ramus, bilateral iliac bones, sacrum, and bilateral humeri. Cultures from paratracheal lymph nodes were positive for Mycobacterium avium. The patient was previously healthy with no prior history of mycobacterial disease. Despite receiving azithromycin, ethambutol, tedizolid, moxifloxacin, and clofazimine, several soft tissue lesions increased in size and the paratracheal collection evolved into a tracheo-esophageal fistula. Anti–IFN-γ autoantibody titers were present (determined by serial 10-fold dilutions of plasma and measuring anti–IFN-γ autoantibody levels by a particle-based technique, as previously described [3]; functional blockade was confirmed by STAT1 phosphorylation assay), rituximab 1 g once monthly was started, and she was referred to the National Institutes of Health and provided informed consent onto an Institutional Review Board–approved protocol 01-I-0202 (NCT identifier NCT00018044) where bedaquiline and meropenem were added to her current regimen. Unfortunately, after 5 more months of rituximab therapy, she had evidence of clinical and radiological progression. In order to decrease autoantibody production, bortezomib (a small-molecule proteasome inhibitor used in the treatment of MM) was started at a dose of 1.3 mg/m² subcutaneous injection following the standard MM regimen. However, it was discontinued after 3 months for aspartate aminotransferase (AST) and alanine aminotransferase (ALT) elevations. Rituximab was continued to maintain CD20 numbers undetectable, but clinical and radiographic disease progressed. After starting daratumumab (16 mg/kg intravenously [IV] weekly for 5 doses), there was clinical and radiographic improvement, with reduced pain and disappearance of multiple soft tissue lesions. During daratumumab therapy, her CD20+ cells remained suppressed as an after-effect of rituximab.

EFFECT OF RITUXIMAB, BORTEZOMIB, AND DARATUMUMAB ON IMMUNOGLOBULIN G AND ANTI–IFN-γ AUTOANTIBODY LEVELS

While on rituximab, total immunoglobulin G (IgG) level and anti–IFN-γ autoantibody levels decreased from 1521 mg/dL to 1069 mg/dL and 3058 relative light units (RLU) to 2504 RLU, respectively. While on bortezomib, total IgG levels remained stable (1031 mg/dL to 1051 mg/dL) and anti–IFN-γ autoantibody levels fell slightly (2504 to 1275 RLU). After initiation of daratumumab, IgG levels decreased from 1100 mg/dL to 434 mg/dL and anti–IFN-γ autoantibody levels decreased from 1275 to 157 RLU (Figure 1). No other immunosuppressants were used other than rituximab, bortezomib, daratumumab, and steroids surrounding daratumumab infusions.

Figure 1.

A, IFN-γ autoantibody titers and IgG levels throughout the treatment with rituximab, bortezomib, and daratumumab. The gray boxes indicate the period of time during which each medication was administered. B, CT scan of the pelvis showing 2 paragluteal soft tissue fluid collections. The arrows indicate the soft tissue collections before and after treatment with daratumumab. Abbreviations: CT, computed tomography; IFN-γ, interferon-γ; IgG, immunoglobulin G; MFI, mean fluorescence index.

ADVERSE EFFECTS

At the time of initial daratumumab, the patient had normal vital signs and was clinically stable, although appearing chronically sick and cachectic, with evidence of ongoing systemic inflammation and acute liver injury (hemoglobin, 9.8 g/dL; creatinine, 0.45 mg/dL; ALT, 552 U/L; AST 393 U/L; alkaline phosphatase, 647 U/L; albumin, 3.5 g/dL; C-reactive protein, 86 mg/L; ferritin, 1071 μg/L). The patient developed an infusion-related reaction that is described in the literature [4] consisting of urticaria, pruritus, and shortness of breath despite premedication with acetaminophen, diphenhydramine, and methylprednisolone 20 mg IV 3 hours before infusion (as per the Food and Drug Administration package insert), which rapidly improved after interrupting the infusion and diphenhydramine administration. No additional doses of steroids were administered to treat the infusion reaction. She tolerated subsequent infusions with the addition of montelukast, methylprednisolone to 100 mg IV 1 day prior to infusion, dexamethasone 20 mg the morning of infusion, dexamethasone 4 mg postinfusion, and methylprednisolone 20 mg IV on the day after infusion [5, 6]. The patient also developed hypogammaglobulinemia requiring IVIG replacement after 3 months of therapy. Of note, after the fifth infusion, she developed nuchal rigidity, fever, and severe headache. Brain magnetic resonance imaging showed stable lesions in the calvarium, and cerebrospinal fluid demonstrated elevated lymphocytes, normal protein and glucose, and negative workup for viral, bacterial, and mycobacterial etiologies.

COMMENTARY

High titers of antibodies to IFN-γ interfere with the IFN-γ–interleukin-12 axis, critical for the control of intracellular pathogens and mycobacteria. In a prior case series, rituximab demonstrated a 2–3-log decrease in IFN-γ autoantibody titers with concurrent clinical improvement [1]. However, patients with persistently high titers ultimately succumb to infection despite prolonged treatment with multiple antimycobacterial agents. Because there are no currently approved therapeutic options, there is an urgent need to evaluate the use of medications that modulate humoral immunity, particularly those that deplete the plasma cell compartment. Daratumumab is an IgG1κ monoclonal antibody that targets CD38, which is highly expressed in plasmablasts and plasma cells, as well as B cells in early maturation stages. Prior studies evaluating daratumumab in MM showed reductions in M protein, tissue plasma cells, and total IgG levels, with no significant effect on total CD19+ numbers. A study seeking to evaluate the effect of daratumumab on autoantibody titers reported a striking reduction of ANA, cANCA, and RF titers in 5 out of 6 patients undergoing treatment for MM [7]. Others have reported successful use of daratumumab in life-threatening autoimmune hemolytic anemia [8] and pure red cell aplasia after an ABO-incompatible hematopoietic stem cell transplant [9]. Our experience suggests that daratumumab is another potentially effective therapeutic agent for patients with anti–IFN-γ autoantibodies who are refractory to rituximab. While this patient received rituximab and bortezomib throughout her disease course, there was minimal overlap between treatments, and the greatest decline in autoantibody titers, IgG, and clinical response was observed after daratumumab administration. While steroids were administered surrounding daratumumab infusions, they have not been found to be effective in the management of autoantibodies to IFN-γ and have been implicated in worsening nontuberculous mycobacteria (NTM) infections. Furthermore, this is the first successful report of therapy with daratumumab in the setting of IFN-γ autoantibodies refractory to optimal antimycobacterial medication and rituximab.

Notes

Acknowledgments. The authors thank their patient and her family for their willingness to participate in the research. They thank all of the nurses and the social work department for their immense help throughout her hospitalizations.

Financial support. This work was supported by the Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.

Potential conflicts of interest. The authors: No potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.