Secondary Antibody Deficiency

THE FIRST POLYVALENT intravenous immune globulin (IVIG) product was approved in the U.S. for treatment of primary humoral immunodeficiency disorders (PI) in 1981. Nearly four decades later, PI still accounts for more than 20 percent of the nearly 90 million grams of IVIG and subcutaneous IG (SCIG) administered in the U.S. last year,^1,2 as newly identified cases continue to add to the PI patient population on chronic IgG replacement therapy.

Similarly, the efficacy of IVIG therapy for several autoimmune neuropathies — chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, myasthenia gravis and Guillain-Barré syndrome — was documented in numerous studies in the 1980s and 1990s.^3,4,5,6 Human IG preparations have been standard therapy for these disorders, which collectively account for about 40 percent of total IG usage, for many years. But as long as new patients starting on treatment outnumber those who discontinue therapy, growth in IG utilization for these disorders is likely to continue.

Much the same applies for most significant autoimmune hematologic, dermatologic and rheumatologic diseases for which IG has been part of the standard treatment armamentarium for many years. However, for many of these disorders — examples include Kawasaki disease, immune thrombocytopenic purpura, pemphigus/pemphigoid and antirejection therapy for solid organ or hematopoietic stem cell transplantation (HSCT) — patients typically require just one or perhaps a few courses of IG treatment. Consequently, the contribution of these typically rare conditions to growth in IG utilization tends to be relatively modest, as there is no chronically treated patient “base” on which demand builds year after year.

All of this has raised an intriguing question for IG product manufacturers tasked with forecasting future demand to decide how much to invest in costly new plasma collection and processing capacity. Since PI and autoimmune neuropathy, which collectively comprise around 60 percent of the IG market, are “maturing” indications for IG therapy, and IG usage growth is limited for most other rare, short-term IG clinical applications, how do we account for nearly 8 percent average annual growth in demand for IG products over the last five years? To put it into clearer perspective, year-over-year IG demand has now reached 7 million grams, more than double the annual growth rate of about 3 million grams just a decade ago.

Several lines of evidence point to the emergence of an important new contributor to IG demand growth: secondary or “acquired” hypogammaglobulinemia associated with potent immunosuppressive drugs and cytotoxic B cell-targeted biologics now in common use to treat hematologic malignancies, as well as other hematologic and immune-mediated disorders.

Acquired Secondary Antibody Deficiency (SAD) in Hematological Disease

Hypogammaglobulinemia and serious infections secondary to intrinsic disease and/or immunosuppressive drug therapy is a leading cause of death in patients with B cell chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL) and plasma cell myeloma (multiple myeloma). Early studies in the 1980s showed prophylactic IVIG can significantly reduce the incidence of major infection in high-risk CLL and plasma cell myeloma patients, but subsequent analyses of these findings did not support a survival benefit or overall improved quality of life when taking into consideration the increased prevalence of IVIG-related adverse events.7,8 Existing practice guidelines recommend IVIG therapy only for hypogammaglobulinemic patients with recurrent bacterial infections and documented failed antibody response against diphtheria, tetanus or pneumococcal vaccines.⁹ Historically, prophylactic IVIG has been selectively prescribed for these hematologic malignancies, and until very recently had been estimated to account for little more than 5 percent of U.S. IG demand.¹

Then, in 1997, the U.S. Food and Drug Administration approved rituximab (Rituxan), a cytolytic mouse/human monoclonal antibody that targets the CD20 antigen present on all peripheral B cells, for relapsed or refractory lowgrade or follicular CD20+ B-cell NHL. Rituximab is now indicated for treatment of essentially all B-cell malignancies, including B-cell CLL, as well as for several autoimmune disorders, including granulomatosis with polyangiitis, pemphigus vulgaris and rheumatoid arthritis. New combinations of immunosuppressive drugs and rituximab continue to be investigated to identify the most optimal treatment regimens for CLL and for follicular, mantle cell, diffuse large B cell and NHLs; well over 200 clinical trials are currently evaluating rituximab in the U.S. and internationally.

Repeated treatment courses and maintenance therapy with rituximab and other potent anti-B cell agents can prolong the duration of remission and the time between relapses. However, they have been shown to be frequently associated with sustained hypogammaglobulinemia and ablation of a functional antibody response to vaccine challenge. Usually co-administered or sequentially administered with other cytotoxic drugs, repeated or long-term rituximab in particular can result in both a variably lower serum IgG concentration and an impaired proliferative B cell response to microbial attack. As the treatment duration is extended and/or as the disease becomes more advanced, the hypogammaglobulinemia defect tends to worsen, increasing the risk of septicemia, cellulitis and serious infections of the respiratory and urinary tract.¹⁰ The hypogammaglobulinemia and recurrent infections commonly seen in patients treated with B cell-depleting therapies have been characterized as a “common variable immunodeficiency (CVID)-like clinical and immunologic phenotype.”¹¹

As with CVID and other PIs, the protective effect of IG replacement therapy has been documented in patients with hematological malignancies accompanied by iatrogenic SAD. Below are examples of studies assessing the value of IG in patients with CLL and NHL:

• Of 132 CLL patients enrolled in a study evaluating ibrutinib, a tyrosine kinase inhibitor, IVIG supplementation was administered in 16 percent of previously treatment-naive participants, and in 53 percent of patients with advanced disease and those receiving rituximab.¹²
• In a large series of 211 NHL patients treated with rituximab, de novo hypogammaglobulinemia developed in 39 percent of those whose serum IgG level was previously normal, while it was exacerbated in 72 percent of those who had baseline hypogammaglobulinemia. Exposure also to fludarabine or other purine analogue was associated with increased risk of developing hypogammaglobulinemia. Patients who received rituximab as maintenance therapy had a higher likelihood of developing hypogammaglobulinemia than those receiving it as immunotherapy (54 percent vs. 33 percent). Of the 14 patients who required IVIG,¹¹ (79 percent) received multiple courses of rituximab, whereas just three patients (21 percent) received IVIG after only one course.¹³

In addition to rituximab, there are now several other licensed anti-CD20 monoclonal antibodies, each of which targets a different B cell epitope. Ofatumumab (ARZERRA) is approved for the treatment of previously untreated CLL, obinutuzumab (GAZYVA) for the treatment of CLL and follicular lymphoma, and tositumomab (BEXXAR) for the treatment of NHL, including patients with rituximab-refractory NHL. As with rituximab, the labeling for these products includes warnings about risks of serious infections.

SCIG as an IgG Replacement Alternative

IVIG has historically been the standard IG replacement therapy for hypogammaglobulinemia secondary to B cell lymphoproliferative disorders. However, the same advantages that make SCIG administration popular for qualifying patients with PI — a lower rate of systemic adverse events, lower overall cost of care and improved health-related quality of life14,15 — may apply as well for patients with SAD who require prolonged IgG replacement therapy. In a recent retrospective review of patients with lymphoproliferative disorders (B cell CLL and NHL), Italian investigators documented similarly low rates of serious and overall bacterial infections with either IVIG or SCIG treatment. But systemic reactions, in particular fever (33 percent vs. 7 percent) and dyspnea (9 percent vs. 0 percent), were less frequent in those receiving SCIG. Premedication was required in 17 of 33 patients receiving IVIG, compared to one of 61 patients receiving SCIG. Most patients who shifted from IVIG to SCIG reported improved quality of life in their questionnaire responses. Tellingly, just two of 33 patients who were crossed over to SCIG returned to IVIG therapy.¹⁶

For some patients there is yet another very tangible benefit with SCIG use beyond the advantages of time-flexible, home-based self-infusion: avoidance of venous access problems that are often a major concern in patients treated with chemotherapy. SCIG infusion can potentially obviate the need to surgically place central and peripheral venous access devices for IVIG infusions, thus reducing the risk of access-related bloodstream infections.

A Growing Piece of the IG Usage Pie

Several reviews cited in this article support the presumption that SAD is an important contributor to growing IG demand, both here in the U.S. and internationally. Population-based longitudinal IG utilization data that might verify and provide a sense of the magnitude of its contribution are not available for the U.S., but our Canadian neighbors have systematically captured and reported diagnosis-specific IG utilization in four eastern provinces,* with a population exceeding three million lives, for well over a decade.

Figure 1 identifies the percentage of IG provided for SAD disorders over a six month baseline period from Oct. 1, 2003, to March 31, 2004, in four eastern Canadian provinces,17 and again over one-year periods in fiscal 2011/12 and 2017/18. While IG prescribing patterns in this limited population does not necessarily reflect U.S. prescribing patterns, the direction over time is still instructive: As a share of all IG directed to patients, IG for patients with SAD nearly doubled from 4.9 percent in 2011/12 to 9.3 percent in 2017/18.^18,19

Australia, a country with per capita IG usage similar to the U.S., also tracks its utilization of IG by diagnostic categories. According to single-month data for August 2019 (Figure 2),²⁰ “acquired hypogammaglobulinemia,” including patients with hematological malignancies and those post-HSCT, accounted for nearly 24 percent of IG utilization nationwide. All other patients with secondary hypogammaglobulinemia accounted for more than 4 percent of IG usage, for a combined total of 28 percent.

Remarkably, the number of grams of IG administered to Australians for acquired or secondary hypogammaglobulinemia in August 2019 was 2.5-fold larger than the number of grams administered for all PIs. Medical practice patterns in Australia and the U.S. undoubtedly differ; Australia’s National Blood Authority has defined detailed patient eligibility criteria for IG access, while in the U.S., patient eligibility for IG is conditional on individual coverage policies of hundreds of health insurers. Nevertheless, the Australian experience strongly implies SAD now accounts for a considerable share of total IG usage here in the U.S.

Other Disorders That May Boost Need for IG

Already estimated to be 30 times more common than PI, the prevalence of treatment-induced SAD can be expected to increase going forward. In addition to CLL, lymphomas and plasma cell myeloma, an ever-expanding number of new B cell-targeted biological response modifiers and other immunosuppressive therapies are in use or are being evaluated as primary or maintenance therapy for a range of other clinical disorders, including:²¹

• Acute and chronic myeloid leukemia
• Myelodysplastic syndrome
• Waldenstrom macroglobulinemia
• Post-hematopoietic stem cell transplant
• Post-solid organ transplant
• Rheumatological disorders (e.g., rheumatoid arthritis, giant cell arteritis, polymyalgia rheumatica)
• Neurological disorders (e.g., autoimmune encephalitis, myasthenia gravis, relapsing-remitting multiple sclerosis, neuromyelitis optica)

With the benefits of more aggressive B cell-ablative treatments comes a cost in serious infections and hospitalization. For patients rendered unable to mount a protective IgG antibody response, and for whom antibiotic prophylaxis proves inadequate, prophylactic IG replacement therapy is clearly indicated.

The plasma therapeutics industry is continuously working to expand its production capacity to address this growing demand. Like blood itself, when IG is needed, there is simply no substitute.

* The Atlantic provinces of Nova Scotia, Prince Edward Island, Newfoundland and Labrador, and New Brunswick.