Haematology News Volume 13 - Issue 1, January 2018

Secondary Immunodeficiency Back

The challenge of secondary immunodeficiency in immunosuppressed patients and its treatment with IV immunoglobulins

Intravenous immunoglobulin (IVIG) can influence the immune system via multiple mechanisms including neutralisation of pathogens and anti-inflammatory effects. Its therapeutic role has expanded greatly since the first reported therapeutic use in 1952 and it is now widely prescribed in the management of primary and secondary immunodeficiencies. These lectures, supported by Biotest and held during the annual European Society for Immunodeficiencies meeting in Edinburgh in September 2017, reviewed the clinical significance of secondary immunodeficiency in the era of cancer survivorship and improved outcomes for autoimmune disorders and the role of IVIG in management.

Secondary immunodeficiency – survival is no longer sufficient

Dr Alex Richter, Birmingham, UK
The current prevalence of secondary immunodeficiency is a consequence of the success of medicine. Survival has increased markedly among people with serious long-term disorders including cancers, autoimmune diseases and post-transplantation. The management focus is now shifting to better management of survival and less toxic treatment strategies. However, the importance of secondary immunodeficiency is still not fully recognised.
Rituximab is a case in point. There were early warning signs that hypogammaglobulinaemia occurred in some patients treated for lymphoma, with reported prevalence ranging from 14% to 56%.1-4 Low immunoglobulin levels were found in the majority of patients with non-neutropenic sepsis after rituximab therapy.5 Treatment with intravenous immunoglobulins can prevent recurrent infections after rituximab therapy.
It is well established that immunodeficiency secondary to chemotherapy is severe, with both cellular and humoral defects, but it is less widely known that immunoglobulin levels may not recover after treatment ends. Laboratory monitoring can mislead: for example, after stem cell transplantation, total serum immunoglobulin levels may recover but levels of functional antibodies do not. Analysis of laboratory data for 7,481 Birmingham inpatients from an 8-day period showed that the prevalence of low immunoglobulins (<6 g/L) was 0.86%; this had not been recognised. Most frequently, patients had been admitted to haematology, with transplantation, cancer, surgery, neurology and renal disorders accounting for most of the remainder.
The management of secondary immunodeficiency begins with optimising medical care through patient education, prompt antibiotic treatment, vaccination (including booster doses) and, if possible, reducing immunosuppression. The role of prophylactic anti¬biotics should be guided by local microbiological guidelines and tolerability. A trial of immunoglobulin therapy is warranted for patients with low immunoglobulins (IgG <5 g/L excluding paraproteins) and recurrent infections who fail to respond to vaccination. UK national guidelines for IgG treatment recommend a dose of 0.4 g/kg/month, adjusted to achieve a trough level of at least the lower limit of the age-specific range.6

Secondary immunodeficiency in multiple myeloma and its management

Dr Guy Pratt, Birmingham, UK
There are 15,000-20,000 people in the UK living with multiple myeloma (MM), with about 4,000 new cases a year. MM is associated with multiple immunological abnormalities. One in ten newly diagnosed patients registered onto MRC trials die within 60 days of their diagnosis. Infection accounts for 45% of these deaths7 and in most cases, is associated with hypogammaglobulinaemia, not neutropenic sepsis.8 The prevalence of low immunoglobulin levels in patients with MM, with or without paraprotein, is 80% – 90% (Drayson, unpublished data). A major contributory factor is high-dose steroid therapy.9
Almost all patients with MM go through a premalignant stage of monoclonal gammo¬pathy of uncertain significance (MGUS). This benign asymptomatic condition, due to a clone of plasma cells in the marrow, is present in 3% of the over-75s and 5% of the over-80s; the risk of progression to MM is 1%. MGUS is associated with a 2-fold increased risk of bacterial or viral infection regardless of M-protein levels.10
Infection is a risk throughout the patient’s journey following a diagnosis of MM (Fig. 1). Evidence for antibiotic prophylaxis is limited to small studies with conflicting findings11,12 but the randomised TEAMM trial (Tackling Early Morbidity and Mortality in Myeloma; n=977), to be published shortly, showed that prophylaxis with levofloxacin significantly reduced the number of fatal febrile episodes compared with placebo though it did not alter overall survival. In clinical trials, prophylaxis with IVIG protected against life-threatening and recurrent infections when patients were in remission13 but not when initiated at diagnosis (Medical Research Council, unpublished data). Vaccination against S pneumoniae, H influenzae and influenza is recommended for patients in remission but the response during treatment is poor. Bortezomib is associated with reactivation of herpes virus14 and treatment requires prophylaxis with low-dose aciclovir.15
UK guidelines on the management of MM recommend vaccination and antiviral prophylaxis.16,17 They were developed before results of the TEAMM trial were known and their recommendation against antibiotic prophylaxis may change in light of this new evidence. Both state that immunoglobulin replacement therapy should be considered for people who have hypogammaglobulinaemia and recurrent infections. Patient education to enable individuals to recognise symptoms and seek help is very important.

IVIGs – specialised medication for complex patients

Dr Shailesh Chavan, Boca Raton, USA
Quality and safety are paramount in the manufacture of IVIGs. The risk of infection from pooled plasma donations prompted the development of thorough quality assurance measures using approved donation centres, donor registration and routine serological testing. The multi-stepped manufacturing process involves additional validated steps to remove pathogens.
Product purity directly affects safety. Residual coagulation factors can increase the risk of thrombosis in patients with risk factors. The need of elimination of residual active coagulation factors (especially FXIa and kallikrein) led to industry-wide improvements in the manufacturing process and stricter regulations governing manufacture. Haemolysis, usually associated with high-dose IVIG, is a rare event due to administration of a product with high titers of isoagglutinins to a vulnerable patient. IVIGs with low titers of anti-A and anti-B isoagglutinins are recommended for use.
The commercially available IVIG products are not identical in terms, manufacturing processes and final composition. Their safety and tolerability profiles cannot be predicted from product specification alone. Tolerability of IVIG is determined by the type and severity of illness, comorbidities, the protein concentration and the total dose. To achieve the best outcomes, treatment should be tailored to individual patient need according to the medical history. A conservative approach is best for vulnerable patients who need high dose IVIG, using a slow infusion and a product with a low concentration of protein. In such cases, therapy with a 5% solution is more safe and tolerable than a 10% IVIG.

References

 1. McLaughlin P, Grillo-López AJ, Link BK et al. J Clin Oncol 1998;16:2825-33.
 2. Roberts DM, Jones RB, Smith RM et al. J Autoimmun 2015;57:60-5.
 3. Casulo C, Maragulia J, Zelenetz AD. Clin Lymphoma Myeloma Leuk 2013;13:106-11.
 4. De La Torre I, Leandro MJ, Valor L et al. Rheumatology (Oxford) 2012;51:833-40.
 5. Cabanillas F, Liboy I, Pavia O et al. Ann Oncol 2006;17:1424-7.
 6. Department of Health. Clinical guidelines for immunoglobulin use. 2nd edition update. November 2011.
 7. Augustson BM, Begum G, Dunn JA et al. J Clin Oncol 2005;23:9219-26.
 8. San Miguel J, Weisel K, Moreau P et al. Lancet Oncol 2013;14:1055-66.
 9. Rajkumar SV, Jacobus S, Callander NS et al. Lancet Oncol 2010;11:29-37.
10. Kristinsson SY, Tang M, Pfeiffer RM et al. Haematologica 2012;97:854-8.
11. Teh BW, Harrison SJ, Worth LJ et al. Br J Haematol 2015;171:100-8.
12. Oken MM, Pomeroy C, Weisdorf D et al. Am J Med 1996;100:624-8.
13. Chapel HM, Lee M, Hargreaves R et al. Lancet 1994;343:1059-63.
14. Chanan-Khan A, Sonneveld P, Schuster MW et al. J Clin Oncol 2008;26:4784-90.
15. Minarik J, Pika T, Bacovsky J et al. Br J Haematol 2012;159:111-3.
16. Snowden JA, Greenfield DM, Bird JM et al. Br J Haematol 2017;176:888-907.
17. National Institute for Health and Care Excellence. Myeloma: diagnosis and management. NICE Guideline NG35. February 2016.