Treatment of patients with haematological malignancies and secondary immunodeficiency

Secondary antibody deficiency (SAD) is common in patients with haematological malignancies, such as chronic lymphocytic leukaemia (CLL) and multiple myeloma (MM).

SAD predisposes patients to infections, which are a major cause of morbidity and mortality in patients with CLL or MM. Immunoglobulin replacement therapy (IgRT) significantly reduces the risk of infection in patients with SAD.

In 2019, the European Medicines Agency (EMA) approved an expanded indication for IgRT in patients with secondary immunodeficiency. However, European guidelines on the use of IgRT in patients with haematological malignancies and SAD are lacking and regional differences in treatment approaches to reduce infection burden, including strategies for initiation, dosing and discontinuation of IgRT, remain.  

Consensus statements were developed to provide guidance on the use of IgRT and to support harmonisation of clinical practice across Europe.

  • Patel, S.Y. et al., Front Immunol. 2019; 10:33
  • Blimark, C. et al., Haematologica. 2015; 100:107-13
  • Compagno, N. et al., Front Immunol. 2014; 5:626
  • Seppänen, M. Clin Exp Immunol. 2014; 178(Suppl 1):10-3
  • Benbrahim, O. et al., Hematology. 2019; 24:173-82
  • Cooperative Group for the Study of Immunoglobulin in Chronic Lymphocytic Leukemia, N Engl J Med. 1988; 319:902-7
  • EMA. Guideline on core SmPC for human normal immunoglobulin for intravenous administration (IVIg) 2019   
  • Jolles, S. et al., Eur J Haematol. 2021; DOI: 10.1111/ejh.13580

Development of consensus statements for use of IgRT

A Task Force comprising 8 immunologists and haemato-oncologists from France, Germany, Ireland, Italy, and the United Kingdom developed definitions and statements on various aspects of IgRT therapy.

The definitions and statements were reviewed by an Expert Panel of 32 experts from 7 European countries in a Delphi exercise. Experts were selected based on their level of expertise in the treatment of SAD and their country of practice.

SID Visuals 02 Task Force Mobile f01
SID Visuals 02 Task Force d02
SID Visuals 03 Expert Panel Mobile f01
SID Visuals 03 Expert Panel Desktop f01
  • Jolles, S. et al., Eur J Haematol. 2021; DOI: 10.1111/ejh.13580

The Task Force developed definitions and statements based on a thorough literature review and their knowledge and experience.

SID Visuals 04 Delphi Exercise f01

In Delphi Round 1, the definitions/statements were refined based on the feedback of the Expert Panel.

In Round 2, the experts were asked to rate their agreement with the definitions/statements on a six-point Likert-type scale from 1 (totally disagree) to 6 (totally agree). If ≥ 70% of the experts rated their agreement as 5 or higher, then consensus was achieved.

In Round 3, if consensus was not reached in Round 2, experts who had scored their agreement level as ≤ 4 had the opportunity to review their agreement level in light of the overall feedback from the Expert Panel.

A total of 23 definitions and statements were developed and 21 reached consensus, covering the following important aspects of use of IgRT:

  • Definition of infections
  • Measuring Ig levels
  • Initiating IgRT
  • IgRT dosing
  • Use of SCIg
  • Discontinuing IgRT

Statements that achieved a consensus are described below. For more information about the Delphi process, the difference in agreement level between haemato-oncologists and immunologists, and the statements that did not achieve consensus, please download the associated presentation.

  • Jolles, S. et al., Eur J Haematol. 2021; DOI: 10.1111/ejh.13580

Definition of infections

IgRT is indicated in patients with severe or recurrent infections. The following definitions clarify what constitutes a severe, recurrent or persistent infection. Truly neutropenic patients (i.e. those with an absolute neutrophil count < 1500/μL) should be excluded from these definitions because there is no evidence that they would benefit from IgRT.

SID Icons 01 Definition of infections-Icon

In patients with haematological malignancies*, a severe infection requires acute IV intervention, immediate or prolonged hospitalisation or emergency intensive care treatment. (Agreement level of Expert Panel 97%)

SID Icons 01 Definition of infections-Icon

In patients with haematological malignancies*, recurrent infections occur at least 3 times over a 12-month period despite appropriate anti-infective treatment. (Agreement level of Expert Panel 90%)

SID Icons 01 Definition of infections-Icon

In patients with haematological malignancies*, persistent infection is one which does not improve despite appropriate anti-infective treatment. (Agreement level of Expert Panel 90%)

  • Jolles, S. et al., Eur J Haematol. 2021; DOI: 10.1111/ejh.13580
  • *excluding neutropenic patients; IV: intravenous

Measuring Ig levels

Decreased immunoglobulin G (IgG) levels have been associated with an increased risk of infection. Monitoring IgG levels before and during anti-cancer therapy may help identify patients who are at risk of developing severe infections and who may benefit from timely IgRT. For this reason, it is crucial to regularly monitor IgG levels.

SID Icons 02 Measuring Ig levels-Icon

In patients with haematological malignancies* who are about to start anti-cancer therapy, IgG levels is a baseline factor which can help guide treatment decisions, especially to assess the patient’s risk of developing infections. (Agreement level of Expert Panel 80%)

SID Icons 02 Measuring Ig levels-Icon

In paediatric patients with haematological malignancies, IgG levels need to be interpreted according to age-specific normal values (Agreement level of Expert Panel 100%)

  • Jolles, S. et al., Eur J Haematol. 2021; DOI: 10.1111/ejh.13580
  • *excluding MM

Initiating IgRT

IgRT should be considered in patients with low levels of IgG and severe, persistent or recurrent infection. In the absence of low IgG levels, further testing to ascertain the cause of an infection is important before initiating IgRT. Patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT) are highly immunocompromised and IgRT should be considered to reduce the risk of infection.

IgRT is generally well tolerated. Most IgRT-related adverse reactions are mild or moderate. In rare cases severe adverse reactions may occur, such as hypersensitivity, renal failure, thromboembolism or haemolysis, and patients should be closely monitored during intravenous immunoglobulin (IVIg) therapy.

SID Icons 03 Initiating IgRT-Icon

In patients with haematological malignancies whose IgG levels are < 4 g/L and who have received appropriate anti-infective therapy, initiation of IgRT is warranted during or after a single severe infection or recurrent or persistent infections. (Agreement level of Expert Panel 77%)

SID Icons 03 Initiating IgRT-Icon

In patients with haematological malignancies who suffer from persistent, recurrent or severe infections despite appropriate anti-infective treatment, test immunisation* could be a tool to help decide if IgRT should be initiated, particularly in patients whose serum Ig levels do not reflect the functional status of their immune system. (Agreement level of Expert Panel 84%)

SID Icons 03 Initiating IgRT-Icon

In patients with haematological malignancies who suffer from severe, recurrent or persistent infections despite appropriate anti-infective treatment, IgRT should be considered if IgG levels are < 4 g/L or if test immunisation has failed.** (Agreement level of Expert Panel 80%)

SID Icons 03 Initiating IgRT-Icon

All patients undergoing allogeneic*** HSCT should be considered as candidates for IgRT, particularly in patients with low IgG levels (< 4 g/L) or with GVHD on immunosuppressive treatment. (Agreement level of Expert Panel 83%)

SID Icons 03 Initiating IgRT-Icon

When initiating IgRT to prevent infections, discontinuing anti-infective treatment can be considered when infection burden has been reduced, unless it is warranted by specific risk factors or other complications. (Agreement level of Expert Panel 81%)

SID Icons 03 Initiating IgRT-Icon

IgRT is generally well tolerated in patients with haematological malignancies. IgRT can on rare occasions lead to adverse events such as hypersensitivity, renal failure, thromboembolism and haemolysis. IVIg administration should be closely monitored, particularly in patients with risk factors. Adequate hydration is important. SCIg administration might present a lower risk of systemic adverse events. (Agreement level of Expert Panel 90%)

  • Jolles, S. et al., Eur J Haematol. 2021; DOI: 10.1111/ejh.13580
  • Frenzel, W. et al., Int J Clin Pharmacol Ther. 2016; 54:847-55
  • Kobayashi R.H. et al., Front Immunol. 2019; 10:40
  • * polysaccharide and polypeptide pneumococcal vaccines
  • ** not achieving a two-fold rise in specific antibody levels
  • *** including haploidentical transplants
  • GVHD: graft-versus-host disease, SCIg: subcutaneous immunoglobulin

IgRT dosing

The dose of IgRT may need to be adjusted to the individual patient. The initial dose should be based on the weight of the patient. In obese patients, the initial dose should be based on an ideal or adjusted body weight in order to minimise the risk of adverse events and costs while maximising the efficacy. The maintenance dose may need to be increased in patients whose infections are not controlled with standard dosing.

SID Icons 04 IgRT dosing-Icon

When initiating IgRT in patients with haematological malignancies, the dose should be weight-based. (Agreement level of Expert Panel 90%)

SID Icons 04 IgRT dosing-Icon

In obese patients, IgRT dose should be based on an ideal or adjusted body weight. (Agreement level of Expert Panel 90%)

SID Icons 04 IgRT dosing-Icon

In patients with haematological malignancies and in patients undergoing HSCT, the minimum IgG maintenance dose should be 0.4 g/kg body weight over a 3 to 4-week period. (Agreement level of Expert Panel 73%)

SID Icons 04 IgRT dosing-Icon

In patients with haematological malignancies and complications, whose infections are not adequately controlled on 0.4 g/kg body weight over a 3 to 4-week period, increasing the Ig dose should be considered. (Agreement level of Expert Panel 72%)

  • Jolles, S. et al., Eur J Haematol. 2021; DOI: 10.1111/ejh.13580

Use of SCIg

The increasing availability of SCIg therapy allows physicians to choose the administration route that best fits the needs of the individual patient. SCIg is as efficacious as IVIg. However, it can be self-administered and may be more convenient for patients than IVIg. The use of SCIg should therefore be considered when initiating IgRT, and patients should be involved in the treatment decision.

SID Icons 05 Use of SCIg-Icon

The subcutaneous administration of Ig induces fewer systemic side-effects, allows more stable Ig trough levels and the self-administration of Ig at home may offer quality-of-life benefits to patients wishing to self-infuse. All patients with haematological malignancies whose secondary immunodeficiency requires IgRT should have access to SCIg as a treatment option. (Agreement level of Expert Panel 97%)

SID Icons 05 Use of SCIg-Icon

In patients undergoing treatment for haematological malignancies who are about to start IgRT, both SCIg and IVIg should be discussed. Patients should be involved in the decision on the best route of administration considering their indication, ability and preference. (Agreement level of Expert Panel 94%)

  • Jolles, S. et al., Eur J Haematol. 2021; DOI: 10.1111/ejh.13580

Discontinuing IgRT

The decision to stop IgRT should be made based on the clinical situation of each individual patient, and discontinuation should only be considered after the patient has been free of infections for a clinically significant period of time. Ideally, IgRT discontinuation should be undertaken outside periods of high incidence of infection (e.g. winter).

IgG levels and infection rates should be monitored regularly after IgRT has been discontinued to assess whether IgRT should be resumed.

SID Icons 06 Discontinuing IgRT-Icon

In patients with haematological malignancies who require IgRT, discontinuation should be considered after a clinically significant period without infections or if there is evidence of immunological recovery*. (Agreement level of Expert Panel 93%)

SID Icons 06 Discontinuing IgRT-Icon

In patients with haematological malignancies who require IgRT, discontinuation should be considered after at least 6 months without infections and if there is evidence of immunological recovery*. (Agreement level of Expert Panel 87%)

SID Icons 06 Discontinuing IgRT-Icon

In patients with haematological malignancies whose IgRT is discontinued, infection rates should be closely monitored and IgG levels should be tested during routine patient visits. (Agreement level of Expert Panel 90%)

SID Icons 06 Discontinuing IgRT-Icon

In patients with haematological malignancies whose IgRT had been discontinued and severe or persistent infections recur, restarting IgRT should be the treatment of choice if hypogammaglobulinaemia is present. (Agreement level of Expert Panel 97%)

  • *outside periods of high incidence of infectious diseases
  • Jolles, S. et al., Eur J Haematol. 2021; DOI: 10.1111/ejh.13580

The Delphi exercise revealed differences in current clinical practice, both geographically and between specialties.

Haemato-oncologists generally agreed to a lesser extent than immunologists with regular IgG monitoring and with increasing IgRT dosing. While immunologists can draw on their experience of IgRT use in patients with primary immunodeficiency and are primarily focused on treating the immunodeficiency, haemato-oncologists tend to be primarily concerned with treating the malignancy.

Variation between countries

  • French haemato-oncologists tend to favour measuring overall Ig levels with electrophoresis and do not regularly assess IgG levels
  • Some experts (e.g. from France and Italy) stated that test immunisation is only done in specialist centres in their countries and that results are hard to reproduce even within the same centre
  • Guidelines in the UK limit the use of IgRT to patients with IgG levels < 4 g/L, and off-label use would not be reimbursed

Variation between specialties

  • Immunologists measure IgG levels at every routine visit, while haemato-oncologists tend to measure IgG only when an infection is diagnosed
  • Immunologists are more willing than haemato-oncologists to increase the IgRT dose if the patient does not respond to standard dosing
  • Jolles, S. et al., Eur J Haematol. 2021; DOI: 10.1111/ejh.13580

The publication is available online. For more information about this European consensus, download the presentation.

 

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