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Vaccination of patients with haematological malignancies who did not have transplantations: guidelines from the 2017 European Conference on Infections in Leukaemia (ECIL 7)

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Summary

Patients with haematological malignancies are at high risk of infection because of various mechanisms of humoral and cell-mediated immune deficiencies, which mainly depend on underlying disease and specific therapies. Some of these infections are vaccine preventable. However, these malignancies are different from each other, and the treatment approaches are diverse and rapidly evolving, so it is difficult to have a common programme for vaccination in a haematology ward. Additionally, because of insufficient training about the topic, vaccination is an area often neglected by haematologists, and influenced by cultural differences, even among health-care workers, in compliance to vaccines. Several issues are encountered when addressing vaccination in haematology: the small size of the cohorts that makes it difficult to show the clinical benefits of vaccination, the subsequent need to rely on biological parameters, their clinical pertinence not being established in immunocompromised patients, scarcity of clarity on the optimal timing of vaccination in complex treatment schedules, and the scarcity of data on long-term protection in patients receiving treatments. Moreover, the risk of vaccine-induced disease with live-attenuated vaccines strongly limits their use. Here we summarise guidelines for patients without transplantations, and address the issue by the haematological group—myeloid and lymphoid—of diseases, with a special consideration for children with acute leukaemia.

Introduction

Patients with haematological malignancies are at increased risk for various infections, including some (eg, influenza and invasive pneumococcal disease) that are vaccine preventable.1, 2, 3, 4 Vaccination has been widely pursued after haemopoietic stem cell transplantation to favour pathogen-specific immune reconstitution, and previous guidelines exist.5, 6, 7, 8 Although transplantation recipients can be different, they share a time marker, which is the transplant date. In patients with haematological malignancies who are not transplanted, infectious risk and immune deficiencies are heterogeneous, including differences between adults and children; these differences preclude a single vaccination programme.8 Patients with lympho-proliferative disorders and those with chronic myeloproliferative neoplasms (MPNs) suffer from distinct immune deficiencies and receive different treatments9, 10, 11 that variously affect the vaccine response. Moreover, therapies have changed considerably over the past decades, which have made some conclusions from previous studies obsolete in patients treated with traditional approaches. Although patients with haematological disorders have lower responses than healthy individuals to most vaccines, vaccination may prevent infections in this population, decrease their severity, avoid hospitalisations, and save lives. In 2017, the European Conference on Infections in Leukaemia (ECIL 7) group addressed the issue of vaccination in patients with haematological disorders. Here we summarise the guidelines in patients who have not had a transplantation. In a companion report we summarise the guidelines for haemopoietic stem-cell transplantation recipients.12

Section snippets

Guideline development overview

ECIL is a joint venture of the Infectious Diseases Working Party of the European Society for Blood and Marrow Transplantation, the Infectious Diseases Group of the European Organization for Research and Treatment of Cancer, the Immunocompromised Host Society, and the European Leukaemia Net. Its objective is to develop evidence-based guidelines for the management of infection in haematology and haemopoietic stem-cell transplantation patients. The ECIL method has been previously described.13 A

Overview of essential aspects of vaccination in patients with haematological disorders

Many issues need to be addressed when vaccinating patients with haematological disorders. Clinical efficacy is difficult to show because of the small size of most studies and low incidence of some infections. Therefore, most of our recommendations are based on serological response. Seroprotection is defined using data from healthy individuals, which might not be relevant to immunocompromised patients. Data on long-term persistence of protection are scarce. Live-attenuated vaccines (LAVs) pose

Vaccination in myeloid diseases

Myeloid malignancies (eg, AML, myelodysplastic syndromes [MDS], chronic myeloid leukaemia [CML], and other MPNs represent a heterogeneous group of diseases in which therapeutic approaches differ widely.

Multiple myeloma

The ECIL group recommends patients with multiple myeloma receive a yearly single dose of IIV and pneumococcal vaccination, and other inactivated vaccines should be considered 3–6 months after the end of treatment according to age and country recommendations (table 3).

Multiple myeloma patients are at high risk of infections because of B, T, natural killer, and dendritic cell dysfunctions, with a hazard ratio of infection of 7·1,40 and infections causing a fifth of the deaths in Sweden and Asia.40

Lymphoma

The ECIL group recommends patients with lymphoma receive a yearly single dose of IIV and pneumococcal vaccination, preferably before treatment or during maintenance. Other inactivated vaccines, including human papillomavirus (HPV), should be provided 3–6 months after the end of chemotherapy (6 months after the last dose of rituximab) according to age and country recommendations (table 3).

Patients with lymphoma have impaired T cell or B cell immunity, and B cell immunity is further affected by

Chronic lymphocytic leukaemia

The ECIL group recommends patients with CLL receive a yearly single dose of IIV, and pneumococcal vaccination, preferably before treatment or during maintenance, and other inactivated vaccines should be administered 3–6 months after the end of treatment (6 months after the last dose of rituximab, table 3).

The high rate and severity of pneumococcal and Hib infections in patients with CLL are correlated with low IgG levels and specific antibody titres. In a cohort of 263 patients, including 66

Role of rituximab on the immune response to vaccination in chronic lymphoproliferative diseases

Rituximab is widely used in both B-cell lymphoma and CLL. However, it strongly impairs—often annihilates—the response to IIV,38, 70, 71, 93 even in case of two doses71 or ASO3-adjuvanted vaccine.38, 67, 70, 71 When patients were vaccinated at 6–10 months38, 67 or even within a median of 29 months66 after the last rituximab dose, the response was 0–29%. Similar effects are expected with other B-cell monoclonal antibodies. Moreover, there are no data on the duration of response after

Vaccination in children with acute leukaemia

For children with acute leukaemia the ECIL group recommends: during induction and re-induction chemotherapy, only HBV vaccination in settings with high risk of HBV transmission; during maintenance therapy, a yearly IIV and PCV vaccination; varicella LAV in seronegative children preferably at 3–6 months after the end of chemotherapy rather than during maintenance; and after the end of chemotherapy, a booster dose of all vaccines in those previously vaccinated and a full vaccination course

Safety of vaccination in patients with haematological malignancies who did not have a transplantation

There are no safety concerns with inactivated vaccines. There might be mild adverse events, mostly local reactions at the site of injection, which are similar with immunocompetent hosts. There is no evidence of an increased rate of relapse of the haematological disease.

In acute leukaemia, postponing varicella LAV after completion of chemotherapy is a safer option than vaccinating during chemotherapy.5, 121 There is one report of a paediatric patient with ALL who erroneously received the

Recommendations for vaccination of health-care workers in a haematology ward

Hospital haematology staff should receive IIV annually (A II h). This measure reduced the proportion of nosocomial influenza infections in cancer patients.138 They should additionally be vaccinated according to country and hospital guidelines. Caregivers who are seronegative for measles or varicella-zoster virus should be vaccinated. In case of a rash post varicella-zoster virus vaccine, they should avoid contact with patients until resolution.

Future directions and areas of research

Studies on vaccine response are warranted in different diseases and under different therapies that might have negative effect on vaccine response. For example, patients with MPNs have an increasing life expectancy but they often receive ruxolitinib, which has potential immuno-suppressive effects. Similarly, the vaccine response of patients with acute leukaemia and MDS receiving new therapies (eg, blinatumomab, anti-CD19/20/22 CAR T cells, midostaurin, and venetoclax) should be assessed. In most

Conclusion

Patients with CML usually have good responses to influenza and pneumococcal vaccines. In patients with other MPNs, considering safety and the expected benefit of inactivated vaccines, influenza, and S pneumoniae vaccination should be provided. Patients with chronic lymphoproliferative diseases have a low response to most vaccines, but because of the high risk of infection, they can potentially benefit most from vaccine protection. Once the treatment is over, patients with haematological

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