Blood Reviews 30 (2016) 139147

Contents lists available at ScienceDirect

Blood Reviews
journal homepage: www.elsevier.com/locate/blre

REVIEW

Vaccinations in patients with hematological malignancies

C. Tsigrelis a,b, P. Ljungman c,d,
a

Division of Infectious Diseases, University Hospitals Case Medical Center, Cleveland, OH, USA
Case Western Reserve University, Cleveland, OH, USA
c
Depts. of Hematology and Allogeneic Stem Cell Transplantation, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
d
Div. of Hematology, Dept. of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
b

a r t i c l e

i n f o

Keywords:
Vaccination
Stem cell transplantation
Hematological malignancy
Inuenza
Pneumococci
Varicella-zoster virus

a b s t r a c t
Patients with hematological malignancies are at risk for a number of infections that are potentially preventable by
vaccinations such as pneumococcal infections and inuenza. Treatment, especially with anti-B-cell antibodies
and hematopoietic stem cell transplantation (HSCT), negatively impacts the response to vaccination for several
months. It is therefore recommended that patients be vaccinated before initiating immunosuppressive therapy
if possible. The risk of side-effects with inactivated vaccines is low, but care has to be taken with live vaccines,
such as varicella-zoster virus vaccine, since severe and fatal complications have been reported. HSCT patients require repeated doses of most vaccines to achieve long-lasting immune responses. New therapeutic options for
patients with hematological malignancies that are rapidly being introduced into clinical practice will require additional research regarding the efcacy of vaccinations. New vaccines are also in development that will require
well-designed studies to ascertain efcacy and safety.
2015 Elsevier Ltd. All rights reserved.

Contents
1.
2.
3.
4.
5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
When is it meaningful to start vaccinations? . . . . . . . . . . . . . .
Should we vaccinate all HSCT patients according to the same schedule? . .
What data do we have regarding uptake of vaccination recommendations?
Pneumococcal conjugate and polysaccharide vaccines . . . . . . . . . .
5.1.
Patients with hematological malignancies . . . . . . . . . . . .
5.2.
HSCT patients . . . . . . . . . . . . . . . . . . . . . . . . .
6.
Inuenza . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.1.
Patients with hematological malignancies . . . . . . . . . . . .
6.2.
HSCT patients . . . . . . . . . . . . . . . . . . . . . . . . .
6.3.
Varicella-zoster virus (VZV) vaccines . . . . . . . . . . . . . .
6.4.
Patients with hematological malignancies . . . . . . . . . . . .
6.5.
HSCT patients . . . . . . . . . . . . . . . . . . . . . . . . .
6.6.
Measles, mumps, and rubella (MMR) vaccine . . . . . . . . . .
6.7.
Papillomavirus vaccines . . . . . . . . . . . . . . . . . . . .
6.8.
Travel vaccines . . . . . . . . . . . . . . . . . . . . . . . .
Conict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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139
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145

1. Introduction
Corresponding author at: Department of Hematology and Center for Allogeneic Stem
Cell Transplantation, Karolinska University Hospital, 14186, Stockholm, Sweden.
Tel.: +468 58582507.
E-mail address: per.ljungman@ki.se (P. Ljungman).

http://dx.doi.org/10.1016/j.blre.2015.10.001
0268-960X/ 2015 Elsevier Ltd. All rights reserved.

Over the past several decades, the number of immunocompromised

patients has rapidly increased. These patients are vulnerable to numerous
infections against which vaccines exist. The 2009 H1N1 inuenza A pandemic illustrated the importance of rapid design and implementation of

140

C. Tsigrelis, P. Ljungman / Blood Reviews 30 (2016) 139147

vaccination strategies for patients with hematological malignancies including hematopoietic stem cell transplant (HSCT) recipients. Immunosuppressed patients were recognized early during the pandemic to be at
increased risk for severe complications and vaccines were rapidly tested
in these patient groups [16]. Safety of vaccines is also an important
issue since severe and life-threatening complications can develop from
live attenuated vaccines [7].
Vaccination in patients with hematological malignancies is complex
as the background and characteristics of immunosuppressed states differ between different patient categories. Patients undergoing allogeneic
HSCT are the most deeply immunocompromised and new transplant
techniques are constantly developing that are challenging the knowledge regarding the immune responses to vaccination collected from
earlier studies. Therapy for hematological malignancies has also
changed substantially during the last decade with the introduction of
drugs having different modes of action, including monoclonal antibodies, drugs with immunomodulatory effects such as lenalidomide, and
targeted drugs such as thyrosine kinase inhibitors. Therefore prior vaccination studies might not accurately represent the current risks and
benets of vaccinations. In general, almost all vaccination studies have
assessed surrogate endpoints, namely immune responses, since true efcacy studies are difcult to perform due to the number of patients required to assess prevention of infection or disease.
2. When is it meaningful to start vaccinations?
Since all types of immunosuppressive therapy, including transplantation, are likely to suppress the response to vaccination, it might be
benecial to administer vaccines before the start of therapy for hematological malignancies or before HSCT. Recovery of immune function after
cessation of immunosuppressive therapy is an important factor that
impacts the development of an adequate response to vaccination. Furthermore, vaccine safety has to be considered. The optimal time to administer vaccines after initiation of immunosuppressive therapy or
after HSCT depends on a number of factors. Tables 1 and 2 outline indications for select vaccines before and after the initiation of immunosuppressive therapy. The recommendations are adapted by the authors
from Rubin et al. [8] and Ljungman et al. [9].
For patients with hematological malignancies, cancer chemotherapy
can result in severe impairment of immune function, and the timing of
recovery of immune function is variable depending on the duration
and type of chemotherapy. In one study of children with ALL, the number of blood B-lymphocytes increased to normal levels one month after

stopping chemotherapy, although it took 6 months for serum IgG to recover in most patients suggesting defective B-lymphocyte function [10].
In another study of children with ALL and Hodgkin lymphoma, although
improvement occurred during the 1st year after cessation of chemotherapy, 81% of patients continued to show one or more immune abnormalities after 912 months [11]. Severe impairment of immune function
similarly occurs following HSCT, including a loss of pre-transplant immunity to a number of vaccine-preventable conditions including measles, mumps, and rubella [12], poliovirus [13], and tetanus [14], which
underscores the importance of vaccination after HSCT. However, preexiting recipient immunity can frequently be retained for several
months after HSCT; therefore if indicated and if patients are not already
immunosuppressed, vaccination prior to HSCT may provide transient
protection until vaccination can be performed later on in the patient's
course [8,15].
Inactivated vaccines are safe to administer in immunocompromised
patients but the strength of the elicited immune responses can vary depending on the timing of vaccine administration with respect to the
given immunosuppressive therapy. For patients with hematological
malignancies, good responses can be obtained with inactivated vaccines
if there is sufcient time prior to initiation of chemotherapy (e.g. N=2
weeks) [16,17]. However, patients receiving intensive chemotherapy,
such as induction or consolidation chemotherapy for leukemia, have
poor immune response to vaccination [18]. Patients with hematological
malignancies are likely to respond favorably to vaccination after chemotherapy has been completed, while there has been a more variable response to vaccination during maintenance chemotherapy [1922].
Existing guidelines suggest administering inactivated vaccines at least
two weeks prior to chemotherapy or during maintenance chemotherapy, or 3 months after cancer chemotherapy is completed, with the exception of those receiving anti-B-cell antibodies, where administration
should be delayed for at least 6 months [8,15,23].
Similarly, for HSCT patients, who are not already immunosuppressed, vaccination prior to transplant may improve immunity [24],
and guidelines suggest administering inactivated vaccines prior to
HSCT if there is an interval of 2 weeks before initiation of immunosuppressive therapy [8,15]. Following HSCT, patients may develop an adequate immune response to vaccination as early as 36 months after
allogeneic HSCT. This was shown in a randomized study with 7-valent
pneumococcal conjugate vaccine (PCV7) in which the immune response at 3 months was similar to the response at 9 months after
HSCT [25]. Following HSCT, guidelines recommend administering
inactivated vaccines starting as early as three months with PCV13,

Table 1
Vaccinations in patients with hematological malignancies.
Vaccine

Whena

Recommendations

PCV13 followed by
PPSV23

Before therapy
After therapy

Inactivated inuenza
vaccine

Before therapy
After therapy

Varicella vaccine

Before therapy
After therapy

Zoster vaccine

Before therapy
After therapy

MMR

Before therapy
After therapy

Travel vaccines

After therapy

Indicated in lymphoma, myeloma, and CLL patients if possible

Response to vaccination is poor for at least 612 months after treatment with anti-B cell antibodies. Unclear if repeated doses of PCV13 are
benecial.
Likely to be benecial although studies are lacking
Administer annually to all patients
Intensive immunosuppressive therapy will decrease response to vaccination
Anti-B-cell antibody therapy suppresses response to vaccination for 612 months
Negative risk benet ratio in patients with active diseaseb
For patients in remission, administer no earlier than 3 months after completion of chemotherapy and at least 12 months after
anti-B-cell antibody therapy
Negative risk benet ratio in patients with active diseaseb
For patients in remission, administer no earlier than 3 months after completion of chemotherapy and at least 12 months after
anti-B-cell antibody therapy
Negative risk benet ratio in patients with active diseaseb
Seronegative adults depending on the local epidemiological situation. For patients in remission, administer no earlier than 3 months
after completion of chemotherapy and at least 12 months after anti-B-cell antibody therapy
Efcacy of inactivated vaccines (e.g. hepatitis, poliovirus, diphtheria) are unclear, although they lack risks
Live vaccines (e.g. yellow fever) have unclear efcacy and safety

PCV13: 13-valent pneumococcal conjugate vaccine; PPSV23: 23-valent pneumococcal polysaccharide vaccine; MMR: measles, mumps, rubella vaccine.
a
Timing of vaccine administration with respect to initiation of immunosuppressive therapy.
b
Do not administer live vaccines unless indicated, patient is not immunosuppressed, and there is 4 weeks before start of immunosuppressive therapy.

C. Tsigrelis, P. Ljungman / Blood Reviews 30 (2016) 139147

141

Table 2
Recommendations for vaccinations in hematopoietic stem cell transplant (HSCT) patients.
Vaccine

When

Comments

Tetanus toxoid + diphtheria toxoid

Before transplantation
After transplantation
Before transplantation
After transplantation
Before transplantation
After transplantation
Before transplantation
After transplantation

Not indicated
Three doses (DT) starting at 612 months after transplantation
Not indicated
Three doses starting at 612 months after transplantation
Might result in improved transfer of immunity
Annually beginning 46 months after transplantation depending on season
Can improve transfer of immunity
Three doses starting 36 months after transplantation. Booster at 12 months for
patients with chronic graft-vs-host disease (GVHD)
Not effective
After three doses of pneumococcal conjugate vaccine have been given, administer pneumococcal
polysaccharide booster at 12 months for patients without GVHD
Can improve transfer of immunity
Three doses starting 36 months after transplantation. Booster at 12 months for patients with chronic GVHD

Inactivated poliovirus + pertussis

Inactivated inuenza
Pneumococcal conjugate

Pneumococcal polysaccharide

Before transplantation
After transplantation

Conjugated H. inuenzae group B

Before transplantation
After transplantation

Papilloma virus

Before transplantation
After transplantation
Before transplantation
After transplantation

Varicella vaccine

Zoster vaccine
MMR
Travel vaccines

Before transplantation
After transplantation
Before transplantation
After transplantation
After transplantation

No data
No data, but recommended starting at 6 months if not current with recommendations
Seronegative patients at least 4 weeks before start of conditioning
Seronegative patients, not before 24 months after HSCT; not to be given to patients with GVHD or ongoing
immunosuppression
No data
Not recommended
Seronegative patients at least 4 weeks before start of conditioning
Not before 24 months after HSCT; not to be given to patients with GVHD or ongoing immunosuppression
Inactivated vaccines are likely to have positive risk benet ratio.
Live vaccines - not before 24 months after HSCT; not to be given to patients with GVHD or ongoing
immunosuppression

DT: diphtheria toxoid, tetanus toxoid; MMR: measles, mumps, rubella vaccine.

four months (inuenza vaccine in a community outbreak setting), or six

months after HSCT (inuenza, Haemophilus inuenzae b conjugate, meningococcal, tetanus/diphtheria/pertussis, hepatitis A and B, inactivated
polio, and human papillomavirus) [8,15].
Live vaccines on the other hand, such as measles, mumps, and rubella (MMR) vaccine and varicella vaccine are contraindicated in immunocompromised patients. They may be considered prior to chemotherapy
or HSCT if they are indicated and patients are not already immunosuppressed and there is an interval of at least N=4 weeks prior to initiation
of immunosuppression [8,15,26]. Live vaccines such as MMR have been
given safely 36 months after completion of chemotherapy, although
similar safety data with varicella are not available [8,15]. After HSCT,
live vaccines including MMR and varicella should not be administered
unless there is an interval of at least 24 months after HSCT, the patient
is not immunosuppressed, there is no ongoing chronic graft-versus-host
disease (GVHD), and the patient is seronegative [8,15].
3. Should we vaccinate all HSCT patients according to the same
schedule?
HSCT recipients may be immunosuppressed from their underlying
disease, pre-transplant treatments of the disease, immunosuppressive
medications given either as pre-transplant conditioning or posttransplant immunosuppression, or GVHD. Current recommendations
do not differ for different categories of HSCT recipients, although it is obvious that the mechanisms behind patient's immunosuppressed states
vary between autologous and allogeneic HSCT recipients. Current recommendations also do not take into account the different types of allogeneic HSCT, despite that fact the speed of immune reconstitution is
different between for example cord blood graft recipients, patients receiving peripheral blood stem cells, and bone marrow from HLAidentical donors. This is mainly due to the lack of appropriate studies
in these separate patient populations. There are certainly factors that
must be taken into account when deciding on the timing and schedule
of vaccinations. One such factor is the use of anti-B-cell antibodies
such as rituximab. There is clear evidence that rituximab severely inhibits the response to vaccines for several months after the last dose.
Other factors include the speed and completeness of immune

reconstitution. It has been reported that the number of CD4+ cells can
be used as a marker for when vaccinations can be started, with better responses being obtained in patients with CD4+ cells above 200/l [27,
28]. However, as discussed below, there is a problem with underutilization of vaccinations and it is likely easier to get patients vaccinated if
straightforward measures such as time from HSCT are used. An additional important factor to consider is whether patients with GVHD
should be immunized according to the same schedule as patients without GVHD. It is clear that patients with GVHD should not be vaccinated
with live vaccines due to the risk for severe side effects. It is probably
also reasonable that patients with severe GVHD receiving intensive immunosuppression should have vaccinations deferred, although studies
are lacking. Regarding patients with moderate GVHD there are two
questions: Will GVHD inuence the response rate to vaccination and
is there a risk of activating GVHD? Existing data support that patients
with GVHD have lower response rates or more rapidly lose immunity
to at least some vaccines [25,2932], but there are also data showing
no effect of GVHD [33,34]. On the other hand, patients with GVHD are
at higher risk for severe infections and therefore could benet more
from vaccination. The risk of activation of GVHD seems to be low
based on the reported safety data from prospective vaccination studies
[3,25,35] and clinical experience, although this risk cannot be completely ruled out in individual cases. Finally, the immune status of the stem
cell donor also inuences the patient's response to vaccination and several studies have shown that donor vaccination followed by early recipient vaccination can improve the immune response in HSCT recipients
[24,3638].
4. What data do we have regarding uptake of vaccination
recommendations?
A number of recommendations regarding vaccination of hematology
and transplant patients have been published [39,40]. Most recently, the
Infectious Diseases Society of America (IDSA) in collaboration with
other organizations published recommendations regarding vaccinations in the immunocompromised host [8,15]. Despite the availability
of guidelines, surveys of immunization practices in patients with hematological malignancies over the past 2 decades have shown that

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C. Tsigrelis, P. Ljungman / Blood Reviews 30 (2016) 139147

immunizations are underutilized in this patient population. In a survey

performed in allogeneic HSCT patients in 1994 in US transplantation
centers, prior to the publication of above guidelines, rates of vaccination
ranged from 50% - 97%, depending on the patient's age and the type of
vaccine [41]. In another survey reported in 1995 among European transplantation centers, 65% of centers routinely immunized allogeneic HSCT
patients, while 37% routinely immunized autologous HSCT patients
[42]. A follow up survey in pediatric HSCT patients performed in 2009
reported 22%93% compliance with CDC guidelines published in 2000
[43]. A recent survey was performed in HSCT patients from 2010 to
2013 at the MD Anderson Cancer Center evaluating the awareness and
adherence with vaccination guidelines [44]. The vast majority (N 95%)
of survey respondents reported being familiar with post-HSCT vaccination protocols. However, chart reviews showed only 38% of patients
having received their rst series of vaccinations by 6 months, and only
60% had received vaccinations by 1 year after HSCT. The most common
given reasons were relapsed disease within 6 months after transplant,
receipt of rituximab in previous 6 months, receipt of IVIG, or acute or
chronic GVHD, while in 25% of cases no clear reason for withholding
vaccinations were found. To attempt to improve vaccination adherence,
one center used vaccination administration cards and telephone outreach; however, despite these interventions, 33% of HSCT patients
missed at least 1 vaccine set and 26% received 1 vaccine set later than
recommended [45]. These data underscore the importance of improving vaccination adherence.

of this strategy is that the subsequent dose of PPSV23 could broaden

the immune response due to coverage of additional pneumococcal serotypes. This strategy is also recommended by the CDC Advisory Committee on Immunization practices (ACIP) and by the UK Green book for
immunocompromised patients [57,58]. It is, however, unclear how effective this strategy is for patients with hematological malignancies
since data are lacking.
5.2. HSCT patients

Pneumococci are important causes of infection in patients with hematological malignancies. Risk factors include poor B-cell function
such as in patients with CLL and multiple myeloma and HSCT recipients,
especially those with chronic GVHD. There are two types of pneumococcal vaccines available. The rst vaccine developed was the 23-valent
pneumococcal polysaccharide vaccine (PPSV23), which is T-cell independent and therefore unable to create an immunological memory,
but has the advantage of coverage of several important pneumococcal
serotypes. The second more recently developed vaccines are the pneumococcal conjugate vaccines (PCV), which today include either 13 or
10 of the most common serotypes found in young children. These vaccines are T-cell dependent and repeated doses result in a booster effect.

PPSV23 is also usually ineffective when given during the rst year
after HSCT and particularly for patients with chronic GVHD [59
63].The efcacy of additional doses of PCV has been studied in HSCT recipients. In three prospective trials, the 7-valent PCV was more immunogenic than historical controls given PPSV23 [25,64,65] and in a
comparative trial of PCV7 and PPSV23 in adult HSCT recipients, PCV7
given to donors and recipients was more immunogenic than PPSV23
given to donors and recipients [66]. Cordonnier et al. furthermore
showed that there were similar antibody responses to vaccination
with a 3 dose PCV7 series whether started at 3 months (early) or 9
months (late) after HSCT [25]. A dose of PPSV23 could broaden the antibody response to additional serotypes [67]. Early vaccination may,
however, result in a shorter duration of protective concentrations of antibody and a booster fourth dose may be indicated if vaccination is given
early after HSCT [25]. A recent uncontrolled study with four doses of the
13-valent PCV showed very strong immune responses to the 4th dose,
although it was associated with an increased rate of side-effects [35].
In that study, there was no broadening of the immune response when
a dose of PPSV23 was given, but this vaccine was probably given too
early after the 4th PCV dose. The current recommendations are therefore to give three doses of PCV to all HSCT patients and a 4th dose to patients with chronic GVHD, while patients without chronic GVHD should
receive a dose of PPSV23. It is also most likely necessary to give additional pneumococcal vaccine doses during follow-up based on the loss
of immunity, but the exact schedule needs to be dened by further studies [68].
Based on these data from HSCT recipients, either two or three doses
of PCV followed by one dose of PPSV23 could also be more efcacious in
non-transplanted patients with hematological malignancies; however,
this requires additional investigation.

5.1. Patients with hematological malignancies

6. Inuenza

Many of the early studies were performed with PPSV23 and the results of these studies illustrate the problem with PPSV23 in high risk patients. In patients with multiple myeloma, less than 40% obtained
protective antibody levels after vaccination with PPSV23 [46]. Patients
with Hodgkin lymphoma who had vaccinations administered after receiving chemotherapy and/or radiotherapy showed very poor antibody
responses [47,48]. In contrast, good responses could be obtained before
therapy was initiated [16,17]. Vaccinations with PPSV23, given both before and after splenectomy, were able to induce repeated antibody responses [49,50]. Due to the poor immune responses obtained with
PPSV23, studies have assessed the effects of PCV. A single dose of a
PCV7 led to suboptimal responses in patients who had been treated
for Hodgkin lymphoma [51] or chronic lymphocytic leukemia [52]. Furthermore, one dose of PCV13 administered early after diagnosis resulted
in an immune response of only 58% in CLL patients as compared with
100% of healthy controls [53]. Svensson et al. showed in a noncontrolled small study that PCV13 led to better responses than PPSV23
in lymphoma patients 12 months after treatment with rituximab [54].
In a non-controlled follow-up study to the study by Molrine et al.,
Chan et al. showed that priming with PCV7 improved the response to
PPSV23 in patients with previously treated Hodgkin lymphoma [55].
The prime-boost strategy has also been studied in patients with
sickle-cell anemia [56] and in HIV-infected individuals. The advantage

The morbidity of inuenza is increased in patients with cancer. For

example, patients with malignancies were more likely to die during
hospitalization for inuenza [69]. Inuenza might also interrupt scheduled chemotherapy with a negative impact on disease outcome. HSCT
patients infected with the 2009 pandemic H1N1 virus were at high
risk for pneumonia, frequently required mechanical ventilation, and
had high mortality despite oseltamivir therapy [2,6]. There is also significant morbidity and mortality in HSCT patients who develop seasonal
inuenza. Inuenza vaccination with the inactivated trivalent vaccine
is therefore generally recommended for immunocompromised patients
[15].

5. Pneumococcal conjugate and polysaccharide vaccines

6.1. Patients with hematological malignancies

The results of inuenza vaccination studies in patients with hematological malignancies have been variable depending of the type of patients included. In a study including patients with multiple myeloma,
the immune response to one dose of vaccine was only 19% [46]. A strategy to improve vaccine efcacy or effectiveness is to give repeated doses
of vaccine, however the results have been variable among studies.
Adults with lymphoma receiving a two-dose schedule showed responses of approximately 30% after one dose and approximately 45%
after two doses of vaccine [70]. However, two other studies in patients

C. Tsigrelis, P. Ljungman / Blood Reviews 30 (2016) 139147

with various hematological malignancies failed to show an improvement by addition of a second dose [23,71].
Another potential way of improving immune response is to use
adjuvanted vaccines. There are no controlled studies, however valuable
information was gathered by the vaccines used against the pandemic
H1N1 virus. De Lavallade et al. reported results of two doses of pandemic 2009 H1N1 vaccine in patients with chronic myeloid leukemia and Bcell malignancies and compared the results to one dose given to immunocompetent controls [72]. The immune response improved after the
second dose, although the response after 2 doses was still lower than
after a single dose given to immunocompetent controls.
Another factor to consider is when to vaccinate in relation to the
administration of anti-malignancy therapy. The situation is unique
for inuenza as compared with other vaccines due to the epidemiology with yearly outbreaks and therefore it is frequently not possible
to wait to vaccinate until the patient's immune system has recovered. Patients receiving intensive chemotherapy, such as for acute
leukemia or intensive repeated chemotherapy courses are likely to
respond poorly [23]. Many studies have shown that the immune
responses are better when the interval from the end of immunosuppressive therapy to vaccination is longer. For example, de Lavaillade
showed that the immune response was better in patients with a
greater than 12 month interval from the end of chemotherapy to
vaccination and no patient who received maintenance rituximab
responded to vaccination. Patients having received rituximab have
impaired immune response for a prolonged time after nishing therapy. None of 67 lymphoma patients responded to adjuvanted H1N1
vaccine within the rst 6 months after rituximab therapy [73]. Furthermore, in lymphoma patients who had completed a rituximabcontaining regimen, the response to inuenza vaccine was even further impaired if patients had been treated with udarabine [74]. It
must be recognized that vaccine effectiveness is likely to be low in
those patients who are at the highest risk for severe disease.
6.2. HSCT patients
In general, vaccination is more likely to be effective when the time
interval after HSCT is longer, preferably no earlier than six months
after HSCT [3,72,75]. Machado et al. showed a decreased rate of laboratory veried inuenza in vaccinated compared to non-vaccinated individuals when vaccinations were given at 6 months after HSCT [76].
However, during community outbreaks, it is recommended that HSCT
recipients be vaccinated if they are more than 4 months after HSCT [8,
77]. For trivalent inuenza vaccine (TIV), data regarding the effectiveness of a 2nd dose in older children and adults have given conicting results [3,72,78]. Children younger than 9 years of age who are receiving
inuenza vaccine for the rst time require two doses administered
four or more weeks apart. Even in cases where there is no serological response, T-cell responses may be elicited that could prevent serious disease [79]. It is also possible that adjuvanted vaccines might improve
immune responses, although no controlled trials have been performed
[80]. Live attenuated inuenza vaccine should not be used because the
safety and efcacy of this vaccine in HSCT patients has not been
established and an inactivated vaccine alternative exists.
6.3. Varicella-zoster virus (VZV) vaccines
Varicella vaccine contains live-attenuated VZV (Oka strain) and it is
indicated for individuals who do not have evidence of varicella immunity [8,15]. It is, however, contraindicated in immunosuppressed patients
due to the potential for causing severe disease. Vaccination may, however, be considered for seronegative patients prior to chemotherapy or
HSCT if they are not already immunosuppressed and if there is an interval of at least 4 weeks prior to planned initiation of immunosuppression
[8,15,26]. Zoster vaccine also contains live-attenuated VZV, however it
contains 14-fold more (at expiry) virus than does the varicella vaccine

143

[8,15]. It is contraindicated in immunosuppressed patients due to the

potential for causing severe disease. It is indicated for prevention of herpes zoster in patients who have had varicella or zoster infection or are
VZV seropositive with no history of varicella vaccination [8,15,39]. Patients with varicella immunity that was induced by varicella vaccination
are at lower risk for zoster, and zoster vaccine is not recommended in
this setting [8,15].
6.4. Patients with hematological malignancies
In one study of 191 children with leukemia in remission who were
given varicella vaccination, there were no severe adverse effects and
the efcacy was high [81]. In another study, 437 children in remission
from leukemia were given varicella vaccination; 372 were getting maintenance chemotherapy when immunized and 149 (40%) of those patients developed a rash, which in 4 patients became severe but not
fatal [82].
There are three case reports of fatal disseminated infection due to
the vaccine strain after receiving varicella vaccination. The rst report
of fatal disseminated varicella infection caused by the VZV Oka vaccine
strain was reported in a patient with ALL who was on maintenance chemotherapy, which was interrupted for 1 week before and after varicella
vaccination was given [83]. Another case of fatal disseminated varicella
infection caused by the VZV Oka vaccine strain was reported in a
15 month old child who was given varicella vaccine and suspected
have a primary or acquired immune deciency [84]. A more recent report was of a patient who had diffuse large B-cell lymphoma but was
not on chemotherapy, who developed fatal disseminated zoster 7
months after varicella vaccination conrmed to be caused by the VZV
Oka vaccine strain [7]. Therefore, it has been suggested that the risk of
natural varicella infection, since effective antiviral therapy exists, does
not outweigh the risks of vaccination [85]. For seronegative patients
with hematological malignancies who are in remission and have completed chemotherapy, the recommendation is to wait at least three
months after completion of chemotherapy to administer varicella vaccine (12 months after anti-B-cell antibodies; Table 1).
There are limited data on the use of zoster vaccine in patients
with hematological malignancies. One study reported 31 patients
with hematological malignancies who were given zoster vaccine
[86]. Most patients were given chemotherapy N3 months prior to
the administration of zoster vaccine, with some exceptions, including 3 patients who received rituximab within 3 months prior to vaccination. There were no adverse events reported and no patients
developed herpes zoster in follow up. If zoster vaccine is given to patients with hematological malignancies, the precautions noted above
with varicella vaccine should be considered, including if there is
suspected inadequate immunity or ongoing immunosuppression
that zoster vaccination should be avoided.
6.5. HSCT patients
Varicella vaccination has been safely given to HSCT patients 24
months after transplant, who were not immunosuppressed, did not
have GVHD, and in some studies, a CD4+ T-cell lymphocyte count
200 cells/mm3 [8,15,27]. Guidelines recommend that varicella vaccine
should only be administered if there is an interval of at least 24 months
after HSCT, the patient is not immunosuppressed, there is no ongoing
chronic GVHD, and the patient is seronegative [8,15].
For HSCT patients, guidelines do not recommend giving the zoster
vaccine, particularly since safe prophylactic alternative antiviral drugs
exist [8,15,39,40]. However, HSCT patients remain at high risk for zoster
even after stopping prophylactic antiviral therapy, and boosting immunity against VZV with zoster vaccination might decrease the risk of reactivation. One center reported their safety experience with use of zoster
vaccine in 110 HSCT patients who were about 2 years after HSCT, free of
GVHD, and not receiving immunosuppression [87]. The vaccine was

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C. Tsigrelis, P. Ljungman / Blood Reviews 30 (2016) 139147

well tolerated with 2 vaccine recipients (1.8%) developing a skin rash, 1

zoster like, and 1 varicella like, that resolved with anti-viral therapy. In
another study of 31 HSCT patients who were given zoster vaccine, 1 patient developed herpes zoster 5 months after autologous HSCT that resolved with antiviral therapy [86]. The vesicles were not cultured to
assess if the strain was wild type VZV vs Oka VZV vaccine strain. No severe adverse reactions were reported. Inactivated varicella and zoster
vaccines have been studied, but are not currently available. In one
study in HSCT patients, heat-inactivated varicella vaccine was given at
1, 2, and 3 months after transplant, and compared with unvaccinated
patients, vaccinated patients had a dramatic decrease in disease severity
associated with VZV infection [88]. In a subsequent randomized trial in
autologous HSCT patients, heat-inactivated varicella vaccine was given
1 month prior to transplantation, followed by vaccine at 1, 2, and 3
months after transplantation [89]. T-cell responses were signicantly
higher in vaccinated patients up to 12 months follow up, and the rate
of zoster was signicantly decreased (33% in unvaccinated vs 13% in
vaccinated).

6.6. Measles, mumps, and rubella (MMR) vaccine

The MMR vaccine contains live, attenuated viral strains and could
therefore cause severe side effects if given to immunocompromised individuals. Recently measles has resurged, causing widespread outbreaks
in several countries due to lower vaccine coverage among healthy children [90,91]. This poses an increased risk for patients with hematological malignancies and HSCT recipients. HSCT recipients are also likely to
lose protective immunity to measles especially if previously vaccinated
and with the increased number of long-term survivors after HSCT, this
will also increase the pool of individuals that might become infected
and thereby contribute to the spread of measles in the community. It
has been shown that MMR vaccine can be given safely to patients at
least two years after HSCT without GVHD and off immunosuppression
[9294].

6.7. Papillomavirus vaccines

Human papillomavirus (HPV) is associated with cervical, vulvar,
vaginal, anal, and oropharyngeal cancers in females, and anal, oropharyngeal, and penile cancers in males [95]. These cancers are most commonly due to HPV types 16 or 18, with additional types accounting for a
minority of cancer cases, including types 31, 33, 45, 52, and 58 [95]. HPV
is also associated with anogenital warts, most commonly due to HPV
types 6 or 11. There are several HPV vaccines available, all inactivated
vaccines, including bivalent (HPV 16 and 18), quadrivalent (HPV 6, 11,
16, and 18), and 9-valent vaccines (HPV types 6, 11, 16, 18, 31, 33, 45,
52, 58) [95]. HPV vaccination is recommended in a 3-dose schedule routinely at age 11 or 12 years, and up to age 26 for those who have not
been previously vaccinated.
The incidence of cervical cancer appears to be increased after HSCT;
therefore, HPV vaccination is a potentially important strategy for reducing the risk of HPV related cancers [96,97]. However, there are no data
regarding HPV vaccination in HSCT recipients or patients with hematological malignancies. IDSA clinical practice guidelines suggest HPV vaccination in patients with hematological malignancies aged 1126 years
if not current with recommendations, during the following time periods: 2 or more weeks prior to chemotherapy or during maintenance
chemotherapy, 3 months after chemotherapy or 6 months after
anti-B-cell antibodies, 2 weeks prior to HSCT if patient is not already
immunosuppressed, or starting 6 months after HSCT [8,15]. Further
studies assessing HPV vaccination are needed, and a clinical trial is currently in progress assessing the safety and immune response of HPV
vaccination in female HSCT recipients (ClinicalTrials.gov Identier:
NCT01092195).

6.8. Travel vaccines

Immunosuppressed patients who travel may be at signicant risk
of vaccine preventable conditions such as hepatitis A, typhoid fever,
and yellow fever, depending on the destination and itinerary. It is
therefore essential that patients with hematological malignancies
be assessed prior to travel, preferably by a specialist in travel medicine and ideally at least 46 weeks before travel [98,99]. However,
pre-travel health advice appears to be underutilized. In a survey of
516 HSCT patients performed between 2005 and 2010 at The Memorial Sloan Kettering Cancer Center, 44% reported international travel
outside of the US or Canada. Only 55% of travelers reported seeking
pre-travel health advice, and only 70% of travelers to high-risk destinations reporting seeking pre-travel care [100]. Reasons for not
seeking pre-travel evaluation included not thinking it was necessary
(66%), were not aware about needing evaluation (30%), and not been
advised by their provider regarding needing pre-travel evaluation
(20%). Travel-related illness occurred in 7% of travelers overall, and
in 14% of travelers to high-risk areas.
Guidelines suggest allogeneic HSCT recipients or those with GVHD
not travel to developing countries for 612 months after HSCT, and
that autologous HSCT recipients defer travel to developing countries
for at least 36 months after HSCT [40]. For patients with hematological
malignancies that travel to developing countries, several vaccines merit
further discussion. Travelers to developing countries are at substantial
risk for acquiring hepatitis A, it is one of the most common vaccinepreventable diseases acquired during travel [101]. It is known that
there is signicant loss of hepatitis A antibody after HSCT, ranging
from 11% to 43% in a number of studies [102]. Hepatitis A vaccination
is currently recommended during the following time periods: 2 or
more weeks prior to chemotherapy or during maintenance chemotherapy, 3 months after chemotherapy or 6 months after anti-Bcell antibodies, 2 weeks prior to HSCT if patient is not already immunosuppressed, or starting 6 months after HSCT [8,15]. Typhoid
fever, caused by Salmonella enterica serotype Typhi, is another common
vaccine-preventable disease that may be acquired during travel [103].
There are two typhoid vaccinations available with comparable efcacy
[103]. There is an oral live attenuated typhoid vaccine that should not
be used in immunocompromised patients. There is also an intramuscular inactivated capsular polysaccharide vaccine. There are no data regarding immunogenicity or efcacy of inactivated typhoid vaccine
among HSCT patients [40]. Yellow fever is a mosquito-borne virus endemic to certain areas of Africa and South America, and there are an estimated 200,000 cases and 30,000 deaths annually worldwide [104].
Yellow fever vaccine is a live attenuated vaccine and is contraindicated
in immunocompromised patients, and it is recommended that immunocompromised patients avoid travel to areas endemic for yellow
fever [8,15]. Yellow fever vaccination can potentially be considered in
patients N2 years after HSCT who do not have chronic GVHD or ongoing
immunosuppression that must travel to endemic areas [39], and there
are case reports of yellow fever vaccine being safely administered in
HSCT patients with these criteria [39,105,106].
Conict of interest
Constantine Tsigelis has no conicts to declare. Per Ljungman has received research grants from Pzer and Merck and been a member of an
advisory board for Astellas and Vical.
Research Agenda
The rapid development of treatments for both hematologic malignancies and HSCT patients challenges current vaccination recommendations since studies including patients treated with these new
modalities are lacking.
The optimal schedules for PCV and inuenza vaccination are not welldened and require further study.

C. Tsigrelis, P. Ljungman / Blood Reviews 30 (2016) 139147

There are vaccines commonly used in the population for which efcacy and safety data are lacking. These include vaccines against tick
borne encephalitis, yellow fever, human papillomavirus, and hepatitis
A, among others.
Vaccination of stem cell donors might improve the immune status of
HSCT patients. Donor vaccination has been studied for different vaccines and has been recently reviewed by Harris et al. [24]. Most studies
show the need for vaccination of both the donor and then vaccination
of the patient early after HSCT. However, further studies are needed
before introducing this strategy in clinical practice.
New vaccines are in development such as against cytomegalovirus
with the leading candidate currently undergoing a phase III clinical
trial. Phase II data showed approximately 50% reduction in CMV viremia [107].
Inactivated VZV vaccines are in development. In a safety and immunogenicity study of heat-treated zoster vaccine, a 4-dose vaccine series
was given to various immunosuppressed patients [108]. Patients
with hematological malignancies and autologous HSCT patients had
an increase in VZV-specic T-cell responses, whereas allogeneic
HSCT patients did not. In a recently randomized controlled trial of an
inactivated adjuvanted zoster vaccine in 15,411 patients, the vaccine
efcacy against zoster was 97.2%; however, immunocompromised patients were excluded from the trial [109]. Further studies of these vaccines are needed.
Practice Points
Physicians should assess whether pneumococcal and inuenza vaccination is indicated before therapy for the hematological malignancy.
Physicians should ascertain that patients with hematological malignancies receive recommended vaccines such as inuenza during and
after therapy.
Physicians caring for patients undergoing HSCT should ascertain that
these patients receive recommended vaccines before and after transplantation.
Patients with hematological malignancies and HSCT patients should
be appropriately advised regarding the benets and risks of travel
vaccines.

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