Chronic Lymphocytic Leukemia and
Autoimmune Cytopenias: Pathogenesis,
Diagnosis and Treatment
Fergun Yilmaz1*, Demet Kiper1, Filiz Vural2
1Izmir Katip Celebi University, Ataturk Training and Research Hospital, Karabaglar, Izmir, Turkey
2Ege University Medical School, Bornova, Izmir, Turkey
Fergun Yilmaz, MD, Izmir Katip Celebi University, Ataturk Training and Research Hospital Izmir Turkey, E-mail:
Received: May 11, 2017; Accepted: May 20, 2017; Published: May 29, 2017
Chronic Lymphocytic Leukemia (CLL) is a clonal proliferation of
B cells in bone marrow, lymph nodes, peripheral blood, spleen and
other lymphoid tissues. CLL is mostly associated with dysregulated
immune system. Intrinsic immune dysfunction results in increased
frequency of autoimmune disorders and susceptibility to infections
at the time of diagnosis or during course of the disease. Autoimmune
cytopenias especially Autoimmune Hemolytic Anemia (AIHA) is
observed frequently. AIHA is the most common immune cytopenia
ranging between 5-10 % and it is followed by less frequent Immune
Thrombocytopenia (IT) (1-5%). Autoimmune Neutropenia (AIN) and
Pure Red Cell Aplasia (PRCA) are rare entities (< 1%). In CLL patients,
the differential diagnosis of autoimmune cytopenias is important
since there are many confounding factors which may cause cytopenia
in CLL patients such as infiltration of bone marrow by malignant cells,
chemotherapy and infections. A careful diagnostic workup should be
performed including history taking, physical examination, laboratory
tests and bone marrow aspiration and biopsy. The treatment of AIHA
and IT is similar to their counter parts primary AIHA and IT where
the steroids are the treatment of choice. In PRCA, steroids are mostly
ineffective and immunosuppressive agents should be tried. AIN is a
very rare entity in CLL patients. Granulocyte stimulating factors,
immunosuppressive therapies may be options in symptomatic
Chronic Lymphocytic Leukemia (CLL) is a clonal
proliferation of B cells in bone marrow, lymph nodes, peripheral
blood, spleen and all other lymphoid tissues. The B cells have
a distinctive immunophenotype characterized by CD5, CD19,
CD20 and CD23 positivity [1,2]. Among other leukemias,
CLL is mostly associated with dysregulated immune system.
Intrinsic immune dysfunction results in increased frequency of
autoimmune disorders and susceptibility to infections at the time
of diagnosis or during the course of the disease. Quantitative
and qualitative dysfunction may be observed in both humoral
and cellular immune system. Defects in B cells may result in
poor response to vaccinations and hypogammaglobulinemia.
Defects in T cells, natural killer cells, macrophages, complement
system and neutrophils can also be detected. All these alterations
are responsible for increased incidence of infections in these
patients even in the absence of chemotherapy. Therapy induced
immunosuppression also add additional risks [3-7]. Bacterial
lower respiratory tract infections with S. pneumonia, S aureus
and H. influenza are most commonly observed infections in these
patients. Viral infections including H. simplex and H. zoster are also
documented in CLL patients [6,8,9]. Particular attention should
be given to the treatment and prophylaxis of these infections to
decrease the mortality and morbidity. The risk factors, type of
infections, treatment and prophylaxis approaches and associated
impairment in immunity is beyond the scope of this review.
Other spectrum in dysfunctional immunity in CLL
patients is autoimmunity. Both hematologic and non-hematologic
autoimmune disorders can be observed. The incidence of
secondary malignancies is also increased in these patients,
another entity related to altered immune system. Autoimmune
cytopenias especially Autoimmune Hemolytic Anemia (AIHA) are
most common autoimmune diseases. The rest of the article will
be focused on autoimmune cytopenias.
Epidemiology of autoimmune disorders
Association of autoimmune diseases with CLL was
recognized more than fifty years ago . In a study including 2017
patients, it was reported that although cytopenias in CLL patients
may be due to many factors such as bone marrow infiltration,
chemotherapy or splenomegaly, autoimmune cytopenias may
contribute a considerable number of cases . AIHA is the most
common immune cytopenia ranging between 5-10 % that is
followed by less frequent Idiopathic Thrombocytopenia (IT) (1-5
%). Autoimmune Neutropenia (AIN) and Pure Red Cell Aplasia
(PRCA) are rare entities (< 1%) [11-15]. The prevalence of AIHA is
related to stage of the disease and the presence or absence of the
IGVH mutation. Although the prevalence of AIHA in early stage
disease is approximately 3%, nearly 10% of CLL patients in Binet
B and C may develop AIHA. Also, the prevalence is high in patients
with unmutated IGVH .
The interaction between CLL cells and autoimmunity
is complex. Many possible mechanisms and hypothesis try to
explain the pathogenesis. In some autoimmune diseases such
as cold agglutinin and paraneoplastic pemfigus, CLL cell itself
may secrete autoantibodies that react with specific self-antigen.
In paraneoplastic pemfigus, the self-antigens are at the dermal
epidermal junction and in cold agglutinin, M type antibodies
react with red blood cell antigens. CLL cells may also process
the antigens and act as aberrant antigen presenting cells. After
interaction with T cells, normal B cells will be activated to produce
polyclonal antibodies against red blood cell antigens . Hall et
al also agreed that malignant cells might drive an autoimmune
response by acting as antigen presenting cells . Another
possible mechanism is that cytokines produced by malignant
clone may cause loss of tolerance to self-antigens and increase
the possibility of escape of self-reactive clones. Autoantigens
may also activate malignant B cells [12,15,16]. None of these
mechanisms alone may explain the underlying pathogenesis in
all autoimmune diseases.
Both T and B cells are involved in the pathogenesis
of autoimmune disorders. Thrombocytopenia and AIHA are
mostly associated with polyclonal immunoglobulins (Ig)
mainly Ig G type directed against antigens on erythrocytes and
thrombocytes, respectively [15,17]. When these autoantibodies
are reacted with antigens on erythroblasts in the bone marrow
or neutrophils, this will result in PRCA and AIN, respectively
[15,18]. The exact source of these antibodies is not well defined.
B cells belonging to malignant clone or normal B cells activated
by several possible mechanisms may produce autoantibodies. It
is thought that resting normal B cells may be activated to produce
auto-antibodies against antigens on normal blood cells including
erythrocytes, neutrophils or platelets via T cell dysfunction and
abnormal interaction between T and B cells [15,19]. Regulatory
T cells (T reg) also plan an important role in pathogenesis in
development of autoimmune diseases in CLL patients. Their
abnormal expression or dysregulation in CLL patients will lead
to escape of self-reactive cells that cause autoimmune diseases
Autoimmune diseases in CLL patients may be observed
during chemotherapy especially with fludarabine. But fludarabine
related AIHA will not be discussed in this review.
Autoimmune cytopenias and prognosis
In the literature, there are conflicting data about the
effect of autoimmune cytopenias on prognosis. It is not well
defined if patients with autoimmune cytopenias have a poor
prognosis or not. First of all, autoimmune cytopenias should be
differentiated from cytopenias due to bone marrow infiltrations
since patients with cytopenia due to bone marrow infiltrations,
namely anemia and thrombocytopenia are classified as advanced
staged disease according to Rai and Binet staging and have
poorer prognosis [22,23]. Moreno et al analyzed 960 CLL
patients. Autoimmune cytopenia was documented in 7% of these
patients at the time of diagnosis, before diagnosis or during the
course of the disease. Patients with autoimmune cytopenia had
higher lymphocyte count, higher expression of ZAP 70 and CD 38
and rapid blood lymphocyte doubling time but outcome of these
patients was not significantly different when compared to those
without autoimmune cytopenia. But it was evident in this study
that patients with cytopenia due to bone marrow involvement
had a worse prognosis than patients with cytopenia due to
autoimmunity . This data confirmed by another study by Zent
et al. They evaluated 1750 patients with CLL. They reported that
survival was significantly better in patients with autoimmune
cytopenias when compared to patients with cytopenias related
to bone marrow infiltration. The median survival was 9.1 years
in patients with autoimmune cytopenia and 4.4 years in patients
with cytopenias due to bone marrow infiltration (p< 0.001). In
this study, although cytopenia with bone marrow involvement
was associated with poor prognosis, this was not demonstrated
in patients with autoimmune cytopenias . On the other hand,
Visco et al, suggested that autoimmune cytopenias at the diagnosis
of CLL might have a negative effect on prognosis . In another
study, Direct Antiglobulin Test ( DAT ) positivity with or without
AIHA and AIHA were found to be associated with reduced overall
survival . Visco et al, retrospectively analyzed 1278 newly
diagnosed CLL patients. In this large study, unmutated IGVH, a
positive DAT test, and occurrence of AIHA was associated with
development of IT significantly. They also demonstrated a poorer
prognosis in CLL patients with IT .
Autoimmune cytopenias are also associated with welldefined
clinical and biologic prognostic factors such as advanced
stage disease, age, high number of white cells, unmutated IGVH,
short lymphocyte doubling time [11,16, 24, 28, 29]. The impact
of these factors on the effect of autoimmune cytopenias on
prognosis should be clarified.
Since there is conflicting data in the literature related
to prognostic significance of autoimmune cytopenias, long term
follow up studies are needed to resolve this question.
AIHA should be suspected in patients with CLL when
there is an unexpected fall in hemoglobin level. This fall will be
gradual or sudden and the presentation of the patient is based
on the rate of development of anemia. As in idiopathic AIHA,
high Lactate Dehydrogenase (LDH) and indirect bilirubin levels,
reticulocytosis, reduced haptoglobin and positive DAT test is the
hallmark for the diagnosis. Peripheral blood smear may reveal
spherocytes and polychromasia. Contrast to idiopathic AIHA,
in CLL patients high LDH levels may be due to active disease
or reticulocytosis may not be obvious because of bone marrow
infiltration or anemia because of PRCA. So, careful work up
should be performed to rule out other reasons of anemia in
CLL patients. Bone marrow aspiration and biopsy should be the
part of this work up. DAT test has a special consideration in CLL
patients. DAT positivity is not always associated with hemolysis
and anemia. It may be observed alone without any evidence of
hemolysis. The incidence of pretreatment DAT positivity was 14%
in the UK LRF CLL4 trial . In addition, all the patients with
DAT positivity did not develop AIHA. It was also demonstrated
that DAT positivity was associated with poorer outcome
[6,12,26]. So , in the presence of DAT positivity accompanying
anemia and hemolysis must be documented before the diagnosis
of AIHA. On the other hand, DAT negative AIHA may also be
observed. Ig A type autoantibodies or low affinity antibodies
may explain the negative results. In addition, the amount the
auto-antibodies are also important in evaluating the DAT results.
When the amount of antibody is below the threshold level of the
test, these antibodies will not be detected and the test will reveal
negative results although the autoantibodies are present. More
sensitive tests or anti IgA antibodies may resolve these problems
but these tests could not be performed in all laboratories in
routine practice . DAT positivity in CLL patients is not always
related to autoantibodies. Especially in pretransfused CLL
patients, hemolysis due to alloantibodies, delayed type hemolytic
transfusion reaction, should be also ruled out to confirm the
diagnosis as DAT positive AIHA.
Evans syndrome should also be kept in mind in CLL
patients with AIHA although Evans syndrome is rare than AIHA
Essential diagnostic workup is summarized in [Table 1]
Table 1: Essential parameters in diagnosis of AIHA
Complete blood count
Anemia should be documented.
Rule out other reasons
Peripheral blood smear
Spherocytosis (not always detected)
Reticulocytosis predict AIHA
(May be low in PRCA or bone marrow involvement)
May be increased due to underlying inflammatory processes
Biochemical parameters including LDH, bilirubin
High levels (high LDH levels may also be associated with underlying progressive disease or liver disease. İndirect bilirubin levels may be normal if the liver is intact.)
DAT test positivity is the hallmark of the disease. But negative test does not rule out AIHA and positive test is not always associated with AIHA
Bone marrow aspiration and biopsy
Massive infiltration, lack of erythroid precursors may explain the reason for anemia
*look at the text for detailed information,
AIHA: Autoimmune hemolytic anemia, PRCA: pure red cell aplasia,
DAT: direct antiglobulin test, LDH: lactate dehydrogenase level
IT is a less common complication than AIHA in CLL
patients. Bleeding is not associated even with very low platelet
counts. It may be due to splenomegaly and hipersplenism,
bone marrow infiltration, myelotoxic effects of chemotherapy
Although thrombocytopenia due to bone marrow involvement
is mostly observed in late stages, IT may occur at any stage.
Since there is not a routine test similar to DAT used in AIHA, the
diagnosis of CLL associated secondary IT is more complicated.
Some criteria are postulated to make the diagnosis [Table 2]
[13, 27]. First of all, the number of the thrombocytes should be
decreased more than 50 % from the basal level and the absolute
number should be less than 100.000/μl. The number of the
thrombocytes should be confirmed with peripheral blood smear
to rule out pseudo-thrombocytopenia and macro thrombocytes.
The decrease in platelet number should not be explained by
another reason such as chemotherapy or splenomegaly and
hipersplenism. Other reasons causing thrombocytopenia such
as infections, disseminated intravascular coagulation, Human
Immunodeficiency Virus (HIV), hepatitis C, and drug induced
thrombocytopenia should be ruled out by appropriate tests
[13,32-34]. Table 3 demonstrates some of the possible causes
of thrombocytopenia in CLL patients. Bone marrow biopsy
or aspiration should reveal normal or increased number of
megakaryocytes due to reactive pattern. Demonstrating anti
platelet antibodies is not recommended routinely in CLL patients.
First of all, these antibodies are not sensitive and specific
and secondly, they are not routinely performed in most of the
Table 2: Criteria for the diagnosis of CLL associated secondary ITP
1. Decrease in number of platelets
>50% from the baseline and <100.000/ml
2. No splenomegaly
Limited splenomegaly that can not be palpated
3. Normal or elevated megakaryocytes
in the bone marrow
4. No chemotherapy related
5. Exclusion of other
Other autoimmune secondary cytopenias
related to infections such as HIV, hepatitis
or drug induced
The diagnosis of CLL associated IT is sometimes so
difficult to confirm. Under these circumstances, after all the
possible causes are excluded by a careful history (including drugs
and clues for recent infections) and laboratory tests, a trial of
Intravenous Immunoglobulin (IVIG) and steroid or response to
platelet suspensions may help to confirm the diagnosis [13,31].
Rapid response to IVIG or steroid will be a clue for autoimmune
cytopenia. Refractoriness to platelet transfusion may also support
the diagnosis of IT. When there is isolated thrombocytopenia in a
CLL patient, this is favor of IT since anemia mostly accompanies
thrombocytopenia in patients with bone marrow involvement.
But this is not true in the case of Evans syndrome in which IT and
anemia coexist. So, essential attention should be given to evaluate
patients presenting with both anemia and thrombocytopenia to
make the correct diagnosis.
In daily practice, rapid decrease in platelet count
without evidence of bone marrow involvement and other possible
causes, supports an autoimmune nature. A trial of intravascular
immunoglobulin and/or steroid will confirm the diagnosis .
Table 3: Possible causes of thrombocytopenia in CLL patients
1. CLL associated autoimmune thrombocytopenia
2. Splenomegaly and hipersplenism
3. Bone marrow infiltration
4. infectious agents
a. acute infections: sepsis, bacterial or viral infections
b. chronic infections: Hepatitis C, HIV, Helicobacter pylori
a. drugs causing bone marrow suppression: chemotherapeutic agents
b. drug induced thrombocytopenias
8. Thrombotic thrombocytopenic purpura
9.Heparin induced thrombocytopenia
HIV: human immunodeficiency virus, DIC: disseminated intravascular hemolysis
PRCA is a rare entity in CLL patients. The recommended
criteria for the diagnosis includes anemia, reticulocytopenia and
absence of erythroid precursors in the bone marrow in a patient
with CLL without an obvious cause [13,18,31]. Vitamin B12 and
folic acid levels should be checked especially in patients with
macrocytosis . Other causes especially viral infections should
be ruled out. In a case series, Xu et al reported seven patients
with PRCA related to CytoMegaloVirus (CMV) and Epstein – Barr
virus (EBV). The diagnosis was confirmed by Polymerase Chain
Reaction (PCR) for CMV infection and Ig M antibodies against EBV
capsid antigen and PCR for EBV infection . A Parvovirus B19
infection should also be ruled out since its association with PRCA
is demonstrated in the literature . Other possible associated
viral infections are HIV or hepatitis B and C. Bone marrow biopsy
and aspiration should be performed to document the absence of
erythroid precursors in the marrow [Table 4].
Table 4: Criteria for the diagnosis of PRCA
Can not be explained by other causes
Hemoglobin <11 gr/dl
Be careful that reticulocytopenia may be
associated with bone marrow infiltration
in a patient with anemia and bone marrow infiltration
Bone marrow biopsy and aspiration
<1 % of bone marrow cells
Granulocytic and megakaryocytic lines
should be relatively normal
Rule out other possible causes
No recent chemotherapy
No parvovirus infection
Normal LDH and bilirubin levels
DAT: Direct antiglobulin test, LDH: lactate dehydrogenase,
It is also a rare entity in CLL patients. Neutropenia
without any other cause is the hallmark of the disease. Antineutrophil
antibodies can be detected in serum of the patients
but negative results cannot be ruled out of the AIN. In addition,
presence of the auto-antibodies against neutrophil antigens is not
always associated with the clinical scenario . The diagnosis is
mainly based on exclusion of all other causes . The long-term
bone marrow suppression effect of chemotherapeutic agents
should be taken into consideration in the differential diagnosis
because more than one year of neutropenia may be observed
after fludarabine- cyclophosphamide – rituximab combination
. Bone marrow aspiration and biopsy should be performed
to rule out other reasons such as myelodysplastic features and
infiltration by malignant cells .
There are no randomized controlled trials for the
treatment of autoimmune cytopenias related to CLL so decision to
treat should be personalized. In the case of absence of progressive
disease, the treatment modalities are similar to the treatment of
primary counterparts [38,39].
In the treatment of AIHA, the first step is to decide if
transfusion is mandatory or not. Hemoglobin levels, signs and
symptoms of the patient and patient characteristics such as
comorbidities, age should be taken into account for the decision
of transfusion. Due to the presence of autoantibodies against red
blood cell antigens, compatible cross match is nearly impossible
and incompatible cross matched erythrocyte transfusion is
not contraindicated under selected circumstances [38,39]. In
relatively emergent cases in whom rapid increase in hemoglobin
level is preferred, intravenous immunoglobulin (IVIG) can be
First line therapy is similar to patients with primary
AIHA. If warm antibody is the cause of hemolysis, prednisone 1
mg / kg /day is the preferred regimen. The starting dose can be
continued up to 3-4 weeks. Afterwards, the dose should be tapered
slowly within 1-2 months. Alternatively high dose dexamethasone
( 40 mg/day) for four days can be used as first line therapy when
the patient is not suitable for long term steroid therapy .
But there is not enough data for its use in CLL associated AIHA.
Especially during prolonged usage of steroids treatment with
vitamin D and calcium preparations should be remembered.
Gastro-protective therapy, folic acid supplementation and
observation for steroid induced diabetes should be kept in mind
in all patients. It is important to differentiate warm AIHA from
cold agglutinin disease because cold agglutinin disease is mostly
refractory to steroids and rituximab (375 mg/m2/day) weekly
for four weeks is the preferred regimen [6,13].
In refractory patients and patients who need high dose
maintenance steroid therapy, second line treatments should
be considered. Rituximab is a good option in refractory AIHA
patients [40,41]. The overall response (complete remission
and partial remission) rate is as high as 70% with a durable
transfusion free period . The therapy scheme for rituximab
is of 375 mg/m2 weekly for four weeks . Although lower
doses, a total of 100 mg weekly for four weeks, were effective
and safe in primary AIHA, its role in CLL related AIHA should
be clarified [42,43]. Rituximab plus chemotherapy is also an
alternative regimen in steroid refractory patients . Several
combinations of rituximab with cytotoxic agents were studied
in small number of patients. Rituximab plus Cyclophosphamide
plus Dexamethasone (RCD) is one of the options [44,45]. RCD
revealed an overall response rate as high as 89.5% with a 24
months’ median duration of response . Good response rates
were also reported by a combination regimen of rituximab,
cyclophosphamide, vincristine and prednisone (RCVP) .
Rituximab bendamustine (BR) combination was studied in a
multicentric retrospective study by Quinquenel et al. The overall
response rate was 81% and median time to next treatment was
28.3 months. It was concluded that BR was a safe and effective
therapy in CLL patients with refractory AIHA . Other
monoclonal antibodies such as ofatumumab or alemtuzumab
may be tried but there is very limited data about their use in CLL
related AIHA . Splenectomy in eligible patients should also be
kept in mind .
In refractory patients, cyclophosphamide and other
immunosuppressive agents such as cyclosporine, mycophenolate
mofetil, or azathioprine may be used. Although safety and efficacy
data is lacking, these agents may be tried in refractory patients
based on limited data on patients with primary AIHA [13,48-50].
Patients with IT are treated when the platelet count
is below 30.000/μl or thrombocytopenia is associated with
bleeding. Similar to AIHA, prednisone therapy 1mg/kg/day is
recommended for a period of 3-4 weeks. Afterwards, gradual
tapering of the dose is required. IVIG can be considered in
patients with bleeding or prior to surgery. In refractory patients,
rituximab 375 mg/m2 weekly for four weeks is an alternative
[29,40]. D’Arena et al evaluated the efficacy and safety of
rituximab monotherapy in 21 patients with CLL associated
IT. The infusion side effect was observed in only one patient.
Complete and partial rates were 57% and 29%respectively
with a mean duration of response of 21 months . Similar
to AIHA, rituximab in combination with cytotoxic agents such
as RCD or RCVP can be considered in eligible patients [40,44-
46]. Splenectomy is not always suitable in this elderly patient
group. In addition, it increases the risk of infections. Under these
circumstances, splenectomy can be performed inhighly-selected
Another option in refractory patients is thrombopoietin
mimetics. Although there is only small case series evaluating its
activity in CLL associated IT, it should be considered in suitable
The treatment of PRCA is somewhat different from
AIHA and IT since it does not respond well to steroids. In the case
of PRCA, cyclosporine is the treatment of choice [53,54]. Long
term therapy is required so side effects such as hypertension,
renal insufficiency, immune suppression and hyperlipidemia
should be carefully followed especially in elderly patients. IVIG
( 400 mg/kg/day for 5 days) may be an alternative especially
in patients with PRCA associated with Parvovirus 19 infection.
The alternative effective therapies include rituximab alone or in
combination with dexamethasone and cyclophosphamide .
Since it is a rare entity, there is very limited data about
the treatment options and efficacy. Spontaneous remissions
may be observed. Immunosuppressive therapies, steroids or
rituximab and granulocyte stimulating factors may be tried in
symptomatic patients [13,40].
In conclusion, CLL patients may experience autoimmune
cytopenias at the time of diagnosis or during the course of the
disease. A careful work up should be carried out to make the right
diagnosis and to choose the appropriate treatment. Since large
prospective studies are lacking in the literature, the treatment
approach should be personalized. New targeted therapies and
new monoclonal antibodies should be studied in especially
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