Rituximab therapy for chronic lymphocytic leukemia-associated autoimmune hemolytic anemia.
ABSTRACT Autoimmune hemolytic anemia (AIHA) is a well-known complication of chronic lymphocytic leukemia (CLL). In recent years the anti-CD20 monoclonal antibody rituximab has been used for the therapy of steroid-refractory AIHA and autoimmune thrombocytopenia, either idiopathic or in association with CLL. We report the results of rituximab treatment for 14 patients suffering from CLL-associated AIHA. They developed a direct antiglobulin test positive AIHA at a mean time of 47 months (range 0-135 months) from the diagnosis of CLL. In 3 cases AIHA was diagnosed at the same time as CLL. Only 1 patient had fludarabine-related AIHA. All patients received steroids as first-line treatment. At a mean time of 46 days (range 1-210 days) from the diagnosis of AIHA all patients received rituximab at a dosage of 375 mg/m(2)/weekly for 4 weeks. All patients except 3 (2 died of cardiac failure or sepsis soon after the third cycle and 1 HCV-positive patient experienced a rise in serum amino transferases) completed the scheduled four programmed cycles. First injection side effects of rituximab were minimal. All but 2 patients showed an increase in hemoglobin levels in response to rituximab (mean value 3.6 g/dl; range 0.7-10 g/dl) and a reduction in the absolute lymphocyte count and lymph nodes and spleen volume. Nine patients required packed red cell transfusions before starting rituximab; 5 no longer needed transfusions just after the second cycle and another patient after the fourth cycle. Three patients (22%) were considered to fully respond and 7 (50%) only responded partially. At a mean follow-up of 17 months, 8 patients were still alive, 6 of them transfusion-free. Our results prove that the anti-CD20 monoclonal antibody is an effective and well-tolerated alternative treatment for CLL-associated AIHA.
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ABSTRACT: Autoimmune neutropenia (AIN), resulting from granulocyte-specific autoantibodies, is much less frequent than other autoimmune hematologic disorders including autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP). These autoimmune disorders may precede, synchronize, or follow collagen disorders, viral infections, and lymphoid neoplasms. Herein we present the first case of AIN in association with Helicobacter pylori-negative mucosa-associated lymphoid tissue (MALT) lymphoma with nodal dissemination. In our case, AIN, accompanied by ITP, occurred prior to the clinical manifestation of lymphoma. AIN and ITP were well managed afterwards, but they relapsed in accordance with the recurrence of lymphoma. The administration of prednisolone at 0.5 mg/kg daily alleviated the cytopenias within a week. In general, combination chemotherapy is performed for the treatment of lymphoma-associated autoimmune hematologic disorders and indeed seems to be effective. Our case indicates that corticosteroid monotherapy may be effective for lymphoma-associated AIN especially when AIN precedes the onset of lymphoma.International journal of clinical and experimental pathology. 01/2014; 7(9):6386-90.
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ABSTRACT: Autoimmune hemolytic anemia (AIHA) is a relatively uncommon disorder caused by autoantibodies directed against self red blood cells. It can be idiopathic or secondary, and classified as warm, cold (cold hemagglutinin disease (CAD) and paroxysmal cold hemoglobinuria) or mixed, according to the thermal range of the autoantibody. AIHA may develop gradually, or have a fulminant onset with life-threatening anemia. The treatment of AIHA is still not evidence-based. The first-line therapy for warm AIHA are corticosteroids, which are effective in 70-85% of patients and should be slowly tapered over a time period of 6-12 months. For refractory/relapsed cases, the current sequence of second-line therapy is splenectomy (effective approx. in 2 out of 3 cases but with a presumed cure rate of up to 20%), rituximab (effective in approx. 80-90% of cases), and thereafter any of the immunosuppressive drugs (azathioprine, cyclophosphamide, cyclosporin, mycophenolate mofetil). Additional therapies are intravenous immunoglobulins, danazol, plasma-exchange, and alemtuzumab and high-dose cyclophosphamide as last resort option. As the experience with rituximab evolves, it is likely that this drug will be located at an earlier point in therapy of warm AIHA, before more toxic immunosuppressants, and in place of splenectomy in some cases. In CAD, rituximab is now recommended as first-line treatment.Haematologica 10/2014; 99(10):1547-1554. · 5.94 Impact Factor
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ABSTRACT: Bendamustine is an alkylating agent approved for the treatment of chronic lymphocytic leukemia (CLL) and B-cell non-Hodgkin lymphoma. There are scant reports on bendamustine-induced immune hemolytic anemia occurring mainly in CLL patients. We report a case of immune hemolytic anemia that developed after exposure to bendamustine in a 70-year-old female with CLL who was previously exposed to fludarabine. Previous exposure to fludarabine is a common finding in the majority of reported cases of bendamustine drug-induced immune hemolytic anemia (DIIHA), including our case. Bendamustine should be suspected as the cause of any hemolytic anemia that develops while on this drug, especially in CLL patients treated previously with fludarabine.Hematology/ Oncology and Stem Cell Therapy 04/2014;
Rituximab Therapy for Chronic Lymphocytic
Leukemia-Associated Autoimmune Hemolytic Anemia
Giovanni D’Arena,1*Luca Laurenti,2Silvana Capalbo,3Alfonso Maria D’Arco,4
Rosaria De Filippi,1Gianpaolo Marcacci,1Nicola Di Renzo,5Sergio Storti,6Catello Califano,4
Maria Luigia Vigliotti,1Michela Tarnani,2Felicetto Ferrara,7and Antonio Pinto1
1Hematology and Bone Marrow Transplantation Unit, National Cancer Institute, IRCCS Fondazione ‘‘G. Pascale,’’ Naples, Italy
2Hematology Department, Catholic University of ‘‘Sacred Heart’’ Rome, Italy
3Hematology Department, University of Bari, Italy
4Hematology Oncology Unit, ‘‘Umberto I’’ Hospital, Nocera Inferiore, Italy
5Hematology Oncology Unit, CROB Hospital, Rionero in Vulture, Italy
6Hematology Oncology Unit, Catholic University, Campobasso, Italy
7Hematology and Bone Marrow Transplantation Unit, ‘‘A. Cardarelli’’ Hospital, Naples, Italy
Autoimmune hemolytic anemia (AIHA) is a well-known complication of chronic lymphocytic
leukemia (CLL). In recent years the anti-CD20 monoclonal antibody rituximab has been used
for the therapy of steroid-refractory AIHA and autoimmune thrombocytopenia, either idio-
pathic or in association with CLL. We report the results of rituximab treatment for 14 pa-
tients suffering from CLL-associated AIHA. They developed a direct antiglobulin test positive
AIHA at a mean time of 47 months (range 0–135 months) from the diagnosis of CLL. In
3 cases AIHA was diagnosed at the same time as CLL. Only 1 patient had fludarabine-related
AIHA. All patients received steroids as first-line treatment. At a mean time of 46 days (range
1–210 days) from the diagnosis of AIHA all patients received rituximab at a dosage of
375 mg/m2/weekly for 4 weeks. All patients except 3 (2 died of cardiac failure or sepsis soon
after the third cycle and 1 HCV-positive patient experienced a rise in serum amino transfer-
ases) completed the scheduled four programmed cycles. First injection side effects of rituxi-
mab were minimal. All but 2 patients showed an increase in hemoglobin levels in response
to rituximab (mean value 3.6 g/dl; range 0.7–10 g/dl) and a reduction in the absolute lympho-
cyte count and lymph nodes and spleen volume. Nine patients required packed red cell
transfusions before starting rituximab; 5 no longer needed transfusions just after the sec-
ond cycle and another patient after the fourth cycle. Three patients (22%) were considered
to fully respond and 7 (50%) only responded partially. At a mean follow-up of 17 months,
8 patients were still alive, 6 of them transfusion-free. Our results prove that the anti-CD20
monoclonal antibody is an effective and well-tolerated alternative treatment for CLL-associ-
ated AIHA. Am. J. Hematol. 81:598–602, 2006.
C 2006 Wiley-Liss, Inc.
Key words: chronic lymphocytic leukemia; autoimmune hemolytic anemia; rituximab
Autoimmune hemolytic anemia (AIHA) may de-
velop as a complication of, or may rarely herald, a
lymphoproliferative disorder [1–3]. AIHA is the best
known autoimmune complication of chronic lym-
phocytic leukemia (CLL), occurring in 10–20%
cases [4,5]. Although the origin of the warm or cold
autoantibodies against antigens on the red blood cell
surface in CLL-associated AIHA is controversial
(malignant B-cell clone or residual normal B-lym-
phocytes), steroids are the first-line treatment choice.
Different immunosuppressive agents are also used
for steroid-refractory disease. Some authors report
the prognosis of CLL-associated AIHA patients to
be poor, while others feel that this complication is
unchanged for the overall survival of CLL patients
[4,5]. In recent years the chimeric anti-CD20 mono-
*Correspondence to: Giovanni D’Arena, Hematology and Bone
Marrow Transplantation Unit, IRCCS Fondazione ‘‘G. Pas-
cale,’’ Via Mariano Semmola, 80131 Naples, Italy.
Received for publication 12 July 2005; Accepted6 February 2006
Published online in Wiley InterScience (www.interscience.wiley.com).
American Journal of Hematology 81:598–602 (2006)
C 2006 Wiley-Liss, Inc.
clonal antibody rituximab has been used in the ther-
apy of AIHA and autoimmune thrombocytopenia,
including cases with concomitant CLL [6–12]. We
report the results of rituximab treatment in 14 pa-
tients suffering from CLL-associated AIHA, mostly
PATIENTS AND METHODS
Fourteen patients (8 males and 6 females) suffer-
ing from immunologically typical CLL (CD19þ
CD5þCD23þsIglow) were treated for AIHA at our
centers between March 2001 and September 2004.
The mean age at CLL diagnosis was 64 years old
(range 48–87 years old) and 68 years old (range 48–
87 years old) at AIHA diagnosis. A direct antiglo-
bulin test (DAT) positive AIHA developed at a
mean time of 47 months (range 0–135 months) from
the diagnosis of CLL. In 3 cases AIHA was diag-
nosed at the same time as CLL. For only 1 patient
(case 10, in Table I) AIHA was considered fludara-
bine-related in terms of a limited time interval
within the use of this purine analog (1 month
before). In all patients, laboratory signs of hemolysis
were present (high serum levels of LDH and indirect
bilirubin as well as reticulocytosis). Finally, in 2 pa-
tients (cases 5 and 6) a sudden reduction of platelet
levels was observed (Fisher-Evans syndrome). No
patient displayed monoclonal gammopathy on serum
electrophoresis or any autoantibodies that could sug-
gest the presence of an autoimmune disorder other
than AIHA. Three patients carried antibodies against
hepatitis C virus (cases 6, 11, 12) and 1 against hepa-
titis B virus (case 7).
All patients received steroids at therapeutic dos-
ages (methylprednisolone 1-1,5 mg/kg body wt daily)
as first-line treatment.
As second-line treatment of AIHA, some patients
were given intravenous Cytoxan (cases 6, 7 and 8)
and in 1 case (case 8) 2 mg of vincristine was intra-
venously infused. After a mean time of 46 days
(range 1–210 days) from the diagnosis of AIHA all
patients received rituximab (Mabthera, Roche S.p.A.,
Milan, Italy) at a dosage of 375 mg/m2/weekly for
4 weeks. All patients remained on steroids when rit-
uximab was started, and the dose was tapered after
2 weeks in responding patients. Moreover, the dose
of steroids was not increased in nonresponding sub-
jects. Eleven of 14 patients were considered steroid-
refractory because they did not experience a rise in
hemoglobin level and/or a stable improvement of
their AIHA after therapy. In 3 patients (cases 10, 11,
and 12) the anti-CD20 monoclonal antibody was
given a few days after starting steroids (mean 4 days;
range 1–6 days). In all 3 patients receiving immuno-
suppression therapy, Cytoxan and vincristine were
stopped before rituximab was administered.
Response criteria to rituximab treatment for AIHA
were defined as follows: (a) complete response: nor-
malization of hemoglobin levels, transfusion-free and
absence of clinical and laboratory signs of hemolysis;
(b) partial response: rise in hemoglobin levels ? 2 g/dl,
transfusion-free either without or reduced trasfusion
requirement, and improvement of clinical and labora-
tory signs of hemolysis.
Table I shows hemoglobin (g/dl) levels, platelets
(PLT) ? 103/L and absolute lymphocyte count
(LC) ? 103/L, before and after rituximab treatment.
All but 3 patients (cases 6 and 8, who died of car-
diac failure and sepsis, respectively, soon after the
third cycle, and case 12, who was HVC-positive and
experienced a rise in AST and ALT serum levels),
completed the scheduled four cycles. First infusion
side effects of rituximab were mild (fever in 1 case
and fever and chills in another case). All but 2
patients (cases 8 and 10) showed an increase in Hb
levels (mean value 3.6 g/dl, range 0.7–10 g/dl) in
response to rituximab. In 3 patients the steroids and
rituximab cycles were begun within a few days of
each other. Thus, we cannot draw a firm conclusion
that any response noted in these 3 patients is only
due to rituximab. At the same time, a reduction in
absolute lymphocyte counts and in the size of lymph
nodes and spleen was observed. Nine patients
required packed red cell transfusions before starting
rituximab. Five of them became transfusion-free
after the second infusion while a 6th patient became
transfusion-independent after the fourth cycle. Four
patients had converted from a positive to a negative
DAT by the end of the scheduled four rituximab
doses (cases 1, 2, 3, and 9). Only 3 patients (22%)
were considered complete responders and 7 (50%)
partial responders. Three patients continued with a
maintenance program of rituximab with different
schedules: four weekly infusions every 6 months
(case 1); one infusion every 4 weeks for 6 months
(case 5); 4 weekly doses every 4 months (case 9).
Two patients, both complete responders (cases 1
and 9), received further rituximab infusions in order
to treat CLL, not for AIHA. Finally, at a mean fol-
low-up of 17 months, 8 patients were still alive, 6 of
them transfusion-free (Table I).
CLL is considered either a malignant disease or a
complex immunologic disorder. In fact, an autoim-
599Rituximab for CLL-Associated AIHA
American Journal of Hematology DOI 10.1002/ajh
TABLE I. Personal Characteristics of Each Individual Patient, Response to 4-Week Rituximab Therapy for AIHA, and Follow-up
Cy (23 days)
Cy (20 days)
Cy (24 days)VCR
Hgb (g/dl) pre/
LC (? 103/ml) pre/
PLT (? 103/ml) pre/
No. of weekly
DAT after four
doses of rituximab
Side effects to
Cause of death
Note: CR, complete response; PR, partial response; NR, no response; Hgb, hemoglobin; LC, lymphocytes; PLT, platelets; MPL, methylprednisolone (the dose reported is that taking when rituximab was initiated; the time interval between the
initiation of steroid and the initiation of rituximab therapy is in parentheses); Cy, cytoxan (the time interval between the last dose infused and the initiation of rituximab is in parentheses); VCR, vincristine (the time interval between the dose infused and the initiation of rituximab is in parentheses); Flu, fludarabine; FN, fludarabine, mitoxantrone; Flu-Cy, fludarabine, Cytoxan; CHL, chlorambucil; CHOP, cytoxan, Adriamycin, oncovin, prednisone; CVP, cytoxan, oncovin,
mune derangement is hypothesized with the so-
called paradoxical finding of an immune deficiency
status along with an excess of autoimmune phenom-
ena . Moreover, warm type AIHA is the most
common autoimmune disease associated with CLL,
which is considered the most common cause of
AIHA [4,13]. Previous studies reported AIHA as a
poor prognostic indicator in CLL [14,15]. However,
more recently, Mauro et al., by means of multivari-
ate analysis, found that AIHA has no effect on sur-
Historically, first-line treatment of autoimmune
complications in CLL was immunosuppression by
means of glucocorticoids. Cytoxan, vincristine, intra-
venous immunoglobulins, and splenectomy have also
been used, mainly in cases with steroid-refractory
More recently, the chimeric anti-CD20 monoclo-
nal antibody rituximab has been used in the manage-
ment of steroid-refractory AIHA, including CLL-
associated cases, and has shown significant activity.
This molecule is active against normal and neoplastic
B-lymphocytes that express the CD20 antigen, in-
cluding B-CLL cells, despite their lower density of
CD20 compared to normal B-lymphocytes, and in
other B-lymphoproliferative disorders . How rit-
uximab works in CLL-related AIHA is not fully
understood. This molecule is a human-mouse chi-
meric monoclonal antibody specific for the CD20
antigen, present on the surface of normal and malig-
nant B-lymphocytes, and acts through complement-
dependent cytotoxicity and antibody-dependent cellu-
lar cytotoxicity . B-cell depletion is thus induced
by rituximab. Red blood cell autoantibodies are gen-
erally polyclonal, suggesting the productive role of
normal B-cells. In other cases remnant normal B-
lymphocytes seem to produce autoantibodies . In
a very recent study, Hall et al. showed that malig-
nant B-cells themselves were able to present Rh auto-
antigen to helper T-cells in CLL. In light of this, rit-
uximab-induced B-cell depletion in CLL could simul-
taneously eliminate the antigen presenting B-cells as
well as the B-cells producing the pathogenic autoanti-
Few CLL patients have been treated with rituxi-
mab for AIHA. The largest series was published in
2002 by Gupta et al. . They reported their experi-
ence with eight CLL-related steroid-refractory AIHA
patients using the so-called RCD treatment regimen.
Rituximab, Cytoxan, and dexamethasone were given
at 4-week intervals for two to five cycles until the
best response was obtained. All eight patients ac-
hieved remission of AIHA. Subsequenty, Zaja et al.
used weekly rituximab at a dosage of 375/m2intrave-
nously for 4 weeks to treat four CLL patients with
warm AIHA . Only one patient achieved complete
remission. Several other authors have mentioned
cases with encouraging results [9–12].
We treated 14 patients with B-CLL-related warm
AIHA with a weekly rituximab infusion schedule
for 4 consecutive weeks. In our series, a response
rate of 72% was observed (3 complete and 7 partial
responses). Most importantly, no significant side
effects to rituximab were observed, even in elderly
patients (82 and 87 years old, respectively). In fact,
neither one experience side effects to rituximab, but
died of cardiac failure due to severe anemia. In
1 patient who responded partially and was carrying
serum antibodies against the hepatitis C virus, a rise
in serum ALT and AST levels prevented continua-
tion of the treatment after the third cycle. The rela-
tionship between the rise in amino transferases and
rituximab infusion is not clear in view of the fact
that safe use of the anti-CD20 monoclonal antibody
has been reported in HCV-infected patients, albeit
with an increase in viremia .
The relationship between fludarabine and CLL-
associated AIHA is still a controversial issue. Sev-
eral studies reported that AIHA is more frequently
observed in heavily pretreated CLL patients, while
the incidence in subjects receiving fludarabine as
first-line treatment is not different from that ob-
served in untreated patients [21–25]. In light of this,
it appears ever more evident that AIHA is most
probably due to an immune dysregulation with loss
of lymphocytic control of aberrant autoimmune
clones rather than to the direct drug action. How-
ever, fludarabine appears to be effective by inducing
an imbalance in the CD4 and CD8 ratio, which
could be involved in the loss of immunological con-
trol of autoimmune phenomena. As far as our pa-
tients are concerned, a relationship between fludara-
bine use and AIHA was found only in 1 case. More-
over, he exhibited no response to rituximab.
In conclusion, we have reported our experience
with rituximab-induced B-cell depletion as treatment
for CLL-related AIHA. A response to this therapy
has been obtained in 72% of patients, with no life-
threatening or relevant toxicity, even in the elderly.
However, further investigation is needed in order to
identify the optimal administration schedule and
duration of treatment.
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