Idiopathic autoimmune pancytopenia treated with rituximab/Case report

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Idiopathic Autoimmune Pancytopenia Treated With Rituximab. Athena Kritharis MD,
Shyamal Bastola MD, Xinmin Zhang MD, Scott Z Fields MD; Department of Medicine, North
Shore-Long Island Jewish Health System
ABSTRACT
Autoimmune pancytopenia is a rare entity often described in association with a preexisting
condition. Although first reported in 1949, there is a paucity of literature detailing autoimmune
pancytopenia as a single entity and its management. Treatment with rituximab has achieved
variable response in autoimmune disorders such as cold agglutinin disease, immune
thrombocytopenia purpura (ITP) and/or autoimmune hemolytic anemia (AIHA). We describe an
illustrative case of a 19-year-old African-American female with no prior medical history who
presented with fatigue and easy bruising. WBC was 0.8 x10^9/l, Hgb 7.3 g/dl, and platelets
8x10^9/l. Direct coomb’s test (IgG), anti-platelet antibodies and anti-granulocyte antibodies
were positive. Extensive work-up excluded rheumatologic, infectious, and malignant etiologies
of her autoimmune pancytopenia. She had transient improvement with prednisone and IVIG with
recurrent pancytopenia three weeks post-IVIG treatment. The patient received rituximab weekly
for four weeks with response in leukocyte, erythrocyte and platelet lineages after first infusion.
She maintained normal levels of peripheral blood counts in one year follow-up without treatment
side effects or the need of splenectomy. To our knowledge, this is the first reported case of
idiopathic autoimmune pancytopenia treated with rituximab. We recommend considering
rituximab as a potential treatment option for count recovery.
INTRODUCTION
Autoimmune pancytopenia is a rare disease composed of immune thrombocytopenia purpura
(ITP), autoimmune neutropenia (AIN) and autoimmune hemolytic anemia (AIHA). There is a
paucity of literature describing this condition and its presentation as a single entity. First
described in 1949, Evans and Duane indicated the coexistence of antibodies to leukocytes,
platelets and/or erythrocytes, coined “combined immunocytopenias” by Weisneth et al. 1,2
Although the association of immune mediated cytopenias in two or more hematologic lineages
has been identified, the spontaneous presentation of autoantibodies to all three lineages has been
infrequently reported; in patients with AIHA and/or ITP, Martino et. al found an association with
these conditions and idiopathic neutropenia in 8 of 55 patients. 3 Moreover, the development of
multilineage cytopenia is often associated with a preexisting condition, such as DiGeorge
syndrome, HIV, systemic lupus erythematosus, chronic lymphocytic leukemia, or with
chemotherapy or linezolid. 4,5
We present a case of a patient with the rare presentation of idiopathic autoimmune pancytopenia.
CASE PRESENTATION
A 19-year-old African American female presented with several days of fatigue and heavy
menstrual bleeding. She was otherwise in her normal state of health prior to the onset of these
symptoms.
Physical exam revealed anicteric sclerae, no oral mucosal bleeding, no palpable
lymphadenopathy, no hepatosplenomegaly and no petechiae. Labs were significant for
pancytopenia; white blood cell (WBC) 0.8 x10^9/l, hemoglobin (Hb) 7.3 g/dl, platelets 8x10^9/l,
MCV 80 μm3, and reticulocyte 9%. The remaining laboratory data was remarkable for elevated
total bilirubin at 1.3 mg/dl, LDH of 561 U/l, and haptoglobin of 19 mg/dl. Peripheral blood
smear was notable for paucity of white blood cells, but of mature lineage and no dysplasia.
Patient was transfused packed red blood cells and platelets with an appropriate increase in
hemoglobin level but without an improvement in platelet count.
Bone marrow biopsy revealed hypercellular marrow with panhyperplasia (full
myeloid and erythroid maturation, normal megakaryocyte morphology), and mild perivascular
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plasmacytosis. [Fig 1]. Iron stores were absent.
Further testing was positive for direct coomb’s test (IgG), anti-platelet antibodies and antigranulocyte antibodies. Rheumatological work-up was negative including ANA, anti-dsdna, antiRNP, as was testing for HIV and Hepatitis C serologies by PCR. Imaging revealed multiple
enlarged lymph nodes, with the largest at 2.4 cm in the right axilla. An excisional biopsy was
performed of the right axillary lymph node which revealed hyperplasia. Given the constellation
of findings, she was diagnosed with idiopathic autoimmune pancytopenia.
Treatment with prednisone 100 mg daily was initiated. As there was no response after five days,
intravenous gamma globulin (IVIG) was given at a dose of 400 mg/kg intravenously for 5 days.
One day later, her blood counts improved. She was continued on prednisone 100 mg daily
following discharge. Three weeks later, she was hospitalized with recurrent pancytopenia. She
was given two days of IVIG 1gm/kg with improvement in her counts (Fig 2). She was sent home
on tapering doses of steroids and folic acid. As an outpatient, she received Rituximab at 375
mg/m^2 weekly for four weeks. After the first week, her Hgb/Hct was stable, while WBC and
platelet showed improvement after the third and fourth weeks; WBC, Hb and platelet improved
to 3 x10^9/l, 11 x10^1 g/l, and 166 x10^9/l respectively (Fig 2). One year later, the patient
remained in remission.
DISCUSSION
The diagnosis of idiopathic autoimmune pancytopenia in this patient was one of exclusion but
consistent with her clinical improvement. This case introduces several key points: (1) the
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etiology of concurrent leucopenia, anemia and thrombocytopenia, (2) the use of prednisone and
IVIG, and (3) the use of rituximab in achieving remission.
The etiology of automminue pancytopenia is unknown. It has not been described independently,
and so treatment has targeted total cell destruction.2 This patient was screened for rheumatologic,
infectious and autoimmune disorders but had a negative work-up. Her bone marrow biopsy was
consistent with autoimmune destruction of peripheral blood cells. The pathophysiology of her
pancytopenia is likely one of autoimmune dysregulation, whether secondary to lymphoid
hyperactivity or deficiency in lymphocyte apoptotic pathway eg Fas, but the exact cause is
unknown.2
IVIG has been used to treat autoimmune disease since 1952 and prednisone shortly thereafter. 6
The uses of prednisone and IVIG have shown varied response. Tom et al noted a platelet
recovery after 2 days of IVIG at 2 gm/kg followed by oral prednisone 1 mg/kg daily, as well as
undetectable autoantibodies while tapering steroids over a 4 month period. 7 Other reports
indicate a lack of improvement despite elevated amounts of prednisone as high as 90mg daily,
and have utilized regimens such as cyclophosphamide, splenectomy, 6-mercaptopurine,
methotrexate and vincristine. 8 Rituximab has also been used in cytopenias, such as ITP, AIHA,
Evans syndrome, and autoimmune pancytopenia in association with other diseases, such as
autoimmune hepatitis. 9 Its use in idiopathic autoimmune pancytopenia has not been reported to
our knowledge. After lack of response to prednisone, IVIG was administered with partial to
complete recovery but her pancytopenia recurred.
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The decision was then made to treat the patient with rituximab. Rituximab, an anti-CD20
monoclonal antibody, eliminates B-cells by complement fixation and cell-mediated cytotoxicity.9
In a retrospective study, and in a separate review of patients with AIHA and ITP, rituximab has
shown mixed success, ranging from complete remission to transient effects. It has rendered
positive results in single cytopenias such as AIHA and ITP, and refractory ITP; Shanafelt et al
achieved 42% complete remission against ITP and 40% complete remission against AIHA with
rituximab. 10 However, 50% of ITP patients were previously receiving steroids and/or
immunosuppressants, and response in Evans syndrome was either exclusively in ITP or AIHA.10
We therefore administered rituximab following prednisone and IVIG, as four weekly treatments.
The patient experienced multilineage improvement, with leukocyte, hemoglobin and platelet
counts remaining normal one year later. She was without significant side effects from rituximab
or the need for splenectomy.
Rituximab should therefore be considered in idiopathic autoimmune pancytopenia for count
recovery.
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FIGURE LEGENDS
Fig 1 Morphologic findings in bone marrow biopsy specimen (H&E, x 400). The biopsy shows
hypercellular marrow with erythroid predominant panhyperplasia, increased pronormoblasts,
myeloid and erythroid elements with complete maturation, and mild perivascular plasmacytosis.
The number of megakaryocytes in this field is increased and their morphology is unremarkable.
Fig 2 Leukocyte, hemoglobin and platelet counts pre- and post-rituximab
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REFERENCES
1
Evans RS, Duane RT. Acquired hemolytic anemia; the relation of erythrocyte antibody
production to activity of the disease; the significance of thrombocytopenia and leucopenia.
Blood, 1949; 11: 1196-1213.
2
Wiesneth M, Pelieger H, Frickhofen N, et al. (1985) Idiopathic combined immuncytopenia.
British Journal of Hematology, 1985; 61: 339-348.
3
Martino R, Muñiz-Díaz E, Arilla M, et al. Combined autoimmune cytopenias. Haematologica,
1995; 80 : 305-310.
4
MacCallum S, Groves M, Brass D, et al. Autoimmune pancytopenia following combination
chemotherapy for chronic lymphocytic leukaemia. Journal of Clinical Pathology, 2009; 62:
468-470.
5
Michel M, Chanet V, Dechartres A, et al. The spectrum of Evans syndrome in adults: new
insight into the disease based on the analysis of 68 cases. Blood, 2009; 114: 3167-3172.
6
Hooper JA. Intravenous immunoglobulins: evolution of commercial IVIG preparations.
Immunology and Allergy Clinics of North America, 2009; 28: 765-778.
7
Tom WL, Miller MD, Hurley MY, et al. Efalizumab-induced autoimmune pancytopenia.
British Journal of Dermatology, 2006; 155: 1045-1047.
7
8
Erdozain JG, Ruiz-Irastorza G, Egurbide MV, et al. Sustained response to rituximab of
autoimmune hemolytic anemia associated with antiphospholipid syndrome. Haematologica,
2004; 89: ECR34-ECR34.
9
Reale LD, & Besa EC. Rituximab in autoimmune pancytopenia: a case report and review of
literature. Annals of Hematology, 2007; 86: 913-916.
10
Shanafelt TD, Madueme HL, Wolf RC, et al. Rituximab for Immune Cytopenia in Adults:
Idiopathic Thrombocytopenic Purpura, Autoimmune Hemolytic Anemia, and Evans Syndrome.
Mayo Clinic Proceedings, 2003; 78: 1340-1346
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Fig 1
Fig 2
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Idiopathic autoimmune pancytopenia treated with rituximab/Case report

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