Use of obinutuzumab for refractory autoimmune thrombocytopenia secondary to CLL

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a common hematologic malignancy that is complicated by frequent secondary autoimmune complications, including hemolytic anemia and immune thrombocytopenic purpura (ITP), occurring in 10-25%of cases [1,2]. Pure red cell aplasia and autoimmune granulocytopenia have also been identified. These complicationsmaypose riskof seriousmorbidity andmortality [3]. First-line management of ITP in CLL consists of corticosteroids. Secondary immunosuppressive modalities include intravenous immunoglobulin (IVIG), rituximab, and splenectomy [2]. Rituximab is a useful adjunct in therapy of autoimmune cytopenias related to CLL [2,3]. Splenectomy has high success rates but exacerbates susceptibility to encapsulated organisms and requires prophylactic immunizations. Limited data sets have demonstrated benefit of the thrombopoietin (TPO) receptor agonists romiplostim and eltrombopag, which are FDA approved for ITP that is nonresponsive to steroids, IVIG, or splenectomy [4]. Anti-CD20 monoclonal antibodies directed against CD20 have the potential to neutralize both autoimmune and malignant B cells. AntiCD20 antibody mechanisms of action include antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis [5]. Anti-CD20 antibodies are classified as type 1 (rituximab and ofatumumab) or type 2 (obinutuzumab). Type 1 antibodies organize CD20molecules into “rafts” and exert their effects primarily by ADCC and CDC, and less by apoptosis. Type 2 antibodies utilize apoptosis to a greater degree and also exert more potent ADCC [6]. The type 1 antibody rituximab has demonstrated efficacy in management of auto-immunehemolysis and thrombocytopenia due toCLL, including patientswhohavenot responded toother interventions [2,3]. Wepresent a case inwhich the type 2 antibody obinutuzumab successfully treated ITP secondary to CLL.


INTRODUCTION
Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a common hematologic malignancy that is complicated by frequent secondary autoimmune complications, including hemolytic anemia and immune thrombocytopenic purpura (ITP), occurring in 10-25% of cases [1,2]. Pure red cell aplasia and autoimmune granulocytopenia have also been identified. These complications may pose risk of serious morbidity and mortality [3].
First-line management of ITP in CLL consists of corticosteroids.
Secondary immunosuppressive modalities include intravenous immunoglobulin (IVIG), rituximab, and splenectomy [2]. Rituximab is a useful adjunct in therapy of autoimmune cytopenias related to CLL [2,3]. Splenectomy has high success rates but exacerbates susceptibility to encapsulated organisms and requires prophylactic immunizations. Limited data sets have demonstrated benefit of the thrombopoietin (TPO) receptor agonists romiplostim and eltrombopag, which are FDA approved for ITP that is nonresponsive to steroids, IVIG, or splenectomy [4].
Anti-CD20 monoclonal antibodies directed against CD20 have the potential to neutralize both autoimmune and malignant B cells. Anti-CD20 antibody mechanisms of action include antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis [5]. Anti-CD20 antibodies are classified as type 1 (rituximab and ofatumumab) or type 2 (obinutuzumab). Type 1 antibodies organize CD20 molecules into "rafts" and exert their effects primarily by ADCC and CDC, and less by apoptosis. Type 2 antibodies utilize apoptosis to a greater degree and also exert more potent ADCC [6]. The type 1 antibody rituximab has demonstrated efficacy in management of auto-immune hemolysis and thrombocytopenia due to CLL, including patients who have not responded to other interventions [2,3].
We present a case in which the type 2 antibody obinutuzumab successfully treated ITP secondary to CLL.

CASE PRESENTATION
The patient was diagnosed with CLL in January 2012 after presentation with leukocytosis, lymphadenopathy, and drenching night sweats.
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DISCUSSION
Our patient's case was notable for a history of brief or no response to steroids on three occasions, including high-dose methylprednisolone.
She also received high-dose IVIG, which only yielded a brief response.
Her secondary ITP recurred despite evidence of remission on therapy with idelalisib. She had a prior excellent response to rituximab that was unfortunately suspected to be complicated by the life-threatening adverse event of DAH, and further rituximab was thought to be contraindicated [7,8]. We wished to obtain a prolonged platelet response, as experienced with rituximab, but with less risk to the patient. Therefore, we turned to the second-generation anti-CD20 monoclonal antibody obinutuzumab.
ITP patients may experience life-threatening complications due to low platelet counts [3]. ITP requires urgent and effective control. We believed that obinituzumab might yield response kinetics similar to those seen previously with rituximab. Obinutuzumab is a novel type 2 anti-CD20 monoclonal antibody [9]. Possible explanations for efficacy in an autoimmune condition [10] and avoidance of the pathophysiologic process that led to DAH include its fully humanized sequence or its different epitope specificity from rituximab. We also anticipated that obinutuzumab would provide disease control [11], which has also been shown in the single-agent treatment setting [12]. Obinutuzumab induced a dramatic platelet response, which we attribute primarily to its immunosuppressive activity. Its action on the primary disease may have helped control the magnitude and the root cause of ITP.
To the best of our knowledge, this is the first report of obinutuzumab's efficacy in either primary or secondary ITP. We believe that our case demonstrates that obinutuzumab is a viable option for patients with secondary ITP, especially those who cannot receive rituximab, and that prospective study of this agent in patients with secondary ITP is warranted.

CONFLICT OF INTEREST
The authors declare that there is no conflict of interest.

CONSENT
The patient has given consent to the inclusion of material pertaining to herself and acknowledges that she is not identifiable via the paper. We have fully anonymized the patient.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.