Rituximab-Induced Acute Thrombocytopenia in a Patient with Relapsed Follicular Lymphoma
Authors: Yujie Jiang , Wang Na , Yuan Dai , Qu Huiting , Feng Lili , Fan Juan , Wang Xin 
Published: October 2019

Abstract
Introduction
Rituximab is a well-tolerated monoclonal antibody which is commonly used in the treatment of B cell lymphomas that bear CD20 antigen. Most of the adverse effect induced by rituximab are infusion-related symptoms. Rituximab-induced acute thrombocytopenia (RIAT) are rare than other side-effects such as serum sickness-like syndrome and most of the reports are described as case reports. Here, we reported a serious acute thrombocytopenia caused by rituximab in a refractory and relapsed (R/R) follicular lymphoma (FL) patient with massive tumor burden. To our knowledge, this is the third case that we can retrieve
Methods
A 56-year-old woman was enrolled in our ward in 2011. The patient was diagnosed as FL (grade 2, stage IV, group B, IPI score 2) and received three cycles of R-CHOP without rituximab-associated serum sickness or obvious evidence of bone marrow toxicity. A partial response (PR) was achieved but the patient rejected to receive further therapy. She had experienced night sweats, fatigue, and floating during the preceding 7 months and came to the clinic in April 2018. Physical examination found multiple sites of shallow lymphadenopathy, especially in her right neck. The spleen was 7.5 cm palpable below the left costal margin and the ascites sign was positive. Re-biopsy was done in her right neck lymph node and FL (grade 3a) was confirmed again by IHC. The routine blood test showed WBC of 2,710, neut 1,100, Hb 90 g/L, and platelets count of 84. The bone marrow biopsy showed lymphocytic cells infiltration. So the diagnosis of the relapsed FL (grade 3a, stage IV, group B, FLIPI-1 Score 4) was made. We chose R-CHOP regimen again and rituximab was administrated at day 0 with a dose of 600mg. She developed shiver and fever one hour after the rituximab infusion. Blood culture showed no bacteria growth and inflammation index has no positive result. On the next day, repeat hemogram showed a platelet count of 26,000. The coagulation profile was within normal limits. The patient didn't show any sign of bleeding and did not meet the threshold criteria for platelet transfusion. On the third day post-rituximab infusion, the platelet count was 45,000 and recovered to baseline of the platelets level within one week. She had a similar episode during the following treatment contained rituximab (one cycle of R-CHOP and two cycles of R-GDP). No more intervention was given and the platelet count recovered again within one week. After two cycles of R-GDP, no obvious response was achieved and the patient died of progression of the disease.
Results
We conducted a literature review about RIAT. It is a rare adverse event and usually occurs within 1 to 3 days after rituximab infusion. Most of the patients with RIAT share the common clinical characteristics: MCL was the predominant histological subtype; many patients present infusion-associated symptoms; they often had comorbidity of massive tumor burden, bone marrow infiltration, and splenomegaly; re-exposure to rituximab usually will not induce a repetitive RIAT but there are exceptions; RIAT is s usually transient and self-limiting. Compared to MCL, RIAT in FL is not a frequent adverse event. To the best of our knowledge, we only found two recent reports associated RIAT developed in patients with FL reported by Japanese researchers. The possible mechanisms of RIAT remain unclear and they might lie in the following ways: 1. The presence of CD20 antigen on the platelets themselves can lead to the antibody-mediated cell lysis through Fc receptors. 2. The patient had soluble CD20 antigen in the circulation, binding them to platelets causing immune-mediated cell lysis. 3. The splenomegaly also contributed to the delay and the destruction of platelets. 4. With a rapid lysis of lymphoma cells and changes in the levels of cytokines and complements, thrombocytopenia can be initiated by the induction of a disseminated intravascular coagulation. 5. P38 mitogen-activated protein kinase and Akt anti-apoptotic survival pathways might play important roles in leading to cell death.
Conclusion
Here we reported a patient diagnosed as R/R FL with a massive tumor burden developed repetitive and self-recovered RIAT. Massive tumor burden, bone marrow infiltration, and splenomegaly might be risk factors to develop a RIAT. Hence, rituximab should be used with caution in patients who have these factors, and routine blood count monitoring should be considered after the administration of rituximab.

Disclosures
No relevant conflicts of interest to declare.