Rituximab-induced acute thrombocytopenia: a case report and review of the literature
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- Yi, J.H., Kim, S.J., Ahn, H.K. et al. Med Oncol (2009) 26: 45. doi:10.1007/s12032-008-9079-6
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Rituximab is a chimeric monoclonal antibody directed against the phosphoprotein CD20. Because of its efficacy and acceptable toxicity profile, rituximab is now commonly used for the treatment of CD20-positive B-cell malignancies, including B-cell non-Hodgkin’s lymphoma. However, rituximab-induced acute thrombocytopenia is an extremely rare side effect. We report a case of acute thrombocytopenia occurring immediately after rituximab infusion in a mantle cell lymphoma patient with bone marrow involvement and massive splenomegaly. Although the mechanism of thrombocytopenia is still unclear, it is possible that tumor burden, bone marrow involvement, the presence of infusion-related symptoms, and mantle cell histology are related to this rare complication of rituximab therapy. Hence, rituximab should be used with caution in patients who have these factors, and clinicians must be aware of this rare, but serious, side effect.
KeywordsThrombocytopenia Rituximab Mantle cell lymphoma
CD20, a 33–37 kDa transmembrane phosphoprotein, is an integral part of the cell surface of most B-cells, including malignant cells. It is believed to play a major role in cell activation and proliferation . Rituximab is a chimeric monoclonal antibody directed against CD20. Because of its efficacy and acceptable toxicity profile, rituximab is now commonly used for the treatment of CD20-positive B-cell malignancies, including B-cell non-Hodgkin’s lymphoma. Some of the most common adverse effects of rituximab therapy are infusion-related symptoms, such as fever, chills, rigors, and flushing. These typically occur during the first infusion. Other side effects include reactivation of viral infections (such as hepatitis B virus) and cardiovascular and renal toxicity [2, 3].
Generally, rituximab-associated hematologic toxicities have known as transient and self-limited. Although an episode of delayed-onset neutropenia associated with rituximab therapy has been reported , acute thrombocytopenia is extremely rare. Herein, we report a case of acute thrombocytopenia that occurred immediately after rituximab infusion in a mantle cell lymphoma patient.
Protocol of rituximab plus Hyper-CVAD alternating with rituximab plus high-dose MTX/Ara-C
Cycle 1, 3, 5, 7
Rituximab plus Hyper-CVAD
Cycle 2, 4, 6, 8
Rituximab plus MTX/Ara-C
Rituximab 375 mg/m2 D1
Rituximab 375 mg/m2 D1
Cyclophosphamide 300 mg/m2 IV q 12 hrs D2–4
MTX 200 mg/m2 IV D2
Doxorubicin 16.6 mg/m2 IVCI over 72 hrs D5–7
MTX 800 mg/m2 IVCI over 22 hrs D2
Vincristine 1.4 mg/m2 IV (maximum 2 mg) D5, D12
Ara-C 3000 mg/m2 IV over 2 hrs q12 hrs D3–4
Dexamethasone 40 mg IV or PO D 2–5 & D12–15
Summary of literature reporting acute thrombocytopenia following rituximab infusion
Plt. count (×/μl) Pre/post
Symptoms, signs notable laboratory findings
Management outcomes (Plt. count)
Rosado et al. (2007)
R-Hyper-CVAD (1st cycle)b
157 k/15 k
R-Hyper-CVAD (2nd cycle)b
135 k/11 k
Coagulation profile: normal
Thachil et al. (2006)
31 k/6 k
Arthralgia, petechiae, GI bleeding
DIC features (Fibrinogen↓, D-dimer↑)
Pamuk et al. (2005)
92 k/7 k
Otrock et al. (2005)
85 k/7 k
Minor infusion-related symptoms
90 k/10 k
Shah et al. (2004)
R-CHOP (1st cycle)
151 k/8 k
R-CHOP (2nd cycle)
133 k/8 k
Anti-mouse antibody (−)
Rigamonti et al. (2001)
86 k/7 k
Fever, chill, malaise, epistaxis
Plt. transfusion, steroid
Coagulation profile: normal
Although the underlying mechanism of thrombocytopenia is not fully understood, the presence of CD20 antigen on the platelets themselves or soluble CD20 antigen in the circulation have been suggested as possible mechanisms . Thus, active turnover of malignant B-cells may result in the presence of circulating CD20, and high levels of circulating CD20 have been correlated with worse clinical outcomes . Thus, it is possible that CD20 can be present in the circulation in patients with massive tumor burden, such as those with advanced stage and bone marrow involvement. Based on these results, there is a possibility that pre-treatment tumor burden, especially bone marrow involvement, may be a risk factor for the development of rituximab-induced acute thrombocytopenia. In our case, the degree of platelet drop-out in the third cycle became less than the first and second cycle. Considering the decrease of tumor burden after two cycles of chemotherapy, these findings also support the relationship of tumor burden with the occurrence of rituximab-induced acute thrombocytopenia. It has been suggested that platelet destruction is due to the formation of a soluble CD20/rituximab complex, which is destroyed via antigen–antibody reaction in the spleen and through complement-mediated cell lysis. Previous reports, most patients with acute thrombocytopenia associated with rituximab had infusion-related symptoms like our case. Considering the infusion-related symptoms could be related with the result of cytokine release syndrome, these findings suggest these patients might have active peripheral blood cell lysis. Thus, the presence of infusion-related symptoms could be a possible factor predicting the occurrence of this unusual acute thrombocytopenia.
Review of previous reports demonstrates that mantle cell lymphoma and hairy cell leukemia are the dominant histological subtypes associated with rituximab-induced acute thrombocytopenia. They may have some characteristics that perpetuate the development of this rare thrombocytopenia. Although these histological subtypes belong to the class of chronic B-cell-derived leukemia/lymphoma, it has been reported that the number of CD20 molecules per cell is higher in mantle cell lymphoma and hairy cell leukemia than in other types, such as B-cell chronic lymphocytic leukemia . Furthermore, the level of CD20 expression has been reported to be higher in peripheral lymphocytes than in bone marrow cells . Thus, elevated expression of CD20 may contribute to an increase in circulating CD20; this is a possible reason for the relatively frequent occurrence of rituximab-induced acute thrombocytopenia in this histological subtype.
The outcome of rituximab-induced acute thrombocytopenia has been good in all reported cases, and clinically significant bleeding has occurred in only one case . However, considering most patients were in an advanced stage, we would do well to look out for rituximab-induced acute thrombocytopenia. Although the incidence of rituximab-induced acute thrombocytopenia is very low in relation to the drug’s frequent use in lymphoma treatment, it is likely that its incidence has been underestimated because platelet counts are not routinely checked early after rituximab administration in the outpatient setting.
In conclusion, although the mechanism and incidence of rituximab-induced acute thrombocytopenia are still unclear, rituximab should be used with caution in patients who have mantle cell lymphoma with significant bone marrow involvement and who begin manifesting infusion-related symptoms.