Medical Oncology

, Volume 26, Issue 1, pp 45–48

Rituximab-induced acute thrombocytopenia: a case report and review of the literature

  • Jun Ho Yi
  • Seok Jin Kim
  • Hee Kyung Ahn
  • Su Jin Lee
  • Myung Hee Chang
  • Won Seog Kim
Original Paper

DOI: 10.1007/s12032-008-9079-6

Cite this article as:
Yi, J.H., Kim, S.J., Ahn, H.K. et al. Med Oncol (2009) 26: 45. doi:10.1007/s12032-008-9079-6

Abstract

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.

Keywords

Thrombocytopenia Rituximab Mantle cell lymphoma 

Introduction

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 [1]. 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 [4], 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.

Case summary

A 58-year-old male presented with splenomegaly extending 8 cm below the costal margin. He had experienced night sweats and easy fatigue during the preceding 6 months. Laboratory tests revealed leukocytosis with mild anemia: white blood cell count 127,590/μl, hemoglobin 11.5 g/dl, and platelet count 139,000/μl, along with high serum LDH. Peripheral blood smear demonstrated that more than 90% of the white blood cells were atypical blastoid lymphocytes. Bone marrow examination showed hypercellular marrow packed with malignant lymphocytes. Although erythropoiesis and granulopoiesis were suppressed, megakaryopoiesis was normal on the bone marrow section. The immnophenotype of malignant lymphocytes in the bone marrow was CD10+, CD20+, CD5+, HLA-DR+, CD22+, CD23+, FMC7+, KAPPA+. Chromosomal analysis revealed 46,XY, t(11;14)(q13;q32), and FISH analysis using IGH/CCND1 probe showed 87% of fusion signal. The patient was diagnosed with mantle cell lymphoma of blastoid variant, stage IVB. His international prognostic index (IPI) risk was high-intermediate. We started the patient on rituximab plus Hyper-CVAD, alternating with rituximab plus high-dose methotrexate/cytarabine. On the first day of each cycle, rituximab was administered. After that, chemotherapeutic agents was infused from day 2 (Table 1).
Table 1

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

 

Abbreviations: Hyper-CVAD, cyclophosphamide, vincristine, doxorubicin, dexamethasone; MTX, methotrexate; Ara-C, cytarabine; D, day; IVCI, intravenous continuous infusion; IV, intravenous; hrs, hours; q, every; PO, per os

During the first cycle, the patient complained of chills, diaphoresis, and shortness of breath when the infusion rate of rituximab was increased from 50 to 100 mg/h. After we withheld the rituximab infusion, the patient’s symptoms improved. He resumed the rituximab infusion and finished without further adverse effects. However, the next morning after the administration of rituximab, the patient’s platelet count had decreased from 132,000/μl to 24,000/μl (Fig. 1). The coagulation profile was within normal limits, but serum LDH had increased from 994 IU/l to 3018 IU/l. Over the next 3 weeks, the patient’s platelet count recovered to 139,000/μl, and we started the second cycle of therapy. When the infusion rate was increased to 200 mg/h, infusion-related adverse effects occurred as before. However, his symptoms improved similar to the first cycle. By the way, 8 h after the infusion had been started, the platelet count was 48,000/μl, down from the pre-infusion count of 139,000/μl. Follow-up blood count 4 h later revealed a platelet count of 9,000/μl. He was transfused with 7 units of platelet-concentrates, and his platelet count rebounded to 34,000/μl. The patient’s platelet count normalized around day +19, similar to the first cycle. Follow-up CT scan showed a marked regression of splenomegaly. During the third cycle, his platelet count dropped, but the degree of decrease (platelet count 57,000/μl) was less than that seen in the two previous cycles.
Fig. 1

Platelet counts during the chemotherapy period (×103/μl). The platelet counts (solid line) show a rapid-drop after rituximab infusion. However, the recovery of platelet count is observed before next cycle comes. Left Y axis represents platelet and white blood cell counts (×103/μl) and right Y axis represents serum LDH (IU/l). The meaning of abbreviations is as follows: WBC, white blood cell; LDH, lactate dehydrogenase; R, rituximab; CTx, chemotherapy

Discussion

Since rituximab was approved by the FDA in 1997, a few cases of rituximab-induced acute thrombocytopenia have been reported [5, 6, 7, 8, 9, 10]. In all these cases, thrombocytopenia occurred within a few hours after rituximab infusion, making this phenomenon distinguishable from thrombocytopenia associated with chemotherapy-induced marrow suppression. Clinical features of all the previous cases are summarized in Table 2. The common characteristics of these previous cases were as follows. First, all patients had massive tumor burden, and almost all of them had bone marrow involvement and huge splenomegaly. Second, except for two cases that have no description of symptoms, all patients complained of infusion-related symptoms including fever, rigor, and chills. Third, mantle cell lymphoma and hairy cell leukemia were the predominant histological subtypes. Our case also shares these features: bone marrow involvement with huge splenomegaly, presence of infusion-related symptoms, and mantle cell histology.
Table 2

Summary of literature reporting acute thrombocytopenia following rituximab infusion

Authors (year)

Age/sex

Dx.

Regimen

Plt. count (×/μl) Pre/post

Extranodal involvement

Symptoms, signs notable laboratory findings

Management outcomes (Plt. count)

BM

Spleen

Rosado et al. (2007)

63/M

MCL

R-Hyper-CVAD (1st cycle)b

157 k/15 k

N/Da

N/Da

N/D

Plt. transfusion

  

R-Hyper-CVAD (2nd cycle)b

135 k/11 k

  

Coagulation profile: normal

Recovered

Thachil et al. (2006)

44/M

HCL

Rituximab

31 k/6 k

(+)

N/D

Arthralgia, petechiae, GI bleeding

Plt. transfusion

      

DIC features (Fibrinogen↓, D-dimer↑)

Recovered

Pamuk et al. (2005)

75/M

PL

Rituximab

92 k/7 k

(+)

(+)

N/D

Plt. transfusion

      

N/D

Recovered

Otrock et al. (2005)

41/M

HCL

Rituximab

85 k/7 k

(+)

(+)

Minor infusion-related symptoms

Plt. transfusion

      

N/D

Recovered

64/M

MCL

Rituximab

90 k/10 k

(+)

N/D

Fever, chill

Plt. transfusion

      

N/D

Recovered

Shah et al. (2004)

57/M

MCL

R-CHOP (1st cycle)

151 k/8 k

(+)

(+)

Fever, chill

Plt. transfusion

  

R-CHOP (2nd cycle)

133 k/8 k

  

Anti-mouse antibody (−)

Recovered

Rigamonti et al. (2001)

60/F

LPL

Rituximab

86 k/7 k

(+)

(+)

Fever, chill, malaise, epistaxis

Plt. transfusion, steroid

      

Coagulation profile: normal

Recovered

aNo description of involvement site. However, staging is described as IVb

b Rituximab was infused on the first day of the regimen

Abbreviations: N/D, Not described; k, × 103; Dx., diagnosis; Plt., platelet; MCL, mantle cell lymphoma; HCL, hairy cell leukemia; BM, bone marrow; PL, prolymphocytic leukemia; LPL, lymphoplasmacytoid lymphoma

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 [6]. 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 [11]. 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 [12]. Furthermore, the level of CD20 expression has been reported to be higher in peripheral lymphocytes than in bone marrow cells [12]. 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 [5]. 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.

Copyright information

© Humana Press Inc. 2008

Authors and Affiliations

  • Jun Ho Yi
    • 1
  • Seok Jin Kim
    • 1
  • Hee Kyung Ahn
    • 1
  • Su Jin Lee
    • 1
  • Myung Hee Chang
    • 1
  • Won Seog Kim
    • 1
  1. 1.Division of Hematology and Oncology, Department of Medicine, Samsung Medical CenterSungkyunkwan University School of MedicineGangnam-GuSouth Korea

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