Oxaliplatin hypersensitivity complicated by thrombocytopenia during desensitization

Oxaliplatin is a platinum-based chemotherapeutic used to treat gastrointestinal malignancies,¹ infused every 2 weeks often in combination with leuvocorin and 5-fluorouracil (FOLFOX). Significant adverse events, including hypersensitivity reactions, are noted with oxaliplatin use. Desensitization has proven safety and efficacy for oxaliplatin hypersensitivity reactions.^2,3

Significant thrombocytopenia occurs in 0.2% to 1.5% of oxaliplatin cycles.¹ The following 3 main mechanisms explain thrombocytopenia observed with oxaliplatin therapy: myelosuppression, perisinusoidal injury leading to splenic sequestration, and oxaliplatin-induced immune thrombocytopenia (OIIT).⁴ The third mechanism, OIIT is a type of drug-induced immune thrombocytopenia⁵, reported in case series^6–9, in which platelet avid antibodies prompt thrombocytopenia only in the presence of oxaliplatin. The mechanism of OIIT is unclear, but proposed pathogenesis includes drug-dependent (1) immune complexes activating platelets through Fc receptors, (2) haptendependent antibody, or (3) production of immunoglobulin G (IgG) to platelet surface glycoproteins such as GP IIb/IIIa.⁴ A diagnosis of OIIT is supported by flow cytometric detection of platelet-avid antibodies only in the presence of oxaliplatin.⁵

Oxaliplatin-related immune-mediated thrombocytopenia has been reported during desensitization in 1 patient.² We report 3 detailed cases of OIIT first observed during desensitization and detail the treatment outcomes.

Clinical information was obtained from retrospective chart review and was a quality improvement initiative at our hospital.

Patient 1 was diagnosed as having metastatic colorectal cancer at age 39 years. Treatment was initiated with FOLFOX and bevacizumab. The patient experienced a grade II hypersensitivity reaction on her 18th lifetime oxaliplatin exposure. Skin testing result to oxaliplatin was negative at the prick and intradermal levels; desensitization was pursued owing to reaction severity. During the 12th step of the fourth lifetime desensitization (12-step protocol), the patient developed mouth and vaginal bleeding, and desensitization was stopped. Platelet count dropped to 7000/μL (Fig 1), and the patient was admitted to our hospital, transfused with 2 units of platelets with improvement and given a 5-day course of dexamethasone. No further hemorrhagic complications were noted; coagulation laboratory parameters were normal. Oxaliplatin-dependent platelet antibodies (IgG) were detected by flow cytometry. Treatment with oxaliplatin was discontinued owing to the diagnosis of OIIT.

Figure 1.

Platelet counts (K/uL) and oxaliplatin desensitization intervals from patient 1, patient 2, and patient 3.

Patient 2 was diagnosed as having metastatic colon cancer at age 31 years. Treatment was initiated with FOLFOX/bevacizumab. During the 15th lifetime exposure to oxaliplatin, the patient experienced a grade II hypersensitivity reaction. Skin testing result to oxaliplatin was negative at the prick and intradermal levels; desensitization was pursued owing to reaction severity. He developed back pain during his fifth desensitization (4-step protocol), which improved with ketorolac. Nevertheless, the patient noted frank dark red-colored urine 1 hour after completion. His platelet count was found to be 71,000/μL, a decrease from 188,000/μL before the start of chemotherapy (Fig 1). He was admitted to our hospital for monitoring and had 1 subsequent episode of dark red-colored urine. His urinalysis result revealed 3+ blood but few red blood cells on urine sediment analysis, suggesting hemoglobinuria from intravascular hemolysis. Initially, coagulation studies were consistent with disseminated intravascular coagulation (DIC) with prothrombin time of 21.4 seconds, international normalized ratio of 1.9, activated partial thromboplastin time of 42.4 seconds, fibrinogen level of 126 mg/dL, and D-dimer level greater than 4000 ng/mL, but all coagulation and platelet laboratory values normalized in 48 hours without intervention. Peripheral blood smear result revealed no morphologic features consistent with microangiopathy. Oxaliplatin-dependent platelet antibodies (IgG) were detected by flow cytometry. Given limited treatment options, the patient consented to a trial of oxaliplatin desensitization with 50% dose reduction and close monitoring of platelet count (pre- and immediately post-desensitization, and 48-72 hours after desensitization completion). He tolerated 3 subsequent desensitizations without any hypersensitivity or hematologic complications. The patient experienced another episode of red-colored urine and urinalysis consistent with hemoglobinuria at the last step of his 10th lifetime desensitization; desensitization was stopped. His platelet count was 65,000/μL (decreased from 109,000/μL). He was readmitted and did not have laboratory evidence of DIC. Treatment with oxaliplatin was discontinued owing to the recrudescent thrombocytopenia.

Patient 3 was diagnosed as having metastatic colon cancer at age 55 years. Treatment was initiated with FOLFOX/bevacizumab. The patient experienced a grade II hypersensitivity reaction on his 13th lifetime oxaliplatin exposure. Skin testing to oxaliplatin was negative at the prick and intradermal levels; desensitization was pursued owing to reaction severity. He tolerated desensitization (12-step protocol) without signs of hypersensitivity reactions. He was evaluated by hematology for chronic thrombocytopenia (between 52,000/μL and 92,000/μL; Fig 1); oxaliplatin-dependent platelet antibodies (IgG) were detected by flow cytometry. He continued to receive oxaliplatin by desensitization, and platelet counts were monitored pre- and immediately post-desensitization and 48 to 72 hours after desensitization completion. No hemorrhagic complications were noted with 3 subsequent desensitizations; treatment was discontinued owing to disease progression.

We report 3 cases of OIIT with concomitant oxaliplatin hypersensitivity undergoing desensitization with varied clinical and decision outcomes. The reported timing of OIIT during oxaliplatin infusion is unknown. In patients 1 and 2, OIIT was noted either during the last step or the end of desensitization. Desensitization was terminated in patient 2 owing to hemorrhagic complications.

As platelet-avid antibodies are exclusively detected by flow cytometry during oxaliplatin exposure, the increased infusion time during desensitization may place oxaliplatin hypersensitivity patients with OIIT at a higher risk of OIIT complications. Allergists who perform oxaliplatin desensitization should be aware of this potentially life-threatening complication. Acute thrombocytopenia in OIIT can lead to hemorrhagic complications, DIC, and require transfusion support. In patients with thrombocytopenia suspected to be due to oxaliplatin, complete blood cell count with differential, peripheral blood smear, liver function tests, prothrombin time, activated partial thromboplastin time, international normalized ratio, fibrinogen, fibrin degradation products or D-dimer, lactate dehydrogenase, haptoglobin, and importantly, drug-dependent platelet antibody immunofluorescence by flow cytometry, should be checked.

In patients with an acute and significant platelet decrease after oxaliplatin infusion owing to OIIT in the setting of hypersensitivity, alternative chemotherapeutic agents should be considered. If no alternative exists, risks and benefits need to be carefully discussed given the potential for continued, life-threatening hemorrhagic complications as OIIT can recur despite dose reduction. The authors suggest that after OIIT is diagnosed, if oxaliplatin therapy is continued, platelet counts should be closely monitored, with platelet count measured immediately before and after oxaliplatin infusion, with any symptoms, and 48 to 72 hours after, to not to miss a platelet nadir and potential risk of hemorrhagic complications.