Oxaliplatin-Induced Immune Thrombocytopenia: A Case Report and Literature Review

Abstract

Oxaliplatin-induced immune thrombocytopenia is a rare manifestation of oxaliplatin hypersensitivity, presenting as an acute onset of severe thrombocytopenia after oxaliplatin administration. No standard therapeutic approach outside of permanent discontinuation of oxaliplatin exists. Here, we present a case of oxaliplatin-induced immune thrombocytopenia occurring after oxaliplatin retreatment for metastatic colon cancer. Possible mechanisms of disease and approach to treatment are discussed.

Introduction

Oxaliplatin is a standard component of fluorouracil-based therapy for gastrointestinal cancers, prolonging progression-free survival in metastatic colorectal cancer and overall survival when used as adjuvant therapy in stage III colon cancer.^1,2 While toxicities include bone marrow suppression and gastrointestinal effects, the dose-limiting toxicity is neurotoxicity, manifesting acutely as cold-induced perioral or distal extremity paresthesias, or chronically as a distal sensory neuropathy.^3,4 A stop-and-go administration strategy can reduce neurotoxicity while maintaining clinical efficacy; however, this has recently been associated with an increased incidence of oxaliplatin-associated allergic complications.^5–7

Drug-induced immune cytopenias have recently been recognized as an uncommon complication of oxaliplatin therapy. A constellation of findings, collectively termed “oxaliplatin induced immune syndrome” has been identified and encompasses a broader range of immunogenic cytopenias, including thrombotic microangiopathies, Evans syndrome, immune hemolysis and immune thrombocytopenia.⁸ As of yet, little is known about the risk factors or pathogenesis of these phenomenon. We present a case of oxaliplatin-induced immune thrombocytopenia, occurring after oxaliplatin reintroduction for the treatment of metastatic colon cancer.

Case Description

A 58-year-old woman with celiac disease and asthma was diagnosed with stage III-B right-sided colon cancer in 2010 and underwent a right hemicolectomy followed by 12 cycles of adjuvant 5-fluoruracil, leucovorin, and oxaliplatin (FOLFOX). Treatment was complicated by neutropenia after Cycle 5 and by thrombocytopenia, with a nadir of 77,000/μL, after Cycle 10 requiring dose reductions of oxaliplatin. She was found to have metastatic KRAS mutated, microsatellite stable, and BRAF wild-type colon cancer in the bilateral ovaries one year after completion of adjuvant therapy, and underwent a total hysterectomy with bilateral salpingo-oophorectomy, followed by 5-fluoruacil, leucovorin, and irinotecan (FOLFIRI) and bevacizumab for 6 months. One year later, a localized pelvic recurrence was found and treated with concurrent infusional 5-fluoruracil and whole-pelvis radiation, followed by FOLFIRI for 8 cycles. Peritoneal disease was found one year later, treated with cytoreduction and FOLFIRI/bevacizumab for 12 cycles. She again recurred in mesenteric lymph nodes 18 months later, resuming FOLFIRI/bevacizumab followed by maintenance 5-fluorouracil/bevacizumab that ultimately was discontinued for progressive disease after 10 months. She was then treated with irinotecan/bevacizumab without response.

As she had not previously progressed on FOLFOX, she was retreated with FOLFOX with bevacizumab continuation. Oxaliplatin was initiated at a reduced dose of 65 mg/m² due to her history of cytopenias and she was pretreated with dexamethasone 20 mg to prevent hypersensitivity reactions. Cycle 4 was delayed due to neutropenia and diarrhea, requiring a further oxaliplatin dose reduction to 55 mg/m². Cycle 8 was delayed due to pneumonia, which was treated with cefuroxime and doxycycline. Nine days after completing her antibiotics, Cycle 8 was initiated with dexamethasone reduced to 10 mg and bevacizumab held due to worsening pedal edema and proteinuria on 24-hour urine collection.

On Cycle 8 Day 2, she awoke with spontaneous epistaxis and petechiae covering her lower extremities and tongue. Labwork demonstrated a platelet count of 7,000/μL, decreased from 301,000/μL at the start of the cycle one day prior. She did not have any other cytopenias or significant changes in her haptoglobin, LDH, coagulation labs, transaminases, bilirubin, creatinine or electrolytes. No schistocytes, left shift, immature cells or platelet clumping were seen on her peripheral blood smear and she was transfused four pools of platelets without response. She was admitted to the hospital and initiated intravenous dexamethasone 40 mg daily for four days and immunoglobulin (IVIG) on hospital days 3 and 4 after no improvement was seen with steroids alone. Finally, four days after oxaliplatin administration, the patient’s platelet count began to recover (Figure 1). Platelet suspension immunofluorescence testing by the American Red Cross confirmed the presence of oxaliplatin-dependent antibodies. Oxaliplatin was permanently discontinued and she was treated with trifluridine/tipiracil followed by regorafenib without further thrombocytopenic episodes, ultimately expiring from progressive disease.

Figure 1:

Blood counts after oxaliplatin infusion (day 0).

Discussion

Oxaliplatin, a third-generation platinum analogue, was designed to overcome tumor resistance to cisplatin while maintaining the favorable side effect profile of carboplatin.⁹ Oxaliplatin-based chemotherapy is the standard adjuvant treatment of high risk stage II and stage III colorectal cancer (CRC) and first and second line therapy for metastatic CRC.^10–12 While toxicities such as sensory neuropathy, gastrointestinal effects and asymptomatic cytopenias are common, allergic and thrombocytopenic phenomenon have been increasingly recognized. Allergic hypersensitivity, referring to type-I IgE mediated reactions, are a well-known complication of oxaliplatin therapy, with incidence varying from 10% to 23.8%.^7,12–19 Manifestations include respiratory or cutaneous symptoms and fever within minutes of oxaliplatin initiation.²⁰ In contrast to type-I hypersensitivity reactions, a type-II antibody-mediated mechanism has been identified as the mediator of oxaliplatin-induced immune thrombocytopenic reactions.

Oxaliplatin produces thrombocytopenia by three mechanisms. The first, bone marrow suppression, likely explains most of the 77% incidence demonstrated in clinical trials.¹² Platelet counts ≤75,000/μL occur approximately ten days after oxaliplatin infusion and are rarely symptomatic.²¹ The second mechanism is due to splenic sequestration. Though the pathophysiology is unknown, oxaliplatin is associated with hepatic sinusoidal injury, believed to cause secondary portal hypertension, splenomegaly and sequestrant thrombocytopenia.^22,23 Indeed, a retrospective analysis of 136 patients receiving either adjuvant FOLFOX or fluoropyrimidine monotherapy demonstrated a ≥50% increase in spleen size in 24% of patients receiving FOLFOX versus none in patients receiving fluoropyrimidine monotherapy.²² Splenomegaly was significantly associated with cumulative doses of oxaliplatin and thrombocytopenia, characteristically gradual and mild with a nadir greater than 100,000/μL occurring 3-4 months after treatment initiation.²²

The third mechanism for oxaliplatin-induced thrombocytopenia, as demonstrated by our patient, is by type-II hypersensitivity mediated drug-induced immune thrombocytopenia. Case reports have identified oxaliplatin dependent IgG antibodies targeting platelet surface antigens, namely GP IIb/IIIa, GP Ib/Ix and GP Ia/IIa.^24,25 As previously noted, a distinction exists between allergic hypersensitivity (type-I) and humoral hypersensitivity (type-II). While the primary immunogenic drivers mediating these distinct reactions remain unknown, a retrospective analysis of 42 patients experiencing allergic hypersensitivity reactions found a 7.1% incidence of concurrent immune thrombocytopenia, suggesting an overlapping mechanistic relationship.²⁰ Indeed, cases of oxaliplatin-induced immune thrombocytopenia (OIIT) heralded by fevers, rash and bronchospasm have been reported.²⁶

Recently, a systemic review of oxaliplatin-related cytopenias was published.⁸ Termed “oxaliplatin induced immune syndrome” (OIIS), the key elements include acute thrombocytopenia and/or hemolytic anemia with or without evidence of organ dysfunction, including acute renal failure and transaminitis. While clinical presentation may vary, the syndrome typically includes fevers, chills, hematuria, hematemesis, back pain and signs of thrombocytopenia such as purpura, bruising and mucosal bleeding.³³ OIIS typically presents within two hours of starting an oxaliplatin infusion, although the initial presentation has been reported up to six days later.^33,34 The syndrome typically occurs after significant exposure to oxaliplatin (after 16 cycles); however, patients rechallenged with oxaliplatin may experience the syndrome much earlier (after 4-5 cycles).⁸ It has been reported after oxaliplatin exposure in the context of both XELOX and FOLFOX regimens for colon, rectal and gastric carcinomas.^25,35–40

In general, drug-induced immune thrombocytopenia (DIIT) is uncommon, with an incidence of approximately 1 case per 100,000 annually.²⁷ Clinical criteria have been established, whereby a drug’s culpability could effectively be identified as unlikely, possible, probable or definitely related to thrombocytopenia.²⁸ Increasingly, direct laboratory evidence has been used to identify drug-dependent antibodies. A recent systemic review of drug-dependent antibodies applied specific criteria to the quality of laboratory assessment used in published case reports.²⁹ Of the 153 drugs that were clinically implicated as “definite” or “probably” associated (by application of the George Criteria²⁸), 72 were associated with quality laboratory evidence of drug-dependent antibodies. Validated laboratory methods included flow cytometry, monoclonal-based antigen capture assays, platelet associated IgG and immunofluorescence, which was used in our case. Sixteen drugs were considered definitely associated, defined by having proven antibody binding by two independent laboratories, including oxaliplatin²⁹.

Several major mechanisms of DIIT have been suggested.³⁰ A hapten-dependent mechanism has been rarely described in penicillin-mediated thrombocytopenia, whereby covalent drug-protein conjugates form on the surface of cell membranes and induce drug-protein complex antibodies. A second mechanism, studied in quinine-related thrombocytopenia, suggests native production of weakly binding autoantibodies. Upon exposure, quinine combines with native surface proteins (mainly GP IIb/IIIa), allowing for enhanced antibody binding and subsequent thrombocytopenia. Finally, for unknown reasons, some drugs can trigger production of platelet-specific autoantibodies, leading to a clinical condition identical to immune thrombocytopenic purpura. This condition usually requires soluble drug to be present in the system for antibody binding to occur; however, occasionally drug-independent autoantibodies can be produced as well.³¹ In OIIT, antibody reactions occur in the presence of soluble oxaliplatin but only weakly or not at all in platelets pre-coated with oxaliplatin, indicating that a hapten mediated mechanism is not the origin of this reaction.²⁵ Notably, in addition to DNA adducts (which mediate oxaliplatin’s cytotoxic mechanism of action), oxaliplatin has been shown to form covalent bonds with serum proteins, possibly contributing to its immunogenicity.³² While the precise pathophysiologic mechanism of OIIT is unknown, it is most likely the latter of these three mechanisms.

The optimal management strategy for OIIT has yet to be defined, but typically includes permanent discontinuation of oxaliplatin as drug-induced antibodies can persist for many years.⁴¹ Recovery of platelets can be expected within days of discontinuation, while other cytopenias can persist.³³ Although the value of steroids and IVIG in DIIT has not been proven, a trial of these in the event of sudden onset thrombocytopenia after oxaliplatin therapy is reasonable. While not useful for immediate management decisions, we suggest testing for oxaliplatin-specific antibodies if acute severe thrombocytopenia is noted, as further oxaliplatin therapy is contraindicated if OIIT is confirmed.

Conclusion

Drug-induced immune thrombocytopenia is a rare, life-threatening complication of oxaliplatin therapy. Here, we presented a case of acute thrombocytopenia in a 58-year-old woman after her 20^th cycle of FOLFOX, during her 8^th cycle of retreatment for metastatic colon cancer. Literature regarding the pathogenesis, risk factors, and optimal treatment of this condition is sparse; however, permanent discontinuation of oxaliplatin is strongly recommended. Future studies should focus on methods for predicting patients at risk for this condition, as well as strategies for optimal treatment and primary and secondary prevention.

Clinical Practice Points:

1. Oxaliplatin can cause hypersensitivity mediated immune thrombocytopenia, placing patients at risk for spontaneous bleeding.

2. Presentation includes severe acute thrombocytopenia that occurs within hours to days of oxaliplatin exposure.

3. Treatment includes permanent discontinuation of oxaliplatin, although a standard treatment approach has not been defined.

4. Testing for oxaliplatin-specific antibodies can confirm the diagnosis.