Case Report

Acute Oxaliplatin-induced Hemolytic Anemia,

Thrombocytopenia, and Renal Failure: Case
Report and a Literature Review
Pooja Phull,1 Karen Quillen,2 Kevan L. Hartshorn2
Clinical Practice Points
 Oxaliplatin is commonly used for treatment of colo-  This case is distinct from previous reports in the
rectal, gastric, and pancreatic cancers. specific constellation of findings and the detailed
 Acute hypersensitivity reactions, thrombotic throm- analysis of red cell autoantibodies involved.
bocytopenic purpura, and Evan syndrome (autoim-  Treating providers should be aware of the spectrum of
mune hemolysis and thrombocytopenia) have been immune reactions that can occur in patients previ-
described after repeated administration of oxaliplatin. ously sensitized to oxaliplatin.
 We describe a case in which acute autoimmune
hemolysis and renal failure and thrombocytopenia
occurred after re-treatment with oxaliplatin.

Clinical Colorectal Cancer, Vol. -, No. -, --- ª 2016 Elsevier Inc. All rights reserved.
Keywords: Colorectal cancer, Evan syndrome, Hemolysis, Hypersensitivity, Immune thrombocytopenia

Introduction Case
Oxaliplatin is an alkylating platinum analogue that is considered A 57-year-old man of Brazilian origin with recurrent metastatic
a cornerstone in the combination chemotherapeutic treatment of colon cancer was admitted with complaints of black-colored urine.
metastatic colorectal cancer.1 The primary dose-limiting side effect The patient had been previously diagnosed with obstructing colon
associated with oxaliplatin is the development of a sensory neuro- cancer 5 years before this admission. He underwent left hemi-
toxicity.2 Other common side effects include gastrointestinal and colectomy with diverting ileostomy and, because he was found to
hematologic toxicities.3 In addition to these toxicities, oxaliplatin is have stage IIIC adenocarcinoma, he received 12 cycles of FOLFOX
associated with hypersensitivity reactions, and the incidence of such (using standard oxaliplatin dose of 85 mg/m2 and standard doses of
reactions increases with each subsequent administration of this 5-fluorouracil with 400 mg/m2 bolus and 2400 mg/m2 continuous
agent. Indeed, studies report an incidence of <1% in patients who infusion of 48 hours and leucovorin bolus of 400 mg/m2) chemo-
receive 5 cycles, in contrast to an incidence of up to 27% in therapy followed by takedown of his ileostomy. Reimaging studies
patients who receive >7 cycles of treatment.4 Interestingly, these and colonoscopy performed after this therapy showed no recurrence
hypersensitivity reactions have been associated with carboplatin as of cancer until 3.5 years later, at which time a computed tomog-
well as cisplatin, which suggests that this property is not unique to raphy scan showed new enlarged pericardiac lymph nodes, and
oxaliplatin but rather is related to the larger family of platinum- subsequent magnetic resonance imaging confirmed the presence of
based chemotherapeutic agents. Autoimmune hemolytic reactions these nodes as well as peritoneal nodules in the subdiaphragmatic
to oxaliplatin are less common but also appear to be associated with region consistent with metastatic disease. The patient underwent
more protracted treatment courses. surgery for resection of the pericardiac lymph node, at which time
another lesion involving the diaphragm was also found and resected.
1
Department of Medicine The resected nodes showed metastatic adenocarcinoma consistent
2
Section of Hematology Oncology, Boston University School of Medicine, Boston, with his colon primary. After this procedure, a new chemotherapy
MA
regimen of a combination of FOLFOX and bevacizumab was
Submitted: Jul 5, 2016; Revised: Oct 5, 2016; Accepted: Nov 14, 2016 initiated. The patient presented to his oncology appointment 2 days
Address for correspondence: Kevan L. Hartshorn, MD, Boston University School of after receiving cycle 6 of this chemotherapy (cycle 18 of FOLFOX
Medicine, EBRC 414, 650 Albany St, Boston, MA 02118 when including previous cycles). He reported black-colored urine.
Fax: 617-638-7530; e-mail contact: [email protected]
He was noted to have a platelet count of 70,000/UL, new-onset

1533-0028/$ - see frontmatter ª 2016 Elsevier Inc. All rights reserved.

http://dx.doi.org/10.1016/j.clcc.2016.11.005 Clinical Colorectal Cancer Month 2016 -1
 Oxaliplatin-induced Hemolysis
anemia with hemoglobin and hematocrit at 7.5 and 22.8, respec- thrombocytopenia, and renal failure. He was tested for glucosee6-
tively, and an acutely elevated creatinine of 2.85 (with a known phosphate dehydrogenase months after resolution of the hemolysis
baseline of 0.93; Figure 1). Further workup revealed an elevated and this showed normal activity.
bilirubin level with a low haptoglobin level, and a urinalysis was
found to be heme-positive, but with few red cells, consistent with Discussion
hemoglobinuria. Urine sediment also showed some pigmented Oxaliplatin is a third-generation platinum derivative that is now
granular casts consistent with acute tubular necrosis (ATN). A considered to be an integral component of the first-line treatment of
peripheral blood smear showed spherocytes without schistocytes, colon cancer.3 Although this drug is more commonly associated
thus favoring the diagnosis of autoimmune hemolytic anemia over with neurologic and gastrointestinal toxicities, oxaliplatin has been
alternative diagnoses such as hemolytic uremic syndrome or shown to induce a hemolytic anemia via several proposed mecha-
thrombotic thrombocytopenic purpura (TTP). This diagnosis was nisms. These include microangiopathic anemia linked to drug-
confirmed via positive direct and indirect Coombs testing, which induced hemolytic uremic syndrome, TTP or to disseminated
showed the presence of immunoglobulin (Ig)G and complement on intravascular coagulation, as well as antibody-mediated destruction
the patient’s red blood cells (RBCs). Analysis of the antibody eluted of erythrocytes as well as platelets, similar to the findings reported in
from the patient’s RBCs was pan-reactive with a test panel of red this case report.5 Smaller studies have also proposed another
cells. The serum antibody manifested anti-e specificity. Although mechanism of erythrocyte destruction related to oxaliplatin
the patient’s blood type was A-negative, his red cells were positive involving nonimmunologic protein adsorption.6 We report a very
for the e antigen (which is within the Rh system). Relative autoanti- well characterized case of autoimmune hemolysis and thrombocy-
e specificity is not uncommon for warm autoantibodies. The anti-e topenia, including determination of red-cell antibody specificities.
antibody was no longer present in his serum when retested 2 years An unusual feature of this case is the rapid nature of the hemolysis
after the hemolytic episode. with evidence of passage of hemoglobin in the urine and associated
The patient was managed with steroid therapy and discontinua- ATN. This might have been related to the presence of complement
tion of oxaliplatin. After completing a 2-week oral prednisone taper, on red cells, which was not reported in a previous case of oxaliplatin-
bilirubin and creatinine normalized, and anemia and thrombocyto- induced Evan syndrome.7
penia improved significantly (Figure 1). Now, 2.3 years later, the We performed a PubMed search using the following combina-
patient continues treatment. He has received 12 cycles of irinotecan, tions of key terms: “oxaliplatin and hemolysis” or “oxaliplatin and
fluorouracil, leucovorin, and bevacizumab followed by 15 cycles of hemolytic.” This search effectively yielded 36 results, of which 28
irinotecan, fluorouracil, leucovorin, and panitumumab, 2 months of were pertinent to the topic of this case report. These studies
oral trifluridine-tipiracil, and most recently began regorafenib. He included a retrospective cohort analysis of patients previously
has had no recurrence of the hemolysis, thrombocytopenia, or renal diagnosed with thrombotic microangiopathy to identify a drug-
failure during treatment with any of these regimens. This clearly induced etiology of this phenomenon as well as a meta-analysis
implicates oxaliplatin as the causative agent of the hemolysis, that analyzed drugs associated with immune hemolytic anemia,
and both studies reported that oxaliplatin was one of the drugs
linked to the production of drug-dependent antibodies underlying
subsequent hemolytic processes.8,9 Another study reported the
Figure 1 This Graph Shows the Patient’s Laboratory Values
presence of “oxaliplatin hypersensitivity,” proven using skin testing,
Over a 16-Week Period. The Dark Arrows Indicate the
Day of Hospital Admission for Total Bilirubin and and reported a median onset after the eighth course of therapy.
Creatinine and the Day After for Hemoglobin and Within this 48-patient analysis, 2 patients developed drug-induced
Platelets (Because These Decreased Further After thrombocytopenia and 1 developed drug-induced hemolytic ane-
Admission). The Nadir Hemoglobin and Platelet mia.10 These findings are relevant to the patient in this case study,
Counts Were 6.7 g/dL and 70,000 Cells per Microliter,
because the immune cytopenias linked to oxaliplatin constitute a
Respectively. The Peak Total Bilirubin and Creatinine
Were 5.1 and 2.85 mg/dL, Respectively. The Scales delayed type II hypersensitivity reaction. If this is the case, then a
are Provided to the Left of Each Panel. The Green cumulative number of exposures would put a patient at a higher risk
Lines Indicate Lower Limit of Normal for the Various of developing such reactions rather than the cumulative dose itself.11
Values (ie, 13.5, 150,000, 0.3, and 0.7, Respectively, A similar retrospective cohort study that evaluated oxaliplatin
for Hemoglobin, Platelets, Total Bilirubin, and
hypersensitivity also noted immune-mediated anemia in <1% of
Creatinine)
the study population, and an equivalent number of cases of
immune-mediated thrombocytopenia.12 The remaining literature
was comprised of case reports and small case series documenting 39
additional cases of oxaliplatin-induced hemolytic anemia attribut-
able to immunologic causes.5-7,11,13-31 At least 4 of these cases also
involved a concomitant thrombocytopenia, which was suspected to
also be immunologic in origin. It is important to note that hyper-
splenism can be attributed to oxaliplatin use, and has therefore been
implicated as another causative mechanism of thrombocytopenia
associated with this agent.32 However, the patient described in this
case report had a normal-appearing spleen in imaging studies, and,

2 - Clinical Colorectal Cancer Month 2016

 Pooja Phull et al
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chemotherapeutic agent whose value has been well established in the 24. Kurian S, Macintyre J, Mushtaq M, Rocha-Lima CM, Ahn Y. Oxaliplatin induced
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Disclosure 29. Ogura T, Tajika M, Niwa Y, et al. Recurrent autoimmune hemolytic anemia
induced by XELOX chemotherapy for colon cancer [in Japanese]. Nihon Shoka-
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topenia. Transfusion 2005; 45:704-8.
31. Ulusakarya A, Misra S, Haydar M, et al. Acute renal failure related to oxaliplatin-
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