Immunotherapy-associated autoimmune hemolytic anemia
© The Author(s). 2017
Received: 26 December 2016
Accepted: 23 January 2017
Published: 21 February 2017
Immunotherapy has been widely used in the treatment of several solid and hematologic malignancies. Checkpoint inhibitors have been the forefront of cancer immunotherapy in recent years. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1) pathway are the prototypic checkpoint targets for immunotherapy. When combined, CTLA-4 and PD-1 checkpoint inhibitors work synergistically, but with increased probability of toxicity. The following case represents an unusual adverse effect of combined treatment with ipilimumab and nivolumab used for treatment of metastatic melanoma.
A 43-year-old woman with metastatic melanoma presented with severe generalized weakness and fatigue. She has received two cycles of ipilimumab and nivolumab, last administered 3 weeks prior to her presentation. Initial investigations revealed severe anemia with appropriate reticulocytosis, severely elevated lactate dehydrogenase, undetectable haptoglobin level and positive direct coombs test. Patient was diagnosed with severe autoimmune hemolytic anemia secondary to ipilimumab and nivolumab. She was successfully treated with high dose steroids and rituximab.
In our case, we present a rare but serious adverse effect of immunotherapy. We illustrate the clinical presentation and management of immunotherapy associated autoimmune hemolytic anemia. Immunotherapy has revolutionized the treatment of many malignant conditions; therefore, it is imperative for health care professionals caring for cancer patient to be familiar with the adverse effects of immunotherapy, which allow for early recognition and management of these potentially lethal side effects.
KeywordsImmunotherapy Nivolumab Ipilimumab Autoimmune hemolytic anemia
Immunotherapy has been widely used in the treatment of several solid and hematologic malignancies . It has led to paradigm shift in management of advanced cancers with potential for long-term and durable responses . There are several immunotherapy agents approved for use in oncology practice and many others under investigation including chimeric antigen receptor T-cells (CAR T-cells), use of checkpoint inhibitors, interleukin therapy, oncolytic viruses and vaccines. Checkpoint inhibitors have been the forefront of cancer immunotherapy in recent years. Their use have revolutionized the treatment of various malignancies including melanoma, head and neck cancers, lung cancer, renal cell carcinoma, bladder cancer and Hodgkin’s lymphoma. Endogenous immune checkpoints terminate immune response after antigen activation . Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1) pathway are the two prototypic checkpoint targets for immunotherapy. CTLA-4 and PD-1 checkpoint inhibitors also work synergistically  which enhances their efficacy, but with increase risk of adverse effects as well. The following case represents an unusual adverse effect of combined treatment with ipilimumab and nivolumab used for treatment of metastatic melanoma.
A 43-year-old woman with history of metastatic melanoma presented to emergency room with severe fatigue. Patient stated that she started having generalized weakness and shortness of breath 2 weeks ago. She denied any fever, cough, chest pain or any bleeding episodes. Her history was significant for recently diagnosed metastatic melanoma to brain, liver and right iliac lymph node. B-raf and c-kit mutations were negative. After completing a course of whole brain radiation therapy, she was started on immunotherapy using ipilimumab and nivolumab. She received two cycles of treatment with the last treatment given 3 weeks prior to presentation. Her medical history was significant for hypothyroidism and 20 pack-year smoking. She had significant family history of melanoma in multiple relatives as well. Her medications include hydrocodone, acetaminophen, dexamethasone 4 mg three times a day, levetiracetam and levothyroxine; none of them was recently introduced. She denied using any over-the-counter medications or supplements. Physical examination was unremarkable except for obesity.
Laboratory findings at the time of diagnosis of AIHA
Positive for both anti-Ig G and anti-complement 3d
Peripheral smear findings
Spherocytes and polychromatic cells
Melanoma is a highly malignant tumor of skin. It is the fifth most common tumor in men and seventh in women in United States . The prognosis of metastatic melanoma is poor with a 5-year survival of only 15–20%. There is great progress made in recent years in the management of advanced melanoma resulting in approval of several drugs by Food and Drug Administration (FDA). Ipilimumab and nivolumab are two of the several drugs recently approved for metastatic melanoma (http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm465274.htm). Ipilimumab is a CTLA-4 inhibitor and nivolumab is a PD-1 inhibitor, both results in enhanced anti-tumor immune response .
Approximately 50% of AIHA cases are idiopathic  but in the remaining cases, underlying inciting factor can be found. Common etiology includes underlying malignancy, autoimmune disorders, drugs and infections . Diagnosis of AIHA is relatively easy given the constellation of laboratory findings of normocytic or macrocytic anemia, reticulocytosis, low serum haptoglobin levels, elevated LDH level, increased indirect bilirubin level and a positive direct antiglobulin test. Once the diagnosis is established, it is important to rule out any secondary causes as managing the underlying cause can indirectly improve the AIHA, particularly in drug-induced hemolytic anemia . Initial treatment of AIHA involves high dose steroids with slow taper. Steroids work primarily by inducing immunosuppression resulting in reduction of autoantibodies production. Rituximab is usually reserved for refractory and relapsed cases. Rituximab is a chimeric monoclonal antibody that causes apoptosis of B-lymphocytes by binding to CD20 positive B-lymphocytes. Depletion of B-lymphocytes lead to reduction in autoantibodies, inflammatory cytokines and T-cell activation.
Reported cases of immunotherapy associated AIHA
Type of immunotherapy used
No of prior cycles
Type of malignancy
IgG or C3
Treatment of AIHA
Other possible association for AIHA
Schwab KS. et al. 
Metastatic SCC of skin
Tardy MP. et al. 
Yes, 6 more injections. No recurrence of AIHA
Kong BY. et al. 
Initially Ipilimumab then patient was started on Nivolumab
Patient had positive direct anti-globulin test before starting Nivolumab.
Palla AR. et al. 
Metastatic lung cancer
Simeone E. et al. 
Simeone E. et al. 
Stage III melanoma
Simeone E. et al. 
AIHA can be life threatening if not treated promptly. It is always prudent to exclude any inciting factor, particularly drugs because cessation of the drug is often sufficient to resolve the hemolysis. Immunotherapy agents have been approved in several solid and hematologic malignancies , therefore, it is important for all health care professionals caring for cancer patients to recognize the adverse effects of immunotherapy, especially AIHA as depicted in our case.
Autoimmune hemolytic anemia
- CAR T-cells:
Chimeric antigen receptor T-cells
Chronic lymphocytic leukemia
Cytotoxic T-lymphocyte-associated protein 4
Food and Drug Administration
Programmed cell death 1
Programmed death-ligands 1
Squamous cell carcinoma
No funding was required for the case report.
Availability of data and materials
UK, TH and FA wrote the manuscript. MSK and AZ proofread the manuscript. TH and UK primarily took care of patient. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Informed written consent was obtained from patient for publication of this case. Consent is available on request.
Ethics approval and consent to participate
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
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