Abstract
Introduction
Atezolizumab is currently the only immunotherapy used in conjunction with nab-paclitaxel for locally advanced or triple negative breast cancer. Limited data is available regarding hemolytic anemia as a side effect of atezolizumab.
Case report
We describe a 59-year-old female with a history of triple negative breast cancer with bone metastases presenting for follow up on Cycle 1, Day 15 of atezolizumab and nab-paclitaxel (100 mg/m2). Patient’s complete blood count (CBC) showed macrocytic anemia, with further workup significant for autoimmune hemolytic anemia (AIHA) attributed to atezolizumab.
Discussion
Hemolytic anemia induced by atezolizumab is a rare side effect that was successfully treated in this patient with a prednisone taper.
Introduction
Currently, atezolizumab is the only immunotherapy that is FDA approved for the treatment of locally advanced or metastatic triple-negative breast cancer used in combination with nab-paclitaxel. It selectively binds to programmed death ligand 1 (PD-L1) inhibiting a mechanism used by tumors to downregulate T-cells. 1 As the use of PD-L1 becomes more integral into treatment of cancer, rare side effects will continually become more prominent. Limited data is available regarding the use of PD-L1 inhibitors and hemolytic anemia as a side effect, 2 with a current reported incidence of less than 1 percent. 3 The following case is a report of hemolytic anemia as a side effect of atezolizumab for the treatment of metastatic triple-negative breast cancer.
Case presentation
In June 2019, a 56-year-old female with a history of triple negative breast cancer with bone metastases presented to the clinic for follow up on Cycle 1, Day 15 (C1D15) of atezolizumab 840 mg on days 1 and 15 and nab-paclitaxel 100 mg/m2 on days 1, 8, and 15 every 28 days. The patient is 5′5″ with a body surface area of 2.04 m2. The patient was originally diagnosed in 2009 with ER/PR positive, HER2 negative invasive carcinoma treated with neoadjuvant fluorouracil, epirubicin, and cyclophosphamide (FEC) for three cycles followed by docetaxel for 3 cycles. Patient underwent a lumpectomy achieving complete response. She received 48.6 Gy radiation followed by tamoxifen until 2012 when she switched to exemestane. Later that year she was switched to anastrozole due to arthralgias and myalgias. In 2015, she was diagnosed with ER/PR and HER2 negative bone metastases and received radiation. In 2017, the patient experienced disease progression with the pathology revealing weak estrogen receptor positive metastatic disease and was started on fulvestrant and palbociclib. In May 2018, she was diagnosed with liver metastasis and initiated eribulin. Treatment was held in January 2019 due to progressive disease. She was then started on paclitaxel 90 mg until May 2019 due to disease progression. Beginning of June, she was started on fourth line atezolizumab 840 mg and nab-paclitaxel 100 mg/m2 for palliative intent.
The patient has comorbid anemia, Vitamin B-12 deficiency (treated with cyanocobalamin since 2017), hypertension, hypercholesterolemia, restless leg syndrome, anxiety, and tinnitus secondary to disease. Her past surgical history includes gastric bypass in 2010. Other concurrent medications included denosumab 120 mg every 4 weeks, cyanocobalamin 1000 mcg and darbepoetin alfa 300 mcg. On C1D1 of atezolizumab and nab-paclitaxel, patient’s hemoglobin was 12.1, requiring a hold on darbepoetin that day. Prior to treatment on C1D15, patient had a complete blood count (CBC) drawn showing macrocytic anemia (see Table 1). Darbepoetin alfa and iron sucrose 200 mg were given in addition on C1D15. Patient returned to clinic one week later for follow up with provider, which showed blood counts were lower (Table 1). Further workup was requested by the provider to determine source of hemolytic anemia.
Baseline laboratory values for patient prior to initiation of atezolizumab through the first cycle and workup to distinguish autoimmune hemolytic anemia (AIHA) from anemia of disease.a,b
aValues significant for AIHA are in bold.
bRBC = red blood cells, HGB = hemoglobin, HCT = hematocrit, MCV = mean corpuscular volume.
cNot reported.
Follow up blood labs included reticulocyte count and fractionation, lactate dehydrogenase (LDH), haptoglobin, fibrinogen, iron panel, Vitamin B12, folate. As can be seen in Table 1, the patient had an elevated reticulocyte count and LDH and decreased haptoglobin. These lab findings are indicative of hemolytic anemia. 4 Of note, the patient’s fecal occult blood test was negative, and her total bilirubin was normal. The patient’s lymphocyte count remained normal, even with continued nab-paclitaxel. Using the Naranjo algorithm, the immune-mediated hemolytic anemia experienced by the patient is a probable adverse drug reaction (score = 6) of atezolizumab. 5
Treatment of the hemolytic anemia included a prednisone taper for 16 days. On C1D27 the prednisone taper was shortened to decrease by 20 mg every three days. She was started on folic acid 1 mg daily for 5 days. At the office visit on C1D27, her MCV increased to 117. As a result, her folic acid was increased to three times daily. As of publication, patient is still receiving folic acid 1 mg three times daily and darbepoetin alfa 300 mcg every two weeks. Iron sucrose was administered every two weeks, with the last dose in August 2019. In mid-July, patient’s CBC was stable after the prednisone taper was complete, showing recovery from the AIHA. Cycle 2 was initiated with no additional pre-medications added.
Discussion
Leaf et al, define immune checkpoint inhibitor (CPI) autoimmune hemolytic anemia (AIHA) as a quick decrease in hemoglobin ≥2 g/dL, at least 2 laboratory features indicative of hemolysis, occurrence of AIHA after initiation of immune checkpoint inhibitor, exclusion of other sources of anemia, and the immunotherapy deemed the likely source by the hematologist or oncologist. 2
Treatment of AIHA includes high dose glucocorticosteroids and supportive care including hydration. 3 Starting on C1D23, patient was prescribed a prednisone taper of 80 mg daily for 5 days followed by 60 mg for 5 days, 40 mg for 5 days and then, 20 mg until follow up clinic visit. Iron sucrose and darbepoetin alfa every two weeks was started. Folic acid 1 mg daily was initiated due to macrocytic anemia, and as seen in Table 1, eventually resolved.
There is limited data regarding atezolizumab induced hemolytic anemia. A case report from Spain documented hemolytic anemia after the patient received their first cycle of atezolizumab requiring a blood transfusion and treatment with corticosteroids. 6 However, there is more documentation of other checkpoint inhibitors inducing hemolytic anemia. As with atezolizumab, nivolumab induced hemolytic anemia can occur during various treatment cycles. In a case report by Palla and colleagues (2016), patients that experienced AIHA were treated with nivolumab as second- or third-line treatment. AIHA was treated with high dose corticosteroids, and most commonly resolved. 7 Providers should be vigilant of AIHA occurring during any treatment cycle with a low threshold to use corticosteroids. 5 Rituximab and intravenous immune globulin (IVIG) has been shown to be an effective treatment in addition to steroids, or a second line treatment option in steroid refractory AIHA. 2 , 6 Previous case reports demonstrated successful continuation of atezolizumab with no further signs of AIHA. 2 For the patient presented here, the provider felt that atezolizumab was the best treatment choice for the patient, who was able to continue treatment with no further evidence of hemolytic anemia.
Footnotes
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
