Autoimmune Cytopenias

Section Editor

David Hughes, PharmD, BCOP

Boston Medical Center and Boston University

Section Editor

Frances Blevins, PA-C

Boston Medical Center

Featured Case Study

Treatment With Rituximab for Relapsed Warm Autoimmune Hemolytic Anemia

Presentation and Diagnosis

A 45-year-old Caucasian male was diagnosed with autoimmune hemolytic anemia (AIHA) in March 2015 during workup for a syncopal event. At presentation, his hemoglobin level was 6 g/dL and his platelet count was 120,000/µL. His medical history was significant for obesity, diabetes, and immune thrombocytopenia (ITP). His ITP was diagnosed in October 2004 and treated only with intravenous immunoglobulin (IVIg) in 2004, 2008, and 2014. He did not require treatment for chronic ITP.

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Presentation and Diagnosis

A 45-year-old Caucasian male was diagnosed with autoimmune hemolytic anemia (AIHA) in March 2015 during workup for a syncopal event. At presentation, his hemoglobin level was 6 g/dL and his platelet count was 120,000/µL. His medical history was significant for obesity, diabetes, and immune thrombocytopenia (ITP). His ITP was diagnosed in October 2004 and treated only with intravenous immunoglobulin (IVIg) in 2004, 2008, and 2014. He did not require treatment for chronic ITP.

His lactate dehydrogenase (LDH) level was elevated, his haptoglobin was undetectable (< 8 mg/dL), and his initial direct antiglobulin test (DAT, also known as the Coombs test) was positive for IgG and C3 and suggestive of warm AIHA. Treatment with prednisone was initiated at 1 mg/kg/day (100 mg PO daily).

At his hematology follow-up 1 week later, his hemoglobin improved to 10.2 g/dL and his LDH dropped from 582 U/L to 447 U/L, while haptoglobin remained undetectable. Of note, the platelet count remained normal at 232,000/µL. His prednisone was further tapered to 60 mg daily for 2 weeks, then to 40 mg daily for 2 weeks. He was also started on daily folic acid. At his next visit in April, his hemoglobin levels continued to improve to 13.8 g/dL, and the prednisone dosage was subsequently dropped to 20 mg PO daily. One week later his hemoglobin remained stable at 13.1 g/dL and repeat DAT demonstrated the presence of anti-IgG but was negative for C3. Haptoglobin had normalized (105 mg/dL) but LDH remained elevated (469 U/L). He continued to tolerate the prednisone taper, and prednisone was discontinued in July without any evidence of recurrent hemolysis.

In October 2017, the patient presented with an ITP flare. He was also admitted in late October for a seizure and found to have leptomeningeal/pachymeningeal enhancement on MRI and a platelet count of 1,000/µL. He was started on dexamethasone at 40 mg PO daily for 4 days and transfused with 3 units of platelets in preparation for a lumbar puncture (LP). His platelet counts improved to > 100,000/µL and he was started on levetiracetam at 750 mg PO twice daily for seizure prophylaxis.

In late November 2017, when he visited his primary care provider, his platelet count was found to be 2,000/µL. He was seen in hematology clinic the next day and the platelet count had improved to 15,000/µL. He was treated with IVIg and started on prednisone at 60 mg PO daily with plans for a slow taper and ultimately rituximab therapy. He was admitted to the hospital that day due to an IVIg infusion reaction involving nausea, vomiting, and syncope. There was no evidence of seizure activity. He was given a second dose of IVIg as an inpatient without incident and discharged home on prednisone at 40 mg PO daily. Of note, his hemoglobin level did drop to 9.7 g/dL during this ITP flare but it was not believed to indicate a relapse of his AIHA. He continued to be followed closely in clinic and tolerated a taper of prednisone to 10 mg daily with platelets improving to 113,000/µL and hemoglobin levels at 11.8 g/dL. He was then admitted in December 2017 for newly diagnosed supraventricular tachycardia. Following this admission his platelets dropped further to 39,000/µL and his prednisone was increased to 60 mg PO daily.

In January 2018 he was started on rituximab for 4 weekly doses. During his course of rituximab, he tolerated a prednisone taper to 10 mg PO daily and it was decided that he should continue maintenance rituximab every 3 months for 1 year. He then tolerated a slow taper off prednisone and by August his counts were back to normal, with platelets at 228,000/µL and hemoglobin at 13.7 g/dL.

He completed rituximab maintenance therapy in February 2019 and has not required additional therapy since that time. At his most recent follow-up in June 2021, his platelet count remained normal at 156,000/µL and his hemoglobin level was 15.2 g/dL.

Discussion

There are several clinical pearls in this case. First, steroids are generally the first-line therapy for warm AIHA. The optimal dosing of steroid used in warm AIHA is currently prednisone at 1.0-1.5 mg/kg/day or a fixed 60- or 100-mg dose. This should be followed by a slow, prolonged taper over 3-6 months to avoid rapid relapse and maintain remission.1-3 This is in contrast to the management of cold AIHA, which does not typically respond to steroid therapy, and ITP, for which short courses of high-dose steroids are often sufficient.

Second, when glucocorticoids (eg, prednisone) are initiated, there is an increased risk of upper gastrointestinal complications; therefore, antacid therapy such as a proton pump inhibitor is recommended. Patients on prolonged steroid therapy (> 3 months) should be counseled on bone health and started on calcium and vitamin D supplementation with consideration of bisphosphonate therapy. Folic acid supplementation (1 mg PO once daily) should also be initiated because of chronic hemolysis that may lead to folate deficiency due to increased utilization of folate.4

Third, there is a lack of consensus on the treatment of relapsed patients with AIHA. Some commonly used treatments include anti-CD20 monoclonal antibodies (eg, rituximab) or splenectomy. Rituximab is dosed at 375 mg/m2 intravenously weekly times 4 doses or given as a flat 100-mg dose for a total of 2 to 4 doses. Overall response rates range between 70% and 90%.5 If rituximab is used, then appropriate screening and monitoring for hepatitis B should be completed.6

Splenectomy can induce responses in 60% to 90% of patients but many will relapse within months of therapy.7,8 Patients undergoing splenectomy should receive appropriate antimicrobial prophylaxis since they are at risk for bacterial infections secondary to encapsulated bacteria (eg, Streptococcus).9

In summary, treatment of AIHA and the supportive care associated with treatment warrant close monitoring and careful titration in order to achieve the best patient outcomes.

References

  1. Lechner K, Jager U. How I treat autoimmune hemolytic anemias in adults. Blood. 2010;116(11):1831-1838.
  2. Zanella A, Barcellini W. Treatment of autoimmune hemolytic anemias. Haematologica. 2014;99(10):1547-1554.
  3. Packman CH. Hemolytic anemia due to warm autoantibodies. Blood Rev. 2008;22(1):17-31.
  4. Go RS, Winters JL, Kay NE. How I treat autoimmune hemolytic anemiaBlood.2017;129 (22):2971-2979.
  5. Maung SW, Leahy M, O’Leary HM, et al. A multi-centre retrospective study of rituximab use in the treatment of relapsed or resistant warm autoimmune haemolytic anaemia. Br J Haematol. 2013;163(1):118-122.
  6. Hwang JP, Feld JJ, Hammond SP, et al. Hepatitis B virus screening and management for patients with cancer prior to therapy: ASCO provisional clinical opinion update. J Clin Oncol. 2020;38(31):3698-3715.
  7. Coon WW. Splenectomy in the treatment of hemolytic anemia. Arch Surg. 1985;120(5):625-628.
  8. Patel NY, Chilsen AM, Mathiason MA, Kallies KJ, Bottner WA. Outcomes and complications after splenectomy for hematologic disorders. Am J Surg. 2012;204(6):1014-1019.
  9. Konradsen HB, Rasmussen C, Ejstrud P, Hansen JB. Antibody levels against Streptococcus pneumoniae and Haemophilus influenzae type b in a population of splenectomized individuals with varying vaccination status. Epidemiol Infect. 1997;119(2):167-174.
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