Autoimmune Hemolytic Anemia with Myelodysplastic Syndrome

Risk factors for development of MDS include prior chemotherapy, radiation therapy, smoking, and exposure to benzene. The most common cytogenetic alteration in MDS is a deletion of the short arm of chromosome 5. We report a patient with an isolated trisomy 21, which constitutes about 1.1-2.2 % of the total cytogenetic alterations in MDS. 3,4 To our knowledge, this is the first reported case of autoimmune hemolytic anemia (AIHA) and MDS with isolated trisomy 21.


Introduction
The myelodysplastic syndromes (MDS) are a heterogeneous group of clonal cell disorders characterized by ineffective hematopoiesis manifested by one or more cytopenias. 1The incidence is higher in men, and is about 3-4 individuals per 100,000 in the United States and may exceed 20/ 100,000 persons after the age of 70 years. 2isk factors for development of MDS include prior chemotherapy, radiation therapy, smoking, and exposure to benzene.The most common cytogenetic alteration in MDS is a deletion of the short arm of chromosome 5.We report a patient with an isolated trisomy 21, which constitutes about 1.1-2.2% of the total cytogenetic alterations in MDS. 3,4To our knowledge, this is the first reported case of autoimmune hemolytic anemia (AIHA) and MDS with isolated trisomy 21.

Case Report
A 62-year-old Caucasian male was initially admitted for generalized weakness and fatigue.The symptoms started three months prior to presentation at the referring hospital.The patient reported anorexia, weight loss, and exercise intolerance.He denied any bleeding symptoms to suggest infection.On admission to our hospital, his vital signs were within normal limits.His physical exam showed pallor, but otherwise was unremarkable.Initial labs are summarized in Table 1.His peripheral smear showed 65% neutrophils, 9% bands, 9% blasts, 2% metamyelocytes, and 1% myelocytes.He underwent a bone marrow biopsy, which was consistent with myelodysplastic syndrome (RAEB-1).His cytogenetics showed trisomy 21 as the sole abnormality.Testing for vitamin B 12 and folic acid were unremarkable.The patient was diagnosed with AIHA and treatment was started with prednisone at 1 mg/kg.The patient's hemoglobin improved with prednisone.The prednisone was tapered over two months and his Coombs testing became negative shortly after the course.The patient's platelet count continued to deteriorate and treatment was initiated with the hypomethylating agent, decitabine.The patient tolerated this treatment well and had improvement in his cytopenia.His course was complicated by gastrointestinal bleeding and a pneumonic infection.The patient died from complications of an empyema.

Discussion
This case illustrates a commonly overlooked association between two different hematologic diseases, myelodysplastic syndrome and autoimmune hemolytic anemia.Our patient had evidence of intravascular hemolysis, manifested by his reticulocytosis, high LDH and bilirubin, Table 1.Initial labs obtained on admission.and low haptoglobin.There was evidence of autoimmunity with the Coombs test positive for pan agglutinating IgG.This improved with standard first line treatment.The bone marrow biopsy result was consistent with myelodysplastic syndrome, refractory anemia with excess blasts (RAEB-1 with 7% blasts in the bone marrow).
Autoimmune hemolytic anemia is due to the immunologic destruction of red blood cells mediated by autoantibodies directed against red blood cells antigens. 5The antibodies can be of "warm" or "cold" subtype.The majority of warm agglutinins are IgG subclass antibodies.They react to antigens at body temperature in contrast to cold agglutinins which are mostly IgM subclass, and react to RBC antigens at a temperature lower than the body's core temperature.The diagnosis usually is made with the finding of an elevated reticulocyte count, increased lactate dehydrogenase, and indirect bilirubin in the setting of a positive direct Coombs test (direct antiglobulin test).
There is increasing evidence that autoimmunity plays an important role in myelodysplastic syndromes.Autoimmune manifestations (AIM) are more common than thought in the setting of MDS.Their frequency ranges from 10-18.5% of patients with MDS. 6,7These manifestations can be classified into five classes: 4 1) Acute systemic vasculitis or autoimmune disorder.
2) Chronic or isolated autoimmune phenomena.3) Classical connective tissue disorders.4) Immune-mediated hematological abnormalities.5) Asymptomatic serological immunologic abnormalities.The association of AIM and MDS was first described in 1982 as AIHA one year after the diagnosis of MDS. 6 Subsequently, multiple cases and studies have been published emphasizing the relationship between autoimmunity and MDS.
In a study by Sokol et al., 8 15 of 46 patients with MDS had clinically important autoimmune hemolysis.Pendry et al. 9 reported a case of MDS presenting as AIHA.The first pediatric case was reported by Ören et al. 10 The improvement of both disorders was noticed with mycophenolate mofetil. 11João et al. 12 and Terpos et al. 13 described two cases of MDS, AIHA, and non-Hodgkin's lymphoma.Giagounidis et al. 14  AIHA in MDS may be underdiagnosed for several reasons including the assumption that anemia is due to MDS. 14 Besides, Coombs-negative hemolytic anemia can be masked by reticulocytopenia caused by MDS.
It is unclear if autoimmune manifestations carry any prognostic implications to the diagnosis of MDS.In a study by Enright et al., 17 patients with the combination of the two disorders were younger, more often had MDS related to prior chemotherapy, and had additional cytogenetic abnormalities.The onset of AIM was associated with clinical deterioration, as the median survival after AIM diagnosis was only nine months compared to 25 months after MDS diagnosis.In addition, the initial response to steroids carried a better prognosis.

Conclusion
Autoimmune hemolytic anemia is a rare, but commonly overlooked cause of anemia in patients with myelodysplastic syndrome.Further reports may delineate the association of autoimmune manifestations and MDS better and its potential prognostic and therapeutic implications.A link may be found between chromosomal abnormalities and their concomitant incidence.