"Differential diagnoses in patients with bicytopenia—particularly those with preserved platelets—are broad and require careful physical examination."
A 78-year-old man presents to the clinic. He has a medical history of prostate cancer, which was treated with prostatectomy; skin cancers—including basal cell, squamous cell, and melanoma, all treated with excision; and osteoarthritis. He served in the US military between the 1960s and 1990s and had occupational exposure to solvents. He has also worked in a nuclear plant.
When he visits his primary care provider, he expresses concern about progressive dyspnea on exertion and decreased exercise tolerance for several months. A complete blood cell count (CBC) is conducted, and the results suggest bicytopenia; the patient has a white blood cell count (WBC) of 2.5 × 109/L, a macrocytic anemia with hematocrit of 32.2%, and mean corpuscular volume of 111.8 fL.
Differential diagnoses in patients with bicytopenia—particularly those with preserved platelets— are broad and require careful physical examination. A review of systems, recent illnesses, and medications medications, as well as thoughtful laboratory testing, is necessary. Causes of cytopenias include bone marrow infiltration/replacement, bone marrow aplasia, and blood cell destruction or sequestration.1 Macrocytic anemia alone can be broken into 3 categories: reticulocytosis, megaloblastic anemia, and multifactorial causes.2 A reticulocyte count can be helpful to determine whether the process is hypoproliferative or destructive.2 A peripheral blood smear should be evaluated for abnormal cells.1 Coagulation studies should be obtained to rule out coagulopathies.1 A bone marrow biopsy is important when a primary marrow disorder is suspected.1 Vitamin B12, folate, and copper levels should be obtained in patients who have hypoproliferative cytopenias.1
This patient, on evaluation by hematology, had no recent illnesses to report and no constitutional symptoms such as fevers, chills, night sweats, or unintentional weight loss. He denied any abdominal surgeries and he was not taking any medications that were obviously responsible for his symptoms. Results from his physical examination were normal. Notably, there was a lack of lymphadenopathy and no signs of splenomegaly, rashes, jaundice, or ascites. Laboratory values, including CBC, complete metabolic profile, reticulocyte count, flow cytometry, iron studies, B12, folate, copper, immunoglobulins, light chains, serum protein electrophoresis, haptoglobin, and thyroid function, were normal except for the WBC, now 1.7 × 109/L, neutrophils (0.8 × 109/L), hemoglobin (10.9 g/dL), and platelets (127 × 109/L). Of note, the reticulocyte counts were normal but that was an abnormal finding given his anemia. His vitamin B12 was at the low end of normal.
UNCOVERING A DIAGNOSIS
This patient was started on parenteral B12 supplementation and was monitored for improvement in his counts. Unfortunately, after approximately 1 year, the leukopenia and neutropenia did not improve significantly (2.3 × 109/L and 1.34 × 109/L, respectively), and the anemia worsened (8.8 g/dL), although his platelets remained stable. Another bone marrow biopsy was performed, and the findings were consistent with a myelodysplastic syndrome (MDS); 0.5% blasts, with erythroid and megakaryocytic dysplasia. No ringed sideroblasts were noted. Cytogenetics and fluorescence in situ hybridization test results were normal. Molecular testing revealed a DDX41 mutation that was also indicative of MDS; his serum erythropoietin level was 95 mIU/mL.
The National Comprehensive Cancer Network (NCCN) separates treatment for patients with MDS based on high-risk vs low-risk disease using the Revised International Prognostic Scoring System (IPSS-R) that evaluates hemoglobin absolute neutrophil count, platelets, bone marrow blasts, and cytogenetic category to assign a risk category as well as the World Health Organization type of MDS.3,4 Once the type of MDS and risk category are determined, treatment decisions can begin.
Hematopoietic cell transplantation is the only curative option for MDS. Other treatment options include observation, transfusion support alone, erythropoietin-stimulating agents, granulocyte colony stimulating factor, luspatercept-aamt (Reblozyl), lenalidomide (Revlimid), which is specifically for del(5q) disease, immune suppression therapy in rare instances, and hypomethylating agents, including azacitidine, decitabine (Dacogen), and oral decitabine/ cedazuridine (Inqovi). It is important to note that in August 2023, luspatercept-aamt received an expanded approval for patients with ringed sideroblasts greater than or equal to 15% in the absence of an SF3B1 mutation. The original indication for patients with a SF3B1 mutation and ring sideroblasts less than 5% remains. Of note, the FDA also recently approved ivosidenib (Tibsovo) for patients with IDH1-mutated MDS, although this patient would not be eligible.
This patient is now 80 years old with IPSS-R 3 (low-risk) disease. In MDS, not otherwise specified with multilineage dysplasia, normal cytogenetics are considered a good risk, as opposed to a very good risk.
He was started on darbepoetin injections of 300 μg every 3 weeks. There was no improvement in his hemoglobin level (8.7 g/dL at time of discontinuation), his neutrophils worsened to 0.23 × 109/L, and his platelets continued to worsen into the 60 × 109/L range. A repeat bone marrow biopsy confirmed bilineage dysplasia with less than 5% blasts, and risk stratification remained the same (low risk). Given the lack of erythroid response and worsening neutrophil response, we opted to switch to a hypomethylating agent in accordance with NCCN guidelines. The patient preferred the ease of oral treatments, so he started taking decitabine/cedazuridine at 35-mg and 100- mg doses, respectively, on days 1 through 5 of a 28-day cycle. After 2 months on therapy, his neutrophils and platelets have normalized, and his hemoglobin counts have improved to approximately 9 to 10 g/dL.
MESSAGE FOR APPS
It is imperative to rule out other causes of cytopenias.1-3 A diagnosis may take more than 1 visit and require more than 1 bone marrow biopsy. Once a diagnosis has been established, providers should treat according to risk stratification and national guidelines with regular reassessments to ensure that their patient is benefiting from the treatment.