Bone Marrow Failure Disorders

Presentation, History, and Testing

The patient, a 77-year-old Hispanic male with a past medical history of benign prostatic hypertrophy, hypertension, and ulcerative colitis, was referred for evaluation of thrombocytopenia by his primary care provider after routine laboratory testing revealed a low platelet count, at about 40,000 per cubic millimeter of blood. An extensive workup revealed the following:

• The patient was negative for hepatitis B and C.
• B12, folate, and haptoglobin levels were all within normal limits.
• The bone marrow biopsy was hypocellular with decreased megakaryocytes and no evidence of dysplasia.
• Cytogenetics were negative with the exception of 45X-Y and NGS (next-generation sequencing)-positive ASXL1 and NOTCH1 mutations; both mutations were outside of a functional domain.
• The patient was positive for small clusters of large granular lymphocytes (LGL) and paroxysmal nocturnal hemoglobinuria (PHN) cell clones, but these findings were not clinically significant.

Differential Diagnoses

The differential diagnoses in this case include megaloblastic anemia, hypoplastic myelodysplastic syndrome (MDS), LGL leukemia, PNH, reversible infectious or toxic etiology, hypersplenism, and infiltrative malignancies (myeloproliferative neoplasms, acute myeloid leukemia, lymphomas, myeloma).

Final Diagnosis and Recommendations for Treatment

The patient was presumptively diagnosed with immune thrombocytopenia and treated with steroids, rituximab, and eltrombopag. He later developed pancytopenia and was referred to a national comprehensive cancer center. A bone marrow biopsy was performed there and the results—showing hypocellularity (5%), lack of dysplasia, and concomitant clinically insignificant PNH and LGL clones—were most consistent with a diagnosis of aplastic anemia. Additionally, there were no somatic mutations identified, which is not characteristic of MDS. The ASXL1 and NOTCH1 mutations were both outside of functional .

Given his weekly transfusions and diagnosis of aplastic anemia, the patient was treated with anti-thymocyte globulin (ATG), cyclosporine (CsA), and eltrombopag but did not respond to therapy. Subsequently, treatment with alemtuzumab was initiated but there was no response. The patient was then referred to the bone marrow transplant unit for an allogeneic stem cell transplant. Unfortunately, his donor was found to have anemia and was unable to donate. The androgen danazol was recommended to the patient, but he could not afford the monthly copay for the prescription. He has since started therapy with the bone marrow stimulant romiplostim off label and is waiting for another transplant donor to become available.

Patients diagnosed with aplastic anemia who are younger than 40 should initially be referred to the bone marrow transplant team for allogeneic transplant. Patients over the age of 40 should proceed with immunosuppressive therapy including ATG and CsA, with or without eltrombopag; if remission is not achieved or relapse occurs in these patients, then they should be evaluated for transplant. Salvage therapies include administering a second course of ATG/CsA using rabbit ATG or reinitiating full-dose CsA monotherapy. Additional salvage therapies include danazol, cyclophosphamide, and alemtuzumab.

The advanced practitioner will need to monitor patients with aplastic anemia closely to assess for their response to therapy. Additionally, because the treatment regimen for this condition, particularly CsA, has an extensive side effect and toxicity profile, patients need to undergo routine physical examination and laboratory evaluations should include a complete blood cell count, comprehensive metabolic profile, and CsA trough level. Transfusions are also commonly required following immunosuppressive therapy. The advanced practitioner must educate patients about the side-effect profile associated with treatment and provide them with guidelines on when to notify their healthcare providers. When relapse is suspected, patients should be referred to the transplant team. Additional referrals may include a nephrologist if the patient develops renal insufficiency while receiving treatment with CsA.