Case Presentation: Myelodysplastic Syndromes

Normal Blood Cell Development

Myelodysplastic syndromes (MDS) are a group of hematological conditions affecting the blood stem cells in the bone marrow. In patients with MDS, the blood stem cells fail to mature into functioning red blood cells, white blood cells (WBCs), and platelets. Within normal developing marrow cells, normal myelobasts develop into neutrophils, eosinophils, and basophils. The emergence of abnormal myeloblasts gives rise to nonfunctioning WBCs, which leads to low blood cell counts, which can cause anemia, increased risk of infection, and easy bleeding or bruising. Other symptoms include fevers and sweats, poor appetite, and weight loss. MDS can develop into acute myeloid leukemia (AML), an aggressive cancer of the bone marrow.

At presentation, the majority of MDS patients are aged >60 years. Diagnosis of MDS is made through bone marrow biopsy. There are several types of MDS, including refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, refractory cytopenia with multilineage dysplasia, and myelodysplastic syndrome associated with an isolated del(5q) chromosome abnormality (5q- syndrome).

The case study below highlights a patient with 5q- syndrome, which is characterized by a deletion of part of the long (q) arm of human chromosome 5. The MDS subtype is considered low-risk with a relatively low likelihood of developing into AML (Giagounidis AA, et al. Clin Cancer Res. 2006;12[1]:5-10).

Background

Chief complaint: Increase in moderate amounts of fatigue and dyspnea on exertion for 6 months.

History of present illness: The patient is a woman aged 72 years who has developed macrocytic anemia over the past year. Gastroenterology evaluation resulted in a negative colonoscopy. The patient was referred to hematology for an evaluation in August 2010. Laboratory studies from August 5, 2010, revealed a WBC count of 3.3 with 1200 neutrophils, hemoglobin 9.4, an MCV of 108, and a platelet count of 344,000. She had normal vitamin B12 and folic acid levels. Her reticulocyte count was unusually low at 2.2%. She had normal iron stores and normal iron saturation. The patient’s renal and hepatic functions were confirmed to be normal.

She subsequently underwent a bone marrow biopsy on September 20, 2010, which was consistent with MDS. Specifically, the marrow was described as being normocellular 40% with a relative megakaryocytic hyperplasia, including dysplasia. There were also approximately 6% to 8% immature myeloid cells present with interstitial clustering. Stainable iron was present. Flow cytometry confirmed 5% to 6% blast forms, expressing the myeloid antigens CD33, CD13, CD34, CD117, and HLA-DR. Cytogenetics revealed a deletion of 5q in 16 out of 20 examined cells. There were no additional clonal abnormalities. FISH studies also confirmed the presence of the 5q abnormality. Past medical history: Significant for hiatal hernia and hypertension. Diagnosed with breast cancer in 1975 and treated with 1 year of oral melphalan.

Past surgical history: Mastectomy in 1975. Medications: Atenolol, nifedipine, hydrochlorothiazide.

Social history: The patient is widowed. She previously was employed as a nurse. Rare alcohol use. One-half pack per day tobacco use. No illicit substances. No toxic exposures.

Family history: Father died from pancreatic cancer at age 57. Mother died from supranuclear palsy at age 87. No siblings. Three children in good health.

GYN: Postmenopausal since age 39. Gravida 3, para 3.

Physical Examination

General: White woman. Well dressed and well nourished. In no acute distress.

Vital signs: Temperature, 98.7 F; heart rate, 59 beats/min; blood pressure, 125/78 mm Hg; central venous oxygen saturation, 99%; height, 59 in; weight, 174 lb.

Head Ears Eyes Nose Throat: No pallor, icterus. Oropharynx clear.

Neck: Supple, no jugular venous distention, no significant lymphadenopathy.

Respiratory: Clear to auscultation.

Cardiovascular: Regular rate and rhythm, no murmurs.

Abdomen: Soft, nontender, and good bowel sounds in all 4 quadrants. No organomegaly.

Extremities: No edema, cyanosis, clubbing. Blood count, September 20, 2010: WBC, 3.9; hemoglobin, 9.4; platelets, 321,000.

Jayshree Shah, RN, APN-C, MSN, BSN, BS

Nurse Practitioner, Leukemia Division

John Theurer Cancer Center Hackensack University Medical Center, New Jersey

Nurse Practitioner Commentary

The patient is aged 72 years with a past history of breast cancer treated with mastectomy and 1 year of oral melphalan therapy. In 2010, she was noted to have a mild macrocytic anemia with a mild leukopenia. She underwent gastrointestinal evaluation, which was unremarkable. She then had a bone marrow biopsy, which was consistent with having MDS. Her cytogenetics revealed a sole abnormality consisting of deletion 5q.

MDS are a heterogeneous group of bone marrow failure disorders. If left untreated, MDS will progress into the development of acute leukemia. This patient has a unique subtype of myelodysplasia, the 5qsyndrome, which places her in a median survival group of >63 months (Mathew P, et al. Blood. 1993;81(4):1040-1045).

This subtype of MDS is considered favorable, according to the International Prognostic Scoring System (IPSS) developed by Greenberg and colleagues in 1997. The IPSS utilizes the number of lines of cytopenias, the type of cytogenetic abnormalities, and the presence of blast forms to place patients into prognostic groupings. Using these factors, patients with MDS are assigned to 1 of 4 risk groups: low risk, intermediate-1, intermediate-2, or high risk.

The patient has only severe anemia and would get <1 point on the IPSS scale. She has a favorable 5q minus, which receives 0 points. She does have between 5% and 6% blast forms, giving her a half point. Therefore, she is categorized as low risk when evaluating her prognosis.

There are several treatment choices available for patients diagnosed with MDS. The treatments include growth factors such as Procrit (epoetin alfa) and Neupogen (filgrastim). Hypomethylating agents, such as 5-azacytidine and decitabine, are often used as low-intensity therapies. Anti-thymocyte globulin (ATG, often used in conjunction with cyclosporine) is another treatment choice. Lenalidomide (Revlimid) is FDA-approved for patients with MDS containing a 5q- abnormality.

It was decided that the patient would receive lenalidomide. The drug’s FDA approval was based on a series of trials. The MDS-001 trial (List A, et al. N Engl J Med. 2005;352(6):549-557) demonstrated that lenalidomide was able to improve hematopoiesis in a cohort of patients with myelodysplasia. In a retrospective review of the study, the authors noted that those patients who had a 5q abnormality had a significantly higher rate of response.

The subsequent MDS-003 trial (List A, et al. N Engl J Med. 2006;355(14):1456-1465) clearly demonstrated the responsiveness of patients with 5q- syndrome to lenalidomide. Overall, approximately two-thirds of patients who were transfusiondependent with 5q- syndrome became transfusion independent within 4 to 6 weeks, representing an extremely dramatic response. Patients who had low blast percentages also saw significant reduction. Patients were also noted to have improvement in the clonal cytogenetic abnormality.

It is important as a nurse practitioner to review the side effects with both the patient and caregivers if present at each office visit. Side effects related to taking lenalidomide include thrombocytopenia, serious birth defects (thus, it is important not to become pregnant while taking Revlimid), neutropenia, blood clots, skin reactions including rashes, and tumor lysis syndrome. Patients are asked to come to the oncologist’s office on a weekly basis for 8 weeks to review the blood counts and any side effects the patient may be having, or to answer any questions pertaining to starting this therapy.

The patient was prescribed 10 mg of lenalidomide daily. The process to fill the prescription involves several steps. The oncologist’s office first enrolls the patient into a RevAssist program database. A Revlimid patient-physician agreement provides information on safety risks. Additional information reviewed includes how the patient should properly handle the medication upon receiving a shipment from the specialty pharmacy. Ultimately, a contract is signed by both the patient and his or her oncologist. A review of prescription benefits is also done by the specialty pharmacy in order to dispense the medication. If there is a high copayment or the patient does not have any prescription benefits, Revlimid’s manufacturer, Celgene, offers a patient assistance program.

In this particular case, the patient’s copayment was very high and she had to apply for assistance through Celgene. She met all of the criteria to receive Revlimid at no cost for 1 year, with the eligibility to reapply at the end of the year. The patient came to the office weekly for 8 weeks, experiencing only thrombocytopenia, which eventually resolved, with the remaining blood counts showing normal levels. Her blood counts as of February 14, 2011, were WBC, 4.7; hemoglobin, 12.3; and platelets, 159. Her blood counts as of April 14, 2011, were WBC, 3.4; hemogloblin, 12.5; and platelets, 80. She is still transfusion-independent and continues to take 10 mg of Revlimid daily.

Special thanks to Stuart Goldberg, MD, chief of the Leukemia Division at the John Theurer Cancer Center, for his assistance with the analysis.