CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL
Case 27-2010 — A 73-Year-Old Woman with Chronic Anemia
Richard C. Cabot, Nancy Lee Harris, M.D., Jo-Anne O. Shepard, M.D., Eric S. Rosenberg, M.D., Alice M. Cort, M.D., Sally H. Ebeling, Christine C. Peters
Eyal C. Attar, M.D., Robert P. Hasserjian, M.D.
N Engl J Med 363:1060-1068 | September 9, 2010
Presentation of Case
A 73-year-old woman was seen in the cancer center at this hospital for management of a myelodysplastic syndrome.
Approximately 2.5 years earlier, exertional dyspnea developed and worsened during the subsequent 6 months. Two years before this evaluation, a transthoracic echocardiogram showed moderate aortic stenosis. Furosemide was administered, with little improvement. Increasing shortness of breath at rest and a brief episode of syncope occurred. The patient came to the emergency department at this hospital. On examination, the blood pressure was 137/70 mm Hg, the pulse 112 beats per minute, the respiratory rate 20 breaths per minute, and the body temperature 35.3°C. There was a grade 3/6 systolic murmur that radiated to the carotid arteries, and 1+ nonpitting edema of the legs. Measurements of serum electrolytes, calcium, magnesium, total protein, albumin, globulin, total and direct bilirubin, amylase, lipase, iron, iron-binding capacity, ferritin, folate, vitamin B12, thyroxine, thyrotropin, immunoglobulins, and serum protein electrophoresis were normal; results of renal- and liver-function tests were normal; and tests for myocardial infarction were negative. Other laboratory-test results are shown in Table 1. An electrocardiogram revealed a normal sinus rhythm with evidence of left atrial enlargement and right bundle-branch block. A chest radiograph was normal.
Table 1
Laboratory Data.
She was admitted to this hospital, and 4 units of packed red cells were transfused; the hematocrit rose to 31.6% by the third day. Pathological examination of a bone marrow–biopsy specimen revealed normal marrow cellularity with trilineage maturing hematopoiesis in normal proportions. Some megakaryocytes appeared small, with hypolobated nuclei. Cytogenetic analysis of the bone marrow was not performed. Epoetin alfa was administered; the hematocrit rose to 35.8% by the fifth day. Cardiac catheterization showed stenosis of the left main and left anterior descending coronary arteries and moderate aortic stenosis. Coronary-artery grafting (one vessel) and aortic-valve replacement with a bovine pericardial prosthesis were performed, and the patient was discharged on the 17th day; medications included epoetin alfa and warfarin. Anticoagulation medication was discontinued after 3 months.
Fourteen months before this evaluation, the patient reported worsening dyspnea, and findings on a ventilation–perfusion scan suggested a high probability of pulmonary emboli. She was readmitted to this hospital, and heparin administration was begun. The blood type was A, Rh-positive, with positive antibody screening and direct antiglobulin tests. The level of anticardiolipin IgM antibodies was 20.4 (reference range, 0 to 15 IgM phospholipid units); other tests of hypercoagulability were negative. Additional test results are shown in Table 1. The administration of warfarin was begun and heparin was discontinued, and the patient was discharged on the eighth hospital day.
Eleven months before this evaluation, the patient was readmitted for red-cell transfusions because of persistent fatigue and dyspnea and a hematocrit of 20%. She had a history of hypertension, dyslipidemia, hypothyroidism, deep venous thrombosis after a motor vehicle accident 13 years earlier, asthma, hiatal hernia, and colonic polyps. Previous surgical procedures included resection of a malignant melanoma 5 years earlier, hysterectomy, appendectomy, tonsillectomy, adenoidectomy, diskectomy, and arthroscopic knee surgery. Medications included lisinopril, ranitidine, albuterol, atorvastatin, cetirizine, fluticasone, salmeterol, levothyroxine, furosemide, acetylsalicylic acid, warfarin, iron supplementation, and epoetin alfa (20,000 U subcutaneously twice weekly). She was allergic to penicillin, cephalexin, vancomycin, meperidine, codeine, and morphine. She was retired, lived with her daughter, and independently performed activities of daily living. She did not smoke or drink alcohol. Her father had died of a myocardial infarction at 56 years of age, and her mother from hemorrhage from a gastric ulcer at the age of 61; a sister had colonic polyps, and a brother had coronary artery disease. Her children were well.
On examination, the patient appeared pale. The temperature was 36.4°C, the blood pressure 140/60 mm Hg, the pulse 93 beats per minute, the respiratory rate 21 breaths per minute, and the oxygen saturation 91% while she was breathing 2 liters of oxygen. A grade 1/6 murmur was heard throughout the precordium. The examination was otherwise normal. Testing for fecal blood was negative. Laboratory-test results are shown in Table 1. An electrocardiogram was unchanged from previous recordings. Two units of red cells were transfused.
The next day, the hematocrit was 30.7%. Bone marrow biopsy and aspiration were performed. Examination of the specimens revealed dysplasia in erythroid precursors and megakaryocytes. No ring sideroblasts were identified on an iron stain. Two percent of the cells on the aspirate smear were blasts. On cytogenetic analysis, 15 of 20 metaphase cells contained an interstitial deletion of the long arm of chromosome 5 as the only abnormality; the remaining five metaphases were normal. Epoetin alfa was discontinued, and the patient was discharged from the hospital that day. Thereafter, she received red-cell transfusions approximately every 6 to 8 weeks to maintain a hematocrit of 30%. Two months later, she was readmitted to the hospital because she had had 1 week of fever and chills. Echocardiography, blood and sputum cultures, and sputum smears were negative; the fever resolved after the administration of gentamicin and vancomycin, and the patient was discharged after 10 days.
Nine months later, the patient's primary care physician referred her to the cancer center at this hospital for advice on management of her myelodysplastic syndrome. The physical examination was normal. Laboratory-test results are shown in Table 1. Specimens from repeat bone marrow biopsy and aspiration were examined, and a management decision was made.
Differential Diagnosis
Dr. Eyal C. Attar: I am aware of the diagnosis in this case. This patient had chronic anemia without evidence of blood loss or deficiencies of hematopoietic substrates, including iron, vitamin B12, and folate. The reticulocyte percentage was low for her level of anemia, and the erythropoietin level was elevated. Taken together, these findings are suggestive of bone marrow failure. Possible causes include a myeloid or lymphoid neoplasm of the bone marrow, aplastic anemia, infection, medication-induced bone marrow suppression, and an infiltrative bone marrow process such as a metastatic cancer.
The initial evaluation of anemia due to bone marrow failure involves careful history taking, with attention to any previous genotoxic injury, such as chemotherapy or radiation, alcohol consumption, occupational exposures, and use of medications. Assessment of the complete blood count is an important initial study, with attention to the presence of numeric and morphologic abnormalities of red cells, leukocytes, and platelets. This patient had an elevated mean corpuscular volume, a common finding in persons with myelodysplastic syndromes. Further evidence of a myelodysplastic syndrome would be the presence of dysplasia in the myeloid cells on the peripheral-blood smear, including hypogranulated neutrophils and pseudo-Pelger–Huët cells. In the proper clinical setting, additional tests for infection may be considered, including tests for antibodies to Epstein–Barr virus, parvovirus, and the human immunodeficiency virus; a test for cytomegalovirus antigen; and blood cultures.
A bone marrow aspiration and biopsy specimen are required to ascertain the cause of chronic anemia when it cannot be determined on the basis of peripheral-blood testing. The biopsy specimen provides information regarding the bone marrow cellularity and architecture, and the aspirate provides cytologic details of the hematopoietic cells (including assessment of morphologic dysplasia) and permits assessment of iron stores and ring sideroblasts. Cytogenetic analysis of the bone marrow is critical to the diagnosis and treatment of chronic anemia. Examination of this patient's previous bone marrow specimen had revealed erythroid and megakaryocytic dysplasia, without an increase in the percentage of blasts, and the karyotype showed deletion within the long arm of chromosome 5 — del(5)(q13q34) — findings that are consistent with a myelodysplastic syndrome. A repeat bone marrow biopsy and aspiration were performed to confirm the diagnosis and rule out evolution to a more severe form of myelodysplastic syndrome or even transformation to acute myeloid leukemia (AML).
Pathological Discussion
Dr. Robert P. Hasserjian: The morphologic findings in the bone marrow samples obtained at the time of the current evaluation and at the patient's admission 11 months previously were similar. The marrow was 40% cellular (normal for the patient's age) and showed trilineage maturing hematopoiesis with a normal myeloid-to-erythroid ratio. The percentage of megakaryocytes was increased and included numerous small, dysplastic forms. The smear of the bone marrow aspirate showed trilineage maturation with mild erythroid dysplasia and striking megakaryocytic dysplasia (Figure 1A and 1B). Neither the bone marrow nor the peripheral-blood smear showed evidence of granulocytic dysplasia. A differential count of 200 cells from the smear of the bone marrow aspirate revealed 46% maturing myeloid precursors, 26% erythroid precursors, 12% lymphocytes, 1% monocytes, 4% eosinophils, no basophils, 2% promyelocytes, 4% blasts, and 5% plasma cells. Cytogenetic analysis of the bone marrow from the current evaluation revealed an abnormal karyotype — 46,XX,del(5)(q13q34),inv(9)c — in all 20 metaphases analyzed (Figure 1C). The inversion of chromosome 9 is a clinically insignificant constitutional chromosomal variant, but the deletion within the long arm of chromosome 5, del(5q), is an acquired chromosomal abnormality that is characteristic of myeloid neoplasms.1
Figure 1
Bone Marrow Specimens.
The proper evaluation of diagnostic bone marrow samples obtained from patients with cytopenia requires an integration of morphologic features, clinical features, and cytogenetics. In this case, the presence of a normocellular marrow in a patient with persistent, transfusion-dependent anemia without evidence of hemolysis suggests ineffective hematopoiesis. Ineffective hematopoiesis may be secondary to non-neoplastic alterations in the bone marrow microenvironment (such as those caused by a metabolic deficiency), but in this case, the morphologic dysplasia and cytogenetic abnormality indicate a primary clonal stem-cell abnormality and confirm a diagnosis of myelodysplastic syndrome. The World Health Organization (WHO) classification of myeloid neoplasms (updated in 2008) recognizes several myelodysplastic syndromes with differing clinical features and prognoses (Table 2).2 A myelodysplastic syndrome with isolated del(5q), the diagnosis in this patient, is characterized by the presence of anemia (usually macrocytic) and no excess of blasts in the blood or bone marrow; it is commonly associated with a striking megakaryocytic dysplasia characterized by normal-size-to-small forms with abnormal, unilobate nuclei (Figure 1B).1 In contrast to most other forms of myelodysplastic syndrome, the platelet count in a myelodysplastic syndrome with isolated del(5q) may be elevated, as it was in this patient, and is usually not decreased. Relative erythroid hypoplasia is often present (but was absent in this patient), and erythroid dysplasia can be mild or absent. The deleted area on the long arm of chromosome 5 varies, but bands q31, q32, and q33 are invariably absent. One study showed no significant difference in prognosis among cases with different deleted areas.3 When del(5q) is the sole cytogenetic abnormality, as was the case in this patient, the disease course is typically indolent (median survival, 12 years) and there is a relatively low rate of progression to AML (<10%) as compared with other types of myelodysplastic syndrome. The rates of survival are lower among patients who have a myelodysplastic syndrome with del(5q) and excess blasts or additional acquired cytogenetic abnormalities than among patients who have a myelodysplastic syndrome with isolated del(5q); the latter entity thus excludes cases with additional cytogenetic abnormalities or excess blasts.1,3
Table 2
WHO Classification of Myelodysplastic Syndromes (MDS).
Discussion of Management
Dr. Attar: The myelodysplastic syndromes are diseases of the elderly, with diagnosis at a median age of 70 years, as in this patient. Cytopenias in a myelodysplastic syndrome can evolve over a period of months or longer and may involve only a single blood lineage; anemia, the sole cytopenia in this patient, is the most common cytopenia in myelodysplastic syndromes, followed by leukopenia and then thrombocytopenia. Myelodysplastic syndromes that arise with no preceding hematologic abnormalities or known exposures to chemotherapy or radiation, as in this patient, are called primary myelodysplastic syndromes. Alternatively, myelodysplastic syndromes may be secondary to toxic exposures, chemotherapy, or radiation used to treat other diseases such as malignant tumors and autoimmune disorders. Patients with secondary or therapy-related myelodysplastic syndromes have a worse prognosis than do patients with primary myelodysplastic syndromes. AML develops in approximately one third of persons with a primary myelodysplastic syndrome and in a higher fraction of those with a secondary myelodysplastic syndrome.
Prognosis
An International Prognostic Scoring System (IPSS) has been developed to provide prognostic information at the time of the diagnosis for persons with a primary myelodysplastic syndrome.4 The IPSS incorporates the percentage of blasts in the bone marrow, karyotype, and number and degree of cytopenias into a risk group (low-risk, intermediate-1-risk, intermediate-2-risk, or high-risk) that predicts both the median survival (range, 5.7 to 0.4 years) and the time by which 25% of patients will progress to AML (range, 9.4 to 0.2 years). This patient received a score of 0 for the percentage of bone marrow blasts (<5%), 0 for a favorable karyotype, and 0 for cytopenias, with only anemia, which placed her disease in the low-risk IPSS category, with a median survival of 5.7 years and 9.4 years until AML will develop in 25% of patients. However, her age of over 70 years is associated with a lower overall survival in the low-risk group (median, 3.9 years).4 This patient also had a hemoglobin level of less than 9 g per deciliter (5.6 mmol per liter) and an elevated level of lactate dehydrogenase; in one large study, patients with isolated del(5q) and these added risk factors had a median survival of only 6 years.3
Treatment Goals
The main objectives of therapy are to control symptoms due to cytopenias, improve quality of life, and improve overall survival while preventing or delaying progression to AML. Blood-product transfusions, colony-stimulating factors, and antibiotics (when required) provide the backbone of supportive care for patients with a myelodysplastic syndrome, either alone or during other treatments. Three drugs have been approved by the Food and Drug Administration for the treatment of myelodysplastic syndromes. Two — azacitidine and decitabine — are hypomethylating agents, which inactivate genes associated with proliferation and survival in myeloid precursors. The third, lenalidomide, is an immunomodulatory agent derived from thalidomide. Other options for treatment include allogeneic stem-cell transplantation, which currently offers the only possibility for cure for patients with myelodysplastic syndrome, or enrollment in clinical trials of new agents. The choice of treatment depends on the patient's age, the presence or absence of coexisting conditions, whether the myelodysplastic syndrome is primary or secondary, the IPSS score, and the presence or absence of specific genetic abnormalities in the neoplastic cells.
This patient had symptomatic anemia; transfusion of packed red cells resulted in improvement in her energy and activity levels. She did not have leukopenia or thrombocytopenia, and thus did not require myeloid growth factors or platelet transfusions.
For some patients, both azacitidine and decitabine may produce hematologic responses and delay progression to AML; for patients with intermediate-2-risk or high-risk myelodysplastic syndrome, azacitidine may also prolong survival, as compared with supportive care.5–8 This patient did not have an elevated percentage of blasts in the bone marrow or an advanced IPSS score that would have supported initial treatment with a hypomethylating agent.6
Allogeneic stem-cell transplantation should be considered in all patients who have a myelodysplastic syndrome — particularly younger persons, those with intermediate-2-risk or high-risk disease according to the IPSS, and those with secondary myelodysplastic syndrome — and can be performed in older patients (60 to 75 years of age) with the use of reduced-intensity conditioning regimens.9,10 Since the patient under discussion had low-risk disease according to the IPSS, had favorable cytogenetics, and presented at 73 years of age, allogeneic stem-cell transplantation was not initially recommended.
Treatment of del(5q)-Associated Myelodysplastic Syndrome
This patient had deletion within the long arm of chromosome 5, which is the most common cytogenetic abnormality in persons with myelodysplastic syndrome, occurring in 15% of the patients in one large series.11 Patients with this abnormality have a high rate of response to immunomodulatory agents such as thalidomide and lenalidomide, regardless of the presence or absence of additional cytogenetic abnormalities.1,12 Hematologic and cytogenetic responses are most prominent in patients with low-risk and intermediate-1-risk disease, but responses may also be seen in those with intermediate-2-risk and high-risk disease, according to the IPSS, who have del(5q).13 The commonly deleted region, 5q31 to 5q33, is rich in genes important in hematopoiesis, including granulocyte–macrophage colony-stimulating factor receptor, interleukin-3, and interleukin-4.14–16 The exact gene or genes involved in the 5q? phenotype are still under investigation, but haploinsufficiency of the ribosomal protein RPS14 may contribute to the anemia,17 and loss of the microRNAs 145 and 146a, negative regulators of toll–interleukin-1 receptor domain–containing adaptor protein (known as TIRAP) and tumor necrosis factor receptor–associated factor-6 (known as TRAF6), may contribute to the thrombocytosis.18 Susceptibility to lenalidomide in this disease appears to be mediated by means of Cdc25C and PP2Acalpha phosphatases.19
This patient was enrolled in a clinical trial of lenalidomide for patients with a myelodysplastic syndrome and del(5q31) (ClinicalTrials.gov number, NCT00065156), the results of which have since been published.12 In the study, 67% of the patients became transfusion-independent, and the median duration of transfusion independence was not reached at 104 weeks of follow-up. The complete cytogenetic response rate was 45%. This patient had an excellent response to lenalidomide (Figure 2A and 2B). Her blood counts approached the normal range within a few weeks after she started therapy.
Figure 2
Graph of Hematocrit and Platelet Counts during Lenalidomide Therapy.
Dr. Hasserjian: A repeat bone marrow–biopsy specimen obtained 5 months after the initiation of lenalidomide therapy was 15% cellular, with a decreased myeloid-to-erythroid ratio. Megakaryocytes appeared morphologically normal (Figure 1D), and their number was decreased. A differential count of 200 cells from the smear of the bone marrow aspirate revealed 25% maturing myeloid precursors, 48% erythroid precursors, 12% lymphocytes, 1% monocytes, 6% eosinophils, no basophils, 3% promyelocytes, 2% blasts, and 3% plasma cells; megakaryocytes appeared morphologically normal. Cytogenetic analysis of the bone marrow revealed a 46,XX,del(5)(q13q34),inv(9)c abnormality in only 1 of 20 metaphases analyzed, with the remaining metaphases showing the constitutional 46,XX,inv(9)c karyotype. These findings indicate morphologic normalization of the marrow, with increased erythropoiesis and a near-complete cytogenetic response to lenalidomide.
Dr. Attar: The patient's disease was controlled for 5 years, but then recurrent anemia and thrombocytopenia developed. A repeat bone marrow aspiration and biopsy were performed.
Dr. Hasserjian: A bone marrow aspirate obtained 5 years after the initial evaluation showed recurrent morphologic dysplasia, with abnormal hypogranulated myeloid cells, dyserythropoiesis, and megakaryocytes that were small and hypolobated; in contrast to the previous bone marrow samples from this patient, the percentage of myeloblasts was increased, and they now composed 11% of the cells (Figure 1E). Cytogenetic analysis of the bone marrow revealed an abnormal karyotype — 46,X,?X,del(5)(q15q34), del(7)(q21.2), inv(9)c,?12, add(17)(q22), +mar1,+mar2 — in 10 of 20 metaphases (Figure 1F), with additional chromosomal abnormalities in 4 metaphases; only 6 metaphases showed isolated del(5q). These findings indicate progression of the patient's myelodysplastic syndrome, with the presence of more severe dysplasia in all hematopoietic lineages, excess blasts, and karyotypic evolution. According to the WHO classification of myeloid neoplasms, this case would now be considered to represent refractory anemia with excess blasts (RAEB). RAEB is characterized by an increased percentage of myeloblasts in the bone marrow, the blood, or both and is divided into two categories on the basis of the blast count (Table 2). This patient now has RAEB2, an aggressive subtype of myelodysplastic syndrome.
Dr. Attar: At this time, the patient had both anemia and thrombocytopenia, with an increase in the percentage of blasts and an unfavorable karyotype, a situation in which additional treatment was indicated. Therapeutic options for her included azacitidine, decitabine, or treatment on another clinical trial. She elected to enroll in a phase 1 clinical study involving a combination of lenalidomide and bortezomib (NCT00580242). She was treated for two cycles, after which a complete blood count showed the presence of myeloblasts.
Dr. Hasserjian: A bone marrow sample showed 32% myeloblasts, confirming evolution to AML.
Dr. Eric S. Rosenberg (Pathology): Dr. Ballen, what happened next to your patient?
Dr. Karen K. Ballen (Hematology): This woman faced the challenges of multiple medical issues and personal loss with grace and dignity. When the diagnosis of AML was made, Linda Kafkas (her nurse) and I met with the patient, her sisters, and her children to review the management options for acute leukemia arising from a myelodysplastic syndrome. Options included supportive care with blood products and antibiotic treatment, low-dose chemotherapy (e.g., decitabine, azacitidine, or cytarabine), inpatient induction chemotherapy, transplantation, or another clinical trial. In view of her age and coexisting conditions, transplantation was not an option. We thought that induction chemotherapy with daunorubicin and cytarabine, which is standard treatment for patients with AML, would be likely to result in prolonged hospitalization and a very high likelihood of death owing to bone marrow suppression and the risk of bleeding and infection, and would probably not result in a prolonged remission. The patient elected supportive care only. She was able to live at home and work in her garden during the summer, and she underwent red-cell and platelet transfusions as needed. She had several episodes of skin infections and pneumonia. She died at home, surrounded by her family, 7 months after the diagnosis of AML and 7 years after the diagnosis of myelodysplastic syndrome.
Dr. Rushdia Z. Yusuf (Hematology): How does haploinsufficiency of RPS14 result in the 5q? anemia phenotype?
Dr. Attar: Inhibition of RPS14 stabilizes levels of TP53, which in turn activates expression of downstream target genes MDM2, p21, Bax, and Wig-1. This effect, seen specifically within erythroid cells, leads to arrest within the G1 phase of the cell cycle, possibly explaining the erythroid defect seen in these patients.
A Physician: If a patient with myelodysplastic syndrome doesn't have any symptoms, should the patient be treated for myelodysplastic syndrome?
Dr. Attar: Myelodysplastic syndrome is very heterogeneous, and each patient must be considered individually. The patient's age and coexisting conditions, the primary or secondary nature of the disease, and the risk according to the IPSS should be considered, as should the patient's quality of life and preferences.
Anatomical Diagnosis
Myelodysplastic syndrome with isolated del(5q), with progression to acute myeloid leukemia.
Dr. Hasserjian reports receiving consulting fees from Genzyme and honoraria from Roche and Novartis.
This case was discussed at the Cancer Center Grand Rounds, May 21, 2009.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
No other potential conflict of interest relevant to this article was reported.
We thank Dr. Karen Ballen for her assistance in the preparation of the case history.
References
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