Newly Diagnosed CML
Illustrative Case Series
Newly Diagnosed CML
By Charles Hesdorffer, MD
Hematology/Immunology Unit, National Institute on Aging, NIH Dr. Hesdorffer reports no financial relationships relevant to this field of study.
A 64-year-old man was referred because of leukocytosis. He had been in his usual state of health until approximately two months prior to a visit, when he was diagnosed by his primary care provider with pneumonia. At that time, he presented with fever and cough, and chest X-ray revealed a lingular infiltrate. A complete blood count (CBC) revealed leukocytosis with a white blood count of 17x103/cu mm, with 68% neutrophils, 8% band forms, and 8% metamyelocytes, 6% myelocytes, 2% basophils, and 2% eosinophils. Hemoglobin was 12.9 g/dL and platelet count was 480K/cu mm. Sputum and blood cultures were negative, and he was treated with antibiotics. At a follow-up visit two weeks later, he complained of fatigue and diminished appetite. His fever and cough had resolved, but he remained unable to return to work because of general malaise. At a follow-up visit two weeks later, he reported some improvement, but he had noticed abdominal "bloating" and loss of appetite had persisted. Physical examination revealed slight pallor, no palpable lymphadenopathy, and no adventitial breath sounds. His spleen was palpable 4 cm below the left costal margin. A repeat CBC revealed a WBC of 108x103/cu mm, with 52% neutrophils, 14% band forms, 6% metamyelocytes, 10% myelocytes, 5% progranulocytes, 2% blasts, 10% basophils, and 3% eosinophils. Hemoglobin was 12.1 g/dL and platelet count was 480K/cu mm. Bone marrow revealed a hypercellular marrow with prominent myeloid hyperplasia, with 15% blast forms. Cytogenetic studies were sent to a reference laboratory but the results were pending at the time of referral.
CASE DISCUSSION
This patient most certainly has chronic myelogenous leukemia (CML), but with pending cytogenetic confirmation, other considerations are worthy of mention. Occasionally, patients with acute or chronic inflammatory disease or other myeloproliferative diseases will be found to have white blood counts of greater than 50,000/cu mm. For some patients, the presence of occult infection might present a diagnostic challenge. However, in general, leukemoid reactions associated with inflammation exhibit less of a leftward shift than observed in this case. Also, the presence of a greater percentage of myelocytes than metamyelocytes (so called "leukemic hiatus") is an unlikely occurrence as a result of infection. Furthermore, the increase in basophils is another tip that the diagnosis in this case is more in line with myeloproliferative disease than inflammation-associated leukemoid reaction. The leukocyte alkaline phosphatase (LAP) score may be a useful adjunct to help distinguish CML from leukemoid reaction, as such would be low in CML but normal in those with infection.
Patients with other myeloproliferative disorders, such as polycythemia vera or primary myelofibrosis, may also present with leukocytosis and a large spleen. In these cases, the LAP score would be normal. In the case presented, polycythemia would seem unlikely (in the absence of erythrocytosis), and myelofibrosis would have been evident with the bone marrow aspirate/biopsy.
In this case, the diagnosis of CML is likely to be confirmed by the presence of the Philadelphia (Ph) chromosome (reciprocal translocation between chromosomes 9 and 22) on karyotypic analysis of the bone marrow or molecular analysis for the BCR-ABL fusion product of the CML translocation. Almost all patients with CML have demonstrable Ph chromosome. However, in approximately 2%, there is an insertion of ABL1 adjacent to BCR, resulting in a normal-appearing chromosome 22.1
Assuming the clinical suspicion of CML is confirmed by the cytogenetic study, a treatment strategy should be developed promptly, especially in light of the rapid rise in white count in the month prior to referral. For patients with markedly elevated white counts, particularly if clinical symptoms of leukostasis are apparent (stupor, hypoxia, tinnitus, papilledema, priapism, etc.), treatment should be initiated with leukapheresis and hydroxyurea. In the current case, these symptoms were not reported, but I would still favor initial control with hydroxyurea in light of the rapid change in counts over the prior few weeks.
Since the early reports of the IRIS trial were published,2,3 the standard first-line treatment for chronic phase CML has been with imatinib mesylate. In the trial, imatinib was associated with a superior response rate and improved progression-free survival as compared to interferon alfa plus low-dose cytarabine.
New tyrosine kinase (TK) inhibitors have proven efficacy in patients who have either not achieved cytogenetic response or have progressed while being treated. Thus, both nilotinib (Tasigna®) and dasatinib (Sprycel®) are currently approved for use in this setting.
In a recently published report of a phase 3 multisite, randomized trial of nilotinib vs. imatinib for first-line treatment of chronic-phase CML, nilotinib proved more successful in achieving both complete cytogenetic response (CCR) and major molecular response (MMR) after 12 months of treatment.4 In the trial, patients were assigned 1:1:1 to nilotinib 300 mg twice daily, nilotinib 400 mg twice daily, or imatinib 300 mg twice daily. At 12 months, patients assigned to nilotinib at either 300 mg or 400 mg had significantly higher rates of CCR (80%, 78%) compared to those treated with imatinib (65%; p < .001 for both comparisons). Similarly, nilotinib treatment at either dose resulted in greater rates of MMR than imatinib (44%, 43% vs. 22%; p < .001 for both comparisons). On the basis of these data, the FDA recently expanded the indication for dasatinib to include its use in the first-line treatment of chronic-phase CML.
Although there is experience with concurrent use of hydroxyurea and imatinib for the initial treatment of CML for those who present with markedly elevated white counts, the data for nilotinib in this regard is yet to become available. Thus, I would recommend initial treatment with hydroxyurea alone at a dose of 1-2 gm q 12 hours until the white blood count is approximately 20,000/cu mm. At that time, I would taper off the hydroxyurea while adding nilotinib 300 mg twice daily. During the early treatment, it would be important to maintain hydration and keep an eye on uric acid levels and renal function. Once blood counts normalize, it would be useful to determine BCR-ABL transcript level with the hopeful expectation that MMR will be achieved in due time.
References
1. Godley LA, Le Beau MM. Cytogenetics and molecular abnormalities. Williams Hematology. 8th ed. New York: McGraw Hill Medical; 2010:145-160.
2. Druker BJ, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408-417.
3. O'Brien SG, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348:994-1004.
4. Saglio G, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362:2251-2259.
A 64-year-old man was referred because of leukocytosis. He had been in his usual state of health until approximately two months prior to a visit, when he was diagnosed by his primary care provider with pneumonia.Subscribe Now for Access
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