Cml And Other Myeloproliferative Disorders

CML is a classic example of a malignant disease whose development proceeds through three phases: chronic, accelerated, and blast. At diagnosis, more than 85% to 90% of patients are found to be in chronic phase. Presentations in accelerated or blast phase are rare. CML is characterized by expansion of myeloid progenitor cells at various stages of their maturation, their premature release into the circulation, and a tendency to home to extramedullary sites. Symptoms at presentation therefore reflect the increase in mass and turnover of the leukemic cells. Patients may complain of lethargy and weakness, night sweats, and weight loss. Occasionally, an increase in abdominal girth and abdominal discomfort are caused by an enlarged spleen. A less common finding is easy bruising and bleeding, resulting from platelet dysfunction. Infections are infrequent. Rarely encountered are bone pains, exacerbations of gout, lower-extremity edema, and priapism. Generalized lymphadenopathy and fever, which are rare in patients with chronic-phase CML, may indicate an accelerated disease course. Extramedullary myeloid tumors (granulocytic sarcoma) may occur at any organ site (e.g., lymph nodes, skin, subcutaneous tissue, central nervous system) and by definition indicate blast transformation. There has been a noteworthy trend toward earlier diagnosis of CML. Whereas in older series, 10% to 20% of patients displayed no symptoms, currently, as many as 50% of patients are asymptomatic at diagnosis. Early diagnosis occurs mainly through unexpected findings on routine blood tests (e.g., as part of a regular physical examination or preoperative assessment).

More than half of the patients with myelofibrosis with myeloid metaplasia (MMM) present with anemia and thrombocytosis. Most commonly, symptoms such as weakness, fatigue, or dyspnea are caused by anemia. Bleeding problems and nonspecific constitutional symptoms may accompany the clinical course. Cachexia accompanied by profound fatigue, night sweats, weight loss, and, in some cases, low-grade fevers is not infrequent. Splenomegaly and hepatomegaly occur in up to 70% of patients. Splenomegaly may be massive and reflects, at least partly, the amount of extramedullary hematopoiesis taking place in MMM. Leukoerythroblastosis and the presence of teardrop cells (myelophthisis) in the peripheral blood are typical laboratory features. Bone marrow aspiration will frequently reveal a so-called dry tap, whereas biopsy demonstrates extensive fibrosis, megakaryocyte hyperplasia, and sometimes osteosclerosis.

Indications for therapy in essential thrombocytosis are based on the risk of thrombohemorrhagic complications. Risk factors include age older than 60 years, a history of a thrombotic or bleeding event, and a platelet count above 1,500 ( 109/L. The risk of thrombosis can be safely and effectively reduced with the combination of low-dose aspirin and cytoreductive therapy. A 2005 study compared the efficacy of aspirin in combination with either hydroxyurea or anagrelide in 809 patients with ET who were at high risk for vascular events. Long-term control of the platelet count was achieved in both groups. However, anagrelide-treated patients were significantly more likely than patients in the hydroxyurea group to experience arterial thrombosis, serious hemorrhage, and transformation to myelofibrosis. On the other hand, the rate of venous thromboembolism was lower with anagrelide. These researchers concluded that hydroxyurea plus low-dose aspirin is superior to anagrelide. Interferon alfa has demonstrated activity in reducing the platelet count in ET, but the toxicity of this agent has been responsible for a high rate of early discontinuance. On the other hand, a high number of durable responses and improved compliance have been reported in a study of treatment using pegylated interferon. Observations that interferon-based therapy preferentially targets JAK2-V617F mutated clones await further confirmation.

In the differential diagnosis of erythrocytosis, the main consideration is exclusion of secondary forms of erythrocytosis. These include any condition that produces a hypoxic state, because hypoxia is typically followed by a physiologically appropriate increase in serum erythropoietin levels; in addition, a number of pathologic conditions may result in excessive production and secretion of erythropoietin (e.g., renal cell carcinoma, Wilms tumor, hepatoma, cerebellar hemangioma, benign renal conditions such as polycystic kidney disease, and endocrine disorders). Administration of erythropoietin-stimulating hormones (e.g., androgens) or erythropoietic substances themselves should be excluded.

Tyrosine kinase inhibitor (TKI) therapy, introduced with imatinib, has revolutionized the treatment of patients with CML and has profoundly changed every treatment algorithm for CML. Although the long-term impact of TKIs on a cure of CML cannot yet be assessed, consistently high cytogenetic and molecular response rates, low rates of disease progression, and a safe toxicity profile are predictive of long-term disease-free survival for most patients. TKIs have proved to be the most effective therapy in CML. Although stem cell transplantation continues to be regarded as the only treatment modality with a proven track record of cure (in the sense of a molecular cure) in CML, the morbidity associated with this form of therapy vis-Ã -vis the ease and efficacy of TKI therapy has has caused TKI therapy to eclipse stem cell transplantation as the initial therapeutic choice. TKIs have completely supplanted interferon alfa-based treatment and virtually rendered irrelevant busulfan, hydroxyurea, and other cytotoxic chemotherapeutics. Hydroxyurea is useful only for temporary control of leukocytosis until definitive therapy can be instituted.