The natural history of CML initially is one of slow progression. Even without treatment, the median survival is 3 years. After a variable (and unpredictable) period, approximately half of CML cases enter an accelerated phase marked by increasing anemia and new thrombocytopenia, the appearance of additional cytogenetic abnormalities, and finally transformation into a picture resembling acute leukemia (blast crisis). In the remaining 50% of cases, blast crisis occurs abruptly, without an accelerated phase. Of note, in 30% of cases the blast crisis resembles precursor-B cell ALL, further attesting to the origin of CML from hematopoietic stem cells. In the remaining 70% of cases, the blast crisis resembles AML. Less commonly, CML progresses to a phase of extensive bone marrow fibrosis resembling primary myelofibrosis.
Fortunately for those affected, the natural history of CML has been altered dramatically by the emergence of targeted therapy. Treatment with tyrosine kinase inhibitors, particularly in patients with early disease, induces sustained remissions with manageable toxicity and prevents progression to blast crisis, apparently by suppressing the proliferative drive that leads to the acquisition of additional mutations. When patients on tyrosine kinase inhibitors relapse, their tumors frequently are found to have acquired mutations in the kinase domain of BCR-ABL that prevent the drugs from binding. The selective outgrowth of these cells is explained by the powerful anti-tumor effects of BCR-ABL inhibitors, and indicates that many resistant tumors are still “addicted” to the progrowth signals created by BCR-ABL. In some instances resistant tumors can be treated with “third-generation” BCR-ABL inhibitors. For others, hematopoietic stem cell transplantation offers a chance of cure, but carries with it substantial risks, particularly in the aged.
Polycythemia vera is strongly associated with activating point mutations in the tyrosine kinase JAK2. JAK2 normally acts in the signaling pathways downstream of the erythropoietin receptor and other growth factor receptors. The most common JAK2 mutation, sharply lowers the dependence of hematopoietic cells on growth factors for growth and survival. This produces excessive proliferation of erythroid, granulocytic, and megakaryocytic elements (panmyelosis), but most clinical signs and symptoms are related to an absolute increase in red cell mass. Polycythemia vera must be distinguished from relative polycythemia, which results from hemoconcentration. Unlike reactive forms of absolute polycythemia, polycythemia vera is associated with low levels of serum erythropoietin, which is a reflection of the growth factor–independent growth of the neoplastic clone.
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MORPHOLOGYThemajoranatomicchangesinpolycythemiaverastemfromincreasesinbloodvolumeandviscositybroughtaboutbythepolycythemia.Congestion ofmanytissuesischaracteristic.Theliverisenlargedandoftencontainssmallfociofextramedullaryhematopoiesis.Thespleenusuallyisslightlyenlarged(250to300g)becauseofvascularcongestion.Asaresultoftheincreasedviscosityandvascularstasis,thromboses and infarctions are common, particularlyintheheart,spleen,andkidneys.Hemorrhagesalsooccurinaboutathirdofthepatients.Thesemostoftenaffectthegastrointestinaltract,oropharynx,orbrainandmayoccurspontaneouslyorfollowingsomeminortraumaorsurgicalprocedure.Plateletsproducedfromtheneoplasticcloneoftenaredysfunctional,aderangementthatcontributestotheelevatedriskofthrombosisandbleeding.AsinCML,theperipheralbloodoftenshowsbasophilia.