A 37-year-old man is referred after a routine employment physical reveals anabnormal blood cell count. He has felt well and noticed no obvious symptomsexcept for mild fatigue, which he attributes to excessive work. He denies fever,unusual or frequent infections, and abnormal bleeding.
A 37-year-old man is referred after a routine employment physical reveals anabnormal blood cell count. He has felt well and noticed no obvious symptomsexcept for mild fatigue, which he attributes to excessive work. He denies fever,unusual or frequent infections, and abnormal bleeding.HISTORYHe had an appendectomy at age 19 years and knee arthroscopy at age26 years, but he has had no major medical diagnoses. His only medications areoccasional acetaminophen and ibuprofen as needed. His father has diabetes;otherwise, his parents and 3 siblings are healthy.PHYSICAL EXAMINATIONThe patient appears healthy and has normal vital signs. No mucosal palloror lymphadenopathy is noted. Chest and heart are normal. Abdomen is softand nontender; however, a firm nontender spleen tip is palpable 3 fingerbreadthsbelow the left costal margin. No petechiae or purpura are evident.LABORATORY RESULTSResults of a chemistry panel are normal. A hemogram reveals a hemoglobinlevel of 12.5 g/dL, a white blood cell (WBC) count of 22,300/μL, and aplatelet count of 745,000/μL. The differential reveals 24% lymphocytes, 36%polymorphonuclear neutrophils, 10% band neutrophils, 8% metamyelocytes,8% myelocytes, 5% promyelocytes, and 3% blast forms. An occasional nucleatedred blood cell is also reported.In this patient's subsequent evaluation, which of the following wouldnot be an expected finding or indicated study?A. HLA typing of the patient and his siblings.B. A positive but fluctuating result on an IgM mononucleosis spot test.C. The detection of a chromosome (9;22) translocation.D. The presence of an abnormal tyrosine kinase protein.E. A very depressed level of leukocyte alkaline phosphatase.CORRECT ANSWER: BThis patient most likely has chronic-phase chronic myelogenous leukemia(CML). CML has been known as a distinct clinical entity since 1845. The diseasehas been grouped with the myeloproliferative disorders and is caused bymutation(s) in the pluripotential hematopoietic stem cell lineage, which cansubsequently differentiate into either lymphoid or myeloid lineages.Clinically and phenotypically, CML presents with hyperproliferation of thegranulocytic line out of proportion to the other cell lines--although elevatedplatelet counts, as seen in this man, are also a common finding. The marrowand peripheral smear differentials usually show orderly maturation (more matureelements than immature ones), but with a markedly abnormal left shift;early forms, such as myelocytes, promyelocytes, and even blast forms makean abnormal appearance in the peripheral blood.CML was one of the first diseasesto be defined by a chromosomalabnormality--specifically, thePhiladelphia chromosome (Ph), a reciprocaltranslocation of portions ofchromosome 22 and chromosome 9(choice C).1 Traditionally, this abnormalityhas been detected by chromosomeanalysis; the Ph chromosomehas been found in 90% of cases ofphenotypic CML. This chromosomalmarker can be found not only in themyeloid WBC precursors but also inall of the erythroid and megakaryocyticprecursors in the marrow.In the 1980s, research revealedthat the fused chromosome 22 generatedan active fusion oncogeneknown as BCR-ABL, which is translatedinto an active oncogene protein--a tyrosine kinase (choice D). This tyrosinekinase acts as a neoplastic growth factor that is capable, in the presence ofcertain as yet poorly defined contributing host factors, of initiating an abnormal,neoplastic expansion of the pluripotential stem cells of the marrow, whichresults in clinical CML.2In addition to the detectable aspects of the molecular and genetic pathogenesisof CML discussed above, other clinical markers for the disease traditionallyinclude splenomegaly--sometimes quite impressive--and a markedlydepressed level of leukocyte alkaline phosphatase activity (choice E) despitethe elevated peripheral WBC count, which would usually be associated withthe reverse physiologic response.The course of CML is typically divided into 3 reasonably recognizablephases. The initial, chronic phase varies in length (median, 3 to 6 years) and ischaracterized by little morbidity and relatively easy control of signs and symptomswith a variety of agents, such as hydroxyurea and interferon. However,even when clinical markers such as blood cell counts and spleen size seem toindicate remission, the genetic and biochemical markers remain present inmarrow cells and precursors. The disease gradually degenerates into a myeloproliferativeacceleration phase, characterized by a more profound and difficult-to-control hyperproliferation of marrow precursors; roughly 15% of patients per year pass into this phase. In its final, or blast crisis, phase, CML behaveslike an acute leukemia (a particularly virulent and treatment-refractory variant)and usually ends fatally within 6 months.Before the 1980s, CML was regarded as a disease that was easily controlledin its chronic phase but incurable and inexorably fatal once it had begunto progress. However, the molecular research mentioned above, alongwith advances in stem cell transplantation techniques, have made CML a landmarkdisease for the development of effective therapeutics. Cures are nowpossible with bone marrow transplantation techniques, specifically allogenicstem cell transplantation. Currently, this is the therapy of choice for curativeintent in patients who fulfill requirements for bone marrow transplantation.These include:
Initial screening shows this patient to be a candidate for bone marrowtransplantation. Thus, HLA typing of him and his siblings (choice A) is indicatedearly on so that the process can proceed before progression to more advancedphases of CML--provided a matched donor is found.The elucidation of the role of the abnormal neoplastic fusion oncogeneand its tyrosine kinase in CML has opened one of the most exciting therapeuticinitiatives in hematology-oncology in many decades. Biochemical techniquesthat probe the molecular structure of the oncogene and the oncoproteintyrosine kinase are being developed in an attempt to inhibit the tyrosinekinase and its proliferative effects. Imatinib has significant clinical activityagainst the tyrosine kinase, and after a period of therapy with this agent, themarrows of many patients with CML have become chromosomally, genetically,and biochemically normalized (ie, the Ph chromosome, the BCR-ABL oncogene,and abnormal tyrosine kinase protein have disappeared).
How longthis effect will last, whether it has curative potential, when and how to incorporatethis modality into CML therapy protocols, and how this treatment compareshead-to-head with bone marrow transplantation techniques are questionsthat define an area of intense research at this time.The IgM mononucleosis spot test is very specific for acute Epstein-Barrmononucleosis. This patient's leukocytosis is
usuallyseen in mononucleosis. The clinical picture is also not at all typical of thatdisease (ie, constitutional symptoms, pharyngitis, and lymphadenopathy are allabsent). A positive result on this test (even if fluctuating) would be most unlikelyin this setting; thus, choice B--the one unexpected finding--is correct.
Rowley JD. Letter: a new consistent chromosomal abnormality in chronic myelogenous leukaemia identifiedby quinacrine fluorescence and Giemsa staining.
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