Page 1490 - Williams Hematology ( PDFDrive )

1464 Part X: Malignant Myeloid Diseases Chapter 89: Chronic Myelogenous Leukemia and Related Disorders 1465

transformation of CML, but such deletions are not seen in the chronic and collagen fibrosis develop. Additional clonal cytogenetic abnormal-
804
phase and in myeloid blast crisis. p16 is also known as the cyclin- ities develop in as many as half the patients in accelerated phase (see
dependent kinase 4 inhibitor gene and is located on chromosome “Cytogenetic Studies” below).
9p21. 805,806 This gene inhibits the kinase CDK-4, which regulates a cell-
cycle checkpoint prior to commitment to DNA synthesis. The Wilms
tumor (WT) gene on chromosome 11p13 encodes a zinc finger motif- EXTRAMEDULLARY BLAST CRISIS
containing transcription factor found in CML patients only after pro- A variety of symptoms or signs may occur as a result of the specific
807
gression to blast crisis. Overexpression of the EVI-1 gene has also been effects of new extramedullary blastic tumors, referred to as extramed-
found in CML blast crisis. 808,809 Microsatellite instability has not been ullary blast crisis. 821–824 Extramedullary blast crisis is the first mani-
810
found to be involved with progression to blast crisis. BCL-2, c-MYC, festation of accelerated phase in approximately 10 percent of patients
RUNX1, IKZF1, ASXL1, WT1, TET2, IDH1, NRAS, KRAS, CBL, and var- with CML. Lymph nodes, 822–824 serosal surfaces, 825,826 skin and soft
ious other genes have also been implicated in the evolution of CML. 811–815 tissue, 821–824 breast, 824,827 gastrointestinal or genitourinary tract, 822,824
Approximately 50 genes have been identified that could play a role bone, 822,824,824–831 and central nervous system 822,832–836 are among the prin-
in the progression to accelerated phase or blast crisis, including genes cipal areas involved. Isolated or diffuse lymphadenopathy may occur.
775
identified by expression profiling that are dysregulated in accelerated Bone involvement may lead to severe pain, tenderness, and pathologic
phase compared to chronic phase. 816,817 These include the WNT-β- fracture, and may be evident on imaging of the involved area. Central
catenin and JunB pathways. nervous system involvement usually is meningeal and may be preceded
by headache, vomiting, stupor, cranial nerve palsies, and papilledema
CLINICAL FEATURES and is associated with an increase in cells, protein, and the presence of
blasts in the spinal fluid.
824,832–834
Signs and Symptoms Appropriate histochemical and immunologic tests are required
The features that might signal the conversion of the chronic to the accel- to determine if the extramedullary disease is composed of phenotypic
erated phase include unexplained fever, bone pain, weakness, night myeloblasts or lymphoblasts. Because the tumor cells may have features
sweats, weight loss, loss of sense of well-being, arthralgia, and left upper of lymphoma cells, the terms myeloid or granulocytic sarcoma, chloroma,
quadrant pain related to splenic enlargement or infarcts. These features and myeloblastoma can be misnomers, and the term extramedullary
may occur weeks in advance of laboratory evidence of the accelerated blast crisis is used for this circumstance in CML. 833,835–837 The lympho-
phase. Localized or diffuse lymphadenopathy or enlarging masses blasts, like the myeloblasts, are Ph chromosome–positive. A combi-
in extralymphatic and extramedullary sites containing BCR-ABL1– nation of morphology, histochemistry (e.g., peroxidase, lysozyme),
positive myeloblasts or lymphoblasts may develop. A poor response terminal deoxynucleotidyl transferase assay, and monoclonal antibod-
of blood cell counts and splenic enlargement despite previously effec- ies specific for lymphoid or myeloid cells can be used to classify the
tive therapy may be evident. 767,782,818–820 Symptoms caused by histamine extramedullary blast cells.
excess in basophilic crisis can be present. 821
Several of these changes may occur in series or in parallel. The time
of onset of transformation and the appearance of a blast crisis and its MARROW BLAST CRISIS
clinical expression are unpredictable. Approximately half of patients with CML enter the accelerated phase
by developing acute leukemia. The onset of blast crisis can develop
LABORATORY FEATURES from days 838–840 to decades after diagnosis of CML. The signs and
symptoms may include fever, hemorrhage, bone pain, and lymphade-
Blood Findings 782,818–820 nopathy. 776,838–840 The morphology of the acute leukemia usually is mye-
Anemia may worsen and be associated with increasing poikilocytosis, loblastic or myelomonocytic. 776,841 A substantial proportion of myeloid
anisocytosis, and anisochromia. The number of nucleated red cells in leukemia in this setting may not have myeloperoxidase demonstrable
842
the blood may increase. These red cell changes may be accentuated fur- by cytochemistry. The proportion of cases classified as erythroblastic
843
ther if advancing marrow fibrosis is a feature of the disease. leukemia is approximately 10 percent, based on morphologic features,
The total leukocyte count may fall without treatment. The propor- but may be as high as 20 percent if expression of glycophorin-A is used
tion of blasts increases to greater than 10 percent in blood and marrow as the determinant. Occasional cases have megakaryoblastic transfor-
844
in the accelerated phase and when blast crisis ensues represents 20 to mation. 803,845 These cases may be difficult to identify by light micros-
90 percent of the cells. The morphology of the blast cells may be lym- copy because the megakaryoblasts may be mistaken for lymphoid cells
phoid or myeloid. Myelocytes decrease in number. Hyposegmented or undifferentiated blasts. Myelofibrosis is a feature of this variant.
neutrophils (Pelger-Huët cells) and other dysmorphic changes may Antiplatelet glycoprotein antibodies and other monoclonal antiplatelet
become evident. Basophils increase and often represent 20 to 80 percent antibodies now are available as reagents to identify megakaryoblasts
of the total blood leukocytes. A decrease of the platelet count to less without the need for ultrastructural studies. Promyelocytic 846–848
845
849
9
than 100 × 10 /L develops. Giant platelets, micromegakaryocytes, and and eosinophilic blast crises also can occur. Basophilic leukemia is a
850
megakaryocyte fragments may enter the blood. Decreased progenitor known variant of CML. Patients with promyelocytic crisis often have
cell growth in culture is present, akin to that in acute leukemia. t(15;17) in addition to the Ph chromosome, and some have presented
with disseminated intravascular coagulation. 851
Marrow Findings 782,818–820 CML may transform into acute lymphoblastic leukemia in approx-
The marrow findings are widely variable. Marked dysmorphic changes imately 30 percent of blastic crisis cases. 767,852–856 The lymphoid cells
in one, two, or three of the major cell lineages; an increase in blast count generally express terminal deoxynucleotidyl transferase (TdT) 852,853 and
to greater than 10 percent; marrow morphology simulating subacute are of the B-cell lineage, 856–878 as judged by antiimmunoglobulin stain-
myelomonocytic leukemia; or, in the extreme, florid blastic transfor- ing. TdT is a DNA polymerase that adds deoxynucleoside monophos-
mation with blast counts greater than 30 percent can occur. Reticulin phates from triphosphate substrates to single-stranded DNA by end
859
fibers may increase in prominence, and occasionally severe reticulin addition, differing in the latter respect from replicative polymerases.

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