Page 1489 - Williams Hematology ( PDFDrive )

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

where the eventual outcome will be poor. These landmarks at 3, 6, 12, Molecular and Genetic Alterations
and 18 months are associated with poorer overall survival and cytoge- The transformation of chronic phase CML to accelerated and then blast
netic responses. Only 60 percent of patients on the IRIS trial were in crisis or directly to blast crisis is thought to be the result of seven molec-
505
CCyR on imatinib after 6 years of therapy, indicating the need for close ular processes: (1) maturation arrest, (2) failure of genome surveillance,
765
monitoring and for alternative therapies. There is also evidence that (3) failure of adequate DNA repair, (4) development of a mutator phe-
the BCR-ABL1 transcript doubling-time more reliably assesses CML notype, (5) telomere shortening, (6) loss of tumor-suppressor function,
relapse as compared to the fold rise in BCR-ABL1 transcripts. A short and (7) unknown factors. 775,776
doubling-time for a patient in chronic phase should raise suspicion of Progression of chronic phase to accelerated phase is marked by an
nonadherence. 766 increase in BCR-ABL1 expression. 777,778 Superimposed on the increased
transcription of mRNA BCR-ABL1 are additional cytogenetic abnormali-
ACCELERATED PHASE AND BLAST ties that are added to the persistent Ph chromosome in approximately
In lymphoid blast crisis, in which the
50 to 65 percent of patients.
779–781
CRISIS OF CHRONIC MYELOGENOUS blast cells have a lymphocytic phenotype, acquisition of mutations in
LEUKEMIA tumor suppressor genes, such as p16/ARF, occurs in approximately
50 percent of cases, and RB gene mutations occurs in approximately
DEFINITION 20 percent of cases. In myeloid blast crisis, in which blast cells have a
In all patients with chronic phase CML, the disease has the potential myeloid phenotype, approximately 25 percent of cases have cells con-
taining a p53 mutation. The possible role of loss of p53 function in
782
to evolve into a more aggressive, more symptomatic, and troublesome fostering transformation of a human chronic phase CML clone has
phase, which is poorly responsive to the therapy that formerly con- been demonstrated in transgenic mice in which p53 function was
trolled the chronic phase. The failure of therapy to restore or main- abrogated. 783,784 Progression of the clone to a more malignant clone is
tain near-normal red cell and white cell counts, increased spleen size, reflected in a more disordered growth and maturation pattern of pro-
increased numbers of marrow blasts and blood basophils, loss of the genitor cells in culture, ultimately mimicking the growth failure of
sense of well-being, and appearance of extramedullary tumors are acute leukemia, and in increased morphologic and functional abnor-
779
the most consistent clinical hallmarks of the metamorphosis of the malities of blood cells, 785,786 eventuating in a block in maturation and
chronic to the accelerated phase of CML. The most objective findings replacement of blood and marrow by blast cells.
are a blood blast percentage greater than 10, a platelet count less than Approximately 65 percent of patients have cytogenetic abnormal-
100 × 10 /L, blood basophils greater than 20 percent, and new clonal ities in addition to the Ph chromosome. A double Ph chromosome,
9
cytogenetic abnormalities accompanying the Ph chromosome. 767 trisomy 8, and isochromosome 17p are the secondary changes most
Several criteria have been published to define accelerated phase commonly seen. 782,787 Because the frequency of trisomy 8 was greater
and blast crisis. 768–770 The terminology used has included accelerated after treatment with busulfan compared to hydroxyurea, the frequency
phase, acute phase, acute transformation, or, in its most dramatic expres- of secondary chromosomal changes may be quite different after imatinib
sion, blast crisis, but the metamorphosis, which can be acute, often is therapy. Clonal instability has also been found in cases of lymphoid
782
more gradual, hence the preference for transformation or accelerated blast crisis. Clones distinct from those identified later may be detected
phase to describe this transition from a controllable to a poorly con- before overt lymphoid transformation. Identification of these abortive
trolled malignancy. Blast phase is the most severe manifestation of the clones suggests clonal instability before the onset of transformation,
accelerated phase and can occur abruptly or after a period of worsening which might have prognostic value. FISH has been used to determine
788
disease. Blast crisis is in effect the evolution to overt acute leukemia, which cells have secondary cytogenetic abnormalities, and these cells
either myeloid or lymphoid. often are not the blast cells. This finding suggests that some chromoso-
mal abnormalities merely denote genomic instability. The abnormal
789
PATHOGENESIS mRNA and protein product p210 BCR-ABL1 are present in the marrow and
Effect of Tyrosine Kinase Inhibitors in Rate of Progression blood cells of patients who have transformed to acute leukemia. 790–792
The advent of TKI therapy for CML has resulted in a marked increase in Although the breakpoint site on M-bcr was thought to be correlated
793
the duration of a subclinical chronic phase, with normal blood counts with the time of the onset of the accelerated phase, subsequent studies
and spleen size, often with the loss of identifiable Ph chromosome- have not indicated a correlation between length of chronic phase and
794
bearing cells in blood and marrow, and sometimes with the loss of lab- the specific site of the BCR-ABL1 fusion. Rare cases have displayed
oratory evidence of the BCR-ABL1 oncogene as judged by PCR. This deletion of the BCR-ABL1 fusion gene, loss of transcription of the mes-
therapeutic advance has greatly delayed the evolution to accelerated sage, and loss of expression of the p210 tyrosine kinase after transfor-
phase and blast crisis, but the risk for such a conversion exists since mation, the latter finding indicating the abnormal protein kinase may
795
under experimental conditions CML stem cells do not undergo apop- not always play a unique role in sustaining the acute state. In con-
tosis when exposed to BCR-ABL1 TKIs and BCR-ABL1–positive cells trast, the frequent response, albeit temporary, to imatinib suggests that
return in virtually all patients if tyrosine kinase therapy is interrupted. the mutant BCR-ABL1 product usually plays a role at this stage of the
There is evidence that genomic instability may derive from an ima- disease.
tinib-refractory CML stem cell. 771 Numerous molecular changes identified in the cells of patients with
acute transformation that might contribute to the increased malignant
Blast Crisis Stem Cells behavior of the CML clone, include activation of the N-RAS gene, 796,797
The onset of accelerated phase is thought to occur in a BCR-ABL1– rearrangement of the p53 gene, 797–800 hypermethylation of the calcitonin
802
bearing granulocyte-monocyte progenitor. Experimental 772,773 and the- gene, and methylation of the ABL1 gene. One report described p53
801
774
oretical evidence supports this concept. This progenitor for clonal mutations in 17 percent of blast crisis patients. An association between
evolution also could explain the reversion to chronic phase in some the failure of CML cells to express the RB1 gene product and acute
802
patients in whom the suppression of the advanced phase of the disease blast crisis with a megakaryoblastic phenotype has been reported.
is achieved. Homozygous deletions of the p16 gene are associated with lymphoid

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