Philadelphia Chromosomenegative

In 5 to 10 percent of patients with the clinical picture of CML, no Ph can be demonstrated by cytogenetic analysis.162 However, one-third of these patients have rearrangements of BCR-ABL that can be detected by molecular studies such as Southern blotting, FISH, or PCR. Patients with Ph-negative, BCR-ABL-posi-tive CML have similar characteristics, clinical course, and outcome compared with Ph-positive patients.163 The remaining two-thirds of Ph-negative cases have no detectable BCR-ABL rearrangements and comprise a spectrum of heterogeneous disorders including chronic myelomonocytic leukemia (CMML), other myelodysplastic syndromes with a myeloproliferative component, and "atypical" CML.164 Guidelines to distinguish CML, atypical CML, and CMML on the basis of morphological characteristics have been proposed.165 It should be emphasized, however, that some of the Ph-negative patients may carry variants of the BCR-ABL mRNA transcript that may evade detection by using molecular probes for rearrangements of the M-BCR or m-BCR region only.166 Hochhaus and colleagues167 used multiplex RT-PCR and demonstrated the presence of an e6a2 BCR-ABL transcript when analyzing the sequence of the fusion region of the amplified cDNA fragment. This finding could be confirmed by Southern blotting when using a specific probe for intron 6 of the BCR gene, whereas Southern blotting with conventional probes for M-BCR were negative.

Compared with BCR-ABL-negative CML and CMML, patients with Ph-negative and BCR-ABL-positive CML and Ph-positive CML are younger, have a higher white blood cell count at presentation, a higher incidence of thrombocytosis and peripheral blood and bone marrow basophilia, and a lower incidence of anemia, thrombocytopenia, bone marrow blast percentage, and peripheral blood and bone marrow monocyto-sis.162,168 Patients with BCR-ABL-negative CML respond poorly to therapy and have significantly worse survival rates, with a prognosis that is intermediate between Ph-positive CML and CMML. Only 25 to 50 percent of these patients transform into blastic phase. Most develop an increasing leukemic cell burden, organomegaly, and extramedullary infiltrates, culminating into bone marrow failure and eventually death of the patient.162,163

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