| Session: Chronic myelogenous leukemia |
| Case number: 052 |
Submitter(s): Cordelia E. Sever, James Liebmann, Mohammed Vasef.
Clinical history
The patient is a 72 year old man who presented 7/2004 with aWBC 18.5, Hgb/Hct 11.7/37, plt 389,000 with a left shift to promyelocyte, 3% basophils. He had no prior history of malignancy, significant medical conditions or prescribed medications. Bone marrow examination was diagnostic of chronic myelogenous leukemia, stable phase, t(9;17;22) positive. He responded to 400 mg daily imatinib therapy, normalizing WBC and decreasing BCR/ABL transcript ratios. His WBC was rising again in 1/2005 and was refractory to dose increase of imatinib to 600mg. In 7/2006 he was switched to dasatinib therapy but his WBC continued to rise to 80,400 in 1/ 2007 with left shift, 2% blasts, 5% basophils, Hgb/Hct 10.7/31, plt 367,000. BCR/ABL transcripts were undetectable. Repeat bone marrow examination demonstrated morphologic features most suggestive of chronic idipathic myelofibrosis, prompting JAK2V617F mutation analysis which was positive for the mutated phenotype.
Details of gross/microscopic pathology:
BM biopsy in7/2004 (acetic acid zinc formalin fixed) showed 80% cellularity, an M:E ratio of 5:1 and full maturation on aspirate smears. Megakaryocytes were mostly small and hypolobulated, focal atypical large forms were present. Repeat biopsy in 1/2007 demonstrated a 90% cellular marrow with clusters of markedly dyspoietic, large megakaryocytes, preserved myelopoiesis and erythropoiesis, dilated sinusoids containing hematopoietic islands, and moderate reticulin fibrosis.
Immunophenotype (flow cytometry/immunohistochemistry):
Cytogenetics:
BM Karyotype 7/2004:
46,XY,t(9;17;22)(q34;p12pq11.2)[6]/46,XY[4]
BM Karyotype 1/2007:
46,XY[20].
Molecular analysis:
P. Blood 3/2006: RT-PCR positive for t(9;22)-associated BCR-ABL fusion mRNA, b3a2 fusion transcript, weak intensity
P. Blood 5/2006: RT-quantitative PCR positive for BCR-ABL transcript at the limit of the detection sensitivity with BCR-ABL/ABL ratio of 0.000064.
P. Blood 1/2007: RT-quantitative PCR negative for BCR-ABL transcript; alleleic discrimination real time PCR assay positive for JAK2V617F mutation
BM clot, AZF fixed, paraffin embedded 7/2004: insufficient DNA for retrospective JAK2V617F mutation analysis.
Interesting feature(s) of submitted case:
The case demonstrates a patient with Ph+ CML who attained molecular remission on imatinib/desatinib therapy but developed JAK2 mutation positive myelofibrosis. This provides further evidence that patients with myeloproliferative disorders harbor hematopoietic stem cell abnormalities preceding the disease defining translocations or mutations. Therefore, patients who attain molecular remissions on bcr/abl inhibitor treatment require continued monitoring and complete bone marrow re-evaluation when there are unexplained changes in peripheral blood counts.
Proposed diagnosis:
Chronic myelogenous leukemia, Ph+, followed by chronic idiopathic myelofibrosis, JAK2V617F+.
Panel diagnosis:
Features of both CML and CIMF/PMF were present in the initial diagnostic specimen
Comments:
PowerPoint:
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