| Session: Chronic myelogenous leukemia |
| Case number: 090 |
Submitter(s): Dan Jones, Cameron Yin.
Clinical history
70 year old woman diagnosed with chronic phase CML in 6/97, initially treated with interferon (IFN) and ara-C (+/- ATRA) with cytogenetic remission through 1/00. Patient was switched to imatinib (Gleevec, 600 mg qd) due to clonal evolution/accelerated phase (sample #1). Patient had a major cytogenetic response for several years but developed fulminant relapse after 43 months of imatinib (#2); dasatinib was started but patient rapidly developed blast transformation and was switched to nilotinib (AMN-107, #3) which was associated with hematologic response and partial cytogenetic response (#4).
After 11 months of nilotinib therapy, loss of hematologic and cytogenetic response occurred with codon T315I kinase domain (KD) mutation in all BCR-ABL transcripts (#5). Patient was started on the MK-0457 kinase inhibitor and had complete regression of the T315I clone with partial persistence of blasts and an additional cytogenetic abnormality noted (#6). Patient developed pneumonia and died in 9/06.
Details of gross/microscopic pathology:
2/05, 12/05 and 2/06 bone marrow aspirates (#4, 5 & 6) were hypercellular with left-shifted myeloid hyperplasia, dysplastic erythroid hypoplasia. Basophilia and blasts with basophilic granules with cytoplasmic vacuolation prominent in 2/05; blasts in 6/06 samples had less prominent basophlic granules.
PB (2/05, #3): WBC 41.5, Hgb 11.1, Plt 37, Blasts 39%, Basos 33%
PB (12/05, #4): WBC 6.1, Hgb 13.3, Plt 79, Eos 10%, Basos 1%
PB (2/06, #5): WBC 23.5, Hgb 9.9, Plt 14, Blasts 78%, Eos 12%
PB (6/06, #6): WBC 7.2, Hgb 10.7, Plt 11, Baso 28%, Eos 4%.
Immunophenotype (flow cytometry/immunohistochemistry):
Flow cytometry on #4, 5 & 6 demonstrated similar myeloid immunophenotype in the blast population, positive for CD9, CD13, CD33, CD34, CD38, CD117, negative for CD14, CD41, myeloperoxidase, TdT and lymphoid markers.
Cytogenetics:
(1) 42,XX,-7,t(9;22)(q34;q11),-11,-13,-19[2/14]
(2) 46,XX,t(9;22)(q34;q11.2)[20/20]
(3) 47,XX,+8,t(9;22)(q34;q11.2),i(17)(q10)[20/20]
(4) 47,XX,add(8)(p23),t(9;22)(q34;q11.2),i(17)(q10)[9/20]
(5) 47,XX,add(8)(p23),t(9;22)(q34;q11.2),i(17)(q10)[18/20]
(6) Two distinct Ph+ clones:
47,XX,del(2)(q31q37),add(7)(p22),+add(8)(p23),t(9;22)(q34;q11.2),i(17)(q10) Ph+ metaphase 47,idem,t(8;11)(q24;q13).
Molecular analysis:
See attached Figure 3.
Interesting feature(s) of submitted case:
Case documents the strong influence of therapy on the course of transformation in CML, especially following 2nd- and 3rd-generation kinase inhibitors.
Shifts in related and genetically distinct CML subclones is illustrated by the rapid development and regression of the T315I mutated clone due to effects of.targeted therapy.
The complexity of correlating morphologic progression (e.g. blasts and basophlia) with molecular events (e.g. KD point mutation, or acquisition of a particular chromosomal aberration) highlighted.
Proposed diagnosis:
Chronic myeloid leukemia in blast transformation with shifts in genetically related but distinct CML clones following sequential introduction of effective bcr-abl kinase inhibitors.
Panel diagnosis:
agree with proposed diagnosis
Comments:
Images:
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Figure 1 |
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Figure 2 |
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Figure 3 |
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