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A female child (10 years) diagnosed in 1994 with typical chronic myeloid leukaemia (CML), Presented as a classic Ph-Positive CML and on follow up appeared to be clinically in remission, with further bone marrow aspirates showing a reduction in the proportion of Ph-Positive cells detected. Despite a pre-transplant sample showing only normal cells, in February 1996, after treatment with interferon, the patient underwent an allogeneic bone marrow transplant. The transplant was unsuccessful (confirmed by immunophenotyping). Cytogenetic analyses post transplant showed previously undetected, multiple unrelated chromosomally abnormal clones but no evidence of the previously detected Ph-Chromosome (confirmed by Molecular Cytogenetics). Three years post-transplant this patient remains mildly dysplastic but otherwise clinically well.
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PRE-TRANSPLANT |
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26/01/94 |
46,XX,t(9;22)(q34;q11) [30] |
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21/07/94 |
46,XX,t(9;22)(q34;q11) [16]/ |
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03/11/94 |
46,XX,t(9;22)(q34;q11) [2]/ |
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23/03/95 |
46,XX [50] |
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POST-TRANSPLANT |
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20/11/96 |
46,X,t(X;4)(q22;p16), add(1)(p1?1),
der(14)t(14;?)(q31:?),t(?;15)(?;15), -15, +mar [5]/ |
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02/05/97 |
47,XX, -4, add(6)(p11), der(8)t(4;8)(p14;p11),
add(22)(q13), +mar1, +mar2 [2]/ |
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09/10/97 |
47,XX, +mar1 [2]/ |
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16/01/98 |
46,XX,del(7)(q32) [3]/ |
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23/04/98 |
46,del(7)(q32) [1]/ |
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28/10/98 |
47,XX,-4, der(8)t(4;8)(p14;p11),add(22)(q13), +mar1,
+mar2 [5]/ |
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25/02/99 |
44-46,XX,-4 [3], der(8)t(4;8)(p14;p11) [2], add(22)(q13)
[4],+mar [2] [cp4]/ |
Seven follow up samples over two years each revealed the emergence of subsequent unrelated clones along with clonal evolution of those previously detected. These Cytogenetic results were confirmed by M-FISH using the PSI PowerGene M-FISH Imaging System and the SpectraVysion M-FISH probe kit from Vysis. The M-FISH technique also revealed certain anomalies undetected by conventional Cytogenetics including a complex rearrangement involving chromosomes 1, 14 and 15 (Fig. 2). This patient had only one Leukaemic cell population and did not undergo clinical transformation during the course of the disease. Such unrelated clones have been described in the literature to be uncommon but confer a poor prognosis. Nevertheless this patient survives 5 years post diagnosis with only mild dysplasia.
There are two possible origins for these unrelated clones:
An independent series of mutations, due to bone marrow transplantation therapy, give rise to the multiple clones with unrelated chromosome abnormalities which have no clinical significance.
The unrelated clones arise from a multistep process that originates in a chromosomally normal cell, and the unrelated changes may have been derived from the common leukaemia clone without chromosomal changes. The chromosomal abnormalities found are therefore secondary genetic changes in leukaemogenesis and will lead to relapse to a secondary leukaemia. (Musilova et al,1996).
There are two possible conclusions for the prognostic outcome of this patient:
The abnormalities found represent secondary genetic changes that are part of a multifactorial leukaemogenesis which will, sooner or later, manifest as a secondary leukaemia.
The abnormalities found originate in a stem cell damaged during the treatment. This will eventually become eradicated.