Karyotypic findings as an independent prognostic marker in chronic myeloid leukaemia blast crisis

Nanjangud, Gouri J.; Kadam, P; Saikia, Tapan; Bhisey, A.N.; Kumar, Ashok; Ramakrishnan, G.; Chopra, Harpreet; Nair, Chandrika N.; Advani, Suresh H.

doi:10.1016/0145-2126(94)90023-x

Cited by 25 publications

(16 citation statements)

References 21 publications

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“…However, such an association has not been confirmed by later studies [53, 57]. Swolin et al [162]described a higher incidence of trisomy 8 in busulfan (Bu)-treated CML than in patients receiving hydroxyurea (Hy), and Nanjangud et al [163]found a generally higher frequency of secondary changes in patients treated with Bu. That +8 is more common after Bu therapy seems to hold true; this anomaly is found in 44% after treatment with Bu, but only in 12% after Hy therapy (table 3).…”

Section: The Impact Of Previous Treatment On the Cytogenetic Evolutiomentioning

confidence: 72%

Cytogenetic and Molecular Genetic Evolution of Chronic Myeloid Leukemia

2002

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Chronic myeloid leukemia (CML) is genetically characterized by the presence of the reciprocal translocation t(9;22)(q34;q11), resulting in a BCR/ABL gene fusion on the derivative chromosome 22 called the Philadelphia (Ph) chromosome. In 2–10% of the cases, this chimeric gene is generated by variant rearrangements, involving 9q34, 22q11, and one or several other genomic regions. All chromosomes have been described as participating in these variants, but there is a marked breakpoint clustering to chromosome bands 1p36, 3p21, 5q13, 6p21, 9q22, 11q13, 12p13, 17p13, 17q21, 17q25, 19q13, 21q22, 22q12, and 22q13. Despite their genetically complex nature, available data indicate that variant rearrangements do not confer any specific phenotypic or prognostic impact as compared to CML with a standard Ph chromosome. In most instances, the t(9;22), or a variant thereof, is the sole chromosomal anomaly during the chronic phase (CP) of the disease, whereas additional genetic changes are demonstrable in 60–80% of cases in blast crisis (BC). The secondary chromosomal aberrations are clearly nonrandom, with the most common chromosomal abnormalities being +8 (34% of cases with additional changes), +Ph (30%), i(17q) (20%), +19 (13%), –Y (8% of males), +21 (7%), +17 (5%), and monosomy 7 (5%). We suggest that all these aberrations, occurring in >5% of CML with secondary changes, should be denoted major route abnormalities. Chromosome segments often involved in structural rearrangements include 1q, 3q21, 3q26, 7p, 9p, 11q23, 12p13, 13q11–14, 17p11, 17q10, 21q22, and 22q10. No clear-cut differences as regards type and prevalence of additional aberrations seem to exist between CML with standard t(9;22) and CML with variants, except for slightly lower frequencies of the most common changes in the latter group. The temporal order of the secondary changes varies, but the preferred pathway appears to start with i(17q), followed by +8 and +Ph, and then +19. Molecular genetic abnormalities preceding, or occurring during, BC include overexpression of the BCR/ABL transcript, upregulation of the EVI1 gene, increased telomerase activity, and mutations of the tumor suppressor genes RB1, TP53, and CDKN2A. The cytogenetic evolution patterns vary significantly in relation to treatment given during CP. For example, +8 is more common after busulfan than hydroxyurea therapy, and the secondary changes seen after interferon-alpha treatment or bone marrow transplantation are often unusual, seemingly random, and occasionally transient. Apart from the strong phenotypic impact of addition of acute myeloid leukemia/myelodysplasia-associated translocations and inversions, such as inv(3)(q21q26), t(3;21)(q26;q22), and t(15;17)(q22;q12–21), in CML BC, only a few significant differences between myeloid and lymphoid BC are discerned, with i(17q) and TP53 mutations being more common in myeloid BC and monosomy 7, hypodiploidy, and CDKN2A deletions being more frequent in lymphoid BC. The prognostic significance of the secondary genetic changes is not uniform, althoug...

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Section: The Impact Of Previous Treatment On the Cytogenetic Evolutiomentioning

confidence: 72%

Cytogenetic and Molecular Genetic Evolution of Chronic Myeloid Leukemia

2002

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“…Trisomies of chromosomes 4, 10, 17, and 18 have been associated with a particularly good outcome in Phnegative ALL. [47][48][49] Although trisomy of chromosome 4 was frequent (80% of HH Ph þ patients), trisomy of chromosome 10, 17, or 18 was infrequent in the HH Ph þ patients (25-30% of HH Ph þ patients). The impact of the particular chromosomes present as trisomies on the better outcome of HH Ph þ ALL patients has not been investigated.…”

Section: Discussionmentioning

confidence: 99%

Secondary cytogenetic aberrations in childhood Philadelphia chromosome positive acute lymphoblastic leukemia are nonrandom and may be associated with outcome

Heerema

Harbott²,

Galimberti

et al. 2004

Leukemia

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Additional chromosomal aberrations occur frequently in Philadelphia chromosome positive (Ph þ ) acute lymphoblastic leukemia (ALL) of childhood. The treatment outcome of these patients is heterogeneous. This study assessed whether such clinical heterogeneity could be partially explained by the presence and characteristics of additional chromosomal abnormalities. Cytogenetic descriptions were available for 249 of 326 children with Ph þ ALL, diagnosed and treated by 10 different study groups/large single institutions from 1986 to 1996. Secondary aberrations were present in 61% of the cases. Chromosomes 9, 22, 7, 14, and 8 were most frequently abnormal. Most (93%) karyotypes were unbalanced. Three main cytogenetic subgroups were identified: no secondary aberrations, gain of a second Ph and/or 450 chromosomes, or loss of chromosome 7, 7p, and/or 9p, while other secondary aberrations were grouped as combinations of gain and loss or others. Of the three main cytogenetic subgroups, the loss group had the worst event-free survival (P ¼ 0.124) and disease-free survival (P ¼ 0.013). However, statistical significance was not maintained when adjusted for other prognostic factors and treatment. Karyotypic analysis is valuable in subsets of patients identified by molecular screening, to assess the role of additional chromosomal abnormalities and their correlation with clinical heterogeneity, with possible therapeutic implications.

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“…7,8 The major advantage of chromosome analysis compared to FISH and RT-PCR is the possibility of detecting chromosome aberrations in addition to the Philadelphia translocation that may have prognostic impact. 9,10 On the other hand, chromosome banding analysis is cumbersome, time-consuming, labor-intensive and dependent on high numbers of viable, dividing cells. For FISH and RT-PCR less cells are needed and also cryptic BCR-ABL rearrangements that are missed by banding studies can be detected.…”

Section: Introductionmentioning

confidence: 99%