“Double‐hit” chronic lymphocytic leukemia: An aggressive subgroup with 17p deletion and 8q24 gain

Abstract

Chronic lymphocytic leukemia (CLL) with 17p deletion (17p-) is associated with a lack of response to standard treatment and thus the worst possible clinical outcome. Various chromosomal abnormalities (including unbalanced translocations, deletions, ring chromosomes and isochromosomes) result in the loss of 17p and one copy of the TP53 gene. The objective of the present study was to determine whether the type of chromosomal abnormality leading to 17p- and the additional aberrations influenced the prognosis in a series of 195 patients with 17p-CLL. Loss of 17p resulted primarily from an unbalanced translocation (70%) with several chromosome partners (the most frequent being chromosome 18q), followed by deletion 17p (23%), monosomy 17 (8%), isochromosome 17q [i(17q)] (5%) and a ring chromosome 17 (2%). In a univariate analysis, monosomy 17, a highly complex karyotype (≥5 abnormalities), and 8q24 gain were associated with poor treatment-free survival, and i(17q) (P = .04), unbalanced translocations (P = .03) and 8q24 gain (P = .001) were significantly associated with poor overall survival. In a multivariate analysis, 8q24 gain remained a significant predictor of poor overall survival. We conclude that 17p deletion and 8q24 gain have a synergistic impact on outcome, and so patients with this "double-hit" CLL have a particularly poor prognosis. Systematic, targeting screening for 8q24 gain should therefore be considered in cases of 17p- CLL.

The complex karyotype and chronic lymphocytic leukemia: prognostic value and diagnostic recommendations

“…This was also true for the IGHV status: CK was associated with a significantly shorter TTFT even when the patient carried a mutated IGHV (40 out of 447 [8.9%], P = .009) 36 . Lastly, the combination of a CK and TP53 abnormalities (del17p and/or TP53 mutations) appears to be associated with the shortest OS time and/or TTFT 47,48 …”

“…As we have seen above, a CK can modify the good prognosis associated with a single del13q detected by FISH or with mutated IGHV status, and CLL patients with a CK respond less well than patients without a CK. Lastly, it is important to karyotype the CLL B cells after in vitro stimulation with CpG oligodeoxynucleotides and interleukin 2; and the cytogeneticist must detect the specific chromosomal abnormalities within these CKs ‐ for example, 2p gain, 8q gain, or 8p deletion ‐ that might flag patients who could potentially be treated with novel drugs in the near future 25,48,72,73 …”

Linear and circular PVT1 in hematological malignancies and immune response: two faces of the same coin

“…Differently from other hematological malignancies, 8q24 rearrangements are generally rare (3.7% of amplified cases [78]) in B-cell chronic lymphocytic leukemia (CLL) and they are often acquired during the disease course [79]. Gain of 8q24 associates with poor overall survival and/or shorter time to first treatment [78,80,81] and is frequently detected in 17p-deleted CLL, where it has a negative prognostic value [82]. PVT1 has been investigated in a single CLL case with complex karyotype, t(8;13)(q24;q14) translocation and a deletion on the derivative chromosome 8 mapping downstream the MYC oncogene and encompassing the PVT1 locus [53].…”

“Double-Hit” Chronic Lymphocytic Leukemia, Involving the TP53 and MYC Genes

“…It should be noted that there were not t( MYC ) cases in our del(17p) CLL series (n=195). By analogy with double-hit HGBL, we identified double-hit CLL as an aggressive form of the disease ( Figure 1 ) ( 1 , 6 ).…”

“…In our del(17p) CLL series, MYC gain and del(17p) were in the same clone in 8 (62%) of the 13 evaluable cases, MYC was gained before the del(17p) in 3 cases (23%), and MYC was gained after the del(17p) in 2 cases (15%). It is noteworthy that 6 of the 13 (46%) cases carried the der(17)t(8;17) abnormality, with an unbalanced translocation between the short arm of chromosome 17 and the long arm of chromosome 8; this results in both MYC gain and del(17p) ( 1 ). Regarding t( MYC ) in CLL, Put et al.…”