Single-Nucleotide Polymorphism Array-Based Karyotyping of Acute Promyelocytic Leukemia

<div><p>Acute promyelocytic leukemia (APL) is characterized by the t(15;17)(q22;q21), but additional chromosomal abnormalities (ACA) and other rearrangements can contribute in the development of the whole leukemic phenotype. We hypothesized that some ACA not detected by conventional techniques may be informative of the onset of APL. We performed the high-resolution SNP array (SNP-A) 6.0 (Affymetrix) in 48 patients diagnosed with APL on matched diagnosis and remission sample. Forty-six abnormalities were found as an acquired event in 23 patients (48%): 22 duplications, 23 deletions and 1 Copy-Neutral Loss of Heterozygocity (CN-LOH), being a duplication of 8(q24) (23%) and a deletion of 7(q33-qter) (6%) the most frequent copy-number abnormalities (CNA). Four patients (8%) showed CNAs adjacent to the breakpoints of the translocation. We compared our results with other APL series and found that, except for dup(8q24) and del(7q33-qter), ACA were infrequent (≤3%) but most of them recurrent (70%). Interestingly, having CNA or <i>FLT3</i> mutation were mutually exclusive events. Neither the number of CNA, nor any specific CNA was associated significantly with prognosis. This study has delineated recurrent abnormalities in addition to t(15;17) that may act as secondary events and could explain leukemogenesis in up to 40% of APL cases with no ACA by conventional cytogenetics.</p></div

IBRORS-MCL study: a Spanish retrospective and observational study of relapsed/refractory mantle-cell lymphoma treated with ibrutinib in routine clinical practice.

This retrospective study evaluated 66 patients diagnosed with relapsed and/or refractory mantle cell lymphoma (R/R MCL) treated with ibrutinib in Spain in routine clinical practice. At diagnosis, patients had a median age of 64.5 years, 63.6% presented with intermediate/high sMIPI (simplified prognostic index for advanced-stage mantle cell lymphoma), 24.5% had the blastoid variant, and 55.6% had a Ki67 > 30%. Patients had received a median of 2 prior lines of therapy (range 1-2; min-max 1-7). Overall response rate was 63.5%, with 38.1% of patients achieving complete response (CR). With a median duration of ibrutinib exposure of 10.7 months (range 5.2-19.6; min-max 0.3-36), the median progression-free survival (PFS) and overall survival (OS) were 20 months [95% confidence interval (CI) 8.8-31.1] and 32 months (95% CI 22.6-41.3), respectively, and were not reached in patients achieving CR. No grade ≥ 3 cardiovascular toxicity or bleeding was reported. This study supports that treatment with ibrutinib leads to high response rates and favorable survival outcomes in patients with R/R MCL

Comparison of type, size and number of SNP-A abnormalities in reported APL series.

<p>*one Uniparental Tetrasomy has been included both in duplication and CN-LOH group.</p><p>CNA: Copy-Number Abnormality. CN-LOH: Copy-Neutral Loss of Heterozygocity.</p

Schematic representation of CNA adjacent to the translocation breakpoints found in our series.

<p>On the left panel, the Smooth Signal of chromosome 15 and 17 from case APL_32 are represented. Results from diagnosis sample are shown in blue and from complete remission sample, in green. On the right, chromosomes 15 and 17 are depicted with G-banding and arrows pointing the location of the <i>PML</i> and <i>RARA</i> genes. Areas shaded in blue show regions duplicated and in red, deleted. Panel (A) corresponds to isochromosome der(17)t(15;17); Panel (B) shows a small duplication of the <i>PML</i> gene, and in panel (C) both the <i>PML</i> and the <i>RARA</i> genes are duplicated. These two cases had a cryptic t(15;17) by CC, that was revealed by FISH. In panel (D) two small deletions are found distally to the translocation breakpoints.</p

Detailed list of abnormalities found in our series (n = 48).

<p>Detailed list of abnormalities found in our series (n = 48).</p

Karyogram of APL according to SNP-A analysis in our series.

<p>Coloured bars depict the extension of abnormalities. Gains appear in blue at the right of each chromosome; losses in red and CN-LOH in green, at the left side of it.</p

Heatmap and pie chart depicting abnormalities found in our series in addition to the t(15;17).

<p>Each column represents one patient. Abnormalities are listed in the Y axis and coloured in the corresponding row of the heatmap. Abnormalities detected by Conventional Cytogenetics (CC) (red) and <i>FLT3</i> mutations (green) are frequent events; however, SNP-A revealed an important proportion of patients with potentially leukemogeneic abnormalities (blue). Dup: duplication: del: deletion; CNA: copy-number abnormality.</p

Main characteristics of our series.

<p>*PML-RARA was diagnosed by FISH or RT-PCR.</p