Cytogenetic Predictors of Response to Lenalidomide In Myeloid Malignancies without Del(5q)
Authors: Sugimoto Yuka , Sekeres Mikkael A. , Makishima Hideki , O'Keefe Christine L. , Guinta Kathryn , Afable Manuel , McGraw Kathy Rocha , List Alan F. , Maciejewski Jaroslaw 
Published: October 2019

Abstract
Abstract 4016
Lenalidomide (LEN) is effective in patients with myelodysplastic syndromes (MDS) and the del(5q) cytogenetic abnormality, and has activity in a proportion of patients without this chromosomal defect. To date, no clinically actionable biomarkers, other than the presence of del(5q) detected by metaphase cytogenetics, have been identified to predict response to LEN. The diagnostic yield of metaphase cytogenetics can be enhanced by application of fluorescence in situ hybridization (FISH) for targeted chromosomal lesions including del(5q), as this technique is more sensitive. Similarly, single nucleotide polymorphism array (SNP-A)-based karyotyping, due to its superb resolution, allows for detection of previously cryptic unbalanced chromosomal defects. Both techniques can be preformed on interphase cells and thereby do not require cell division. We hypothesized that application of these technologies may allow for better identification of putative responders to LEN in patients with MDS without del(5q); we stipulated that i) we may detect previously unrecognized cases of del(5q) and that ii) more precise analysis of the karyotypes may allow for recognition of other chromosomal markers of response or refractoriness to LEN. In patients with MDS (N=82), MDS/myeloproliferative neoplasm (MPN) (N=13), acute myeloid leukemia (AML) (N=23), and MPN (N=4), the detection rate of del(5q) increased only marginally with use of additional techniques, from 24% (metaphase cytogenetics (MC) + FISH), to 25% (MC + SNP-A), 25% (FISH + SNP-A) and 26% (all 3 methods). Within this cohort, we then analyzed by FISH and SNP-A karyotype a subset of 42 patients with myeloid malignancies without del(5q) by MC who received LEN. This cohort included 33 MDS (RA, N=5; RARS, N=12; RARS-T, N=1; RCMD, N=1; RAEB1, N=4; RAEB2, N=6; MDS-U, N=4), 6 MDS/MPN and MPN patients (CMML1, N=1; CMML2, N=3, IMF; N=2) and 3 secondary AML. By MC, 32 (76%) showed normal karyotype, 1 (2.4%) no growth and 9 (21%) abnormal karyotype other than del(5q). The overall response rate (ORR) (2006 International Working Group criteria) was 44%, including 3 CR, 3 PR and 8 HI. Previously cryptic del(5q) was detected in an additional 1/18 patient by both SNP-A and FISH (secondary AML with normal metaphase cytogenetics), but this case was refractory to LEN. Del(5q) was also revealed by FISH in 1 patient with unsuccessful MC, but, due to the small size of the clone (8%), SNP-A did not detect this lesion. This patient had a sustained PR with transfusion independence. In 28 patients who received LEN for more than 3 months, the ORR to LEN in patients with normal metaphase cytogenetics was 62%, and 17% for those with chromosomal aberrations (p=.08); the addition of SNP-A did not improve the predictive value of normal cytogenetics. We also analyzed 10 patients without del(5q) by MC who received combination therapy with azacitidine (AZA) and LEN, for whom the ORR was 80% (7 CR, 1 PR). By metaphase cytogenetics, 7/10 patients had a normal karyogram and a response of 86%, compared to 3 patients with chromosomal lesions, 1 of whom responded. Similar to the results in LEN alone, inclusion of defects detected by SNP-A or FISH did not allow for better separation of responders based on normal cytogenetics by MC. Six out of 38 LEN-treated patients had a gain of chromosome 8 material by FISH or SNP-A. 4 out of 6 patients had CR (all of them received combination therapy of AZA and LEN), 1 out of 6 had HI, and 1 with complex karyotype had NR (ORR was 83%), while ORR in patients with other chromosomal abnormalities by FISH or SNP-A was 18%. In conclusion, FISH and SNP-A, when added to routine metaphase cytogenetics, marginally increased the diagnostic yield leading to detection of only 2/42 additional cases with del(5q). In our cohort, the non-del(5q) patients with normal karyotype and those with trisomy 8 or microduplication on chromosome 8 were associated with a favorable response to LEN.

Disclosures:
Sekeres: Celgene: Consultancy, Honoraria, Research Funding. List:Celgene: Research Funding. Maciejewski:Celgene: Research Funding.