MDS with Isolated Trisomy 8. a Type of MDS Frequently Associated with Myeloproliferative Features? A Report from the GFM

Introduction

Isolated trisomy 8 is a frequent cytogenetic abnormality in MDS, but hematological characteristics of MDS with isolated trisomy 8 have not been reported in detail.

Patients and Methods

This was a retrospective analysis of cases of MDS with isolated trisomy 8 diagnosed in 6 French centers of the Groupe Francophone des Myélodysplasies (GFM) between 2003 and 2013. Only patients with isolated trisomy 8 diagnosed as MDS or MPN/MDS (other than CMML) according to WHO were eligible, excluding AML, well characterized MPN (PV, ET) and CMML. Myeloproliferative (MP) features were defined by repeated presence (in the absence of infection) of one of the following: WBC > 10G/L, circulating immature granulocytes (myelemia ) > 2%, or palpable splenomegaly.

Results

103 patients with isolated trisomy 8 were identified, with a median age of 75 years, and M/F 1.7. At diagnosis, median WBC count was 4.1 G/L, with WBC ≥ 10 G/L in 13 patients (12.6 %), myelemia ≥ 2% in 27 patients (26.2 %), palpable splenomegaly in 9 patients (8.7 %). WHO diagnosis included 20 RA, 2 RARS, 22 RCMD, 1 RCMD-RS, 1 RCUD, 21 RAEB-1, 18 RAEB-2, 7 MDS-U, 10 MDS/MPN, 1 hypoplastic MDS. IPSS was intermediate 1 (72.2 %), intermediate 2 (19.6 %), high (8.2 %) ; IPSS-R was low (37.1 %), intermediate (29.9 %), high (22.7 %), very high (10.6 %).

MP features were found in 50 patients (48.5 %): 31 at diagnosis, 19 during evolution (in patients without MP features at diagnosis).

Bone marrow morphological features could be reviewed in 15 MP cases, showing hypercellular marrow in 60 % cases, granulocytic hyperplasia (E/G<0.25) in 53%, marked neutrophil hypogranularity in 87% and abnormal chromatin clumping in neutrophils in 53 %. Somatic mutations were studied in 31 patients on diagnostic samples (16 MP and 15 non MP) for 27 most frequently mutated genes in MDS and MPN: ASXL1, CBL, DNMT3A, ETV6, EZH2, IDH1, IDH2, JAK2, cKIT, KRAS, NRAS, MPL, PHF6, PTPN11, RIT, RUNX1, SETBP1, SF3B1, SRSF2, TET2, TP53, U2AF1, WT1, ZRSR2, FLT3-TKD, FLT3-ITD, NPM1 (FLT3-TKD, FLT3-ITD and NPM1 were studied in only 15 patients).

Mutations were seen, for MP cases, in ASXL1 (64%), EZH2 (50%), TET2 (40%), RUNX1 (33%), SRSF2 (27%), DNMT3A (15%), JAK2 (14%), IDH2 (14%), NRAS (8%), SF3B1 (9%), U2AF1 (8%); for non MP cases in ASXL1 (33%), SRSF2 (27%), SF3B1 (27%), TET2 (20%), DNMT3A (13%), JAK2 (13%), RUNX1 (13%), EZH2 (7%), IDH2 (7%), ZRSR2 (7%), NRAS (0%). In spite of a trend for more mutations of ASXL1 (p=0.128), and EZH2 (p=0.053) in MP forms, the difference with non MP forms was not significant, possibly due to small patient numbers.

40 patients received an HMA (AZA in 36, DAC in 4) and 27.3% responded (4 CR, 1 PR, 1 marrow CR, 3 HI), including 11.7% of MP cases and 43.8% of non MP cases (p=0.057). 5 patients received intensive chemotherapy (with 2 CR). 42 (40.8%) received an ESA, with 60% responses, including 50% in MP and 73% in non MP patients (p= NS).10 (9.7%) received hydroxyurea.

With a median follow up of 30 months, progression to AML was seen in 26% and 18.9% in MP and non MP patients, respectively (p= NS). Median survival was 35 months in the whole cohort, without difference between patients who, at diagnosis had MP features and no MP features (35 months for both).

Conclusion

Myeloproliferative (MP) features were found at diagnosis or during evolution in our experience in about 50% of MDS with isolated trisomy 8, a finding not previously reported, to our knowledge, and suggesting that some of those patients may have to be reclassified among MDS/MPN. The subset of patients with MP features tended to have a higher frequency of ASXL1 and EZH2 mutations (findings that will have to be confirmed on larger patient numbers), and seemed to respond poorly to HMA, although its survival was not lower than that of non MP forms in our experience.