Characterization of MDS and CMML Patients Harboring Trisomy 8 Abnormality: Clinical, Autoimmune, and Mutational Features

Introduction

Trisomy 8, seen in 5-7% of MDS and CMML patients, is regarded as an intermediate-risk cytogenetic abnormality in IPSS-R but not an MDS-defining cytogenetic abnormality. Recent studies have demonstrated an association between systemic autoimmune disease and trisomy 8, attributed to CD8 positive T-cell expansion and WT1 over-expression resulting in inflammation and suppression of hematopoiesis. Further, MDS and CMML with trisomy 8 respond favorably to immunosuppressive therapy. In this study, we investigated the clinical (including autoimmune manifestations), molecular and outcome characteristics of MDS/CMML with trisomy 8 in comparison to MDS with normal karyotype.

Methods

We retrieved all patients with trisomy 8 by conventional cytogenetic studies from our cytogenetic files between 2015 and 2023 who underwent bone marrow examination and met the WHO/ICC criteria for MDS/CMML diagnosis. In some cases, FISH testing was performed for confirmation. Majority of patients underwent amplicon-based targeted next-generation sequencing with a panel of 81 genes associated with myeloid malignancies (2500X coverage; LOD: 2% VAF). Clinicopathologic features were collected from medical records. For comparison, we retrieved a control cohort of all MDS patients diagnosed within the same period with normal karyotype (MDS-NK) at our institution.

Results

From a total of 362 patients with trisomy 8 (215 treatment naïve) detected at any time point during the disease course, we identified 165 MDS/CMML patients with trisomy 8 at baseline. These included 57 (35%) with isolated trisomy 8, 21 (13%) with 1 additional and 78 (53%) with ≥2 additional cytogenetic abnormalities (meeting the criteria for complex karyotype). Recurrent additional cytogenetic abnormalities included del(13)(q11q22) (n=3) and trisomy 21, del(5q), del(11q) involving KMT2A, and loss of Y, all seen in 2 patients each. We focused our subsequent analysis on 57 treatment naïve MDS/CMML patients with isolated trisomy 8 and compared them to 162 treatment naïve MDS/CMML patients with diploid karyotype (MDS-NK) at baseline.

The median age was 74 years (range, 30-90) and 34 (60%) were men, with baseline characteristics shown in Table 1. There were no significant differences in age, gender distribution, median hemoglobin, ANC, MCV or platelet counts when comparing the two populations. Trisomy 8 MDS/CMML had a higher median baseline BM blast percentage [5% (1-18%) vs. 3% (0-17%); p=0.034] compared to MDS-NK. Distribution of IPSS-R subgroups in trisomy 8 MDS/CMML revealed a significantly lower representation of “Very Low” [0% vs. 13%; p=0.0027] and “High” [18% vs. 49%; p=0.0001], and higher representation of “Very High” [16% vs. 3%; p =0.0004] categories.

NGS data was available in 36 (63%) of treatment naïve patients with isolated trisomy 8. The most frequent mutation was seen in ASXL1 (n=20, 56%), followed by TET2 (n=12, 33%), RUNX1 (n=12, 33%), SRSF2 (n=8, 25), KRAS/NRAS (n=8, 22%), and EZH2 (n=7, 19%). Compared to MDS-NK, the following mutations were significantly enriched in trisomy 8: ASXL1, EZH2, STAG2, RUNX1, KRAS/NRAS, IDH2 and PTPN11.

Over a median follow-up time of 19 months, 28 (49%) with trisomy 8 and 19 (12%) MDS-NK patients died. MDS/CMML with trisomy 8 had a significantly lower median overall survival (OS) compared to MDS-NK [23.7% vs. not reached; p-value: <0.0001].

A total of 27 (7.6%) MDS/CMML patients with trisomy 8 (21 with trisomy 8 at baseline) were found to have a bona fide autoimmune disease, including autoimmune uveitis/scleritis (n=3), (rheumatoid and psoriatic), polyarteritis nodosa, giant cell arteritis with polymyalgia rheumatica, autoimmune sclerosing pancreatitis, immune hemolytic anemia, synovitis, and Grave’s disease.

Conclusions

MDS/CMML with trisomy 8 showed unique clinicopathologic characteristics compared to MDS-NK: higher baseline BM blasts, higher representation of “Very High” IPSS-R risk categories with characteristic mutational signatures and a variety of underlying autoimmune diseases.