Page 181 - Haematologica May 2022

Letters to the Editor
SF3B1-mutant myelodysplastic syndrome/myelopro- liferative neoplasms: a unique molecular and prog- nostic entity
Molecular abnormalities are prognostically relevant in morphological subtypes of myelodysplastic/myeloprolif- erative neoplasms (MDS/MPN), giving rise to contempo- rary molecularly integrated prognostic models.1-3 Established adverse prognostic associations include trun- cating ASXL1 mutations in chronic myelomonocytic leukemia (CMML)1 and MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T),3 TP53 and CBL mutations in unclassifiable MDS/MPN (MDS/MPN-U),4 and TET2 mutations in BCR-ABL1-negative atypical chronic myeloid leukemia.2 Recently, molecular signa- tures have been used to further stratify MDS/MPN-U patients into CMML-like (ASXL1, SRSF2, RUNX1, and/or NRAS mutant), MDS/MPN-RS-T-like (JAK2 and/or SF3B1 mutant), atypical chronic myeloid leukemia-like (SETBP1 and/or ASXL1 mutant), TP53 mutant and an “others” category.5,6 Despite their prognostic impact, these mutations are not specific for underlying disease entities. Recently, SF3B1 mutations were shown to be disease-defining in a subset of patients with MDS7,8 and CMML.9 Whether SF3B1 mutations are similarly disease- defining in other myeloid subgroups is not known. Given the relative rarity of MDS/MPN patients, we assembled a large, molecularly annotated cohort of MDS/MPN patients to assess the clinical and prognostic impact of SF3B1 mutations, agnostic of disease morphology.
After Mayo Clinic institutional review board approval, clinical data from adult (age at diagnosis >18 years) patients with a World Health Organization (WHO)- defined diagnosis of MDS/MPN (CMML, MDS/MPN-U and MDS/MPN-RS-T), from 1994 to 2020, were included in the analysis. Patients with atypical chronic myeloid leukemia were excluded due to lack of uniform genetic annotation, limited SF3B1 mutations (n=2), and patient numbers (n<50). A separate cohort of SF3B1-mutant MDS patients diagnosed between 1994 to 2017 was included for comparison. An external cohort of patients from H. Lee Moffitt Cancer Center (Tampa, FL, USA) was used for independent validation after institutional review board approval. Next-generation sequencing for myeloid relevant genes was done at diagnosis or first referral, using institutional or commercially available myeloid malignancy-specific gene panels according to previously published methods.4 The distribution of continuous vari- ables was statistically compared using nonparametric (Mann-Whitney or Kruskal-Wallis) tests, while nominal variables were compared using the c2 test. Time-to-event analyses (for overall [OS] and acute myeloid leukemia- free survival [LFS]) were performed using the method of Kaplan-Meier, with death (for OS), transformation to acute myeloid leukemia (for LFS), and allogeneic hematopoietic stem cell transplantation (for both OS and LFS) used as censors.
Overall, 778 consecutive WHO-defined MDS/MPN patients were included in the primary cohort (CMML, n=578 [74%]; MDS/MPN-RS-T, n=79 [10%] and MDS/MPN-U, n=121 [16%]). The median age was 72 (range, 18-95) years with 511 (66%) males (Table 1). Four (3%) patients in the MDS/MPN-U group met proposed criteria for oligomonocytic CMML and had an absolute monocyte count between 0.5 to 0.9 x 109/L, with mono- cytes constituting >10% of the total white blood cell count.10 Cytogenetic abnormalities (excluding sole -Y) were present in 197 (28%) of 695 assessable patients; 138
(70%) patients with a single karyotypic abnormality, 35 (18%) with a complex karyotype (defined as ≥3 inde- pendent structural/numerical abnormalities, excluding autosomal monosomies) and 26 (13%) with monosomal karyotypes, with frequent cytogenetic abnormalities including 51 (26%) +8, 49 (25%) -7/7q-, 23 (12%) 20q-, 12 (6%) 5q- (2 as sole abnormalities, classified as MDS/MPN based on morphology), 11 (6%) 13q-, 6 (3%) inv(3)/3q26 (3 GATA2-EVI1 fusion), and 5 (3%) with-11/11q23 (KMT2A). Cytogenetic risk stratification as per the CMML-specific scoring system (CPSS) cytogenetic stratification11 was predictive of OS (P<0.0001) in our cohort with 498 (72%) in the low-risk category (median OS 41 months [95% CI: 32-50]), 120 (17%) in the intermediate-risk category (median OS 21 months [95% CI: 16-33]), and 77 (11%) in the high-risk category (median OS 16 months [95% CI: 11-23]). Next-generation sequencing information at diag- nosis was available for 444 (57%) patients with frequent molecular abnormalities being ASXL1 (n=235; 45%), SRSF2 (n=179; 40%), TET2 (n=155; 39%), SF3B1 (n=78, 15%), and DNMT3A (n=30, 7%) mutations (Table 1). At last median follow-up of 44 (95% CI: 37-50) months, transformation to acute myeloid leukemia had occurred in 123 (16%) patients, and 414 (53%) deaths had been documented. The Kaplan-Meier estimate of median OS was 32 (95% CI: 28-38) months (CMML 31 [95% CI: 27- 37] months, MDS/MPN-RS-T 67 [95% CI: 43-101] months, and MDS/MPN-U 25 [95% CI 21-36] months), while the median was not reached for LFS. In the MDS/MPN cohort, there were 78 patients with SF3B1 mutations: 18 (23%) with CMML, 45 (58%) with MDS/MPN-RS-T, and 15 (19%) with MDS/MPN-U. There were 15 SF3B1 mutation hotspots (evaluable in 53 patients) with the most common abnormalities being K700E (n=24, 45%), H662Q (n=8, 15%), and K666R (n=6, 11%). The clinical and genomic characteristics are outlined in Online Supplementary Table S1.
We then combined all SF3B1-mutant MDS/MPN patients into one category (n=78) and compared them to their wild-type counterparts (n=446) (Table 1). The two groups had significant differences in clinical and molecu- lar features as highlighted in Table 1. The median variant allele frequency (VAF) of mutant SF3B1 was 43% (range, 8-65) overall, being 43% (range, 8-65) in CMML patients, 43% (range, 12-50) in MDS/MPN-RS-T patients, and 40% (range, 16-52) in MDS/MPN-U patients (P=0.9), and was comparable to the median variant allele frequency of mutant ASXL1 at 37% (range, 11-52): CMML 37% (range, 27-37), MDS/MPN-RS-T 32% (range, 18-52), and MDS/MPN-U 29% (range, 11-43). As expected, a higher frequency of SF3B1-mutant versus SF3B1-wild type MDS/MPN patients (21% vs. 2%, P<0.0001) were treated with lenalidomide and erythropoiesis-stimulating agents (64% vs. 39%, P<0.0001), but the frequency of hypomethylating agent therapy use was similar (21% vs. 32%, P=0.1) (Table 1). The SF3B1 mutant cohort had a lower rate of transformation to acute myeloid leukemia (5% vs. 18%, P=0.0006) in comparison to the SF3B1-wild type cohort. The Kaplan-Meier estimates of LFS (median not reached in both groups, P=0.0002) and OS (57 vs. 31 months, P=0.03) were higher in the SF3B1-mutant MDS/MPN patients (Table 1 and Figure 1). These find- ings were validated in an external MDS/MPN cohort from Moffitt Cancer Center comprising 380 patients, 253 with CMML, 80 with MDS/MPN-RS-T, and 47 with MDS/MPN-U. The validation cohort was similar to the Mayo Clinic cohort in terms of age (P=0.4) and median follow-up (P=0.1). Importantly, SF3B1-mutant VAF was not predictive of OS in either the Mayo Clinic cohort
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