SF3B1 Mutation Significance in Myeloid Neoplasms without Anemia
Authors: Camarillas Sergi , Alonso Esther , Calvo Xavier , Arenillas Leonor , Mesa Alba , Zamora Lurdes , Rivero María Eugenia , Casanova Evelin , Restrepo Juan , Brey Nuria , Rozman María , Muzio Sofia , Medina Irene , Gallur Laura , Gabarrós-Subirà María , Blanco Adoracion , Ortega-Blanco Margarita , Hidalgo-Gomez Gloria , Montoro Julia , Jerez Andres , Acha Pamela , Valcarcel David , Saumell Silvia 
Published: December 2024

Introduction. The proposed classifications (WHO2022/ICC) define Myelodysplastic Neoplasms/Syndromes with SF3B1 mutation (MDS-SF3B1) and myelodysplastic/myeloproliferative neoplasms with SF3B1 mutation and thrombocytosis (MDS/MPN-SF3B1-T) based on the presence of SF3B1 mutation (SF3B1mut), regardless ring sideroblasts (RS). However, at least one cytopenia must be present, and it must be anemia in the case of MDS/MPN-SF3B1-T. Cases with SF3B1mut that do not meet these defining features are classified as clonal hematopoiesis of indeterminate potential (CHIP) or are unclassifiable. The aim of this analysis was to assess the significance of SF3B1mut in patients without anemia and to evaluate the current diagnostic classification criteria.
Methods. We conducted a multicentric retrospective analysis from a series of 30 cases with SF3B1mut (Sanger or NGS) without anemia at diagnosis (Hb &lt;120g/L for women / Hb&lt;130g/L for men) from February 2016 to March 2024. We analyzed their clinical-biological characteristics as well as the evolution of their blood counts.
Results. Patients had been classified according to WHO2022 as follows: 3 chronic myelomonocytic leukemia (CMML) for persistent monocytosis, 4 myelodysplastic neoplasms (MDN) for the presence of other cytopenia (n=2) and/or increased blasts (n=2), 1 myelofibrosis (MF), 1 chronic eosinophilic leukemia for persistent eosinophilia, 5 CHIP and 16 unclassifiable cases.
Among all cases, 90% showed dyserythropoiesis, 70% &gt;15% of RS and 50% had an increased mean corpuscular volume (&gt;95ft). Variant allele frequency (VAF) of SF3B1mut was available for 20 of the cases, being VAF ≥10% in 75% of them.
The median follow-up for the entire was 33,2 months. During this period, 60% of patients developed anemia, with a median time to onset of 23,2 months (IC 95%, 16.8-50.63).
All cases with VAF ≥10% presented dyserythropoiesis and ≥15% of RS, among them 60% became anemic. Median time to anemization was 18.5 months (CI 95% 7 - NR) with a mean hemoglobin drop of 18 g/L. Besides, cases with VAF &lt;10% (3 CHIP, 1 MF, 1 CMML) did not show significant dyserythropoiesis and RS were &lt;15% at diagnosis. Among them, the CMML and one of the CHIP cases, which evolved to CMML at 27 months, became anemic; both presented 2 co-mutations in TET2.
Finally, we analyzed the 16 cases that could not be initially classified due to lack of anemia but they met the other criteria for MDS/MPN-SF3B1-T. All cases with available data presented dyserythropoiesis, ≥15% of RS (15/16) and a VAF ≥10% (11/16). In addition, 94% of them had a typical mutation associated with myeloproliferative neoplasms (JAK2/MPL/CALR), and 56% developed anemia within 17 months (CI 95%, 15 - NA).
Conclusions. Based in our findings, patients with SF3B1mut with a VAF ≥10%, along with dyserythropoiesis and ≥15% of RS, should be classified as MDS-SF3B1 or MDS/MPN-SF3B1-T if they meet the remaining criteria, regardless of hemoglobin levels at diagnosis. Conversely, cases with SF3B1mut and a VAF &lt;10% should be considered as CHIP.