Improved Overall Survival Among Luspatercept Responders and Predictors of Response
Authors: Consagra Angela , Lanino Luca , Al Ali Najla H , Aguirre Luis E. , Xie Zhuoer , Chan Onyee , Andreossi Gloria , Rigodanza Luca , Sanna Alessandro , Raddi Marco Gabriele , Walker Alison R. , Kuykendall Andrew T. , Lancet Jeffrey , Padron Eric , Sallman David A , Restuccia Francesco , Perego Alessandra , Ubezio Marta , Fattizzo Bruno , Riva Marta , Campagna Alessia , Della Porta Matteo Giovanni , Santini Valeria , Komrokji Rami S. 
Published: December 2023

Introduction
Luspatercept (luspa) is a first-in-class erythroid-maturation agent approved for red blood cells transfusion dependent (RBC-TD) lower risk myelodysplastic syndrome (LR-MDS) with ring sideroblast (RS) based on MEDALIST clinical trial.
We aimed to explore impact of luspa on overall survival (OS) and predictors of response in a large cohort of pts treated with luspa, collected from Moffitt Cancer Center (MCC) and from Fondazione Italiana Sindromi Mielodisplastiche (FISiM).
Methods
We evaluated all pts with LR-MDS-RS treated with luspa from MCC cohort since FDA approval, and from a multicenter observational trial of FISiM for pts treated on a compassionate use program . Baseline RBC transfusion burden (TB) was defined as: non-transfusion dependent (NTD) (0 units in 8 weeks prior luspa), low TB (LTB) (1-5 units/8 weeks ) and high TB (HTB) (≥ 6 units/8 weeks). A hematological response (HI) was defined as an (i) objective Hgb increase of &gt; 1.5 g/dl in NTD, and (ii) RBC-TI with Hgb increase of 1.5 g/dl, or RBC-TI without Hgb 1.5 g/dl increase, or &gt;50% reduction in RBC TB among RBC-TD. Somatic mutation (MT) data were available for 137 pts.
Results
Between January 2020 and March 2023, 331 pts were treated with Luspa (Table-1). The median age was 69 years; 308 pts (93%) had MDS-RS, 86,1% were intermediate, low or very low risk MDS by R-IPSS and 82% (105/128) were moderate low (ML), low (L) or very low (VL) by IPPS-M. SF3B1 MT was detected in 86.3% (120/139) with a median VAF of 37.7. The mean Hgb level was 7.97 g/dl and 93.7% were RBC-TD. Majority had prior erythroid stimulating agents (ESA) (93.6%). In the MCC cohort 42.9% (52/121) had prior hypomethylating agents (HMA) therapy, and 31.4% (38/121) had prior lenalidomide (len).
With a median follow up of 14.6 mos from starting luspa treatment, the median OS was not reached (NR) among responders to luspa compared to 24.5 mos for non-responders (p &lt;.001) (Figure-1). The median OS benefit was more pronounced among pts with RBC-TI and Hgb&gt; 1.5 g/dl increase compared to other categories of response. In the NTD group at baseline, the median OS among luspa responders was NR compared to 22.7 mos among non-responders (P&lt; .001). In the LTB group at baseline median OS was NR as well among luspa responders compared to 29.9 mos in non-responders (p=.002) and finally among HTB group at baseline, the median OS among luspa responders was 35.4 mos compared to 21.2 mos in non-responders (p=.007). In multivariable analysis adjusting for IPSS-M and baseline RBC-TD, response to luspa was independently associated with improved OS, HR .39 (95% CI .18-.83), p= .015
The overall HI rate to luspa was 40.6% (134/330) (Table-1), 85% of pts needed dose escalation, HI correlated with baseline RBC-TB where 80% (16/20) NTD, 60.2% (65/108) LTB and 41.8% HTB (77/184) achieved HI respectively, p&lt; .001. By IPSS-M, there was a trend for lower HI with higher risk disease (100% in VL, 60.3% in L, 36.7% in ML, 56.3% in MH, 16.7% in H risk pts, p=.051). There was a mild trend for higher response among SF3B1 MT pts compared to wild type, 54% (64/119) versus 42% (8/19), p=.34.The segregation of SF3B1 MT cases into three independent groups based on IPSS-M, showed that HI rate was better in SF3B1 β ( SF3B1 and any gene from BCOR, BCORL1, NRAS, RUNX1, SRSF2 or STAG2) and SF3B1 α (as any other mutant) than SF3B1 5q(concomitantpresence with isolated del5q): 50% (7/14), 58.8% (57/97), and 0% (0/5) respectively, p=.03. Among SF3B1 5qpts, 4 had been treated with len before luspa and only 1 had achieved an HI with prior len.
Among pts with SF3B1 MT, we observed a trend for higher response in pts with the hotspot K700E, 62.7% (37/59) vs 47.4% (27/57) in non-K700E, p=.097. In pts with SF3B1 MT, divided by median VAF, we observed a trend for better HI with VAF was &gt;38, 63.5% (33/52) vs 45.3% (24/53), p=.062.
Among responders, the median duration of response was 14.1 mos. As of last follow up, 85% pts (191/224) discontinued treatment. Reason of discontinuation was lack of response in 126 pts, loss of response in 26 patients and adverse events in 6 pts. The most common reported adverse events were fatigue (n=10), GI symptoms (n=4), shortness of breath and arthralgia (1 each).
Conclusions
Our RWD in the largest luspa treated cohort demonstrates OS benefit to luspa response. Low baseline RBC-TB dependency, lower risk IPSS-M, SF3B1 MT, SF3B1-K700E mutation and SF3B1 α co-mutations correlated with higher response rates. Our data emphasizes the impact of RBC-TI in LR-MDS.