1. ASH Review 2018: Update on Myelodysplastic Syndrome
Barry Skikne, MD, FACP, FCP(SA)
Professor of Medicine
University of Kansas Medical Center

2. CURRENT MDS THERAPY STATUS
No new therapies approved for MDS in >10 years
Current therapy primarily based on stratification into Lower and Higher Risk disease
Only 3 agents approved- 5-azacytidine, decitabine and lenalidomide
HSCT only treatment that can potentially cure - but not for all

3. Gene Mutation Profiling
Increased understanding of biology of MDS
Knowledge used for:
earlier diagnosis
more precise risk stratification
guide therapy in a rational biologic pathway
Promise of effective targeted therapies is real if not yet realized

4. Fenaux P, et al. ASH 2018. The MEDALIST Trial…
The MEDALIST Trial: Results of a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Luspatercept to Treat Patients With Very Low-, Low-, or Intermediate-Risk Myelodysplastic Syndromes (MDS) Associated Anemia With Ring Sideroblasts (RS) Who Require Red Blood Cell (RBC) Transfusions
Fenaux P, et al. ASH The MEDALIST Trial…

5. Background and Rationale
Patients with lower-risk (LR) transfusion-dependent MDS have poorer prognosis, greater risk of progression to AML, inferior overall survival compared with transfusion-independent MDS patients
RBC transfusion-dependent LR, non-del(5q) MDS may have a transient response to ESAs, risk of iron overload and secondary organ complications
Few treatment options exist for patients who are refractory to, or become unresponsive to ESAs
Fenaux P, et al. ASH The MEDALIST Trial…

6. Fenaux P, et al. ASH 2018. The MEDALIST Trial…

7. ACE Targets TGF-b Family

8. Edited from: Fenaux P, et al. ASH 2018. The MEDALIST Trial…

9. A Special Thanks to Rascal the Animation Producer!

10. MEDALIST Trial Patient Population
MDS-RS (WHO): ≥ 15% RS or ≥ 5% with SF3B1 mutation
< 5% blasts in bone marrow
No del(5q) MDS
IPSS-R Very Low-, Low-, or Intermediate-risk
Prior ESA response
Refractory, intolerant
ESA naive: EPO > 200 U/L
Average RBC transfusion burden ≥ 2 units/8 weeks
No prior treatment with disease- modifying agents (e.g. iMIDs, HMAs)
Luspatercept 1.0 mg/kg (s.c.) every 21 days
n = 153
Randomize
2:1
Dose titrated up to a maximum of 1.75 mg/kg
Placebo (s.c.) every 21 days
n = 76
Disease & Response Assessment
Week 24 & every 6 months
Treatment discontinued for lack of clinical benefit or disease progression per IWG criteria; no crossover allowed
Fenaux P, et al. ASH The MEDALIST Trial…

11. Fenaux P, et al. ASH 2018. The MEDALIST Trial…
Study Endpoints
Primary endpoint:
Red blood cell transfusion independence ≥ 8 weeks
Key secondary endpoint:
Red blood cell transfusion independence ≥ 12 weeks
Additional secondary endpoint:
HI-E (IWG 2006 criteria1 ) for any consecutive 56-day period
Reduction in red blood cell transfusion burden ≥ 4 RBC units/8 weeks or
Mean Hb increase of ≥ 1.5 g/dL/8 weeks
Duration of response
Hb change from baseline
Fenaux P, et al. ASH The MEDALIST Trial…

12. Demographics and Baseline Disease Characteristics
Luspatercept
(n = 153)
Placebo
(n = 76)
Age, median (range), years
71 (40–95)
72 (26–91)
Male, n (%)
94 (61.4)
50 (65.8)
Time since original MDS diagnosis, median (range), months
44.0 (3–421)
36.1 (4–193)
RBC transfusion burden, median (range), units/8 weeks
5 (1–15)
5 (2–20)
≥ 6 units/8 weeks, n (%)
66 (43.1)
33 (43.4)
< 6 units/8 weeks, n (%)
87 (56.9)
43 (56.6)
Pre-transfusion Hb, median (range), g/dL
7.6 (6–10)
7.6 (5–9)
IPSS-R risk category
Very Low, Low, n (%)
127 (83.0)
63 (82.9)
Intermediate, n (%)
25 (16.3)
13 (17.1)
SF3B1 mutation, n (%)
141 (92.2)
65 (85.5)
Serum EPO
< 200 U/L, n (%)
88 (57.5)
≥ 200 U/L, n (%)
64 (41.8)
26 (34.2)
Fenaux P, et al. ASH The MEDALIST Trial…

13. Primary and Secondary Endpoints
Primary Endpoint:
Red Blood Cell Transfusion Independence ≥ 8 Weeks
RBC-TI ≥ 8 weeks
Luspatercept
(n = 153)
Placebo
(n = 76)
Weeks 1–24, n (%)
58 (37.9)
10 (13.2)
95% CI
30.2–46.1
6.5–22.9
P value
<
Key Secondary Endpoint:
Red Blood Cell Transfusion Independence ≥ 12 Weeks
RBC-TI ≥ 12 weeks
Luspatercept
(n = 153)
Placebo
(n = 76)
Weeks 1–24, n (%)
43 (28.1)
6 (7.9)
95% CI
21.14–35.93
2.95–16.40
P value
0.0002
Weeks 1–48, n (%)
51 (33.3)
9 (11.8)
25.93–41.40
5.56–21.29
0.0003
Fenaux P, et al. ASH The MEDALIST Trial…

14. Duration of RBC-TI Response in Primary Endpoint Responders
Fenaux P, et al. ASH The MEDALIST Trial…

15. Secondary Endpoint: Erythroid Response (HI-E)
Luspatercept
(n = 153)
Placebo
(n = 76)
Achieved HI-E (weeks 1–24), n (%)
81 (52.9)
9 (11.8)
Reduction of ≥ 4 RBC units/8 weeks
(baseline transfusion burden ≥ 4 units/8 weeks)
52/107 (48.6)
8/56 (14.3)
Hb increase of ≥ 1.5 g/dL
(baseline transfusion burden < 4 units/8 weeks)
29/46 (63.0)
1/20 (5.0)
95% CI
44.72–61.05
5.56–21.29
P Value
<
Achieved HI-E (weeks 1–48), n (%)
90 (58.8)
13 (17.1)
58/107 (54.2)
12/56 (21.4)
32/46 (69.6)
50.59–66.71
9.43–27.47
Fenaux P, et al. ASH The MEDALIST Trial…

16. Fenaux P, et al. ASH 2018. The MEDALIST Trial…
Safety Summary
Luspatercept
(n = 153)
Placebo
(n = 76)
Patients with ≥ 1 TEAE, n (%)
150 (98.0)
70 (92.1)
Patients with ≥ 1 serious TEAE
48 (31.4)
23 (30.3)
Patients with ≥ 1 Grade 3 or 4 TEAE
65 (42.5)
34 (44.7)
Patients with TEAEs leading to death
5 (3.3)
4 (5.3)
Patients with ≥ 1 TEAE causing discontinuation, n (%)
13 (8.5)
6 (7.9)
TEAEs were balanced between the arms
Progression to AML occurred in 4 patients (3/153 [2.0%] in the luspatercept arm; 1/76 [1.3%] in the placebo arm)
Fenaux P, et al. ASH The MEDALIST Trial…

17. Fenaux P, et al. ASH 2018. The MEDALIST Trial…
MEDALIST Conclusions
Treatment with luspatercept in lower-risk RARS MDS, resulted in a significantly higher percentage of RBC-TI, major RBC transfusion reduction, or hemoglobin increase, compared with placebo
Erythroid responses durable, ~40% of patients achieving RBC-TI sustained at 12 months of treatment
Generally well tolerated
Potential new therapy for lower-risk RARS MDS with RBC transfusion-dependent anemia
Fenaux P, et al. ASH The MEDALIST Trial…

18. Sallman D, et al. H Lee Moffitt Cancer Center
Clonal Suppression of TP53 Mutant MDS/Oligoblastic AML (blasts <30%)with Hypomethylating Agent Therapy Improves Overall Survival
Sallman D, et al. H Lee Moffitt Cancer Center

19. TP53 mutations occur in 5-10% patients with MDS
Conflicting response rates/outcomes in TP53 mutant MDS patients
azacytidine vs decitabine (Welch NEJM 2016; Garcia-Manero NEJM 2017)
TP53 mutant patient numbers - small, heterogenous – treatment naïve and or relapsed/refractory
Evaluated outcomes of TP53 mutant (by NGS) MDS patients who received frontline HMA therapy

20. 71 patients with TP53 mutation
63 with TP53 WT
14 had multiple mutations in TP53 gene
Age 68(39-82)
58 treated with 5-azacytidine
51 with aza monotherapy
7 with aza in combination (2 lenalidomide, 5 other)
13 with decitabine
Median number of treatment cycles 4(1-33), 13 proceeded to allogeneic BMT
Median follow-up 20 months, median OS 9.7 months
13(18%) achieved CR, 28(39%) ORR
Transplanted patients OS 14.5 months vs 7.9 months (if VAF <5% OS months)

21. Sallman D

22. VAF < 5%
VAF ≥ 5%
14.5 mnths
7.5 mnths
Sallman D

23. TP53 MT
TP53 WT CR
18%
14%
ORR
39%
40%
15.4 mnths
9.7 mnths
Sallman D

24. Conclusions
TP53 MT patients have inferior OS to TP53 WT with HMA therapy BUT have similar response rates
No OS difference according to specific HMA used
TP53 MT patients with max clonal suppression (VAF<5%) have improved OS as well as improved outcome with HSCT
Need new therapies targeting TP53 mutant MDS/AML
APR reactivates mutant TP53 to induce programmed cell death
Phase 1b/2 safety/efficacy study with azacytidine ongoing
Sallman D

25. Phase 1b/2 Combination Study of APR-246 and Azacitidine (AZA) in Patients with TP53 mutant Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML)
David Sallman, et al.

26. Safety, AEs, DLTs and Response
Hypomethylator naïve mTP53 MDS and oligoblastic AML (RAEB-T)
APR-246 given IV in 3+3 regimen, escalation dose – 50, 75, 100 mg/kg/d x 4 THEN same dose, d 1-4 followed by Vidaza 75mg/m2 x 7 d - 28 day cycles
Serial NGS and TP53 by IHC evaluation- clonal suppression and remission depth, MRD, nanostring RNA expression
Sallman D

27. Sallman D

28. Sallman D

29. Questions