1. Azacitidine 75 mg/m2 per day x 7 days q28
CALGB 9221: A Phase III Trial of Azacitidine (AZA) versus Best Supportive Care in Patients with MDS
* Crossover to AZA permitted after 4 months R
Supportive care*
Azacitidine 75 mg/m2 per day x 7 days q28
Eligibility (n = 191)
No prior treatment AZA, G-CSF, GM-CSF or other hematopoietic cytokines except erythropoietin
No history of leukemia
Stratification: FAB subtype
AZA
Supportive care
p-value
Overall response
60% 5%
<0.001
Overall survival (landmark analysis)
18 mo
11 mo
0.03
Silverman LR et al. J Clin Oncol 2002;20(10):

2. Phase III Trial of Decitabine with Best Supportive Care (BSC) versus BSC in Patients with MDS
Decitabine IV 15 mg/m2
over 3 hrs every 8 hrs
x 3 days q6wk
Eligibility (n = 170)
Confirmed diagnosis of MDS
IPSS score ≥0.5
No AML or other progressive malignant disease
Decitabine
BSC
p-value
Median time to AML progression or death
12.1 mo
7.8 mo
0.16
Grade 3/4 neutropenia
87%
50% —
Grade 3/4 thrombocytopenia
85%
43%
Grade 3/4 leukopenia
22% 7%
Kantarjian H et al. Cancer 2006;106(8):

3. Oral azacitidine 300 mg/day + BSC (first 21 days of 28-day cycle)
Phase III Study of Oral Azacitidine (CC-486) as Front-Line Treatment for Low-Risk MDS
Target Accrual: 386
Eligibility
MDS with anemia requiring RBC infusion
Thrombocytopenia
No prior azacitidine, decitabine, other hypomethylating agent and lenalidomide
Oral azacitidine 300 mg/day
+ BSC (first 21 days of 28-day cycle) R
Placebo + BSC
Accessed May 2016.
NCT

4. ASTX727 Combined Oral Decitabine (DAC) with Oral Cytidine Deaminase Inhibitor (CDAi) E7727 for MDS
The primary PK objective was met in this Phase I trial (n = 24)
AUC of oral ASTX727 (40 mg DAC combined with 100 mg E7727) was comparable to AUC of 20 mg/m2 IV decitabine
Objective clinical responses:
1 complete response (CR)
1 marrow CR
1 partial response
2 hematologic improvements
No dose-limiting toxicities or Grade ≥3 drug-related nonhematologic adverse events (AEs) were observed
Savona MR et al. Proc ASH 2015;Abstract 1683.

5. Discontinuation of Hypomethylating Agent (HMA) Therapy in Patients with MDS or AML
Retrospective analysis of 16 patients with higher-risk MDS (n = 5) or AML (n = 11) who achieved PR (n = 1) or CR (n = 15) and stopped HMA therapy while in response
Received a median of 12 courses (range 1-24) and achieved response after a median of 1 course of therapy (1-4)
Loss of response after discontinuation of therapy was rapid, with a median progression-free survival of 4 months
Median OS from the time of therapy discontinuation was 15 months
Patients who received 12 cycles of therapy or more had significantly better OS (median: 20 months) than those who received fewer than 12 cycles (median: 4 months)
Poor-risk cytogenetics were also associated with lower 1-year OS (33% versus 69%)
Cabrero M et al. Leuk Res 2015;39(5):520-4.

6. Predictability of Response to Hypomethylating Agents (HMAs) with TET2 Mutations in MDS
Samples from 213 patients with MDS collected before treatment with azacitidine or decitabine were sequenced for 40 recurrently mutated myeloid malignancy genes in tumor DNA
Mutations were examined for association with response (RR) and overall survival (OS)
RR were highest in patients with TET2 mutations without clonal ASXL1 mutations (OR 3.65, p = 0.009)
Clonal TET2 mutations predicted response (OR 1.99, p = 0.036)
TET2 mutations can identify patients more likely to respond to HMAs
Bejar R et al. Blood 2014;124(17):

7. Deferasirox iron chelator
TELESTO: A Phase II Trial of Iron Chelation Therapy in Patients with Low/Int-1-Risk MDS and Transfusional Iron Overload
Eligibility (n = 223)
MDS low/int-1 risk by IPSS
Ferritin > 1,000 mcg/L
History of PRBC transfusions
To be transfused ≤8 times annually during study 2
Deferasirox iron chelator R 1
Placebo
Composite primary endpoint: Event-free survival
Accessed May 2016.

8. Phase II Open-Label Trial of 3 Alternative Dosing Schedules of Azacitidine (AZA) in Patients with MDS
Eligibility
MDS with refractory anemia (RA)
RA with ringed sideroblasta, excess blasts or excess blasts in transformation
BM sample within 30 days of first AZA dose
ECOG PS 0-3
AZA 5-2-2
q28d x 6 R
AZA 5-2-5
q28d x 6
AZA 5
q28d x 6
AZA 5-2-2: 75 mg/m2 per day SC x 5 days  2 days rest  75 mg/m2 per day SC x 2 days; AZA 5-2-5: 50 mg/m2 per day SC x 5 days  2 days rest  50 mg/m2 per day SC x 5 days; AZA 5: 75 mg/m2 per day SC x 5 days
Lyons RM et al. J Clin Oncol 2009;27(11):

9. Phase II Open-Label Trial of 3 Alternative Dosing Schedules of Azacitidine in Patients with MDS
Most patients were FAB lower risk (63%) or RAEB (30%)
Patient FAB classification
AZA 5-2-2
(n = 50)
AZA 5-2-5
(n = 51)
AZA 5 RA
44%
41%
RARS
14%
RAEB
28%
33%
RAEB-T 2% 4%
CMML
12%
10%
Conclusion:
All 3 alternative dosing produced hematologic improvement, RBC transfusion independence and safety responses consistent with the currently approved AZA regimen.
Lyons RM et al. J Clin Oncol 2009;27(11):

10. Azacitidine 75 mg/m2 per day x 7 days, q28d Hazard ratio (p-value)
Open-Label Phase III Trial of Azacitidine (AZA) versus Conventional Care for Higher-Risk MDS
Conventional care (best supportive care, low-dose cytarabine or intensive chemotherapy)
Eligibility (n = 358)
No prior treatment with AZA or secondary MDS
No planned ASCT R
Azacitidine 75 mg/m2 per day x 7 days, q28d
≥6 cycles
AZA
Conventional care
Hazard ratio (p-value)
Overall survival*
24.5 mo
15.0 mo
0.58 (p = )
* At 21.1 months median follow-up
Fenaux P et al. Lancet Oncol 2009;10(3):

11. RBC Transfusion Independence in Baseline RBC Transfusion-Dependent Patients
Phase II Study: 5-, 7-, 10-day azacitidine dosing regimens
AZA 5-2-2
AZA 5-2-5
AZA 5
% of patients who became transfusion independent (95% CI)
Lyons RM et al. J Clin Oncol 2009;27:

12. Factors Prognostic for CR in Phase II Trial of Lenalidomide in Intermediate-2 or High-Risk MDS
Factor category
Number of CRs (%)
p-value
Cytogenetic
Isolated del 5q, (n = 9)
Single additional abnormality, (n = 11)
>1 additional abnormality, (n = 27)
6 (67%)
1 (9%)
0 (0%)
<0.001
Baseline platelet count, mg/L
>100,000, (n = 20)
<100,000, (n = 27)
7 (35%)
Bone marrow blasts, %
<20%, (n = 29)
>20%, (n = 18)
6 (21%)
1 (5%)
0.16
Ades L et al. Blood 2009;113(17):

13. Randomized Phase III Study of Lenalidomide (Len) with or without Erythropoietin in Transfusion-Dependent Lower-Risk MDS without Del(5q)
Lenalidomide 10mg/day for 21 days per 4 weeks
Eligibility (n = 131)
Low-risk non del(5q) MDS
RBC transfusion dependent
ESA refractory R
Lenalidomide 10mg/day for 21 days per 4 weeks + EPO beta, 60,000U/wk
Len
Len + EPO
p-value
Erythroid response after 4 cycles (HI-E)
23.1%
39.4%
0.044
RBC transfusion independence
13.8%
24.2%
0.13
Predictors of HI-E:
G polymorphism of cereblon gene and low baseline serum EPO
Toma A et al. Leukemia 2016;30(4):

14. Expression of PD-L1, PD-L2, PD-1 and CTLA-4 in MDS is Enhanced by Hypomethylating Agents
Analysis of sequential mRNA expression from PBMCs of 61 patients (n = 24 with MDS) treated with hypomethylating agents
During first course of therapy, mRNA expression of PD-L1, PD-L2, PD-1 and CTLA-4 increased (≥twofold) in 57%, 57%, 58% and 66% of patients, respectively.
Analyses of relationship between mRNA expression of the 4 genes and response to hypomethylating agents in cohort of patients from study (azacitidine + vorinostat) showed a trend toward increased expression of the 4 genes in resistant versus sensitive patients.
Yang H et al. Leukemia 2014;28(6):

15. Ongoing Trials of Checkpoint Inhibitors in MDS
Phase
Protocol ID and title
Study arms II
NCT : Combination of nivolumab and ipilimumab with 5-azacitidine in patients with MDS
Nivolumab + AZA
Ipilimumab + AZA
Nivolumab + ipilimumab + AZA
NCT : Combination of lirilumab and nivolumab with 5-azacitidine in patients with MDS
Lirilumab
Lirilumab + nivolumab
AZA + lirilumab
AZA + lirilumab + nivolumab I
NCT : Ipilimumab or nivolumab in patients with relapsed hematologic malignancies after HSCT
Ipilimumab + nivolumab
Accessed May 2016.

16. NCT : A Phase II/III Trial of Imetelstat in Transfusion-Dependent Subjects with IPSS Low or Intermediate-1-Risk MDS
Part 1: Imetelstat 7.5 mg/kg IV q4wk
Eligibility (target n = 200)
MDS low or int-1 risk by IPSS
Relapsed/refractory to erythropoiesis-stimulating agent (ESA)
RBC transfusion dependent
ECOG 0-2
Satisfactory risk/benefit profile
Part 2: Imetelstat 7.5 mg/kg IV q4wk R
Placebo
Primary endpoint: Percentage of participants without any RBC transfusions during any consecutive 8-week period
Accessed May 2016.

17. Phase II BMT CTN 1102: Allogeneic Hematopoietic Cell Transplant versus Hypomethylating Therapy or Best Supportive Care for Int-2 and High-Risk MDS
Eligibility (n = 400)
De novo MDS with current/previously determined int-2 and high- risk disease
<20% marrow blasts within 60 days
50-75 years old
No formal unrelated donor search activated prior to consent
Allogeneic hematopoietic cell transplant (RIC alloHCT) R
Nontransplant: Hyomethylating therapy or best supportive care*
* At physician’s discretion
Primary outcome: Overall survival
Accessed May 2016.

18. Predictability of Outcomes After Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) Based on Mutated Genes in MDS
Coding mutations in 40 recurrently mutated MDS genes were examined in tumor samples collected before HSCT from 87 patients with MDS. Mutations were identified in 92% of patients.
Mutations independently associated with shorter overall survival (OS):
TP53 (HR = 2.30, p = 0.027)
TET2 (HR = 2.40, p = 0.033)
DNMT3A (HR = 2.08, p = 0.049)
46% of patients carried a mutation in TP53, TET2 or DNMT3A. Three-year overall survival for these patients was 19% compared to 59% for patients without these mutations.
Bejar R et al. J Clin Oncol 2014;32(25):

19. Allogeneic hematopoietic cell transplant
UPCI (NCT ): A Phase II Trial of 5-Azacitidine (5-AZA) Maintenance After Transplant for High-Risk AML or MDS
Eligibility (n = 35)
MDS or high-risk AML
Transplant candidates with HLA-matched sibling or unrelated donor with ≥8/8 match
Allogeneic hematopoietic cell transplant
Complete response
No active GVHD
5-AZA SC or IV
32 mg/m2–75 mg/m2
Primary endpoint: 1-year relapse rate
Accessed May 2016.

20. INSPIRE: A Phase III Trial of Rigosertib versus Physician Choice of Treatment for MDS After Failure of a Hypomethylating Agent (HMA)
Eligibility (n = 225)
MDS confirmed within 8 weeks
Cytopenia (ANC <1,800/uL, plt <100,000/uL or Hgb <10 g/dL)
Progression or failure to achieve PR or CR or HI after initiation of AZA or DEC treatment
Failure to respond/ineligible for or relapse after ASCT
Rigosertib, IV + best supportive care (BSC) R
Physician’s choice of treatment + BSC
Primary endpoints: Overall survival, safety
PR = partial response; CR = complete response; HI = hematological improvement; AZA = azacitidine; DEC = decatibine
Accessed May 2016.