Post on 09-Aug-2020
The role of the darbepoetin alfa
in the treatment for Low-risk of MDS
Jun Ho Jang
ProfessorDivision of Hematology Oncology
Samsung Medical Center15 MAR 2019 in ICKSH
I have no personal or financial interests to declare:
I have no financial support from an industry source at the current presentation.
Use the following slide to disclose any conflicts of interest
Form A: no conflicts of interest to declare.
대한혈액학회 Korean Society of Hematology
COI disclosureName of author : Jun Ho Jang
Papaemmanuil et al. Blood 2013
Normal Low-risk MDS High-risk MDS AML
MDS as a disease model of leukemogenesis
years
% blasts
MDS is predominantly a disease of the elderly (> 60 yrs old, 86%)
IPSS Scoring SystemPrognostic Variables 0 0.5 1.0 1.5 2.0% Marrow Blasts <5 5-10 11-20 21-30Karyotype Good Int PoorCytopenia 0/1 2/3
Risk ScoreLow 0Int 1 0.5-1.0Int 2 1.5-2.0High ≥ 2.5u
Greenberg et al., BLOOD 89(6):2079-2088, 1997
0
20
40
60
80
100
0 3 6 9 12 15 18
YearsP
erce
nt
0
20
40
60
80
100
0 3 6 9 12 15 18
Years
Per
cent
International MDS Risk Classification
Greenberg P, et al. Blood. 1997:89(6):2079-88.
Low 235 pts
Int-1 295 pts
Int-2 171 pts
High 58 pts
Low 267 pts
Int-1 314 ptsInt-2 179 ptsHigh 56 pts
AML Transformation Survival
IPSS-R: Prognostic scores and risk groups*
Risk category ScoreVery low ≤ 1.5
Low > 1.5–3
Intermediate > 3–4.5
High > 4.5–6
Very high > 6
Very low Low Intermediate High Very highMedian OS, years 8.8 5.3 3.0 1.6 0.8
AML 25%, years NR 10.8 3.2 1.4 0.73
OS by IPSS-Rn = 7,0121.0
0.8
0.6
0.4
0.2
00 50 100 150 200
Very goodGoodIntermediatePoorVery poor
Prop
ortio
nsu
rviv
ing
Duration, months
AML-free survival
0 50 100 150 200
1.0
0.8
0.6
0.4
0.2
0
AML-
free
pro
port
ion
Duration, months
Very goodGoodIntermediatePoorVery poor
* Values for 70-year-old patient (for consideration of age: [age in years − 70] x 0.04, add result to sum of other variables).Age, PS, ferritin, and LDH were significant additive features for OS but not for AML transformation.
Greenberg PL, et al. Blood. 2012;120:2454-65 and updated data.
NR, not reached
IPSS-Low IPSS-Intermediate 1LR-PSS category 1 LR-PSS category 2 LR-PSS category 3
DefiniteTreatment
Unmet needs
Clinical Trials
▪ Non-leukemic death in males/females with LR-MDS according to Hb levels
Malcovati L, et al. Haematologica. 2011;96:1433-40
Males Females
Symptomatic anemia
del(5q) ± other cytogenetic abnormalities No del(5q)
NR or Intolerance
Lenalidomide
EPO ≤500 EPO >500
EPO±G-CSF IST HMA or LEN*
▪ HI with Lenalidomide: 50-70% in del5q, 20-30% in non-del5q▪Median DoR: >2 years in del5q, 8~10 months in non-del5q
Study Published N Key findings
MDS-001both
List A, et al. NEJM 2005
43 Hematologic improvement in 24 (56%)Response rate was highest (83%) among -5q31.1
MDS-002non-Del(5q)
Raza, et al.Blood 2008
214 25% of RBC-TI > 8 weeksMedian DoR 41 weeks9% CCyR
MDS-003Del(5q)
List A, et al.NEJM 2006
148 67% transfusion independent Median DoR > 2 years45% CCyR
MDS-004Del(5q)
Fenaux P, et alBlood 2011
205 55% transfusion independentMedian DoR > 2 years30% CCyR
MDS-005non-Del(5q)NR to ESA
Santini, et alJCO 2016
239 26.9% of RBC-TI ≥ 8 week [vs. placebo (2.5%)]Median DoR 32.9 weeks
Chen B et al. Leukemia 2005;19:767Lee JH et al. Leukemia 2003;17:305Lee DS et al. Cancer Genet Cytogenet 2002;132:97Toyama K et al. Leukemia 1993;7:499Matsushima T et al. Blood 2003;101:3386
Morel P et al. Leukemia 1993;7:1315Suciu S et al. Cancer Genet Cytogenet 1990;44:15Pfeilstocker M et al. Br J Haematol 1999;106:455Greenberg P et al. Blood 1997;89:2079
IPSS-Low IPSS-Intermediate 1LR-PSS category 1 LR-PSS category 2 LR-PSS category 3
DefiniteTreatment
Unmet needs
Clinical Trials
Lenalidomide
IPSS-Low IPSS-Intermediate 1LR-PSS category 1 LR-PSS category 2 LR-PSS category 3
DefiniteTreatment
Unmet needs
Clinical Trials
Lenalidomide
Erythropoietin (Darbepoetin)
▪ Non-transferrin bound plasma iron + oxygen = oxygen radicals→ damage of cell-membrane, DNA, RNA, and protein by lipid peroxidation
Mainous AG, et al. Br J Haematol. 2014;167:720-3
Lyons RM et al. ASH 2013. Abstract 2775
p < .0001 for chelated vs nonchelated
• Decreased organ damage• Diminished risk of infection • Improved hematopoiesis, esp. anemia• Anti-leukemic effect• Improved outcome of HSCT
: Improving survival, probably
IPSS-Low IPSS-Intermediate 1LR-PSS category 1 LR-PSS category 2 LR-PSS category 3
DefiniteTreatment
Unmet needs
Clinical Trials
Lenalidomide
Erythropoietin (Darbepoetin)
Iron chelation
IPSS-Low IPSS-Intermediate 1LR-PSS category 1 LR-PSS category 2 LR-PSS category 3
DefiniteTreatment
Unmet needs
Clinical Trials
Lenalidomide
Erythropoietin (Darbepoetin)
Iron chelation
HSCT
MDS is predominantly a disease of the elderly (> 60 yrs old, 86%)
▪ A randomized placebo-controlled phase III trialhATG + CsA showed (vs. placebo);
higher hematologic response (29% vs. 9%; p = 0.0156)with a durable response duration (median 16.4 months)
▪ Who can be benefited from IST?aged < 60 years with < 5% marrow blastwith hypocellular marrowwith HLA-DR15 class II phenotypewith PNH cloneswith STAT-3-mutant cytotoxic T-cellswith trisomy 8
Passweg JR, et al. J Clin Oncol. 2011;29:303-9Almeida A, et al. Leuk Res. 2017;52:50-7
IPSS-Low IPSS-Intermediate 1LR-PSS category 1 LR-PSS category 2 LR-PSS category 3
DefiniteTreatment
Unmet needs
Clinical Trials
Lenalidomide
Erythropoietin (Darbepoetin)
Iron chelation
HSCT
HMA
IST
IPSS-Low IPSS-Intermediate 1LR-PSS category 1 LR-PSS category 2 LR-PSS category 3
DefiniteTreatment
Unmet needs
Clinical Trials
Lenalidomide
Erythropoietin (Darbepoetin)
Iron chelation
HSCT
HMAESA failure anemia
IST
Low/int. non-5q-MDS with prior erythroid failure/low response
(N = 163)
Lenalidomide 10 mg/day on Days 1-21
(n = 81)
Lenalidomide 10 mg/day on Days 1-21 +
Epoetin alfa 60,000 units SC QW(n = 82)
▪Primary endpoint: MER - TI for ≥ 8 wks + ↑Hb ≥ 1 g/dL from baseline or if no TD, a ↑Hb ≥ 2 g/dL from baseline for ≥ 8 wks
x four 28-day cycles
Stratification- serum EPO (≥ vs < 500 mU/mL)- prior ESA (EA vs DA vs none)
Crossover permitted in lenalidomide arm
NR
Major ER (MER)
Continue treatment
▪ Rationale: LEN potentiates EPO signaling through the EPO receptor (from preclinical study)
List AF et al. ASH 2016. Abstract 223
OutcomeLenalidomide
(n = 81)Lenalidomide + EA
(n = 82)P Value
Intent to treat, n (%) (N = 163)MERMinor EROverall ER
9 (11.1)15 (18.5)24 (29.6)
21 (25.6)13 (15.9)34 (41.5)
.025.68.14
MER after crossover n = 34 7 (21)
Wk 16 evaluable, n (%) (n = 117)
MERMinor EROverall ER
8 (14.3)13 (23.1)21 (37.5)
20 (32.8)13 (21.3)33 (54.1)
.029.83.09
Median duration of MER, mos 13.0 25.4 .37
List AF et al. ASH 2016. Abstract 223
Toma A et al. Leukemia. 2016;30:897-905
▪ Results (N = 131)- HI-E (IWG 2006) after 4 cycles (primary endpoint)
23.1% (95% CI 13.5-35.2) vs. 39.4% (95% CI 27.6-52.2%; p = 0.044)- RBC-TI: 13.8% vs. 24.2% (p = 0.13) - Response duration 15.1 vs. 18.1 months (p = 0.47)
▪ Luspatercept (ACE-536)-a modified activin receptor type IIb (ActRIIb) fusion protein,acts as a ligand trap for GDF11 and other TFG-β family ligands to suppress Smad2/3 signaling
→ Inhibit erythropoiesis
Fenaux P et al. ASH 2018
Fenaux P et al. ASH 2018
Fenaux P et al. ASH 2018
Fenaux P et al. ASH 2018
Steensma et al. ASH 2018 Oral Presentation
single arm
open label
Background: IMerge/NCT02598661 (Part 1) Study Design1
1o Endpoint: 8-Week RBC TI2o Endpoints: 24-Week RBC TI / Time to TI / TI duration / TR (HI-E: Transfusion Reduction by ≥ 4 RBC units over 8 weeks) / MDS response per IWG / Overall survival / Incidence of AML / SafetyExploratory: telomerase activity / hTERT / telomere length / genetic mutations
Pre-medication: diphenhydramine, hydrocortisone 100-200 mg (or equivalent)Supportive care: RBC transfusions, myeloid growth factors per local guidelines
1. Fenaux P, et al. HemaSphere 2018;2(S1):S1557 [oral presentation]
Patients with MDS
• IPSS Low or Int-1• Relapsed / refractory to ESA or ineligible for
ESA• Transfusion dependent (≥ 4u RBC/8 weeks)• ANC ≥ 1.5 x 109/L • Platelets ≥ 75 x 109/L
Imetelstat Treatment
7.5 mg/kg IV q4w (2-hr infusion)
AML, acute myeloid leukemia; ANC, absolute neutrophil count; HI-E, hematologic improvement-erythroid; IWG, International Working Group; TI, transfusion independence; TR, transfusion reduction.
51
Steensma et al. ASH 2018 Oral Presentation
IMerge: Baseline Characteristics
Parameters N=38
Median age (range), years 71.5 (46-83)
Male, n (%) 25 (66)
ECOG PS 0-1, n (%) 34 (89)IPSS risk, n (%)
LowIntermediate-1
24 (63)14 (37)
Baseline median (range) RBC transfusion burden, units/8 weeks 8 (4–14)
WHO 2001 category, n (%)RARS or RCMD-RSAll others
27 (71)11 (29)
Prior ESA use, n (%) 34 (89)
sEPO > 500 mU/mL, n (%) 12a (32)aOf the 37 patients with sEPO levels reported.
52
Steensma D et al. ASH 2018
Lenalidomide and HMA naïve and Non-del (5q)
(n=38)
14 (37)
10 (26)
8.1 (0.1-33.1)
NE (17.0-NE)
27 (71)
-68
8 (21)
Steensma et al. ASH 2018 Oral Presentation
IMerge: Efficacy Results in EPO and RS Subgroups
Similar efficacy was observed across these subgroups
EPO, erythropoietin; RARS, refractory anemia with ringed sideroblasts; RCMD-RS, refractory cytopenia with multilineage dysplasia and ringed sideroblasts; RS, ring sideroblast; TI, transfusion independence.
0 10 20 30 40
EPO > 500 mU/mL (n=12)
EPO ≤ 500 mU/mL (n=25)
Other (n=11)
RARS/RCMD-RS (n=27)
8-week TI rate
% of Patients
37%
36%
40%
33%
54
Steensma et al. ASH 2018 Oral Presentation
IMerge: Most Common Treatment-Emergent Adverse Events
19 patients (50%) had dose reductions and 26 patients (68%) had cycle delays
Reversible grade 3 LFT elevations were observed in 3 (8%) patients on studyo Independent Hepatic Review Committee
considered these not drug-related
ALT, alanine aminotransferase; AST, aspartate aminotransferase; LFT, liver function test; TEAE, treatment-emergent adverse event.
2123
7 7
3 2 1 2 2
1
2
2
3 55 4 6 6 6 4
0
5
10
15
20
25
Num
ber o
f pat
ient
s with
≥ 1
TEA
E
Most common TEAEs
Grade ≥3
Grade 1-2
55
IPSS-Low IPSS-Intermediate 1LR-PSS category 1 LR-PSS category 2 LR-PSS category 3
DefiniteTreatment
Unmet needs
Clinical Trials
Lenalidomide
Erythropoietin (Darbepoetin)
Iron chelation
HSCT
HMAESA failure anemia
Lenalidomide + ESALuspatercept, Imetelstat, Roxadustat
IPSS-Low IPSS-Intermediate 1LR-PSS category 1 LR-PSS category 2 LR-PSS category 3
DefiniteTreatment
Unmet needs
Clinical Trials
Lenalidomide
Erythropoietin (Darbepoetin)
Iron chelation
HSCT
HMAESA failure anemia
Lenalidomide + ESALuspatercept, Imetelstat, Roxadustat
HMA in LR-PSS category 1 & 2
IST
LD-HMAs in LR-MDS: a Head to Head Phase II Study
▪ An open-label phase II study- Randomized by Bayesian adaptive design; patients more likely to be
assigned to better-performing treatment arm- Primary endpoint: ORR defined as CR, PR, marrow CR, or HI- 2ndary endpoints: safety, Cy response, TI, EFS, OS
Adults with de novo or secondary IPSS low- or
intermediate-1–risk MDS, including CMML, ECOG PS
≤ 3, adequate organ function, no prior HMA
(N = 113)
Decitabine 20 mg/m2 IV Days 1-3 Q4W
(n = 73)
Azacitidine 75 mg/m2 IV/SC Days 1-3 Q4W
(n = 40)
Jabbour EJ et al. Blood. 2017. Epub ahead of print
LD-HMAs in LR-MDS: a Head to Head Phase II Study
Jabbour EJ et al. Blood. 2017. Epub ahead of print
▪ Both low-dose HMAs showed activity, and were well tolerated ORR: 62%, 1-yr EFS: 65%, 1-yr OS: 85%▪ Significantly higher ORR of decitabine vs azacitidine
; particularly among pts with ≥ 5% blasts▪ No difference in terms of EFS and OS
*Median F/U 20 months Median treatment cycles 9 (1-41)
IPSS-Low IPSS-Intermediate 1LR-PSS category 1 LR-PSS category 2 LR-PSS category 3
DefiniteTreatment
Unmet needs
Clinical Trials
Lenalidomide
Erythropoietin (Darbepoetin)
Iron chelation
HSCT
HMAESA failure anemia
Lenalidomide + ESALuspatercept, Imetelstat, Roxadustat
HMA in LR-PSS category 1 & 2
Low Dose HMAOral Vidaza
IST
Kubasch A et al. Hemasphere 2018;2(S2): 135-137
ESA (Erythropoietic Stimulating Agent)
Bunn HF. Harrison's principles of internal medicine. 13th ed. New York: McGraw-Hill; 1994
Erythroidburst-formingunit (BFU-e)
Erythroidcolony-formingunit (CFU-e) Normoblasts
Pluripotentstem cell
NeutrophilsMonocytesMegakaryocytesLymphocytes
Pro-erythroblast Hemoglobinaccumulation
Globin mRNAaccumulation
Erythropoietinresponsiveness
ReticulocyteRed cell
1) Prevention of apoptosis for BFU-e, CFU-e2) Induction of proliferation and differentiation for
BFU-e, CFU-e
EPO
BFU-e CFU-e
Mechanism of EPO
Egrie JC, et al. Nephrol Dial Transplant 2001: 16(Suppl 3): 3-13
Difference in biochemical structure between Nesp and Espo• Darbepoetin Alfa (NESP®) is a compound in which five amino acid residues are replaced
with different amino acids and two N-linked oligosaccharide chains are added.• NESP® shows comparable efficacy and safety to ESPO®, with less dosing frequency.
▪ Erythrocyte-stimulating agents (ESA)• 1st-line treatment for symptomatic anemia • 40~60% of HI-E up to 18~24 months • Addition of G-CSF may be synergistic • Long-acting darbepoietin alfa
Hellstrom-Lindberg E, et al. Blood. 1998;92:68-75Jadersten M, et al. J Clin Oncol. 2008;26:3607-13Park S, et al. Blood. 2008;111:574-82Kelaidi C, et al. Ann Hematol. 2013;92:621-31
ESA ± G-CSF No. RR Leukemic TF. Duration of Res.Hellstrom-Lindberg
Phase II 50 (L+H) 38% 28% @43 mos median 24 months
Jadersten Phase II 121 (vs.237) 39% Not increased median 23 months
Park Retrospect. 403 50% N/A 20~24 months
Kelaidi Phase II 99 56% 14.5% @ 3yr Not reached @ 52wks
Ref) A. Villegas et. Al. CMRO Vol.27, No.5, 2011, 951-960
[Design] Single-arm, open-label, multi-center, phase 2 trial,
Patients with low or intermediate-risk MDS, EPO<500IU/L, DA 300mcg wk.
* For patients who did not achieve MaR by 8 weeks, filgrastim 300 mg weekly was added.
[Result] Erythroid response 70.5%(31/44) at week8, 70.5% at week16, 72.7% at week24
Randomized, double-blind, placebo-controlled, multicenter study, evaluating Epoetin-alfa versus placebo in anemic patients with IPSS Low-Int1 risk MDS
Fenaux et al, EHA 2016, Abstract: P248
Pre- randomizationphase
Epoetin AlfaN=85
Matching Placebo
N=45
Matching Placebo
Epoetin Alfa
Week -3 Screening evaluations
Baselin(D1)Double-blind treatmnet Week24* Week28* Week48* EOS**
Responders continue to Extension phase
Extension phaseWith continued Double-blind treatment(for responders at Wk24)
Fenaux et al. EHA 2016
EPO-alpha trial hematological response
Placebo n=45
Epoetin alfa n=85 p
Subjects achieving erythroid response (primary endpoint) 2 (4.4%) 27 (31.8%) <0.001
Subjects with erythroid response at any time during the first 24 weeks* 2 (4.4%) 39 (45.9%) <0.001
*Ad hoc analysis
0
10
20
30
40
50
60
Placebo
Epo alfa
% Hematological Improvement(IWG)
Any response in 24wks
EPOANE 3021 trial
Number of patients with abnormalities (n=79)
Kosmider et al. Haematologica 2016
86% of the pts had at least one mutation (median number 2, range 0-6) >10 % of pts had 6 mutations.
Molecular markers and response to ESAs
Kosmider et al. Haematologica 2016
Distribution of mutations according to response to ESA
Presence of >2 mutations predicted worse HI-E to ESA in lower risk MDS.≤2 mutations: 74%, vs > 2 mutations: 46% (p=0.01)
Number of mutations
HI-E (%)
0 73
1 71
2 79
3 47
4 38
• Study design
• Efficacy of darbepoetin alfa
24week Double-blind 48 week Open-label
24week Double-blind 48 week Open-label
59.2%(29/49)
36.1%(29/49)
14.7%(11/75)0%
(0/35)
P=0.008
P=0.016
34.7% (34/98)
Informed Consent and screening
Enrollment
60mcg DA
weekly
• Dose escalationNon-responder can increase the DA dose up to 240mcg
• Change of dose frequencyResponder can change the DA dose frequency from weekly to biweekly
End of study
120mcg DA
weekly
240mcg DA
weekly
Initial dose evaluation phase(16weeks)
Extended treatment evaluation phase(32weeks)
• Study design
Jang JH, et al. Int J Hematol. 2015; 102(4): 401-412.
• Efficacy
Jang JH, et al. Int J Hematol. 2015; 102(4): 401-412.
• Efficacy
Jang JH, et al. Int J Hematol. 2015; 102(4): 401-412.
• Safety
Jang JH, et al. Int J Hematol. 2015; 102(4): 401-412.
• Safety
Jang JH, et al. Int J Hematol. 2015; 102(4): 401-412.
• Safety
Jang JH, et al. Int J Hematol. 2015; 102(4): 401-412.
▪Who will benefit from ESA?Serum EPO < 500 U/LLow serum ferritinLower pre-treatment RBC transfusion (< 2u/month)Lower IPSS(-R) risk patients (RA or RARS; low blast percentage)Normal cytogeneticsAbsence of aberrant CD5/CD7 expressionActivated ERK pathway (pERK+)
▪ Risk of ESA• ↑mortality & VTE in non-MDS pts. if Hb target > 12 g/dL (2007 U.S. FDA)
: Use with caution, to LR-MDS patients, targeting Hb of 10~12 g/dL
86
Thank you