The role of the darbepoetin alfa in the treatment for Low-risk of...

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


DefiniteTreatment

Unmet needs

Clinical Trials

Lenalidomide


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


DefiniteTreatment

Unmet needs

Clinical Trials

Lenalidomide


Iron chelation


DefiniteTreatment

Unmet needs

Clinical Trials

Lenalidomide


Iron chelation

HSCT

MDS is predominantly a disease of the elderly (> 60 yrs old, 86%)

http://en.wikipedia.org/wiki/File:Azacitidine.svg

http://en.wikipedia.org/wiki/File:Azacitidine.svg

http://en.wikipedia.org/wiki/File:Decitabine.svg

http://en.wikipedia.org/wiki/File:Decitabine.svg

▪ 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


DefiniteTreatment

Unmet needs

Clinical Trials

Lenalidomide


Iron chelation

HSCT

HMA

IST


DefiniteTreatment

Unmet needs

Clinical Trials

Lenalidomide


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

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


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)


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


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


DefiniteTreatment

Unmet needs

Clinical Trials

Lenalidomide


Iron chelation

HSCT


Lenalidomide + ESALuspatercept, Imetelstat, Roxadustat


DefiniteTreatment

Unmet needs

Clinical Trials

Lenalidomide


Iron chelation

HSCT



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)


DefiniteTreatment

Unmet needs

Clinical Trials

Lenalidomide


Iron chelation

HSCT



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


• Safety


▪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

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