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“Terapias alvo nas síndrome mielodisplásicas. Algo além do 5q- ? ”
Breno Moreno de GusmãoBP, a Beneficência Portuguesa de São Paulo
Hospital Santa Lúcia – [email protected]
@morenodegusmao
Conflitos de interesse
• Speaker: Amgen, Celgene, Janssen, MSD, United medical
• Ad. Board: Libbs, Gilead
Clasificación FAB% blastos sp % blastos mo % Sb en anillo
en moMonocitos sp
AR < 1 < 5 < 15 < 1x109 / L
ARSA < 1 < 5 ≥ 15 < 1x109 / L
AREB < 5 5 – 20 Indiferente < 1x109 / L
AREB-t ≥ 5 21 – 30 Indiferente < 1x109 / L
LMMCMD: < 13 × 109 leucocitos/LMP: > 13 × 109 leucocitos/L
< 5 0 – 20 Indiferente ≥ 1x109 / L
AR: Anemia Refractaria Simple.ARSA: Anemia Refractaria con Sideroblastos en Anillo.AREB: Anemia Refractaria con Exceso de Blastos.AREB-t: Anemia Refractaria con Exceso de Blastos en transformación.LMMC: Leucemia MieloMonocítica Crónica.
OMS 2008
% blastos sp % blastos
mo
% Sb en anillo
en moCitopenias Displasia
AR < 1 < 5 < 15 Anemia Sólo eritroide
ARSA 0 < 5 ≥ 15 Anemia Sólo eritroide
CRDM < 1 < 5 < 15 Bicitopenia o pancitopenia
≥ 2 líneas
CRDM con
Sb en anillo< 1 < 5 ≥ 15 Bicitopenia o
pancitopenia≥ 2 líneas
AREBTipo1 Tipo2
< 5 5 - 19
5 – 9 10 – 19
Indiferente Citopenia /s Indiferente
Sd. 5q- < 5 < 5 Indiferente Anemia Indiferente
SMD
inclasificable< 1 < 5 Indiferente Citopenia /s 1 línea
CRDM: Citopenia Refractaria con Displasia Multilínea.
CRDM con Sb en anillo: Citopenia Refractaria con Displasia Multilínea y Sideroblastos en anillo.
Sd. 5q-: Síndrome 5q- (presencia de la alteración citogenética aislada 5q-).
SMD inclasificable: Síndrome Mielodisplásico Inclasificable.
NOTA: los SMD que comparten signos de mielodisplasia y mieloproliferación se encuadran en la categoría de SMD / SMP), cuyo prototipo es la LMMC.
OS Transformation to AML
Schanz J, et al. J Clin Oncol. 2012;30:820-829.
IPSS-R: OS and Transformation to AML by Risk Group
1.0
0.8
0.6
0.4
0.2
0
Frac
tio
n S
urv
ival
35050 100 150 200 250 300
Mos
Very good (n = 81; events: 34)
Good (n = 1809; events: 890)
Intermediate (n = 529; events: 312)
Poor (n = 148; events: 109)
Very poor (n = 187; events: 158)
Log-rank P < .001
1.0
0.8
0.6
0.4
0.2
0
Frac
tio
n A
ML-
Free
Su
rviv
al
35050 100 150 200 250 300
Mos
Very good (n = 72; events: 6)Good (n = 1611; events: 284)Intermediate (n = 457; events: 145)Poor (n = 129; events: 56)Very poor (n = 167; events: 47)
Log-rank P < .001
0 0
Papaemmanuil E, et al. Blood. 2013.
Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia
N Engl J Med 2013
Impact on survival of mutation TP53 mutations in patients
with MDS treated with allogeneic stem cell transplantation
N Engl J Med. 2017;376(6):536–547
Luspatercept in Ring Sideroblast+ Myelodysplastic Syndrome (MEDALIST): Background
• MDS characterized by ineffective erythropoiesis, anemia requiring lifelong RBC transfusions
• Anemia treatment is unmet need in lower-risk transfusion-dependent MDS that is refractory to ESAs
• Luspatercept: first-in-class erythroid maturation agent
• Blocks aberrant Smad2/3 signaling to augment late-stage erythropoiesis
• Promising clinical activity in lower-risk MDS patients with anemia[1]
• MEDALIST: randomized, double-blind, placebo-controlled phase III trial evaluating safety and efficacy of luspatercept in pts with very low- to intermediate-risk MDS with ring sideroblasts who require regular RBC transfusions[2]
1. Platzbecker. Lancet Oncol. 2017;18:1338. 2. Fenaux. ASH 2018. Abstr 1.
MEDALIST: Study Design• International, randomized, double-blind, placebo-controlled phase III trial
Slide credit: clinicaloptions.comFenaux. ASH 2018. Abstr 1. NCT02631070.
Primary endpoint: RBC TI for ≥ 8 wks between Wk 1 and Wk 24
Secondary endpoints: RBC TI for ≥ 12 wks between Wk 1 and Wk 24, modified hematologic improvement–erythroid response per IWG 2006 criteria, DoR, Hb change from baseline
Patients ≥ 18 yrs of age with non-del(5q) MDS and ring
sideroblasts per WHO 2016 criteria; IPSS-R risk that is very
low, low, or intermediate; refractory, intolerant, or ineligible for ESAs; RBC transfusion dependent
(N = 229)
Luspatercept1.0 mg/kg* SC Q3W for ≥ 24
wks (n = 153)
PlaceboSC Q3W for ≥ 24 wks
(n = 76)
Randomized 2:1
*Could be titrated up to 1.75 mg/kg if needed.
Treatment continued
until lack of clinical
benefit or PD
MEDALIST: EfficacyOutcome, %
Luspatercept(n = 153)
Placebo(n = 76)
P Value
RBC TI ≥ 8 wks in Wks 1-24 37.9 13.2 < .0001
RBC TI ≥ 12 wks in Wks 1-24 28.1 7.9 .0002
RBC TI ≥ 12 wks in Wks 1-48 33.3 11.8 .0003
mHI-E* ≥ 8 wks in Wks 1-24
Reduction of ≥ 4 RBC units/8 wks
Hb increase of ≥ 1.5 g/dL
52.948.663.0
11.814.35.0
< .0001
mHI-E* ≥ 8 wks in Wks 1-48
Reduction of ≥ 4 RBC units/8 wks
Hb increase of ≥ 1.5 g/dL
58.854.269.6
17.121.45.0
< .0001
Fenaux. ASH 2018. Abstr 1.
*Defined as transfusion reduction of ≥ 4 units/8 wks or mean hemoglobin increase ≥ 1.5 g/dL/8 wks in absence of transfusions
Among primary endpoint responders, the median duration of RBC TI response was 30.6 wks in the luspatercept arm vs 13.6 wks in the placebo arm
MEDALIST: Conclusions• Luspatercept significantly reduced RBC transfusion burden
compared with placebo in transfusion-dependent patients with very low- to intermediate-risk MDS with RS
• Met primary endpoint of improving proportion of patients achieving RBC transfusion independence for ≥ 8 wks in Wks 1-24
• Significantly more patients achieved RBC transfusion independence for ≥ 12 wks in Wks 1-24 and in Wks 1-48
• Significantly more patients achieved increase in Hb of ≥ 1.5 g/dL
• Luspatercept significantly improved mHI-E of ≥ 8 wks
• Treatment generally well tolerated
• Investigators conclude that luspatercept may offer new treatment option for transfusion-dependent anemia in lower-risk RS-positive MDS patients
Slide credit: clinicaloptions.comFenaux. ASH 2018. Abstr 1.
Venetoclax + HMAs in Elderly Patients With Untreated AML: Background• BCL-2: antiapoptotic protein overexpressed in AML, including AML stem
cells[4]
• Venetoclax: oral BCL-2 inhibitor • Promising activity seen when combined with HMAs in elderly patients with
untreated AML[5]
• Venetoclax in combination with azacitidine or decitabine or low-dose cytarabine granted accelerated approval in November 2018 by FDA for treatment of newly diagnosed AML in patients aged ≥ 75 yrs or who have comorbidities preventing use of intensive induction chemotherapy[6]
• Current dose-escalation and dose-expansion study assessed safety of venetoclax with azacitidine or decitabine in older patients with untreated AML ineligible for intensive chemotherapy[5,7]
• CR/CRi rate: 67%; median DoR: 11.3 mos; median OS: 17.5 mos; venetoclax 400 mg established R2PD[5]
• Current analysis reports data from expansion cohort of patients receiving venetoclax 400 mg + HMA[7]
1. National Cancer Institute. AML Stats. 2018. 2. Kantarjian. Blood. 2010;116:4422. 3. Krug. Dtsch Arztebl Int. 2011;108:863. 4. Tzifi. Adv Hematol. 2012;2012:524308. 5. DiNardo. Blood. 2018;[Epub]. 6. FDA. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm626499.htm. 7. Pollyea. ASH 2018. Abstr 285. Slide credit: clinicaloptions.com
Venetoclax + HMAs in Elderly Patients With Untreated AML: Study Design
Multicenter, open-label phase Ib dose-escalation and dose-expansion study
Endpoints: Safety, CR/CRi, OS, DoRPollyea. ASH 2018. Abstr 285. Slide credit: clinicaloptions.com
Patients aged ≥ 60 yrs with untreated AML ineligible for
standard induction therapy;
ECOG PS 0-3; no favorable risk cytogenetics or
active CNS involvement
Safety, PK, dose
finding
Expansion stage:
safety and efficacy
confirmation
Venetoclax 400 mg + DEC(n = 6)
Venetoclax 400 mg + AZA(n = 4)
Venetoclax 400 mg + DEC(n = 25)
Venetoclax 400 mg + AZA(n = 25)
Venetoclax 800 mg + DEC(n = 25)
Venetoclax 800 mg + AZA(n = 25)
Venetoclax 400 mg + AZA(n = 55)
Escalation PhaseExpansion Phase
Analysis population includes only the
400-mg venetoclax dose patient cohort:
VEN + AZA, n = 84VEN + DEC, n = 31
Dosing: Venetoclax 100 mg Day 1, 200 mg Day 2, 400 mg Days 3-28; azacitidine 75 mg/m2 Days 1-7; decitabine 20 mg/m2 Days 1-5.Main exclusion criteria: previous treatment for AML or other hematologic disorder; favorable risk cytogenetic (NCCN); CNS involvement; WBC > 25 x 109/L; HIV, HBV, or HCV coinfection.
Venetoclax + HMAs in Elderly Patients With Untreated AML: Patient Population
Text…
Pollyea. ASH 2018. Abstr 285. Slide credit: clinicaloptions.com
Characteristic
Venetoclax 400 mg +
AZA(n = 84)
Venetoclax 400 mg +
DEC(n = 31)
Median age, yrs (range) ≥ 75 yrs, n (%)
75 (61-90)42 (50)
72 (65-86)8 (26)
ECOG PS, n (%) 0-1 2
58 (69)24 (29)
27 (87)4 (13)
Baseline BM blasts, n (%) < 30% ≥ 31% to <
50% ≥ 50%
24 (29)29 (34)31 (37)
7 (23)14 (45)10 (30)
Characteristic
Venetoclax 400 mg +
AZA(n = 84)
Venetoclax 400 mg +
DEC(n = 31)
Mutational analyses, mutated/tested (%)
TP53 IDH1/2 FLT3 NPM1
20/74 (27)20/74 (27)11/74 (15)14/74 (19)
7/22 (32)5/22 (23)3/22 (14)3/22 (14)
Cytogenetic risk, n (%) Intermediate Poor
50 (60)33 (39)
16 (52)15 (48)
Secondary AML, n (%)
21 (25) 9 (29)
Venetoclax + HMAs in Untreated AML: Responses
Slide credit: clinicaloptions.com
OutcomeVenetoclax 400 mg +
AZA(n = 84)
Venetoclax 400 mg + DEC
(n = 31)
CR 44 55
CRi 27 19
Median time to CR, mos (range) 1.2 (0.7-5.5) 1.9 (0.9-4.6)
Median no. treatment cycles in patients with CR, n (range)
6 (1-32) 6 (1-29)
Median DoR after CR/CRi, mos (95% CI) 12-mo EFS in patients with CR/CRi, % (95% CI)
21.2 (14.4-30.2)69 (52-80)
15.0 (5.0-22.5)57 (32-76)
12-mo overall EFS, % (95% CI) 12-mo EFS in patients with CR/CRi, % (95% CI) 12-mo EFS in patients with no CR/CRi, % (95%
CI)
57 (46-67)72 (58-81)19 (6-37)
61 (42-76)74 (51-87)25 (4-56)
Median overall OS, mos (95% CI) Median OS in patients with CR/CRi, mos (95% CI) Median OS in patients with no CR/CRi, mos (95%
CI)
16.9 (11.3-NR)40.3 (16.9-NR)
4.5 (2.4-8.9)
16.2 (9.1-27.8)18.2 (12.3-42.7)
4.8 (0.7-17.0)
MRD negativity, n/n (%) 29/60 (48) 9/23 (39)
Pollyea. ASH 2018. Abstr 285.
Venetoclax + HMAs Venetoclax + HMAs in Elderly Patients With Untreated AML: CR/CRi by Subgroup
Slide credit: clinicaloptions.com
Patient Group, CR/Crin/n (%) of Each Subgroup
Venetoclax 400 mg + AZA
Venetoclax 400 mg + DEC
Cytogenetic risk
Intermediate 38/50 (76) 11/16 (69)
Poor 22/33 (67) 12/15 (80)
AML type
de novo 48/63 (76) 16/22 (73)
Secondary 12/21 (57) 7/9 (78)
Mutations
TP53 13/20 (65) 6/7 (86)
IDH1/2 18/20 (90) 5/5 (100)
FLT3 8/11 (73) 1/3 (33)
NPM1 11/14 (79) 3/3 (100)Pollyea. ASH 2018. Abstr 285.
Venetoclax + HMAs in Elderly Patients With Untreated AML: Investigator Conclusions
• In older patients with untreated AML ineligible for intensive chemotherapy, venetoclax 400 mg with azacitidine or decitabine was active and tolerable
• CR/CRi: 71% vs 74% with venetoclax + azacitidine or decitabine, respectively• Baseline genetic mutations, cytogenetic risk had little effect on CR/CRi rates
• 12-mo DoR: 69% vs 57% with venetoclax + azacitidine or decitabine, respectively
• Median OS: 16.9 vs 16.2 mos with venetoclax + azacitidine or decitabine, respectively
• Most common serious AEs• Febrile neutropenia: 31% vs 45% with venetoclax + azacitidine or decitabine,
respectively• Pneumonia: 23% vs 29% with venetoclax + azacitidine or decitabine,
respectively • Ongoing phase III trial evaluating venetoclax 400 mg plus azacitidine in
untreated AML ineligible for standard induction therapy (NCT02993523)
Slide credit: clinicaloptions.comPollyea. ASH 2018. Abstr 285.
Immune Checkpoint Inhibitors in MDS: Background
PD-1, PD-L1, and CTLA-4 are expressed by CD34+ MDS cells
‒ Overexpressed in the presence of HMAs both in vitro and in vivo[1]
Immune checkpoints: emerging therapeutic targets in many cancers
New therapies needed for treating MDS in frontline setting and after HMA failure
Current analysis evaluated safety and efficacy of ICI treatment, alone for MDS after HMA failure or in combination with an HMA for frontline treatment of patients with MDS[2]
1. Yang. Leukemia. 2014;28:1280. 2. Garcia-Manero. ASH 2018. Abstr 465. Slide credit: clinicaloptions.com
Checkpoint Inhibitors in MDS: Study Design
Garcia-Manero. ASH 2018. Abstr 465. Slide credit: clinicaloptions.com
Exploratory phase II basket trial*
Patients ≥ 18 yrs of age with WHO MDS,
untreated or HMA failure; acceptable PS,
hepatic, and renal function; no prior inflammatory or
autoimmune disease(N = 76†) 5-azacitidine 75 mg/m2 IV x 5 days Q28d +
Nivolumab 3 mg/kg IV Days 6, 20
(n = 20)
5-azacitidine 75 mg/m2 IV x 5 days Q28d +
Ipilimumab 3 mg/kg IV Days 6
(n = 21)
*Data for 2 cohorts (ipilimumab + nivolumab and 5-azacitidine + ipilimumab + nivolumab) not included in this analysis. †Maximum 20 patients/ cohort. ‡5-azacitidine added back if no response after 6 cycles of ICI.
Untreated
HMA failure
Nivolumab 3 mg/kg IV Q2W‡
(n = 15)
Ipilimumab 3 mg/kg IV Q3W‡
(n = 20)Stopping rules for toxicity and
response
Primary endpoints:
ORR (CR + PR + HI) in patients with HMA failure
ORR in untreated patients
Checkpoint Inhibitors in MDS: Response
3 patients were not evaluable
Median number of cycles: 4 (range: 1-29)
Median number of cycles to response: 3 (reang: 1-15)
Garcia-Manero. ASH 2018. Abstr 465. Slide credit: clinicaloptions.com
Response, n (%)
Frontline HMA Failure
Nivo + AZA(n = 20)
Ipi + AZA(n = 21)
Nivo(n = 15)
Ipi(n = 20)
ORR 14 (70) 13 (62) 0 6 (30)
CR 8 (40) 3 (14) 0 0
mCR + HI 2 (10) 0 0 1 (5)
mCR 3 (15) 7 (33) 0 3 (15)
HI 1 (5) 3 (14) 0 3 (15)
SD 0 1 (5) 0 0
NR 5 (25) 5 (24) 15 (100) 13 (65)
Checkpoint Inhibitors in MDS: OS in Untreated Patients
Garcia-Manero. ASH 2018. Abstr 465. Slide credit: clinicaloptions.com
Median OS, MosNot reached
11.8
1-Yr OS, %6850
2120
1417
1110
48
04
01
1.00
0.75
0.50
0.25
0
OS
0 6 12 18 24 30Mos
P = .36
StrataAZA + IpilimumabAZA + Nivolumab
Number at risk
AZA + IpilimumabAZA + Nivolumab
Checkpoint Inhibitors in MDS: OS after HMA Failure
Garcia-Manero. ASH 2018. Abstr 465. Slide credit: clinicaloptions.com
1-Yr OS, %4525
Median OS, Mos8.5 8.0
2015
127
93
63
32
00
1.00
0.75
0.50
0.25
0
OS
0 6 12 18 24 30Mos
StrataIpilimumabNivolumab
P = .48
IpilimumabNivolumab
Number at risk
Checkpoint Inhibitors in MDS: Conclusions Treatment with immune checkpoint inhibitors showed significant activity
in MDS, both as single agents and in combination with 5-AZA
‒ Single-agent activity of ipilimumab after HMA failure: ORR, 30%; 1-yr OS, 45%
‒ High response rates with nivolumab + AZA: CR, 40%; ORR, 70%
‒ Median OS not reached with ipilimumab + AZA
Acceptable toxicity profile
Investigators concluded that the incorporation of ipilimumab or nivolomab into treatment of MDS is feasible, but further randomized studies needed
Garcia-Manero. ASH 2018. Abstr 465. Slide credit: clinicaloptions.com
Ivosidenib in Mutant IDH1 AML:
Background Somatic mutations in enzymes IDH1 and IDH2 cause accumulation of
oncometabolite 2-HG[1]
– 2-HG accumulation results in epigenetic changes and impaired cellular differentiation
mIDH has been found in solid and hematologic tumors, including AML
– mIDH1 found in approximately 6% to 10% AML pts
– mIDH2 found in approximately 9% to 13% AML pts
Ivosidenib (AG-120), investigational, first-in-class, oral, reversible targeted inhibitor of mIDH1 enzyme[2]
Current phase I study investigating dosage, safety, and clinical activity of ivosidenib in pts with mIDH1-positive R/R AML, untreated AML, and other hematologic malignancies[3]
1. Dang L, et al. Ann Oncol. 2016;27:599-608. 2. Birenda KC, et al. Clin Lymphoma
Myeloma Leuk. 2016;16:460-465.3. DiNardo CD, et al. ASH 2017. Abstract 725. Slide credit: clinicaloptions.com
Ivosidenib in Mutant IDH1 AML:
Phase I
Study Design Multicenter, open-label, dose-escalation/expansion trial
Pts with mIDH1
advanced
hematologic
malignancies
Ivosidenib PO daily, 28-day cycles
100 mg BID, or 200 mg, 500 mg,
800 mg, or 1200 mg QD
(n = 78)
Dose Escalation
Primary endpoints: safety and tolerability, MTD and/or RP2D, and clinical activity* in mIDH1 R/R AML
Secondary endpoints: DLTs, PD, PK, preliminary clinical activity in advanced hematologic malignancies
Exploratory endpoints: determination of comutations and mIDH1 VAFIvosidenib 500 mg PO QD
28-day cycles
(n = 180)
DiNardo CD, et al. ASH 2017. Abstract 725.
Dose Expansion
Pts with R/R AML in second
relapse, relapse after SCT,
refractory to induction or
reinduction, relapse ≤ 1 yr
(n = 126)Pts with untreated AML
ineligible for SoC (n = 25)
Pts with non-AML mIDH1
R/R advanced
hematologic malignancy
(n = 11)Pts with R/R AML not
eligible for other R/R AML
arm (n = 18)
Slide credit: clinicaloptions.com
*CR CRh
Ivosidenib in Mutant IDH1 AML:
Baseline Characteristics
CharacteristicPrimary R/R AML Set
(n = 125)
Median age, yrs (range) 67.0 (18-87)
Male, % 52
ECOG PS 0 at screening, %
ECOG PS1 at screening, %
21.6
51.2
De novo AML, %
Secondary AML, %
History of MDS, %
Therapy-related AML, %
66.4
33.6
14.4
11.2
Median no. of previous
therapies (range)2.0 (1-6)
Earlier AML therapy
outcomes,* %
Relapsed after transplant
In second or later relapse
Refractory to initial
induction/reinduction
therapy
Relapsed ≤ 1 yr of initial
therapy
28.8
16.0
68.8
10.4
CharacteristicPrimary R/R AML Set
(n = 125)
Cytogenetic risk status,†%
Favorable
Intermediate
Poor
Unknown
Missing
0
52.8
30.4
3.2
13.6
Comutation rates,‡%
FLT3
• FLT3-ITD
• FLT3-TKD
NPM1
CEBPA
8.1
2.4
5.6
19.4
2.4
DiNardo CD, et al. ASH 2017. Abstract 725.
*Not mutually exclusive. Individual pt may be in
> 1 category.†Determined by investigator.‡n = 124.
Slide credit: clinicaloptions.com
Median treatment duration for primary R/R AML set: 3.9 mos (range: 0.1-25.8)
Ivosidenib in Mutant IDH1 AML: Response in
Primary R/R AML Set
Duration of Best Overall Response in
Responders (n = 52)
Duration of
Response
CR +
CRhCR All
Median, mos 8.2 9.3 6.5
At 6 mos, % 59.3 67.5 55.0
At 12 mos, % 32.4 41.2 24.6
OutcomePrimary R/R AML Set
(n = 125)
CR + CRh, % (95% CI)
Median time to CR/CRh, mos (range)
Median duration of CR/CRh, mos (range)
30.4 (22.5-39.3)
2.7 (0.9-5.6)
8.2 (5.5-12.0)
CR, % (95% CI)
Median time to CR, mos (range)
Median duration of CR, mos (95% CI)
21.6 (14.7-29.8)
2.8 (0.9-8.3)
9.3 (5.6-18.3)
CRh, %* 8.8
ORR, % (95% CI)
Median time to first response, mos
(range)
Median duration of response, mos (95%
CI)
41.6 (32.9-50.8)
1.9 (0.8-4.7)
6.5 (4.6-9.3)
Best response, %
CR
CRi or CRp
MLFS
SD
PD
NA
21.6
12.8
7.2
35.2
10.4
12.8
DiNardo CD, et al. ASH 2017. Abstract 725. Slide credit: clinicaloptions.com
*6 pts w/investigator-assessed
CRi/CRp, 5 w/MLFS
Ivosidenib in Mutant IDH1 AML: OS and
Transfusion Independence in R/R AML
DiNardo CD, et al. ASH 2017. Abstract 725. Slide credit: clinicaloptions.com
Independence from Transfusion by
Best Response*
OS by Best Response (n = 125)Median OS,
Mos
NE
9.3
3.9
8.8
Pts, n
38
14
73
125
Pro
ba
bil
ity o
f S
urv
iva
l
CR + CRh
Non-CR/CRh
responders
Nonresponders
Overall
Censored
CR
CRh
Non-CR/CRh
responders
Nonresponders
Overall
Po
stb
as
eli
ne
Tra
ns
fus
ion
Ind
ep
en
de
nc
e (
%)
Platelet
(n = 69)
RBC
(n = 68)
*Transfusion independence: no transfusion for at least 1 56-day period.
1.0
0.8
0.6
0.4
0.2
0
0.9
0.7
0.5
0.3
0.1
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32
Mos
100100
80
60
40
20
0
84.6
71.475.0
58.3
50.0
16.7 15.4
39.1 39.7
Ivosidenib in Mutant IDH1 AML: Response in
Untreated AML and MDS
Outcome Untreated AML (n = 34) MDS (n = 12)
Median age, yrs (range) 76.5 (64-87) 72.5 (52-78)
Male, % 55.8 75
ECOG PS 0 at screening, n (%)
ECOG PS 1 at screening, n (%)
8 (23.5)
20 (58.8)
4 (33.3)
6 (50.0)
Previous MDS, n (%) 18 (52.9) NA
ORR, % (95% CI)
Median duration of response, mos (95% CI)
Median duration of CR, mos (95% CI)
55.9 (37.9-72.8)
9.2 (1.9-NE)
NE (5.5-NE)
91.7 (61.5-99.8)
NE (2.3-NE)
NE (2.8-NE)
Best response, n (%)
CR
CRi or CRp
PR
MLFS
SD
PD
NA
7 (20.6)
7 (20.6)
1 (2.9)
4 (11.8)
10 (29.4)
3 (8.8)
2 (5.9)
5 (41.7)
NA
NA
6 (50.0)
0
1 (8.3)
0
DiNardo CD, et al. ASH 2017. Abstract 725. Slide credit: clinicaloptions.com
Ivosidenib in Mutant IDH1 AML:
Conclusions
Ivosidenib was well tolerated, most AEs grade 1/2
In pretreated pts with IDH1-positive R/R AML, ivosidenib associated with durable responses
– CR + CRh: 30.4%; duration: 8.2 mos
– ORR: 41.6%; duration: 6.5 mos
Transfusion independence achieved across best response categories
Preliminary evidence of durable responses in pts with untreated AML
Young G, et al. ASH 2017. Abstract 85. Slide credit: clinicaloptions.com
Enasidenib in mIDH2 MDS: Background
• IDH2 gene mutated in approximately 5% of MDS pts[1]
• Critical for the citric acid cycle; mutant form can alter gene expression, block differentiation of hematopoietic progenitor cells
• mIDH2 produces 2-HG, an oncometabolite that blocks cellular differentiation by altering DNA methylation
• May represent a therapeutic target
• Enasidenib (AG-221): first-in-class, potent oral inhibitor of mIDH2enzyme[2]
• Current analysis assessed efficacy, safety of enasidenib in MDS ptswith mIDH2[3]
1. Medeiros BC, et al. Leukemia. 2016;[Epub ahead of print]. 2. Chen J, et
al. Mini Rev Med Chem. 2016;16:1344-1358. 3. Stein EM, et al. ASH
2016. Abstract 343. Slide credit: clinicaloptions.com
Enasidenib in mIDH2 MDS: Study Design
• Subset analysis of open-label phase I/II dose escalation/expansion study of enasidenib in hematologic malignancies with IDH2 mutation (N = 239)
• MDS pts with mIDH2 R/R RAEB-1/RAEB-2, IPSS-R high-risk disease, or ineligible for other treatment (n = 17)
• Oral daily enasidenib (50-650 mg in dose escalation; 100 mg in expansion) in continuous 28-day cycles
• Key endpoints: safety, tolerability, ORR per local investigator (IWG 2006 MDS criteria)
• Co-molecular profiling with next-generation sequencing
Slide credit: clinicaloptions.comStein EM, et al. ASH 2016. Abstract 343.
Enasidenib in mIDH2 MDS: Baseline Characteristics
Characteristic MDS Pts
(N = 17)
Median age, yrs (range) 67 (45-78)
Male, % 71
Mean time since diagnosis, mos (SD) 16.8 (14.5)
IDH2 mutation: R140/R172, % 88/12
Prior anticancer regimens: 0/1/≥ 2, % 24/41/35
Hematology, median (range)
ANC, 109/L
Platelets, 109/L
WBC, 109/L
Hemoglobin, g/dL
0.7 (0.2-32.1)
71 (19-246)
2.1 (0.5-44.4)
8.9 (7.3-12.2)
ECOG PS 0-1/2, % 76/24
Slide credit: clinicaloptions.comStein EM, et al. ASH 2016. Abstract 343.
*Data missing for 4 of 17 pts.†Sorafenib, n = 2; cytarabine + clofarabine,
pracinostat, epoetin alfa, rigosertib, ruxolitinib,
vosaroxin, n = 1 each.
Characteristic, % MDS Pts (N = 17)
IPSS risk status*
Intermediate-1/intermediate-2 or
high29/47
MDS cytogenetic risk*
Good/intermediate/poor 47/24/6
IPSS-R risk status*
Low/intermediate/high or very
high 18/12/47
Prior treatment
HMA
Lenalidomide
Other†
None
76
12
47
24
Response, n/N (%) MDS Pts
(N = 17)
ORR* 10/17 (59)
CR† 1/11 (9)
PR† 1/11 (9)
mCR† 3/11 (27)
Any HI
Erythrocytes
Platelets
Neutrophils
Trilineage
improvement
Bilineage improvement
5/17 (29)
3/15 (20)
4/12 (33)
4/10 (40)
2/5 (40)
2/5 (40)
Enasidenib in mIDH2 MDS: Response
• 7 of 13 pts (54%) with prior HMA responded to enasidenib
• Median time to response: 21 days (range: 10-87)
Slide credit: clinicaloptions.comStein EM, et al. ASH 2016. Abstract 343.
*CR + PR + mCR + HI.†Investigator-assessed; pts had ≥ 5%
BM blasts at BL.
Enasidenib in mIDH2 MDS: OS• Median OS not
reached at median follow-up of 7.5 mos
Slide credit: clinicaloptions.comStein EM, et al. ASH 2016. Abstract 343. Reproduced with permission.
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Novel approaches to MDS currently in clinicle trials.