Targeted Treatment

in MDS

Luca Malcovati, MD

Department of Molecular Medicine,

University of Pavia Medical School,

& Department of Hematology Oncology,

IRCCS Policlinico S. Matteo Foundation,

Pavia, Italy

DISCLOSURE

Luca Malcovati, MD

No relevant financial relationships to disclose.

Which of the following statements relevant to targeted treatment in MDS

is correct?

a) Degradation of a kinase encoded by a gene within the common deleted region

provides the therapeutic window for targeting the del(5q) clone.

b) Haploinsufficiency may offer a prefential vulnerability for therapeutic targeting of

MDS clones.

c) Mis-splicing by mutated splicing factors results in a non-classical path to

haploinsufficiency of target genes in spliceosome-mutant MDS.

d) Inhibition of wild-type spliceosome may provide a way to preferentially target

MDS with splicing factor mutations.

e) All the above.

Outline

• Critical issues for targeted therapy in

MDS

• Targeting MDS-defining genetic lesions

• Targeting pan-myeloid drivers in MDS

• Targeting functional consequences of

MDS driver genetic lesions

Critical issues for targeted treatment in MDS

• Genetic heterogeneity

• Genetic complexity

• Extra clonal and context-dependent variables

• Patient-related variables (age, extra-hematologic comorbidities)

Landscape of somatic mutations in MDS

Papaemmanuil et al. Blood. 2013;122:3616-27

Genetic heterogeneity of MDS

UniPv

Registry

N=442 pts

205

Genetic

Profiles

232

Genotypes

Genetic complexity of MDS

Del(5q)

SF3B1 mutation

Blood. 2013;122:3616-27University of Pavia - Registry

Targeting MDS-specific genetic lesions

the paradigm of del(5q)

Nature 2008;451:335; Nat Med 2010;16:49; Nat Med 2010;16:59; Cancer Cell. 2014;26:509-20.

miRNA-145

miRNA-146a RPS14 CSNK1A1

Presumptive evidence of

primary MDS

N Engl J Med 2006;355:1456-65

Lenalidomide in the Myelodysplastic Syndrome

with Chromosome 5q Deletion

Eligibility: IPSS Low/Int-1 del(5)(q31), Transfusion dependent

Erythroid response 99/148 (67%)

Median baseline Hb 7.8 g/dL

Median Hb at response 13.4 g/dL

Complete cytogenetic remission 38/85 (45%)

Alan List, M.D., Gordon Dewald, Ph.D., John Bennett, M.D., Aristotle Giagounidis, M.D., Azra Raza, M.D., Eric Feldman,

M.D., Bayard Powell, M.D., Peter Greenberg, M.D., Deborah Thomas, M.D., Richard Stone, M.D., Craig Reeder, M.D.,

Kenton Wride, M.S., John Patin, M.S., Michele Schmidt, R.N., Jerome Zeldis, M.D., Robert Knight, M.D., for the

Myelodysplastic Syndrome-003 Study Investigators

Vulnerability of 5q- clone to lenalidomide

consequent to gene haploinsufficiency

Cancer Cell. 2014;26:509-20; Nature. 2015;523:183-188; Leukemia. 2019

Persistent malignant stem cells in MDS del(5q) in remission

Tehranchi R et al. N Engl J Med 2010;363:1025-1037.

Predictive value for disease progression during lenalidomide

of mutations in TP53 in MDS del(5q)

J Clin Oncol 2011;29:1971-1979; Blood 2013;122:2943-2964

Diagnosis and treatment of primary MDS in adults: Recommendations from the European

LeukemiaNet

Patients with 5q deletion, a low or intermediate-1 IPSS score, and evidence of TP53 mutation have a

significantly higher risk of transformation to AML, which should be considered in the choice between

lenalidomide and alternative therapeutic options (recommendation level D).

Summary

• Targeting of MDS founding lesions is effective and may result in (cyto)genetic remission

• Haploinsufficiency represents a targetable vulnerability of MDS clones

Mis-splicing patterns associated with spliceosome mutations contribute

to MDS through a non-classical path to haploinsufficiency

Shiozawa Y et al. Nat Commun. 2018;9:3649

SF3B1 mutation is a founding driver mutation in MDS and identifiesa distinct subset of MDS with ring sideroblasts

Blood 2011;118:6239-46; Blood 2013;122:3616-27; Nat Commun. 2015;6:10004; Blood 2017;130:881-890

SF3B1-mutated

SF3B1-unmutated

Genetic determinants of clinical phenotype and disease outcome in

SRSF2P95-mutated myeloid neoplasms

Todisco et al. Manuscript submitted

Pladienolides

Therapeutic targeting of RNA splicing in MDS

Nat Med. 2018;24:497-504.

H3B-8800

Session: 637. Myelodysplastic Syndromes—Clinical Studies: Targeting Gene Mutations in MDS

Monday, December 9, 2019: 10:30 AM

W311ABCD, Level 3 (Orange County Convention Center)

673 - Steensma et al. Results of a Clinical Trial of H3B-8800, a Splicing Modulator, in Patients with

Myelodysplastic Syndromes (MDS), Acute Myeloid Leukemia (AML) or Chronic Myelomonocytic

Leukemia (CMML)

Therapeutic targeting of RNA splicing in MDS

Han et al. Science 2017;356:eaal3755

Sulfonamides

Cancer Cell. 2019;36:194-209.e9.

PRMTs inhibitors

Summary

• Targeting of MDS founding lesions is effective and may result in (cyto)genetic remission

• Haploinsufficiency represents a targetable vulnerability of MDS clones

• Hematopoietic cells with spliceosomal gene mutations are preferentially susceptible to additional

splicing perturbations as compared to cells without such mutations.

• Modulation of spliceosome function may provide a new therapeutic avenue in genetically defined

subsets of individuals with MDS or AML.

Outline

• Critical issues for targeted therapy in

MDS

• Targeting MDS-defining genetic lesions

• Targeting pan-myeloid drivers in MDS

• Targeting functional consequences of

MDS driver genetic lesions

Landscape of somatic mutations in MDS

Papaemmanuil et al. Blood. 2013;122:3616-27

IDH2IDH1

TP53

Prognostic and predictive value of TP53 mutations in MDS

Science. 2019;365:599-604; Leukemia 2019; NEJM 2017;376:536-547; NEJM 2016;375:2023-2036

All

o-S

CT

Decit

ab

ine

Pharmacological reactivation of p53

as a strategy to treat cancer

Synergistic effects of PRIMA-1Met (APR-246) and Azacitidine in TP53-mutated MDS and AML

Maslah et al. Haematologica 2019

NCT Number Title Status Study Results Conditions Interventions Phases

NCT03931291 APR-246 in Combination With Azacitidine for TP53 Mutated AML or

MDS Following Allogeneic SCT

Recruiting No Results

Available

AML

MDS

Drug: APR-246 Phase 2

NCT03745716 APR-246 & Azacitidine for the Treatment of TP53 Mutant MDS Recruiting No Results

Available

MDS Drug: APR-246 + azacitidine

Drug: Azacitidine

Phase 3

NCT03072043 Phase 1b/2 Safety and Efficacy of APR-246 w/Azacitidine for tx of

TP53 Mutant Myeloid Neoplasms

Active, not

recruiting

No Results

Available

MDS, AML

MPN, CMML

Drug: APR-246

Drug: Azacitidine

Phase 1|2

NCT03588078 Study of the Safety and Efficacy of APR-246 in Combination With

Azacitidine

Active, not

recruiting

No Results

Available

MDS, AML

MPN, CMML

Drug: APR-246

Drug: Azacitidine

Phase 1|2

J Intern Med. 2015;277:248-259

Session: 637. Myelodysplastic Syndromes—Clinical Studies: Targeting Gene Mutations in MDS

Monday, December 9, 2019: 10:30 AM

W311ABCD, Level 3 (Orange County Convention Center)

676 - Sallman et al. Phase 2 Results of APR-246 and Azacitidine (AZA) in Patients with TP53 mutant

Myelodysplastic Syndromes (MDS) and Oligoblastic Acute Myeloid Leukemia (AML)

677 – Cluzeau et al. APR-246 Combined with Azacitidine (AZA) in TP53 Mutated Myelodysplastic Syndrome

(MDS) and Acute Myeloid Leukemia (AML). a Phase 2 Study By the Groupe Francophone Des

Myélodysplasies (GFM)

Durable Remissions with Ivosidenib in IDH1-

Mutated Relapsed or Refractory AML

Enasidenib in mutant IDH2 relapsed or

refractory AML

Official Title (NCT02074839):

A Phase I, Multicenter, Open-Label, Dose-Escalation and Expansion,

Safety, Pharmacokinetic, Pharmacodynamic, and Clinical Activity

Study of Orally Administered AG-120 in Subjects With Advanced

Hematologic Malignancies With an IDH1 Mutation

Key Inclusion Criteria:

•≥18 years of age.

•IDH1 R132 gene-mutated advanced hematologic malignancy.

•ECOG PS of 0 to 2.

Patients

•268 patients enrolled

•258 received study medication

•179 patients with relapsed or refractory AML

N Engl J Med 2018;378:2386-2398

Official Title (NCT01915498):

Phase 1/2 Study of AG-221 in Subjects With Advanced Hematologic

Malignancies With an IDH2 Mutation

Inclusion Criteria:

• Phase 1:

• Refractory or relapsed AML or untreated AML (≥60 yrs not

candidates for standard therapy);

• Diagnosis of MDS-EB-1 or -EB-2, or high-risk IPSS-R, recurrent

or refractory, or intolerant to established therapy.

• Phase 2: IDH2 gene-mutated relapsed or refractory AML

Patients

239 patients enrolled

176 patients relapsed/refractory AML

Blood 2017;130:722-731

NCT Number Title Status Conditions Interventions Phases

NCT03503409 IDH1 (AG 120) Inhibitor in Patients With IDH1 Mutated MDS RecruitingMDS

AMLDrug: AG-120 Phase 2

NCT04013880 ASTX727 and FT-2102 in Treating IDH1-Mutated Recurrent/Refractory MDS or AMLRecruiting

AML

MDS

Drug: CDA Inhibitor

E7727/Decitabine Combination

Agent ASTX727

Drug: IDH-1 Inhibitor FT-2102

Phase 1|Phase 2

NCT04044209

A Study of the IDH1 Inhibitor AG-120 in Combination With the Checkpoint Blockade

Inhibitor, Nivolumab, for Patients With IDH1 Mutated Relapsed/Refractory AML and

High Risk MDS

Not yet recruitingMDS

AML

Drug: AG-120

Drug: NivolumabPhase 2

NCT03839771

A Study of Ivosidenib or Enasidenib in Combination With Induction Therapy and

Consolidation Therapy, Followed by Maintenance Therapy in Patients With Newly

Diagnosed AML or MDS-EB2, With an IDH1 or IDH2 Mutation, Respectively,

Eligible for Intensive Chemotherapy

RecruitingAML

MDS-EB-2

Drug: AG-120

Drug: AG-221Phase 3

NCT02719574Open-label Study of FT-2102 With or Without Azacitidine or Cytarabine in Patients

With AML or MDS With an IDH1 MutationRecruiting

AML

MDS

Drug: FT-2102|

Drug: Azacitidine

Drug: Cytarabine

Phase 1|Phase 2

NCT02492737Study of Orally Administered AG-881 in Patients With Advanced Hematologic

Malignancies With an IDH1 and/or IDH2 MutationCompleted

AML

MDS

HM

Drug: AG881 Phase 1

NCT03471260Ivosidenib and Venetoclax With or Without Azacitidine in Treating Participants With

IDH1 Mutated Hematologic MalignanciesRecruiting

High Risk MDS

MPN

AML

Drug: Azacitidine

Drug: Ivosidenib

Drug: Venetoclax

Phase 1|Phase 2

NCT02074839Study of Orally Administered AG-120 in Subjects With Advanced Hematologic

Malignancies With an IDH1 MutationActive, not recruiting

AML

Other IDH1-mutated HMDrug: AG-120 Phase 1

NCT02381886A Study of IDH305 in Patients With Advanced Malignancies That Harbor IDH1R132

MutationsActive, not recruiting

HM That Harbor IDHR132

MutationsDrug: IDH305 Phase 1

NCT03744390 IDH2 (AG 221) Inhibitor in Patients With IDH2 Mutated MDS RecruitingMDS

AMLDrug: AG-221 Phase 2

NCT03383575 Azacitidine and Enasidenib in Treating Patients With IDH2-Mutant MDS Recruiting

AML - Blasts 20-30%

CMML

IDH2 Gene Mutation

MDS-EB

Drug: Azacitidine

Drug: EnasidenibPhase 2

NCT03839771

A Study of Ivosidenib or Enasidenib in Combination With Induction Therapy and

Consolidation Therapy, Followed by Maintenance Therapy in Patients With Newly

Diagnosed AML or MDSE-B2, With an IDH1 or IDH2 Mutation, Respectively,

Eligible for Intensive Chemotherapy

RecruitingAML

MDS-EB-2

Drug: AG-120

Drug: AG-221Phase 3

NCT02492737Study of Orally Administered AG-881 in Patients With Advanced Hematologic

Malignancies With an IDH1 and/or IDH2 MutationCompleted

AML

HMDrug: AG881 Phase 1

NCT01915498Phase 1/2 Study of AG-221 in Subjects With Advanced Hematologic Malignancies

With an IDH2 MutationActive, not recruiting HM Drug: AG-221 Phase 1|Phase 2

Session: 637. Myelodysplastic Syndromes—Clinical Studies: Targeting Gene Mutations in MDS

Monday, December 9, 2019: 10:30 AM

W311ABCD, Level 3 (Orange County Convention Center)

674 – Cortes et al. Olutasidenib (FT-2102) Induces Rapid Remissions in Patients with IDH1-Mutant

Myelodysplastic Syndrome: Results of Phase 1/2 Single Agent Treatment and Combination with

Azacitidine

678 - Richard-Carpentier et al. Preliminary Results from the Phase II Study of the IDH2-Inhibitor

Enasidenib in Patients with High-Risk IDH2-Mutated Myelodysplastic Syndromes (MDS)

SRSF2-IDH1/2 mutant represent a biological continuum

spanning from MDS to AML

Nature. 2019;574:273-277; Todisco et al. Manuscript submitted

Outline

• Critical issues for targeted therapy in

MDS

• Targeting MDS-defining genetic lesions

• Targeting pan-myeloid drivers in MDS

• Targeting functional consequences of

MDS driver genetic lesions

Targeting ineffective erythropoiesis

Luspatercept Response in Patients

with Low-Intermediate Risk MDS

• Phase 2, multicenter, open-label

study

• Endpoints: IWG HI-E, RBC-TI (≥ 8

weeks)

• High proportion of responses in

patients with ring sideroblasts (69%

vs 43%), and SF3B1 mutation (77%

vs 40%)

Nat Med. 2014;20:334-5. Lancet Oncol. 2017;18:1338-1347

Relationship between SF3B1 mutation, erythroid marrow activity and hepcidin to ferritin ratio in MDS

Ambaglio I et al. Haematologica 2013;98:420-423

A Phase 3, Double-blind, Randomized Study to Compare the Efficacy and Safety of Luspatercept (ACE-

536) Versus Placebo for the Treatment of Anemia Due to the IPSS-R Very Low, Low, or Intermediate Risk

Myelodysplastic Syndromes in Subjects With Ring Sideroblasts Who Require Red Blood Cell

Transfusions (NCT02631070)

Methods:

IPSS-R-defined Very low-, Low-, or Intermediate-risk MDS-RS according to the WHO 2016 criteria; refractory, intolerant, or

ineligible to receive erythropoiesis-stimulating agents (ESAs); required RBC transfusions.

Patients were randomized 2:1 to receive either luspatercept, at a starting dose level of 1.0 mg/kg with titration up to 1.75

mg/kg, if needed, or placebo, subcutaneously every 3 weeks for ≥ 24 weeks.

The primary endpoint was RBC transfusion independence (RBC-TI) for ≥ 8 weeks between week 1 and week 24.

Results:

Patients received a median of 5 RBC units (range 1-20) transfused over 8 weeks during the 16 weeks prior to treatment.

At baseline, 138 (60.3%), 58 (25.3%), and 32 (14.0%) patients had serum erythropoietin levels < 200 IU/L, 200-500 IU/L, and

> 500 IU/L, respectively. A total of 218 (95.2%) patients had previously received ESAs. Overall, 206 (90.0%) patients had an

SF3B1 mutation.

Of 153 patients receiving luspatercept, 58 (37.9%) achieved the primary endpoint of RBC-TI for ≥ 8 weeks compared with

10 of 76 patients (13.2%) receiving placebo (odds ratio [OR] 5.1, P < 0.0001).

Of those receiving luspatercept, 43 of 153 (28.1%) achieved the key secondary endpoint of RBC-TI for ≥ 12 weeks

(weeks 1-24) compared with 6 of 76 (7.9%) receiving placebo (OR 5.1, P = 0.0002).

Conclusions:

Treatment with luspatercept resulted in a significantly reduced transfusion burden compared with placebo in patients with

anemia due to IPSS-R-defined Very low-, Low-, or Intermediate-risk MDS with RS, who require RBC transfusions.

Fenaux et al. Blood 2018 132 (Supplement 1): 1.

The role of Bcl-2-related proteins in MDS

and AML secondary to MDS

Blood. 2000;96:3932-8

Blockade of BCL-2 proteins efficiently induces apoptosis in high-risk MDS

Leukemia 2016;112–123

Combined loss of function of miR-15/16 drives

the progression of MDS into AML

Lovat et al. Manuscript submitted

NCT NumberTitle Results Phases

04160052 Venetoclax and Azacitidine for the Treatment of High-Risk

Recurrent or Refractory MDS

No Results

Available

Phase 1|2

04146038 Salsalate, Venetoclax, and Decitabine or Azacitidine for the

Treatment of AML or Advanced MDS/MPN

No Results

Available

Phase 2

04140487 Azacitidine, Venetoclax, and Gilteritinib in Treating Patients With

Recurrent/Refractory FLT3-Mutated AML or High-Risk MDS

No Results

Available

Phase 1|2

04017546 CYC065 CDK Inhibitor and Venetoclax Study in

Relapsed/Refractory AML or MDS

No Results

Available

Phase 1

03940352 HDM201 in Combination With MBG453 or Venetoclax in Patients

With AML or High-risk MDS

No Results

Available

Phase 1

03661307 Quizartinib, Decitabine, and Venetoclax in Treating Participants

With Untreated or Relapsed AML or High Risk MDS

No Results

Available

Phase 1|2

03613532 Venetoclax Added to Fludarabine + Busulfan Prior to Transplant

for AML, MDS, and MDS/MPN

No Results

Available

Phase 1

03471260 Ivosidenib and Venetoclax With or Without Azacitidine in Treating

Participants With IDH1 Mutated Hematologic Malignancies

No Results

Available

Phase 1|2

03218683 Study of AZD5991 in Relapsed or Refractory Haematologic

Malignancies.

No Results

Available

Phase 1

04140487 Azacitidine, Venetoclax, and Gilteritinib in Treating Patients With

Recurrent/Refractory FLT3-Mutated AML or High-Risk MDS

No Results

Available

Phase 1|2

03613532 Venetoclax Added to Fludarabine + Busulfan Prior to Transplant

for AML, MDS, and MDS/MPN

No Results

Available

Phase 1

03113643 SL-401 in Combination With Azacitidine or

Azacitidine/Venetoclax in AML or High-Risk MDS

No Results

Available

Phase 1

02966782 A Study Evaluating Venetoclax Alone and in Combination With

Azacitidine in Subjects With Relapsed/Refractory MDS

No Results

Available

Phase 1

02942290 A Study Evaluating Venetoclax in Combination With Azacitidine

in Subjects With Treatment-Naïve Higher-Risk MDS

No Results

Available

Phase 1

02250937 Venetoclax and Sequential Busulfan, Cladribine, and Fludarabine

Phosphate Before Donor Stem Cell Transplant in Treating

Patients With AML or MDS

No Results

Available

Phase 2

02115295 Cladribine, Idarubicin, Cytarabine, and Venetoclax in Treating

Patients With AML, High-Risk MDS, or Blastic Phase CML

No Results

Available

Phase 2

Session: 637. Myelodysplastic Syndromes—

Clinical Studies

4241 - Brian et al., Combined Venetoclax and

Hypomethylating Agent (HMA) Therapy Induces High

Response Rates in Patients with Myelodysplastic

Syndrome Including Patients Previously Failing HMA.

568 – Wei et al. A Phase 1b Study Evaluating the

Safety and Efficacy of Venetoclax in Combination with

Azacitidine in Treatment-Naïve Patients with Higher-

Risk Myelodysplastic Syndrome.

565 – Zeidan et al. A Phase 1b Study Evaluating the

Safety and Efficacy of Venetoclax As Monotherapy or

in Combination with Azacitidine for the Treatment of

Relapsed/Refractory Myelodysplastic Syndrome.

Elisa Bono

Silvia Catricalà

Chiara Elena

Anna Gallì

Virginia Valeria Ferretti

Elisabetta Molteni

Sara Pozzi

Ettore Rizzo

Martina Sarchi

Gabriele Todisco

Mario Cazzola

Eva Hellström-Lindberg Andrea Pellagatti

Jaqueline Boultwood

Ulrich Germing

Andrea Kuendgen

Elli Papaemmanuil

Yusuke Shiozawa

Seishi Ogawa

Guillermo Sanz

Esperanza Such

Claudia Haferalch

Torsten Haferlach

Ghulam Mufti

Judith Marsh

Which of the following statements relevant to targeted treatment in MDS

is correct?

a) Degradation of a kinase encoded by a gene within the common deleted region

provides the therapeutic window for targeting the del(5q) clone.

b) Haploinsufficiency may offer a prefential vulnerability for therapeutic targeting of

MDS clones.

c) Mis-splicing by mutated splicing factors results in a non-classical path to

haploinsufficiency of target genes in spliceosome-mutant MDS.

d) Inhibition of wild-type spliceosome may provide a way to preferentially target

MDS with splicing factor mutations.

e) All the above.