targeted treatment in mds · 2019. 12. 6. · subsets of individuals with mds or aml. outline •...
TRANSCRIPT
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.