for Myelodysplastic Syndromes Andrew M. Brunner, MD Massachusetts - - PowerPoint PPT Presentation

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for Myelodysplastic Syndromes Andrew M. Brunner, MD Massachusetts - - PowerPoint PPT Presentation

Aug 24, 2022 254 likes •595 views

New and Emerging Therapies for Myelodysplastic Syndromes Andrew M. Brunner, MD Massachusetts General Hospital Cancer Center July 21, 2018 Myelodysplastic Syndromes - MDS Bone marrow cancers characterized by dysplasia, clonality, and

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New and Emerging Therapies for Myelodysplastic Syndromes

Andrew M. Brunner, MD Massachusetts General Hospital Cancer Center July 21, 2018

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Myelodysplastic Syndromes - MDS

  • Bone marrow cancers

characterized by dysplasia, clonality, and ineffective hematopoiesis

  • Disease of older individuals
  • Slightly more common among

men than women

  • Survival varies months to years

depending on subtype

Am J Med. 2012 Jul; 125(7 Suppl): S2–S5.

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MDS is a spectrum of diseases

Type and Maturity of Blood cells

MDS-SLD MDS-MLD MDS-RS MDS-del(5q) MDS-EB1 MDS-EB2 MDS-U

Variation in Blood Counts Variation in Driver Mutations

Wong T et al. Nature. 2015 Feb 26; 518(7540): 552–555.

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MDS treatment is based on disease risk

Risk of Serious or Life-threatening Complication related to MDS: Infection Bleeding Risk of Progression to Acute Myeloid Leukemia

Risk Stratification by IPSS or IPSS-R Blood Counts, Blasts, and Karyotype

IPSS and IPSS-R Risk do not always match the risk of the WHO disease subtype

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Updates in Estimating Disease Risk

  • New understanding about mutations in MDS
  • Competing risks in often older patients
  • Changes in MDS risk over time
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Recurrent Somatic Mutations

Blood 2013 122:3616-3627

Common Mutations: SF3B1 – ringed sideroblasts TET2 SRSF2 ASXL1 DNMT3A RUNX1 U2AF1 TP53 EZH2 IDH2 STAG2 ZRSR2

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Mutations are common – and not all MDS!

Jaiswal S et al. N Engl J Med 2014; 371:2488-2498

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Mutations add to diagnosis and prognosis

(and treatment?)

Secondary AML MDS MPN BMF Therapy De novo AML Linear Evolution Branching Evolution Healthy Clonal Hematopoiesis Baseline Hematopoiesis

Biology of secondary leukemia AM Brunner and TA Graubert. EHA Learning Center. Jun 17, 2018; 219205

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Mutations in Healthy Persons and Heart Disease

Ebert and Libby. Ann Intern Med. 2018;169(2):116-117.

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Competing Risks in MDS

Proportion of Deaths (%) Proportion of deaths attributed to MDS/Leukemia, CVD, and Other Causes

Brunner et al. Blood Adv. 2017 Oct 18;1(23):2032-2040

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Disease Risk: Fixed or Fluctuating?

Pfeilstöcker M, et al. Blood 2016 128:902-910

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MDS Management

MDS Diagnosis Lower Risk Disease Low/INT-1 Higher Risk Disease (INT-2/High or IPSS-R > 4.5) HCT Candidate Not HCT Candidate

HMA Induction Clinical Trial

HMA Induction Allo-HCT Risk Stratification

Good QOL, no

transfusions

Single Cytopenia Multiple Cytopenias

Follow CBC Transfuse/ Growth Factor HMA or Lenalidomide CsA/ATG ?Autoimmune

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MDS Management

MDS Diagnosis Lower Risk Disease Low/INT-1 Higher Risk Disease (INT-2/High or IPSS-R > 4.5) HCT Candidate Not HCT Candidate

HMA Induction Clinical Trial

HMA Induction Allo-HCT Risk Stratification

Good QOL, no

transfusions

Single Cytopenia Multiple Cytopenias

Follow CBC Transfuse/ Growth Factor HMA or Lenalidomide CsA/ATG ?Autoimmune

MODIFY SYMPTOMS Transfusion Dependence

MODIFY DISEASE Risk of Death and AML

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MDS Management

Lower Risk Disease Low/INT-1

Good QOL, no

transfusions

Single Cytopenia Multiple Cytopenias

Follow CBC Transfuse/ Growth Factor HMA or Lenalidomide CsA/ATG ?Autoimmune

MODIFY SYMPTOMS Transfusion Dependence

Specific Cytopenia EPO Level Neutropenia 5q- Syndrome Transfusion Dependence Hypoplastic MDS/AA

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MDS Management

Higher Risk Disease (INT-2/High or IPSS-R > 4.5) HCT Candidate Not HCT Candidate

HMA Induction Clinical Trial

HMA Induction Allo-HCT

MODIFY DISEASE Risk of Death and AML

More Immediate Risk of Death Due to Disease

  • r AML

Transplant Candidacy Chemotherapy

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MDS Management – Integrating Many Factors

Transfusion Needs

AML Risk Travel Time

“Targetable” Mutations Toxicity Profile

?

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Therapeutic Targets in MDS

Sallman et al. Clinical Lymphoma, Myeloma & Leukemia, 2017-10-01, Volume 17, Issue 10, Pages 613-620

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New Therapies to Target MDS

  • Pathway Driven
  • TGF-β pathway
  • Immune Checkpoint Blockade
  • Apoptosis – Bcl2
  • Mutation Driven
  • Spliceosome mutations
  • Mutated IDH enzymes

2HG

TGFB SMAD2/3 SMAD4 CytoC

T-cell

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New Therapies to Target MDS

  • Pathway Driven
  • TGF-β pathway
  • Immune Checkpoint Blockade
  • Apoptosis – Bcl2
  • Mutation Driven
  • Spliceosome mutations
  • Mutated IDH enzymes

2HG

TGFB SMAD2/3 SMAD4 CytoC

T-cell

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TGF-B Ligand Traps and Erythropoiesis

Paulson RF. Nature Medicine volume20, pages334–335 (2014) Blank U and Karlsson S. Blood 2015 125:3542-3550

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Luspatercept

  • Activin receptor IIIB protein, TGFB family member ligand trap
  • EPO >500 or intolerant of ESAs, no prior HMA

Platzbecker U et al. Lancet Oncology Volume 18, Issue 10, October 2017, Pages 1338-1347

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New Therapies to Target MDS

  • Pathway Driven
  • TGF-β pathway
  • Immune Checkpoint Blockade
  • Apoptosis – Bcl2
  • Mutation Driven
  • Spliceosome mutations
  • Mutated IDH enzymes

2HG

TGFB SMAD2/3 SMAD4 CytoC

T-cell

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Immune Checkpoints in Cancer

Pardoll DM. Nature Reviews Cancer 2012;12, 252-264 Ribas A. N Engl J Med 2012;366:2517-2519.

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DNMTI and Interferon Response

  • increased expression
  • f endogenous

retroviral transcripts (ERVs)

  • increases dsRNA
  • CTLA-4 + AZA

synergistic in a mouse melanoma model

Chiappinelli et al. Cell 2015;162:974

Ovarian cell lines

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PD-L1 in MDS

  • PD-L1 is upregulated in MDS blasts after exposure to IFNy and TNFa

Proliferative MDS cells are PD-L1+

Kondo et al. Blood 2010 116:1124-1131

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New Therapies to Target MDS

  • Pathway Driven
  • TGF-β pathway
  • Immune Checkpoint Blockade
  • Apoptosis – Bcl2
  • Mutation Driven
  • Spliceosome mutations
  • Mutated IDH enzymes

2HG

TGFB SMAD2/3 SMAD4 CytoC

T-cell

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Apoptosis in MDS

  • BCL2 is a regulator of apoptosis
  • “priming” apoptosis may be attractive in

treating MDS

Roberts AW et al. CCR. Volume 23, Issue 16, pp. 4527-4533 Letai A. CCR. Volume 21, Issue 22, pp. 5015-5020

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New Therapies to Target MDS

  • Pathway Driven
  • TGF-β pathway
  • Immune Checkpoint Blockade
  • Apoptosis – Bcl2
  • Mutation Driven
  • Spliceosome mutations
  • Mutated IDH enzymes

2HG

TGFB SMAD2/3 SMAD4 CytoC

T-cell

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SLIDE 29

Spliceosome mutations in MDS

Joshi et al. Blood 2017 129:2465-2470

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Possible Spliceosome Targets

Agrawal et al. Current Opinion in Genetics & Development Volume 48, February 2018, Pages 67-74

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New Therapies to Target MDS

  • Pathway Driven
  • TGF-β pathway
  • Immune Checkpoint Blockade
  • Apoptosis – Bcl2
  • Mutation Driven
  • Spliceosome mutations
  • Mutated IDH enzymes

2HG

TGFB SMAD2/3 SMAD4 CytoC

T-cell

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SLIDE 32

Targeting mutated IDH proteins

http://targetedcancercare.massgeneral.org/My-Trial-Guide/Diseases/Leukemias/IDH2.aspx

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Conclusions

  • Our understanding of MDS has grown significantly
  • This knowledge may help us to identify new targets for treatment
  • A number of therapies are in development and have exciting potential
  • New targets continue to be identified
  • Questions? abrunner@partners.org