2/24/2020

UNDERSTANDING YOUR DIAGNOSIS: ACUTE MYELOID LEUKEMIA (AML)

Eunice S. Wang, MD Chief, Leukemia Service Professor of Oncology Department of Medicine Roswell Park Comprehensive Cancer Institute Buffalo, NY

DISCLOSURES Understanding Your Diagnosis: Acute Myeloid Leukemia (AML)

Eunice S. Wang, MD, has affiliations with AbbVie, Agios, Amgen, Astellas, Daiichi, Gilead, Jazz, Macrogenics, Pfizer, Stemline (Consultant); Astellas, Jazz, Novartis, Pfizer, Stemline (Speakers Bureau).

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1 2/24/2020

Understanding Acute Myeloid Leukemia

Eunice S. Wang MD Chief, Leukemia Service

Understanding AML: 2020

• Diagnosis and Time to treatment • Improving Venetoclax therapy • Combination approaches • New agents on the horizon

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Acute Myeloid Leukemia: Biology

Disease of older adults (median 67-70 years) Biologically diverse (karyotype, mutations, antigens) Clinically aggressive disease with survival in weeks-months

“Young” < 60 years old “Old” ≥ 60 years old 200 Males 180 Females 160 All 21,380 cases 140

10,590 deaths 120 100

Incidence 80 60 40 20 0 16-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89 90+ Pa ent Age (yrs)

Lee et al Blood 129(2): 257, 2017. 5

How to diagnose AML

Morphology Flow Cytometry FISH Cytogenetics

Mutation Profiling Ÿ Risk stratification Ÿ Drug targeting Ÿ Disease monitoring

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AML is characterized by many mutations

Overall Overall Gene Gene Frequency, % Frequency, %

FLT3 RUNX1 37 (30,7) 5 (ITD, TKD) MLL-PTD 5 NPM1 29 ASXL1 3 DNMT3A 23 PHF6 3 NRAS 10 KRAS 2 CEBPA 9 PTEN 2 TET2 8 TP53 2 WT1 8 HRAS 0 IDH2 8 EZH2 0 IDH1 7 KIT 6

Papaemmanuil E et al NEJM 374(23): 2209-221, 2016 7

History of AML Therapy

US FDA approvals

1. First FLT3 inhibitor midostaurin US FDA approved 2. First IDH2 inhibitor enasidenib US FDA approved 3. Liposomal cytarabine/daunorubicin US FDA approved Roswell Park Memorial Institute, Buffalo, NY 4. Gemtuzumab Ozogamicin re-US FDA approved

1. Ivosidenib is FDA approved in 2018 for relapsed or refractory AML with a suscepQble IDH1 mutaQon

2. AZA+VEN and LDAC+Ven approved for older AML (Nov 21 2018) 7+3 = 1973 to 2017 (44 years!) 3. LDAC+glasdegib approved for older AML (Nov 21 2018)

4. GilteriQnib for relapsed FLT3 AML (Dec 2018)

Year 1975 1980 1990 1995 2000 2005 2009 2013 2022

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AML Therapy: Many new drugs

Attributed to John Ozell’s translation of a French play (1738); Translated in 1725 as The Plague of Riches

Definition: Generally used to describe an abundance of something, (typically positive) with the idea that there are so many of these good things that it’s difficult to pick just one.

8 Drugs approved for AML in last 2 years Midostaurin, Enasidenib, CPX-351, Gemtuzumab Ivosidenib, Gilteritinib, Glasdegib, Venetoclax

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Therapy for AML patients based on mutations

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5 2/24/2020

Safe to wait for genetic information to start AML therapy

2263 patients with newly dx AML from 46 centers across Germany Time from diagnosis to intensive induction did NOT affect outcome or survival

+ 0 – 5 days + 6 – 10 days + 11 – 15 days + > 15 days

1.00 1.00 1.00

All ages+++++++ ≤60 yrs >60 yrs ++++++++++++++++ 0.75 0.75 0.75 ++++++++++++++++++++++++++++++ ++++++++++++++++++++++++++++++++++ +++ + +++++++++ +++++++++++++++++ +++++++++++ ++++++ +++ +++++++++++++++++++++++ + +++++++++++++++++++++++++++ + +++++++ ++ +++++++++++++++++++++++++++++++++++++ +++++++++++++++++++++++++++++++++++++++ + + +++ ++++++++ +++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ +++++++++++++++++++++++++++ + ++++++++++++++++ ++++++++++++++++++++++++++++++++++++++++++++++++++++++++ + +++ +++++ ++++++++++++++++++++++++++++++ +++++++ +++++ + + ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ ++++++++ + ++++++++++++++++ ++++++++++++++++++++ + + +++++++ ++++++ + + + ++ ++ +++++++++++ +++++++++++++++++++++++++++++++++++++++++++ 0.50 +++ ++ + + +++ 0.50 +++++++++ ++ 0.50 + +++++++++++ +++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ +++++++++ ++++ ++ ++++++++++++++++++++ +++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ ++++++++++ + ++++++++++ ++ +++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ ++++++++++++++++ +++ +++++++++++++++++++++ +++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ ++++++++++ + + + +++++++++++ +++++++++++++++++ +++++++++++++++++++++++++ +++ ++++++ ++ ++ +++++++++++++ ++++++ +++ + +++ ++ + + ++++++++++++++++++ + ++ + + +++++++++++++++++++++ +++ ++++++ ++++++++++++ Survival probability + + + ++++++++++++ Survival probability Survival 0.25 + Survival probability Survival 0.25 0.25 + +++++++ +++ +++++++ ++++++++++++ + + p = 0.21 p = 0.47 p = 0.88 + + + ++++++++

0.00 0.00 0.00 0 12 24 36 48 60 0 12 24 36 48 60 0 12 24 36 48 60 Time Time Time

Röllig et al ASH 2019. Abstr 13. 11

Novel combinations to improve outcomes

Backbone Novel agents Combina ons Chemo tailored to individual pa ents

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6 2/24/2020

Venetoclax: BCL-2 inhibitor

Cancer cells evade cell death through Venetoclax is a potent small molecule BCL-2 inhibitor which binds to BCL-2, overexpression of BCL-2 which “freeing” pro-apoptotic proteins which then initiate cell death sequesters pro-apoptotic proteins

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Venetoclax + Chemo for Older Patients

HMA + Venetoclax 400 mg 200 mg 100 mg

Indicated for: Decitabine: 20 mg/m2 days 1–5

- Newly DxAML Azacitidine: 75 mg/m2 days 1–7 - Age > 75 yrs Venetoclax Day 1 Day 2 Days 3-28 OR - ECOG 2-3 - Cardiac, lung, LDAC + Venetoclax liver or renal disease

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Venetoclax + Chemo: High response rate

Venetoclax with HMAs induces rapid, deep, and durable responses in older pa ents with AML | ASH 2018 13

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Venetoclax-based therapy followed by transplant

. 31 of 304 patients (10%) treated with venetoclax + chemo underwent transplant . . Over two thirds (68%, 21 of 31) patients were alive 12 months after transplant . 55% (17/31) of all patients undergoing transplant have remission of ≥12 months after transplant . 71% (12/17) of those patients remained in remission for ≥ 2 years

Pratz K et al, ASH 2019 16

8 2/24/2020

Adding Venetoclax to intensive AML chemotherapy

. Single-center, phase Ib/II trial with FLAG-IDA plus venetoclax

Adult, fit patients Phase II: Dose expansion with AML; ECOG Phase Ib: Dose escalation Consolidation Filgrastim 5 mcg/kg D1-7* Filgrastim 5 mcg/kg D1-7* + Filgrastim 5 mcg/kg PS ≤ 2; AML or + Fludarabine 30 mg/m2 IV D2-6 Fludarabine 30 mg/m2 IV D2-6 + high-risk MDS (≥ D1-7* + Fludarabine + Idarubicin 6 mg/m2 D4-6 + Idarubicin 6 mg/m2 D4-6 + 2 10% blasts); 30 mg/m IV D2-6 + Cytarabine + Venetoclax† Cytarabine 1.5 g/m2 IV D2-6 + 2 satisfactory organ Cytarabine 1.5 g/m Venetoclax 400 mg D1-14 function (N = 16 R/R AML) IV D2-6 + Venetoclax (N = 14 ND, 26 R/R‡ AML) 400 mg D1-14 *Or peg-filgrastim 6 mg x 1 after D5 †3-level dosing of cytarabine + venetoclax: ‡Including the 16 R/R AML patients from 1) CYT 2 g/m2 D2-6 /VEN 200 mg D1-21; 2) phase I CYT 1.5 g/m2 D2-6 /VEN 200 mg D1-14; 3) Maintenance (if no ASCT) CYT 1.5 g/m2 D2-6 /VEN 400 mg D1-14 Venetoclax 400 mg D1-14 up to 1 year

Aboudalle. ASH 2019. Abstr 176. 17

IDH mutations in AML

• Isocitrate dehydrogenase (IDH) is a Tumor cell

critical enzyme regulating tumor Mitochondrion Citrate metabolism Citrate Isocitrate

Isocitrate IDH1

• IDH mutations promote AML IDH2 aKG

development aKG NADPH IDH1 IDH2 mutant mutant 2-HG • IDH mutations infrequent in AML NADPH

– IDH1 mut found in 6-9% of AML Epigenetic changes Impaired cellular – IDH2 mut found in 8-12% of AML differentiation

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IDH1 and IDH2 inhibitors in AML

Ivosidenib (IDH1 inhibitior) 500 mg daily

Enasidenib (IDH2 inhibitor) Differentiation Syndrome 100 mg daily New onset or worsening of fever, rapid weight gain or swelling in legs, respiratory symptoms, fluid in lungs or surrounding the heart, ;ow blood pressure, kidney problems

DiNardo CD, et al. NEJM. 2018;378(25):2386-2398.; Stein EM, et al. Blood. 2017;130(6):722-731. 19

Enasidenib + Azacitidine for newly dx IDH2 mutant AML

. Randomized phase I/II study ‒ Phase I portion consisted of 3 + 3 dose-finding for enasidenib + azacitidine Randomized 2:1

Enasidenib 100 mg QD + Adult patients with Azacitidine 75 mg/m2/day SQ x 7 days/28-day cycle mutant IDH2 ND AML, (n = 68) ineligible for intensive CT and no history of treatment with Azacitidine Monotherapy 75 mg/m2/day SQ x 7 days/28-day cycle hypomethylating agents (N = 101) (n = 33)

. PrimaryResults: endpoint:Higher response ORR rates with combination therapy . KeySafety: secondary Combination endpoints: therapy CR, was safety, tolerated OS, EFS well by patients

DiNardo. ASH 2019. Abstr 643 20

10 2/24/2020

Enasidenib + Azacytidine for newly dx IDH2 mutant AML

. Enasidenib + azacitidine showed significantly greater reduction in maximal mutant IDH2 VAF suppression from baseline vs azacitidine alone: median reductions -83.4% vs -17.7%, respectively (P = .0008) Enasidenib + Azacitidine vs Azacitidine Monotherapy ENA + AZA: Maximum Mutant IDH2 VAF Reductions From Baseline Mutant IDH2 VAF Clearance Azacitidine Only Enasidenib + Azacitidine Not Detected* 100 (n = 23) 100 (n = 54) < 0.5% Molecular remission 75 75 * ≥ 0.5% CR 100 50 50 R 14 13 NR 25 25 80 P = .007 ********* VAF (%) Change 0 * VAF (%) Change 0 60 -25 -25 IDH2 IDH2 40 9

-50 -50 Patients (%)

Mutant -75 Mutant -75 20 8 1 -100 -100 0 1 *Mutant IDH2 VAF below the limit of detection (0.02% to 0.04%) Data cutoff: August 19, 2019. CR NR Mutant IDH2 VAF in bone marrow mononuclear cells were assessed by digital PCR.

DiNardo. ASH 2019. Abstr 643 21

Maintenance therapy for AML

Induc on Consolida on Observation only vs. 7+3 HIDAC x 2-4 Maintenance therapy

HMAs, lenalidomide FLT3i, IDH1/2i, ven, glasdegib

BMBxMRD BMBxMRD Allogeneic CR CR Maintenance therapy Stem cell Transplant vs. Observation only

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11 2/24/2020

Oral azacitidine: First drug for AML maintenance?

Hematopoietic Leukemic Stem Cell Stem Cell CC-486

Day 1 2 3 4 5 6 7 8 910111213 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Sustained Activity Leukemic Myeloid Blast Extended 14-day oral dosing provides prolonged pharmacodynamic (PD) effect over a 28-day cycle

G C A C A G C A C A Ribosome

G T G T G T G T G U G U DNMT DNA Damage6-8 RNA Disruption6,7,9 DNA Hypomethylation4-8 Causes replication stress Inhibits protein synthesis Re-expresses tumor suppressor and cellular differentiation genes Cell Death and Apoptosis Functional Hematopoiesis Erythrocytes Granulocytes Monocytes

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Oral azacitidine (CC-486): First drug for AML maintenance?

PRE-RANDOMIZATION RANDOMIZATION TREATMENT PHASE

Screening Randomization (1:1) Response Assessment Assessment Response ± CC-486 300 mg CR/CRi

Key eligibility criteria: Within 4 months ( 7 Cycles 3 Every • First CR / CRi with days) of CR/CRi QD ×14 days Continue IC ± consolidation (Optional) Treatment Stratified by: 5%–15% • Age ≥55 years 28-day cycles CC-486/PBO • de novo or secondary AML • Age: 55–64 / ≥ 65 BM Blasts ×21 days • ECOG PS score 0-3 • Prior MDS/CMML: Y / N • Intermediate- or poor-risk • Cytogenetic risk: Placebo cytogenetics QD×14 days > 15% Stop End of Intermediate / Poor Treatment Study • Ineligible for HSCT BM Blasts • Adequate bone marrow • Consolidation: Y / N recovery (ANC ≥0.5 × 109/L, FOLLOW-UP platelet count ≥20 × 109/L) • Follow until death, withdrawal of consent, study termination, or loss Patients randomized to CC-486 had improved survival to follow-up

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Low dose Decitabine can also be used as maintenance

Stratified by: age ≥ 70 yrs, unfavorable cytogenetics, induction therapy

Decitabine 20 mg/m2 on Follow-up: AML patients Days 1-3 Q4W for 1 yr ≥ 60 yrs of age with BM . (n = 59) CBC Q1M for 1 yr, biopsy-confirmed then Q3M CR/CRi after . BM biopsy Q3M consolidation therapy* Observation for 2 yrs after (N = 120) (n = 61) randomization

*Cytarabine after 7+3 induction, or clofarabine after clofarabine induction. . Primary endpoint: disease-free survival (relapse or death from any cause) . TrendMaintenance to improved study survival had onlyin FLT3 70% negative accrual AML due patients to early receiving suspension decitabine of parent trial

Foran. ASH 2019. Abstr 115. 25

FLT3 mutations in AML

• FLT3-ITD occurs in ~25-37% of AML Immunoglobulin-like loops

• FLT3-TKD occurs in ~10% of AML Transmembrane domain • More frequent in younger patients, Extracellular de novo AML and diploid cytogenetics • Associated with resistance to 7+3 Juxtamembrane domain ITD • Increased risk of relapse Up to 30% Kinase 1 domain of patients

Kinase 2 domain TK domain • Many FLT3 inhibitors developed C-terminus

Activated proliferation and pro-survival pathways

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FLT3 inhibitors for AML

ClassOLD 3vs RTK’s: NEW Targets FLT3 inhibitory FLT3,Generation KIT, CSF1R, dose FLT3PDGFRA/B inhibitors Lestaurtinib FLT3, JAK2,TrkA 700 nM Midostaurin* FLT3, KIT, PKC, 1000 nM PDGFR, VEGFR Sorafenib* FLT3, KIT, PDGFR, 265 nM RAF, VEGFR Quizartinib FLT3, KIT, 18 nM PDGFR, RET Crenolanib FLT3, PDGFR 48 nM Gilteritinib* FLT3, AXL 43 nM Midostaurin

(Many targets) QuizarQuizartinibnib *FDA approved drugs (few(AC220) targets)

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Best FLT3 inhibitor is context dependent

Clinical setting Standard of care

Midostaurin Quizartinib Newly diagnosed Midostaurin plus 7+3 GI (N/V, diarrhea) QTc prolongation GI (diarrhea, N/V) mut Fatigue, Infection FLT3 Myelosuppression Pulmonary toxicities Older newly Sorafenib plus Crenolanib Toxicity Profiles GI (diarrhea, N/V) diagnosed Azacitidine Peripheral edema FLT3mut Sorafenib Liver, Rash Hand-foot syndrome FLT3mut after Sorafenib GI (diarrhea, N) Gilteritinib Infection, rash Myelosuppression transplant Liver toxicity Relapsed FLT3mut Gilteritinib Infection, GI

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APR-246: New drug for p53 mutant AML

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APR-246: New drug for p53 mutant AML

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Anti-CD47: Telling immune cells to “eat” AML cells

Control mAb: No Phagocytosis

5F9

CD47 l

l

SIRPα e c

y t h al He CD47“don’t eat me” signal

Anti-CD47 mAb: Phagocytosis

l l

e

c

r e c n Ca “Eat me” M signal ac ro ph age

Macrophages Cancer cells

Sallman D et al ASH 2019 31

Anti-CD47: Telling immune cells to “eat” AML cells

Magrolimab is a an anti-CD47 antibody First line AML: 14 of 22 (64%) - Targets CD47 on AML cells CR 41%, CRi 14% - Induces macrophage cells to “eat” AML cells - Eliminates leukemic stem cells in AML models - Azaciditine induces CD47 expression on AML blasts and increases efficacy of magrolimab

Sallman D et al ASH 2019 32

16 2/24/2020

Immunotherapy for AML

Bispecific AntibodyBiTE (BiTE) CAR T-Cell Gene cally modified CD33-targeted T-cell

T-cell TCR CAR CD3 TCR CD33 Bispecific Ab CD33

AML AML

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Understanding AML: 2020

• Diagnosis and Time to treatment • Improving Venetoclax therapy • Combination approaches • New agents on the horizon

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Example of pediatric ALL

Outcomes of pediatric B-ALL 2012: 90% Current survival rate for childhood ALL = >90%

To cure AML, we need to:

- Introduce new drugs - Design combo Rx - Conduct clinical trials

1968: 90%

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Q&A SESSION Understanding Your Diagnosis: Acute Myeloid Leukemia (AML)

• Ask a question by phone: – Press star (*) then the number 1 on your keypad.

• Ask a question by web: – Click “Ask a question” – Type your question – Click “Submit” Due to time constraints, we can only take one question per person. Once you’ve asked your question, the operator will transfer you back into the audience line.

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LLS EDUCATION & SUPPORT RESOURCES

• Information Specialists Master’s level oncology professionals, available to help cancer survivors navigate the best route from diagnosis through treatment, clinical trials and survivorship. – EMAIL: [email protected] – TOLL-FREE PHONE: 1-800-955-4572

• Free Education Booklets: – www.LLS.org/booklets

• Free Telephone/Web Programs: – www.LLS.org/programs

• Live, weekly Online Chats: – www.LLS.org/chat

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LLS EDUCATION & SUPPORT RESOURCES

• LLS Podcast, The Bloodline with LLS

Listen in as experts and patients guide listeners in understanding diagnosis, treatment, and resources available to blood cancer patients: www.thebloodline.org • Education Videos

Free education videos about survivorship, treatment, disease updates and other topics: www.LLS.org/educationvideos

• Patti Robinson Kaufmann First Connection Program

Peer-to-peer program that matches newly diagnosed patients and their families: www.LLS.org/firstconnection

• Free Nutrition Consults Telephone and email consultations with a Registered Dietitian: www.LLS.org/nutrition

• What to Ask

Questions to ask your treatment team: www.LLS.org/whattoask

• Other Support Resources

LLS Community, discussion boards, blogs, support groups, financial assistance and more: www.LLS.org/support

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THANK YOU

We have one goal: A world without blood cancers

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