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Disclosures- Richard M. Stone, MD

Consulting relationships past three years:

AbbVie*; Actinium, Agios*; Amgen; Argenix (DSMB); Arog*; Astellas; AztraZenaca; Biolinerx, BMS/Celgene (includes DSMB and steering committee); Elevate Bio, Fujifilm, Janssen; Jazz, Juno; Macrogenics; Novartis*; Ono; Orsenix; Pfizer; Roche; Stemline, Sumitomo; Syndax*; Syntrix (DSMB only); Syros; Takeda (DSMB), Trovagene
* denotes support to my institution for clinical trials on which I was local PI

Securities, employment, promotional activities, intellectual property, gifts, grants

None

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Leukemia: Definition

Overabundance of white blood cells in peripheral blood

If Immature ( like stem cells) then acute leukemia
If mature ( like normal cells) then chronic leukemia

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AML: Where does it fit?�Acute and Chronic Leukemias and MDS

Acute Leukemias

Acute Myeloid Leukemia ( AML)*
Acute Lymphoblastic Leukemia (ALL)

Chronic Leukemias

Chronic Myeloid Leukemia ( CML)*
Chronic Lymphoid Leukemia ( CLL)

Myelodysplastic Syndrome (MDS)*
Myeloproliferative Neoplasms (MPN)*

*Myeloid Neoplasms

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Acute Leukemias arise from stem cell (SC) and commited SCs

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Myeloid Malignancies

Monocytosis

Erythrocytosis

Granulocytosis

Thrombocytosis

Eosinophilia

Mastocytosis

Dyserythropoiesis

Dysgranulopoiesis

Absence of cytosis

Myelodysplastic

Syndromes

Myelodysplastic/

Myeloproliferative

overlap

Myeloproliferative

Neoplasms

Acute Myeloid Leukemia

≥20% blasts

<20% blasts

>1000/μL

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AML: What is it and how did it get there?

Unbridled proliferation of hematopoietic stem cells (myeloid lineage) resulting in marrow failure and patient death unless successfully treated
Risk factors: AGE, prior chemo for other cancers, ionizing radiation, industrial solvents (last 3 probably <10% of incidence=15K new US cases annually); unusual but kindreds exist w germ-line mutations in >10 genes

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Acute Leukemia:�Blasts on Wright stain

feature myeloid lymphoid
cytoplasm ample scant
granules a few absent
chromatin open less so
nucleoli many few
Auer Rods in 50% no

Cytochem: perox-AML, NSE-AMo/ML; PAS-ALL

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Acute Leukemia:�Immunophenotypic Diagnosis

AML: CD33 (in 90%), CD15, CD117 (c-kit); CD14, CD11c- monocytic
ALL:

pre-B cell: CD19, CD20, CD10 (CALLA) in most
B-cell: CD19, surface immunoglobulin
T-cell: CD2, CD7, CD3

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Acute Myeloid Leukemia : �Clinical Presentation

Bone marrow failure

neutropenia- infection/fever
anemia- fatigue/SOB
thrombocytopenia- bleeding

Metabolic abnormalities

hypokalemia- renal tubular damage from myeloblasts
hyperkalemia, hyperphosphatemia, hypocalcemia, hyperuricemia- tumor lysis syndrome

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Key Points from de novo AML Genome Atlas

9 key categories:

transcription-factor fusions (18%)

nucleophosmin (NPM1) (27%)

tumor-suppressor genes (16%)

DNA-methylation–related genes (44%)

signaling genes (59%)

chromatin-modifying genes (30%)

myeloid transcription-factor genes (22%)

spliceosome-complex genes (14%)

Cohesin complex (15%)

The Cancer Genome Atlas Research Network

NEJM 2013; 368:2059-2074.

Döhner H et al, NEJM 2015; 373:1136-1152

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Current Risk Assessment in AML

Key Prognostic Data in AML in 2021
Patient age, Comorbidities, Family History
Cytogenetics / karyotype
Primary versus secondary disease (secondary = post-antecedent hematologic disorder, or therapy-related)
Molecular studies:
FLT3 ITD (internal tandem duplication) mutation	Unfavorable
NPM1 mutation	Favorable
CEBPA biallelic mutation	Favorable
ASXL1, RUNX1, TP53; KIT ( in CBF)	Unfavorable

Of Future Importance: mutation status of IDH1/2, DNMT3A, TET2, etc.

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Acute Leukemia: General treatment principles

Goal 1: Induction rx to reduce gross leukemia to undetectable levels (2-3 log cell kill)

Goal 2: Reduce 10⁹ - 10¹⁰ cells, undetectable by standard means, present at CR, to a level low enough to achieve prolonged disease-free survival (‘cure’)

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AML: Key Endpoints

Overall survival (OS)
Event-free survival (event= no CR, relapse, death)

Somewhat correlated with OS
Has intrinsic value to pts: when no event they are in CR with acceptable counts

Complete remission ( CR)

CR with incomplete plt ( or ANC) recovery has value
CR at MRD negative level has most value !

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The MRD concept. x-axis represents time; y-axis represents tumor burden.

Hokland P , Ommen H B Blood 2011;117:2577-2584

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Acute Leukemia : Selected Clinical Issues

Infection

Do not delay antileukemic therapy while infection resolves
Early use of antifungals
Raw fruit and vegetables probably OK

Thrombocytopenia

Platelet transfusion threshold of 10K/ul
Obligate use of single donor platelets is contoversial

Tumor Lysis Syndrome

Hydration, allopurinol, and judicious use of sodium bicarbonate is effective
Single dose of recombinant urate oxidase can be considered if pt cannot take po

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Treatment of Acute Promyelocytic Leukemia

Key Principles of APL Management
Suspect the disease!
Risk of death is greatest in the first two weeks after diagnosis, especially if ATRA initiation is delayed…
So, if the clinical setting suggests the possibility of APL (e.g., clefted blasts, strong CD33+, DIC) do not wait for molecular confirmation to start ATRA
Document disease
Use cytogenetics or FISH for t(15;17), or RT-PCR for PML-RARA fusion
Variant translocations are rare, but important to know about, since several do not respond to ATRA
Assess risk
If WBC >10 x 10⁹/L: high risk
If WBC ≤10 x 10⁹/L: standard risk (lowest risk if platelets also >40 x 10⁹/L)
Is the patient an anthracycline candidate?

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APL 0406 Study

Acute Promyelocytic Leukemia

Low/intermediate risk patients

(WBC ≤10 x 10⁹/L, AGE 16-70)

ATO

ATRA

Chemotherapy

ATRA

LoCoco et al NEJM 369: 111-121, 2013

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Treatment

Estey et al, Blood 2006

Lo-Coco et al, Blood 2010

Induction

ATRA

ATO

Until CR

Consolidation

ATO

4 weeks on / 4 weeks off

2 weeks on / 2 weeks off

Induction

Consolidation

Maintenance

ATRA

MTX + 6MP

IDA

MTZ

Until CR

2 years

3 monthly cycles

Chemo

Arm

ATO

arm

LoCoco et al NEJM 2013

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Overall survival probability

Months from diagnosis

98.7%

91.1%

p = 0.02

ATRA+ATO

ATRA+Chemo

Overall Survival

LoCoco et al (Abs #6), ASH 2012

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AML: Treatment of those under age 60 (non-APL)- The Old Days

Induction

anthracycline (3d) plus cytarabine (7d, IV continuous infusion)

Post-remission Therapy

intensive chemo
autologous Stem Cell Transplant ( SCT)
Allogeneic stem cell trnasplant

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AML Therapy for Patients Age <60 Years:

INDUCTION

Daunorubicin 60-90 mg/m²/d x 3 ( or ida 12 mg/m2/d x3)

Cytarabine 100-200 mg/m²/d x 7 continuous infusion*

Add Midostaurin 50 mg bid day 8-21 for mut FLT3
Add GO 3 mg/m2 d 1, 4, and 7, esp in CBF
CPX-351, d 1, 3, and 5 for h/o MDS, MDS-type cytogenetics
??Substitute HMA-VEN based regimens in adverse risk

POST-REMISSION

CBF: High dose ara-C 3 g/m2/3h q12h d1, 3, and 5 x 4 cycles
NPM1 mut/FLT3 WT: as above, ex ? 1.5 g/m2
Adverse risk: Allo SCT w best available donor
Intermediate risk: AlloSCT
?? What to do with MRD results
?? Oral aza maintenance in age >55 non-tx

*FLAG-IDA may have a role in the very fit

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Older Patients With AML Continue to Have Inferior Outcomes

Data are based on CALGB & MRC trials

for which adults of all ages were eligible

Age group	Complete remission rate (with “3&7”-like regimens)	Early mortality	Disease-free survival	Long-term overall survival	Median survival
<60 years	70%	5%	45%	30%	24 months
≥60 years	45%	15%	<20%	10%	10-15 months

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Why Do Older Patients With AML �Experience Inferior Outcomes?

Decreased host tolerance of intensive therapy

Impaired hematopoietic stem cell reserve
Presence of comorbid diseases
Decreased chemotherapy clearance

Increased resistance of disease to therapy

Ratio of favorable (eg, t[8;21]) to unfavorable (eg, -7) cytogenetics is lower than for younger patients
Higher expression of drug resistance proteins (eg, PGP)
Higher incidence of antecedent hematologic disorders

PGP = p-glycoprotein.

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AML: What is unfit?

Current ( FDA) definition: age >74 and /or significant co-mordid ds (Ferrara Criteria, see VIALE-A eligibility; Ferrara et al. Leukemia, 2013)
Perhaps: use geriatric assessment to define who will benefit ( Klepin H, et al, J Geri Oncol 2019)

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Therapy of older and or ‘unfit’ patients with AML

Induction

fit, de novo, likely to benefit:

daunorubicin 60-90 mg/m²/d x 3d + cytosine arabinoside 100-200 mg/m²/d by IVCI for 7 d

Add midostaurin days 8-21 if FLT3 mutation
? Add GO 3 mg/m2 days 1, 4, and 5

Fit, secondary ( s/p MDS or w MDS-type cytogenetics):

CPX-351

Unfit ( age>70-75, PS>2, co-morbid ds; regardless of molecular status)

HMA/VEN or ara-C/VEN

Post-remission therapy

Keep going with HMA/VEN
RIC allo SCT if feasible
?Repeat induction for others
Maintenance oral AZA ( for intensively treat non-tx pts)

Daunorubicin and cytosine arabinoside remain the standard induction regimen for older patients with acute myeloid leukemia. While idarubicin was apparently superior to daunorubicin based on several randomized trials conducted in the 1980s, recent trials in which various anthracyclines (idarubicin, mitoxantrone) have been compared during induction specifically in older patients have not shown a benefit compared to daunorubicin. There is no basis for reducing the dose of daunorubicin in this cohort.

The benefit of adding etoposide to standard anthracycline and cytosine arabinoside induction for acute myeloid leukemia is debated in younger patients. Randomized trials have suggested a benefit in disease-free, but not overall survival. The use of etoposide is not recommended in older patients with acute myeloid leukemia due to increased potential toxicity without added benefit.

AML Collaborative Group. A systematic collaborative overview of randomized trials comparing idarubicin with daunorubicin (or other anthracyclines) as induction therapy for acute myeloid leukaemia. Br J Haematol. 1998;103:100-109.

Lowenberg B, Suciu S, Archimbaud E, et al for the European Organization for the Research and Treatment of Cancer and the Dutch-Belgian Hemato-Oncology Cooperative Hovon Group. Mitoxantrone versus daunorubicin in induction-consolidation chemotherapy--the value of low-dose cytarabine for maintenance of remission, and an assessment of prognostic factors in acute myeloid leukemia in the elderly: final report. J Clin Oncol. 1998;16:872-881.

Rowe J, Neuberg D, Friedenberg W, et al. A Phase III study of daunorubicin vs idarubicin vs mitoxantrone for older adult patients (>55 years) with acute myelogenous leukemia (AML): A study of the Eastern Cooperative Oncology Group (E3993) {Abstract]. Blood. 1998; 92:1284a.

Kahn SB, Begg CB, Mazza JJ, Bennett JM, Bonner H, Glick JH. Full dose versus attenuated dose daunorubicin, cytosine arabinoside, and 6-thioguanine in the treatment of acute nonlymphocytic leukemia in the elderly. J Clin Oncol. 1984;2:865-870.

Bishop JF, Matthews JP, Young GA, Bradstock K, Lowenthal RM. Intensified induction chemotherapy with high-dose cytarabine and etoposide for acute myeloid leukemia: a review and updated results of the Australian Leukemia Study Group. Leuk Lymphoma. 1998;28:315-327.

[AU: Please identify the 3 most important references to include on the slide.]

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CPX-351

CPX-351 is a liposomal co-formulation of cytarabine and daunorubicin designed to achieve synergistic antileukemia activity

5:1 molar ratio of cytarabine:daunorubicin provides synergistic leukemia cell killing in vitro¹
In patients, CPX-351 preserved delivery of the 5:1 drug ratio for over 24 hours, with drug exposure maintained for 7 days²
Selective uptake of liposomes by bone marrow leukemia cells in xenograft models³

1. Tardi P et al. Leuk Res. 2009;33(1):129–139.

2. Feldman EJ et al. J Clin Oncol. 2011;29(8):979–985;

3. Lim WS et al. Leuk Res. 2010;34(9):1245–1223.

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Venetoclax: BCL-2 Selective Inhibitor

Konopleva M, et al. Cancer Discov. 2016. Epub ahead of print. Lin T, et al. ASCO 2016. Abstract 7007.

BCL-2 overexpression allows cancer cells to evade apoptosis by sequestering pro-apoptotic proteins

Venetoclax binds to BCL-2, freeing pro-apoptotic proteins that initiate apoptosis

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AZA ± VEN in AML: Overall Survival

	No. of events/No. of patients (%)	Median duration of study treatment, months (range)	Median overall survival, months (95% CI)
Aza+Ven	161/286 (56)	7.6 (<0.1 – 30.7)	14.7 (11.9 – 18.7)
Aza+Pbo	109/145 (75)	4.3 (0.1 – 24.0)	9.6 (7.4 – 12.7)

Hazard ratio: 0.66 (95% CI: 0.52 – 0.85), P <.001

Median follow-up time: 20.5 months (range: <0.1 – 30.7)

DiNardo CD et al. NEJM 2020

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QUAZAR AML-001: Study design and eligibility criteria,�Wei et al NEJM, 2020. ORAL AZACITIDINE MAINTENANCE

^aBM aspirates were collected every 3 cycles through cycle 24, at cycle 30 and cycle 36, and as clinically indicated thereafter. BM assessments were also performed as clinically indicated. ^bPatients were followed until death, withdrawal of consent, study termination, or loss to follow-up.

AML, acute myeloid leukemia; ANC, absolute neutrophil count; AZA, azacitidine; BM, bone marrow; CMML, chronic myelomonocytic leukemia; CR, complete remission; CRi, CR with incomplete blood count recovery; ECOG PS, Eastern Cooperative Oncology Group performance status; HRQoL, health-related quality of life; HSCT, hematopoietic stem cell transplant; IC, induction chemotherapy; IWG, International Working Group; MDS, myelodysplastic syndromes; PBO, placebo.

PRE-RANDOMIZATION

Key eligibility criteria:

First CR/CRi with IC �± consolidation
Age ≥55 years
De novo AML or AML secondary to MDS/CMML
ECOG PS score 0–3
Intermediate- or poor-risk cytogenetics
Not candidate for HSCT
ANC ≥0.5 ×10⁹/L
Platelets ≥20 ×10⁹/L

FOLLOW-UP^b

1:1 Randomization

Within 4 months �(± 7 days) from CR/CRi

Stratified by:

Age: � 55–64 / ≥65 years
Prior MDS/CMML: � Yes / No
Cytogenetic risk:� Intermediate / Poor
Consolidation: � Yes / No

RANDOMIZATION

Continue Treatment

TREATMENT PHASE

(Optional)�Oral-AZA/PBO x21 Days

Response Assessment �(BM Aspirate)�Every 3 Cycles^a

>15% �BM Blasts

5%–15% �BM Blasts

CR/CRi

Oral-AZA 300 mg �QD x 14 Days

Placebo �QD x 14 Days

End of Study

28-day cycles

Stop Treatment

International, multicenter, placebo (PBO)-controlled, double-blind, randomized, phase III study of �Oral-AZA as maintenance Tx in pts with AML in first remission post-IC

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Overall and relapse-free survival

1. Wei et al. NEJM 2021.

OS was defined as the time from randomization to death by any cause. Kaplan-Meier estimated OS was compared for Oral-AZA vs. placebo by stratified log-rank test. HRs and 95%CIs were generated using a stratified Cox proportional hazards model.

AZA, azacitidine; mo, months; No., number; OS, overall survival; PBO, placebo; RFS, relapse-free survival.

Oral-AZA 300 mg QD was associated with significantly improved overall survival (OS) (P = 0.0009) and relapse-free survival (RFS) (P = 0.0001) vs. PBO¹

OVERALL SURVIVAL

No. at risk:

Oral-AZA 238 213 168 133 115 87 59 37 26 18 15 5 1 0

Placebo 234 183 127 96 82 58 34 27 19 14 11 6 1 0

Survival Probability

No. at risk:

Oral-AZA 238 143 92 68 47 30 8 5 3 2 1 1 0

Placebo 234 96 55 37 29 23 6 4 3 1 0

Months from randomization

Relapse-free Survival Probability

RELAPSE-FREE SURVIVAL

Months from randomization

Wei et al NEJM, 2020

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Relapsed AML: Induce CR2, then allo SCT

FLAG-IDA, MEC are typical salvage regimens (can repeat 3+7 if >1 y ds-free interval). ? Add ven
If IDH2 mutant: consider enasidenib
IF IDH1 mutant: consider ivosidenib
IF FLT3 mutant: gilteritinib/quizartinib
Fractionated gemtuzumab if unfit
Clinical trial (spliceosome inhib, HH pathway, pro-apoptotic [BCL-2i, MDM2i], chemo + E-selectin inhibitor, MENINi, AntiCD47, anti CD123)

Smith, BD, et al. Blood 2004

Knapper, S, et al. Blood 2006

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Isocitrate Dehydrogenase (IDH) Mutations as a Target in AML

IDH is an enzyme of the �citric acid cycle

Mutant IDH2 produces 2-hydroxyglutarate (2-HG), which alters DNA methylation and leads to a block in cellular differentiation

AG-221 (CC-90007) is a selective, oral, potent inhibitor of the mutant IDH2 (mIDH2) enzyme

Tumor Cell

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Gilteritinib: Phase 3 ADMIRAL Trial

Gilteritinib; n = 247

Chemotherapy; n = 124

2:1

FLT3-positive R/R AML

HSCT

Gilteritinib

HSCT

Perl AE, et al. N Engl J Med. 2019;381:1728-1740.

Perl, A et al , NEJM, 2019

These materials are provided to you solely as an educational resource for your personal use. Any commercial use or distribution of these materials or any portion thereof is strictly prohibited.

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AML: Novel Promising Strategies

APR-246 for p53 mutant AML

Anti-CD70 Ab

Anti-CD47 antibody (5F9) macrophage phagocytosis

Schurch CM. Front Oncol. 2018;8:152.

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PDX

0.1% VTP

Menin-MLL Inhibitor is Effective Against

Mouse MLL-AF9 Leukemia

VTP-50469

Dramatic PDX responses as well in MLL-rearranged ALL/AML

and in NPM1c AML , Uckelmann et al., Science 2020

NH³-terminous of MLL-fusions binds to a pocket on the Menin (MEN1) protein, ‘VTP’ disrupts

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Acknowledgements

Clinical Team at DFCI:

Dan DeAngelo, Martha Wadleigh, David Steensma, Jackie Garcia, Goyo Abel, Eric Winer, Marlise Luskin, Max Stahl
Ilene Galinsky, NP
Andrian Penicaud, PA, Kat Edmonds, NP, Sarah Cahill, PA, Mary Girard, PA, Theresa Ngyuen NP, Elizabeth Herrity, DNP

BMT Team: Alyea, Antin, Armand, Cutler, Gooptu, Ho, Koreth, Romee, Nikiforow, Shapiro, Soiffer
DFHCC Team: Avigan, Rosenblatt, Amrein, Fathi, Brunner, Hobbs, Graubert

Scientific Team at Dana-Farber/Harvard Cancer Center

Ben Ebert; Andy Lane, Coleman Lindsley, Jim Griffin, Tony Letai, David Weinstock, David Frank, Kim Stegmeier, Donna Neuberg, Tom Look, S Armstrong, T Graubert

Worldwide Collaborators

Alliance: R Larson, G Marcucci, W Blum, G Uy, G Roboz, S Mandrekar
Worldwide: C Schiffer, T Fischer, H Dohner, K Dohner, C Thiede, R Schlenk, and others