Oncology Conference Optimizing the Management of Acute Myeloid - - PowerPoint PPT Presentation

2020 Spring Oncology Conference

Optimizing the Management

• f Acute Myeloid Leukemia:

Individualized Therapy

3

• Describe diagnostic testing for risk stratification in AML and the role of cytogenetic

and molecular factors in treatment selection

• Identify individualized AML treatment approaches based on efficacy and safety

data, as well as patient- and disease-related characteristics

• Implement strategies to recognize, monitor, and manage toxicities associated with

new agents used in the treatment of AML

Learning Objectives

AML = acute myeloid leukemia.

4

• Heterogeneous hematologic malignancy

‒ Accounts for largest number of annual deaths from leukemia in the United States ‒ Survival influenced by biological features of the disease and patient age

AML: Most Common Form of Acute Leukemia in Adults

American Cancer Society. www.cancer.org/cancer/acute-myeloid-leukemia/about/key-statistics.html. Accessed Mar 20, 2020; National Cancer

• Institute. seer.cancer.gov/statfacts/html/amyl.html. Accessed Mar 20, 2020; NCCN Guidelines. Acute myeloid leukemia.

www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed Mar 20, 2020.

5

1992 2003 2016

Year

New cases Deaths

Number per 100,000 Persons

Estimated New Cases in 2020 % of All New Cancer Cases Estimated Deaths in 2020 % of All Cancer Deaths 19,940 1.2% 11,180 1.8% 5-Year Survival (2009-2015)

28.3%

5

• Most frequently diagnosed in people aged 65 to 74

years ‒ Median age at diagnosis: 68 years ‒ ~1/3 of patients with newly diagnosed AML are ≥75 years of age

• Slightly more common in men than in women
• Lifetime risk: ~0.5% in both sexes

‒ De novo ‒ Secondary

• AML-MRC
• Therapy-related
• Poor prognosis in people aged 75 to 84 years due

to adverse patient characteristics and comorbidities

AML Incidence Increases With Age

AML-MRC = AML with myelodysplasia-related changes. Granfeldt Østgård LS, et al. J Clin Oncol. 2015;31:3641-3649; Klepin HD, et al. Am Soc Clin Oncol Educ Book. 2019;39:421-432; National Cancer

• Institute. seer.cancer.gov/statfacts/html/amyl.html. Accessed Mar 20, 2020; Vardiman JW, et al. Blood. 2009;114:937-951.

<20 20-34 35-44 45-54 55-64 65-74 75-84 >84 Age, Years

30 25 20 15 10 5 New Cases (%)

5.3%

New AML Cases by Age Group

5.7% 4.5% 9.1% 16.8% 25.1% 22.7% 11.0%

6

CR = complete response; R/R = relapsed or refractory. NCCN Guidelines. Acute myeloid leukemia. www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed Mar 20, 2020.

AML Treatment Paradigm and Goals

Risk Stratify

• Performance

status, age, comorbidities

• Preexisting

myelodysplasia

• Prior cytotoxic

therapy

• Cytogenetics
• Genomic mutations

Induction Therapy Goal:

• Achieve CR

Consolidation Chemotherapy Goals:

• Prevent recurrence
• Bridge to transplant

R/R Therapy/Clinical Trial Goal: Achieve CR Nonintensive Therapy Goals:

• Stable disease
• Slow disease progression

Relapse Risk Stratify

• Performance status,

age, comorbidities

• Cytogenetics
• Genomic mutations

Allogeneic HSCT Goal

• Cure

Relapse (6-9 months)

• r Refractory

Low Intensity Therapy Goal:

• Achieve CR or

stable disease

7

Lipof JJ, et al. Cancers. 2018;10:179.

Allogeneic HSCT

• Allogeneic HSCT is a potentially curative therapy that may be used in patients with

intermediate- or high-risk AML who have a suitable donor source and are considered to be good candidates

• Historically, older patients with AML have not been considered for allogeneic HSCT

due to the presence of comorbidities and the perceived risk of increased mortality

• Reduced intensity and non-myeloablative conditioning regimens have enabled the

use of allogeneic HSCT in a greater number of older patients with AML

• Recent data support the use of allogeneic HSCT in selected, fit, older patients with

AML after intensive chemotherapy; however, the number of older patients who receive allogeneic HSCT remains low

8

Individualizing Treatment Goals in AML

EXAMPLE:

• Novel low-intensity induction regimens may provide patients ≥75 years old and those who

have comorbidities with the goal of a complete response BUT:

• Stable disease may be a reasonable therapeutic goal for some patients such as those

who are elderly and/or frail BUT:

• Patients may request high-intensity induction regimens and/or potentially curative,

allogeneic HSCT regardless of age, performance status, and comorbidities

NCCN Guidelines. Acute myeloid leukemia. www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed Mar 20, 2020.

9

Recently Approved Targeted Therapy for AML

Drug Description Indication

Midostaurin Multikinase inhibitor with inhibitory activity against FLT3-ITD and FLT3- TKD mutations

• Adults with newly diagnosed FLT3-mutated AML

in combination with standard cytarabine and daunorubicin induction therapy and cytarabine consolidation therapy Gilteritinib Inhibitor of multiple receptor tyrosine kinases, including FLT3

• Adults with R/R FLT3-mutated AML

Enasidenib Oral IDH2 inhibitor

• Adults with R/R IDH2-mutated AML

Ivosidenib Oral IDH1 inhibitor

• AML with a susceptible IDH1 mutation in:

⎻ Adults with newly diagnosed AML who are aged ≥75 years or who have comorbidities that preclude the use of intensive induction chemotherapy ⎻ Adults with R/R AML

TKD = tyrosine kinase domain. Idhifa [prescribing information]. Celgene Corporation; 2019; Rydapt [prescribing information]. Novartis Pharmaceuticals; 2019; Tibsovo [prescribing information]. Agios Pharmaceuticals, Inc; 2019; Xospata [prescribing information]. Astellas Pharma US, Inc.;2019.

10

Recently Approved Novel Agents for AML

Drug Description Indication

Gemtuzumab

• zogamicin

CD33-directed antibody- drug conjugate

• Adults with newly diagnosed CD33-positive AML (in combination with

daunorubicin and cytarabine or as a single-agent regimen)

• R/R CD33-positive AML in adults and in pediatric patients aged ≥2

years Glasdegib Hedgehog pathway inhibitor

• Newly diagnosed AML in combination with LDAC in adults who are

aged ≥75 years or who have comorbidities that preclude the use of intensive induction chemotherapy Venetoclax BCL-2 inhibitor

• Newly diagnosed AML in combination with azacitidine, decitabine, or

LDAC in adults who are aged ≥75 years or who have comorbidities that preclude intensive induction chemotherapy CPX-351 Liposomal combination of daunorubicin and cytarabine

• Adults with newly diagnosed therapy-related AML or AML-MRC

BCL-2 = B-cell lymphoma 2; LDAC = low-dose cytarabine. Daurismo [prescribing information]. Pfizer Inc; 2020; Mylotarg [prescribing information]. Pfizer Inc; 2018; Venclexta [prescribing information]. AbbVie Inc; 2019; Vyxeos [prescribing information]. Jazz Pharmaceuticals; 2019.

11

• Presents to ED complaining of

extreme fatigue and abrupt onset of shortness of breath

• 2-week history of worsening exercise

tolerance

• No significant past medical history
• Enjoys bicycling, swimming, and

painting

Case Study 1: Tom, 58 Years Old

Hgb = hemoglobin.

• Laboratory results:

– WBCs: 120,000 cells/mm3 – Hgb: 6.9 g/dL – Platelets: 27,000/mm3 – Blasts: 47%

• Admitted to hospital for further

testing

12

Diagnostic Testing and Karyotyping for Risk Stratification

• Bone marrow core biopsy and aspirate analysis, including immunophenotyping and cytochemistry
• Molecular analyses: FLT3 (ITD and TKD), NPM1, CEBPA, IDH1, IDH2, TP53, c-KIT, RUNX1, ASXL1
• Karyotyping is an important prognostic factor for predicting remission rates, relapse risk, and OS

‒ Complex karyotype: independent unfavorable risk factor

• With each additional karyotype abnormality, the risk of failing to achieve CR increases
• SWOG analysis:
• Complex cytogenetics without involvement of chromosome 5 or 7:

CR 50%; OS 20%

• Complex cytogenetics + involvement of chromosome 5 or 7:

CR 37%; OS 3% ‒ Monosomal karyotype: very poor prognosis

• 4-year OS 4%

OS = overall survival; SWOG = Southwest Oncology Group. NCCN Guidelines. Acute myeloid leukemia. www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed Mar 20, 2020; Orozco JJ, et al. Oncology (Williston Park). 2012;26:706-712; Slovak ML, et al. Blood. 2000;96:4075-4083; Xu J, et al. Turk J Haematol. 2017;34:126-130.

13

AML Disease Prognosis Influenced by Genetic Abnormalities

NCCN Guidelines. Acute myeloid leukemia. www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed Mar 20, 2020.

Risk Category Genetic Abnormality 5-Year Survival

Favorable

• t(8;21)(q22;q22.1); RUNX1-RUNX1T1
• inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
• Mutated NPM1 without FLT3-ITD or with FLT3-ITDlow
• Biallelic mutated CEBPA

34% to 65% Intermediate

• Mutated NPM1 and FLT3-ITDhigh
• Wild-type NPM1 without FLT3-ITD or with FLT3-ITDlow (without adverse-risk genetic lesions)
• t(9;11)(p21.3;q23.3); MLLT3-KMT2A
• Cytogenetic abnormalities not classified as favorable or adverse

13% to 41% Poor/Adverse

• t(6;9)(p23;q34.1); DEK-NUP214
• t(9;22)(q34.1;q11.2); BCR-ABL1
• inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2);

GATA2,MECOM(EVI1)

• –5 or del(5q); –7; –17/abn(17p)
• Complex karyotype, monosomal karyotype
• t(v;11q23.3); KMT2A rearranged
• Wild-type NPM1 and FLT3-ITDhigh
• Mutated RUNX1
• Mutated ASXL1

Mutated TP53 2% to 14%

14

• MRCs are characterized by a history of myelodysplastic syndrome (MDS),

significant morphologic dysplasia, or MDS-related cytogenetic features

• Patients with MRCs have a worse prognosis
• Can occur in patients with or without a history of MDS or myeloproliferative

neoplasms (MPN)

• Also includes AML with morphologic features or cytogenetic abnormalities

characteristic of MDS

MRCs in AML

National Cancer Institute. www.cancer.gov/publications/dictionaries/cancer-terms/def/aml-mrc. Accessed Mar 20, 2020; NCCN Guidelines. Acute myeloid leukemia. www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed Mar 20, 2020.

15

Optimizing Testing

• Communication between clinician and pathologist ensures necessary testing

‒ Pertinent patient history

• Prior hematologic disorder or known predisposing conditions
• Prior malignancy
• Exposure to cytotoxic therapy, immunotherapy, radiotherapy, or other

possibly toxic substances

• Presence or absence of MRC

‒ Comprehensive genomic profiling at diagnosis for disease classification, risk stratification, prognosis, and treatment selection

NCCN Guidelines. Acute myeloid leukemia. www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed Mar 20, 2020. Waterhouse M, et al. Biol Blood Marrow Transplant. 2011;17:1450-1459.

16

• ECOG PS: 1
• Cytogenetics: diploid karyotype 46,XY[20]
• Bone marrow core biopsy: hypercellular marrow (90% cellularity)

with 56% myeloblasts

• Flow cytometry: CD33+/CD117+/HLA-DR+/MPO+/CD34−
• Molecular studies:

‒ Wild-type CEBPA and NPM1 ‒ FLT3-ITD/wildtype allelic ratio of 0.55

Case Study (cont’d): Tom’s Test Results

ECOG PS = Eastern Cooperative Oncology Group performance status.

17

RATIFY: Frontline Standard 7+3 ± Midostaurin in FLT3-ITD and FLT3-TKD Mutated Disease

CI = confidence interval; NR = not reported. Rydapt [prescribing information]. Novartis Pharmaceuticals; 2019; Stone RM, et al. N Engl J Med. 2017;377:454-464.

Median OS: Months (95% CI)

100 80 60 40 20 Probability of Survival (%) 24 12 48 36 72 60 90 84 Midostaurin Placebo 74.7 (31.5-NR) 25.6 (18.6-42.9) 1-sided P = .009 by stratified log-rank test Months Midostaurin Placebo 360 357 269 221 208 163 181 147 151 129 97 80 37 30 1 1 Patients at Risk, n

Midostaurin Placebo

Complete remission by day 60 59% 53% Event-free survival (EFS) 8 months 3 months 4-year OS 51% 44%

Midostaurin is indicated for use in patients with FLT3-mutated AML in combination with standard cytarabine and daunorubicin induction therapy and cytarabine consolidation therapy.

18

• Because Tom has a FLT3-ITD mutation, induction chemotherapy is initiated

with 7+3 (daunorubicin 60 mg/m2) and midostaurin 50 mg orally twice a day

• n days 8 to 21

Case Study (cont’d)

19

• No statistically significant differences in grade 5 AEs between midostaurin and placebo

‒ Significantly more grade ≥3 anemia and rash vs placebo ‒ Significantly more nausea with placebo

• AEs with 7+3 and midostaurin: febrile neutropenia, nausea, mucositis, vomiting, headache,

petechiae, musculoskeletal pain, epistaxis, device-related infection, hyperglycemia, and upper respiratory tract infection

• Administer prophylactic antiemetics before treatment with midostaurin
• Instruct patients to take with food; do not open or crush capsules
• Consider interval assessments of QT if taken concurrently with medications that can prolong

the QT interval

Standard 7+3 ± Midostaurin: AEs

AE = adverse event. Cessna MH, et al. www.hematology.org/Clinicians/Guidelines-Quality/Quick-Reference.aspx. Accessed Mar 20, 2020; NCCN Guidelines. Acute myeloid leukemia. www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed Mar 20, 2020; Rydapt [prescribing Information]. Novartis; 2019; Stone RM, et al. Blood. 2015;126:6; Stone RM, et al. N Engl J Med. 2017;377:454-464.

20

• Approved for newly diagnosed and R/R

CD33+ AML ‒ May be used in combination with 7+3

• r as monotherapy in certain patients
• Meta-analysis of 5 randomized

controlled trials (N = 3325)

• Absolute survival benefit at 6 years

especially apparent in patients with favorable cytogenetic characteristics

Gemtuzumab Ozogamicin + Chemotherapy: OS by Risk Category

GO = gemtuzumab ozogamicin; SD = standard deviation. Hill RK, et al. Lancet Oncol. 2014;15:986-996; Mylotarg [prescribing information]. Pfizer Inc; 2018.

77.5%

Annual event rates: GO No GO Years 1 to 5 5.8% SD 1.1 14.1% SD 1.9 Years 6+ 2.3% SD 1.3 0.0% SD 0.0 Estimated % Still Alive Years 100 80 60 40 20 1 2 3 4 5 6+

Deaths/person-years: Favorable cytogenics GO No GO 12/117 20/109 7/104 18/93 6/93 10/76 1/81 5/61 1/70 1/45 3/129 0/84

20.7% SD 6.5 (log-rank P = .0006) – allocated GO (% ± SD) – allocated No GO (% ± SD) 75.5% 55.0% 54.8%

21

• Prescribing information carries a boxed warning for hepatotoxicity, including severe or fatal VOD,

also known as sinusoidal obstruction syndrome

• VOD risk higher in patients:

‒ With moderate or severe hepatic impairment prior to receiving gemtuzumab ozogamicin ‒ Treated with gemtuzumab ozogamicin before or after HSCT

• Assess ALT, AST, total bilirubin, and alkaline phosphatase prior to each dose
• After treatment, monitor frequently for VOD signs/symptoms

‒ Elevations in ALT, AST, and total bilirubin ‒ Hepatomegaly ‒ Rapid weight gain ‒ Ascites

Gemtuzumab Ozogamicin: AEs

ALT = alanine transaminase; AST = aspartate aminotransferase; VOD = veno-occlusive disease. Hill RK, et al. Lancet Oncol. 2014;15:986-996; Mylotarg [prescribing information]. Pfizer Inc; 2018.

22

CPX-351: Median OS in Newly Diagnosed Older Patients With High-risk Secondary AML

Lancet JE, et al. J Clin Oncol. 2018;36:2684-2692.

• Approved for newly diagnosed, therapy-

related, or AML-MRC

• Improved OS vs standard 7+3 in older

patients with high-risk secondary AML

• Better outcomes after allogeneic HSCT

in older patients with high-risk AML, including 53% fewer deaths within 100 days of transplant

OS (%) Time Since Random Assignment (months)

• No. at risk

CPX-351 153 122 92 79 62 46 34 21 16 11 5 1 7+3 156 110 77 56 43 31 20 12 7 3 2 0

Events/No.

• f patients

Median survival (95% Cl), months CPX-351 104/153 9.56 (6.60 to 11.86) 7+3 132/156 5.95 (4.99 to 7.75) HR, 0.69 One-sided P = .003 0 3 6 9 12 15 18 21 24 27 30 33 36 100 80 60 40 20

23

• Reported AEs are generally consistent with the known safety profile of

cytarabine and daunorubicin therapy

• Boxed warning against interchanging with other products containing

daunorubicin or cytarabine

• Associated with delayed neutrophil and platelet count recovery of

6 to 7 days

• Administered as 90-minute infusion; potential to be given in outpatient

setting

CPX-351: AEs

Lancet JE, et al. Blood. 2016;128:906; Lancet JE, et al. J Clin Oncol. 2016;34(15 Suppl):7000. US Food and Drug Administration. www.fda.gov/newsevents/newsroom/pressannouncements/ucm569883.htm. Accessed March 20, 2020; Vyxeos [prescribing information]. Jazz Pharmaceuticals; 2019.

24

• After treatment with 7+3 and midostaurin, Tom achieves a CR as assessed

by repeat bone marrow biopsy following recovery of blood count

• Manageable side effects

− Myelosuppression managed with transfusions, growth factors − Nausea and vomiting managed with antiemetic combinations

• Tom is sent for allogeneic HSCT

Case Conclusion

25

• History of AML

‒ CR 4 months ago following 1 cycle of cytarabine with idarubicin and 3 cycles of intermediate-dose cytarabine for consolidation

• Presents with extreme fatigue and pallor, sudden onset of shortness of breath

‒ ECOG PS: 2 ‒ Comorbid COPD

• Complete blood count:

‒ WBCs: 1300 cells/mm3; absolute neutrophils: 570 cells/mcL; Hgb: 8.3 g/dL; platelets: 95,000/mm3

• Bone marrow biopsy consistent with relapse

‒ 80% cellular with 16% myeloblasts

Case Study 2: Edith, 68 Years Old

26

• Molecular studies:

‒ IDH1 mutation-positive ‒ FLT3 negative ‒ NPM1 negative

• Cytogenetics: 46,XX[20]

Case Study (cont’d): Edith’s Test Results

27

Ivosidenib

• First-in-class oral targeted IDH1 inhibitor for R/R AML
• Also approved for newly diagnosed adults aged ≥75 years or

with comorbidities precluding intensive induction chemotherapy

• Single-arm trial in adult patients with R/R AML and

IDH1 mutation

• 24.7% of 174 patients achieved CR

‒ 8.0% experienced CRh

• Boxed warning: IDH-DS
• Most common AEs of any grade:

‒ Fatigue, leukocytosis, arthralgia, diarrhea, dyspnea, edema, nausea, mucositis, ECG QT prolongation, rash, pyrexia, cough, constipation

Targeting IDH Mutations: Ivosidenib and Enasidenib in R/R AML

CRh = complete remission with partial hematologic recovery; CRi = complete remission with incomplete hematologic recovery; CRp = complete remission with incomplete platelet recovery. DiNardo CD, et al. N Engl J Med. 2018;378:2386-2398; Idhifa [prescribing information]. Celgene Corporation; 2019; Stein EM, et al. Blood. 2017;130:722-731; Tibsovo [prescribing information]. Agios Pharmaceuticals; 2019.

Enasidenib

• First-in-class oral targeted IDH2 inhibitor for R/R AML
• Single-arm trial in adult patients with R/R AML and

IDH2 mutation

• 19.3% of 176 patients achieved CR

− 6.8% experienced CRp/CRi

• Boxed warning: IDH-DS
• Most common AEs of any grade:

− Nausea, vomiting, diarrhea, elevated bilirubin, decreased appetite

28

• You start Edith on ivosidenib for her relapsed AML
• 4 weeks later, she is admitted to the hospital with shortness of breath,

cough, diarrhea, and rapid weight gain despite loss of appetite

• She believes the therapy is making her sicker and asks to discontinue

treatment

Case Study (cont’d): Edith’s Second-line Therapy

29

• Leukocytosis, lung infiltrates, pleural or pericardial effusions, rapid

weight gain, edema, azotemia

• Monitor closely when diagnosis is uncertain, as patients can rapidly

deteriorate

• For severe or rapidly progressing IDH-DS, hospitalize patient for

management

IDH-DS: Signs and Symptoms

DiNardo CD, et al. N Engl J Med. 2018;378:2386-2398; Stein EM, et al. Blood. 2017;130:722-731.

30

• Promptly initiate corticosteroids when IDH-DS is first suspected; upon improvement,

progressively reduce steroid dose ‒ Interrupt IDH inhibitor therapy at clinician’s discretion or if severe pulmonary symptoms and/or renal dysfunction persist after 48 hours of treatment ‒ Resume therapy when symptoms improve

• In patients with elevated WBC count, promptly initiate hydroxyurea
• Furosemide may be used for substantial fluid accumulations
• Monitor patients with rapidly increasing peripheral blood cells for disseminated

intravascular coagulopathy and hemorrhage

Clinical Management of IDH-DS

DiNardo CD, et al. N Engl J Med. 2018;378:2386-2398; Fathi AT. ASCO 2017; Stein EM, et al. Blood. 2017;130:722-731.

31

• Dexamethasone 10 mg is initiated
• Differentiation syndrome resolves after 48 hours of therapy
• Edith agrees to continue ivosidenib
• CR is achieved after 5 months of treatment

Case Study (cont’d)

32

Multicenter, Phase 1b Dose-escalation and Expansion Study

Venetoclax: CR/CRi and OS in Elderly or Frail Patients

HMA = hypomethylating agent; VEN = venetoclax. DiNardo CD, et al. Blood. 2019;133:7-17; US Food and Drug Administration. www.fda.gov/Drugs/DrugSafety/ucm634120.htm. Accessed Mar 20, 2020.

BCL-2 inhibitor for newly diagnosed AML in adults age ≥75 or with comorbidities that preclude intensive induction therapy in combination with azacitidine, decitabine, or LDAC

Cohort N Composite Response Rate, (CR + CRi) n (%) Overall Response Rate (CR + CRi + PR) n (%) Median Duration of CR + CRi (95% CI) Median OS (95% CI) All patients 145 97 (67) 99 (68) 11.3 (8.9-NR) 17.5 (12.3-NR) VEN 400 mg + HMA 60 44 (73) 44 (73) 12.5 (7.8-NR) NR (11.0-NR) VEN 800 mg + HMA 74 48 (65) 50 (68) 11.0 (6.5-12.9) 17.5 (10.3-NR)

• Common AEs (>30%): nausea, diarrhea, constipation, febrile neutropenia, fatigue, hypokalemia, decreased

appetite, and decreased WBC count

• FDA warning of increased risk of death in investigational use in R/R multiple myeloma but not in approved

indications

33

• Median OS = 10.1 months
• Median DOR = 8.1 months
• 54% of patients achieved CR/CRi
• Patients without prior HMA exposure

– CR/CRi = 62% – Median DOR = 14.8 months – Median OS = 13.5 months

Phase 1b/2 Study: Venetoclax + Low-dose Cytarabine in Previously Untreated Patients With AML

DOR = duration of response. Wei AH, et al. J Clin Oncol. 2019;37:1277-1284.

• Common grade ≥3 AEs:

– Febrile neutropenia (42%) – Thrombocytopenia (38%) – Decreased WBC count (34%)

34

BRIGHT: Glasdegib in Elderly or Frail Newly Diagnosed Patients

HR = hazard ratio. Cortes JE, et al. Leukemia. 2019;33:379-389.

• CR

− Glasdegib/LDAC: 17.0% (15/88) of patients vs LDAC: 2.3% (1/44 ) of patients (P <.05)

• Most common AEs (>20%)

− Anemia, fatigue, hemorrhage, febrile neutropenia, musculoskeletal pain, nausea, edema, thrombocytopenia, dyspnea, decreased appetite, dysgeusia, mucositis, constipation, rash

• Boxed warning

− Embryo-fetal death or severe birth defects when administered to pregnant women

5 10 15 20 25 30 35 40 Time (months) 1.0 0.8 0.6 0.4 0.2 0.0 Survival Probability

Median OS, months (80%) Glasdegib/LDAC 8.8 (6.9-9.9) LDAC 4.9 (3.5-6.0) HR = 0.513 80% CI: 0.394-0.666, P = .0004 Glasdegib/LDAC LDAC

Randomized, International, Phase 2 BRIGHT 1003 Trial

Hedgehog pathway inhibitor; for newly diagnosed AML in adults aged ≥75 years or with comorbidities that preclude intensive induction therapy

• In combination with LDAC

35

ADMIRAL: Gilteritinib vs Salvage Chemotherapy

GIL = gilteritinib; SC = salvage chemotherapy (LDAC, azacitidine, mitoxantrone/etoposide/cytarabine, or fludarabine/cytarabine/GCSF/idarubicin). Perl AE, et al. AACR 2019. Abstract CT184; Xospata [prescribing information]. Astellas Pharma US, Inc; 2019.

• Efficacy:

‒ OS: 9.3 months GIL; 5.6 SC (HR for death = 0.637; P = .0007) ‒ CR/CRh rate: 34.0% GIL; 15.3% SC (P = .0001) ‒ Median EFS: 2.8 months GIL; 0.7 months SC (HR 0.793; P = .0830)

• Common grade ≥3 AEs for GIL: anemia (19.5%), febrile neutropenia (15.4%), thrombocytopenia (12.2%),

decreased platelet count (12.2%) ‒ Serious treatment-emergent AEs less common with GIL (7.1%) vs SC (9.2%)

• Boxed warning for GIL: differentiation syndrome

Phase 3, open-label, multicenter, randomized trial Patients with FLT3-ITD or -TKD mutations randomized to gilteritinib (n = 347) or SC (n = 124)

Kinase inhibitor for R/R FLT3+ AML

36

AML and Patient Counseling

• In one survey, 67% of patients aged ≥60 years did not realize that there was more than one

treatment option ‒ Respondents failed to understand their chances of cure, 1-year survival, or treatment-related mortality, regardless of final treatment choice

• Educate patients and families on all appropriate treatments: risks and benefits, length of

treatment, AE management, treatment expectations and perceptions ‒ Compared with chemotherapy, patients take longer to achieve CR on biologics such as enasidenib

• Address any misconceptions and specific needs

‒ Financial assistance available for many therapies ‒ Current evidence on allogeneic HSCT in elderly patients with AML

Devillier R. https://ashpublications.org/blood/article/132/Supplement%201/209/261662/Allogeneic-Hematopoietic-Stem-Cell-Transplantation. Accessed March 20, 2020; LeBlanc TW, et al. J Clin Oncol. 2019;37(suppl):7040; Sekeres MA, et al. Leukemia. 2004;18:809-816; Stein EM, et al. Blood. 2017;130:722-731.

37

• Edith continues ivosidenib
• Following blood count recovery, she proceeds to allogeneic HSCT

Case Conclusion

38

• Second-generation FLT3 inhibitors

− Crenolanib − Quizartinib − CG-806

Investigational Treatment Approaches in AML

PD-1 = programmed cell death protein 1. Broderick JM. www.onclive.com/web-exclusives/fda-panel-votes-against-quizartinib-approval-for-aml. Accessed Mar 20, 2020; Cortes JE, et al.

• Leukemia. 2019;33:379-389; Lichtenegger FS, et al. J Hematol Oncol. 2017;10:142; Liu H, et al. Front Immunol. 2017;8:38; Montesinos P, et al.

J Clin Oncol. 2019;37(15 suppl):TPS7063. Papayannidis C, et al. Int J Mol Sci. 2019;20:e2721; Ternyila D. www.targetedonc.com/news/daver- investigates-combination-therapy-in-tp53-flt3mutated-aml. Accessed Mar 20, 2019; Zhang H, et al. AACR 2019.

• Immunotherapeutic agents

‒ Bispecific T-cell engager ‒ Dual affinity retargeting ‒ PD-1 inhibitors ‒ CTLA-4 inhibitors ‒ Chimeric antigen receptor therapies

39

• Randomized, double-blind, placebo-controlled trial investigating the epigenetic modifier

CC-486 (oral formulation of azacitidine) in patients aged ≥55 years with AML in first remission following induction chemotherapy

• Primary endpoint

‒ OS

• Secondary endpoints

‒ RFS, health-related quality of life, safety

• Patients randomized to receive CC-486 300 mg or placebo once daily on days 1 to 14 of

repeated 28-day treatment cycles

QUAZAR AML Maintenance Trial: Design and Methods

RFS = relapse-free survival. Roboz GJ, et al. Future Oncol. 2016;12(3):293-301; Wei AH, et al. Blood. 2019;134(suppl 2):LBA-3.

40

• 472 patients (median age, 68 years) were randomized to receive CC-486

(n = 238) or placebo (n = 234) ‒ At median follow-up of 42 months, median OS from time of randomization with CC-486 and placebo was 24.7 months vs 14.8 months, respectively ‒ Median RFS with CC-486 and placebo was 10.2 months vs 4.8 months, respectively ‒ Most common grade 3/4 AEs: neutropenia (CC-486, 41%; placebo, 24%), thrombocytopenia (23% and 22%, respectively), and anemia (14% and 13%, respectively)

QUAZAR AML Maintenance Trial: Results

Roboz GJ, et al. Future Oncol. 2016;12(3):293-301; Wei AH, et al. Blood. 2019;134(suppl 2):LBA3.

41

• Phase 1/2 dose-finding study of CC-486 maintenance therapy after

allogeneic HSCT in patients with AML or MDS who were in morphologic CR at the time of treatment initiation

• Patients received 1 of 4 CC-486 dosing schedules per 28-day cycle for

up to 12 cycles

• Endpoints: safety, pharmacokinetics, incidence of graft-versus-host

disease, relapse/progression rate, and survival

CC-486 Maintenance Trial After Allogeneic HSCT: Design and Methods

de Lima M, et al. Biol Blood Marrow Transplant. 2018;24:2017-2024.

42

• The intention-to-treat population consisted of 30 patients (median age, 64.5 years) who received ≥1

dose of CC-486 between July 2013 and November 2015

CC-486 Maintenance Trial After Allogeneic HSCT: Results

de Lima M, et al. Biol Blood Marrow Transplant. 2018;24:2017-2024.

• At 19-month follow-up, median OS was not reached

in any dosing cohort; the range for all patients was 86 to 1324 days

• Rate of relapse or progressive disease during

treatment in 28 assessable patients: 21%

• 1-year cumulative incidence of acute or chronic

graft-versus-host disease: 50%

• Grade 3/4 AEs were uncommon and occurred with

similar frequency across the dosing regimens

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0

Survival Probability

Median OS was not reached (NR, 95% CI 15.1 months, NR) Censored

Time (months)

6 12 18 24 30 36 42 48 30 25 23 19 12 5 3 1 Patients at Risk

43

PCE Action Plan

✓ Consider patient factors and preferences when establishing treatment goals for AML ✓ Risk-stratify patients by karyotype and genetic abnormalities in order to help predict remission, relapse, and OS ✓ Order comprehensive genomic profiling at both diagnosis and relapse, as genomic alterations can evolve throughout the disease course ✓ Enhance shared decision-making by addressing patient and family perceptions and knowledge of all appropriate treatments

PCE Promotes Practice Change

2020 Spring Oncology Conference