acute myeloid leukemia - mayo clinic · leukemia nccn. acute myeloid leukemia. 3.2017 american...

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Acute Myeloid Leukemia in 2018:The Era of Individualized Therapy

Sila Shalhoub, PharmDPGY2 Oncology Pharmacy [email protected]

Pharmacy Grand Rounds February 6, 2018


Objectives• Describe the impact of patient and disease characteristics on outcomes of acute myeloid leukemia (AML) with standard therapy

• Identify unique patient subtypes that may benefit from one of the four new medications approved for AML in 2017

• Integrate diagnostic information into the development of a personalized treatment approach to optimize AML outcomes


Leukemia

NCCN. Acute Myeloid Leukemia. 3.2017American Cancer Society. Key Statistics for Acute Myeloid Leukemia. 2017

American Cancer Society. Cancer Facts & Figures. 2017

• Cancer of the bone marrow and blood

• 2018 estimates: • 60,300 new cases

• AML: 19,520 • 24,370 deaths

• AML: 10, 670

AML31%

CML10%ALL

10%

CLL37%

Others 12%

Types of Leukemia

AML: acute myeloid leukemia CML: chronic myeloid leukemia ALL: acute lymphoblastic leukemia CLL: chronic lymphocytic leukemia


Acute Myeloid Leukemia

• Incidence: 3‐5 cases/100,000 individuals

• Median age 67 years

• Overall 5‐year survival • < 65 yo: 40%• ≥ 65 yo: 5%

Kouchkovsky ID, et al. Blood Cancer J. 2016 Jul; 6(7): e441Almeida AM, et al. Leuk Res Rep. 2016; 6: 1–7https://commons.wikimedia.org/wiki/File:0337_Hematopoiesis_new.jpg


Risk Stratification

Prognostic Cytogenetics /Molecular abnormalities

FavorableInv(16), t(16;16), t(8;21), t(15;17)Normal karyotype with NPM1 mutation or CEBPA mutation

Intermediate +8 alone, t(9;11)KIT mutation

Poor Complex (≥3 clonal abnormalities) -5,5q-, -7, 7q-, 11q23, t(6;9)FLT3+, TP53 mutation

NCCN. Acute Myeloid Leukemia. 3.2017


AML Treatment Paradigm

HypomethylatingAgents

Best Supportive

Care

Transplant Monitor

Fit

Induction

Unfit

Consolidation

Intermediate/High Risk Intermediate/Low Risk


Standard Therapy Since the 1970’s • Induction with 7+3

• 7 days of cytarabine 100 or 200mg/m2 daily as a continuous IV infusion

• 3 days of either Idarubicin 12mg/m2 or daunorubicin 60mg/m2 as an IV push

• If complete remission (CR) achieved consolidation • High dose cytarabine

• 3000mg/m2 q12h day 1,3,5 for 3‐4 cycles

• High risk in CR Allogeneic stem cell transplant

Estey E, et al. Am J Hematol. 2016 Aug;91(8):824‐46Dombret H, et al. American Society of Hematology. 59th ASH Annual Meeting and Exposition. 2017


Outcomes of Standard Therapy

Prognostic CR rate RR w/ chemotherapy w/o allogeneic HCT

RR w/ chemotherapy w/ allogeneic HCT

Favorable > 80‐90% 35‐40% 15‐20%

Intermediate 50‐80% 50‐60% 20‐25%

Poor < 50% > 90% 40‐50%

Estey E, et al. Am J Hematol. 2016 Aug;91(8):824‐46Ossenkoppele GJ, et al. Haematologica. 2016 Jan; 101(1): 20–25

CR: complete remission, HCT: hematopoietic cell transplantation, RR: relapse rate


Historically, what characteristics may affect induction treatment selection in AML patients ?

A. Molecular abnormalities (ex. FLT3 status) B. Disease features (ex. sAML)C. Performance status (ex. fit vs. unfit)D. B & C E. All of the above


MidostaurinMidostaurin

Timeline of AML Therapies

7+3

Enasidenib

Gemtuzumab Ozogamicin*

Daunorubicin:Cytarabine liposomal

1960 1970 1980 1990 2000 2010 2017


FLT3 Mutations • FLT3: cytokine receptor, regulate early myeloid and lymphoid stem and progenitor cells’ growth and survival

• Occur in 25‐30% of AML patients

• Two subtypes:• Internal tandem duplication (ITD) – 25%

• Poor prognosis, high relapse rate • Tyrosine kinase domain (TKD) – 5‐10%

• Prognosis uncertain

Stone RM, et al. N Engl J Med. 2017 Aug 3;377(5):454‐464Perl A. American Society of Hematology. 59th ASH Annual Meeting and Exposition. 2017


FLT3 inhibitor: MidostaurinMechanism of Action • Multi‐target tyrosine kinase receptor inhibitor

• Inhibit receptor signaling and cell proliferation

• Induces apoptosis in leukemic cells expressing ITD and TKD mutant FLT3 receptors

• Can also inhibit other signaling pathways• KIT, PDGFRα/β, VEGFR2, PKC

Rydapt® [package insert]. Novartis Pharmaceuticals Corporation, Inc., East Hanover, NJ. 2017


CALGB 10603 – RATIFY Trial

7+3 plus midostaurin

7+3 plus placebo

Induction 1‐2 cycles (28days)

Consolidation 4 cycles (28days)

Midostaurin

Maintenance 12 cycles (28days)

Placebo

Primary Endpoint: Overall Survival

7+3 consisted of cytarabine IV 200mg/m2 + daunorubicin IV 60mg/m2

Midostaurin PO 50mg BID given on day 8‐21HiDAC: high dose cytatabine of 3000mg/m2 q12h on day 1,3,5

HiDAC plus placebo

CR

CR

Stone RM, et al. N Engl J Med. 2017 Aug 3;377(5):454‐464

Transplant

De‐novo AML dx FLT3‐mutationAge 15‐59yo (n= 717)

HiDAC plus midostaurin


Baseline Characteristics

Midostaurin(n= 360)

Placebo(n=357) p‐value

Age (median) 47.1 48.6 0.22

Female 186 (52%) 212 (59%) 0.04

Subtype of FLT3

mutation

TKD 81 (22%) 81 (23%) 1

ITD 279 (78%) 276 (77%) 1

WBC median 35,600 33,000 0.72



Results: Efficacy


Midostaurin(n= 360)

Placebo(n= 357) p‐value

Median Overall Survival 74.7 months 25.6 months 0.009

4‐year Overall Survival Rate 51.4% 44.3% ‐‐‐

Complete Remission 212 (59%) 191 (54%) 0.15

Median Event‐Free Survival (months) 8.2 3 0.002

Transplantation 213 (59%) 196 (55%) ‐‐‐


Results



Midostaurin(n= 360)

Placebo(n= 357) p‐value

Anemia 92.7% 87.8% 0.03

Rash 14.1% 7.6% 0.008

Nausea 9.6% 5.6% 0.05

Median Time for ANC Recovery 26 days 26 days ‐‐‐

Median Time forPlatelet Recovery 21 days 21 days ‐‐‐

Adverse Events


ANC: absolute neutrophil count


Conclusion • First targeted therapy in high risk AML

• Midostaurin was associated with • 22% reduction in the hazard ratio for death • 7% increase of 4‐year overall survival• Cost: 14‐days course= $9000

• Unanswered questions:• Role of maintenance therapy• Role after transplant

• Future FLT3 inhibitors • Quizartinib, crenolanib , gilteritinib


Daunorubicin:Cytarabine liposomal


7+3

Enasidenib


1960 1970 1980 1990 2000 2010 2017

MidostaurinFLT3 positive MidostaurinFLT3 positive


Daunorubicin:Cytarabine Liposomal

• Daunorubicin:Cytarabine Liposomal formulation in a 1:5 molar ratio

• Daunorubicin: anthracycline

• Cytarabine: antimetabolite

• Rational• Efficacy = maximum dose intensity • Synergy without antagonism • Peak effect vs. constant cytotoxic drug delivery


CLTR0310‐301: Daunorubicin:Cytarabine Liposomal

tAML or AML‐MRCAge 60‐75yo (n= 309)

Daunorubicin:CytarabineLiposomal

7+3

Induction 1‐2 cycles (28days)

Daunorubicin:CytarabineLiposomal

Consolidation 1‐2 cycles (28days)

Primary Endpoint: Overall Survival

Liposomal induction: dauno 44mg/m2 + cytarabine 100mg/m2 on day 1,3,5 (day 1,3 in the second induction)Liposomal consolidation: dauno 29mg/m2 + cytarabine 65mg/m2 on day 1,37+3 1st induction: cytarabine IV 100mg/m2 day 1‐7+ daunorubicin IV 60mg/m2 day 1‐37+3 2nd induction & consolidation: cytarabine IV 100mg/m2 day 1‐5+ daunorubicin IV 60mg/m2 day 1‐2

CR

Vyxeos® [package insert]. Jazz Pharmaceuticals, Inc., Palo Alto, CA. 2017Lancet JE, et al. Journal of Clinical Oncology34, no. 15_suppl (May 2016) 7000‐7000

7+3CR

tAML: therapy related AMLAML‐MRC: AML with myelodysplasia‐related changes


Baseline Characteristics All Patients (n= 309)

Median Age 68

Male 61%

ECOG PS 0‐1 88%

t‐AML 20%

AML with antecedent hematologic disorder 54%

De‐novo AML with MDS 25%


ECOG: Eastern Cooperative Oncology GroupPS: performance status MDS: Myelodysplastic syndrome


Results Daunorubicin:

Cytarabine Liposomal (n= 153)

7+3(n= 156)

Received at Least1 Induction Cycle 100% 97%

Received at Least1 Consolidation Cycle 32% 21%

Proceeded to Transplantin First CR 20% 12%

Overall Transplant 34% 25%



Results


(n= 153)7+3

(n= 156)p‐value

Median overall survival 9.6 months 5.9 months 0.005

Complete Response 58 (38%) 41 (26%) 0.036

60‐day Mortality 13.7% 21.2% ‐‐‐


HR 0.69



(n= 153)7+3

(n= 156)

Hemorrhage 74% 56%

Epistaxis 36% 18%

Grade ≥3 12% 8%

Fatal treatment‐emergent CNS hemorrhage 2% 0.7%

Prolonged thrombocytopeniarates past day 42 28% 12%

Prolonged neutropenia rates past day 42 17% 3%

Adverse Events



Adverse Events • Infections (pneumonia, bacteremia)

• Gastrointestinal toxicity

• Rash, swelling, edema, mucositis

• Copper overload : 5mg/mL copper gluconate > 14% elemental copper

• Others:• Extravasation, cardiotoxicity, electrolytes abnormality, fatigue, musculoskeletal pain



Conclusion • First therapy aimed at sAML

• Daunorubicin:Cytarabine Liposomal was associated with• Longer overall survival • Higher complete responses and transplant rate • Hemorrhage incidence and prolonged myelosuppression

• Cost of 1 induction course:• BSA ≤ 2m2= $46,500• BSA > 2m2 = $69,750

• Unanswered questions• Benefits of efficacy vs. risks of toxicity?


How is Daunorubicin:CytarabineLiposomal formulation different than the conventional daunorubicin + cytarabine?

A. Less cardiotoxic on mg per mg basis of daunorubicin

B. More prolonged thrombocytopenia and neutropenia

C. Higher CR and OS rates across AML subtypes

D. Less healthcare resources utilized during induction




7+3

Enasidenib

1960 1970 1980 1990 2000 2010 2017

MidostaurinFLT3 positiveMidostaurinFLT3 positive

Daunorubicin:Cytarabine liposomalsAML


CD33 Cell Surface Marker • Limited to myeloid progenitors

• Not present on normal hematopoietic stem cells

• Expressed on >90% of AML blasts

• Negative regulator of immunoreceptor signal transduction

• Gemtuzumab ozogamicin (GO) mechanism of action

Perl A. American Society of Hematology. 59th ASH Annual Meeting and Exposition. 2017

CD33+Leukemia

Calicheamicin (antitumor antibiotic)

GO binds to CD33 Ab‐Ag complexinternalizes

Calicheamicinreleased

Cell death


Gemtuzumab ozogamicin (GO) • Accelerated approval in 2000 for relapsed AML

• International, randomized, phase 3 (SWOG S0106) trial• GO at a dose of 6mg/m2 added to 7+3 in newly dx AML• <60 years of age • Interim analysis

• GO failed to improve CR and OS rate • Increase in induction mortality rate 5% vs 1.4% • Increase in grade 4 toxicities 21% vs 12%

• GO increase risk of VOD

• Voluntarily withdrawn from the market in 2010

Perl A. American Society of Hematology. 59th ASH Annual Meeting and Exposition. 2017

OS: overall survival VOD: veno‐occlusive disease


Gemtuzumab ozogamicin

French ALFA‐0701 AML‐19 MyloFrance‐1

Population 278 newly dx AML Age 50‐70

237 newly dx AML Age ≥ 61, ECOG >2

57 R/R CD33 positive AML

Design Randomized, phase 37+3 ± GO

Randomized, phase 3GO vs. BSC

Phase 2single‐arm

Dosing 3mg/m2 on day 1,4,7 6mg/m2 on day 1 and 3mg/m2 on day 8

3mg/m2 on day 1,4,7 consolidation with Ara‐C

Outcomes EFS: 17.3 vs 9.5 monthsHR 0.56, p<0.001

OS: 4.9 vs 3.6 months HR 0.69, p=0.005

RFS: 11.6 months CR: 15 (26%)

Castaigne S, et al. Lancet. 2012 Apr 21;379(9825):1508‐16Amadori S, et al. J Clin Oncol. 2016 Mar 20;34(9):972‐9

Mylotarg® [package insert]. Wyeth Pharmaceuticals, Inc., Philadelphia, PA. 2017

EFS: event‐free survival RFS: relapse‐free survival


Adverse Events • Veno‐occlusive disease (5%)

• Elevated AST/ALT, Tbili• Weight gain • Ascites

• Prolonged thrombocytopenia (3% ‐ 35%)• Hemorrhage

• QTc prolongation – due to calicheamicin

• Post marketing: • Neutropenic colitis, infections, hemorrhagic cystitis

Mylotarg® [package insert]. Wyeth Pharmaceuticals, Inc., Philadelphia, PA. 2017


Conclusion • GO: CD33‐directed antibody‐drug conjugate

• Approved for • Newly diagnosed AML (monotherapy or combined therapy)• Relapsed/Refractory AML (monotherapy)

• At lower doses, GO was associated with• Longer event‐free, relapsed‐free, and overall survival • Veno‐occlusive disease

• Cost of 1 cycle= $32,800

• Place in therapy is not well defined



7+3

Enasidenib

1960 1970 1980 1990 2000 2010 2017

MidostaurinFLT3 positiveMidostaurinFLT3 positive

Daunorubicin:Cytarabine liposomalsAML

Gemtuzumab Ozogamicin*CD33 positive


Isocitrate Dehydrogenase 2 (IDH2) • Catalyze conversation of isocitrate to α‐ketoglutarate (αKG)

• Mutation reduction of αKG to R‐2‐hydroxyglutarate (R2‐HG)

• ↑R2‐HG levels differentiation arrest of hematopoietic cells

• Mutations occurs in ~12% of AML patients

• Enasidenib: First‐in‐class, oral selective inhibitor of isocitratedehydrogenase‐2 (IDH‐2) enzyme

Stein EM, et al. Blood. 2017 Aug 10;130(6):722‐731 IDHIFA® [package insert]. Agios Pharmaceuticals, Inc., Cambridge, MA. 2017

Citrate

Isocitrate

α‐KG

2‐HG

IDH3 IDH2

IDH2 mutation

MitochondriaTCA Cycle


AG221‐C‐001: Enasidenib

≥18 yoMutant IDH2 R/R AML (n= 176)

Enasidenib100mg daily

Until disease progression



Results: Efficacy


Enasidenib(n= 176)

Median Overall Survival 9.3 months

Overall Response Rate 71 (40%)

Complete Remission 34 (19%)

Complete Remission with Incomplete Hematologic Recovery 12 (9%)

Partial Remission 11 (6%)

Morphologic Leukemia‐Free State 14 (8%)


Results: Response


Enasidenib(n= 176)

Time to Response 1.9 months

Median Duration of Response 5.8 months

Median Duration of Response in CR patients 8.8 months

Proceeded to transplant 17 (10%)


Adverse Events • Differentiation syndrome (14%)

• Non‐infectious leukocytosis (12%)

• Tumor lysis syndrome (6%)

• GI toxicities (50%)

• Decreased appetite (34%)

IDHIFA® [package insert]. Agios Pharmaceuticals, Inc., Cambridge, MA. 2017


Case46 yo, 72kg, F, with relapsed (IDH2 mutated) AML, WBC 8.2 with 26% blasts.

Today is day 18 after enasidenib initiation. This morning patient developed a fever of 39.2°C, new onset dyspnea, O2 Sat 86% on room air, CXR showed diffuse bilateral interstitial infiltrates, WBC 36.4 with 3% blasts, weight 78kg.

What is the next step for managing this patient’s symptoms ?

IDHIFA® [package insert]. Agios Pharmaceuticals, Inc., Cambridge, MA. 2017


CaseA. Obtain blood cultures and start treatment

with cefepime and vancomycin

B. O2 mask + bronchodilator

C. Stop enasidenib and give dexamethasone

D. Give furosemide 40mg IV x1


Conclusion • Enasidenib was associated with

• 9.3 months median overall survival • Time to response was 1.9 months • 19% achieved CR lasting 8.8 months • Differentiation syndrome

• Cost: 30‐day supply= $24,870

• Phase 1/2 data, mature data outcomes?


Summary • 1970 – 2017: no change in AML treatment

• Four novel therapies were approved in 2017 for the treatment of AML

• 2018: individualized AML treatment • Disease characteristics • Patient characteristics


One Size Does Not Fit All

7+37+3

1960 1970 1980 1990 2000 2010 2017

Midostaurin

EnasidenibEnasidenib

Gemtuzumab OzogamicinGemtuzumab Ozogamicin

FLT3 positive Not as a single agent

Daunorubicin: Cytarabine liposomal

Single Agent in R/R AMLIDH2 mutation

Single Agent in tAML and AML‐MRC

Single Agent or in combination Newly dx or R/R CD33 positive


What characteristics may affect induction treatment selection in AML patients ?

A. Molecular abnormalities (ex. FLT3 status) B. Disease features (ex. sAML)C. Performance status (ex. fit vs. unfit)D. B & C E. All of the above


Questions & Discussion

Sila Shalhoub, PharmDPGY2 Oncology Pharmacy Resident

[email protected]

Acute Myeloid Leukemia in 2018:The Era of Individualized Therapy

acute myeloid leukemia - mayo clinic · leukemia nccn. acute myeloid leukemia. 3.2017 american...

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