Acute Myelogenous Leukemia and

Myelodysplasia- Highlights of ASH 2013

Gary J. Schiller, M.D., F.A.C.P.Professor of Medicine

DirectorHematological Malignancies / Stem Cell Transplant Program

David Geffen School of Medicine at UCLA

A Static Therapeutic Landscape

• Statistical hazards in evaluating new interventions

• Limitations on the definition of response viz. survival

• Limitations in the regulatory pathway toward approval of novel agents

What Defines Risk in Acute Myelogenous Leukemia?

• Clinical Variables– Antecedent hematologic disturbance– Advanced age at presentation– Leukocytosis at presentation– Male gender– Elevated LDH at presentation

What Defines Risk in Acute Myelogenous Leukemia? cont’d…

• Biologic Variables– Adverse Cytogenetics

• Monosomies• Complex (≥ 3) abnormalities• inv(3), t(3;3), t(6;9), t(6;11), t(9;22), 17p

– Less-certain adverse cytogenetic features

• 11q23

Refinements in Risk Stratification

• Recurrent single-gene mutation– Mutations in kit– flt3 ITD

• Routine molecular studies• Investigational molecular studies

Routine Evaluation of AML for the Purpose of Risk-Stratification

• STANDARD: Morphology Flow Cytometry /

Immunohistochemistry F.I.S.H. for common abnormalities: t(8;21) RUNX1-RUNX1T1

inv(16) or t(16;16) CBFβ-MYH11 t(15:17) PML-RARα t(9;11) MLLT3-MLL inv(3) or t(3;3) RPN1-EVI 1

Karyotype Molecular Studies for mutations in flt3,

NPM-1, Kit, CEBPα• POTENTIALLY USEFUL: Molecular studies for mutations in DNMT3a,

TET2, MLL, IDH1, IDH2• INVESTIGATIONAL: Molecular studies for mutations in ASXL1,

PHF6, BCOR, CEBPε

Cytogenetic and Molecular Findings Characteristic of Newly-Diagnosed High-Risk

AML• Cytogenetic Classification

– Intermediate Risk• Normal• +8

– Unfavorable Risk• -5/-7• 11q23• 20q-• ≥ 3 abnormalities

– Favorable-Risk• t(8;21)• inv(16) or t(16;16)

• Mutation– flt3 ITD– Mutant TET2, MLL-PTD,

DNMT3a, ASXL1, PHF6

– Kit

Distribution of acute myeloid leukemia patients with intermediate-risk cytogenetics with intermediate

mutational risk (Patel JP et al. N Engl J Med.2012;366(12):1079-1089)

Further Clinical Features in Risk-Stratification for AML

• Impaired performance status• Co-morbid medical conditions• Disease refractory to conventional

induction• Disease relapsed after

– allogeneic hematopoietic progenitor cell transplant

– recent completion of consolidation chemotherapy

Treatment Strategies for the Management of High-Risk AML

• Dose-intensified induction chemotherapy

Author Patient Characteristics

Dose Follow-Up

Rate of CR

DFS OS

Fernandez, et al.

n = 657age = 17-60

45DNR vs. 90

DNR

23.7 vs. 15.7m

57.3% 70.6%

15.7m23.7m

Lowenberg et al.

n = 813age 60-83

45 DNRvs. 90 DNR

40m 54%64%

26% at 2y31% at 2y

Dose-Intensified Induction Chemotherapy for AML

• No significant survival benefit for AML with flt3 ITD or MLL-PTD.

• Survival advantage in favor of higher-dose DNR among those with intermediate- and favorable-risk cytogenetics, not among those with unfavorable-risk karyotype in ECOG study

• Greatest benefit in the HOVON/AMLSG/SAKK for high-dose DNR achieved in patients age of 60-65, and for patients with CBF leukemias

• No benefit was seen in patients with AML characterized by “very unfavorable” karyotype

Other Dose-Intensification Strategies

• Cytarabine• Mitoxantrone and Etoposide• Autologous transplantation

Hazards of Interpreting Trials of Dose-Intensification

• Enrollment typically not done on the basis of disease-related or clinical variables– analysis of subgroups, and conclusions,

are post-hoc• Randomized trials of novel therapy

generally do not restrict or define post-remission management

• None of the studies attempt to improve outcome based on distinct AML subtypes

When is Investigational Therapy Warranted for AML?

• Refractory and “Early” Relapsed AML• Newly diagnosed AML characterized

by adverse cytogenetic + molecular high-risk factors

• AML in those over age 70 • Potential Options

– Cytotoxic, Molecular, Immunotherapeutic Agents

CLASSIC 1 High-dose Cytarabine +Clofarabine Trial in Refractory

and Relapsed AML• Eligible patients

– Age ≥ 55– At least 1, but no more than 2, prior

inductions– At least 3 months from last HDAC

• Recommended, but not prescribed post-remission treatment plan

CLASSIC 1 Trial Results

• Response Rate• EFS at 4 mos• Response Duration• Deaths as a result of

AE’s

• Survival

ara C (1g/m2/d) araC + Clo (40

mg/m2/d)22.9% 46.9%16.6% 37.7% 3.8m 7.6m5.2% 14.3%

6.3m 6.6m

flt3 Tyrosine Kinase InhibitorsAuthor Agent Study Population Outcome

Stone, et al. Midostaurin R/R AML MDS age ≤ 60

Similar survival as compared to flt3-wt AML

Serve, et al. Sorafenib Newly diagnosed AML, age > 60

No advantage seen for the addition of Sorafenib

Ravandi, et al. Sorafenib + azacitidine

R/R flt3-mutated AML

46% response rate in phase 2 trial

Cortes, et al. Quizartinib R/R flt3-mutated AML

50% single-agent response rate 33% bridged to allo transplant

Results of Agents that Target flt3-ITD in AML

Author Agent Study Population Outcome

Ohanion, et al.#3934

Sorafenib5 + Azacitidine

n = 57relapsed – ref AMLolder untreated

44% CR/CRi/PR62% RR in previously untreated

Uy, et al.# 2653

Sorafenib + cytarabine + daunorubicin

n = 52Older untreatedflt3-ITD + TKD

60% CR/CRi

Cortes, et al.#494

QuizartinibPhase 2

n = 38 in each armrelapsed – ref AML adults

50% CR each groupQTc w/ higher dose

Results of Agents that Target flt3-ITD in AML (cont’d)

Author Agent Study Population Outcome

Altman, et al.#623

Quizartinib + cytarabine + daunorubicin 60

n = 18 in Phase I trial

MTD = 40mg x 14 d or 60 mg x 7d starting d+4

Cooper, et al.#624

Quizartinib n = 22 children w/ relapsed – ref AML

4/6 CR/CRi in flt3-ITD evaluable

Strati, et al.#3949

Midostaurin + Azacitidine

n = 44mostly AML

11/44 achieved CR

Results of Agents that Target flt3-ITD in AML (cont’d)

Author Agent Study Population Outcome

Pollard, et al.#3969

Sorafenib after HSCT p median 66 days or at time of MRD / relapse

n = 13 pediatric patients150 mg/m2/d x 1 year

10/13 remain alive7/13 disease free-MRD+ most effective

Kayser, et al.#1283

Midostaurin + Cytarabine + Daunorubicin 60

n = 72 newly diagnosed flt3-positive

75.5% CR inhib of p-flt3

Takahashi, et al.#2684

Vorinostat + Cytarabine + Idarubicin

n = 26 untreatedn = 13 relapsed / ref

80% CR – untreated30% OR – relapsed / ref

Novel Treatment Strategies for AML

Author Agent Study Population Outcome

Schroeder, et al.#4624

Azacitidine + DLI n = 115 AML + MDS relapsed pallo HSCT

after 3cycles, DLI ->29% CR 7% PR

Jurcic, et al.#1460

225AC Lintuzumab + low dose Cytarabine

n = 7 elderly infirm AML

Blast reductionno CR

Roboz, et al.#621

Plerixafor +Decitabine

n = 69 older AML patients

43% relapse usually in HMA-naïve patientssurvival = 12 months

Immunotherapeutic Approaches of High-Risk AML

• Tumor Antigens• Immunomodulatory Agents• Induction of autologous anti-

leukemia reactivity• Allogeneic hematopoietic stem-cell

transplantation

Allogeneic Hematopoietic Stem-Cell Transplantation in High-Risk

AMLAuthor Study Population Preparative Regimen Outcome

Duval, et al. n = 1673AML relapsed or primary induction failure, retrospective registry study

Multiple Survival at 3 years: 19%Mortality at 100 days: 39%Cause of Death:AML in 42%

Koreth, et al. n = 6007,AML-CR1 meta-analysis donor vs. no donor

Multiple Significant benefit in survival for poor-risk and intermediate-risk

Brunet, et al. n = 206 AML in CR1 with known flt3 status retrospective registry study

Multiple 58% 2-year LFS for flt3-mutated vs. 71% for nonmutated. HR for relapsed = 3.4

More Studies of Allogeneic HSCT in High-Risk AML

Author Study Population Preparative Regimen Outcome

Sakamaki, et al.

n = 165donor vs. no-donor, prospective, multi-center

Multiple 39% DFS w. 19% survival diff. only among older patients

Hospital, et al.

n = 107 donor vs. no donor, retrospective multi-center

Multiple No survival impact. However, among those transplanted OS was 33% vs. 18% for those not transplanted

Potential Flaws in the Methodological Design of Studies in High-Risk AML

• Heterogeneous population and disease biology

• Heterogeneous post-remission therapy

• Heterogeneous end-points that define “success” with an over-reliance on survival as a primary endpoint

• Notwithstanding design flaws, several classes of agents are being actively studied

Agent Study Patient Population

Treatment Key Study Endpoints

Demethylating agentsAzacitidine Phase 1 study

(NCT01839240)

Pts with AML following prior hematologic disorder or with t-AML; pts aged ≥ 18 years with R/R AML

Azacitidine + cytarabine + mitoxantrone induction; azacitidine consolidation followed by allo HSCT or azacitidine maintenance

DLT

Azacitidine + lenalidomide

Phase 2 VIREL2 study (NCT01442714)

Pts ≥ 60 years with AML (de novo or secondary AML following MDS) or high-risk MDS, including pts previously treated with demethylating agents or lenalidomide

Azacitidine plus lenalidomide

ORR, duration of remission, 42-day survival

Phase 2 study (NCT01358734)

Pts ≥ 65 years with newly diagnosed AML; pts with a prior hematologic disorder or t-AML

Lenalidomide, sequential plus lenalidomide, or azacitidine

OS, CR, duration of CR, rates of EFS, RFS, PFS

Decitabine + plerixafor

Phase 1 study (NCT01352650)

Pts ≥ 60 years with AML, with prior hematologic disorder with no prior decitabine or cytotoxic chemotherapy; pts ≥ 60 years with t-AML with no prior chemotherapy for > 6 months

Decitabine + plerixafor

Response to treatment

Agent Study Patient Population

Treatment Key Study Endpoints

Nucleoside analogs

Clofarabine

Phase 1/2 EORTC-LG and GIMEMA AML – 14A study (NCT00838240)

Pts 18-60 years with newly diagnosed intermediate- or high-risk AML or high-risk MDS, including AML after MDS

Idarubicin + cytarabine, plus clofarabine at 1 of 2 dose schedules

Response rate, duration of survival, duration of survival from CR/Cri, DFS from CR,CRi

Phase 1/2 AMLSG 17-10 study (NCT01534702)

Pts with AML at high risk for induction failure

Escalating doses of clofarabine, plus idarubicin and cytarabine administered at does according to patient age

MTD, CR rate, RFS, EFS, OS

Clofarabine Phase 2 study (NCT01193400)

Pts ≥ 70 years with AML; or pts ≥ 60 years with AML with adverse karyotype, prior hematologic disorder, or ECOG PS 2

Clofarabine and low-dose cytarabine induction and consolidation

Rates of CR, CRp, DFS, OS, 30-day mortality

Agent Study Patient Population

Treatment Key Study Endpoints

Nucleoside analogsClofarabine + plerixafor

Phase 1 study (NCT01160354)

Pts ≥ 60 years with newly diagnosed AML with ≥ 2 of the following features: age ≥ 70 years; antecedent hematologic disorder; ECOG PS2; intermediate or unfavorable karyotype

Clofarabine + plerixafor

DLT, rates of CR and PR

Sapacitabine + decitabine

Phase 3 SEAMLESS study (NCT01303796)

Pts ≥ 70 years with newly diagnosed AML eligible for low-intensity therapy or who refused intensive induction therapy

Sapacitabine alternating with decitabine alone

OS, rates and durations of CR, Cri, PR, HI, SD

Agent Study Patient Population Treatment

Key Study Endpoints

FLT3 TKIsQuizartinib

Phase 1 /2 study (NCT01236144 in UK)

Pts ≥ 60 years with de novo or secondary AML or high-risk MDS

DAE chemotherapy plus quizartinib, plerixafor, or HSP90 inhib.

Rates of CR, Cri, PR, 30-day and 8-week mortality, survival

Sorafenib

Phase 2 Study(NCT01253070

Pts ≥ 60 years FLT3-mutated AML, including pts with prior hematologic disorder (without prior treatment with lenalidomide, azacitidine, or decitabine) and pts with t-AML whose primary malignancy is in remission and have not received chemotherapy or radiation for > 3 years

Sorafenib + chemotherapy

OS

Sorafenib + vorinostat

Phase 1 study (NCT00875745)

Pts ≥ 70 years with R/R AML or with treatment-naïve AML who are not eligible for conventional therapy; pts aged 18-69 with R/R AML ineligible for conventional therapy; pts with APL refractory to ATRA and arsenic trioxide

Dose escalation of sorafenib + vorinostat at starting doses of 400 mg BID and 100 mg BID, respectively

MTD, response, duration of response

Sorafenib +

vorinostat +

bortezomib

Phase 1 / 2 study

(NCT01534260

Pts with AML with complex karyotype, monosomy 5/7,

or FLT3-ITD

Escalating doses of

sorafenib, vorinostat,

and bortezomib

DLT, rate of ≥ PR, time to relapse

Agent Study Patient Population Treatment Key Study Endpoints

Additional agents and combinationsLenalidomide + azacitidine

Phase 2 study(NCT01358734)

Pts ≥ 65 years with newly diagnosed AML, including AML with prior hematologic disorder or t-AML

Single-agent lenalidomide, single-agent azacitidine, or lenalidomide + azacitidine

OS, response rate, duration of remission, EFS, RFS

Bortezomib

Phase 2 study (NCT01465386)

Pts with high-risk AML (prior MDS, t-AML, AML with trilineage dysplasia, or AML with adverse cytogenetics) in first remission

Subcutaneous bortezomib given as maintenance therapy in patients in CR1

PFS

Decitabine + bortezomib

Phase 2 CALGB 11002 study(NCT01420926)

Pts aged ≥ 60 years with previously untreated AML; pts with secondary AML without prior cytotoxic chemotherapy, decitabine, or bortezomib; pts with t-AML if they have not received radiation therapy or chemotherapy for their primary malignancy (excluding hormonal therapy) for > 6 months

Decitabine + bortezomib or decitabine alone

OS, CR rate, DFS, PFS

Agent Study Patient Population Treatment

Key Study Endpoints

Additional agents and combinationsCPX-351 + chemotherapy

Phase 3 study (NCT01696084)

Pts aged 60-75 years with newly diagnosed t-AML or AML with antecedent MDS or CMML; pts aged 60-75 years with de novo AML who have cytogenetic abnormalities

Cytarabine/daunorubucine liposome injection CPX-351, vs cytarabine + daunorubucine

OS

Etoposide Phase 3 study (NCT01237808)

Pts ≥ 60 years with NPM1-mutated AML, including de novo AML, secondary AML, and t-AML, who are ineligible for intensive chemotherapy

ATRA + low-dose cytarabine + etoposide

OS, CR rate, relapse rate, EFS, rate of early death

Volasertib Phase 3 POLO-AML-2 study (NCT01721876)

Pts ≥ 65 years with previously untreated AML who are ineligible for intensive induction chemotherapy

Subcutaneous low-dose cytarabine plus volasertib or placebo

Rates of CR and Cri, OS, EFS, RFS

Agent Study Patient Population Treatment Key Study Endpoints

FLT3 TKIsMidostaurin + azacitidine

Phase 1 / 2 study(NCT01093573)

Pts ≥ 70 years with untreated AML ineligible for standard induction therapy; pts ≥ 70 years with high-risk AML (prior hematologic disorder; t-AML; adverse cytogenetics; or complex karyotype)

Azacitidine (days 1-7) and midostaurin (days 8-21)

MTD, rates of CR, PR, and HI, time to progression, OS

Midostaurin + decitabine

Phase 2 study (NCT01846624)

Pts with ≥ 60 years with newly diagnosed de novo or secondary AML, including pts with AML following MDS treated with decitabine or azacitidine

Decitabine (days 1-10) and midostaurin (days 11-28)

CR rate

Midostaurin + bortezomib

Phase 1 study(NCT01174888)

Pts with R/R AML, including pts with secondary AML

Midostaurin + bortezomib and chemotherapy (mitoxantrone, etoposide, and cytarabine)

MTD, CR rate, ORR

Novel Treatment Strategies in Myelodysplasia

Author Agent Study Population Outcome

Prebet, et al.#2777

Azacitidine + Entinostat

n = 472y 70n = 29 ct – MDS/AML

High response to Azacitidine in 10-d schedule alone

Hirai, et al.#1530

Azacitidine + Sub-cutaneous Cytarabine

n = 37 advanced MDS/AML

Responses in the combination armSignificant increase in survival

Nazha Clofarabine +Sub-cutaneous Cytarabine

n = 29no prior response to HMA

Response in 50% survival = 4.8 mos

Novel Treatment Strategies for MDS

Author Agent Study Population Outcome

Ades, et al.#620

Lenalidomide +Cytarabine +Daunorubicin

n = 82 elderly poor-risk MDS

46% CRDFS = 5.8m

Raza, et al.#2745

Rigosertib (PI3K inh)

n = 48 low-risk, Tx-dependent MDS

Synergy c ESA

Ades, et al.#2750

Lenalidomide +Azacitidine

n = 35 all subtypes

Early death = 10 patients6 CR: 2 c^ 5g-OS 39% at 1y

Novel Treatment Strategies in Myelodysplasia

Author Agent Study Population OutcomeLyons, et al.#2775

Chelation n = 599 lower-risk

Any use of chelation was associated with longer OS and t to AML

Xicoy, et al.#2813

ESA n = 99 with CMML

Low-risk predicted response to ESAResponse to ESA predicted survival

de Swart, et al.

Validation of IPSS-R

n = 100 newly diagnosed lower-risk

Superiority of IPSS-R for very low-risk patients

IPSS-R Cytogenic risk groupsCytogenetic prognostic subgroups Cytogenetic abnormalities

Very good -Y, del(11q)

Good Normal, del(5q), del(12p), del(20q), double including del(5q)

Intermediate del(7q), +8, +19, i(17q), any other single or double independent clones

Poor -7, inv(3)/t(3q)/del(3q), double including -7/del(7q), Complex: 3 abnormalities

Very poor Complex: >3 abnormalities

IPSS-R Prognostic Score ValuesPrognostic

variable0 0.5 1 1.5 2 3 4

Cytogenetics

Very Good Good Intermediate

Poor Very Poor

BM Blast % <=2 >2-<5% 5-10% >10%

Hemoglobin =>10 8-<10 <8

Platelets =>100 50-<100 <50

ANC =>0.8 <0.8

IPSS-R Prognostic Risk Categories/Scores

RISK CATEGORY RISK SCORE

Very Low <=1.5

Low >1.5 - 3

Intermediate >3 - 4.5

High >4.5 - 6

Very High >6

IPSS-R: Prognostic Risk Category Clinical Outcomes

No. pts Very Low Low Intermediate High Very High

Patients (%) 7012 19% 38% 20% 13% 10%

Survival*** 8.8 5.3 3.0 1.6 0.8

AML/25%***,^ NR 10.8 3.2 1.4 0.7

***Medians, years ^Median time to 25% AML evolution*Greenberg, Tuechler, Schanz et al, Revised International Prognostic Scoring System (IPSS-R) for Myelodysplastic Syndrome, Blood 120: 2454, 2012.**Schanz J et al, J Clin Oncology 2012; 30:820

High-Risk AML Feature

Investigational Option

Commercially-available option

Newly Diagnosed flt3 ITD or Adverse Cytogenetics

Midostaurin, sorafenib, g-csf + sorafenib + plerixaforSorafenib, vorinostat, bortezomib

7 + 3 ± Sorafenib7 + 3 w/ High-dose Cytarabine

Secondary Azacitidine, lenalidomide, CPX-351

7 + 3 vs. High-dose Cytarabine vs. HMA

Relapsed after brief remission

T-cell therapyTigecycline, TemozolamideDasatinib, Plerixafor

High-Dose Cytarabine alone or in combination

Refractory to induction or re-induction

Other agentsBL-8040, E7070, Eltrombopag

High-Dose Cytarabine alone or in combination

High-risk AML in remission

Oral Azacitidine, Vaccine,Allogeneic cells, PD-1 blockade,Omacetaxine

Allogeneic transplant

AML in patients with adverse clinical features

Crenolanib, AR-42, Gemtuzumab, Phase 1 Agents,Radiopharmaceuticals

HMASingle-agent therapy

Challenges for the Community of Physicians who treat high-risk

AML- Summary• Treatment has been developed on the

basis of clinical features more often than on biological features

• Complete remission has generally been a secondary endpoint of clinical trials

• Heterogeneity of post-remission strategies have a significant impact on the use of survival as a primary endpoint

• The end-result of clinical-trial strategy has been a static treatment paradigm based on limited drugs