ASH review 2012 Acute leukemias

ASH review 2012Acute leukemias

Tibor KovacsovicsCenter for Hematologic

MalignanciesOHSU

Whole genome sequencing in acute leukemia

• AML: - IDH and DMT3A are prototypes of genes

identified by this approach - goal is to sequence a total of 500 AMLs - AML has an average of 3 mutated

recurrent mutationsLey Nature 2008

Mardis New Engl J Med 2009 Ley N Engl J Med 2010

Welch ASH 2011

More gene mutations in AML?• Established genes: - FLT3-ITD - NPM1 - CEBPA - cKIT - Nras/Kras• New genes: - TET, IDH, DMT3A, ASXL1

Clinical objectives of routine molecular work-up in AML

• Risk stratification: distinguish high-risk from low-risk leukemias

- NPM1+, FLT3-ITD- AML: no transplant - FLT3-ITD+ AML: transplant

• Identification of drugable targets: - FLT3-ITD+: FLT3 inhibitors (AC220, sorafenib)

NPM1+ and CEBPA + AML: RFS and OS in young patients

Schlenk N Engl J Med 2008

Consolidation therapy in young NPM1+ FLT3-ITD- AML

• 67% overall survival after consolidation with high-dose AraC

Thomas et al J Clin Oncol 2011• These patients can be consolidated like CBF

leukemia [t(8;21) or inv(16)]

OS in older NPM1+ AML after standard therapy

• ~80% CR and improved overall survival rate in patients >60

• These patients are candidates for 7+3 and consolidation

• >60>60

>70

Becker et al J Clin Oncol 2010

Current cytogenetic and molecular work-up in AML

• Conventional cytogenetics and FISH panel

• PCR: FLT3-ITD, FLT3 variant, NPM1, CEBPA, c-KIT in CBF leukemias

• Sequenom panel for gene mutations

Current AML risk stratification

AML trials• Cytarabine dosing• Mylotarg• ATRA in NPM1+ AML• FLT3 inhibitors: AC220• Vorinostat combination

Cytarabine dosing• 3 randomized trials, with different designs - 2 studies of high-dose AraC to multi-agent

consolidation Thomas J Clin Oncol 2011; Miyazawi Blood

2011 - 1 study of high versus low cumulative

doses of AraC Lowenberg N Engl J Med

Cytarabine dosing• We probably give too much high-dose AraC• High-dose AraC had best outcome in CBF

leukemia• High-dose AraC was more toxic than

multiagent consolidation• In a situation of AraC shortage, there are

alternative consolidation regimens in non-CBF AML

Mylotarg• Mylotarg has been removed by Pfizer in 2009

after increased toxicity was seen in a randomzied SWOG trial

• Ironically, some benefit has been observed since then in randomized clinical trials in CBF leukemias

• New positive studies were reported at ASH

53rd ASH Annual Meeting ♦ San Diego, CA ALFA

A Prospective Randomized Phase 3 Trialfrom the Acute Leukemia French Association (ALFA)

Fractionated Doses of Gemtuzumab Ozogamicin

Combined to Standard ChemotherapyImprove Event-free and Overall

SurvivalIn Newly-Diagnosed de novo AML

PatientsAged 50-70 Years Old.

ALFA


Arm A Arm B

2nd course if BM blasts >10% at D15DNR 60 mg/m2 D1, D2

AraC 1g/m2/12h D1 to D3

INDUCTION

1st CONSOLIDATION

2nd CONSOLIDATION

Treatment armsRandomization

CR or CRp

DNR 60 mg/m2 D1 to D3AraC 200 mg/m2 D1 to D7

DNR 60 mg/m2 D1 AraC 1g/m2/12h D1 to D4

DNR 60mg/m2 D1,D2 AraC 1g/m2/12h D1 to D4

DNR 60 mg/m2 D1 to D3AraC 200 mg/m2 D1 to D7GO 3 mg/m2 D1, D4, D7

DNR 60 mg/m2 D1 AraC 1g/m2/12h D1 to D4GO 3 mg/m2 D1

DNR60 mg/m2 D1,D2 AraC 1g/m2/12h D1 à D4GO 3mg/m2 D1


Control arm A

Experimental arm B (GO)

P-value

Induction cycles, N 139 139 0 1 1 102 (73%) 114 (82%) 2 36 (26%) 25 (18%) 0.15Response CR 99 (71%) 99 (71%) 1.0

CRp 5 (4%) 14 (10%) 0.055 CR + CRp 104 (75%) 113 (81%) 0.25 Failure 29 (21%) 17 (13%) 0.075 Early death 6 (4%) 9 (6,5%) 0.60

Induction results


Overall survival

OS A (control) (n=139)

B (GO)

(n=139)

Deaths 71 59Median 19.2 mo

34 mo

2-year 43.5% 53.1%HR(95% CI)

1 0.70(0.50-0.99)

P= 0.046by the log-rank test

GO arm

Control arm


Relapse-free survival (CR/CRp pts.)

RFS A (control) (n=104)

B (GO)(n=113)

Events 69 50Median 12.5 mo 28.1 mo2-year 21.7% 50.8%HR 1 0.51

(0.36-0.74)

P= 0.00029by the log-rank test

GO arm

Control arm


OS according to cytogenetics risk-groups

Favorable/intermediate cytogenetics

Unfavorable cytogenetics

Control armControl arm

GO arm

GO arm

Effect of Mylotarg in CBF relapsed AML OS by Mylotarg

exposure Post-allo SCT survival

Hospital ASH 2011

Mylotarg• Proof of principle of the benefit of

immmunotherapy in AML • The administration of lower and fractionated

doses of Mylotarg may lead to more durable responses and reduced toxicity

clinicaloptions.com/oncologyMyelodysplastic Syndromes and Acute Leukemia

All-Trans Retinoic Acid + Chemotherapy in NPM-1 Mutant AML: AMLSG 07-04

Primary endpoints: CR after induction therapy, EFS (patients with CR who received allogeneic SCT censored at date of transplantation)

Secondary endpoints: RFS, OS

Patients aged 18-60 yrs

with AML

(N = 1112)

ATRA 45 mg/m2 on Days 6-8, 15 mg/m2 on Days 9-21 +Standard Chemotherapy*

(n = 550)

Standard Chemotherapy*(n = 562)

Schlenk RF, et al. ASH 2011. Abstract 80.

Induction (two 28-day cycles) Consolidation (three 28-day cycles)Genetic profiling prior to randomization

*Standard induction chemotherapy consisted of idarubicin/cytarabine/etoposide initiated on Day 1, with an additional randomization ± valproic acid. Standard consolidation chemotherapy consisted of high-dose cytarabine ± valproic acid. Valproic acid included only from 2004-2006 (n = 374).

ATRA 15 mg/m2 on Days 6-28 +Standard Chemotherapy*

Standard Chemotherapy*


AMLSG 07-04: Efficacy Addition of ATRA to standard

chemotherapy

– Significantly improved odds of CR in NPM1-mutated AML (OR: 2.29; P = .05), but not NPM1–wild-type AML (OR: 1.09; P = .66) in multivariate analysis

– Benefit independent of FLT3 ITD status (OR: 0.70; P = .39)

– Significantly improved EFS in NPM1-mutated AML (P = .03), but not NPM1–wild-type AML (P = .78)

– Significantly improved OS in total patient population (P = .03)

0102030405060708090

100

NPM1-Mutated AML

CR

to In

duct

ion

Ther

apy

(%)

ATRA + standard chemotherapyStandard chemotherapy

NPM1–Wild-Type AML

9084

69 69.5

n = 142 141 345 351

Schlenk RF, et al. ASH 2011. Abstract 80.

A Phase II, Open-Label, AC220 Monotherapy Efficacy (ACE) Study in

Patients With Acute Myeloid Leukemia (AML) With FLT3-ITD Activating

Mutations: Interim Results

Jorge Cortes,1 Alexander Perl,2 Catherine Smith,3 Tibor Kovacsovics,4 Herve Dombret,5 Hartmut Dohner,6 Björn Steffen,7 Arnaud Pigneux,8 Philippe Rousselot,9 Jürgen Krauter,10 Giovanni Martinelli,11 Elihu Estey,12

Alan Burnett13, Anthony Ho14, Norbert Ifrah15, Theo de Witte16, Robert Corringham17, Joyce James17, David Lilienfeld,17 Eugen Leo,17 Mohit Trikha,17 and Mark Levis18

1

Quizartinib:AC220-002 Trial Design

Study Design Cohorts• FLT3-ITD(+/-) AML subjects

• Single-arm, 3-cohort• ~100 sites WW

• Coprimary endpoints• Composite CRc

(CR+CRp+CRi)• CR

• Key secondary endpoints• Duration of response• Progression free survival• Overall survival

• ≥60 y old• FLT3 ITD+• 1st relapse• ~120 subjects

Status

• 1st subjects dosed Nov 2009

• Interim data analysis conducted on first 62 ITD+ subjects (53 evaluable for response)• ≥18 y old

• FLT3 ITD +• 2nd relapse or

post-HSCT

• ~120 subjects• ≥18 y old• FLT3 ITD - cohorts 1

& 2• ~60 subjects

CR=complete remission; CRi=complete remission with incomplete hematologic recovery; CRp=complete remission with incomplete platelet recovery; QD=once daily

AC220-002:Preliminary Efficacy Analysis

Feb 22, 2011 data cut-off

CohortCRc: Composite

Complete Response*

MedianSurvival*

Transitionto HSCT**

≥18 years2nd Relapse

48% Not yet reached22/31 alive

34%

≥60 years1st Relapse

41% 24.1 weeks10/22 alive

8%

Total 45% 24.7 weeks32/53 alive

23%

*Based on efficacy evaluable population (N=53)

** Based on safety population (N=62)

Median survival for all 62 subjects = 24.6 weeks

AC220-002: Summary of Common (>25%) Adverse Events (Safety Population)

Preferred TermOverall(N=62)N(%)

Treatment-related(N=62)N(%)

Any Adverse Event 62 (100.0) 55 (88.7)

Febrile neutropenia 30 (48.4) 14(22.6)

Nausea 29 (46.8) 22 (35.5)

Fatigue 28 (45.2) 16 (25.8)

Diarrhea 24 (38.7) 13 (21.0)

Vomiting 23 (37.1) 18 (29.0)

Electrocardiogram QT prolonged 22 (35.5) 21 (33.9)

Anorexia 21 (33.9) 13 (21.0)

Edema peripheral 17 (27.4) 6 (9.7)

Pyrexia 17 (27.4) 4 (6.5)

Dysgeusia 16 (25.8) 12 (19.4)

Hypokalemia 16 (25.8) 7 (11.3)

Feb 22, 2011 data cut-off

AC220 (quizartinib) planned trials

• Monotherapy phase 3 trial in relapsed FLT3-ITD + AML

• Combination phase 1 induction and consolidation trial in newly diagnosed FLT3-ITD + AML

• Maintenance phase 1 study in post-allogeneic stem cell transplant

Other FLT3 inhibitors• PKC412: - enrollment in randomized upfront study

completed• Sorafenib: - several combination trials ongoing• Several new agents are being tested in phase

1-2 trials


Vorinostat + Idarubicin/Cytarabine in Newly Diagnosed AML or Higher-Risk MDS Single-arm phase II trial conducted in 75 patients aged 19-65 yrs

Induction therapy (1 cycle)

– Oral vorinostat 500 mg TID on Days 1-3

– IV idarubicin 12 mg/m2/day on Days 4-6

– IV cytarabine 1.5 g/m2 as continuous infusion daily for 3-4 days on Days 4-7

Consolidation therapy (5 cycles)

– Oral vorinostat 500 mg TID on Days 1-3

– IV idarubicin 8 mg/m2/day on Days 4-5

– IV cytarabine 0.75 g/m2 on Days 4-6

Maintenance therapy: single-agent oral vorinostat 200 mg TID for 14 days every 28 days for up to 12 mosGarcia-Manero G, et al. ASH 2011. Abstract 763.


First-line Vorinostat/Idarubicin/Cytarabine in AML/Higher-Risk MDS: EfficacyPatient Group ORR, % Median EFS,

Wks (Range)Median OS, Wks (Range)

All patients 85 47 (3-134) 82 (3-134)Subgroups Diploid cytogenetics 93 68 (5-134) 105 (5-134) -5 or -7 59 14 (3-92) 34 (3-92) FLT3 ITD 100 66 (6-134) 91 (6-134)

Garcia-Manero G, et al. ASH 2011. Abstract 763.

An unmatched comparison with historical data showed that response to vorinostat/ idarubicin/cytarabine markedly higher than with standard idarubicin/ cytarabine

– 85% vs 72% (P = .01)


First-line Vorinostat/Idarubicin/Cytarabine in AML/Higher-Risk MDS: SafetyAdverse Events Observed During Induction Therapy (Incidence ≥ 5%)

Grade 1/2 Events, n Grade 3/4 Events, n Total Events, n (%)

Diarrhea 26 27 53 (72)

Nausea/vomiting 40 8 48 (65)

Other GI events* 18 11 29 (39)

Rash, cellulitis, hand-foot reaction25 3 28 (38)

Hepatic events 6 8 14 (19)

Hemorrhage/bleeding 8 5 13 (18)

Cardiac events 4 7 11 (15)

Renal events 3 2 5 (7)

Edema/swelling 4 0 4 (5)

Garcia-Manero G, et al. ASH 2011. Abstract 763.*Mucositis, typhlitis, colitis.

ALL• Ph+ ALL: single agent Dasatinib

• Monoclonal antibodies

Ph+ ALL: single agent dasatinib

• N= 53 • Median age 53 (23-78)• Dasatinib dose 140mg qd with 30 day steroid

• post-remission regimen free after 84d• responses: - hematologic : 100% CR, median day 23

- median OS 30.8 months (unknown in patients on Dasatinib maintenance)

Foá Blood epub 2011

Ph+ ALL: single agent dasatinib

• relapse: at 20 months 20% free of relapse

• median time to relapse 5.9 months• relapse occured in 14/19 patients on TKI alone, in 5/14 on TKI +chemo, in 2/16 allo patients

• prognostic role of BCR-ABL reduction >3 logs


Older Ph+ ALL: single agent dasatinib


Phase II Study of Dasatinib + Chemo in Older Patients With

Ph+ ALL

Rousselot P, et al. ASH 2010. Abstract 172.

Treatment Phase Treatment Schedule

Prephase Dexamethasone 10 mg/m2 Days -7 to -3

Induction (Wks 1-8)

Dasatinib 140 mg*Vincristine 1 mg

Dexamethasone 40 mg

Daily for 8 wksDays 1 and 2 repeated weekly

for 4 wks

Consolidation(Wks 8-16)

Dasatinib 100 mgMethotrexate 1000 mg/m2*

L-asparaginase 10,000 IU/m2*Cytarabine 1000 mg/m2/12 hr*

Daily for 6 cyclesDay 1 of cycles 1, 3, 5Day 2 of cycles 1, 3, 5

Days 1, 3, and 5 of cycles 2, 4, 6

Maintenance(Wks 32-40)

Dasatinib 100 mg/day alternating with 6-mercaptopurine and methotrexate every other mo and dasatinib/vincristine once every 2 mos for ≤ 24 mos

*Dose reduction in patients older than 70 yrs of age.

Response and Survival With Dasatinib Plus Chemotherapy

• Median follow-up: 20 mos• CR: 63 of 71 patients

(88.7%)• Median OS: 27 mos• Median RFS: 25 mos

– Additional chromosomal abnormalities (P = .009) and lack of molecular response during consolidation (P < .0001) associated with lower RFS rate

• 19 patients (27%) relapsed after a median of 4.8 mos– Majority had T315I BCR-ABL

mutation

Patie

nts W

ith M

olec

ular

Res

pons

e (%

)Response Type

Postinduction (MRD1)During consolidation (MRD2)

*Sensitivity 10-4.5

Rousselot P, et al. ASH 2010. Abstract 172.

BCR-ABL/ABL ≤ .1%

MRD negative*

56

71

2328

1009080706050403020100


Inotuzumab Ozogamicin in Patients With Relapsed/Refractory ALL Inotuzumab ozogamicin: monoclonal anti-CD22 antibody conjugated with calicheamicin

Phase I dose-escalation study conducted in 49 patients

Patient eligibility

– 16 yrs of age or older in first 10 patients; children subsequently eligible

– Relapsed/refractory, CD22-positive ALL

Up to 8 treatment cycles administered

– Inotuzumab initiated in first 3 adults and 3 children at 1.3 mg/m2 IV, subsequently increased to 1.8 mg/m2 IV over 1 hr every 3-4 wks

– If SD or no response after 2 courses, patients could also receive rituximab 375 mg/m2 on Day 1 of subsequent cycles (inotuzumab on Day 2)

O’Brien S, et al. ASH 2011. Abstract 875.


Inotuzumab Ozogamicin in Relapsed/Refractory ALL: Efficacy


Cycles CR, n CRp, n CRi, n Total Response Rate, n (%)

All cycles 9 14 5 28 (57) Cycle 1 8 8 0 16 (33) Cycle 2 1 6 4 11 (22) ≥ Cycle 3 0 0 1 1 (2)

Median response duration: 5.0 mos

No clear correlations between response and baseline patient/disease characteristics except regarding karyotype

– Lower response rate in patients with Ph+ ALL: 3 of 7 (43%)

– Lower response rate in patients with ALL with t(4;11): 1 of 5 (20%)

CCyR attained in 89% of 18 evaluable patients with response

Undetectable MRD attained in 63% of 27 evaluable patients with response


Inotuzumab Ozogamicin in Relapsed/ Refractory ALL: Other Outcomes Inotuzumab concentration in blood at 3 hrs postdose significantly associated with

response among 23 patients with evaluable PK data (P = .008)

Inotuzumab generally well tolerated

– Treatment-associated fever (Days 1-2: 90%) and hypotension (Days 1-2: 26%) generally occurred during first cycle only and transient

– Liver function abnormalities also associated with inotuzumab, but reversible and typically mild

22 patients underwent allogeneic SCT after inotuzumab (second transplantation for 5 patients)

– 5 patients developed suspected veno-occlusive disease after transplantation



Inotuzumab Ozogamicin in Relapsed/ Refractory ALL: Conclusions Inotuzumab yielded very high response rates in patients with

relapsed/refractory ALL when administered as single agent

– ORR: 57%

– Response correlated with inotuzumab plasma levels after dosing

Inotuzumab generally well tolerated, with major toxicities including thrombocytopenia and abnormal liver function tests

Plans under way to further investigate inotuzumab in ALL

– Weekly schedule

– In combination with chemotherapyO’Brien S, et al. ASH 2011. Abstract 875.

Immunotherapy in ALL• Various monoclonal antibodies are being

developed in ALL - anti-CD 22 (Inotuzomab) - anti-CD19 (Seattle Genetics) - BITE technology

ASH review 2012 Acute leukemias

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