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Acute Myelogenous Leukemia and Myelodysplasia- Highlights of ASH 2013. Gary J. Schiller, M.D., F.A.C.P. Professor of Medicine Director Hematological Malignancies / Stem Cell Transplant Program David Geffen School of Medicine at UCLA. A Static Therapeutic Landscape. - PowerPoint PPT Presentation
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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