Treatment for Relapsed/refractory AML

(RR-AML) 영남대학교 의과대학

혈액종양내과 김 민 경

Relapsed/refractory AML

• ~50% of AML - relapse or refractory • Probability for CR2 - 20~50% • Long term survival < 20% • Median OS < 1yr

AML is an oligoclonal disease

Welch JS et al Cell 2012;150:264-78

Major clonal evolution patterns during AML relapse

1) The founding clone in the primary tumor gained mutations and evolved into the relapse clone

2) A subclone of the founding clone survived initial therapy, gained additional mutations and expanded at relapse

Ding L et al Nature 2012;481:506-10

RR-AML:definition • Relapsed disease - Reappearance of leukemia cells in BM, PB or elsewhere in the body after CR • Early relapse - Relapse within 6(~12) months after CR1 • Primary refractory disease - Blast ≥ 5% after 1~2 cycles of induction chemotherapy

Cheson BD et al J Clin Oncol 2003;21:4642-9 Döhner H et al Blood 2010;115:453-74

Rowe JM et al Cancer 2010116:5012-21

Considerations

• Allogeneic SCT after attaining 2nd CR - best outcome in general

• In patients with relapsed /refractory AML, - 2nd CR 획득 가능성 - Feasibility for allogenic SCT - Donor availability - Myeloablative SCT 가능여부

Contents

1. Outcome predictors 2. Conventional salvage chemotherapy 3. Role of allogeneic stem cell transplantation 4. Molecular targets & Novel agents

Prognostic factors in RR-AML

• CR1 duration • Cytogenetics at diagnosis • FLT3-ITD status • SCT before first relapse • Age at relapse

Length of first remission

0

10

20

30

40

50

60

70

1개월미만 1-5.9개월 6-11.9개월 12-17.9개월 18개월이상

% of 2nd CR according to length of first CR

Keating MJ et al. J Clin Oncol 1989;7:1071-80

European Prognostic Index

Score 1-6: 1yr OS 70% ,5yr OS 46%

Score 7-9: 1yr OS 49% ,5yr OS 18%

Score 10-14: 1yr OS 16% ,5yr OS 4%

EPI score

CR1 duration 0

≥ 18 mo 3

7-18 mo 5

≤ 6 mo

Cytogenetics at diagnosis

t(16;16) or inv16 0

t(8;21) 3

Other 5

SCT before first relapse

No 0

Yes 2

Age at relapse

≤ 35 y 0

36-45 y 1

> 45 y 2

667 patients with AML in first relapse Age 15-60 years

Breems DA et al J Clin Oncol 2005;23:1969-78

GOELAMS score

Group 2yr EFS 2yr OS

Favorable (0) 46% 59%

Intermediate (1) 30% 37%

High risk (2,3) 12% 12%

N=138 refractory/relapsed AML patients, age 19-70 years

- CR1 duration, FLT3-ITD status, cytogenetics

EFS OS

Chevallier P et al Leukemia 2011;25:939-44

Salvage chemotherapy • Several RCT, no standard • The goal is to attain CR prior to allogeneic SCT • Addition of drugs that have not been used during

the first induction cycle - High dose cytarabine (HiDAC) - Mitoxantrone - Purine analogues - New drugs

Mitoxantrone as alternative anthracycline: MEC/EMA/MAV

• Combinations of mitoxantrone, etoposide & cytarabine • MEC - Mitoxantrone 6-8mg/m2 D1-5(6) - Etoposide 80-100mg/m2 D1-5(6) - Cytarabine 1g/m2 D1-5(6) • CR rate 18-66%1-3

• TRM (or 30day mortality) 3-11%1-3 • Pre-treatment priming with decitabine - CR 30% in phase I4

1Amadori S et al J Clin Oncol 1991;9:1210-4 2Greenberg PL et al J Clin Oncol 2004;22:1078-86

3Kohrt HE et al Am J Hematol 2010;85:877-81 4Halpern AB et al Blood 2014;124:3730

Maximum anthracycline doses

Drug Maximum recommended cumulative dose (mg/m2)

Daunorubicin 600 Doxorubicin 450~550 Epirubicin 900~1000 Idarubicin - i.v. 150 Mitoxantrone 160

• The incidence of chronic cardiomyopathy risk ~ 5% • Other risk factors for cardiotoxicity should be considered.

Floyd et al J Clin Oncol 2005;23:7685-96 Anderlini et al. J Clin Oncol, 1995; 13: 2827-34

Barrett-Lee PJ et al. Ann Oncol 2009;20:816-27

The third drugs

• Purine analogues - Fludarabine - Clofarabine - Cladribine - Sapacitabine

• Elacytarabine

• Liposomal cytarabine:daunorubicin, CPX-351

Fludarabine: FLAG-IDA/FLAG/FLA

• Inhibition of DNA synthesis by interfering with RNR and DNA polymerase, synergistic with cytarabine

- Fludarabine 30mg/m2 D1-5 - Cytarabine 2g/m2 D1-5 +/-G-CSF 300mcg day D6 (D-1/0) until ANC recovery +/-Idarubicin 8~10mg/m2 D1-3

• CR rate 46-63%1-3

• TRM (or 30day mortality) 10-15%1-3 • FLA may be inferior to ara-C/daunorubicin/etoposide3

• Addition of G-CSF - no difference3

1Jackson G et al Br J Haematol 2001;112:127-37 2Pastore D et al Ann Hematol 2003;82:231-5

3Milligan DW et al Blood 2006;107:4614-22

Cladribine: CLAG/CLAG-M • Another RNR inhibiting purine analogue - Cladribine 5mg/m2 D1-5 - Cytarabine 2g/m2 D1-5 - G-CSF 300mcg day D0-5 +/-Mitoxantrone 10mg/m2 D1-3

• CR rate 38-58%1-3

• TRM (or 30day mortality) 0-17%1-3 • CLAG vs MEC (retrospectively) - no difference in CR & OS3

1Wrzesien-Kus A et al Eur J Haematol 2003;71:155-62 2Wierzbowska A et al Eur J Haematol 2008;80:115-26

3Price SL et al Leuk Res 2011;35:301-4

Clofarabine: GCLAC/CA • 2nd-generation deoxyadenosine analogue, RNR inhibitor - Clofarabine 25~40mg/m2 D1-5 - Cytarabine 1~2g/m2 D1-5 +/-G-CSF 300mcg day D0~until ANC recovery

• CR rate 35-51%1-5

• TRM (or 30day mortality) 6-13%1-5 • GCLAC vs FLAG/FLA (retrospectively) - superior CR5

1Faderl S et al Blood 2005;105:940-7 2Scappini B et al Am J Hematol 2012;87:1047-51

3Faderl S et al J Clin Oncol 2012;30:2492-9 4Becker PS et al Br J Haematol 2011;155:182-9 5Becker PS et al Haematologica 2013;98:114-8

Treatment N CR2, % Median duration CR2, mo

Median OS, mo

HDAC vs. HDAC/Mit 162 32 vs. 44 9 vs. 5 8 vs. 6

EMA vs. EMA/GM-CSF 72 81 vs. 89 4 vs. 5 9 vs. 10

MAE vs. MAE/G-CSF 129 25 vs. 17 9 vs. 10 5 vs. 4

MEC vs. MEC/ lintuzumab 191 23 vs. 29 NA 8 vs. 6

HDAC vs. HDAC/ laromustine 178 19 vs. 35 332 vs. 275d 177 vs. 128d

HDAC/Mit vs. IDAC/Mit 186 52 vs. 45 5.3 vs. 3.3 5 vs. NA

HDAC/Amsa vs. HDAC/Mit 52 53 vs. 60 11 vs. 12 8 vs. 11

HDAC vs. HDAC/Amsa 36 14 vs. 53 NA 2 vs. 6

HDAC vs. HDAC/Eto 131 40 vs. 45 12 vs. 25 5 vs. 5

Selected RCTs in RR-AML

HDAC, high-dose cytarabine; Mit, mitoxantrone

Ravandi F. Best Pract Res Clin Haematol. 2013;26:253-9

Limitations of salvage chemotherapy trials in RR-AML

• Heterogeneity of the initial therapy • Comorbid factors complicating the response • Heterogeneity of disease biology

Roboz GJ et al Hematology 2011

Benefit of allogenic SCT over chemotherapy alone in RR-AML

• MDACC, n=599 RR-AML (1995-2004)

Armistead et al. BBMT 2009;15:1431-8

Median OS 5.1mo vs 2.3mo

Median OS 11.7 mo vs 5.6mo

Allogeneic SCT as initial salvage

OS DFS

Jabbour E et al Am J Hematol 2014;89:395-8

N=285 AML patients who were primary refractory to HiDAC-based regimen

CR2 rather than during first relapse

Sierra J et al. BBMT 2000;26:397-404

N=161 AML, unrelated SCT in FHCRC

• Potential favorable prognostic factors to help decide to proceed to allogeneic SCT

- Younger age - Duration of CR - good PS /less comorbidities - Lower BM blast % - Favorable or int- karyotype - availability of HLA-matched donor

Eligibility for allogeneic SCT

CIBMTR data N=1,673 3yr OS 19%

Duval M et al J Clin Oncol 2010;28:3730-8

MAC vs RIC in AML: long-term F/U

Patients in remission Patients in active disease

• RIC is a valid therapeutic option in patients not eligible for MAC, especially when transplanted in remission

Shimoni A et al. Leukemia 2010;24:1050–2

Alternative donor SCT

• Partially matched unrelated donor (i.e. 9/10 or 8/10 matches)

• Single antigen mismatched related donor • Haploidentical sibling donor transplantation • Cord blood transplantation

Haploidentical SCT • EBMT survey data, N=229 acute leukemia • 68% AML, CR1/CR2/CR3 or active ds 34%/24%/42%, RIC 49%

• 100-day CI of aGVHD 32±3% for G2~4, 3yr CI of cGVHD 34±3% • 3yr LFS of CR1, CR2, or others - 44±6%, 42±7%, 12±3% • 3yr OS of CR1, CR2, or others - 55±6%, 51±7%, 14±4%

Piemontese S et al leukemia 2015;29:1069-75

Relapse after allogeneic SCT

• 2nd allogeneic SCT • Donor lymphocyte infusion • Other approaches, such as HMAs

Second allogeneic SCT N=179 AL (73.8% AML, 66.5% CR2, 68.5% non-MAC conditioning)

• CR 74% after HSCT2 • 2yr OS 25%±4% (39%±7% after MRD, 19%±4% after MUD) • 2yr LFS 21%±3% (31%±6% after MRD, 13%±4% after MUD) • NRM 31.8% (28% after MRD, 34.6% after MUD) • Prognostic factors - CR ≥ 6 months after HSCT1, CR at HSCT2

Christopeit M et al J Clin Oncol 2013;31:3259-71

Donor lymphocyte infusion

Schmid C et al J Clin Oncol 2007;25:4938-45

N=399 AML with first hematologic relapse after HSCT ( DLI =171, no DLI= 228)

• 2yr OS 21%±3% in DLI group vs 9%±2% in no DLI group (P<0.0001) • Prognostic factors - the use of DLI, CR ≥ 5 months after HSCT, age < 37yrs • Predictive factors in DLI group - lower tumor burden at relapse, remission at DLI, female sex, favorable cytogenetics

Hypomethylating agents • A survey from EBMT • N=204 pts relapsed after alloSCT (130 AML & 74 MDS, 47 MAC & 157 RIST) • Median time to relapse - 6.5 months after SCT • AZA for 5-7 consecutive days • 32% received DLI during AZA treatment • CR 15%, 2yr OS of CR - 38.5% vs 11% (whole pts) • Comparable to intensive chemotherapy or DLI

Charles C et al 2014 ASH meeting abstr 2506

Candidate targets & new drugs in RR-AML

Thol F et al. Blood 2015;126:319-27

Fms-like tyrosine kinase 3-intenal tandem duplication (FLT3-ITD) mutation

Ravandi F et al Leuk Res 2010;34:752-6

Total N=127, RR-AML patients

OS from the time of relapse

OS for patients with CR2

~30% of AML

Agent Phase Patient population DLT ORR at MTD

Lestaurtanib I RR-AML w FLT3 mutation Nausea, vomiting, fatigue 5/14 (1 CRi)

Midostaurin IIb RR-AML w or w/o FLT3 mutation Nausea, vomiting 32/57 (1 CR)

Sunitinib I RR-AML w or w/o FLT3 mutation Fatigue, hypertension, heart failure

7/16 (1 CRi)

Tandutinib I RR-AML w or w/o FLT3 mutation Muscle weakness, fatigue 2/8 (2 blast reductions)

Sorafenib I RR-AML w or w/o FLT3 mutation

Elevated transaminases, musculoskeletal pain

11/15 (11 SD)

KW-2449 I RR-AML w or w/o FLT3 mutation Nausea, vomiting, fatigue 1/6 (1 blast reduction)

Quizartinib II RR-AML with FLT3-ITDmutation QTc prolongation 44/99 (44 CRc)

Ponatinib I RR-AML w or w/o FLT3 mutation Pancreatitis 3/12 (2 CRi)

• Single agent FLT3 inhibitor studies

Sorafenib with chemotherapy in elderly AML

Serve H et al. J Clin Oncol 2013;31:3110-8

Benefit of Sorafenib in newly diagnosed AML-SORAML trial

• N=267 patients (aged 18~60 years), 17% had FLT3-ITD-positive ds • In FLT3-ITD positive ds, no difference for EFS, but RFS and OS in favor of sorafenib

Sorafenib+DA Placebo+DA P

CR rate 60% 59% NS

EFS 20.5 months 9.2 months 0.013

RFS Not reached 23 months 0.017

3yr OS 63% 56% NS

Röllig C et al 2014 ASH meeting abstr 6

Mechanisms of resistance to FLT3 inhibition

Grunwald MR et al Int J Hematol 2013;97:683-94

HMA plus sorafenib • Azacytidine plus sorafenib in patients with RR-AML

and FLT3-ITD mutation

• 43 RR-AML with a median age of 64 years • 5-AZA 75 mg/m2 for 7 days and sorafenib 400 mg b.i.d • 93% had FLT3-ITD mutation with a median allelic ratio of 0.32

Ravandi F et al. Blood 2013;121:4655-62

Candidate targets & new drugs in RR-AML

Thol F et al. Blood 2015;126:319-27

Gemtuzumab ozogamicin • Anti-CD33 monoclonal Ab conjugated to antitumor antibiotic

calicheamicin

• Accelerated approval by FDA for elderly AML in 2000

• Voluntarily withdrawn in 2010 because of lack of clinical benefit and increased mortality in SWOG 0106 trial

• Four other major RCT in untreated AML - improved survival without increased toxicity

• Promising results in RR-AML, APL, and with various dosing schedule

Study No of patients CR(%) / CRp(%)

Siever EL et al. 2001 142 (median 61 yrs) 23 (16%) / 19 (13%)

Larson RA et al. 2002 101 (≥ 60 yrs) 13 (13%) / 15 (15%)

Novel recurring mutation found by sequencing in AML: IDH1

Maris ER et al N Engl J Med 2009;261:1058-66

• IDH enzyme mutation - 10~30% of de novo AML • Gain of novel activity • Unfavorable prognosis

• IDH1, 2 inhibitors - AG-221, AG-120

Other novel targeted agents

• Cell cycle inhibitors (Polo-like kinase 1 inhibitor volasertib) • MLL-targeting drugs (DOT1L inhibitors EPZ-5676, palbociclib) • Epigenetic modifiers (HDAC inhibitors, HMAs) • Aminopeptidase inhibitors (Tosedostat) • Immunomodulating agents (lenalidomide) • Adaptive immune therapy (CART)

Ramos NR et al J Clin Med 2015;4:665-95 Sasine J et al Blood Rev 2015;29:1-9

www.clinicaltrials.gov

Summary • Alloegeneic SCT has been the only modality to give the best

chance to cure RR-AML patients.

• Prognosis of RR-AML remains poor even with SCT.

• RR-AML is heterogenous group and no uniform treatment will provide cure of RR-AML.

• As the biology of AML is more fully elaborated, new targets and targeted drugs emerge.

• Further studies are needed to identify and validate novel approaches.

M/35yrs

C/C fever & whole body petechia

4년 전 AML M2, normal karyotype으로 진단받고 3+7 ida/cytarabine의 복합항암화학요법과 함께 형으로부터 동종조혈모세포이식을 시행 받은 후 경과관찰 중이었다. 일반혈액검사 및 말초혈액도말검사에서 범혈구 감소증 및 미성숙세포가 30% 관찰되었다. 골수검사결과 blast 89%로 AML 재발로 진단되었다.

문제 1

• 다음 중 이 환자에서 나쁜 예후를 시사하는 인자는?

1) 환자의 나이 (35세) 2) 진단 시 정상 염색체 핵형 (46XY) 3) 1차 완전관해 유지 기간 (4년) 4) 과거 고용량 cytarabine 치료력 5) 동종조혈모세포이식을 시행 받은 과거력

문제 2

• 위 환자의 향후 치료는?

1) HiDAC-based salvage chemotherapy

2) Upfront 2nd allogeneic SCT

3) Hypomethylating agent

4) FLT3 inhibitor

5) Best supportive care