treatment for relapsed/refractory aml · 2016-12-27 · 12-17.9 개월. 18. 개월이상 ... •...
TRANSCRIPT
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