All fit patients w ith Acute Myeloid Leukemia should receive 7+3 induction Martha L. Arellano, MD Associate Professor of Hematology/Oncology Director, Hematology & Medical Oncology Fellowship Program Winship Cancer Institute of Emory University, Atlanta, GA Sea Island July 27, 2017 1
External Industry Relationships * Company Name(s) Role Equity, stock, or options in biomedical NONE industry companies or publishers** Board of Directors or officer NONE Royalties from Emory or from NONE external entity Industry funds to Emory for my Cephalon Oncology Principal investigator, research Omacetaxine for older AML Foundation funds to Emory for my Leukemia & Lymphoma Society Co-investigator, a study to research decrease early deaths in APL Winship Cancer Institute | Emory University 2
I promise this is not going to hurt… Winship Cancer Institute | Emory University 3
Case • 65 year old female with HTN, presents with dyspnea and fever. WBC 40,000 with 90% “other cells”. She is diagnosed with AML. Her performance status is 1. • Cytogenetics show a normal karyotype and next generation sequencing for myeloid malignancies shows a mutation in DNMT3A. • Induction with daunorubicin (90mg/m 2 /d x 3 days and cytarabine (7+3) is recommended. • She asks: Is there anything better than 7+3 for induction in my case? Winship Cancer Institute | Emory University 4
Introduction • 4 /100,000 people per year are diagnosed with AML. • 1.3% of all new cancer cases • 1.8 % of all cancer deaths • Estimated New cases/Deaths: 20,830/10,460 (2015, USA). • Median age at AML diagnosis: 69 years • 7+3 was established as standard AML induction based on studies dating back to early 80’s by CALGB. SEER data Winship Cancer Institute | Emory University 5
“Believe nothing that you hear and half of w hat you see” at national meetings Professor Hanna Jean Khoury Winship Cancer Institute | Emory University 6
“Be careful w ith preliminary and single- institution data…even if it’s a large institution…” ( Morgan McLemore, MD ) http://jamanetwork.com/journals/jama/fullarticle/194975 Winship Cancer Institute | Emory University 7
Is using high dose cytarabine (HiDAC) superior to standard dose cytarabine for AML induction? Winship Cancer Institute | Emory University 8
Is high dose cytarabine better than low er dose cytarabine for AML induction? HiDAC= 3mg/m2 Q 12hr days 1, 3, 5, 7 James Bishop, Jane Matthews, Graham Young, et al. Blood, Vol 87, No 5 (March 1). 1996 Winship Cancer Institute | Emory University 9
HiDAC led to better DFS CR: 71% for HiDAC-3-7 vs. 74% for 7-3-7 James Bishop, Jane Matthews, Graham Young, et al. Blood, Vol 87, No 5 (March 1). 1996 Winship Cancer Institute | Emory University 10
…But no benefit is OS due to early toxicity James Bishop, Jane Matthews, Graham Young, et al. Blood, Vol 87, No 5 (March 1). 1996 Winship Cancer Institute | Emory University 11
Is high dose cytarabine better than low er dose cytarabine for AML induction? HDAC-2: Ara-C 2gm/m 2 (age 50-64; after Dec 1988 only age < 50) q 12hrs on days 1-6. HDAC-3: Ara-C 3gm/m 2 ( pts age < 50 until Dec 1988) q 12hrs on days 1-6. James Weick, Kenneth Kopecky, Frederick Appelbaum, et al. Blood (88), No 8. 1996 Winship Cancer Institute | Emory University 12
Summary of treatment assignments and outcomes for induction by age group P-value for CR with HDAC vs. SDAC = 0.96 P-value for OS with HDAC vs. SDAC = 0.41 James Weick, Kenneth Kopecky, Frederick Appelbaum, et al. Blood (88), No 8. 1996 Winship Cancer Institute | Emory University 13
RFS and OS by age and treatment arm RFS OS P = 0.049 James Weick, Kenneth Kopecky, Frederick Appelbaum, et al. Blood (88), No 8. 1996 Winship Cancer Institute | Emory University 14
What about intermediate dose vs. high dose cytarabine? 200mg-1gm 1gm-2gm Cycle 1: Ida 12mg/m 2 day 5-7 plus Ara-C 200mg/m 2 /d CIV days 1-7 OR 1,000mg/m 2 BID on d 1-5 Cycle 2: amsacrine 120 mg/m 2 on days 3, 5, and 7 plus Ara-C 1000 mg/m 2 for BID on d 1-6 OR 2000 mg/m 2 BID on days 1, 2, 4, 6. Winship Cancer Institute | Emory University 15 Bob Löwenberg, Thomas Pabst, Edo Vellenga. Et al.
No difference in activity betw een high dose and intermediate dose cytarabine for AML induction Bob Löwenberg, Thomas Pabst, Edo Vellenga. Et al. Winship Cancer Institute | Emory University 16
Conclusion Using HiDAC during induction does not improve CR nor overall survival in newly diagnosed AML, when compared to standard dose cytarabine (7+3). James Weick, Kenneth Kopecky, Frederick Appelbaum, et al. Blood (88), No 8. 1996 Winship Cancer Institute | Emory University 17
What about double induction w ith 1-2 courses of HiDAC? Relapse-free survival Overall survival TAD = thioguanine, cytarabine (100mg/m 2 ), and daunorubicin (60) HAM= high-dose cytarabine (3gm/m 2 if < 60 or 1gm/m 2 if > 60) and mitoxantrone N= 1,770 patients (age 16- 85) Winship Cancer Institute | Emory University 18 Thomas Bu¨chner, Wolfgang E Berdel, Hiddemann, et al. JCO (24). N. 16. 2006
Is adding a 3 rd cytotoxic agent better than 7+3 alone for AML induction? Herve Dombret and Claude Gardin. Blood 2016: 127(1): 53-61 Winship Cancer Institute | Emory University 19
Results of MRC AML15 Trial Winship Cancer Institute | Emory University 20 A. Burnett, N Russell, et al. JCO (31) n. 27. Sept 2013.
Randomizations on MRC AML15 3106 patients recruited (median age 49, range 0-73) Winship Cancer Institute | Emory University 21 A. Burnett, N Russell, et al. JCO (31) n. 27. Sept 2013.
MRC AML15 Trial-results Winship Cancer Institute | Emory University 22 A. Burnett, N Russell, et al. JCO (31) n. 27. Sept 2013.
Outcomes FLAG-Ida vs. ADE or DA A. Burnett, N Russell, et al. JCO (31) n. 27. Sept 2013. Winship Cancer Institute | Emory University 23
Is adding an antibody to 7+3 better than 7+3 alone for AML induction? Seattle Genetics has discontinued the phase 3 CASCADE clinical trial and suspended patient enrollment and treatment in all of its other vadastuximab talirine clinical trials due to toxicity. Herve Dombret and Claude Gardin. Blood 2016: 127(1): 53-61 Winship Cancer Institute | Emory University 24
SWOG S1203: Randomized Phase III Study of Standard Cytarabine + Daunorubicin (7+3) vs. Idarubicin w ith High Dose Cytarabine (IA) +/- Vorinostat (IA+V) in Younger Patients w ith Previously Untreated AML Guillermo Garcia-Manero et al. Blood 2016;128:901 Winship Cancer Institute | Emory University 25
SWOG S1203: Randomized Phase III Study of Standard Cytarabine + Daunorubicin (7+3) vs. Idarubicin w ith High Dose Cytarabine (IA) +/- Vorinostat (IA+V) in Younger Patients w ith Previously Untreated AML Complete remission (CR) : 75% for 7+3, 79% for IA, and 77% for IA+V (p=0.58). No significant differences in EFS, RFS or OS among all three arms (all p>0.5). Outcomes: no difference by cytogenetic or molecular group, except for favorable cytogenetics, who had significantly better EFS, RFS and OS with 7+3 therapy compared to IA or IA+V (all p≤0.015). Toxicity: • Grade 5 induction toxicity 4% (7+3), 8% (IA), 9% (IA+V) by arm (p=0.07), • Grade 4 induction toxicity rates were similar across arms (p=0.38). • Toxicities related to therapy , 2%, 7%, 8%, respectively (p=0.01). Guillermo Garcia-Manero et al. Blood 2016;128:901 Winship Cancer Institute | Emory University 26
Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation R.M. Stone, S.J. Mandrekar, B.L. Sanford, K. Laumann, S. Geyer, C.D. Bloomfield, C. Thiede, T.W. Prior, K. Döhner, G. Marcucci, F. Lo-Coco, R.B. Klisovic, A. Wei, J. Sierra, M.A. Sanz, J.M. Brandwein, T. de Witte, D. Niederwieser, F.R. Appelbaum, B.C. Medeiros, M.S. Tallman, J. Krauter, R.F. Schlenk, A. Ganser, H. Serve, G. Ehninger, S. Amadori, R.A. Larson, and H. Döhner NEJM June 23, 2017 Winship Cancer Institute | Emory University 27
What about elderly fit patients w ith AML? • Hypomethylating therapy (palliative for unfit patients) • Intensive therapy (consider post-CR PBSCT/BMT) OS with high dose daunorubicin + Ara-C based on cytogenetic risk in patients > 60 years (HOVON43). Gert Ossenkoppele, and Bob Löwenberg Blood 2015;125:767-774 Winship Cancer Institute | Emory University 28
In summary, • No prospective randomized study has proven better than 7+3 for induction in most fit patients with AML. • Outside of a clinical trial, 7+3 appears still to be the best option for induction of fit AML patients. • Recommended anthracycline: daunorubicin 90mg/m 2 or Idarubicin 12mg/m 2 ) • As an alternative- If “7+3” is not acceptable, consider “3+7” Winship Cancer Institute | Emory University 29
AML Studies at Emory • Omacetaxine for Consolidation and Maintenance in fit older AML patients • (QuANTUM-R): An Open-label Study of Quizartinib Monotherapy vs. Salvage Chemotherapy in AML Subjects Who are FLT3-ITD Positive • Safety Study of MGD006 in Relapsed/Refractory AML (MGD006-01) • Expanded access- AG-120 in Subjects with Advanced Hematologic Malignancies with an IDH1 Mutation, opening soon • Expanded access-Gemtuzumab ozogamicin for relapsed/refractory AML, soon • PRevention Of BLeeding in hEmatological Malignancies With Antifibrinolytic (Epsilon Aminocaproic Acid) (PROBLEMA) • Patient directed transfusion for treatment of anemia. Winship Cancer Institute | Emory University 30
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