All fit patients with Acute Myeloid Leukemia should ... · All fit patients with Acute Myeloid Leukemia should receive 7+3 induction Martha L. Arellano, MD Associate Professor of

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All fit patients with Acute Myeloid Leukemia should receive 7+3

induction

Martha L. Arellano, MDAssociate Professor of Hematology/Oncology

Director, Hematology & Medical Oncology Fellowship ProgramWinship Cancer Institute of Emory University, Atlanta, GA

Sea IslandJuly 27, 2017

2Winship Cancer Institute | Emory University

External Industry Relationships * Company Name(s) Role

Equity, stock, or options in biomedical industry companies or publishers**

NONE

Board of Directors or officer NONE

Royalties from Emory or from external entity

NONE

Industry funds to Emory for my research

Cephalon Oncology Principal investigator,Omacetaxine for older AML

Foundation funds to Emory for my research

Leukemia & Lymphoma Society Co-investigator, a study to decrease early deaths in APL


I promise this is not going to hurt…


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/m2/d x 3 days and cytarabine (7+3) is recommended.

• She asks: Is there anything better than 7+3 for induction in my case?


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


“Believe nothing that you hear and half of what you see” at national meetings

Professor Hanna Jean Khoury


“Be careful with preliminary and single-institution data…even if it’s a large institution…” (Morgan McLemore, MD)

http://jamanetwork.com/journals/jama/fullarticle/194975

http://jamanetwork.com/journals/jama/fullarticle/194975


Is using high dose cytarabine (HiDAC) superior to standard dose cytarabine for AML

induction?


Is high dose cytarabine better than lower dose cytarabine for AML induction?

James Bishop, Jane Matthews, Graham Young, et al. Blood, Vol 87, No 5 (March 1). 1996

HiDAC= 3mg/m2 Q 12hr days 1, 3, 5, 7


HiDAC led to better DFS


CR: 71% for HiDAC-3-7 vs. 74% for 7-3-7


…But no benefit is OS due to early toxicity



Is high dose cytarabine better than lower dose cytarabine for AML induction?

James Weick, Kenneth Kopecky, Frederick Appelbaum, et al. Blood (88), No 8. 1996

HDAC-2: Ara-C 2gm/m2 (age 50-64; after Dec 1988 only age < 50) q 12hrs on days 1-6.HDAC-3: Ara-C 3gm/m2 ( pts age < 50 until Dec 1988) q 12hrs on days 1-6.


Summary of treatment assignments and outcomes for induction by age group

P-value for CR with HDAC vs. SDAC = 0.96P-value for OS with HDAC vs. SDAC = 0.41



RFS and OS by age and treatment arm

RFSOS


P = 0.049


What about intermediate dose vs. high dose cytarabine?

Bob Löwenberg, Thomas Pabst, Edo Vellenga. Et al.

Cycle 1: Ida 12mg/m2 day 5-7 plus Ara-C 200mg/m2/d CIV days 1-7 OR 1,000mg/m2 BID on d 1-5Cycle 2: amsacrine 120 mg/m2 on days 3, 5, and 7 plus Ara-C 1000 mg/m2 for BID on d 1-6 OR 2000 mg/m2 BID on days 1, 2, 4, 6.

200mg-1gm 1gm-2gm


No difference in activity between high dose and intermediate dose cytarabine for AML induction

Bob Löwenberg, Thomas Pabst, Edo Vellenga. Et al.


Conclusion

Using HiDAC during induction does not improve CR nor overall survival in newly diagnosed AML, when compared to standard

dose cytarabine (7+3).



What about double induction with 1-2 courses of HiDAC?

Overall survivalRelapse-free survival

TAD = thioguanine, cytarabine (100mg/m2), and daunorubicin (60) HAM= high-dose cytarabine (3gm/m2 if < 60 or 1gm/m2 if > 60) and mitoxantrone

Thomas Bu¨chner, Wolfgang E Berdel, Hiddemann, et al. JCO (24). N. 16. 2006N= 1,770 patients (age 16- 85)


Is adding a 3rd cytotoxic agent better than 7+3 alone for AML induction?

Herve Dombret and Claude Gardin. Blood 2016: 127(1): 53-61


Results of MRC AML15 Trial

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)


MRC AML15 Trial-results



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Is adding an antibody to 7+3 better than 7+3 alone for AML induction?

Herve Dombret and Claude Gardin. Blood 2016: 127(1): 53-61

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.


SWOG S1203: Randomized Phase III Study of Standard Cytarabine + Daunorubicin (7+3) vs. Idarubicin with High Dose Cytarabine (IA) +/-

Vorinostat (IA+V) in Younger Patients with Previously Untreated AML

Guillermo Garcia-Manero et al. Blood 2016;128:901


SWOG S1203: Randomized Phase III Study of Standard Cytarabine + Daunorubicin (7+3) vs. Idarubicin with High Dose Cytarabine (IA) +/-

Vorinostat (IA+V) in Younger Patients with Previously Untreated AML

Guillermo Garcia-Manero et al. Blood 2016;128:901

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).


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


What about elderly fit patients with AML?• Hypomethylating therapy (palliative for unfit patients)• Intensive therapy (consider post-CR PBSCT/BMT)

Gert Ossenkoppele, and Bob Löwenberg Blood 2015;125:767-774

OS with high dose daunorubicin + Ara-C based on cytogenetic risk in patients > 60 years (HOVON43).


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/m2 or Idarubicin 12mg/m2 )

• As an alternative- If “7+3” is not acceptable, consider “3+7”


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.

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All fit patients with Acute Myeloid Leukemia should ... · All fit patients with Acute Myeloid Leukemia should receive 7+3 induction Martha L. Arellano, MD Associate Professor of