All fit patients w ith Acute Myeloid Leukemia should receive 7+3 - - PowerPoint PPT Presentation

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All fit patients w ith Acute Myeloid Leukemia should receive 7+3 - - PowerPoint PPT Presentation

Feb 14, 2024 18 likes •322 views

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

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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

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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

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I promise this is not going to hurt…

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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?
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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

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

Professor Hanna Jean Khoury

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“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

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

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Is high dose cytarabine better than low er 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

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HiDAC led to better DFS

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

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

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…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

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Is high dose cytarabine better than low er 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.

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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

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RFS and OS by age and treatment arm

RFS OS

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

P = 0.049

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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 1-5 Cycle 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

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

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

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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

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What about double induction w ith 1-2 courses

  • f HiDAC?

Overall survival Relapse-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. 2006

N= 1,770 patients (age 16- 85)

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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

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Results of MRC AML15 Trial

  • A. Burnett, N Russell, et al. JCO (31) n. 27. Sept 2013.
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Randomizations on MRC AML15

  • A. Burnett, N Russell, et al. JCO (31) n. 27. Sept 2013.

3106 patients recruited (median age 49, range 0-73)

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MRC AML15 Trial-results

  • A. Burnett, N Russell, et al. JCO (31) n. 27. Sept 2013.
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Outcomes FLAG-Ida vs. ADE or DA

  • A. Burnett, N Russell, et al. JCO (31) n. 27. Sept 2013.
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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

  • ther vadastuximab talirine clinical trials due to toxicity.
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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

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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

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).
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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

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What about elderly fit patients w ith 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).

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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” 
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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.