SWAMI IYER, MDHouston, USA

• Associate Professor, Leader, early drug development in Oncology, the Methodist Cancer Center

• Dr Iyer is the Leader for Early Drug Development Program in Hematology and Oncology at the Methodist Cancer Center, Houston, Texas. He recently served as the Director of Hematological Malignancies at CTRC, and as an Assistant Professor of Medicine at the University of Texas Health Science Center (UTHSCSA). He is a physician scientist with laboratory interests in Heat shock proteins and has extensive expertise in clinical studies.

Considerations for AML treatment in AYA.

Swami Padmanabhan Iyer, MD

Associate Professor, Weill Cornell Medical College

Houston Methodist Cancer Center

NCI Definition- adolescent and young adult (AYA) are cancer patients between the ages of 15 to 29 years old when they first had a diagnosis of cancer)

Considerations for Treatment in young patients with AML

• Overcome kinetics of AML- dose escalation of chemotherapy,

• Addition of a third chemotherapeutic agent• Are all younger age groups the same?• Understanding the biology-TCGA• Find the right targeted partners• Consolidation Intensification• Bone Marrow Transplantation

• 27 years old with WBC-34.6, Hgb-8.5 and platelets-20K.

• Trilineage dysplasia, t(6,9) and Flt-3 ITD positive.

Patient A

10 1 10 2 10 3 10 4

CD33 PC -->

10

110

210

310

4

CD

13

PE

-->

Age-Specific Incidence Rates for AML

0

5

10

15

20

25

30

35

00-04 05-09 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85+

Av

era

ge

An

nu

al

Ra

te p

er

10

0,0

00 Male

Female

All persons

NCI SEER Program, 1995-1999.

Age (yrs)

1995-1998

• 80% of acute leukemia in adults• Median age of AML = 64 years- Public health• Incidence in USA rises by age group• Most common cause of cancer death in young

*Rates are per 100,000 and are age-adjusted.

Age-Specific Incidence Rates for AML

Survival in Adult AML by Time Period

Kantarjian H, et al. Cancer. 2010;116:4896-4901.

Overall

< 60 yrs

≥ 60 yrs

1.0

0.8

0.6

0.4

0.2

00 1 2 3 4 5 6 7 8

Yrs

Su

rviv

al P

rob

abil

ity

Era1960s1970s1980s1990s2000s

Total104530652

1007909

Died103492586849560

P < .001

1.0

0.8

0.6

0.4

0.2

00 1 2 3 4 5 6 7 8

Yrs

Su

rviv

al P

rob

abil

ity

Era1960s1970s1980s1990s2000s

Total104530652

1007909

Died103492586849560

P < .001

1.0

0.8

0.6

0.4

0.2

00 1 2 3 4 5 6 7 8

Yrs

Su

rviv

al P

rob

abil

ity Era

1960s1970s1980s1990s2000s

Total39

166263495486

Died39

164259461350

P < .001

Survival in AML by Age group

Considerations for Treatment in Adolescent Young Adults with AML

• Overcome kinetics of AML- dose escalation of chemotherapy, third agent, intensification

• Find the right targeted partner• Intensification and Consolidation• Bone Marrow Transplantation

Remission Induction in the young driven by the biology-

activating mutations

Cure

Clinically Detectable Disease

Induction Relapse Relapse

TimeTota

l Le

uke

mic

Cell

Num

ber

Questions to consider

• What is the ideal induction therapy?• What is the best anthracycline?• What is the best dose of cytarabine?• What is the ideal third agent?• Are all younger age groups the

same?• What are the targeted agents?• What is the best consolidation?

Considerations for Treatment in young patients with AML

• Overcome kinetics of AML- dose escalation of chemotherapy,

• Addition of a third chemotherapeutic agent• Are all younger age groups the same?• Understanding the biology-TCGA• Find the right targeted partners• Consolidation Intensification• Bone Marrow Transplantation

Considerations for Treatment in young patients with AML

• Overcome kinetics of AML- dose escalation of chemotherapy,

• Addition of a third chemotherapeutic agent• Are all younger age groups the same?• Find the right targeted partner- Sorafanib

and Gemtuzumabd• Consolidation• Bone Marrow Transplantation

Recent Randomized Trials of Dose-Intensification In AML

1. Fernandez HF, et al. N Engl J Med. 2009;361:1249-1259. 2. Lowenberg B, et al. N Eng J Med. 2009;361:1235-1248. 3. Pautas C, et al. J Clin Oncol. 2010;28:808-814. 4. Burnett AK, et al. ASH 2009. Abstract 484. 5. Lowenberg B, et al. N Engl J Med. 2011;364:1027-1036.

Trial Agent Results

ECOG E1900[1] Daunorubicin 90 mg/m2/day x 3 45 mg/m2/day x 3

Superior OS,CR with higher dose in pts < 60 yrs No benefit with higher dose if age ≥ 50 yrs,

adverse cytogenetics, or FLT3-ITD mutation

HOVON[2] Daunorubicin 90 mg/m2/day x 3 45 mg/m2/day x 3

No significant difference in pts ≥ 60 yrs Superior OS, CR, EFS with high dose in patients

60-65 yrs

ALFA-9801[3] Idarubicin 12 mg/m2/day x 4 or x 3Daunorubicin 80 mg/m2/day x 3

Superior CR with idarubicin x 3 or x 4 vs daunorubicin

No significant differences in EFS, OS, or relapse incidence

MRC AML15[4] FLAG-IdaDAADE

More durable CR with FLAG-Ida than with ADE or DA, but higher initial toxicity; no survival benefit

HOVON/SAKK[5] High-dose cytarabineIntermediate-dose cytarabine

Remission, relapse, survival identical with high- vs intermediate-dose cytarabine for remission induction

Is intermediate dose superior to “standard” dose?

Holoweicki et al, J Clin Onc April 2012

Cladribine better than Fludarabine as third agent

A survival advantage of the DAC arm vs. DA arm was observed among:• age 50 years or

older (P = .005), • leukocyte count >

50 × 109/L (P = .03), and

• unfavorable karyotype (P = .03).

Pediatric vs.Adult Protocol

Treatment approaches in “standard arm” in Phase III US studies

AYA differences between ALL and AML procols

Considerations for Treatment in young patients with AML

• Overcome kinetics of AML- dose escalation of chemotherapy,

• Addition of a third chemotherapeutic agent• Are all younger age groups the same?• Understanding the biology-TCGA• Find the right targeted partner- Sorefanib

and Gemtuzumab• Consolidation• Bone Marrow Transplantation

Considerations for Treatment in young patients with AML

• Overcome kinetics of AML- dose escalation of chemotherapy,

• Addition of a third chemotherapeutic agent• Are all younger age groups the same?• Find the right targeted partner• Consolidation• Bone Marrow Transplantation

Creutzig, et al. Cancer. 2007 562-571

Age Groups in AML- <30 years studies-AML BFM 93/98, AMLCG 92/99 AML

HD93/98

Creutzig, et al. Cancer. 2007 562-571

Age Groups in AML- <30 years studies-AML BFM 93/98, AMLCG 92/99 AML

HD93/98

Creutzig, et al. Cancer. 2007 562-571

Age Groups in AML- <30 years-EFS by age group and cytogenetics

Tanner JA, et al. JCO suppl. 2009, Abstract#9506

MRC 10 study

AYA treated on Adult vs. Pediatric protocols comparison

Woods et al. ASH 2001, Abstract#462

CCG2891 Intensive vs.Standard Timing

Woods et al.Blood, 1996, 4979-4989

CCG2891 Intensive vs.Standard Timing

Woods et al.Blood, 1996, 4979-4989

CCG2891 Intensive vs.Standard Timing

Woods et al.Blood, 1996, 4979-4989

AYA treated on Adult vs. Pediatric protocols- Conclusions

Is survival lagging behind?

Considerations for Treatment in young patients with AML

• Overcome kinetics of AML- dose escalation of chemotherapy,

• Addition of a third chemotherapeutic agent• Are all younger age groups the same?• Understanding the biology-TCGA• Find the right targeted partner- Sorefanib

and Gemtuzumab• Consolidation• Bone Marrow Transplantation

Cytogenetics by Age group –Normal, CBF and 11q23

Grimwade. et al. Blood 1998,92-2322

MRC AML 10 clinical trial

TCGA Characterization of the- “Blackbox”- Mutations in AML.

The Cancer Genome Atlas Research Network. N Engl J Med 2013;368:2059-2074.

• First recognized somatic mutations-Transcription factors

• DNMT3, NPM1, CEBPA, IDH1/2 and RUNX1 mutually exclusive.

• Also for mutations in certain biologic classes- cohesins, splicesosome, signaling proteins and histone modifying proteins.

• TP53 worst outcome

Molecular risk-based therapies for AML with normal karyotype are based on new

markers

• Favorable mutations– NPM1: nucleophosmin member 1 gene– CEBPA: CCAAT/enhancer binding protein alpha– DNMT3

• Unfavorable mutations– FLT3-ITD: internal tandem duplication of the fms-related

tyrosine kinase 3 (FLT3) gene– MLL-PTD: partial tandem duplication of mixed-lineage

leukemia gene– BAALC: brain and acute leukemia gene, cytoplasmic– ERG: v-ets erythroblastosis virus E26 oncogene like (avian)– WT1– TP53

ASH Education Book 2006: Mrosek and Bloomfield

Prevalance of Mutations by age

Grimwade. et al. Blood 1998,92-2322

Hollink. et al. Leukemia, 2009;23-262-270, Schnittger et.al Blood 2005, 106

NPM1

Frohling et al, Blood, 2002, Meschinchi et.al Blood, 2006

Age prevalence of FLT3 ITD

Overall survival for FLT-3 in AYA

Frohling et al, Blood, 2002, Meschinchi et.al Blood, 2006

CBF AML with and without c-kit

Pollard et al, Blood 2010 and Paschka et al, JCO 2006

DNMT3A in AYA AML

Ostronoff et al,Leukemia 2012

NUP98-NSD1 cryptic translocations

NUP98-NSD1 cryptic translocation with FLT3 ITD

Ostronoff et al,ASH, 2012

Ostronoff et al,ASH, 2012

NUP98-NSD1 with FLT3 ITD in COG AML- Outcome

Is survival lagging behind?

Conclusions- Clinical Trials

• Psychosocial Challenges• Fertility Issues• Survivorship

Butow P et al.JCO,2010, 4800

Factors to consider in treating AYA patients with AML

Conclusions- Participation in Clinical Trials!!

Considerations for Treatment in young patients with AML

• Overcome kinetics of AML- dose escalation of chemotherapy,

• Addition of a third chemotherapeutic agent• Are all younger age groups the same?• Find the right targeted partner- Sorefanib,

Bortezomib, Gemtuzumab etc• Consolidation• Bone Marrow Transplantation

New Agents and Strategies for AML

Mechanism of Action Drug

Amino acid depletion Tosedostat

FLT3 kinase inhibition Quizartinib, sorafenib

Modified chemotherapyLiposomal formulationLipid conjugate

CPX-351Elacytarabine

Topoisomerase II inhibition Vosaroxin

Epigenetic modulation Azacytidine/decitabine ± others

Polo-like kinase inhibitor Volasertib

Conjugated monoclonal antibody Gemtuzumab ozogamicin

Risk stratified COG AAML 1031

Guiding Light

55

‘From making the cure of the disease more grievous than the endurance of the same, Good Lord, deliver us.’

Sir Robert Hutchison, 20th century physician, British Medical Journal, 1953; 1: 671.