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(1)

Acute Myeloid Leukemia-

How can we fix it?

Jeffrey W. Taub, M.D.

Division of Hematology/Oncology

Children

s Hospital of Michigan

Wayne State University School of Medicine

Detroit, Michigan

(2)

What is Leukemia?

• Proliferation of immature forms of white blood cells whose development into mature white blood cells is blocked.

• Symptoms related to infiltration of the bone

marrow with ↓production of normal bone marrow cells: neutropenia (low levels of granulocytes/neutrophils, anemia (low red blood cells) and thrombocytopenia (low platelets).

(3)

Subclasses of Leukemia

Acute Lymphoblastic Leukemia (ALL) Acute Myeloid Leukemia (AML)

Subtypes M0-M7 [Cure: 20-50%] 500 pediatric cases/year in the U.S.

Most common acute leukemia in adults. AML is treated with short but intensive

chemotherapy and frequently stem cell transplants are considered part of the front line treatment along with chemotherapy.

AML ALL

(4)

Strategies to Improve AML Treatments

• Identify subgroups which have a good prognosis.

Down syndrome

• Identify selective drugs which may have a broad

range of activity against multiple cancers (including

leukemia).

Histone deacetylase inhibitors (panobinostat)

• Develop or synthesize new selective drugs by

combining the essential/key structures of

chemotherapy drugs.

Histone deacetylase inhibitors + wee1 Kinase

inhibitor.

(5)

Down Syndrome Acute Myeloid Leukemia

(DS-AML)

 Children with Down syndrome (DS) have a 10-20-fold higher risk of developing leukemia (both ALL and AML) compared to children without DS.

 Clinical and biological features of DS-AML are unique including:

 i) pre-leukemia condition, the transient myeloproliferative disorder (TMD) diagnosed in ~25% of DS newborns

which resolves spontaneously. ~20-30% of patients will subsequently develop DS-AML before the age of 4 years.

 ii) 500-fold increased risk of developing the AML subtype, acute megakaryocytic leukemia (AMKL).

(6)

Study Entry

< 4 years of age at diagnosis

Induction I CI-TAD + IT AraC

Induction IICapizzi II Course

Induction III CI-TAD + IT AraC

Induction IV CI-TAD

Intensification I VP/Ara-C

Intensification II VP/Ara-C

Follow-Up

BMA = Bone Marrow Aspirate. MRD = Minimal Residual Disease

CI-TAD: Continuous Infusion Cytarabine (AraC)/Daunorubicin + 6-Thioguanine CR = Complete Response

PR = Partial Response RD = Refractory Diease

Capizzi II: Cytarabine (AraC)/L-asparaginase VP/Ara-C: Etoposide/Cytarabine (AraC) IT AraC: Intrathecal Cytarabine

BMA/MRD Children’s Oncology Group COG AAML0431: The Treatment of Down Syndrome Children with Acute

Myeloid Leukemia and

Myelodysplastic Syndrome Under the Age of 4 Years

(7)

0 0.25 0.5 0.75 1 0 2 4 6 O v er all S u rv iv al

Years from Study Entry

OS: 92.7% N=204 0 0.25 0.5 0.75 1 0 2 4 6 E v e nt Fr e e S ur v iv a l

Years from Study Entry EFS:90% N=204

(8)

Ara-C dCyd Ara-C dCyd dCK dCK Ara-CMP Ara-CTP dCMP dCTP Ara-U CD A dTTP dCTP dC MP DA DNA Ara-UMP Ara-C dUMP dTTP CBS TS Reduced folate/ S-adenosylmethioine pathways dCMPDA N-terminus C-terminus Nf Cf Zinc finger domain

GATA1 (50kDa)

GATA1 Chr Xp11.23

FOG-1

GATCN(A/T)GATA(A/G)

A

Normal megakaryocyte and erythroid cell development

B

I II III IV V VI

I II III IV V VI mutated GATA1 C-terminus

Nf Cf GATA1s (40kDa)

FOG-1 GATCN(A/T)GATA(A/G) Zinc finger domain chromosome 21

trisomy 21

Acute megakaryocytic leukemia transformation

Why does DS-AML have

very high cure rates?

(9)

New Drugs

• Frequently drugs in development or

approved by the FDA for one specific

cancer, may be beneficial for other cancers.

• Histone deacetylase inhibitors are a new

category of chemotherapy drugs which

have multiple different mechanisms which

can kill cancer cells.

• Panobinostat is a newly approved drug by

the FDA for treating multiple myeloma.

(10)

β-Actin RAD51 BRCA1 CHK1

Bone Marrow

Control Panobinostat Cytarabine Combination

Day 11 Day 18 Day 24 Day 32 C P 0 10 20 30 40 0.0 2.5 5.0 7.5 Ara-C Combination Vehicle Panobinostat Time (Days) M e d ian R ad ian ce p /s/ cm ²/ sr ( x10 7 ) 0 10 20 30 40 50 0 20 40 60 80 100 Vehicle (N=10) Ara-C (N=10) Panobinostat (N=8) Combination (N=8) Time (Days) O v e ra ll S u rv iv a l P ro b a b ilit y

(11)
(12)

Designing New Drugs

• The active structure of chemotherapy drugs

can be altered/modified by medicinal

chemists to try and improve their activity

and/or reduce side effects.

(13)

N N N N O N OH N H N N MK-1775 A: m odifi catio ns o n 4-(4 -Met hyl pipe razi no) anili ne N N N N O N OH N H Linker HOHN O N N N N O N H N N NHOH O Linker B : m o do fic ation s o n 2-( 6-B rom op yrid in -2 -yl)-2 -p ro pa nol N N N N O N OH N H N N N HOHN O N N N N O N OH N H HOHN O n n=0 or 1 n=1 to 7 n N N N N O N H N N N HOHN O 1' 4' 5' N N N N O N H N N N N N O NHOH n=1 to 7 n C D E F N H HN NHOH O Panobinostat NH O NHOH O Vorinostat Zinc binding group Cap Linker

Chemical structures of panobinostat,

vorinostat, MK-1775 and the designed

(14)

Proposed synthesis of target

compounds 9-12

N N N N O N OH MeS mCPBA N N N N O N OH MeO2S N N N N O N OH N H R Amine NH2 THPOHN O or THPOHN O NH2 HCl N N N N O N OH N H HOHN O N N N N O N OH N H HOHN O Amine 3,4,5 NH2 N N N N O N OH N H N N N (CH2)n HOHN O or N N N N O N OH N H N N N (CH2)n O NHOH N3 n(H2C) O NHOTHP n=1-7 n=1-7 1 2 3 5 4 11 N N N N O N OH N H 6-8 8 9 10 12 then H+

(15)

Acknowledgments

CHM/KCI/WSU Dr. Yubin Ge Dr. Larry Matherly Dr. Alan Dombkowski Dr. J. Timothy Caldwell Dr. Zhihui Qin Holly Edwards Steven Buck Oakland University Dr. Gerard Madlambayan

References

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