# Presentation: 797193

## Challenges and Considerations in Linking Adult and Pediatric	Leukemias

**David G. Poplack M.D.**
**Texas Children’s Cancer Center**
**Baylor College of Medicine**

## Explore the relationship between pediatric and adult leukemias
Compelling biological evidence of similarities or differences useful in guiding the drug development process

**Compelling biological evidence of similarities or differences useful in guiding the drug development process**

## 	   Are there defined subsets of adult and pediatric leukemias that share biologically relevant features that would mandate they 				be commonly studied?

**Brief overview**
**Discuss rationale and promise**
**Highlight Challenges**

**Linking Adult and Pediatric Leukemias**

##  Adult and Pediatric Leukemias

**	****	****	****	****  ****	****   **_**ADULTS **_**   ****	****  **_**CHILDREN**_
**Acute Lymphocytic****	****	****11%****	****	****   75-80%**
**Acute Myeloid****	****	****	****32%****	****	****	****20%**
**Chronic Myeloid****	****	****	****15%****	****	****	****<5%**
**Chronic Lymphocytic****	****	****26%****	****	****	****N/A****	****	**
**	****	**

## Adults have a worse prognosis!

##  Survival in Acute Leukemias 

**	****	****	****	****	****	**_**Adults**_**	****	**_**Children**_
**Acute Lymphoid****	****	****50-60%****	****	****80-85%**
**Acute Myeloid****	****	****10-20%****	****	****40-50%**

## ACUTE LEUKEMIAS

**A heterogeneous group of disorders!**

## Survival of Children with

**Survival of Children with**
**Acute Lymphoblastic Leukemia**

##  Evidence for Heterogeneity in ALL

**Clinical Behavior**
**Morphology**
**Cytochemistry**
**Immunophenotype**
**Cytogenetics**
**Molecular Phenotyping**

## Impact of Heterogeneity on ALL Therapy

**“****Staging” of patients according to risk; therapy “tailored” accordingly**
**Low risk patients -effective, less toxic therapies**
**High risk patients - more intensive treatment **
**Successful strategy**
**Many prognostic criteria provided little biological insights**

## Technologic Advances

**Improvements in molecular cytogenetics and genomics **
**A new paradigm**
**More biologically relevant basis for classification**
**Identifying molecular targets for therapy**

##  Cytogenetics

**Giemsa banding**
**FISH**
**Molecular cytogenetics (PCR/RTPCR) **
**Spectral karyotyping (SKY)**
**Comparative genomic hybridization (CGH)**

## Case 169

**Case 169**
**Pseudo-tetraploid with two 12-15 translocations**

##  Molecular Geno- and  Phenotyping

**Southern, Northern, and Western Blots**
**PCR technology (single, multiplex, real-time)**
**Differential RNA expression technologies (cDNA microarray, SSH)**
**CGH and SKY on arrays**
**Single Nucleotide Polymorphism (SNPs) chips**
**Proteomics**

## Genome-wide analysis of gene expression using cDNA microarray technology

**Genome-wide analysis of gene expression using cDNA microarray technology**

## CDNA Array in ALL

**CD34 (7.4)**
**FL Cytokine receptor (5.6)**
**CD72 (4.6)**
**NADH ubiquinone oxidoreduct.15kDA protein(4.2)**
**C-Fos (3.5)**
**Multiple ESTs (3-4)**
**Insulin-like growth factor (2.3)**

**Elevated in t(4:11)**

## cDNA Array in ALL

**Membrane metallo-endopeptidase (enkephalinase/CALLA  CD10) (18.6)**
**Arachidonate 5-lipoxygenase (8.5)**
**CGD gene (8.0)**
**CD20 (7.0)**
**Hemoglobin beta (5.7)**
**CD1c antigen (5.7)**
**Human cerebellar degeneration associated protein (4.1)**

**Elevated in pre-B ALL**

## What subsets of adult and pediatric leukemias might be appropriate for common therapeutic studies? 

## Acute Lymphoblastic Leukemia

**t (9;22)/Ph+  - BCR-ABL**
**t (4;11) - MLL-AF4 - and other 11q23 abnormalities**
**t (8;14)  - B-cell**
**Hypodiploidy (<45 chromosomes)**
**Hyperdiploidy (>50 chromosomes)**
**t (12;21) - TEL-AML1****	**

##  Acute Myeloblastic Leukemia

**True **_**De novo**_** AML**
**	****	****- t (15;17) and other APL variants**
**	****	****- t (8;21), inversion 16, trisomy 8**
**Therapy related AML**
**	****	****- Monosomy 7,  5q- , and 11q23**
**MDS**

## The Era of Molecular Targeting 

**BCR-ABL  t(9;22) - target for treatment of Ph****1 ****positive disease - e.g. STI 571**
**t(15;17) - APL treatment with ATRA**
**Provide compelling arguments:**
**	****- confirm  validity of targeting relevant ****	****	****	****molecular lesions **
**	****-  testing targeted agents in all of the relevant ****	****	****populations**

## Can we develop a general principle that might guide the identification of  biological subsets that would be suitable for study both in adults and children? 

**	****	****	****	****	**

**Should be based on characteristics believed to be associated with the establishment , maintenance or progression of the malignant phenotype or linked to its development of resistance to specific treatments.****	**

## Examples of Biological Features that may be Shared by Adult and Pediatric leukemias

**Cytogenetic abnormalities**
**Fusion proteins - downstream events**
**Gene expression patterns**
**Receptors - e.g. growth, anti-apoptosis**
**Drug resistance genes**
**Tumor suppressor genes**

## Challenges to the Design of Common Adult and Pediatric Leukemia Trials

**Biologic basis for selecting grouping may turn out to be incorrect**
**Toxicity Issues **
**Small Patient Numbers (geographical accrual problems)**
**Impact of Transplantation**
**Requires extraordinary cooperation**

**Heterogeniety in location of actual fusions leads to heterogeneity in resulting proteins:**
**	****	****t (9;22) resulting in p190 and p210 kinases**
**Heterogeneity in mRNA expression:**
**	****	**** ****t (1;19) +/- RNA expression**
**Impact of other genetic changes: ****	****	****	****Concomitant aneuploidy**

**Beyond the Breakpoint**

## Benefits of Designing and Implementing Common Adult and Pediatric Leukemia Trials

**New and improved therapies for our patients**
**Better understanding of the underlying biology of these diseases**

## Development of common,comprehensive prospective biological studies should be encouraged

It is important to study both poor and good prognostic groups.

**It is important to study both poor and good prognostic groups.**

##  Summary

**Using current classification techniques there are adult and pediatric leukemia subsets in which joint biology and treatment protocols are justified**
**Significant caveats to this strategy exist**
**Development of coordinated, prospective biological and classification studies of adult and pediatric leukemias, using the latest genomic technologies, is of critical importance.**

## Cytogenetics in Adult and Pediatric ALL

**B Cell  ****t(8:14)**
**B Cell precursor**
**	****Hyperdiploidy (>50)**
**	****TEL-AML1 t(12;21)**
**	****E2A-PBX1 t(1;19)**
**	****BCR-ABL t(9;22)**
**	****MLL-AF4 t(4;11)**
**	****Hypodiploidy (<45)**
**T Cell**
**	**

**30-50@ 3 yr****	****	****80-90@ 5 yr**
**Unknown****	****	****85-90@ 5 yr**
**20-40@ 3 yr****	****	****70-80@ 5 yr**
**<10@ 3 yr****	****	****20-40@ 5 yr**
**10-20@ 3 yr****	****	****10-35@ 5 yr**
**10@ 3 yr****	****	****25-40@ 3 yr**
**50@ 3yr****	****	****65-75@ 5yr**

_**ADULTS**_**	****	**_**CHILDRE_x0008_N**_
**50-55@ 4 yr****	****	****75-85@ 5 yr**

##  Cytogenetics in Adult & Pediatric AML

**t(8;21)**
**t(15;17)**
**11q23**
**Inv (16)**
**-7 or del(7q)**
**-5 or del(5q)**

**AML1-ETO**
**PML-RARalpha,etc.**
**MLL fusions**
**CBFbetaMYH11**

_**Abnormality**_

_**Molecular  Lesion**_