1. Acute lymphoblastic leukemia in adults

2. ALL. Incidence

3. Genotype and survival in chilhood ALL

4. Heterogeneous disease Subtype-oriented therapy
Adult ALL
Heterogeneous disease
Risk-adapted therapy
Subtype-oriented therapy
Future

5. 1. Heterogeneous disease
Adult ALL
1. Heterogeneous disease

6. Immunologic Subtypes in ALL
and corresponding cytogenetic/molecular aberrations
Immunophenotype Freq.
T-lineage TdT+, cyCD3+, CD7+ 24%
Early CD2-, sCD3-, CD1a- 6%
Thymic sCD3±, CD1a+ 12%
Mature sCD3+, CD1a- 6%
B-lineage HLADR+,TdT+,CD19+ 76%
Pro CD10- 11%
Common CD10+ 49%
Pre CD10±, cyIgM+ 12%
Mature TdT±, CD10 ±, sIgM+ 4%
Cytogenetics Mol.genetics
t(10;14) HOX11-TCRa/d
t(11;14) LMO1/2-TCRa/d
t(1;14) TAL1-TCRa/d
p15,16 aberrations
t(4;11) ALL1(MLL)-AF4
t(9;22) BCR-ABL
t(9;22), t(1;19) BCR-ABL, E2A-PBX1
t(8;14) cMYC-IgH
Immunology / Cytogenetics: for ALL subclassification
Molecular genetics: for minimal residual disease

7. T-ALL. Adults GMALL PETHEMA Mature T : 0.29 (N= 35)
Thymic: 0.66 (N=100)
Early T: 0.28 (N= 36)
PETHEMA
Early T/Thymic
Mature T
B Xicoy et al , 2006
Courtesy of D Hoelzer

8. Various cytogenetic abnormalities occur in 60% to 70% of adults with acute lymphoblastic leukemia (ALL) (and in approximately 80% of children with ALL). 1
As noted on the previous slide, the Philadelphia chromosome is the most frequent cytogenetic abnormality. Other common defects include chromosome 9p21 abnormalities (resulting in deletion of genes encoding cyclin-dependent kinase inhibitors), chromosome 11q23 rearrangements (resulting in translocation of the mixed lineage leukemia gene to other chromosome loci), and chromosome 19p13 translocations (most commonly t(1;19)(q23;p13) resulting in generation of a transcriptional activator fusion protein). 1
1. Faderl S, Jeha S, Kantarjian HM. The biology and therapy of adult acute lymphoblastic leukemia. Cancer. 2003;98:

9. (MRC UKALLXII/ECOG 2993, n= 1522)
Genetics and prognosis in adult ALL.
(MRC UKALLXII/ECOG 2993, n= 1522)
Citogenetica
Genes
Tipo LAL
(%)
SLE (5 a)
SG (5 a)
t (9;22)
t (4;11)
Otras tras. 11q23
t (1;19)
t (12;21)
t (8;14)
Hiperploidia
Hipoploidia
t (10;14)
Complejo (5)
Normal
Del 9q
Otras alteracion.
BCR-ABL
MLL-AF4
MLL-?
PBX1-E2A
TEL-AML1
IgH/MYC --
TCR-HOX11
Precursor B
B y T
B madura Precursor B
Precursor T
B >T
B > T
B> T 19 7 2 3 10 4 5 25 9 13
16%
24%
29%
13%
50%
18%
34%
21%
43%
49%
38%
22%
33%
32%
53%
41%
28%
48%
58%
39%
Moorman, AV. et al. Blood 2007; 109:

10. 2. Risk-adapted therapy Chemotherapy Stem cell transplantation
Adult ALL
2. Risk-adapted therapy
Chemotherapy
Stem cell transplantation

11. Adult ALL. Risk stratification
Age (>30, >50 yr)
WBC count
>30x109/L (B-ALL)
>100x109/L (T-ALL)
Genetics
t(9;22) (BCR-ABL)
t(4;11) (MLL-AF4)
Slow response to therapy
Poor MRD clearance
Other
Pro-T, mature T, Pro-B?
Standard-risk (20%) (DFS>50%)
High-risk (35%) (DFS 30-40%)
Very-high-risk (40%) (DFS <20%)
Mature B-ALL Burkitt’s leukemia (5%) (DFS>50%)

12. Results of adult ALL trials: induction therapy
Study Year n Age Drugs CR rate
GMALL 02/ V,P,A,D,C, AC,M,MP 75%
FGTALL n.r. V,P,D/R,C, [AM,AC] 76%
MRC XA >15 V,P,A,D 82%
PETHEMA V,P,D,A,C 86%
CALGB V,P,D,A,C 85%
MDACC V,DX,A,D,C 91%
GMALL 05/ V,P,D,A,C,AC,MP 83%
Lombardia V,P,A,[C] 84%
Sweden V,BX, HDAC,C,D,AM 86%
GIMEMA V,P,A,D,C [HDAC,Mi] 82%
PETHEMA/ALL V,P,D,A,C 82%
MRC/ECOG <35 V,P,A,D,C,AC,MP 91%
OVERALL %

13. Overall Results of Adult ALL Trials. DFS
Group Year N Consolidation DFS
GMALL 02/ V,DX,AD,AC,C,TG,VM 39% (7y)
FGTALL AD,AC,A 32% (4y)
MRC XA [AC,VP,D,TG] 29% (5y)
PETHEMA HDM,V,D,P,A,C,VM,AC 41% (4y)
CALGB C,MP,AC,V,A,M,AD,DX,TG,P 40% (3y)
MRC/ECOG HDM,A [AC,VP,V,DX,D, C,TG] SCT
MDACC HDM,HDAC,C,P 38% (5y)
GMALL 05/ V,DX,AD,AC,C,TG,VM,AC,
HDM, A, C [HDAC,Mi]
Lombardia I,V,C,VM,HDAC,HDM,DX SCT 49% (3y)
Sweden AD,HDAC,V,BX,C,D,VP SCT 30% (5y)
GIMEMA V,HDM,HDAC,DX,VM 29% (9y)
PETHEMA V,Dx,AD, HDM, HDACSCT 34% (7y)
Overall %

14. History of Treatment in Acute Lymphoblastic Leukemia
Cure Rate
(%)
Subtype / MRD
Adjusted Tx 90
Chemotherapy ? 80
Single
Combined
High Dose
MTX 70
CNS
Prophylaxis 60
Stem Cell
Transplant
50% ? 50 40 30 20 10
1950
1960
1970
1980
1990
2000
D. Hoelzer, adapted

15. Allogeneic SCT. Adult ALL in CR1: comparative studies
Autor (yr) Result Comment
Sebban Absence of bennefit Comparative
(1994) Bennefit HR-ALL (DFS 39% vs 14%) Includes Ph(+) ALL
Uderzo Absence of bennefit Case-control
(1997) TRM  in alloSCT (39%)
Attal Benefit (DFS: 68% vs 18%) Comparative
(1995)  relapse in alloSCT (<20%)
Thomas Bennefit HR ALL (DFS: 45% vs 23%) Comparative
(2004)
Labar Absence of bennefit Comparative
Hunault Bennefit HR ALL (OS: 75% vs 39%) Comparative
(2004)  relapse in alloSCT (<20%)
Includes Ph(+) ALL
Ribera Absence of bennefit HR-ALL Comparative
(2005)
Rowe Absence of bennefit HR-ALL Comparative
(2006) Bennefit SR-ALL

16. Current status in therapy of adult ALL
Low probabilty of improvement
with conventional chemotherapy
Low probabilty of significant
improvement of results of allo SCT
Clínical and biological heterogeneity in ALL
Subtype-oriented therapy
New drugs/Clinical trials

17. ALL- Modifications in conventional drugs
Drug Effect
Liposomal vincristine Low neurotoxicity
PEG-Asparaginase Better tolerance
Liposomal antracyclins Low cardiotoxicity
Liposomal depot cytarabine Longer half-life in CSF
Low probability of improvement in the results

18. ALL- New drugs Activity Comments AcMo
Rituximab Anti-CD20 Mature B- ALL, Precursor B-ALL?
Epratuzumab Anti-CD22 B-lineage LAL
Alentuzumab Anti CD52 Precursor B and TALL. Clinical trials
Gemtuzumab Anti CD33 ALL CD33+
Antimetabolites
Clofarabine Nucleoside analog Approved (USA) childhood LAL in relapse
Nelarabine Inhibitor PNP Effective in T-ALL. EC
Forodesine Inhibitor PNP In evaluation in T and B-ALL
Trimetrexate Inhibitor DHF reductase
Aminopterin Antifolic
Tyrosin kinase inhibitors
Imatinib Inhibitor TK ABL Ph+ ALL
Nilotinib Inhibitor TK ABL Ph+ ALL relapsed/resistant
Dasatinib Inhibitor TK ABL and SRC Ph+ ALL relapsed/resistant
PKC412 and others Inhibe TK FLT3 MLL+ ALL
Gamma secretase inhibitors
MK NOTCH1 interference T-ALL
Otros
FT Inhibitors (tipifarnib),
Histone deacethylase inhibitors,
Proteasome inhibitors

19. Subtype-oriented therapy
Adolescents and young adults
Ph+ (BCR-ABL) ALL
Burkitt’s ALL
T-ALL

20. Conclusions
The response to therapy and prognosis is identical in young adults up to 30 yr. and adolescents with standard risk ALL, in spite of slightly poorer tolerability in young adults.
These results justify the age-unrestricted use of pediatric regimens to treat patients with standard-risk ALL.

21. Imatinib Nilotinib Dasatinib New TK inhibitors
Ph+/BCR-ABL ALL
Imatinib
Nilotinib
Dasatinib
New TK inhibitors

22. Mechanism of Action of STI571
Substrate
ADP
ATP P
activation of
signal pathways
BCR-ABL
Substrate
+ STI571
ATP
STI

23. Mature B-ALL (Burkitt’s)
Specific chemotherapy
Rituximab

24. Mature B-ALL. PETHEMA experience
Specific chemotherapy
Specific chemotherapy + Rituximab
N=31
N=59
A Oriol et al, 2002

25. T-cell acute lymphoblastic leukemia
Nelarabine
Forodesine
Alemtuzumab
NOTCH-1 secretase inhibitors
Imatinib

26. T-ALL. Nucleoside analogs
Fludarabine
Cytarabine
Nelarabine
Cladribine
Clofarabine
Cell death
DNA degradation
cell membrane
dGuo
inhibition of DNA synthesis/repair
NAs
NA-MP
NA-TP
DNA strand breaks
inhibition of ribonucleotide reductase
activation of poly (ADP-ribose)polymerase
NAD & ATP depletion
energy depletion
Programmed cell death
dCK
inhibition of ribonucleotide reductase
dNTP imbalance
dGuo
dGMP
dGTP
endonuclease activation
PNP
5-Nucleotidase
apoptosis
Forodesine

27. New drugs in T-ALL Drug Activity OR (CR+PR) Comment
Nelarabine Nucleoside analog % Neurotoxicity
Forodesine Nucleoside analog % Oral avialability
Good toxic profile
Clofarabine Nucleoside analog % Approved USA
(relapsed/refractory)
Alemtuzumab Anti-CD In clinical trials,
combined with CHT
MRK002 NOTCH-1 secretase Clinical trials
inhibitor
Imatinib Inhibitor TK ABL Clinical trials in NUP214-ABL1

28. Conclusions
Adult ALL curable en 40% cases with conventional therapy (CHT, SCT)
New era in ALL therapy
Improved knowledge of the biology of ALL
New drugs and combinations
Clinical trials

29. Therapy of adult ALL in 2000’s
Risk-adapted
Targeted therapy
New cytotoxic
drugs
Thyrosine
Kinase
inhibitors
MoAb
Other
Standard
High
Very-high

30. History of Treatment in Acute Lymphoblastic Leukemia
Cure Rate
(%)
Subtype / MRD
Adjusted Tx 90
>90%?
Chemotherapy 80
Single
Combined
High Dose
MTX 70
Targeted Tx
CNS
Prophylaxis 60
Stem Cell
Transplant
50%? 50 40 30 20 10
1950
1960
1970
1980
1990
2000

31. Philadelphia positive ALL

32. Genetická heterogenita a potenciál cielených liekov u ALL dospelých

33. Mutácie v BCR-ABL géne u Ph+ALL (GMALL - štúdia)
* 4 pacienti s kombinovanou mutáciou

34. Hughes a spol., ASH 2009

35. CNS prophylaxis in lymphoma and ALL Interim results of the GELTAMO trial

36. Who is at risk of CNS relapse?
Overall rate of CNS disease in lymphoma is ranging from 0% to 50%
Lymphoma subtype (aggressive)
Extranodal involvement
Advanced disease
Clinical risk factors (controversial)

37. Rationale for CNS prophylaxis
Lymphoblastic or Burkitt lymphoma
Prophylaxis accepted
Diffuse large B-cell lymphoma
Prophylaxis in high-risk patients
Mantle cell lymphoma
Prophylaxis controversial
Follicular lymphoma (low-grade)
Not recommended, unless transformation

38. Rationale for CNS prophylaxis
ALL, Lymphoblastic or Burkitt lymphoma
Prophylaxis accepted
Diffuse large B-cell lymphoma
Prophylaxis in high-risk patients
Mantle cell lymphoma
Prophylaxis controversial

39. Prophylaxis in DLBCL Site-specific risk (extranodal)
CNS relapse rate
Testicular
15%
Breast
19%
Paranasal sinuses
23%
(orbital 43%)
Epidural space
50% (?)
Intravascular (IVL)
23% - 63%

40. CNS prophylaxis in aggressive NHL
Overall incidence of CNS relapse
Risk Factor for
CNS Relapse, %
CNS Relapse
Relapse at extranodal sites
≤ 1 site
1.9
> 1 site
4.4
IPI score
Low to low-intermediate
1.7
High-intermediate to high
4.2 5
4.2 4
3.0 3
CNS Relapse (%)
2.2 2
1.4* 1
n = 225
n = 218
n = 223
n = 233
CHOP
MACOP-B
ProMACE
m-BACOD
No CNS Prophylaxis
CNS Prophylaxis
*P = .24 vs no CNS prophylaxis.
Berenstein et al. ASH 2007: Abstract 520

41. CNS prophylaxis in ALL and lymphoma
Key issues
Presence of “occult” CNS disease
Cytometry vs conventional techniques
Availability of active drugs for IT therapy
DepoCyte

42. Treatment of LM Efficacy of DepoCyte
28 patients
with LM
DepoCyte® injection 50 mg n = 14
Free cytarabine injection 50 mg
n = 14
Induction
Consolidation
Maintenance R
Randomization E
Evaluation 1 4 7 
Months
   
q 2 weeks
q 4 weeks
2x a week
weekly
Glantz et al. J Clin Oncol 1999;17:3110–6

43. IT dexamethasone for prevention of chemical arachnoiditis

44. Summary CNS prophylaxis
Identification of risk patients for CNS involvement is critical
Prognosis of CNS disease is dismal, regardless treatment (median OS < 6 months)
Therapeutic options for CNS disease are scarce
DepoCyte has better PK and at least as effective than cytarabine for treatment of LM1
Potential of DepoCyte for CNS prophylaxis in high-risk DLBCL is under investigation2
1 Glantz et al. J Clin Oncol 1999;17:3110–6
2 Canales et al. submitted to EHA 2008

45. * Assessed by multiparametric flow cytometry in bone marrow samples
Induction
Standard cytologic
response d14
Slow cytologic
response d14
Standard
induction
Intensified
induction CR
Consolidation
B1+B2+B3
MRD<0.05%*
MRD>0.05%*
B1+B2+B3 +
Maintenance
Allogeneic SCT
(sibling, MUD, UCB)
* Assessed by multiparametric flow cytometry in bone marrow samples 45

46. Prognostic factors  coeff. OR (95%CI) p Death in induction
Slow cytologic response d (1.962; ) CR
Advanced age
Slow cytologic response d (0.040; 0.295) <0.001
Death in consolidation
None OS
Slow clearance MRD* >0.1%/>0.05% (2.152; ) <0.001
Remaining (0.926; 4.587)
DFS
Advanced age
EFS
Advanced age
Slow clearance MRD* >0.1%/>0.05% ( )
Remaining ( )
* Baseline category: MRD in induction/consolidation. <0.1%/<0.05%

47. Conclusions
In adults with high-risk Ph-negative ALL with early cytologic response after induction and adequate clearance of MRD (<0.05%) at the end of consolidation the results of therapy without allogeneic SCT are promising.
In adults with high-risk Ph-negative ALL the pattern of clearance of MRD has independent prognostic value, in addition to advanced age.

48. ‘Pediatric type’ vs ‘Adult type’
Can adult ALL can be cured without an SCT?

49. ‘Pediatric type’ vs ‘Adult type’
Can adult ALL can be cured without an SCT?
YES
The “best” chemotherapy.
Induction
Consolidation
Maintenance
Dose intense
Prolonged

50. ‘Pediatric type’ vs ‘Adult type’
Can adult ALL can be cured without an SCT?
YES NO
The “best” chemotherapy.
Induction
Consolidation
Maintenance
Dose intense
Prolonged
Chemotherapy to attain CR
Do not interfere with SCT in CR1
Gentler and shorter consolidations

51. Ph+ ALL < 55 yr. ALL Ph-08 Current assistential protocol
Pre-phase
Ph+ ALL
Induction (I-600)
Consolidation-1
Donor
No donor/No allo SCT feasible
Allo SCT
Auto-SCT
MRD-
MRD+
Imatinib+MP+MTX
(up to 2-yr)
Follow-up
Imatinib*
*Except T315I mutation