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Acute lymphoblastic leukemia in adults

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Title: Acute lymphoblastic leukemia in adults


1
Acute lymphoblastic leukemia in adults
2
ALL. Incidence
3
Genotype and survival in chilhood ALL
4
Adult ALL
  • Heterogeneous disease
  • Risk-adapted therapy
  • Subtype-oriented therapy
  • Future

5
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
Immunology / Cytogenetics for ALL
subclassification Molecular genetics for
minimal residual disease
7
T-ALL. Adults
PETHEMA
Early T/Thymic
Mature T
B Xicoy et al , 2006
Courtesy of D Hoelzer
8
(No Transcript)
9
Genetics and prognosis in adult ALL. (MRC
UKALLXII/ECOG 2993, n 1522)
Citogenetica Genes Tipo LAL () SLE (5 a) SG (5 a)
t (922) t (411) Otras tras. 11q23 t (119) t (1221) t (814) Hiperploidia Hipoploidia t (1014) Complejo (?5) Normal Del 9q Otras alteracion. BCR-ABL MLL-AF4 MLL-? PBX1-E2A TEL-AML1 IgH/MYC -- -- TCR-HOX11 -- -- -- -- Precursor B Precursor B B y T Precursor B Precursor B B madura Precursor B Precursor B Precursor T B gtT B gt T Bgt T B gtT 19 7 2 3 0 2 10 4 2 5 25 9 13 16 24 29 29 -- 13 50 18 34 21 43 49 38 22 24 33 32 -- 13 53 22 41 28 48 58 39
Moorman, AV. et al. Blood 2007 1093189-97
10
Adult ALL
  • 2. Risk-adapted therapy
  • Chemotherapy
  • Stem cell transplantation

11
Adult ALL. Risk stratification
  • Age (gt30, gt50 yr)
  • WBC count
  • gt30x109/L (B-ALL)
  • gt100x109/L (T-ALL)
  • Genetics
  • t(922) (BCR-ABL)
  • t(411) (MLL-AF4)
  • Slow response to therapy
  • Poor MRD clearance
  • Other
  • Pro-T, mature T, Pro-B?
  • Standard-risk (20) (DFSgt50)
  • High-risk (35) (DFS 30-40)
  • Very-high-risk (40) (DFS lt20)
  • Mature B-ALL Burkitts leukemia (5) (DFSgt50)

12
Results of adult ALL trials induction therapy
Study Year n Age Drugs
CR rate GMALL 02/84 1993
562 28 V,P,A,D,C, AC,M,MP 75 FGTALL 1993
572 n.r. V,P,D/R,C, AM,AC 76 MRC XA 1997
618 gt15 V,P,A,D 82 PETHEMA 1998
108 20 V,P,D,A,C 86 CALGB 1998
198 35 V,P,D,A,C 85 MDACC 2000
204 39 V,DX,A,D,C 91 GMALL 05/93
2001 1163 35 V,P,D,A,C,AC,MP 83 Lombardia
2001 121 35 V,P,A,C 84 Sweden 2002
153 42 V,BX, HDAC,C,D,AM 86 GIMEMA 2002
794 28 V,P,A,D,C HDAC,Mi 82 PETHEMA/ALL-93
2005 222 27 V,P,D,A,C 82 MRC/ECOG
2005 1521 lt35 V,P,A,D,C,AC,MP 91 OVERALL 623
6 84
13
Overall Results of Adult ALL Trials. DFS
  • Group Year N Consolidation DFS
  • GMALL 02/84 1993 562 V,DX,AD,AC,C,TG,VM 39
    (7y)
  • FGTALL 1993 572 AD,AC,A 32 (4y)
  • MRC XA 1997 618 AC,VP,D,TG 29 (5y)
  • PETHEMA 1998 108 HDM,V,D,P,A,C,VM,AC 41 (4y)
  • CALGB 1998 198 C,MP,AC,V,A,M,AD,DX,TG,P 40
    (3y)
  • MRC/ECOG 1999 920 HDM,A AC,VP,V,DX,D, C,TG?
    SCT
  • MDACC 2000 204 HDM,HDAC,C,P 38 (5y)
  • GMALL 05/93 2001 1163 V,DX,AD,AC,C,TG,VM,AC,
  • HDM, A, C HDAC,Mi
  • Lombardia 2001 121 I,V,C,VM,HDAC,HDM,DX?
    SCT 49 (3y)
  • Sweden 2002 153 AD,HDAC,V,BX,C,D,VP? SCT 30
    (5y)
  • GIMEMA 2002 794 V,HDM,HDAC,DX,VM 29 (9y)
  • PETHEMA 2005 222 V,Dx,AD, HDM, HDAC?SCT 34
    (7y)
  • Overall 5635 34

14
History of Treatment in Acute Lymphoblastic
Leukemia
Cure Rate ()
Subtype / MRD Adjusted Tx
90
Chemotherapy
?
80
Combined
Single
High Dose MTX
70
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 (19
97) TRM ? in alloSCT (39) Attal
Benefit (DFS 68 vs 18)
Comparative (1995) ?
relapse in alloSCT (lt20) Thomas
Bennefit HR ALL (DFS 45 vs 23)
Comparative (2004) Labar Absence of
bennefit Comparative (2004) Hunault
Bennefit HR ALL (OS 75 vs 39)
Comparative (2004) ? relapse in alloSCT
(lt20) Includes Ph() ALL Ribera
Absence of bennefit HR-ALL Comparative (200
5) 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
  • MK0752 NOTCH1 interference T-ALL

19
Subtype-oriented therapy
  • Adolescents and young adults
  • Ph (BCR-ABL) ALL
  • Burkitts 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
Ph/BCR-ABL ALL
  • Imatinib
  • Nilotinib
  • Dasatinib
  • New TK inhibitors

22
Mechanism of Action of STI571
23
Mature B-ALL (Burkitts)
  • Specific chemotherapy
  • Rituximab

24
Mature B-ALL. PETHEMA experience
Specific chemotherapy
Specific chemotherapy Rituximab
N31
N59
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
NA-TP
NA-MP
NAs
DNA strand breaks
dCK
inhibition of ribonucleotide reductase
dNTP imbalance
dGuo
dGTP
dGMP
endonuclease activation
PNP
5-Nucleotidase
apoptosis
Forodesine
27
New drugs in T-ALL
Drug Activity OR (CRPR)
Comment Nelarabine Nucleoside analog 25-50
Neurotoxicity Forodesine Nucleoside analog
25-35 Oral avialability Good
toxic profile Clofarabine Nucleoside analog
25-40 Approved USA
(relapsed/refractory) Alemtuzumab Anti-CD52
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 2000s
Risk-adapted
Targeted therapy
New cytotoxic drugs
Thyrosine Kinase inhibitors
MoAb
Other
High
Very-high
Standard
30
History of Treatment in Acute Lymphoblastic
Leukemia
Cure Rate ()
Subtype / MRD Adjusted Tx
90
gt90?
Chemotherapy
80
Combined
Single
High Dose MTX
70
Targeted Tx
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 PhALL (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
Risk Factor for CNS Relapse, CNS Relapse
Relapse at extranodal sites
1 site 1.9
gt 1 site 4.4
IPI score
Low to low-intermediate 1.7
High-intermediate to high 4.2
Overall incidence of CNS relapse
5
4.2
4
3.0
3
2.2
CNS Relapse ()
2
1.4
1
n 218
n 223
n 233
n 225
0
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
Glantz et al. J Clin Oncol 19991731106
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 lt 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 19991731106 2
Canales et al. submitted to EHA 2008
45
Induction
Standard cytologic response d14
Slow cytologic response d14
Standard induction
Intensified induction
CR
Consolidation B1B2B3
MRDlt0.05
MRDgt0.05
B1B2B3 Maintenance
Allogeneic SCT (sibling, MUD, UCB)
Assessed by multiparametric flow cytometry in
bone marrow samples
46
Prognostic factors
? coeff. OR (95CI)
p Death in induction Slow
cytologic response d14 1.776
5.907 (1.962 17.788) 0.002 CR
Advanced age -0.045 0.01
Slow cytologic response d 14 -2.220
0.109 (0.040 0.295) lt0.001 Death in
consolidation None -
- -
OS Slow clearance MRD
gt0.1/gt0.05
1.633 5.118 (2.152 12.174)
lt0.001 Remaining
0.723 2.061 (0.926 4.587)
0.076 DFS Advanced age
0.044
0.010 EFS Advanced age
0.037 0.016 Slow
clearance MRD
0.019 gt0.1/gt0.05
1.173 3.230 (1.414 -7.378)
0.015 Remaining
0.113 1.120 (0.523-2.399)
0.771 Baseline category MRD in
induction/consolidation. lt0.1/lt0.05
47
Conclusions
  • In adults with high-risk Ph-negative ALL with
    early cytologic response after induction and
    adequate clearance of MRD (lt0.05) 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 lt 55 yr. ALL Ph-08 Current assistential
protocol
ALL, lt 55yr
Pre-phase
Ph ALL
Induction (I-600)
Consolidation-1
Donor
No donor/No allo SCT feasible
Allo SCT
Auto-SCT
MRD
MRD-
ImatinibMPMTX (up to 2-yr)
Follow-up
Imatinib
Except T315I mutation
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