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Acute lymphoblastic Acute lymphoblastic leukemia in adultsleukemia in adults
ALL. Incidence
Genotype and survival in chilhood ALL
Adult ALLAdult ALL
Heterogeneous diseaseRisk-adapted therapy
Subtype-oriented therapyFuture
Adult ALLAdult ALL
1. Heterogeneous disease
Immunologic Subtypes in ALLImmunologic Subtypes in ALLand corresponding cytogenetic/molecular aberrationsand corresponding cytogenetic/molecular aberrations
ImmunophenotypeImmunophenotype Freq.Freq.
T-lineageT-lineage TdT+, cyCD3+, CD7+TdT+, cyCD3+, CD7+ 24%24%
Early Early CD2-CD2-, sCD3-, CD1a-, sCD3-, CD1a- 6% 6% ThymicThymic sCD3±, sCD3±, CD1a+CD1a+ 12%12%
MatureMature sCD3+,sCD3+, CD1a- CD1a- 6% 6%
B-lineageB-lineage HLADR+,TdT+,CD19+HLADR+,TdT+,CD19+ 76%76%
Pro Pro CD10-CD10- 11%11%
CommonCommon CD10+CD10+ 49%49%
Pre Pre CD10CD10±, ±, cyIgM+cyIgM+ 12%12%
MatureMature TdT±, CD10 ±, TdT±, CD10 ±, sIgM+sIgM+ 4% 4%
CytogeneticsCytogenetics Mol.geneticsMol.genetics
t(10;14)t(10;14) HOX11-TCRHOX11-TCR//t(11;14)t(11;14) LMO1/2-TCRLMO1/2-TCR//t(1;14)t(1;14) TAL1-TCRTAL1-TCR//p15,16 aberrationsp15,16 aberrations
t(4;11)t(4;11) ALL1(MLL)-AF4ALL1(MLL)-AF4
t(9;22)t(9;22) BCR-ABLBCR-ABL
t(9;22), t(1;19)t(9;22), t(1;19) BCR-ABL, E2A-PBX1BCR-ABL, E2A-PBX1
t(8;14)t(8;14) cMYC-IgHcMYC-IgH
Immunology / Cytogenetics:Immunology / Cytogenetics: for ALL subclassificationfor ALL subclassificationMolecular genetics:Molecular genetics: for minimal residual diseasefor minimal residual disease
T-ALL. AdultsT-ALL. Adults
PETHEMAPETHEMA GMALLGMALL
Mature T : 0.29 (N= 35)
Thymic: 0.66 (N=100)
Early T: 0.28 (N= 36) Early T/ThymicEarly T/Thymic
Mature T Mature T
B Xicoy et al , 2006 Courtesy of D Hoelzer
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 (9;22)
t (4;11)t (4;11)Otras tras. 11q23 t (1;19)t (12;21)
t (8;14)t (8;14)Hiperploidia
HipoploidiaHipoploidiat (10;14)
Complejo Complejo ((5)5)NormalDel 9qOtras alteracion.
BCR-ABLMLL-AF4MLL-?
PBX1-E2ATEL-AML1IgH/MYC
----
TCR-HOX11
--------
Precursor B
Precursor B
B y TPrecursor
BPrecursor
BB madura Precursor
BPrecursor
BPrecursor
T B >TB > TB> TB >T
1972302
10425
259
13
16%16%
24%24%29%29%
--
13%13%50%
18%18%34%
21%21%43%49%38%
22%22%
24%24%33%32%
--
13%13%53%
22%22%41%
28%28%48%58%39%Moorman, AV. et al. Blood 2007; 109:3189-97
Adult ALLAdult ALL
2. Risk-adapted therapyChemotherapy
Stem cell transplantation
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%)
Results of adult ALL trials: induction therapyResults of adult ALL trials: induction therapy
StudyStudy YearYear n Age n Age Drugs CR rateDrugs CR rate
GMALL 02/84GMALL 02/84 1993 1993 562 562 2828 V,P,A,D,C, AC,M,MP V,P,A,D,C, AC,M,MP 75%75%FGTALLFGTALL 1993 1993 572 572 n.r.n.r. V,P,D/R,C, [AM,AC] V,P,D/R,C, [AM,AC] 76%76%MRC XAMRC XA 1997 1997 618 618 >15>15 V,P,A,DV,P,A,D 82%82%PETHEMAPETHEMA 1998 1998 108 108 2020 V,P,D,A,CV,P,D,A,C 86%86%CALGBCALGB 1998 1998 198 198 3535 V,P,D,A,CV,P,D,A,C 85%85%MDACCMDACC 2000 2000 204 204 3939 V,DX,A,D,CV,DX,A,D,C 91%91%GMALL 05/93GMALL 05/93 2001 2001 11631163 3535 V,P,D,A,C,AC,MPV,P,D,A,C,AC,MP 83%83%LombardiaLombardia 2001 2001 121 121 3535 V,P,A,[C]V,P,A,[C] 84%84%SwedenSweden 2002 2002 153 153 4242 V,BX, HDAC,C,D,AM V,BX, HDAC,C,D,AM 86%86%GIMEMAGIMEMA 2002 2002 794 794 2828 V,P,A,D,C [HDAC,Mi]V,P,A,D,C [HDAC,Mi] 82%82%PETHEMA/ALL-93PETHEMA/ALL-93 2005 2005 222 222 2727 V,P,D,A,CV,P,D,A,C 82%82%MRC/ECOGMRC/ECOG 2005 2005 15211521 <35<35 V,P,A,D,C,AC,MPV,P,A,D,C,AC,MP 91%91%
OVERALLOVERALL 62366236 84%84%
Overall Results of Adult ALL Trials. DFSOverall Results of Adult ALL Trials. DFS
GroupGroup YearYear N N ConsolidationConsolidation DFSDFS
GMALL 02/84GMALL 02/84 19931993 562 562 V,DX,AD,AC,C,TG,VMV,DX,AD,AC,C,TG,VM 39% (7y)39% (7y)FGTALLFGTALL 19931993 572 572 AD,AC,AAD,AC,A 32% (4y)32% (4y)MRC XAMRC XA 19971997 618 618 [AC,VP,D,TG][AC,VP,D,TG] 29% (5y)29% (5y)PETHEMAPETHEMA19981998 108 108 HDMHDM,V,D,P,A,C,VM,AC,V,D,P,A,C,VM,AC 41% (4y)41% (4y)CALGBCALGB 19981998 198 198 C,MP,AC,V,A,M,AD,DX,TG,PC,MP,AC,V,A,M,AD,DX,TG,P 40% (3y)40% (3y)MRC/ECOGMRC/ECOG 19991999 920 920 HHDMDM,A [AC,VP,V,DX,D, C,TG],A [AC,VP,V,DX,D, C,TG] SCTSCTMDACCMDACC 20002000 204 204 HDMHDM,,HDACHDAC,C,P,C,P 38% (5y)38% (5y)GMALL 05/93GMALL 05/93 20012001 11631163 V,DX,AD,AC,C,TG,VM,AC,V,DX,AD,AC,C,TG,VM,AC,
HDMHDM, A, C [, A, C [HDACHDAC,Mi],Mi] LombardiaLombardia 20012001 121 121 I,V,C,VM,I,V,C,VM,HDACHDAC,,HDMHDM,DX,DX SCTSCT 49% (3y)49% (3y)SwedenSweden 20022002 153 153 AD,AD,HDACHDAC,V,BX,C,D,VP,V,BX,C,D,VP SCTSCT 30% (5y)30% (5y)GIMEMAGIMEMA 20022002 794 794 V,V,HDMHDM,,HDACHDAC,DX,VM,DX,VM 29% (9y)29% (9y)PETHEMAPETHEMA20052005 222 222 V,Dx,AD, V,Dx,AD, HDM, HDACHDM, HDACSCTSCT 34% (7y)34% (7y)OverallOverall 56355635 34%34%
History of Treatment in Acute Lymphoblastic Leukemia
Subtype / MRDAdjusted Tx
Cure Rate (%)
ChemotherapyCombinedSingle
CNSProphylaxis
70
60
50
40
30
20
10
1950 1960 1970 1980 1990 2000
80
90
Stem CellTransplant
High DoseMTX
?
50% ?
D. Hoelzer, adapted
Allogeneic SCT. Adult ALL in CR1: comparative Allogeneic SCT. Adult ALL in CR1: comparative studiesstudiesAutor (yr) Autor (yr) Result Result CommentComment
Sebban Sebban Absence of bennefitAbsence of bennefit Comparative Comparative (1994) (1994) Bennefit HR-ALL (DFS 39% vs 14%)Bennefit HR-ALL (DFS 39% vs 14%) Includes Ph(+) ALL
Uderzo Uderzo Absence of bennefitAbsence of bennefit Case-control(1997) TRM TRM in alloSCT (39%) in alloSCT (39%)
Attal Attal BenefitBenefit (DFS: 68% vs 18%)(DFS: 68% vs 18%) ComparativeComparative(1995) (1995) relapse in alloSCT (<20%) relapse in alloSCT (<20%) Thomas Thomas Bennefit HR ALL (DFS: 45% vs 23%)Bennefit HR ALL (DFS: 45% vs 23%) ComparativeComparative(2004)(2004)
Labar Labar Absence of bennefitAbsence of bennefit ComparativeComparative(2004)(2004)
Hunault Hunault Bennefit HR ALL (OS: 75% vs 39%)Bennefit HR ALL (OS: 75% vs 39%) ComparativeComparative(2004) (2004) relapse in alloSCT (<20%) relapse in alloSCT (<20%)
Includes Ph(+) ALL
Ribera Ribera Absence of bennefit HR-ALLAbsence of bennefit HR-ALL ComparativeComparative(2005)(2005)
RoweRowe Absence of bennefit HR-ALLAbsence of bennefit HR-ALL ComparativeComparative(2006)(2006) Bennefit SR-ALLBennefit SR-ALL
Current status in therapy of adult ALLCurrent status in therapy of adult ALL
Low probabilty of improvementLow probabilty of improvement with conventional chemotherapywith conventional chemotherapy
Low probabilty of significant Low probabilty of significant
improvement of results of allo SCTimprovement of results of allo SCT
Clínical and biological heterogeneity in ALLClínical and biological heterogeneity in ALL
Subtype-oriented therapySubtype-oriented therapy
New drugs/Clinical trialsNew drugs/Clinical trials
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 resultsLow probability of improvement in the results
ALL- New drugs
Activity CommentsAcMo
Rituximab Anti-CD20 Mature B- ALL, Precursor B-ALL?Epratuzumab Anti-CD22 B-lineage LAL Alentuzumab Anti CD52 Precursor B and TALL. Clinical trialsGemtuzumab Anti CD33 ALL CD33+
AntimetabolitesClofarabine Nucleoside analog Approved (USA) childhood LAL in relapseNelarabine Inhibitor PNP Effective in T-ALL. ECForodesine Inhibitor PNP In evaluation in T and B-ALLTrimetrexate Inhibitor DHF reductaseAminopterin Antifolic
Tyrosin kinase inhibitorsImatinib Inhibitor TK ABL Ph+ ALLNilotinib Inhibitor TK ABL Ph+ ALL relapsed/resistantDasatinib Inhibitor TK ABL and SRC Ph+ ALL relapsed/resistantPKC412 and others Inhibe TK FLT3 MLL+ ALL
Gamma secretase inhibitorsMK0752 NOTCH1 interference T-ALL
OtrosFT Inhibitors (tipifarnib), Histone deacethylase inhibitors,
Proteasome inhibitors
Subtype-oriented therapySubtype-oriented therapy
Adolescents and young adults
Ph+ (BCR-ABL) ALL
Burkitt’s ALL
T-ALL
ConclusionsConclusions
• 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.
Ph+/BCR-ABL ALL
ImatinibImatinib
NilotinibNilotinib
DasatinibDasatinib
New TK inhibitorsNew TK inhibitors
Mechanism of Action of STI571Mechanism of Action of STI571
SubstrateSubstrate
SubstrateSubstrateADPADP
ATPATP
ATPATP
PP
activation of activation of signal pathwayssignal pathways
PP PP
BCR-ABLBCR-ABLSubstrateSubstrate
SubstrateSubstrate
+ STI571+ STI571
ATPATP
STISTI
Mature B-ALL (Burkitt’s)Mature B-ALL (Burkitt’s)
Specific chemotherapy
Rituximab
Mature B-ALL. PETHEMA experienceMature B-ALL. PETHEMA experience
Specific chemotherapy Specific chemotherapy + Rituximab
N=59
N=31
A Oriol et al, 2002
T-cell acute lymphoblastic T-cell acute lymphoblastic leukemialeukemia
Nelarabine
Forodesine
Alemtuzumab
NOTCH-1 secretase inhibitors
Imatinib
T-ALL. Nucleoside analogsFludarabine Fludarabine CytarabineCytarabine NelarabineNelarabineCladribineCladribineClofarabineClofarabine
PNP
dNTP imbalance
NA-MP NA-TP
dGuodGuo dGMPdGMP dGTPdGTP
5-Nucleotidase
cell membrane
NAs
dCKdCK
ForodesineForodesine
inhibition of DNAsynthesis/repair
DNA strand breaks
apoptosis
endonuclease activation
dGuo dGuo
inhibition of ribonucleotide reductase
Cell death Cell death
DNA degradationDNA degradation
New drugs in T-ALL
Drug Activity OR (CR+PR) 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 trialsinhibitor
Imatinib Inhibitor TK ABL Clinical trials in NUP214-ABL1
ConclusionsConclusions
• 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
Therapy of adult ALL in 2000’sTherapy of adult ALL in 2000’s
Risk-adaptedRisk-adapted TTargeted therapyargeted therapy
Standard High Very-highMoAb New cytotoxic
drugsThyrosine
Kinaseinhibitors
Other
History of Treatment in Acute Lymphoblastic Leukemia
Subtype / MRDAdjusted Tx
Cure Rate (%)
ChemotherapyCombinedSingle
CNSProphylaxis
70
60
50
40
30
20
10
1950 1960 1970 1980 1990 2000
80
90
Stem CellTransplant
High DoseMTX
>90%?
50%?
Targeted Tx
Philadelphia positive ALL
Genetická heterogenita a potenciál cielených liekov u ALL dospelých
Mutácie v BCR-ABL géne u Ph+ALL (GMALL - štúdia)
* 4 pacienti s kombinovanou mutáciou
Hughes a spol., ASH 2009
CNS prophylaxis in lymphoma and ALL
Interim results of the GELTAMO trial
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)
Rationale for CNS prophylaxis
1. Lymphoblastic or Burkitt lymphoma Prophylaxis accepted
2. Diffuse large B-cell lymphoma Prophylaxis in high-risk patients
3. Mantle cell lymphoma Prophylaxis controversial
4. Follicular lymphoma (low-grade) Not recommended, unless transformation
Rationale for CNS prophylaxis
1. ALL, Lymphoblastic or Burkitt lymphoma Prophylaxis accepted
2. Diffuse large B-cell lymphoma Prophylaxis in high-risk patients
3. Mantle cell lymphoma Prophylaxis controversial
Prophylaxis in DLBCLSite-specific risk (extranodal)
CNS relapse rate
1. Testicular 15%
2. Breast 19%
3. Paranasal sinuses 23%
(orbital 43%)
4. Epidural space 50% (?)
5. Intravascular (IVL) 23% - 63%
CNS prophylaxis in aggressive NHL
CHOP MACOP-B ProMACE m-BACOD
No CNS Prophylaxis CNS Prophylaxis
CN
S R
elap
se (
%)
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
0
1
2
3
4
5 4.2
n = 225 n = 218 n = 223 n = 233
2.2
3.0
1.4*
*P = .24 vs no CNS prophylaxis.
Berenstein et al. ASH 2007: Abstract 520
Overall incidence of CNS relapse
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
Treatment of LMEfficacy of DepoCyte
Glantz et al. J Clin Oncol 1999;17:3110–6
28 patientswith LM
DepoCyte®
injection 50 mgn = 14
Free cytarabineinjection 50 mg
n = 14
Induction Consolidation Maintenance
Induction Consolidation Maintenance
R Randomization E Evaluation
0 1 4 7
Months
q 2 weeks q 4 weeks
2x a week weekly q 4 weeksq 2 weeks
IT dexamethasone for prevention of chemical arachnoiditis
1 Glantz et al. J Clin Oncol 1999;17:3110–62 Canales et al. submitted to EHA 2008
SummaryCNS 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
Induction
Slow cytologicresponse d14
Standard cytologic response d14
Intensified induction
Standardinduction
CR
ConsolidationB1+B2+B3
MRD>0.05%* MRD<0.05%*
Allogeneic SCT(sibling, MUD, UCB)
B1+B2+B3+
Maintenance
* Assessed by multiparametric flow cytometry in bone marrow samples
Prognostic factors coeff. OR (95%CI) p
Death in inductionSlow cytologic response d14 1.776 5.907 (1.962; 17.788) 0.002CR Advanced age -0.045 0.01 Slow cytologic response d 14 -2.220 0.109 (0.040; 0.295) <0.001Death in consolidation None - - - OS Slow clearance MRD* >0.1%/>0.05% 1.633 5.118 (2.152; 12.174) <0.001 Remaining 0.723 2.061 (0.926; 4.587) 0.076 DFS Advanced age 0.044 0.010EFS Advanced age 0.037 0.016 Slow clearance MRD* 0.019
>0.1%/>0.05% 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. <0.1%/<0.05%
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.
‘Pediatric type’ vs ‘Adult type’
Can adult ALL can be cured without an SCT?
‘Pediatric type’ vs ‘Adult type’
Can adult ALL can be cured without an SCT?
YESThe “best” chemotherapy.
InductionConsolidationMaintenance
Dose intenseProlonged
‘Pediatric type’ vs ‘Adult type’
Can adult ALL can be cured without an SCT?
YESThe “best” chemotherapy.
InductionConsolidationMaintenance
Dose intenseProlonged
NOChemotherapy to attain CR
Do not interfere with SCT in CR1
Gentler and shorter consolidations
Ph+ ALL < 55 yr. ALL Ph-08Current assistential protocol
ALL, < 55yr
Pre-phase
Ph+ ALL
Induction (I-600)
Consolidation-1
Donor
Allo SCT
MRD- MRD+
Imatinib*Follow-up
No donor/No allo SCT feasible
Auto-SCT
Imatinib+MP+MTX(up to 2-yr)
*Except T315I mutation