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