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Acute lymphoblastic leukemia in adults. ALL. Incidence.

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Presentation on theme: "Acute lymphoblastic leukemia in adults. ALL. Incidence."— Presentation transcript:

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 ImmunophenotypeFreq. T-lineageTdT+, cyCD3+, CD7+24% Early CD2-, sCD3-, CD1a- 6% Early CD2-, sCD3-, CD1a- 6% ThymicsCD3±, CD1a+12% ThymicsCD3±, CD1a+12% MaturesCD3+, CD1a- 6% MaturesCD3+, CD1a- 6% B-lineageHLADR+,TdT+,CD19+76% Pro CD10-11% Pro CD10-11% CommonCD10+49% CommonCD10+49% Pre CD10±, cyIgM+12% Pre CD10±, cyIgM+12% MatureTdT±, CD10 ±, sIgM+ 4% MatureTdT±, CD10 ±, sIgM+ 4% CytogeneticsMol.genetics t(10;14)HOX11-TCR / t(10;14)HOX11-TCR / t(11;14)LMO1/2-TCR / t(11;14)LMO1/2-TCR / t(1;14)TAL1-TCR / t(1;14)TAL1-TCR / 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 PETHEMAGMALL Mature T : 0.29 (N= 35) Thymic: 0.66 (N=100) Early T: 0.28 (N= 36) Early T/Thymic Mature T B Xicoy et al, 2006Courtesy of D Hoelzer

8

9 Genetics and prognosis in adult ALL. (MRC UKALLXII/ECOG 2993, n= 1522) CitogeneticaGenesTipo 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) HiperploidiaHipoploidia 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 Precursor B B madura Precursor B Precursor B Precursor T B >T 19 7 2 3 0 2 10 4 2 5 25 9 1316%24% 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; 109:3189-97

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

11 Adult ALL. Risk stratification Age (>30, >50 yr) WBC count –>30x10 9 /L (B-ALL) –>100x10 9 /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 Burkitts leukemia (5%) (DFS>50%)

12 Results of adult ALL trials: induction therapy Study Year n AgeDrugs CR rate GMALL 02/84 1993 56228V,P,A,D,C, AC,M,MP 75% FGTALL 1993 572n.r.V,P,D/R,C, [AM,AC] 76% MRC XA 1997 618>15V,P,A,D82% PETHEMA 1998 10820V,P,D,A,C86% CALGB 1998 19835V,P,D,A,C85% MDACC 2000 20439V,DX,A,D,C91% GMALL 05/93 2001116335V,P,D,A,C,AC,MP83% Lombardia 2001 12135V,P,A,[C]84% Sweden 2002 15342V,BX, HDAC,C,D,AM 86% GIMEMA 2002 79428V,P,A,D,C [HDAC,Mi]82% PETHEMA/ALL-93 2005 22227V,P,D,A,C82% MRC/ECOG 20051521<35V,P,A,D,C,AC,MP91% OVERALL623684%

13 Overall Results of Adult ALL Trials. DFS GroupYear NConsolidationDFS GMALL 02/841993 562V,DX,AD,AC,C,TG,VM 39% (7y) FGTALL1993 572AD,AC,A 32% (4y) MRC XA1997 618[AC,VP,D,TG] 29% (5y) PETHEMA1998 108HDM,V,D,P,A,C,VM,AC 41% (4y) CALGB1998 198C,MP,AC,V,A,M,AD,DX,TG,P40% (3y) MRC/ECOG1999 920HDM,A [AC,VP,V,DX,D, C,TG] SCT MDACC2000 204HDM,HDAC,C,P 38% (5y) GMALL 05/9320011163V,DX,AD,AC,C,TG,VM,AC, HDM, A, C [HDAC,Mi] Lombardia2001 121I,V,C,VM,HDAC,HDM,DX SCT49% (3y) Sweden2002 153AD,HDAC,V,BX,C,D,VP SCT 30% (5y) GIMEMA2002 794V,HDM,HDAC,DX,VM29% (9y) PETHEMA2005 222V,Dx,AD, HDM, HDAC SCT34% (7y) Overall 563534%

14 History of Treatment in Acute Lymphoblastic Leukemia Subtype / MRD Adjusted Tx Cure Rate (%) Chemotherapy CombinedSingle CNS Prophylaxis 70 60 50 40 30 20 10 195019601970198019902000 80 90 Stem Cell Transplant High Dose MTX ? 50% ? 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%) (1994) Bennefit HR-ALL (DFS 39% vs 14%) Includes Ph(+) ALL Uderzo Absence of bennefit Uderzo Absence of bennefit Case-control TRM in alloSCT (39%) (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 (2004) 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 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 DrugEffect Liposomal vincristineLow neurotoxicity PEG-AsparaginaseBetter tolerance Liposomal antracyclins Low cardiotoxicity Liposomal depot cytarabineLonger half-life in CSF Low probability of improvement in the results

18 ALL- New drugs ActivityComments AcMo Rituximab Anti-CD20Mature B- ALL, Precursor B-ALL? Epratuzumab Anti-CD22B-lineage LAL Alentuzumab Anti CD52Precursor B and TALL. Clinical trials Gemtuzumab Anti CD33ALL CD33+ Antimetabolites Clofarabine Nucleoside analogApproved (USA) childhood LAL in relapse Nelarabine Inhibitor PNP Effective in T-ALL. EC Forodesine Inhibitor PNPIn evaluation in T and B-ALL Trimetrexate Inhibitor DHF reductase Aminopterin Antifolic Tyrosin kinase inhibitors Imatinib Inhibitor TK ABLPh+ ALL Nilotinib Inhibitor TK ABLPh+ ALL relapsed/resistant Dasatinib Inhibitor TK ABL and SRCPh+ ALL relapsed/resistant PKC412 and others Inhibe TK FLT3MLL+ ALL Gamma secretase inhibitors MK0752 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 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 ImatinibNilotinibDasatinib New TK inhibitors

22 Mechanism of Action of STI571 Substrate Substrate ADP ATPATPP activation of signal pathways PP BCR-ABL Substrate Substrate + STI571 ATPSTI

23 Mature B-ALL (Burkitts) Specific chemotherapy Rituximab

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

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

26 T-ALL. Nucleoside analogs FludarabineCytarabineNelarabineCladribineClofarabine PNP dNTP imbalance NA-MP NA-TP dGuo dGMP dGTP 5-Nucleotidase cell membrane NAs dCK Forodesine inhibition of DNA synthesis/repair DNA strand breaks apoptosis endonuclease activation dGuo inhibition of ribonucleotide reductase Cell death DNA degradation

27 New drugs in T-ALL DrugActivity OR (CR+PR) Comment NelarabineNucleoside analog 25-50% Neurotoxicity ForodesineNucleoside analog 25-35% Oral avialability Good toxic profile ClofarabineNucleoside analog 25-40% Approved USA (relapsed/refractory) AlemtuzumabAnti-CD52 In clinical trials, combined with CHT MRK002NOTCH-1 secretase Clinical trials inhibitor ImatinibInhibitor 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 Standard HighVery-high MoAb New cytotoxic drugs Thyrosine Kinase inhibitors Other

30 History of Treatment in Acute Lymphoblastic Leukemia Subtype / MRD Adjusted Tx Cure Rate (%) Chemotherapy CombinedSingle CNS Prophylaxis 70 60 50 40 30 20 10 195019601970198019902000 80 90 Stem Cell Transplant High Dose MTX >90%? 50%? Targeted Tx

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 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

38 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

39 Prophylaxis in DLBCL Site-specific risk (extranodal) CNS relapse rate 1.Testicular15% 2.Breast19% 3.Paranasal sinuses23% (orbital 43%) 4.Epidural space50% (?) 5.Intravascular (IVL)23% - 63%

40 CNS prophylaxis in aggressive NHL CHOPMACOP-BProMACEm-BACOD No CNS ProphylaxisCNS Prophylaxis CNS Relapse (%) Risk Factor for CNS Relapse, % CNS Relapse Relapse at extranodal sites 1 site1.9 > 1 site4.4 IPI score Low to low- intermediate 1.7 High-intermediate to high 4.2 0 1 2 3 4 5 n = 225 n = 218 n = 223n = 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

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 1999;17:3110–6 28 patients with LM DepoCyte ® injection 50 mg n = 14 Free cytarabine injection 50 mg n = 14 InductionConsolidationMaintenance InductionConsolidationMaintenance R Randomization E Evaluation 0 1 4 7 Months q 2 weeks q 4 weeks 2x a week weekly q 4 weeks q 2 weeks

43 IT dexamethasone for prevention of chemical arachnoiditis

44 1 Glantz et al. J Clin Oncol 1999;17:3110–6 2 Canales et al. submitted to EHA 2008 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 LM 1 Potential of DepoCyte for CNS prophylaxis in high- risk DLBCL is under investigation 2

45 Induction Slow cytologic response d14 Standard cytologic response d14 Intensified induction Standard induction CR Consolidation B1+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

46 Prognostic factors coeff. OR (95%CI) 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) <0.001 Death 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 0.010 EFS 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 i nduction/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 The best chemotherapy. Induction Consolidation Maintenance Dose intense Prolonged NO 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 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


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