Presentation is loading. Please wait.

Presentation is loading. Please wait.

Caesarea, April 2008 D.Hoelzer J.W.Goethe University Frankfurt for the GMALL Study Group German Multicenter Studies for Adult Acute Lymphoblastic Leukemia.

Similar presentations


Presentation on theme: "Caesarea, April 2008 D.Hoelzer J.W.Goethe University Frankfurt for the GMALL Study Group German Multicenter Studies for Adult Acute Lymphoblastic Leukemia."— Presentation transcript:

1 Caesarea, April 2008 D.Hoelzer J.W.Goethe University Frankfurt for the GMALL Study Group German Multicenter Studies for Adult Acute Lymphoblastic Leukemia Adult ALL – therapeutic strategies, including Burkitt and Lymphoblastic Lymphomas

2 Comprehensive Therapeutic Strategy in Acute Lymphoblastic Leukemia 1.MRD evaluation 2. New „targeted“ therapies e.g. Ph+ ALL 3. Antibody Therapy e.g. B-ALL/Burkitt NHL 4. Stem cell transplantation 5. New cytostatic drugs 6. Treatment of subentities and related diseases e.g. Elderly, Adolescents, T-LBL

3 Methods and Definition of Minimal Residual Disease (MRD) in Acute Lymphoblastic Leukemia = leukemic blast cells undetectable by microscopic examination of bone marrow (<1-5% blast cells) Methods of detection Flow – Mol. Gen. TCR, IHgR RT PCR (bcr abl) MRD should be applicable in 95% of ALL pts ! Definition of Mol. CR ≤ 0,01% = ≤1 LBC in but for technical reasons lower %

4 Value of MRD for Adult ALL Induction therapy

5 weeks Phase I Induction Phase II Cons. I CNS 24 Gy       i.th. MTX  i.th. Triple prophylaxis SC- collection V  (HR/VHR)  Stratification I According to Risk Factors SR Molecular Failure HD-MTX ASP III ReInduction VM 26 ARAC HD-MTX ASP CYCLO ARAC HD-MTX ASP 6 MP HR VHR Med 24 Gy MRD based German Multicenter Study for Adult ALL – GMALL 07/2003 Overview Plan SCT Stratification II according to MRD (6 TPs) Intens. Maint. MRD SR MRD HR Stop SZT MRD IMR

6 Patientenrekrutierung in laufende GMALL-Studien de novoN1921 GMALL 07/ GMALL für ph+ Pat. < 55 J. 118 GMALL mit Rituximab (SR) 51 GMALL Elderly 1/ GMALL T-LBL 1/ GMALL B-ALL/NHL RezidivstudienN171 Compound 506U78 (AraG)140 Depocyte für ZNS-Rezidive 19 Campath 12 10/07

7 GroupYearNAgeDrugsEarly DeathCR CALGB V,P,D,A,C8%85% CALGB V,P,D,A,C 8%85% LALA (<60)V,P,D/Z,C,[AM/HDAC]9%76% NILG 08/ V,P,I,A,[C]8%84% NILG 08/ V,P,I,A,[C] 8%84% GMALL 05/ (<65)V,P,D,A,C,AC,MP7%83% GMALL 05/ (<65)V,P,D,A,C,AC,MP 7%83% JALSG-ALL (<60)V,P,AD,A,C6%78% UCLA (<60)V,P,D,A1%93% Sweden V,BX,D,C,HDACn.r.75% GIMEMA (<60)V,P,D,A,C, [HDAC,Mi]11%82% GIMEMA (<60)V,P,D,A,C, [HDAC,Mi] 11%82% MD Anderson V,DX,AD,C,HDM,HDAC5%92% MD Anderson V,DX,AD,C,HDM,HDAC 5%92% EORTC ALL V,P,D,C,[AM/HDAC]n.r.74% LALA (<55)V,P,I/D,C5%84% LALA (<55)V,P,I/D,C 5%84% GOELAL02* (<60)V,P,I,A2%86% MRC/ECOG (<60)V,P,D,A,C,AC,MPn.r.91% MRC/ECOG (<60)V,P,D,A,C,AC,MP n.r.91% GIMEMA (<60)V,P,D,An.r.80% Pethema ALL-93* (<50)V,D,P,A,C6%82% Netherlands (<67)AC,VP,M - V,DX,AD9%88% JCOG (<64)V,C,P,AD,A10%83% Results of Recent Trials in Adult ALL INDUCTION THERAPY N:7262 ED: 7% (2-11%) CR:84% (74%-93%) * HR only

8 CYTOLOGIC CR Rate after induction GMALL Study 07/2003 Total Eval713 CR91% PR/Fail 6% ED 5% StandardHigh %88% 4% 9% 4% 9% 4% 4% 4% 4% Very High (Ph+) % (CH + IMat) 8%  high CR rate for all risk groups !  achievement of hematol. CR important  but no prognostic value for ALL subgroups

9 MOLECULAR CR rate (MRD < after induction) GMALL Study 07/2003 Cyto CRMol CR N Total91%69% SR92% HR88% <35 yrs90% >35 yrs89% B-precursor89% T-ALL90% 71%44% 72%61% 59%84%

10 Cytologic and Molecular CR Subtype: B vs T B-LinN=52550% T-LinN=20260% Survival of CR BMol CRN=8279% No Mol CRN=4837% TMol CRN=5268% No Mol CRN=1428%  B- and T-lineage: need for improvement of Molecular Cr rate

11 Molecular CR after induction therapy Conclusion  New endpoint for effectivity ?  Therapeutic consequences ?  Molecular failure  Immediate SCT  New targeted drugs ?  Molecular CR  SCT still in HR/VHR (Ph+) pts ?  Proof in randomized studies !

12 Why do we need MRD evaluation in addition to „conventional“ risk factors ?

13 Unfavourable Prognostic Factors Unfavourable Prognostic Factors High WBC > /µl in B-precursor Subtypepro B, early T, mature T Late CR> 3 Wo (after induction II) Cytogenetic/t(9;22) - BCR-ABL Molecular Aberrationst(4;11) - ALL1-AF4 Complex aberrant karyotype* Risk Stratification GMALL Study 07/2003 GMALL Study 07/2003 Stratification I: Conventional Prognostic Factors Standard No Factor Very High BCR-ABL High  1 Factor >=3 Aberrationen; mind. 1 Strukturaberration (Ausnahme: >50, t(9;22), 11q23, t(10;14), t(1;19), 8q24, t(14;18), t(11;14) 50%33%17%

14 Adult B-Lineage ALL: Leukemia Free Survival Standard Risk(n=396) High Risk(n=245) Very High Risk(n=152) 55 % 36 % 20 % GMALL Trial 05/93 WKH 06/2004 SCT MRD

15 Survival after SCT in HR ALL According to Type of SCT GMALL Study 07/2003 Allo sibling:0.54(N=42) Allo MUD:0.55(N=81) Auto:0.56(N=10) ~ 50% survival for High Risk pts after allo sib / MUD / Auto SCT

16 Time to achieve Molecular Remission in Standard Risk ALL Kinetics of Mol.CR in B- and T-Lin.ALL GMALL Studies 06/99 – 07/03 No increase of Mol CR > d 71 Lowest MRD level = best time point for SCT

17 Conclusion MRD in Adult ALL I Statements mainly based on GMALL 07/2003 experience 1) Molecular CR after induction therapy of greater prognostic impact than cytol. CR 2) „Slow“ decrease / dissapearance of MRD in adult B/T-lin. ALL compared to children 3) Best time point for MRD decision week 16 = after ind.+cond.

18 Treatment results before the Imatinib era Imatinib / Chemo / SCT in younger patients Value of MRD Imatinib Mono in Elderly Mutations and resistance New TK Inhibitors Dasatinib, Nilotinib, Aurora, others Ph+ ALL

19 Survival of CR Pts in Ph/BCR-ABL+ ALL with and without Stem Cell Transplantation GMALL Study 05/93 Chemo only:0.11 (N=88) Chemo+SCT:0.30(N=95)

20 Imatinib in the Treatment of Adult Ph+ ALL Questions Concomitant with intensive induction therapy ? Increase in (hemato) toxicity ? Other toxicities ?

21 Wassmann et al. (n = 92) Thomas et al. (n = 26) Yanada et al. (n = 80) Lee et al. (n = 20) Oriol et al. (n = 30) Induction regimen DEX, CYP, DNR, VCR, ASP, MP, CYT Hyper-CVADCYP, DNR, VCR, PDN DNR, VCR, PDN, ASP VCR, DNR, PDN CR88%96% 95%90% Induction mortality 8%NR2.5%5%7% Death in remission 5%16%NR15%10% PCR neg 52% 59% 71% 72%n.a.

22 EFSOS 49% 57% Yanada et al. J Clin Oncol 2006 (+IM) (-IM) (+IM) (-IM) Event-free and Overall Survival of PH+ ALL Comparison of ALL202 (+IM) and ALL93 (-IM)

23 No IM:0.14(N=70 IM after Ind.2:0.32(N=37) IM from Ind.2:0.40(N=74) IM from Ind.1:0.74(N=36) GMALL 06/99 and 07/03 Survival of CR VHR < 55 y

24 Imatinib in Adult Ph+ ALL (pts 15 – 55 y) CONCLUSIONS Increase in CR rate from 65-75% to 95% Increase in CR rate from 65-75% to 95% Increase in Mol. CR rates from <5% to ~50% Increase in Mol. CR rates from <5% to ~50% Induction mortality low, but death in CR Induction mortality low, but death in CR Improvement in long-term outcome ? Improvement in long-term outcome ? Effect on SCT? Effect on SCT?

25 Treatment of Elderly Ph + ALL Patients

26 Imatinib Consolidation  Pre- phase R  Randomized induction C1C2Reind.C3C4[C5]*  weeks 1-41 year Chemo- therapy Imatinib Imatinib Versus Chemotherapy Induction GMALL Trial in Elderly de novo Ph + ALL N = 55; median age 68 years (58-79) * Imatinib Mono 400 mg/d for 4 weeks * CR rate Induction-50% Chemo-tx Imatinib96% alone

27 Recent Approaches with Imatinib ± Chemo in Elderly Patients with Ph+ ALL Author Age Therapy IM Year (Median) Induct. Consol. Dose N CR Survival Vignetti 69 y IM + PredIM % 74% (1 yr) Blood 2006 Delannoy 66 y CTX IM + ster % (IM) 66% (1 yr) Leukemia CTX / IM70% (CH) 2006 Ottmann 68 y IM CTX+IM % (IM) 57% (1 yr) Cancer CTX 26 50% (CH) 42% (2 yrs) 2007

28 EFS % GMALL 1 DFS GIMEMA 2 DaysMonths GRAALL 3 AFR09 (+ IM) hist. control (no IM) DFS 1 Ottman et al, Cancer 2007;109: ; 2 Vignetti et al. Blood. 2007;109(9):3676-8; 3 Delannoy et al., Leukemia. 2006; 20: Imatinib-Based Therapy in Elderly Ph(+) ALL: Comparison of Outcome High rate of mutations !

29 Monotherapy with Imatinib in Elderly Ph+ ALL Conclusions  Increase of CR rate to >90%, no induction death  Molecular CR rate ~ 40 %  Improvement of median survival from 6 to 12 mo  Improvement of quality of life - very low toxicity and - partly outpatient treatment  Outcome impaired due to development of resistance

30 BCR-ABL Mutations in Ph+ ALL (GMALL - Elderly)

31 Mechanism of Resistance in Ph+ ALL Hofmann et al, Blood & Lancet 2002  Single point mutation in ATP binding site (e.g. T315I), P-loop or activation loop  Amplification of bcr-abl fusion gene  Up-regulation of bcr-abl transcription  Increase of imatinib efflux / decreased cellular bioavailability  BCR-ABL independence (SRC)

32 CR CR mol REL Time IMATINIB % unmutated BCR-ABL % mutated BCR-ABL Chemotherapy Proportion of Mutant BCR-ABL Alleles in Relation to Treatment Response of de novo Ph+ALL H.Pfeifer,O.G.Ottmann

33 Novel Bcr-Abl inhibitors AMN107Novartis Dasatinib BMS VX-680 (L-00128)MSD(T315i) Aurorakinase-Inh. SGX70393Novartis (T315i) LBH589Novartis HDAC-Inhibitor

34 Experience with Dasatinib in front-line Therapy of Ph+ ALL AuthorNAgeDoseCRMolCR Chemo Ravandi mg bid93%46% ASH 2007, #2814(23-79)HyperCVAD Foa mg bid100%70% ASH 2007, #7(30-74)Pred<10 -2  Tolerable in combination with chemo  Effectivity comparable to Imatinib  Long-term results pending

35 New Drugs in ALL 1.Nelarabine 2.Clofarabine 3.Forodesine HCL 4.Banoxantrone 5.Liposomal ARAC for i.th. use 6.Liposomal VCR 7.Liposomal DNR 8.Anti CD20 9.AntiCD52 10.AntiCD33 11.AntiCD19 / Tcell engager 12.Imatinib 13.Nilotinib 14.Dasatinib 15.Aurorakinase Inhibitors + others Cytostatics Liposomal Antibodies Kinase inhibitors Explored in GMALL studies

36 Antigen Surface Expression in Subtypes of Adult ALL and Monoclonal Antibodies Surface SubtypeExpression onAntibodyEvidence antigen>20% LBC*in ALL CD20B-precursor 41%RituximabTrials de novo Mature B-ALL 86%ALL CD52B-/T-lineage 79% / 77%AlemtuzumabTrials de novo ALL CD33B-/T-lineage 23% / 9%GemtuzumabCase reports Ph+ ALL 40% CD19 B-precursor 95% Mature B-ALL 94% CD22B-lineage 17%Epratuzumab *E.Thiel, S.Schwartz, W.D.Ludwig; Central immunophenotyping for GMALL studies

37 Rituximab in Different Subentities of Adult ALL Mature B-ALL / Burkitt‘s NHL B-precursor ALL -Elderly -Younger -standard risk -high risk Relapsed ALL

38 Treatment Results in Burkitt‘s Lymphoma/Leukemia With Short Intensive Therapies Weighted mean80%59%    CR rate 80%; Survival 59%  Results depend on proportion of B-ALL  Survival around 70% in Burkitt‘s NHL

39 GMALL B-ALL/NHL 2002 Trial

40 Rationale for B-ALL/NHL Study 2002 Anti CD20 (Rituximab) Results from NHL protocols with RituximabResults from NHL protocols with Rituximab Expression of CD20 >80% in mature B-ALLExpression of CD20 >80% in mature B-ALLHDMTX Dose reduction from 3 g/m² to 1.5 g/m² since no improvement but more toxicity in B-NHL90Dose reduction from 3 g/m² to 1.5 g/m² since no improvement but more toxicity in B-NHL90HDAC To improve antileukemic activity and CNS prophylaxisTo improve antileukemic activity and CNS prophylaxis Favourable results from other studies e.g. HyperCVADFavourable results from other studies e.g. HyperCVADG-CSF Lower incidence of severe neutropenia and mucositisLower incidence of severe neutropenia and mucositis Salvage therapies As prophylaxis (CNS, MedTU,extranodal inv.) and salvage therapyAs prophylaxis (CNS, MedTU,extranodal inv.) and salvage therapy SC apheresis in HR pts for potential auto SCTSC apheresis in HR pts for potential auto SCT

41 A1 B1P C1 A2 B2 C2 SC- Apheresis (not obligatory) antiCD20 antiCD20 1 Multicentre Study to Optimize Therapy of B-ALL and High-grade Non-Hodgkin’s Lymphoma in Adults (GMALL-B-ALL/NHL 2002) Patients years Failure of therapy Salvage SCT (allo, auto, MUD) antiCD20 End of therapy in Stage I/II with CR after 2 cycles MedTU CNS-inv. CRu, PR Irradiation Weeks A1 *B1 *PA2 *B2 * A3 *B3 * antiCD20 antiCD20 1 antiCD20 Patients > 55 yrs Failure of therapy Salvage SCT (allo, auto, MUD) End of therapy after 4 cycles in Stage I/II with CR after 2 cycles

42 GMALL Study for Adult B-ALL and High Grade B-NHL (GMALL B-ALL/NHL 2002) days CYCLO200 mg/m²d 1-5 PRED60 mg/m² d 1-5 Pre-phase Block A Anti-CD20375 mg/m²d 0 DEXA10 mg/m² d 1-5 VCR2 mg (abs)d 1 HD-MTX1.5 g/m² *d 1 IFO800 mg/m²d 1-5 ARAC 150 mg/m²x2d 4,5 VM26100 mg/m²d 4,5 DEXA/ARAC/MTX i.th.d 1,5 G-CSFd days 0 * 0.5 g/m² if > 55y

43 Block C Anti-CD20375 mg/m²d 0 DEXA10 mg/m² d 1-5 VDS3 mg/m²d 1 HD-MTX1.5 g/m² *d 1 VP16250 mg/m²d 4,5 HD-AC2 g/m² x 2**d 5 DEXA/ARAC/MTX i.th.d 1,5 G-CSFd 7 G-CSFd days * 0.5 g/m² if > 55y ** 1 g/m² if > 55 y 0 Block B Anti-CD20375 mg/m²d 0 DEXA10 mg/m² d 1-5 VCR2 mg (abs)d 1 HD-MTX1.5 g/m² *d 1 CP200 mg/m²d 1-5 ADR25 mg/m²x2d 4,5 DEXA/ARAC/MTX i.th.d 1,5 G-CSFd 7 G-CSFd days * 0.5 g/m² if > 50y 0 GMALL Study for Adult B-ALL and High Grade B-NHL (GMALL B-ALL/NHL 2002)

44 Accrual period:9/ /2007 N evaluable:381 (minimum 2 cycles completed) Diagnoses:B-ALL 84 (22%) Burkitt 146 (38%) 32 atyp./B-like DLBCL 102 (27%) 70 mediastinal B-LBL 22 (6%) LCAL 25 (7%) GMALL B-ALL/NHL 2002 Evaluable Patients

45 Results of Remission Evaluation GMALL B-ALL/NHL 2002 ResponseCRPRFailure Death under therapy Burkitt/Burkitt like N=129118(91%) 3(2%) 3(2%) 5(4%) 5(4%) 3(2%) 3(2%) B-ALLN=7765(84%)3(4%)2(3%)7(9%) DLBCLN=9471(76%)13(14%)5(5%)5(5%)

46 Burkitt0.93(N=101) B-ALL0.76(N=49) DLBCL0.84 (N=74) Overall Survival (<55 yrs) GMALL B-ALL/NHL 2002 Majority of events < 1 y

47 Overall Survival Burkitt / Burkitt‘s-like Lymphoma GMALL B-ALL/NHL 2002 Burkitt0.93 (N=101) Burkitt-like0.91 (N=28)

48 Rituximab in Combination with Hyper-CVAD in Mature B-ALL/Burkitt‘s NHL Thomas et al, Cancer 2006 Hyper-CVAD+RHyper-CVAD Evaluable31 (14 B-ALL)48 CR86%85% OS (3y)89%53% > 6089%19% Relapses 7% 34% > 60 yrs 0%50% Toxicity ± R comparable HDMTX ARAC ARAC weeks Hyper-CVADHDMTX Hyper-CVADHDMTX Hyper-CVAD HDMTX Hyper-CVAD Rituximab 375 mg/m²

49 Burkitt‘s NHL in HIV+ pts

50 Short Intensive Chemotherapy in HIV+ Adult Burkitt‘s NHL AuthorYearAgeStage III/IVL3-ALLHAARTProtocolNCROS Horst et al2003 n.r. 70%* 8%*60%GMALL B-ALL1687%72% g/m² MTX Wang et al (19-61)* 88% 29%* n.r.CODOX-M863%60% 7 g/m² MTX 7 g/m² MTX Astrow et al (27-59) 83%76%n.r.McMasters2339%39% 200 mg/m² 200 mg/m² Oriol et al (23-65)57%43%36%GMALL B-ALL1471%55% 3 g/m² MTX Costello et al %n.r.n.r.CHOP augm.13n.r.60% 8 g/m² MTX Cortes et al (32-55)29%50%64%HyperCVAD1492%48% 1 g/m² MTX Weighted mean 8868%54% * Whole cohort including arm with less intensive chemotherapy

51 B-ALL/NHL 2002:0.80 (N=272) B-ALL/NHL 90:0.54 (N=270) Overall Survival in Adult B-ALL/B-NHL GMALL B-ALL/NHL 2002 p=0.0001

52 Mature B-ALL/Burkitt‘s NHL Summary and Conclusions Combination of Rituximab and intensive chemo feasible Combination of Rituximab and intensive chemo feasible Response rate 80-90% in Burkitt / DLBCL, overall survival ~ 90% Response rate 80-90% in Burkitt / DLBCL, overall survival ~ 90% Improvement in mature B-ALL, less for pts > 55 y Improvement in mature B-ALL, less for pts > 55 y Irradiation of residual tumors effective salvage therapy Irradiation of residual tumors effective salvage therapy SCT: No prognostic factors  no indication for SCT in CR1  No stem cell apheresis any more SCT: No prognostic factors  no indication for SCT in CR1  No stem cell apheresis any more Major toxicity: mucositis Major toxicity: mucositis

53 Mature B-ALL/Burkitt‘s NHL Future Prospects - I Reduction of toxicity De-escalation in good responders and early stages ? e.g. - Reduced MTX infusion time? - Reduction of cycles? Improved prophylaxis of mucositis and infections Improvment of outcome in elderly B-ALL Intensified CNS prophylaxis e.g. Depocyte HDAC based cycle Increased Rituximab dose-intensity ? Refinition of response evaluation and risk stratification e.g. PET analysis MRD analysis (Mussolin et al, JCO 2007)

54 Study CenterHead D.Hoelzer, Frankfurt CoordinatorN.Gökbuget, Frankfurt Data ManagerR.Reutzel, Frankfurt Central DiagnosisMorphology/CytochemistyH.Horst, Kiel ImmunphenotypingE.Thiel, S.Schwartz, Molecular geneticsT.Burmeister, Berlin Gene expression analysisW.K.Hofmann, Berlin CytogeneticsH.Rieder, Düsseldorf C.Schoch, München MinimalM.Kneba, M.Brüggemann,T. Raff, Kiel Residual DiseaseH. Pfeifer, Frankfurt Molecular therapiesO. Ottmann, Frankfurt SCT coordinatorR.Arnold, Berlin Irradiation therapyR.Fietkau, Rostock StatisticsGMALL Study Center + ~126 participating centers GMALL- Study Group


Download ppt "Caesarea, April 2008 D.Hoelzer J.W.Goethe University Frankfurt for the GMALL Study Group German Multicenter Studies for Adult Acute Lymphoblastic Leukemia."

Similar presentations


Ads by Google