Presentation on theme: "Adult ALL – therapeutic strategies, including Burkitt"— Presentation transcript:
1 Adult ALL – therapeutic strategies, including Burkitt and Lymphoblastic LymphomasD.HoelzerJ.W.Goethe UniversityFrankfurtfor the GMALL Study GroupGerman Multicenter Studies for Adult Acute Lymphoblastic LeukemiaCaesarea, April 20081
2 Comprehensive Therapeutic Strategy in Acute Lymphoblastic Leukemia MRD evaluation2. New „targeted“ therapies e.g. Ph+ ALL3. Antibody Therapy e.g. B-ALL/Burkitt NHL4. Stem cell transplantation5. New cytostatic drugs6. 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)Definition of Mol. CR ≤ 0,01% = ≤1 LBC inMethods of detectionFlow – 10-3Mol. Gen. TCR, IHgRRT PCR (bcr abl)MRD should be applicable in 95% of ALL pts !but for technical reasons lower %
5 MRD based German Multicenter Study for Adult ALL – GMALL 07/2003 Overview PlanStratification IAccording to Risk FactorsStratification IIaccording to MRD(6 TPs)Intens.Maint.MRDSRHRStopSZTIMRHD-MTXASPIIIReInductionVM 26ARACCYCLO6 MPSRMolecularFailureInductionCons. IVPhase IPhase IICNS 24 GyMed 24 GySC-collectionHRVHRSCTi.th. Tripleprophylaxisi.th. MTX (HR/VHR)145791113161922252730333639414346495153weeks
6 Patientenrekrutierung in laufende GMALL-Studien de novo N 1921GMALL 07/GMALL für ph+ Pat. < 55 JGMALL mit Rituximab (SR)GMALL Elderly 1/GMALL T-LBL 1/GMALL B-ALL/NHLRezidivstudien N 171Compound 506U78 (AraG) 140Depocyte für ZNS-Rezidive 19Campath 1210/07
7 Results of Recent Trials in Adult ALL INDUCTION THERAPYGroup Year N Age Drugs Early Death CRCALGB 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%GMALL 05/ (<65) V,P,D,A,C,AC,MP 7% 83%JALSG-ALL (<60) V,P,AD,A,C 6% 78%UCLA (<60) V,P,D,A 1% 93%Sweden V,BX,D,C,HDAC n.r. 75%GIMEMA (<60) V,P,D,A,C, [HDAC,Mi] 11% 82%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,C 5% 84%GOELAL02* (<60) V,P,I,A 2% 86%MRC/ECOG (<60) V,P,D,A,C,AC,MP n.r. 91%GIMEMA (<60) V,P,D,A n.r. 80%Pethema ALL-93* (<50) V,D,P,A,C 6% 82%Netherlands (<67) AC,VP,M - V,DX,AD 9% 88%JCOG (<64) V,C,P,AD,A 10% 83%N: 7262ED: 7% (2-11%)CR: 84% (74%-93%)* HR only
8 CYTOLOGIC CR Rate after induction GMALL Study 07/2003TotalEval 713CR 91%PR/Fail 6%ED 5%Standard High92% 88%4% 9%4% 4%Very High (Ph+)11985% (CH + IMat)8%high CR rate for all risk groups !achievement of hematol. CR importantbut no prognostic value for ALL subgroups
10 Cytologic and Molecular CR Subtype: B vs TSurvival of CRSurvival of CRB Mol CR N=82 79%No Mol CR N=48 37%T Mol CR N=52 68%No Mol CR N=14 28%B-Lin N=525 50%T-Lin N=202 60% B- and T-lineage: need for improvement of Molecular Cr rate
11 Conclusion Molecular CR after induction therapy 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 ?
15 Survival after SCT in HR ALL According to Type of SCT GMALL Study 07/2003Allo 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.ALLGMALL Studies 06/99 – 07/03No increase of Mol CR > d 71Lowest MRD level = best time point for SCT
17 Conclusion MRD in Adult ALL I Statements mainly based on GMALL 07/2003 experience1) Molecular CRafter induction therapy of greater prognosticimpact than cytol. CR2) „Slow“ decrease / dissapearance of MRD in adultB/T-lin. ALLcompared to children3) Best time point for MRD decisionweek 16 = after ind.+cond.
18 Ph+ ALL Treatment results before the Imatinib era Imatinib / Chemo / SCT in younger patientsValue of MRDImatinib Mono in ElderlyMutations and resistanceNew TK InhibitorsDasatinib, Nilotinib, Aurora, others
19 Survival of CR Pts in Ph/BCR-ABL+ ALL with and without Stem Cell TransplantationGMALL Study 05/93Chemo only: (N=88)Chemo+SCT: 0.30 (N=95)
20 Imatinib in the Treatment of Adult Ph+ ALLQuestionsConcomitant with intensive inductiontherapy ?Increase in (hemato) toxicity ?Other toxicities ?
21 DEX, CYP, DNR, VCR, ASP, MP, CYT Wassmann et al.(n = 92)Thomas et al.(n = 26)Yanadaet al.(n = 80)Lee et al.(n = 20)Oriol et al.(n = 30)Induction regimenDEX, CYP, DNR, VCR, ASP, MP, CYTHyper-CVADCYP, DNR, VCR, PDNDNR, VCR, PDN, ASPVCR, DNR, PDNCR88%96%95%90%Induction mortality8%NR2.5%5%7%Death in remission16%15%10%PCR neg % % % % n.a.Thomas, 2004,abstract;Towatari, 2004,preprint, p8,9, 15,16, 28, 29Lee, 2005,p1509, c1, ¶1,p1511, c2, ¶1;Oriol, 2005,EHA absIntegrating imatinib into standard induction chemotherapy regimens improves outcomes as compared with historical cohorts in newly diagnosed Ph+ ALL.In addition to adding imatinib to hyper-CVAD, as discussed on the previous slide, promising results have also been obtained by adding imatinib to other intensive regimens used to treat adults with newly diagnosed Ph+ ALL.Towatari and colleagues from the Japan Adult Leukemia Study Group administered imatinib in combination with their standard age-based intensive chemotherapy regimen to 24 newly diagnosed Ph+ ALL patients (median age, 41.5 years; range years). Imatinib was administered at a dose of 600 mg/d from days 8 to 63 during induction therapy with cyclophosphamide, daunorubicin, vincristine, and prednisolone, then alone for 28 days during second consolidation, and finally during maintenance therapy with vincristine and prednisolone. The regimen produced remission in 96% of patients and molecular remission in 78%. On interim analysis, the 1-year DFS and OS were estimated at 68% and 89%, respectively. These estimates, although preliminary, appear superior to those in an earlier study without imatinib. [Towatari, 2004, preprint p2, 8, 9, 15, 16, 19, 28, 29]Lee and colleagues administered imatinib at 600 mg/d during induction therapy with daunorubicin, vincristine, prednisolone, and L-aspariginase, and then at 400 mg/d during consolidation regimens to 20 newly diagnosed Ph+ ALL patients (median age, 37 years; range, years). The regimen produced remission in 95% of patients.Three-quarters of the cohort underwent allogeneic SCT in CR1. Median CR duration (2.2 years) and median survival (2.4 years) were more than twice those for an historical cohort of Ph+ ALL patients treated with the same chemotherapy regimen but without imatinib. [Lee, 2005, p1509, c1, ¶1; p1510, c1, ¶1]Finally, Oriol and colleagues administered imatinib 400 mg/d during induction with vincristine, daunorubicin, and prednisolone and during consolidation therapy with mercaptopurine, high-dose methotrexate, VM-26, and cyclophosphamide to 30 patients with newly diagnosed Ph+ ALL (median age, 45 years; range, years).The CR rate of 90% was higher than the 70% rate seen in an earlier study conducted without imatinib. Median follow-up was too short to draw valid survival comparisons with the historical cohort. [Oriol, 2005, EHA abs]Lee K-H, Lee J-H, Choi S-J, et al. Clinical effect of imatinib added to intensive combination chemotherapy for newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. Leukemia. 2005;19:Oriol A, Ribera JM, Gonzalez M, et al. Treatment of Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) with concurrent chemotherapy and imatinib mesylate [abstract]. Presented at: European Hematology Association. Stockholm, Sweden; AbstrTowatari M, Yanada M, Usui N, et al. Combination of intensive chemotherapy and imatinib can rapidly induce high-quality complete remission for a majority of patients with newly diagnosed BCR-ABL positive acute lymphoblastic leukemia. Blood. 2004;104:
22 Event-free and Overall Survival of PH+ ALL Comparison of ALL202 (+IM) and ALL93 (-IM)EFSOS(+IM)(+IM)57%49%(-IM)(-IM)Yanada et al. J Clin Oncol 2006
23 Survival of CR VHR < 55 y GMALL 06/99 and 07/03Survival of CRVHR < 55 yNo IM: 0.14 (N=70IM after Ind.2: 0.32 (N=37)IM from Ind.2: 0.40 (N=74)IM from Ind.1: 0.74 (N=36)
24 Imatinib in Adult Ph+ ALL (pts 15 – 55 y) CONCLUSIONSIncrease in CR rate from 65-75% to 95%Increase in Mol. CR rates from <5% to ~50%Induction mortality low, but death in CRImprovement in long-term outcome ?Effect on SCT?
26 Imatinib Versus Chemotherapy Induction GMALL Trial in Elderly de novo Ph+ ALLN = 55; median age 68 years (58-79)RandomizedinductionConsolidationCR rateInduction- 50%Chemo-txImatinib 96%alone*ImatinibC1C2Reind.C3C4[C5]*Pre-phaseRImatinibChemo-therapyweeks 1-41 year* Imatinib Mono 400 mg/d for 4 weeks
27 Recent Approaches with Imatinib ± Chemo in Elderly Patients with Ph+ ALLAuthor Age Therapy IMYear (Median) Induct Consol Dose N CR SurvivalVignetti y IM + Pred IM % % (1 yr)Blood2006Delannoy y CTX IM + ster % (IM) % (1 yr)Leukemia CTX / IM 70% (CH)Ottmann y IM CTX+IM % (IM) % (1 yr)Cancer CTX % (CH) % (2 yrs)2007
28 Imatinib-Based Therapy in Elderly Ph(+) ALL: Comparison of Outcome GMALL1GIMEMA2GRAALL3%EFSDFSDFSAFR09(+ IM)hist. control(no IM)DaysMonthsMonths1Ottman et al, Cancer 2007;109: ; 2 Vignetti et al. Blood. 2007;109(9):3676-8; 3Delannoy et al., Leukemia. 2006; 20:High rate of mutations !
29 Monotherapy with Imatinib in Elderly Ph+ ALL ConclusionsIncrease of CR rate to >90%, no induction deathMolecular CR rate ~ 40 %Improvement of median survival from 6 to 12 moImprovement of quality of life- very low toxicity and- partly outpatient treatmentOutcome impaired due to development of resistance
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 loopAmplification of bcr-abl fusion geneUp-regulation of bcr-abl transcriptionIncrease of imatinib efflux / decreased cellular bioavailabilityBCR-ABL independence (SRC)
32 Proportion of Mutant BCR-ABL Alleles in Relation to Treatment Response of de novo Ph+ALL% unmutatedBCR-ABL% mutatedBCR-ABLRELCRCRmolTimeChemotherapyIMATINIBH.Pfeifer,O.G.Ottmann
34 Experience with Dasatinib in front-line Therapy of Ph+ ALL Author N Age Dose CR MolCRChemoRavandi mg bid 93% 46%ASH 2007, #2814 (23-79) HyperCVADFoa mg bid 100% 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 Explored in GMALL studies Nelarabine Cytostatics ClofarabineForodesine HCLBanoxantroneLiposomal ARAC for i.th. useLiposomal VCRLiposomal DNRAnti CD20AntiCD52AntiCD33AntiCD19 / Tcell engagerImatinibNilotinibDasatinibAurorakinase Inhibitors + othersLiposomalAntibodiesKinase inhibitors
36 Antigen Surface Expression in Subtypes of Adult ALL and Monoclonal Antibodies Surface Subtype Expression on Antibody Evidenceantigen >20% LBC* in ALLCD20 B-precursor % Rituximab Trials de novoMature B-ALL % ALLCD52 B-/T-lineage % / 77% Alemtuzumab Trials de novoALLCD33 B-/T-lineage % / 9% Gemtuzumab Case reportsPh+ ALL %CD B-precursor %Mature B-ALL %CD22 B-lineage % 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 NHLB-precursor ALL- Elderly- Younger- standard risk- high riskRelapsed ALLTherefore mature B-ALL and Burkitt‘s NHL was the first entity in which the GMALL study group tested Rituximab therapy.
38 Treatment Results in Burkitt‘s Lymphoma/Leukemia With Short Intensive TherapiesWeighted mean 80% 59%CR rate 80%; Survival 59%Results depend on proportion of B-ALLSurvival around 70% in Burkitt‘s NHL
40 Rationale for B-ALL/NHL Study 2002 Anti CD20 (Rituximab)Results from NHL protocols with RituximabExpression of CD20 >80% in mature B-ALLHDMTXDose reduction from 3 g/m² to 1.5 g/m² since no improvement but more toxicity in B-NHL90HDACTo improve antileukemic activity and CNS prophylaxisFavourable results from other studies e.g. HyperCVADG-CSFLower incidence of severe neutropenia and mucositisSalvage therapiesAs prophylaxis (CNS, MedTU,extranodal inv.) and salvage therapySC apheresis in HR pts for potential auto SCT
41 SC- Apheresis (not obligatory) Multicentre Study to Optimize Therapy of B-ALL and High-grade Non-Hodgkin’s Lymphoma in Adults (GMALL-B-ALL/NHL 2002)Patients yearsFailure of therapySalvageSCT (allo, auto, MUD)PA1B1C1A2B2C2antiCD20 1antiCD20antiCD20antiCD20antiCD20antiCD20antiCD20antiCD20SC- Apheresis (not obligatory)End of therapy inStage I/II withCR after 2 cyclesMedTUCNS-inv.CRu, PRIrradiationPatients > 55 yrsPA1 *B1 *A2 *B2 *A3 *B3 *antiCD20 1antiCD20antiCD20antiCD20antiCD20antiCD20antiCD20antiCD201258121518212428WeeksFailure of therapySalvageSCT (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)Pre-phaseCYCLO 200 mg/m² d 1-5PRED 60 mg/m² d 1-512345 daysBlock AAnti-CD mg/m² d 0DEXA 10 mg/m² d 1-5VCR 2 mg (abs) d 1HD-MTX 1.5 g/m² * d 1IFO 800 mg/m² d 1-5ARAC 150 mg/m²x2 d 4,5VM mg/m² d 4,5DEXA/ARAC/MTX i.th. d 1,5G-CSF d 71234567 days* 0.5 g/m² if > 55y
43 GMALL Study for Adult B-ALL and High Grade B-NHL (GMALL B-ALL/NHL 2002)Block BAnti-CD mg/m² d 0DEXA 10 mg/m² d 1-5VCR 2 mg (abs) d 1HD-MTX 1.5 g/m² * d 1CP 200 mg/m² d 1-5ADR 25 mg/m²x2 d 4,5DEXA/ARAC/MTX i.th. d 1,5G-CSF d 71234567 days* 0.5 g/m² if > 50yBlock CAnti-CD mg/m² d 0DEXA 10 mg/m² d 1-5VDS 3 mg/m² d 1HD-MTX 1.5 g/m² * d 1VP mg/m² d 4,5HD-AC 2 g/m² x 2** d 5DEXA/ARAC/MTX i.th. d 1,5G-CSF d 71234567 days* g/m² if > 55y** 1 g/m² if > 55 y
48 Rituximab in Combination with Hyper-CVAD in Mature B-ALL/Burkitt‘s NHL Thomas et al , Cancer 2006Hyper-CVADHDMTXARACHyper-CVADHDMTXARACHyper-CVADHDMTXARACHyper-CVADHDMTXARACRituximab 375 mg/m²2468101214161820222426weeksHyper-CVAD+R Hyper-CVADEvaluable 31 (14 B-ALL) 48CR 86% 85%OS (3y) 89% 53%> 60 89% 19%Relapses 7% 34%> 60 yrs 0% 50%Toxicity ± R comparable
50 Short Intensive Chemotherapy in HIV+ Adult Burkitt‘s NHL Author Year Age Stage III/IV L3-ALL HAART Protocol N CR OSHorst et al n.r. 70%* 8%* 60% GMALL B-ALL 16 87% 72%0.5-3 g/m² MTXWang et al (19-61)* 88% 29%* n.r. CODOX-M 8 63% 60%7 g/m² MTXAstrow et al (27-59) 83% 76% n.r. McMasters 23 39% 39%200 mg/m²Oriol et al (23-65) 57% 43% 36% GMALL B-ALL 14 71% 55%3 g/m² MTXCostello et al % n.r. n.r. CHOP augm. 13 n.r. 60%8 g/m² MTXCortes et al (32-55) 29% 50% 64% HyperCVAD 14 92% 48%1 g/m² MTXWeighted mean % 54%* Whole cohort including arm with less intensive chemotherapy
52 Mature B-ALL/Burkitt‘s NHL Summary and Conclusions Combination of Rituximab and intensive chemo feasibleResponse rate % in Burkitt / DLBCL, overall survival ~ 90%Improvement in mature B-ALL, less for pts > 55 yIrradiation of residual tumors effective salvage therapySCT: No prognostic factors no indication for SCT in CR1 No stem cell apheresis any moreMajor toxicity: mucositis
53 Mature B-ALL/Burkitt‘s NHL Future Prospects - IReduction of toxicityDe-escalation in good responders and early stages ? e.g.- Reduced MTX infusion time?- Reduction of cycles?Improved prophylaxis of mucositis and infectionsImprovment of outcome in elderly B-ALLIntensified CNS prophylaxis e.g. DepocyteHDAC based cycleIncreased Rituximab dose-intensity ?Refinition of response evaluation and risk stratification e.g.PET analysisMRD analysis (Mussolin et al, JCO 2007)
54 GMALL- Study Group + ~126 participating centers Study Center Head D.Hoelzer, FrankfurtCoordinator N.Gökbuget, FrankfurtData Manager R.Reutzel, FrankfurtCentral Diagnosis Morphology/Cytochemisty H.Horst, KielImmunphenotyping E.Thiel, S.Schwartz,Molecular genetics T.Burmeister, BerlinGene expression analysis W.K.Hofmann, BerlinCytogenetics H.Rieder, DüsseldorfC.Schoch, MünchenMinimal M.Kneba, M.Brüggemann,T. Raff, KielResidual Disease H. Pfeifer, FrankfurtMolecular therapies O. Ottmann, FrankfurtSCT coordinator R.Arnold, BerlinIrradiation therapy R.Fietkau, RostockStatistics GMALL Study Center+ ~126 participating centers