Terapia del paziente candidato al trapianto

Transcript

1 Clinica Ematologica IRCCS Fondazione Policlinico San Matteo Università di Pavia Terapia del paziente candidato al trapianto Alessandro Corso Gammopatie monoclonali e mieloma multiplo Varese 14 novembre 2011

2 CHT convenzionale Melphalan + Prednisone Risposte complessive 60% Remissioni complete rare ( ( 5%) Stabilizzazione della malattia (plateau) Sopravvivenza mediana: 3 anni Lungo sopravviventi a 10 anni: 10%

3 La risposta completa dovrebbe essere l obiettivo nel mieloma multiplo La RC è l obiettivo in molte patologie ematologiche Il trapianto autologo prima e i nuovi farmaci più recentemente hanno permesso l aumento del numero di risposte complete La RC ha un impatto sul TTP, sulla sopravvivenza e sulla QoL

4 Impact of CR in transplant setting Meta-analysis analysis of 21 studies 10 prospective 11 retrospective 4990 patients Highly significant association between maximal response following induction therapy and long-term outcome (P=0.0027)( Highly significant association between maximal response (CR/nCR/VGPR) during or after HDT/SCT and long-term outcome (OS/EFS/PFS) (P< ( < ) van de Velde et al. Haematologica 2007;92:

5 CR and overall outcome in MM 721 previously untreated patients <65 years Treatment: high-dose dex-based combination (primary therapy) + high-dose melphalan-based regimen + ASCT (intensive therapy) Patient group Median Survival CR after primary therapy years CR after intensive therapy of PR or NR years PR after primary treatment PR after intensive therapy 4.3 years 5.9 years Resistant disease 2 years CR is important regardless of how it is achieved Wang et al. Blood 2006; 108: abstract 403

6 PFS and OS in relation to the type of response after transplant (dati REL 2010) Corso et al. Am.J.Haematol, in press

7 A better quality of response is associated with a better quality of life Progressive disease Stable disease Partial response Complete response Quality of life score Achieving the best possible response results in improved quality of life Ludwig et al. IMW 2007 (Abstract 1103)

8 CRITERIA TO IDENTIFY A MYELOMA PATIENT WHO IS ELIGIBLE FOR AUTOTRANSPLANTATION Patient s chronological age Patient s physiological age Absence of comorbidities Normal organ function Renal failure does not preclude ASCT to support reduced-dose melphalan Cavo M et al, Blood 2011 Mar 29 [Epub ahead of print]

9 PATIENTS ELIGIBLE FOR AUTOTRANSPLANTATION (ASCT) HIGH-DOSE THERAPY Induction therapy Autograft 1 ± 2 Consolidation Maintenance

10 Influence of Response After Induction: Superior Outcome When CR Is Achieved Before ASCT EFS (Probability) CR vs ncr: P=.1 CR vs PR: P=.05 ncr vs PR: P= Mos OS (Probability) CR vs ncr: P=.1 CR vs PR: P=.07 CR vs SD: P=.02 ncr vs PR vs SD: P= Mos CR (n = 101) ncr (n = 96) PR (n = 346) SD (n = 63) PD (n = 26) Lahuerta JJ, et al. J Clin Oncol. 2008;26: Reprinted with permission American Society of Clinical Oncology. All rights reserved.

11 Comparison between different induction regimen: post-induction results 61% VGPR CR 69% 69% 59% Induction: VTD best combination 4 cycles > 3? 6 courses: no adv., + PN CR/nCR 51% CR/nCR 26% 28% 39% CR/nCR n/a 28% 32% 6 VTD CR 31% 4 VTD CR 27% 16% 3 VTD CR 19% G3/4 PN *CR/nCR 3 cicli 4 cicli 4 cicli 6 cicli 4 cicli VTD 9,7% VTD 10% VTD 14%

12 A Phase 3 Prospective, Randomized, International Study (MMY- 3021) Comparing Subcutaneous and Intravenous Administration of Bortezomib in Patients with Relapsed Multiple Myeloma Response rate, % Bortezomib IV ± dex (n=73) Bortezomib SC ± dex (n=145) ORR (CR + PR) CR PR ncr VGPR 3 5 VGPR (CR + ncr + VGPR) Response improvement (cycle 4 8) in patients who received dex, n/n (%) n=39 n=82 PR CR 2/15 (13%) 4/31 (13%) <PR PR 7/23 (30%) 14/47 (30%) Moreau et al. Blood 2010;116(21): Abstract 312, oral presentation

13 Patients with response (%) No. patients at risk IV SC Time to Response / Duration of Response Time to first response (response-evaluable population) IV SC Days from randomization In responding patients Bortezomib IV, n=38 Bortezomib SC, n=76 Median time to first response, months (range) 1.4 ( ) 1.4 ( ) Median time to best response, months (range) 1.5 ( ) 1.6 ( ) Median duration of response, months (95% CI) 8.8 (7.6, 12.1) 9.7 (8.3, 13.6) Moreau et al. Blood 2010;116(21): Abstract 312, oral presentation

14 Time to Disease Progression Patients without PD (%) No. patients at risk IV SC IV SC Days from randomization TTP IV SC P-value Median, days (95% CI) (231.0, 323.0) 9.4 months (259.0, 357.0) 10.4 months Hazard ratio (95% CI) (0.564, 1.249) Moreau et al. Blood 2010;116(21): Abstract 312, oral presentation

15 Pharmacokinetics Bortezomib IV (n=14) Bortezomib SC (n=17) C max (ng/ml), mean (SD) 223 (101) 20.4 (8.87) T max (hours), median (range) 0.03 ( ) 0.50 ( ) AUC last (ng.h/ml), mean (SD) 151 (42.9) 155 (56.8) Mean bortezomib concentration (ng/ml) Bortezomib exposure following SC injection was equivalent to that following IV administration IV (n=14) SC (n=17) Time (hours) Moreau et al. Blood 2010;116(21): Abstract 312, oral presentation

16 Peripheral Neuropathy (PN) Bortezomib IV (n=74) Bortezomib SC (n=148) P- value* Any PN event, % Grade 2, % Grade 3, % Risk factors for PN, % Grade 1 PN at baseline Diabetes at baseline Exposure to prior neurotoxic agents *P-values based on 2-sided Fisher s exact test Moreau et al. Blood 2010;116(21): Abstract 312, oral presentation

17 Recommendations and discussion points: induction treatment Aim of induction: achieve high CR rate prior to transplant VAD should no longer be used TD / Rd sono probabilmente trattamenti subottimali Induction regimens should be bortezomib-based based 3-agent regimens superior to 2-agent 2 combinations 4-agent regimens not superior over 3-agent 3 combinations, but longer follow-up needed Number of cycles: short induction (3 4 4 cycles) With s.c. administration cycles

18 EFFECT OF NOVEL AGENTS ON STEM CELL COLLECTION Thalidomide Adequate collection of stem cells 1,2 Bortezomib Not cytotoxic to bone marrow Successful mobilization and adequate collection of PBSC with variety of induction regimens Breitkreutz et al. Leukemia 2007;21: Cavo et al. Blood 2005;106: Kumar et al. Blood 2009;114: Moreau et al. Leukemia 2010;24: Cavo et al. Lancet 2010;376:

19 EFFECT OF NOVEL AGENTS ON STEM CELL COLLECTION Lenalidomide Cytotoxic effect on bone marrow Evidence of decreased stem cell yield after lenalidomide exposure Recommendation: - Collection of PBSC within 4 months of initiation of therapy - Mobilization with G-CSF + cyclophosphamide after 4 months of therapy and/or in patients aged 65 years Kumar et al. Blood 2009;114:

20 Comparison between different induction regimen: post-asct results 88% 72% VGPR CR 68% 47% 87% 85% 78% VTD CR/nCR Ludwig 76% CR/nCR Cavo 70% 64% VTD MAX CR 57% TD o VAD MAX CR 37% 3 cicli + 2 ASCT (100%) +2 consol *CR/nCR * 4 cicli + 2 ASCT** 4 cicli + ASCT 6 cicli + ASCT ** 33% VD

21 Comparison between different induction regimen: post-asct results 88% 72% VGPR CR 68% 87% 85% 78% 64% VTD MAXVGPR 88% TD MAX VGPR 72% 47% VAD MAX VGPR 47% 3 cicli + 2 ASCT (100%) +2 consol *CR/nCR * 4 cicli + 2 ASCT** 4 cicli + ASCT 6 cicli + ASCT ** 33% VD

22 Raccomandazioni e punti aperti: trapianto nell era era dei nuovi agenti Il trapianto rimane lo standard per i pazienti giovani Uno o due trapianti? In prima linea o alla ricaduta? Alcuni studi in corso che confrontano il trapianto upfront verso i nuovi farmaci

23 Argomenti a favore del trapianto singolo Dati del doppio controversi, TMO migliora la PFS ma non l OSl

24 Argomenti a favore del trapianto singolo Solo i pazienti che ottengono una risposta subottimale sembrano beneficiare di una seconda procedura, ma adesso possibilità di consolidamento con I nuovi farmaci Con i nuovi farmaci inseriti nei programmi di terapia ad alte dosi le risposte VGPR sono spesso >70-80% 25-35% dei pazienti non completa il programma con il II trapianto Pazienti con malattia refrattaria o ad alto rischio non sembrano beneficiare di due procedure

25 Argumenti a favore del trapianto in prima linea I pazienti tollerano meglio una terapia intensiva L esposizione ai nuovi farmaci potrebbe favorire lo sviluppo di cloni resistenti e quindi ridurre la possibilità di risposta al momento della ricaduta Al momento comunque il trapianto ha dato i risultati migliori in prima linea

26 Treatment options after transplantation VGPR following SCT? Yes No No treatment Consolidation with Thal? VTD? Lenalidomide? Second transplant? Consolidation: Thalidomide Dose? Duration? Other novel agent combination? Ludwig et al. Oncologist 2010;15:6 25

27 Malattia residua: sempre presente! La malattia residua, principale responsabile delle ricadute, è sempre presente, dopo CC, trapianto singolo o doppio con o senza nuovi farmaci!! L entità della massa residua è correlata alla rapidità della progressione

28 Phase 3: bortezomib consolidation versus no consolidation following ASCT Efficacy, % Post-ASCT Bortezomib Observation CR/nCR Post-consolidation (6-months post- randomization) CR/nCR <0.005 Improved from PR to CR/nCR Relapse during initial 6 months 1 6 <0.05 Median number of bortezomib injections: 19 (of 20); median 90% of total planned dose Bortezomib held for 1 cycle in 31 patients, mainly due to neuropathy (n=11) or PD (n=8) Conclusion Consolidation with bortezomib given as a single agent is feasible and improves response after ASCT P Grade 3/4 adverse events with bortezomib consolidation Neutropenia 22% Thrombocytopenia 9% Neurologic pain 5% Sensory neuropathy 3% Mellqvist et al. ASH 2009 (abstract 530)

29 Consolidation with VTD Patients: (n=39) ) with VGPR after ASCT Treatment: 4 cycles VTD, started within 6 months Bortezomib: 1.6 mg/m 2, days 1, 8, 15, 22 Thalidomide: initial dose 50 mg/day, with increments up to 200 mgm Dex: 20 mg/day, days 1-4, , Results: at 32 month median follow up Six patients achieved molecular remission; none had clinical relapse 50 month PFS: 100% for patients with MR vs 62% for patients with no MR Ladetto et al. ASH 2009 (abstract 960)

30 Post-ASCT maintenance with thalidomide in multiple myeloma Better response rate and PFS in all studies but discordant results on OS Better results in patients with VGPR after ASCT Prolonged exposure to thalidomide can select clones more resistant to therapy so that successive therapies are less effective in controlling disease Thalidomide-related neuropathy is dose dependent and the possibility of reversibility is related to the length of exposure Probably more effective as consolidation than maintenance

31 Prospective, randomized study of lenalidomide after ASCT (IFM ) Results 542 patients evaluable (received at least one dose of consolidation ion treatment with lenalidomide) 435 patients (80%) could receive the planned 2 cycles of consolidation 64 patients (12%) could receive the 2 cycles with a reduced dose 43 patients (8%) had to definitively discontinue lenalidomide Post-ASCT 2 cycles Len CR 13% 19% VGPR 58 % 68% Placebo Len CR 22% 25% VGPR 70% 77% 3-yrs PFS 35% 80% 68% 88% Median follow up from randomization 24 mos PFS benefit observed in all patients indipendently by induction, type of post-asct response, prognostic factors at onset, cytogenetic abnormalities Attal et al. ASCO 2010

32 Prospective, randomized study of lenalidomide after ASCT (IFM ) Adverse events Study grade 3 neutropenia (%) grade 3 febrile neutropenia (%) Secondary malignancies (%) Discontinuatio n (%) IFM Due to SAEs, 8 CALGB Due to AEs, 12 other reasons, 13 1.Attal et al. Blood 2010; 116(21). Abstract McCarthy et al. Blood 2010; 116(21). Abstract 37

33 Lessons learned from other hematological diseases The better the quality of response, the longer the survival Current definition of CR is suboptimal CR is just the first step to maintain CR Mateos, EHA 2010

34 Depth of response Progression Treatment initiation MR PR VGPR ncr CR scr Time Depth of response is related to TTP

35 Definition of CR EBMT Negative immunofixation in serum and urine Complete Response 1 Complete Response 2 <5% plasma cells in bone marrow No increase in number of lytic lesions Disappearance of soft tissue plasmacytomas IMWG Negative immunofixation in serum and urine Disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow As above plus: Normal free light chain ratio Stringent Complete Response 2 Absence of phenotypically aberrant plasma cells in BM by multiparametric flow cytometry No new bone lesions 1 Maintained for >6 weeks 2 Requires two consecutive assessments done at any time Blade et al. Br J Haematol 1998;102: Durie et al. Leukemia 2006;20: Report of the 2008 International Myeloma Workshop consensus panel

36 Transplant setting: Impact of MRD assessment on survival PFS 62% 30% Median: 71 months Median: 37 months OS 87% 59% Medians: not reached 0 P< years Months Months MRD negative (n=94) MRD positive (n=53) MRD assessed by immunophenotyping in BM obtained 3 months after ASCT in CR patients (negative immunofixation) (n=147) MRD, minimal residual disease 0 P= years Paiva et al. Blood. 2008;112:

37 Importance of achieving durable complete response (Results from TT2*) 100% Survival by 3 year CR 80% 60% 40% 20% 0% Median Deaths/N in years SUS-CR 28/256 NR NON-CR 63/ (4,6) LOS-CR 23/ (1,2) P value: a v b<0.0001, b v c <0.0001, a v c < Years from 3 years from enrollment *Total therapy 2 regimen: Induction: VAD, DCEP, CAD, DCEP (TT2) Double transplantation: MEL 200 x 2 Consolidation: DCEP vs DCEP/CAD Maintenance: Interferon SUS-CR: achieved and sustained CR status NON-CR: never achieved CR status LOS-CR: attained and lost CR status Randomization: thalidomide throughout vs no thalidomide Barlogie et al. Cancer 2008;113:

38 Se la RC è l obiettivo principale della terapia del mieloma multiplo Probabilmente conviene continuare il trattamento anche quando si ottiene una RC Il consolidamento, il mantenimento o entrambi potrebbero avere un ruolo centrale

39 Conclusioni Obiettivo principale del trattamento deve essere l ottenimento di una remissione completa il più profonda (diversi livelli di RC) e duratura possibile La remissione completa è associata con Sopravvivenza prolungata Treatment-free interval prolungato Migliore qualità della vita E vero per tutti i pazienti? Dati non ancora definitivi sul mantenimento