Linfoma di Hodgkin Ruolo del trapianto nella strategia di salvataggio. Angelo Michele Carella U.O.C. Ematologia 1 IRCSS A.O.U. San Martino IST Genova

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1 Linfoma di Hodgkin Ruolo del trapianto nella strategia di salvataggio Angelo Michele Carella U.O.C. Ematologia 1 IRCSS A.O.U. San Martino IST Genova

2 Therapeutic Options for Relapsed/Refractory Patients Radiotherapy Salvage Chemotherapy and ASCT Allogeneic Stem Cell Transplantation New drugs

3 HIGH DOSE CHEMOTHERAPY AND AUTOLOGOUS STEM CELL TRANSPLANTATION

4 High dose chemotherapy with autologous bone marrow transplantation in 50 advanced resistant Hodgkin s disease patients: an Italian study group report. Carella AM, Congiu AM, E Gaozza,, P Mazza, P Ricci, G Visani, G Meloni, G Cimino, L Mangoni and P Coser J.Clin.Oncol ;6:

5 ASCT is the standard therapy for HL relapsing after 1 st line chemotherapy BNLI Trial Mini-BEAM + ABMT vs Mini-BEAM N. of patients TRM EFS (3 ( yrs p value Mini-BEAM Mini-BEAM + ABMT Linch DC, Winfield D, Goldstone AH, Moir D, Hancock B, McMillan A, Chopra R, Milligan D, Hudson GV. Lancet 1993;341: :1051-4

6 Early, late and multiple relapse 2 x Dexa-BEAM CR or PR 2 x Dexa-BEAM CR or PR 2 x Dexa-BEAM BEAM + PBSCT Schmitz N., Pfistener B, Sextro M, Sieber M, Carella AM, Haenel M, Lancet 2002;359:

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9 EBMT Lymphoma Registry SCT for HD Results of ASCT in primary refractory pts are significantly poorer. Should we do something else? n = 75 bx-proven PR ( 39M/36F ) Age: 24 yrs (range, 12 48) Lines of tx before ASCT: 1 line: 42 pts 2 lines: 33 pts Sensitive disease prior to ASCT: 48 pts 100-day TRM: 9% Prognostic factors: Chemosensitivity to second line of tx before ASCT Moskowitz et al. BJH 2004 LWP May 2006

10 Dose Intensity of chemotherapy in patients with relapsed/refractory Hodgkins Lymphoma R E G I S T R DH A P PBSC DH A P RAN DO M IZ BEA M A TI A TI O N DH A P DH A P O N C TX M TX B VP EAM 16

11 The Cologne High-Dose sequential protocol seemed to be an option to improve results of refractory/relapsed patients

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13 Not all patients with relapse HL do equally well after an ASCT

14 Dose intensity of CH in patients with Conclusion: relapsed Hodkgin Lymphoma (A. Josting et al. JCO 2010) Compared with conventional HDC, additional sequential HDC is associated with more adverse effects and does not improve the prognosis of patients

15 Is further improvement in the ASCT setting possible? Inclusion of PET/CT evaluation in the ASCT Maintenance therapy after ASCT. New drugs: LBH589 (Panobinostat( Panobinostat) SGN-35

16 PET Scan can also discriminate those patients with worse outcome after ASCT Progression free survival Overall survival Jabbour et al, Cancer 2007

17 OS OS from relapse after an ASCT. The experience of the LWP 39.5% (95% CI: 35-44) at 3 years 29.7% (95% CI: 25-34) at 5 years Stage at relapse B symptoms at relapse Bulky disease at relapse Extranodal involvement at relapse Poor performance status at relapse Early relapse (<6 m) after 1ASCT Months from relapse Median follow-up of survivors 50 months (75% of cases > 34 months) Martínez et al. (unpublished results)

18 Hodgkin s Lymphoma (NR/Rel Rel < 12 mo., END at the time of ASCT Panobinostat IGEV (ONC ) ASCT* (SGN ) Placebo SGN-35 SGN-35 (SGN ) *Hypofractionated tailored Total Lymphoid Irradiation with Helical Tomotherapy

19 Current Indications for SCT in HL. Recommendations from the EBMT (BMT, 2010) ASCT CR1 GNR/I Sens R / CR2 Refract Disease S/I CO/II S. Standard D. Developmental Levels of Evidence: I, II, III CO. Clinical Option GNR. Generally not recommended The European Group for Blood and Marrow Transplantation

20 Take home messages ( I ) ASCT is the standard therapy for HL patients in chemosensitive relapse. The results of ASCT are significantly worse in those patients with primary refractory disease. New therapeutic options are needed. Maintenance therapy with new drugs would eventually improve the long term outcome of ASCT in patients at high risk of relapse

21 ALLOGENEIC STEM CELL TRANSPLANTATION

22 Allo-SCT vs ASCT Advantages Disadvantages No malignant cells reinfused Lower relapse rate Graft-vs vs-hl effect Higher non-relapse mortality Lack of HLA id donor

23 Reduced-intensity conditioning compared with conventional allogeneic stem-cell transplantation in relapsed or refractory Hodgkin s s lymphoma: an analysis from the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. Sureda A, Robinson S, Canals C, Carella AM, Boogaerts MA, Caballero D, Hunter AE, Kanz L, Slavin S, Cornelissen JJ, Gramatzki M, Niederwieser D, Russell NH, Schmitz N. J Clin Oncol ;26:

24 RIC-allo Compared with MAC in Relapsed or Refractory HL NRM PFS 1.0 RR 2.42 (95% CI ) p< RR (95% CI ) p= Conventional (n=93) RIC (n=97) 0.4 RIC (n=97) Conventional (n=93) Time after SCT Time after SCT Estimate of the NRM and PFS based on a COX model, adjusted by all covariates with impact on the outcomes. RR and p values from multivariate Cox model.

25 1,0 Relapse or Progression (%) Impact of cgvhd after allo-sct in relapse rate and PFS RR 1.89 (95% CI ) p=0.04 1,0 RR 1.57 (95% CI ) p=0.1 0,8 0,6 0,4 0,2 Progression free survival (%) 0,8 0,6 0,4 0,2 0,0 0, Time after allo-sct (months) Time after allo-sct (months)

26 DLIs modulate relapse risk in mixed chimeras and induce durable responses in relapsed patients treated with a T-Cell depleted RIC No DLIs and MC No DLIs because FC agvhd 0-1 agvhd 2-4 / cgvhd DLIs for MC FC with no agvhd Peggs et al, JCO 2011 FC at 9 mo with agvhd

27 Reduced intensity conditioning allogeneic stem cell transplantation for Hodgkin's lymphoma: identification of prognostic factors predicting outcome. Robinson SP, Sureda A, Canals C, Russell N, Caballero D, Bacigalupo A, Iriondo A, Cook G, Pettitt A, Socie G, Bonifazi F, Bosi A, Michallet M, Liakopoulou E, Maertens J, Passweg J, Clarke F, Martino R, Schmitz N; Lymphoma Working Party of the EBMT. Haematologica Feb;94:230-8

28 RIC-Allo for HL: Identification of factors predicting outcome Adverse Fc for NRM: age > 45 years poor performance chemorefract disease Risk of disease progression after 9 months of RIC according to the development of cgvhd (Landmark ( analysis 1.0 NRM 1.0 Progression p= adv Fc ( n=27 ) 0.6 No c GVHD ( n=63 ) c GVHD ( n=57 ) 1 adv Fc ( n=91 ) Months after RIC No adv Fc ( n=124 ) Months after RIC

29 RIC-Allo for HL: Identification of factors predicting outcome 1.0 PFS 1.0 Overall Survival % at 3 yrs % at 3 yrs Months after RIC Months after RIC- SCT PFS and OS for patients with chemosensitive disease and good performance status at SCT treated with a RIC SCT in the period (n=104).

30 HDR-Allo Protocol PBSCs Fludarabine Melphalan ATG (URD) Mtx 10 mg/m 2 CsA Sureda et al (unpublished results)

31 Non-relapse mortality Age > 45 yrs, HR 2.1 ( ), p = 0.05 Performance status 2, HR 3.4 ( ), p = 0.05 Refractory disease, HR 2.8 ( ), p = 0.01 CI NRM (%) % at 100 days 15% at 1 yr 17% at 2 yr 19% at 3 yr Time after RIC-allo (months) Sureda et al (unpublished results)

32 Relapse Incidence 1.0 Refractory disease, HR 2.0 ( ), p = 0.01 CI Relapse Incidence (%) % at 1yr 49% at 2yr 59% at 2yr Time after allo-sct (months) Median time to relapse: 6 (3 35) months Sureda et al (unpublished results)

33 Impact of cgvhd on Relapse Incidence No cgvhd (n = 35) CI cgvhd (%) cgvhd (n = 32) p= Time after RIC-allo (months) Sureda et al (unpublished results)

34 Progression free survival by disease status at RIC-allo p=0.01 PFS (%) Sensitive patients (n = 50) 0.2 Refractory patients (n = 28) Time after RIC-allo (months) Sureda et al (unpublished results)

35 Overall survival by disease status at RIC-allo 1.0 OS (%) Sensitive patients (n = 50) Refractory patients (n = 28) 0.2 p= Time after RIC-allo ( months ) Sureda et al (unpublished results)

36 Current Indications for SCT in HL. Recommendations from the EBMT (BMT, 2010) Allo-SCT HLA Matched Well matched mmurd / >1 Sib URD / 1 Ag Ag mm Sib mm Sib CR1 GNR/III GNR/III GNR/III Sens R / CR2 CO/II CO/II CO/II Refract Disease D/II D/II GNR/II S. Standard D. Developmental CO. Clinical Option GNR. Generally not recommended Levels of Evidence: I, II, III The European Group for Blood and Marrow Transplantation

37 Which are the next steps in the allo-sct setting? Decrease the relapse rate after allo-sct Better selection of the patients. Role of PET Modification of the conditioning regimen Take a better advantage of the GVL effect Maintenance therapy after allo-sct with new drugs

38 Which are the next steps in the allo-sct setting? Evaluate the role of allo-sct in other settings 1 st relapse with adverse prognostic factors

39 Tandem auto/allo transplantation (I) Each modality has its limitations AutoSCT: standard therapy for relapsed patients. The relapses remain the most important causes of treatment failure AlloSCT: lower relapse rate compared to ASCT. High mortality risk (conditioning reg., immunosuppressive drugs, GVHD)

40 Tandem auto/allo transplantation (II) this tactic could provide the benefit of a conventional allograft but with reduction in the typical acute toxicities and associate mortality of myeloablative therapy J.O. Armitage,, Hodgkin Lymphoma, 2 Edition, 2008

41 Autografting followed by non-myeloablative immunosuppressive chemotherapy and allogeneic peripheral blood hematopoietic stem-cell transplantation as treatment of resistant Hodgkin s disease and non-hodgkin s s lymphoma. Carella AM, Cavaliere M, Lerma E, Ferrara R, Tedeschi L, Romanelli A, Vinci M, Pinotti G, Lambelet P, Loni C, Verdiani S, De Stefano F, Valbonesi M, Corsetti MT. J Clin Oncol 2000;18:

42 Tandem autograft/reduced-intensity reduced-intensity allograft for relapsed/refractory refractory Hodgkin s lymphoma: maximizing graft vs. lymphoma effect by early allotransplant after intensive cytoreduction E. Todisco,, A. Santoro, et al. Dipartimento di Onco- Ematologia Istituto Clinico Humanitas,, IRCCS, Milano A.M. Congiu,, A.M. Carella, et al. U.O. Ematologia 1, Azienda Ospedaliera Universitaria IST, IRCCS, Genova

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44 Take home messages ( II ) Allo-SCT is an effective salvage therapy for patients relapsing after an ASCT. Non-relapse mortality is not a significant issue nowadays. Major efforts should be dedicated to decrease the relapse rate after allo-sct. Results of MUD transplants are not significantly different from HLA id sib allo-sct.