ASFA 2016 Annual Meeting

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ASFA 2016 Annual Meeting Palm Springs, May 4-7,

Perseghin, MD Clinical Pathology Dept Apheresis

1 ASFA 2016 Annual Meeting Palm Springs, May 4-7, 2016 Educational Session IV: International Committee Session Extracorporeal Photochemotherapy (ECP) Around the World Paolo Perseghin, MD Clinical Pathology Dept Apheresis Unit Ospedale San Gerardo de Tintori Università di Milano-Bicocca Monza-Italy

Treatment of Cutaneous T-Cell Lymphoma by Extracorporeal Photochemotherapy 9

FDA approval granted for advanced CTCL in 1988, as the first government

Approximately 80% of immunocompetent CTCL patients have a >50% diminution in

Persistent (>18 month) complete responses was corroborated by loss of

2 Treatment of Cutaneous T-Cell Lymphoma by Extracorporeal Photochemotherapy 9 of 37 CTCL patients: >75 response Edelson R et al, NEJM 1987 Pre Post Pre Post FDA approval granted for advanced CTCL in 1988, as the first government sanctioned selective immunotherapy for any cancer. Approximately 80% of immunocompetent CTCL patients have a >50% diminution in cutaneous involvement, while 25% experience complete responses. Persistent (>18 month) complete responses was corroborated by loss of identifiable malignant T cell clone by TCR PCR assessment. Toxicity is remarkably low and less than with all alternative systemic therapies.

3 To be added: Type 1 diabetes So far, published studies on ECP (mostly retrospective) differ in: Devices and methods (Therakos vs two-step technique) Treatment schedule Patient selection criteria

4 ECP and JACIE

5 ECP is the first immunomodulatory treatment largely applied within the clinical setting Very well tolerated even in low weight patients (pediatric), need for suitable devices with low extracorporeal blood volume It allows for steroid and/or immunosuppressive drugs tapering in responding patients Minimal (and easily manageable) side effects, mainly related to ACD-A or to decreased platelet and RBC count (repeated procedures) Medium- long term treatment ( 10 % of patients > 6 months) Needs for suitable venous accesses (peripheral and/or CVC, Midline, etc) Needs for suitable devices ( local regulations, i.e. FDA)

6 Side effects Greinix et al. Blood, 2000

7 Summary Technical details Putative mechanism(s) of action Focus on selected indications Something new Conclusion

8 ECP in Italy from 2000 to 2015 (partial) ECP centers active in Italy (year 2015): 25 ECP procedures mostly performed by using the off-line technique 1) G. De Silvestro et al: National survey of apheresis activity in Italy. Trans Apher Sci ) G. De Silvestro, National survey of apheresis activity in Italy Int J Art Organs ) G. De Silvestro et al: personal comunication

9 On-line method (2) Continuous flow cell separator Therakos Cellex Low extracorporeal blood volume Rangarajan HG et al No data about cell dose/kg

10 24 pts with cgvhd 28 pts with lung Tx rejection Cellex better than UVARXTS

11 Off-line method (1) Off-line: I step = MNC collection

12 Off-line method (2) II and III steps: 8-MOP + UV-A irradiation 8-MOP at 200 ng/mlfinal concentration) UV-A irradiationat 2 J/sqcm (Vilber-Lourmat, France; UVA-PIT, etc) infusion (30-40 min.)

Mechanisms of ECP action modification of endothelial adhesion molecules with reduced T-lymphocyte migration modification of the expression of MHC molecules on the plasmamembrane alteration of the TCR

14 Mechanisms of ECP action modification of endothelial adhesion molecules with reduced T-lymphocyte migration modification of the expression of MHC molecules on the plasmamembrane alteration of the TCR of the activated cells shift in Th1/Th2 balance enhancement in the regulatory action of CD8+ T-cells activated by the antigen 8-MOP cross-linking with DNA leading to apoptotic death of the activated cells within days generation of DCs from monocytes generation of clone-specific suppressor T-cells

16 ECP: Putative mechanism/s of action Klassen J, Curr Oncol 2010 Clearance of apoptotic cells by antigen-presenting cells results in differentiation of those cells into a more tolerogenic phenotype leading to decreased stimulation of effector T cells or their deletion. Production of anti-inflammatory cytokines, especially interleukin 10, is increased. Production of pro-inflammatory cytokines, especially interleukin 12 and tnfα, is decreased. Generation of CD4+, CD25+, GITR+, Foxp3+, CD62L+ T- regulatory cells occurs. It is of considerable interest that the T- and B-cell responses to novel and recall antigens remain intact in patients treated with ECP. Thus, there appears to be a reduced risk of infections with the use of ECP as compared with the use of other immunosuppressive agents

17 Transfusion and Apheresis Science, 2014

18 PHOTOPHERESIS FOR THE PREVENTION OF REJECTION IN CARDIAC TRANSPLANTATION Barr M et al, NEJM, 1998 Prospective, multicenter, randomized study 60 patients

19 Extracorporeal photochemotherapy: a new therapeutic approach for allograft rejection Dall Amico R et al, Transf Apher Sci, patients who underwent renal tx Recurrent/refractory rejection unersponsive to standard immunosuppressive treatment Clinical improvement in 7 out of 11 (63 %) ECP schedule: 1/w x 1 month 1/ 2w x 2 months 1/m x 3 months

20 The Use of Extracorporeal Photopheresis for Allograft Rejection in Liver Transplant Recipients Urbani L et al.transpl Proc, 2004

21 The efficacy of photopheresis for bronchiolitis obliterans syndrome after lung transplantation Morrell M et al., J Heart Lung Transplant 2010;29: Retrospective study 60 patients who developed BO after lung tx Unresponsive to immunosuppressive treatments (PDN, sirolimus, tacrolimus, Azth, etc) Changes in the forced expiratory volume(fev)

22 GvHD: an unresolved issue allo-hsct/yr La ridotta mortalità peri-hsct ha incrementato il n dei long-term survivor e quindi il rischio di sviluppare GvHD agvhd: % matched-related HSCT % matched-urd HSCT - grade III: 25% survivor a 5 anni - grade IV: 5% survivor a 5 anni Terapia standard: PDN ± CSA: risposta %... Altre terapie (MSC) cgvhd: % (PBSC > BM) - Poor prognosis : 40 % survivor a 5 anni - Good prognosis: 70% survivor a 5 anni - Terapia: PDN, CSA, Tacrolimus, MMF, etarnecpt, sirolimus, Rituximab, ECP

23 ECP schedule (1) Author Year/ journal Pts (n ) Diagnosis Method Schedule Cell dose Greinix 2000 Blood 21 agvhd (II-IV) On-line 2/w until improvement then 2/2-4 w No Response: 100%, 67 % and 12 % (gr. II, III and IV) max. after a median of 4 courses (8 ECP or 2 mts) Kanold : agvhd Both 2w x3w, then 2/2w, 2/4w Most no (review) Transf. Aph. Sci 54:cGvHD 3w x 3w then tapering 2w/2w until response 2w/3w x 6 mts Foss 2005 BMT Couriel 2006 Blood Response: agvhd= 63 %, cgvhd=75% 25 cgvhd On-line 2w/2w in 17 pts Response: 66-70% 1w/until response in 8 pts 71 cgvhd On-line 2-4/w then tapering (1/w) to 2/2w Response: 61 % (overall) No No

24 ECP schedule (2) Author Year/ journal Pts n Diagnosis Method Schedule Cell dose Garban 2005 Haematol 27 12:aGvHD 15:cGvHD Off-line 2w x 3w, then according to response (1w) Yes Greinix 2006 Haematol 59 (21 p.r) Response: agvhd=75%, cgvhd= 87 % agvhd On-line 2/1-2 w, then 2/ 2-4 w No Perseghin 2007 Ther Apher Dial Response: 82% skin, 61 % gut and liver, lower when combined 25 cgvhd Off-line 2w x 3w, then 2w/2w and 2w/4w Response : 80% (maintained > 30 mts in 90% pts) Yes

25 95 pazienti

26 T-regs increase in ECP-responders allows immunosuppressive drug tapering Biagi et al. Transplantation, 2007

27 * p<0,05 (compared to CD25-) W/O T-reg With T-reg + transwells With T-reg W/O transwells T-regs show inhibitory capacity towards allo-reactivity Biagi et al. Transplantation, 2007

28 Foxp3+/ CD4+CD25+cells Foxp3+/ CD4+CD25+c ells %CD4+CD25+/ CD4+ cells %CD4+CD25+/ CD4+ cells Patients responding to ECP present a marked increase of T-reg, which is not observed in ECP non-responder patients. T-reg are, as expected, Foxp3-positive Responders to ECP (n=18) ECP- NON Responders (n=9) ECP cycles ECP cycles Responders to ECP, FOXP3 ECP- NON Responders, FOXP ECP cycles ECP cycles

29 CD4+CD25+/CD4+ CELLS %CD4+CD25+/CD4 %CD25CD4(FOX) %CD25CD4(FOX %CD4+CD25+/CD3+CELL S %CD4+CD25+/CD3+ T-regs variations in ECP-responders with acute (left) and chronic (right) GvHD %CD4+CD25+/CD3+ CELLS agvhd %CD4+CD25+/CD3+ CELLS cgvhd ECP cycles ECP cycles %CD25+CD4+(FOX)/CD4 CELLS agvhd %CD25CD4(FOX)/CD4 CELLS cgvhd ECP cycles ECP cycles CD4+CD25+/CD4+ CELLS agvhd %CD4+CD25+/CD4 CELLS cgvhd ECP cycles ECP cycles

30 Blood,2014 Two donor s blood volume (Spectra) T cons separated on CliniMacs by using neg selection, then cryopr. T regs : 1) Cd8/Cd19 depl, then CD25+ positive selection 95 % of patients showed full engrafment, only 15 % had a grade II agvhd

31 SIdEM-GITMO recommendations (1)

32 SIdEM-GITMO recommendations (2)

35 No definite indications for its use as first and second line treatment

37 news

38 Merlin et al. Cytotherapy, healthy donors Cryo-MNC retain their antiproliferative properties

39 Merlin et al. Cytotherapy, 2010

40 3 pts with PDN-resistant agvhd (bw 11-33Kg) 56 BC-preparations 5-8 ml/kg whole blood Close system (for CB collection) RBC and UV-A-treated BC returned to the pts All 3 CR, alive and well

41 Elafin A TNF-α-induced epidermal proteinase inhibitor Elevated only in pts with cutaneous GvHD,not in those with GI involvement or in those w/o GvHD August et al, BMT,2010 T-cell activation markers: scd8,sil-r, scd40 ligand and scd28 Inflammatory marker: stnf-r1

42 2 Consecutive ECP within 4 days before beginning the preparative regimen

43 Group A1: conditioning 920 cgy and post-grafting MTX with ECP at days -2, -1 Group A2: conditioning 920 cgy and post-grafting MTX with ECP at days -6,-5 and pentostatin at days -4,-3 No positive impact of ECP +/- pentostatin

44 ..ECP is a powerful tool and that we are still learning the best ways to use it. It is time to set up a strong and fruitful cooperation between those centers which currently perform ECP, designing multicenter trials, which aim to ascertain the real effectiveness of ECP and the best way to apply it, asking for financial support from central national and /or European institutions to avoid any company interference.

Acknowledgements Clinica Pediatrica-CTMO Università di Milano-Bicocca C. Uderzo, MD A. Balduzzi, MD A. Rovelli, MD E. Biagi, MD, PhD Divisione Ematologia adulti-ctmo Università di Milano-Bicocca Prof.

45 Acknowledgements Clinica Pediatrica-CTMO Università di Milano-Bicocca C. Uderzo, MD A. Balduzzi, MD A. Rovelli, MD E. Biagi, MD, PhD Divisione Ematologia adulti-ctmo Università di Milano-Bicocca Prof. EM. Pogliani, MD P. Pioltelli, MD M. Parma, MD E. Terruzzi, MD D. Belotti, BSc, PhD Centro M.Tettamanti, Clinica Pediatrica Ospedale San Gerardo di Monza: I. Di Biaso, V. Leoni, MD G. D Amico, BSc, PHd E. Dander, BSc, PhD G. Renoldi, BSc G. Gaipa, BSc, PhD C. Bugarin, BSc V. Rossi, LT Prof A.Biondi, MD Unità Aferesi e nuove tecnologie trasfusionali G. Confalonieri, MD E. Bruna, RN L. Meroni, RN E. Casarotto, LT M. Pozzi, LT V. Baldini, MD M. Dassi, BSc A. Incontri, BSc P. Perseghin, MD Dipartimento di medicina preventiva e tecnologie biomediche- Università di Milano-Bicocca S. Galimberti, PhD Thank you!

46 ECP: the role of CYTOKINES Increase of inhibitory CKs (Th2 cells): IL-10 IL-4 TGF-beta Decrease of inflammatory CKs (Th1 cells): IL-2 IFN-gamma TNF-alfa IL-1 Increase of plasmocytoid DC2 Decrease of monocytoid DC1

Kavita Raj Consultant Haematologist KHP

Kavita Raj Consultant Haematologist KHP 1950s Billingham and Brent injection of spleen cells from adult mice into newborn mice Thickening and loss elasticity of skin, red soles, exfoliation, diarrhoea