Novit in Ematologia: la comunicazione, le terapie innova6ve e di - PowerPoint PPT Presentation

Novità in Ematologia: la comunicazione, le terapie innova6ve e di supporto, la sostenibilità MODENA 18-19 MAGGIO 2017 NOVITÀ IN TEMA DI TRAPIANTO ALLOGENICO FRANCESCA BONIFAZI Hematology Seragnoli University Hospital S. Orsola-Malpighi, Bologna

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GITMO Trapianto Allogenico Allotrapianti registrati (N=32570) 2500 2083 2000 168817631718176517381796 1603 14191451 1490 1496 1500 1314 1299 11571214 1065 1055 1000 885 669 743 784 445 472 532 558 500 368 0 <1991 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 ANNI al 22 marzo 2017

GITMO Trapianto Allogenico Passweg 2017 Numero Trapianti per principali Patologie Attività 2016 MDS/MPS Solid Tumour Inherited Disorders of metabolism LY (n=232) (n=3) (n=11) (n=232) (12,9%) AA (12,9%) (n=59) MM/PCD ID (n=64) (n=37) LMC (n=23) Haemoglobinopathy LLC (n=51) (n=19) LAL (n=328) LAM (18,3%) (n=678) al 22 marzo 2017 (36,1%)

GITMO Trapianto Allogenico URD 49.6% Tipo di trapianto Sib HLA id 33.8% Haplos 12% HLA id. sib. Unrelated Donor Passweg 2017 Fam. Mismatch /Aplo Fam. Match 1000 790 785 761 758 753 741 738 717 703 687 664 639 657 N. TRAPIANTI 618 602 589 571 573 520 519 507 511 497 493 486 500 454 432 425 390 315 225 188 180 168 150 122 28 28 29 24 24 21 18 18 18 8 7 6 0 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 ANNI al 22 marzo 2017

Passweg 2017 Passweg BMT 2015 7

PT-CY and Haplos Kanate, Mussetti, Blood 2016 cGVHD cGVHD cGVHD aGVHD cGVHD cGVHD Ciurea et al Blood 2015

Low immunosuppressive burden after HLA- matched related or unrelated BMT using PT-Cy Kanakry, Blood 2017 9

T- repleted HAPLO pla0orms: PT-CY ATG-CSA-MMF-MTX-BASI SIROLIMUS based approach T- depleted HAPLO pla0orms T-conv/reg αβ -depleGon + suicide genes (IC9, Zalmoxis) 10

BP-004 Clinical Trial Sites • OPBG Lead Clinical Site – 3 addi6onal sites in EU • Mul6ple sites in US BP-004 Evalua6on-Non-Malignant & Malignant (EU and US) With > 100 days F/U (as of 1/20/17) N=91 Selected Non-Malignant Subset evalua6on (EU and US) PID (> 100d F/U) (as of 1/20/17) N=25 Thalassemia β 0 β 0 (> 100d F/U) (as of 1/20/17) N=9 Fanconi anemia (> 60d F/U) (as of 3/20/17) N=9 Selected Malignant Subset evalua6on (EU-OPBG only) Acute Leukemia (> 60d F/U) (as of 3/20/17) N=43 ALL & AML (CR1, CR2) BPX-501 T cells with inducible Caspase 9 for improvement of immune recovery after HLA-haploidentical HSCT 11

BP-004 Trial Outcomes: TRM/NRM (N=91 pa6ents with >100d F/U; EU and US) BPX-501 T cells with inducible Caspase 9 for improvement of immune recovery after HLA-haploidentical HSCT 12

HSV-TK cells (Zalmoxis) approach HSV-TK suicide gene approach • 13 13

TK cells clinical trials Phase I-II TK007 NCT00914628 Phase III TK008 NCT00914628 Ciceri, Bonini et al, Lancet Oncol 2009 Haplo-HSCT* Haplo-HSCT* plus TK cells plus TK cells R (3:1) Haplo-HSCT** *T-depleted (T cells, 1x10 4 /Kg) *T-depleted (T cells, 1x10 4 /Kg) **T-depleted (T cells, 1x10 4 /Kg) or ** unmanipulated BMT/PB + HD CTX Dose of TK cells (1-x10 7 /Kg - 1x10 7 /Kg) Dose of TK cells (1x10 7 /Kg) Up to 4 monthly doses up to IR (CD3+ Up to 4 monthly doses up to IR (CD3+ cell count >/= 100/mcl) cell count >/= 100/mcl) Starting 21 to 49 days after HSCT in Starting 21 to 49 days after HSCT in absence of IR and/or GvHD absence of IR and/or GvHD 14

� Italian ac6vity shows a peculiar clinamen in the ajtutude to haplo transplants � Italy is the cradle of new innova6ve approaches to T-depleted haplo plalorms � The extraordinary success of PT-Cy in haplo transplants will extend this op6on also to standard transplants hopefully on the basis of prospec6ve randomised trials. � The poten6al success of new GVHD plalorms could modify the current algorithm of donor choice: this should be done only in an evidence –based approach.

� GVHD IS DIFFICULT TO CURE: � approximately 50% of paGents will not achieve a sustained CR aZer first-line therapy with steroids and <50% of CR are maintained. � GVHD (SR or severe) NEGATIVELY IMPACTS OUTCOME OS in steroid-resistant (SR) aGVHD: 15% at 2 years (median 6 months) . � GOLDEN STANDARD FOR SECOND-LINE THERAPY STILL MISSING 16

� GVHD GR I SHOULD NOT BE TREATED � RESPONSE RATE BUT RELAPSE � SIGNIFICANT IMPACT ON SURVIVAL � SIGNIFICANT IMPACT ON QOL 17

THERAPIES � NEW DRUGS FOR SR GVHD ARE GOING TO BE TESTED 18

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PROPHYLAXIS of acute or/and chronic GVHD? Servais. Exp Opin on invest Drugs 2016;25: 957-972 20

FOCUSING THE SETTING BM SIBL 9 PBSC URD combinations………. CB HAPLO BM MA SIBL Malign PBSC RIC URD Non malign CB NMA HAPLO 54 combinations………. …on the standard transplant 21

GVHD PROPHYLAXIS: THE EVIDENCES Servais. Exp Opin on Invest Drugs 2016;25: 957-972 22

23 Servais. Exp Opin on invest Drugs 2016;25: 957-972

HLA IDENTICAL SIBLING TRANSPLANT: A STANDARD INDICATION A STANDARD GVHD PROPHYLAXIS 25

Which is the “true” incidence of cGVHD after a sibling HLA identical PBSCT? extensive cGVHD any grade cGVHD Stem Cell Trialists CollaboraGve Group JCO 2005. @ 1 yr 40% @ 1 yr 59% @ 3 yrs 47% @ 3 yrs 68% These data apply to myeloablative transplants!

ATGfamilystudy (NCT 00612875) Sponsor University of Hamburg Germany Principal InvesGgator Nicolaus Kröger Hamburg, Germany NaGonal Coordinators Nicolaus Kröger Hamburg, Germany Francesca Bonifazi Bologna, Italy Carlos Solano Valencia, Spain Arnon Nagler Tel Hashomer, Israel

Treatment plan Age: 18-65 years AML / ALL (≥CR 1 ) HLA-iden6cal sibling donor Sufficient organ func6on Conditioning 1. TBI (10-12 Gy) plus Cy (120 mg/kg) ± VP-16 (30-45mg/kg) or 2. Busulfan (16 mg/kg P.O. or 12.8 mg/kg I.V.) plus Cy (120 mg/kg) ± VP-16 (30-45 mg/kg) Arm A Arm B PBSCT transplant CsA and short course MTX plus: CsA and short course MTX ATG-F (10 mg/kg, days -3, -2, -1) Endpoints evaluation on D+100, D+180, 1 and 2 years post-Tx 28

100% 100% Treatment 80% 80% ATG Cumulative incidence Cumulative incidence Non-ATG 60% 60% 69% p<0.001 52.4% 40% 40% p<0.001 7.6% 20% 20% 32% 0% 0% 0 90 180 270 360 450 540 630 720 0 90 180 270 360 450 540 630 720 Number of patients at risk: Number of patients at risk: ATG 83 77 57 47 43 41 38 38 31 ATG 63 58 50 44 41 40 38 37 30 Non-ATG 72 68 38 23 22 22 18 17 14 Non-ATG 47 43 25 18 18 18 17 17 14 cGVHD cGVHD-ext maximum organ involvement according to NIH criteria (NIH score ≥ 2) Organ ATG-arm non ATG arm risk difference and 95% CI Skin 0 (0.0%) 14 (19.4%) -19.4% [-30%; -10.7%] Oral mucosa 1 (1.2%) 7 (9.7%) -8.5% [-17.6%; -1.3%] Eyes 0 (0.0%) 12 (16.7%) -16.7% [-26.9%; -8.5%] Liver 5 (6.0%) 11 (15.3%) -9.3% [-19.9%; +0.5%] GI tract 1 (1.2%) 2 (2.8%) -1.8% [-8.4%; +4.1%] Pulmonary 1 (1.2%) 4 (5.6%) -4.4% [-12.3%; +1.9%] Genitals 1 (1.2%) 0 (0.0%) +1.2% [-4.0%; +6.5%] Joint and fascia 0 (0.0%) 3 (4.2%) -4.2% [-11.5%; +1.0%] Kroger et al N Engl J Med 2016

NRM Relapse 100% 100% Treatment 80% 80% ATG Cumulative incidence Cumulative incidence Non-ATG 60% 60% p=0.60 p=0.17 32% 40% 40% 14% 20% 20% 27% 12% 0% 0% 0 90 180 270 360 450 540 630 720 0 90 180 270 360 450 540 630 720 Number of patients at risk: Number of patients at risk: ATG 83 78 70 64 63 60 57 54 44 ATG 83 76 63 59 57 54 51 48 40 Non-ATG 72 68 65 63 61 60 59 56 42 Non-ATG 72 68 61 60 58 56 54 54 42 cGVHD/relapse free survival 100% CsA d/C @ 1 yr 91% in the ATG arm 80% Cumulative survival p=0.005 39% in the control arm 60% 37% 40% Ongoing cGVHD @ 2 yr 25% in the ATG arm 20% 60% in the control arm 17% 0% 0 90 180 270 360 450 540 630 720 Number of patients at risk: ATG 83 75 49 42 37 35 33 32 27 Non-ATG 72 66 33 20 18 16 15 14 12 Kroger et al N Engl J Med 2016

DEADLINE for data retrieval JUNE 1st 2017 31

QoL evalua6on Analysis ongoing ATGfamilystudy (NCT 00612875) Significant Improvement of QoL by using ATG as part of the conditioning regimen followed by HLA-identical peripheral stem cell transplantation in acute leukemia patients. Results from a prospective, randomized phase III study ( ATGFamilyStudy) 32