Stem Cell Transplantation

Transcription

1 Stem Cell Transplantation Evelyne Willems Centre Hospitalier Universitaire, ULg, Liège Post-ASH meeting, January 11, 2012, Brussels

2 Plan 1. Select the patient: validation of HCT-CI 2. Select the donor and type of transplant Matched vs mismatched UD Role of donor CMV status Cord blood Haploidentical transplantation 3. Select the conditioning regimen: Bu-Cy vs Cy-TBI 4. Select post-transplant immunosuppression: Siro-Tac vs Tac-MTX 5. Predict and treat GVHD Predict development of GVHD Treat agvhd with MSC 6. Engineered T cells To treat infections : third party virus-specific T cells To treat leukemia : autologous anti-cd19 targeted T cells

3 1. Select the patient Prospective Multi-Center Validation of The Predictive Power of the Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) TRM OS HCT-CT score HR p-value HR p-value High-dose regimen < < RIC/NST regimen < Lymphoid disease < < Myeloid disease < < Sorror et al, CIBMTR (#733)

4 Overall Survival % TRM % 100 Cumulative incidences of TRM among 90 all patients as stratified by the HCT-CI 80 p< Lymphoid or myeloid 60 malignancies 50 HCT-CI 1-2 (28%) n= p<0.001 HCT CI 1-2 (47%) HCT CI 0 (54%) HCT CI 3 (38%) Years after HCT HCT-CI 3 (35%) HCT-CI 0 (24%) Months after HCT Sorror et al, #733

5 HCT-CI also effective in non-malignant diseases and for recipients of autologous HCT (#737 and 814) Non-malignant diseases Multivariate analysis: Higher score increased mortality (HR 2.54 for score > or = 3) Autologous transplants

6 2. Select the donor and type of transplant Unrelated donor AML patients: MUD=MRD for OS (Blood 2012) MDS patients? Saber et al, #355 CIBMTR data

7 UD : in vivo T-cell depletion MA conditioning RIC ATG No ATG p CAMPATH ATG Control p N Acute GVHD II-IV 42% 61% % 38% 40%.0001 Acute GVHD III-IV 17% 34%.0007 Chronic GVHD 32% 55% < % 40% 52% <.0001 Chronic extensive GVHD 14% 43% < NRM 29% 40%.02 21% 26% 23% Relapse 28% 27% NS 48% 51% 38% <.001 OS 55% 50% NS 50% 38% 46% <.008 Bacigalupo, ASH Ed program 2012

8 UD : donor age NMDP 2001 (Kollman, Blood 2001) Donor age = independent risk factor for GVHD, EFS and OS EBMT 2012 (Bacigalupo, ASH Ed program 2012) 719 MDS patients > 50 yrs (555 MSD and 164 UD) no effect of donor age for MSD but strong effect for UD 5-yr OS >50% if MUD < 30 yrs 30% if MUD > 30 yrs or MSD (usually > 50 yrs)

9 Overall Survival Variables MUD MSD<60 MSD 60 p TRM (%) 15 ±2 14 ±1 15 ± Relapse (%) 29 ±3 30 ±2 33 ± Leukemia-free survival (%) 55 ±3 52 ±2 52 ± Overall Survival (%) 56 ±3 63 ±2 57 ± n=1102, AML in CR1 MSD<60 MSD 60 MUD Years ASH # 961 Peffault de Latour

10 Donor CMV status Previous EBMT study: seropositive patient transplanted from unrelated seronegative donor increased TRM and decreased OS But controversial Ljungman et al, #465 54,660 patients transplanted between 1992 and 2008 Seronegative patient with seropositive donor: URD : decreased OS, DFS, and increased TRM, no effect on relapse Sib D : no effect Seropositive patient with seropositive donor: URD, MAC : improved OS, DFS, and decreased TRM RIC : no effect Sib D : no effect For MUD transplants : Select a seronegative donor if patient seronegative Select a seropositive donor if patient seropositive and MAC

11 Alternative donor : cord blood US National Marrow Donor Program 2010 Eapen, Lancet Oncol 2010: PBSC (n=888), BM (n=472) or cord blood (n=165) in adults with acute leukemia Higher TRM but lower relapse and GVHD with cord blood Comparable DFS Limitation of CBT: cell dose for adults (recommended TNC : 2.5 x10 E 7/Kg)

12 Double Cord Blood Double cord blood (Barker et al) (vs single unit) - Also after RIC (Barker, Blood 2003; Rocha, ASH 2006, ) - Higher agvhd (MacMillan, Blood 2010) - Lower relapse and increased DFS (Brunstein, Blood 2010, Kindwall-Keller, BMT 2012; Rocha # 232) MacMillan et al, Blood % single unit, 10% dual chimerism - Verneris # 358: Mixed chimerism associated with : * 6/6 HLA matching between units * increased relapse, decreased agvhd Brunstein et al, Blood 2010

13 Improving CBT Improving engraftment (pilot clinical trials) a) ex-vivo HSC expansion - co-culture with MSC (Robinson, BMT 2010; de Lima, NEJM 2012) - with growth factors (Peled, Cytotherapy 2004; Peled, ASH 2006 #725) b) ex-vivo manipulations to improve homing - Improve cell surface fucolsylation (Robinson, Exp Hematol 2012) - Culture with PGE2 (Cutler, ASH 2011) - Inhibition of CD26/dipeptidyl peptidase (Christopherson, J Immunol 2002 & Science 2004) Ex vivo generation of CB-derived immune cells - NK cells - Tregs - Virus-specific cytotoxic T lymphocytes

14 Haploidentical transplantation Usually T-cell depletion : graft failure, infections and NRM strategies needed to improve the results T cell-depleted haplo-sct : improve immune reconstitution Infusion of pathogen-specific T cells Infusion of T cells engineered to express suicide genes Infusion of T cells after ex vivo photodepletion of alloreactive cells Infusion of regulatory T cells before DLI T cell-replete haplo-sct : selective allodepletion Ex vivo anergy induction Ex vivo selective depletion of T-cell subpopulations In vivo post-transplantation high-dose Cyclophosphamide

15 Haplo vs dcb (Brunstein et al Blood 2011)

16 3. Select the conditioning regimen Lower TRM and improved OS for patients with AML in first CR receiving Bu-Cy compared to Cy/TBI. CIBMTR, Copelan et al, #217. All patients (N = 2284) Bu-Cy : less grade II-IV agvhd = cgvhd & TRM less relapse after 1 yr (IV) = OS AML patients Bu-Cy : less relapse after 1 yr better OS (oral = IV) Oral Bu : many targeted Bu? Copelan et al, #217

17 4. Select post-transplant immunosuppression Tacrolimus/sirolimus versus tacrolimus/methotrexate for GVHD prophylaxis BMT CTN 0402, Cutler et al, #739 Phase 3 prospective randomized trial 304 patients randomized 1/1 between sirolimus and MTX Patients AML/ALL in CR, CML CP/AP, MDS Donor = identical sibling Age 2-60 yrs Conditioning Cy or VP-16 + TBI (>= 12 Gy) Primary endpoint Day 114 grade II-IV agvhd-free survival

18 Results For patients receiving sirolimus: Better : Faster PMN and platelet recovery Milder mucositis score (p<0.001) Lower grade II-IV agvhd (26 vs 34%, p=0.17) grade III-IV agvhd (8 vs 15%, p=0.05) Worse : Higher cgvhd (54 vs 43%, p=0.044) Increased endothelial injury syndromes (VOD, p=0.03; and TMA, p=0.05) Equal : 100-day TRM 2-yr relapse rate DFS & OS no real advantage over MTX

19 5. Predict and treat acute GVHD A. PREDICT An algorithm combining clinical characteristics and day 7 biomarker concentrations. Harris et al, #463 Algorithm combining - Pre-HCT characteristics : age, BM vs other type of graft, HLA matching, GVHD prophylaxis, intensity of conditioning, TBI vs no TBI - 4 biomarkers on day 7 : IL-2Rα, TNFR1, Elafin, Reg3α Score = xAge 16.83xBM xMismatch 0.08xGVHD proph xMA xTBI xlogIl2Ralpha 0.06xlogTNFR1 0.12xlogElafin 0.03xlogReg3alpha 75% sensitivity for II-IV agvhd in the first 2 mo post-transplant Relapse rate = TRM and OS better in low-risk pts

20 5. Predict and treat acute GVHD B. TREAT Safe and effective treatment of GVHD with MSC. (Introna et al, #743, and te Boome et al, #736) # patients with steroid-refractory grade II-IV agvhd (15 grade II, 23 gr III, 9 gr IV) - MSC from healthy donors, expanded in human platelet lysate - Median dose 1.6 x 10 E 6/Kg, median 3 MSC infusions - 64% clinical response, complete in 28% - Better RR for grade II agvhd and when MSC infusion within 30 days from onset - Lower TRM (10% vs 88%, p<0.05) and better OS (88% vs 23%, p<0.05) in responders #743 # pts with steroid-refractory agvhd - CR 56% after median of 53 days - If relapse with gut GVHD, again sensitive to steroids - Anti-viral and anti-leukemic reactive T- cells preserved

21 6. Engineered T cells A. TREAT INFECTIONS Third Party virus-specific T Cells (VSTs) to treat Adenovirus, CMV or EBV infections. Leen et al, #457 Study to evaluate feasibility, safety and effectiveness Generation of Trivirus-Specific T-cell lines using Ad5f35 vectors

22 Results Patients and cell infusions - 44 evaluable patients received VSTs 19 for CMV 16 for AdV 9 for EBV - Cell dose : 2 x 10 E 7 VSTs/m² - 1 to 5 infusions given (If PR, additional doses at biweekly intervals) Safety - No immediate adverse reaction - Little acute or chronic GVHD Acute GVHD within 45 days after infusion : 8 patients 6 had prior history of GVHD, 2 de novo GVHD 6 grade I, 1 grade II, 1 grade III Chronic GVHD flare (had discontinued immunosuppression) : 1 patient - Little other toxicity 2 transplant-associated microangiopathies (both on sirolimus)

23 Efficacy Overall RR 82% 90% - CMV 81% - Adv 67% - EBV Also tissue responses Durable 4/35 (11%) subsequent progression/recurrence but may require several infusions to sustain benefit Days post-vst T-cell expansion seen in approx. 50% of responders with appearance of donor VST-derived TCR sequences

24 7. Engineered T cells B. TREAT LEUKEMIA Generation of CAR-modified autologous T cells targeted to CD19 (Porter, NEJM 2011; Kalos, Sci Trans Med 2011) - CD19 expression restricted to normal and malignant B cells - Generation of a chimeric antigen receptor combining a specific antigen recognition domain and the intracellular domain of CD3zeta chain - Development of a lentiviral vector expressing the chimeric antigen receptor, coupled with the costimulatory molecule CD137

25 Chimeric Antigen Receptor T cells directed against CD19 induce durable responses for CD19+ malignancies, and have sustained engraftment (Porter #717, Kalos #756) - 10 patients : 1 ALL, 9 CLL Active refractory disease - Cell infusion : Dose of CART-19 cells : x 10 E 8 No infusional toxicities > grade 2 - Responses in patients: 4 sustained CR (>2 years, 3 CLL and one ALL), 2 PR (transient) 3 non responders (one inevaluable) - Elimination of B cells and prolonged B-cell aplasia - Cytokine release syndrome (CRS) In all responding patients Treatment with Tocilizumab (IL-6 R antagonist) - In vivo expansion of CART-19 cells Maximal expansion by day +30 Intensity of expansion correlated with clinical response

26 Take home messages HCT-CI validated in large cohorts of patients Every patient has a donor (CB or haplo) Donor CMV status important in MUD transplant Bu/Cy (IV/targeted?) better than Cy/TBI for AML in first CR Tacrolimus + sirolimus = Tacrolimus + MTX for MAC transplants Potential algorithm to predict agvhd, but role in clinical practice? MSC safe and effective to treat acute GVHD Third party virus-specific T cells safe and effective to treat refractory viral infections Adoptive immunotherapy with autologous genetically modified T cells safe and effective to treat CLL or ALL patients