Reduced Intensity Allograft Scopes and Limitations Stephen Mackinnon Dept of Haematology, Cancer Institute University College London

Conventional Allogeneic BMT for Hodgkin Lymphoma 100 HLA identical sibling allografts median age 28 yr TRM 61% Relapse 65% DFS 15% Gajewski J Clin Oncol 14:572, 1996

IBMTR – Hodgkin’s

Rationale for Reduced Intensity Conditioning Less toxic immunosuppressive regimen limits TRM / expands patient eligibility allows allogeneic engraftment Cure mediated by GVL effect of donor T cells

The Perfect Regimen Low toxicity and TRM Low incidence of GVHD High level of tumour control Good immune reconstitution Disease responds to DLI

Regimen Intensity Cy / TBI Flu / Mel / Campath Immunosuppressive BEAM Flu / Cy / Ritux TBI 2Gy Tumour Control / Myelosuppression

Cyclosporin A as GVHD prophylaxis from Day -1 Conditioning Regimen Day: - 8 - 7 - 6 - 5 - 4 - 3 - 2 - 1 Alemtuzumab 20mg/d Fludarabine 30mg/m2/d Melphalan 140mg/m2 Unmanipulated PBSC / Marrow Cyclosporin A as GVHD prophylaxis from Day -1

Alemtuzumab Advantages engraftment low GVHD unrelated low TRM Disadvantages CMV infection mixed chimerism lack of GVL

Update of Allogeneic Stem Cell Transplant for Hodgkin Lymphoma

Patient Characteristics Patient Number: 76 Age: Median Range Sex: Male Female 32 13-59 42 34 Donor: Matched related Matched unrelated Histology: Nodular sclerosing Mixed cellularity Lymphocyte predominant Nodular LP 69 3 2 Peggs et al. J Clin Oncol 2011, 29:971

Patient Characteristics Patient Number: 76 Status: Complete response Partial response Refractory Untested relapse 17 32 26 1 Conditioning: Flu / Mel - Campath BEAM – Campath 63 13 Previous lines : 2-10 (median 5) 45 previous autograft Time from diagnosis : 0.6-14.8 years (median 4.8) Peggs et al. J Clin Oncol 2011, 29:971

Engraftment, TRM and GVHD 75 / 76 engrafted Transplant-related mortality 17% siblings 12% unrelated 24% GVHD (II – III acute) pre DLI siblings 7% unrelated 29% GVHD (chronic extensive) pre DLI 13% post DLI 31% Peggs et al. J Clin Oncol 2011, 29:971

Relapse and GVHD Peggs et al. J Clin Oncol 2011, 29:971 No GVHD GVHD

Hodgkin’s - DLI for Mixed Chimerism 22 patients given DLI starting at median 9 mos Median 2 doses given (range, 1 – 5) starting dose 1 x 106 T cells/kg 19 became full donor chimeras, 13 w/o GVHD only 1 of these patients relapsed! 22 patients in CR at 9 mos not given DLI 4 mixed chimeras 18 full donor chimeras Peggs et al. J Clin Oncol 2011, 29:971

Relapse and Chimerism Landmark analysis at 9 months Peggs et al. J Clin Oncol 2011, 29:971 MC – no DLI FD – no DLI MC + DLI Years

Management of Relapse 7 / 31 relapses not given DLI 24 received DLI 3 active GVHD, 2 ref to salvage, 1 IF XRT 1 PR to CSA withdrawal pending DLI 24 received DLI 10 also given salvage chemo 14 CRs + 5 PRs with ORR of 79% 10 / 14 CRs only received DLI 12 / 14 CRs durable at median of 26 mos Peggs et al. J Clin Oncol 2011, 29:971

Graft-versus-lymphoma effect EXCELLENT DEMONSTRATION OF GRAFT VERSUS HODGKIN EFFECT POST DLI

Progression Free Survival Impact of DLI Peggs et al. J Clin Oncol 2011, 29:971 Current PFS PFS

Prognostic Role of PET scanning before and after reduced intensity allogeneic stem cell transplant for lymphoma S Mackinnon, J Lambert, J Bomanji, K Peggs, K Thomson, R Chakraverty, A Fielding, M Roughton, E Morris, A Goldstone, D Linch, P Ell University College London Lambert et al. Blood 115:2763, 2010

PET and AUTO Transplant (PFS) 100 80 60 Cumulative percent surviving PET – PET + 40 20 500 1000 1500 2000 2500 Time (days) Spaepen et al. Blood 2003;102:53–59 Copyright ©2003 American Society of Hematology.

PET and Lymphoma Predictive role pre ALLO transplant unknown Role post ALLO transplant unknown

Trial Aims Is pre-transplant PET predictive of outcome ? Is post-transplant PET clinically useful ? Lambert et al. Blood 115:2763, 2010

Methods Prospective trial 80 consecutive lymphoma patients 43 sibling, 37 unrelated PET and CT pretransplant chemosensitivity assessed by CT Post transplant scans at 3, 6, 9, 15, 24, 36 mo Lambert et al. Blood 115:2763, 2010

Post Transplant Interventions Patients with evidence of relapse given DLI clinical, CT or PET Patients with stable abnormal CT and PET negative were not given DLI Lambert et al. Blood 115:2763, 2010

Disease-free survival PET NEG pre-RIT (n=26) PET POS pre-RIT (n=38) 100 100 p=0.52 p=0.91 80 80 Percent Percent 60 60 40 40 Overall survival Relapse 20 20 20 40 60 80 100 20 40 60 80 100 Time (months) Time (months) 100 100 p=0.78 80 p=0.87 80 Percent 60 Percent 60 40 40 Current DFS 20 Disease-free survival 20 20 40 60 80 100 20 40 60 80 100 Time (months) Time (months)

Diagnosis of Relapse 34 episodes of relapse in 28 patients 4 clinically detected CNS, 3,4, > 36 mos post PET 13 PET + / CT + 17 PET + / CT – 16 / 17 at site positive pretransplant 19 patients were CT + / PET – 13 remained in CR 6 relapsed, 4 at site of prior CT abnormality

Indication for DLI Indication CR / Episode Clinical progression alone 1 / 3 PET + and relapse/progression on CT 6 / 9 PET + and normal/unchanged CT 13 / 14 Lambert et al. Blood 115:2763, 2010

Conclusions A positive pre transplant PET does not preclude a successful outcome in ALLO transplant Post transplant PET picks up relapse earlier and allows optimal efficacy of DLI Lambert et al. Blood 115:2763, 2010

Allo vs autologous transplant 0.0 0.2 0.4 0.6 0.8 1.0 12 24 36 48 60 72 84 96 Months after SCT Cumulative Incidence 0.0 0.2 0.4 0.6 0.8 1.0 12 24 36 48 60 72 84 96 Months after SCT Cumulative Incidence TRM Relapse risk 0.0 0.2 0.4 0.6 0.8 1.0 12 24 36 48 60 72 84 96 Months after SCT PFS PFS OS Auto RIST Robinson et al, ASH, 2008 (updated)

RIC-allogeneic transplant Study 3-yr TRM 3-yr RR 3-yr OS 3-yr EFS/PFS cGVHD Robinson, 2002* 31% 20% 65% 54% 16% (ext: 9%) Vigouroux, 2007 40% 10% 56% 51% 43% (ext: 20%) Rezvani, 2007 14% 52% 43% Ext: 47% Khouri, 2008 NR 85% 83% 60% (ext: 36%) Hari, 2008 28% 17% 62% 55% Ingram, 2008 69% 58% Thomson, 2010** 8% 25% 90% 87% Ext: 11% (30% post DLI) Piñana, 2010** 37% 57% Ext: 53% * at 2 years, ** at 4 years in siblings 3-yr TRM: 8-40%, 3-yr RR: 8-25%, 3-yr OS: 52-90%, 3-yr PFS: 43-87%

Allogeneic transplant Myeloablative should be avoided Sibling / unrelated RIC vs Auto auto failures, marrow involved, failure to mobilise short response duration ≥ CR3 / PR3 PET +ve post salvage Centre effect may be important

Elderly and High-Risk AML High risk of relapse with chemo alone High risk of death with myeloablative transplant Reduced intensity transplants less toxic, but GVHD a major problem in the elderly more relapse with reduced intensity regimens

Patient Characteristics Patients 70 Median age 56 (17 – 70) Disease status CR1 43 CR2 27 standard risk 33 high risk 37 Poor risk cytogenetics, FLT3-ITD mutated, previous MDS / 2° AML

Patient Characteristics Highly selected? Donors siblings 29 unrelated 41 Only 10 pts were < 60 yrs + standard risk AML + a sibling donor Only 2 / 23 patients > 60 yrs + standard risk AML + a sibling donor

Chimerism, GVHD and Relapse Acute II-IV and chronic GVHD prevented relapse 0% vs 27% 28 / 41 were full donor chimeras 11 / 13 mixed chimeras remain in CR GVL good but not essential in preventing relapse regimen intensity may be important

Conclusions Many elderly pts with high-risk AML have durable remissions with RIC transplantation Transplant mortality limited good control of GVHD Relapse risk low even for pts with high-risk AML More pts could and should benefit FLT3-ITD mutated MRD positive chemo

Can we improve the current results? Promote GVL pre-emptive DLI Molecular risk / MRD monitoring Increase regimen intensity without toxicity targeted radiotherapy

Whole body data 24 hrs post infusion Anterior Posterior

For autologous transplant (HD melphalan) D –22 to D –16 In-111 imaging Dosimetry Y-90 labelled Anti-CD66 Review, fbc HD Melphalan D –14 D –7 D –2 D 0 Autologous stem cells

For allogeneic transplantation D –22 to D –16 In-111 imaging Dosimetry Y-90 labelled Anti-CD66 Melphalan 140mg/m2 Fludarabine 30mg/m2 CAMPATH 1H 10mg/m2 D –14 D –7 D –2 D 0 CyA 5mg/kg d –3 3mg/kg d –2 level 100-150 ng/ml tailing from d +60 MTX d 3, 6, 11 10mg/m2 Allogeneic stem cells