The Evolving Role of Transplantation in Lymphoma Stephen Mackinnon Royal Free Hospital / University College London

Theoretical Advantages for Allogeneic Transplantation Tumour free graft Undamaged Stem Cells Avoidance of MDS/secondary AML Graft versus lymphoma effect

Disadvantages of Allogeneic Transplantation in Lymphoma Lack of suitable donors High Treatment Related Mortality Regimen related toxicity Infection GVHD

Allogeneic transplant in NHL No randomised trials available Relapse lower than auto transplant Possibly a graft versus lymphoma effect Can be used in poor mobilisers Higher TRM than autologous transplant

Allogeneic Transplantation Myeloablative or Reduced Intensity?

Auto vs Ablative Allo Transplant TRM Peneket el al, Bone Marrow Transplant 31:667, 2003

Graft Versus Lymphoma effect or effect of tumour free graft Graft Versus Lymphoma effect or effect of tumour free graft? Low Grade Histology Progression Free Survival Relapse Bierman et al. J Clin Oncol 21:3711, 2003

GVL Effects of DLI / GVHD Proven to be good CML DLI shown to be limited or poor AML / ALL / MDS / Hodgkin’s DLI probably good CLL / Follicular NHL / Myeloma Unknown DLBCL

Long-term follow-up of reduced-intensity transplantation with an alemtuzumab- containing regimen: Aggressive NHL J Clin Oncol. 2009;27:426-32

High-grade NHL: Patients (I) Median age 46 years (range 23–64) Median lines therapy 5 (range 2–7) Prior autograft 34 (71%) No autograft 14 (29%) 8 progression through salvage chemo within 3 months of primary treatment, 3 failed mobilization, 3 MDS/lymphoma/lung fibrosis Median follow-up 52 months (range 18–89) Status at transplant CR 9 PR 31 Refractory 8 J Clin Oncol. 2009;27:426-32

High-grade NHL: Patients (II) High-grade HNL (n=48) 18 HG transformation follicular NHL 30 primary DLBCL Donor 30 HLA-matched sibling 18 unrelated 12 HLA-matched 8 HLA-mismatched (4 x 1 locus, 3 x 2 loci, 1 x 3 loci) J Clin Oncol. 2009;27:426-32

Cyclosporin A as GVHD prophylaxis from Day –1 Conditioning regimen Day: –8 –7 –6 –5 –4 –3 –2 –1 Alemtuzumab 20 mg/d Fludarabine 30 mg/m2/d Melphalan 140 mg/m2 Unmanipulated PBSC / Marrow Cyclosporin A as GVHD prophylaxis from Day –1 Thomson et al. J Clin Oncol 2008 (in press)

Aggressive NHL: Treatment-related mortality (n=48) 0.25 0.50 0.75 1.00 Cumulative Incidence 32% Time (years) 2 4 6 8 J Clin Oncol. 2009;27:426-32

Aggressive NHL: Relapse (n=48) 0.25 0.50 0.75 1.00 Cumulative Incidence 33% Time (years) 2 4 6 8 J Clin Oncol. 2009;27:426-32

Aggressive NHL: Overall survival (n=48) 0.25 0.50 0.75 1.0 Survival 47% Time (years) 2 4 6 8 J Clin Oncol. 2009;27:426-32

High-grade NHL: DLI for relapse 15 patients relapsed / progressed Median time to relapse 6 months (2–56) 12 patients given dose-escalated DLI 5 primary high-grade 4 DLI alone, 3 grade 3/4 aGVHD, all had progression 1 surgery + XRT + Ritux then DLI, in CR at 76 months 7 transformed low-grade 3 no GVHD, no response 3 CR ongoing at 7, 27, 37 months – no GVHD in 2/3 1 surgery then DLI in CR at 76 months Summary 5 / 15 relapses back in remission DLI, donor lymphocyte infusion aGVHD/cGVHD, acute/chronic graft-versus-host disease

Current PFS (n=48) Survival 48% Time (years) 2 4 6 8 1.00 0.75 0.50 0.25 0.50 0.75 1.00 Survival 48% Time (years) 2 4 6 8 PFS, progression-free survival

Current PFS by donor type 0.25 0.50 0.75 1.00 Survival 50% 43% Time (years) p=0.65 2 4 6 8 Sibling Unrelated

Current PFS by chemo-responsiveness 0.25 0.50 0.75 1.00 Survival 55% 12% 0 2 4 6 8 Time (years) p=0.006 Chemorefractory Chemosensitive J Clin Oncol. 2009;27:426-32

Conclusions – Aggressive NHL Reduced intensity approaches show: significant TRM in aggressive lymphoma surprising low relapse rate T cell depletion Non ablative regimen long-term remissions – cure probable DLI only benefit a minority Chemosensitivity is a predictor for outcome we no longer transplant refractory aggressive NHL Is there a role for mini allo in preference to auto transplant in patients who remain PET+ following salvage chemo?

Follicular Lymphoma

Seattle Regimen 2 Gy TBI ± Flu Chronic extensive GVHD in 45% Overall Survival Follicular Progression Free Survival Related Transplants Indolent Disease Transformed follicular J Clin Oncol 26:211,2008

Flu / Cy / Rituximab Patients Median age 53yrs (33 – 68) Prior therapy Related 45 Unrelated 2 Median age 53yrs (33 – 68) Prior therapy ≤ 2 regimens 23 3 – 5 regimens 24 auto transplant 9 Disease status at transplant CR 18 PR 29 Refractory 0 GVHD prophylaxis Tacro + MTX Khouri et al. Blood 2008, 111: 5530

Flu / Cy / Rituximab Survival Progression Free Survival Khouri et al. Blood 2008, 111: 5530

Flu / Cy / Rituximab Acute GVHD Chronic GVHD Chronic Chronic Extensive II - IV III - IV Khouri et al. Blood 2008, 111: 5530

Follicular NHL: Patients (I) Median age 45 years (range 26–65) Median lines therapy 3 (range 1–8) Prior autograft 28% Median follow-up 40 months (range 4–103) Thomson et al. ASH 2007; abstr 1661

Alemtuzumab Advantages Disadvantages Low GVHD Mixed chimerism Engraftment Low GVHD Unrelated Low TRM Disadvantages CMV infection Mixed chimerism Lack of GVL

Flu/Mel conditioning & GVHD prophylaxis: CSA/alemtuzumab vs CSA/MTX Alemtuzumab MTX Acute GVHD II–IV 9% 43% Chronic GVHD 5% 67% CMV infection 85% 24% TRM 10% 20% Pérez-Simón et al. Blood 2002;100: 3121–7

Follicular NHL: Patients (II) Donor 39 HLA-matched sibling 39 unrelated 29 HLA-matched 10 HLA-mismatched (7 x 1 locus, 3 x 2 loci) Chemosensitive Yes 69 No 8 Untested 1 Thomson et al. ASH 2007; abstr 1661

Follicular NHL: Non-relapse mortality by donor type 9% Sibling 22% Unrelated 0.25 0.5 0.75 1.0 1000 2000 3000 Cumulative Incidence Days Thomson et al. ASH 2007; abstr 1661

Follicular NHL: Overall survival (n=78) GVHD and donor type Sibling 90% 1.0 1.0 76% p<0.005 0.75 0.75 0.5 0.5 Unrelated 61% Impact of GVHD 0.25 0.25 1.8 3.6 5.4 7.2 9 1.8 3.6 5.4 7.2 9 Years Years Thomson et al. ASH 2007; abstr 1661

Follicular NHL: Overall survival by prior autograft and chemosensitivity 1.0 No 85% 1.0 Yes 79% 0.75 0.75 p<0.002 p<0.04 0.5 0.5 Yes 52% No 50% 0.25 0.25 Chemosensitive Prior Autologous Transplant 1.8 3.6 5.4 7.2 9 1.8 3.6 5.4 7.2 9 Years Years Thomson et al. ASH 2007; abstr 1661

- Donor - Recipient - Post-Transplant +60 Days - Post-transplant +90 Days - Post DLI + 73 Days (Post Transplant + 6 Months)

Relapse and Chimerism Mixed Chimerism 40% p < 0.01 13% Full Donor 0 1 2 3 4 5 6 7 8 9 10 11 0.25 0.50 0.75 1.00 Time (years) Mixed Chimerism 40% p < 0.01 13% Full Donor 34

Follicular NHL: Relapse (n=78) Impact of GVHD acute II–IV or chronic All patients 1.0 1.0 0.75 0.75 0.5 0.5 No GVHD 35% 0.25 0.25 GVHD 14% 1000 2000 3000 1000 2000 3000 Thomson et al. ASH 2007; abstr 1661

Follicular NHL: DLI for relapse 16 patients relapsed / progressed Median time to relapse 8 months (2–43) 10 patients given dose escalated DLI 3 non-responders no GVHD 7 CRs, 3 with rituximab 3 with GVHD, 4 no GVHD 1 progressed after 6 months 6 CRs ongoing at a median of 41 months (21–60) Thomson et al. ASH 2007; abstr 1661

Follicular NHL: cPFS (n=78) by donor type 0.25 0.5 0.75 1.0 1 2 3 4 5 6 7 8 9 10 74% All patients Siblings 87% Unrelated 62% p<0.02 Years Years Thomson et al. ASH 2007; abstr 1661

RIC Sibling Allo preferred over Auto Failure to mobilise autologous PBSC Bone involvement at end of chemotherapy Relapse post autograft Younger patients ? PET+ pretransplant ? Regimen with TRM < 10% ? Patient choice ?

Conclusions – Follicular Lymphoma Allogeneic conditioning regimens: higher TRM with myeloablative conditioning Some reduced intensity regimens may also have a high TRM low relapse rate for chemosensitive patients Lymphoma free stem cells? GVL? long-term remissions – cure probable Chronic GVHD still a problem especially in MUD recipients DLI are effective in the majority of patients Chemosensitivity is a predictor for outcome Role for mini allo in preference to auto transplant?

Prognostic Role of PET before and after Allogeneic Stem Cell Transplantation

PET and Lymphoma PET predictive of outcome of chemotherapy or pre AUTO transplant Predictive role pre ALLO transplant unknown Role post ALLO transplant unknown

Cumulative percent surviving Prognostic value of PET status pre-auto-transplant for aggressive lymphoma: 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.

Trial Aims Is pre-transplant PET predictive of outcome ? Is post-transplant PET clinically useful ?

Methods Prospective trial 80 consecutive lymphoma patients PET and CT pretransplant chemosensitivity assessed by CT Post transplant scans at 3, 6, 9, 15, 24 and 36 months

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

Patient Characteristics Subtype PET negative (n=38) PET positive (n=42) CT positive (n=17) CT negative (n=21) CT positive (n=34) CT negative (n=8) Follicular lymphoma 8 6 12 4 Hodgkin lymphoma 11 3 Mantle cell lymphoma 1 Diffuse large B-cell lymphoma 2 Transformed follicular Peripheral T-cell lymphoma

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)

Follicular Lymphoma cPFS by PET Status Pretransplant PET negative PET positive Months

No DLI n =1 (alive with disease) DLI n = 3 No response n = 1 (died) PET +ve (n = 13) NRM (n = 5) PET +ve (n = 38) PET +ve (n = 21) Pre Tx 1st 6 months Subsequent follow up PET pos n = 38 NRM n = 4 1st relapse n = 13 No DLI n = 5 (died) DLI n = 8 CR n = 6 2nd relapse n = 3 DLI n = 2 CR n = 2 No DLI n = 1 (alive with disease) CR n = 3 Minimal response n = 2 (alive with disease) CR n = 21 NRM n = 2 1st relapse n = 4 No DLI n =1 (alive with disease) DLI n = 3 No response n = 1 (died) CR n = 15 PET pos n = 38 NRM n = 4 1st relapse n = 13 No DLI n = 5 (died) DLI n = 8 CR n = 6 2nd relapse n = 3 DLI n = 2 CR n = 2 No DLI n = 1 (alive with disease) CR n = 3 Minimal response n = 2 (alive with disease) CR n = 21 NRM n = 2 1st relapse n = 4 No DLI n =1 (alive with disease) DLI n = 3 No response n = 1 (died) CR n = 15 PET pos n = 38 NRM n = 4 1st relapse n = 13 No DLI n = 5 (died) DLI n = 8 CR n = 6 2nd relapse n = 3 DLI n = 2 CR n = 2 No DLI n = 1 (alive with disease) CR n = 3 Minimal response n = 2 (alive with disease) CR n = 21 NRM n = 2 1st relapse n = 4 No DLI n =1 (alive with disease) DLI n = 3 No response n = 1 (died) CR n = 15 PET pos n = 38 NRM n = 4 1st relapse n = 13 No DLI n = 5 (died) DLI n = 8 CR n = 6 2nd relapse n = 3 DLI n = 2 CR n = 2 No DLI n = 1 (alive with disease) CR n = 3 Minimal response n = 2 (alive with disease) CR n = 21 NRM n = 2 1st relapse n = 4 No DLI n =1 (alive with disease) DLI n = 3 No response n = 1 (died) CR n = 15

No DLI n =1 (alive with disease) DLI n = 3 No response n = 1 (died) PET +ve (n = 13) NRM (n = 4) PET +ve (n = 38) PET +ve (n = 21) PET -ve (n = 15) Pre Tx 1st 6 months Subsequent follow up PET pos n = 38 NRM n = 4 1st relapse n = 13 No DLI n = 5 (died) DLI n = 8 CR n = 6 2nd relapse n = 3 DLI n = 2 CR n = 2 No DLI n = 1 (alive with disease) CR n = 3 Minimal response n = 2 (alive with disease) CR n = 21 NRM n = 2 1st relapse n = 4 No DLI n =1 (alive with disease) DLI n = 3 No response n = 1 (died) CR n = 15 PET pos n = 38 NRM n = 4 1st relapse n = 13 No DLI n = 5 (died) DLI n = 8 CR n = 6 2nd relapse n = 3 DLI n = 2 CR n = 2 No DLI n = 1 (alive with disease) CR n = 3 Minimal response n = 2 (alive with disease) CR n = 21 NRM n = 2 1st relapse n = 4 No DLI n =1 (alive with disease) DLI n = 3 No response n = 1 (died) CR n = 15 PET pos n = 38 NRM n = 4 1st relapse n = 13 No DLI n = 5 (died) DLI n = 8 CR n = 6 2nd relapse n = 3 DLI n = 2 CR n = 2 No DLI n = 1 (alive with disease) CR n = 3 Minimal response n = 2 (alive with disease) CR n = 21 NRM n = 2 1st relapse n = 4 No DLI n =1 (alive with disease) DLI n = 3 No response n = 1 (died) CR n = 15 PET pos n = 38 NRM n = 4 1st relapse n = 13 No DLI n = 5 (died) DLI n = 8 CR n = 6 2nd relapse n = 3 DLI n = 2 CR n = 2 No DLI n = 1 (alive with disease) CR n = 3 Minimal response n = 2 (alive with disease) CR n = 21 NRM n = 2 1st relapse n = 4 No DLI n =1 (alive with disease) DLI n = 3 No response n = 1 (died) CR n = 15

No DLI n =1 (alive with disease) DLI n = 3 No response n = 1 (died) PET +ve (n = 13) DLI (n = 8) No DLI (n = 5) NRM (n = 4) PET +ve (n = 38) PET +ve (n = 21) PET -ve (n = 15) NRM (n = 2) No DLI (n = 1) Rel (n = 4) DLI (n = 3) Pre Tx 1st 6 months Subsequent follow up PET pos n = 38 NRM n = 4 1st relapse n = 13 No DLI n = 5 (died) DLI n = 8 CR n = 6 2nd relapse n = 3 DLI n = 2 CR n = 2 No DLI n = 1 (alive with disease) CR n = 3 Minimal response n = 2 (alive with disease) CR n = 21 NRM n = 2 1st relapse n = 4 No DLI n =1 (alive with disease) DLI n = 3 No response n = 1 (died) CR n = 15 PET pos n = 38 NRM n = 4 1st relapse n = 13 No DLI n = 5 (died) DLI n = 8 CR n = 6 2nd relapse n = 3 DLI n = 2 CR n = 2 No DLI n = 1 (alive with disease) CR n = 3 Minimal response n = 2 (alive with disease) CR n = 21 NRM n = 2 1st relapse n = 4 No DLI n =1 (alive with disease) DLI n = 3 No response n = 1 (died) CR n = 15 PET pos n = 38 NRM n = 4 1st relapse n = 13 No DLI n = 5 (died) DLI n = 8 CR n = 6 2nd relapse n = 3 DLI n = 2 CR n = 2 No DLI n = 1 (alive with disease) CR n = 3 Minimal response n = 2 (alive with disease) CR n = 21 NRM n = 2 1st relapse n = 4 No DLI n =1 (alive with disease) DLI n = 3 No response n = 1 (died) CR n = 15 PET pos n = 38 NRM n = 4 1st relapse n = 13 No DLI n = 5 (died) DLI n = 8 CR n = 6 2nd relapse n = 3 DLI n = 2 CR n = 2 No DLI n = 1 (alive with disease) CR n = 3 Minimal response n = 2 (alive with disease) CR n = 21 NRM n = 2 1st relapse n = 4 No DLI n =1 (alive with disease) DLI n = 3 No response n = 1 (died) CR n = 15

No DLI n =1 (alive with disease) DLI n = 3 No response n = 1 (died) PET +ve (n = 13) DLI (n = 8) PET -ve (n = 6) PET -ve (n = 3) No DLI (n = 5) PR (n = 2) NRM (n = 4) PET +ve (n = 38) PET +ve (n = 21) PET -ve (n = 15) NRM (n = 2) No DLI (n = 1) PET +ve (n = 1) Rel (n = 4) DLI (n = 3) PET -ve (n = 2) Pre Tx 1st 6 months Subsequent follow up PET pos n = 38 NRM n = 4 1st relapse n = 13 No DLI n = 5 (died) DLI n = 8 CR n = 6 2nd relapse n = 3 DLI n = 2 CR n = 2 No DLI n = 1 (alive with disease) CR n = 3 Minimal response n = 2 (alive with disease) CR n = 21 NRM n = 2 1st relapse n = 4 No DLI n =1 (alive with disease) DLI n = 3 No response n = 1 (died) CR n = 15 PET pos n = 38 NRM n = 4 1st relapse n = 13 No DLI n = 5 (died) DLI n = 8 CR n = 6 2nd relapse n = 3 DLI n = 2 CR n = 2 No DLI n = 1 (alive with disease) CR n = 3 Minimal response n = 2 (alive with disease) CR n = 21 NRM n = 2 1st relapse n = 4 No DLI n =1 (alive with disease) DLI n = 3 No response n = 1 (died) CR n = 15 PET pos n = 38 NRM n = 4 1st relapse n = 13 No DLI n = 5 (died) DLI n = 8 CR n = 6 2nd relapse n = 3 DLI n = 2 CR n = 2 No DLI n = 1 (alive with disease) CR n = 3 Minimal response n = 2 (alive with disease) CR n = 21 NRM n = 2 1st relapse n = 4 No DLI n =1 (alive with disease) DLI n = 3 No response n = 1 (died) CR n = 15 PET pos n = 38 NRM n = 4 1st relapse n = 13 No DLI n = 5 (died) DLI n = 8 CR n = 6 2nd relapse n = 3 DLI n = 2 CR n = 2 No DLI n = 1 (alive with disease) CR n = 3 Minimal response n = 2 (alive with disease) CR n = 21 NRM n = 2 1st relapse n = 4 No DLI n =1 (alive with disease) DLI n = 3 No response n = 1 (died) CR n = 15

No DLI n =1 (alive with disease) DLI n = 3 No response n = 1 (died) PET +ve (n = 13) DLI (n = 8) PET -ve (n = 6) PET -ve (n = 3) No DLI (n = 5) PR (n = 2) 2nd Rel (n = 3) DLI (n = 2) PET -ve (n = 2) NRM (n = 4) No DLI (n = 1) PET +ve (n = 38) PET +ve (n = 21) PET -ve (n = 15) NRM (n = 2) No DLI (n = 1) PET +ve (n = 1) Rel (n = 4) DLI (n = 3) PET -ve (n = 2) Pre Tx 1st 6 months Subsequent follow up PET pos n = 38 NRM n = 4 1st relapse n = 13 No DLI n = 5 (died) DLI n = 8 CR n = 6 2nd relapse n = 3 DLI n = 2 CR n = 2 No DLI n = 1 (alive with disease) CR n = 3 Minimal response n = 2 (alive with disease) CR n = 21 NRM n = 2 1st relapse n = 4 No DLI n =1 (alive with disease) DLI n = 3 No response n = 1 (died) CR n = 15 PET pos n = 38 NRM n = 4 1st relapse n = 13 No DLI n = 5 (died) DLI n = 8 CR n = 6 2nd relapse n = 3 DLI n = 2 CR n = 2 No DLI n = 1 (alive with disease) CR n = 3 Minimal response n = 2 (alive with disease) CR n = 21 NRM n = 2 1st relapse n = 4 No DLI n =1 (alive with disease) DLI n = 3 No response n = 1 (died) CR n = 15 PET pos n = 38 NRM n = 4 1st relapse n = 13 No DLI n = 5 (died) DLI n = 8 CR n = 6 2nd relapse n = 3 DLI n = 2 CR n = 2 No DLI n = 1 (alive with disease) CR n = 3 Minimal response n = 2 (alive with disease) CR n = 21 NRM n = 2 1st relapse n = 4 No DLI n =1 (alive with disease) DLI n = 3 No response n = 1 (died) CR n = 15 PET pos n = 38 NRM n = 4 1st relapse n = 13 No DLI n = 5 (died) DLI n = 8 CR n = 6 2nd relapse n = 3 DLI n = 2 CR n = 2 No DLI n = 1 (alive with disease) CR n = 3 Minimal response n = 2 (alive with disease) CR n = 21 NRM n = 2 1st relapse n = 4 No DLI n =1 (alive with disease) DLI n = 3 No response n = 1 (died) CR n = 15

Diagnosis of Relapse 34 episodes of relapse in 28 patients 4 clinically detected 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

PET + Infection / Inflammation 11 / 475 scans 5 lesions biopsed 2 infections 1 sarcoidosis 1 non-specific 1 bone remodelling 6 cervical uptake with respiratory infection

Potential Problems Relatively small numbers of each lymphoma subtype e.g. only 7 patients with de novo DLBCL Few PET + lesions biopsied – false positives ? majority of abnormalities at site of previous disease All patients either had resolution with DLI or had overt clinical relapse

Conclusions A positive pre transplant PET does not preclude a successful outcome Post transplant PET picks up relapse earlier and allows optimal efficacy of DLI

The Future Challenges Relapse e.g. Hodgkin lymphoma Increase antitumour activity of conditioning regimen Without excess regimen-related mortality Solution? Targeted radiotherapy Anti CD25 Anti CD66

Why radioimmunotherapy? Specific, targeted therapy No grade III/IV non-haematologic toxicity Outpatient-based No effect on future therapies Proven target for lymphoma therapy Expressed only on B-lineage cells Does not shed into circulation Does not modulate upon antibody binding Key Point: CD20 is an ideal target antigen for therapies against B-cell NHL because it is a specific antigen for B-cells that remains bound to the cell and does not modulate upon antibody binding. The CD20 antigen is a cell surface protein expressed at relatively high levels on NHL cells, but not on haematopoietic or mature plasma cells.1 CD20 is not present in the circulation as a free protein that could block monoclonal antibody therapy and is not shed from the cell surface.2 Monoclonal antibodies directed against CD20 have been demonstrated to effectively target B-cell NHL cells.3 Zevalin®, comprising an anti-CD20 monoclonal antibody conjugated to the radioisotope 90yttrium (90Y), targets radioactive particles to the surface of tumour cells, offering an innovative approach for the treatment of NHL. 1. Zelenetz AD. Radioimmunotherapy for lymphoma. Curr Opin Oncol 1999;11:375–380. 2. Press OW, Appelbaum F, Ledbetter JA et al. Monoclonal antibody 1F5 (anti-CD20) serotherapy of human B-cell lymphomas. Blood 1987;69:584–591. 3. Wood AM. Rituximab: an innovative therapy for non-Hodgkin’s lymphoma. Am J Health Sys Pharm 2001;58:215–229.

Principles of Radioimmunotherapy External-beam radiation Radioimmunotherapy “monoclonal antibody mediated cell lysis” Many lymphomas are radio-sensitive but (but delivering an adequate dose to the tumour can result in damage to the surrounding healthy tissue. Coupling a radioisotope to a molecule which would specifically bind to tumour cells could, in theory, deliver an effective radiation dose to the tumour without damage to non-tumour tissues, potentially limiting adverse effects8) that therapy is limited by the fact that it is relatively non-specific in its action- normal tissues, in the path of the radi ation beam are irreversibly injured. Long history of using radionuclides in medicine- treatment of leukaemia by 32Phosphorus (32P) was the first therapy modality with radioisotopes in the early thirties of the previous century 1943 first success when metastatic thyroid cancer was cured by administration of rai. Its unique modality allows to systemically target radiosensitive tumours throughout the body. 3. more sophisticated therapy by radioisotope labelled antibodies i.e. radioimmunotherapy (RIT) for various haematological malignancies, e.g. α- and β emitting radionuclides have been labelled with anti-CD33 antibodyHuM195 for the treatment of myeloid leukaemia.30 High-dose RIT of myeloid leukaemia with β-emitting radionuclides is being investigated for intensifying anti-leukaemia therapy before stem cell transplantation. Another option is the use of targeted α particles with radionuclides such as bismuth-213 or actinium-225, which offers the possibility of selective tumour cell kill with less damage to surrounding normal cells.30 As RIT constitutes the most significant clinical contribution to the treatment options of B-cell lymphomas, the following sections will focus on these haematological malignancies. Long t1/2 of iodine means that protecting the patient’s environment is impt to prevent exposure to others Y90 is a pure beta emitter with a much shorter t1/2 meaning that treatment can be given as an outpatient. MINIMISES EXPOSURE TO NON-MALIGNANT CELLS –IMPORTANT IN ELDERLY PATIENTS WITH CO-MORBIDITIES WHO HAVEOFTEN HADSEVERAL LINES OF THERAPY Key point: Radioimmunotherapy (RIT) targets all sites of lymphoma (known and unknown) with limited exposure of healthy tissue compared with directed external-beam radiation. External-beam radiation delivers radiation at relatively high-dose rates for short periods of time, separated by intervals of hours or days, to the general area of the known lymphoma from an external source.1 As a result, it does not affect remote sites of lymphoma, and a large area of healthy tissue is exposed to high-energy radiation. In contrast, low-energy RIT targets both known and unknown sites of lymphoma, with minimal exposure of healthy tissue. Once the radiolabelled monoclonal antibody is bound to the surface of the tumour cell, radiation is delivered continuously at an exponentially declining rate for days or weeks as the bound isotope decays.1 10–20% of patients with indolent NHL are diagnosed with early-stage disease that responds to external-beam radiation therapy.2 2. Vose JM. Classification and clinical course of low-grade non-Hodgkin’s lymphomas with overview of therapy. Ann Oncol 1996;7(suppl 6):S13–S19. 1. Press OW. Physics for practitioners: the use of radiolabeled monoclonal antibodies in B-cell non-Hodgkin’s lymphoma. Semin Hematol 2000;37(4, suppl 7):2–8.

Principles of radioimmunotherapy These agents consist of mAb bound, through a high affinity chelator, to a radioisotope The mAb specifically targets cell surface antigen, CD20 in the case of licensed RIT for FL, the chelator prevents radio-isotope dissociating and becoming free in the circulation. Might also mention that other conjugates have been used Immunotoxins- not abnle to give repaeated courses of therapy, toxin not interanlaised (CLL). Note adticd22 bound to an anti CD22 was used in the 1980’s at the Royal Free in Phase I studies…..vascular leak syndrome, human anti-mouse immunoglobulin antibody Ibritumomab: Anti-CD20 murine MAb that targets malignant B-cells Tiuxetan: A high-affinity chelator that ensures a stable bond between MAb and 90Yttrium 90Yttrium (90Y): Emits beta radiation that reaches malignant B-cells, 90% deposited within 5 mm (11 mm maximum path length) Key Point: Zevalin® combines the tumour targeting power of an anti-CD20 monoclonal antibody (MAb) and the cytotoxicity of 90yttrium radiation. This slide describes the main components of Zevalin®, i.e. the monoclonal antibody ibritumomab, the chelator tiuxetan and the radioisotope 90Y. Zevalin® is a radioimmunotherapy in which the, MAb ibritumomab, is covalently bound to a high-affinity chelator (tiuxetan) for the 90Y radioisotope.1–3 The tiuxetan chelator provides a stable linkage between the antibody and the radioisotope, resulting in specific radiation targeting of antigen-positive tumour cells. As a result of this stable linkage, clearance rates for patients treated with Zevalin® are predictable and dosimetry/imaging is not generally required in the EU. 1. Harrison A, Walker CA, Parker D et al. The in vivo release of 90Y from cyclic and acyclic ligand-antibody conjugates. Nucl Med Biol 1991;18:469–476. 2. Roselli M, Schlom J, Gansow O et al. Comparative biodistribution studies of DTPA-derivative bifunctional chelates for radiometal labeled monoclonal antibodies. Nucl Med Biol 1991;18:389–394. 3. Chinn PC, Leonard JE, Rosenberg et al. Preclinical evaluation of 90Y-labeled anti-CD20 monoclonal antibody for treatment of non-Hodgkin’s lymphoma. Int J Oncol 1999;15:1017–1025.

Principles of Radioimmunotherapy Naked antibody Radio-labelled antibody Cross-fire principle. Another important principle is its so-called ‘cross-fire’ action, whereby, owing to the larger reach of the radiation in relation to the cell diameter, a tumour cell receives lethal hits also from isotopes in the neighbourhood that are not directly associated with this cell. The treatment is therefore less hampered by inhomogeneous distribution and metabolism than for example chemo- or immunotherapy Also mention Lou Staudt study and effect of RIT on the background cells.!!!!!!! RADIO-IMMUNOCONJUGATES CONSISTING OF ANTI BODY LINKED TO RADIONUCLIDES TARGET RADIATION DIRECTLY OT LYMPHOMA CELLS VIA ANTIBODY MEDIATED TRANSPORTAS WELL AS TO NEIGHBOURING CELLS VIA WHAT IS CALLED CROSS FIRE EFFECT- THIS ADDRESSSES A POTENTIAL LIMITATION OF NAKED ANTIBODY TERAPY- DIFFICULTY ACCESSING ALL TUMOUR IN POORLY VASCULARIESD, BULKY TUMOURS There is targeted delivery of radiation to tumour site as well as the transfer of apoptotoc signals tumour cells from bound anntibody I.E. SYNERGY- IMMUNOLOGIC AND RADIOLYTIC MECHANISMS TO BRING ABOUT CELL DEATH. The choice of radio-isotope is aimed at maximising delivery of ionising radiation to tumour, whilst attempting to minimise the dose given to normal tissues Y90 has advantage- no penetrating gamma emisisons/ t1/2 of 2.5 days/64 hours, path length of 5.3 mm cf 0.8 mm BIG ADVANTAGE IS THAT THESE CHARACTERISTICS ARE IDEAL TREATINGBULKY POORLY VASCULARISED TUMOURS THAT MAY HAVE HETEROGENOUS CD20 ANTIGEN EXPRESSION,FOLLOWING PREVIOUS MABTHERAPY.. Radiation induced cell death is induced in BOTH the targeted cells and adjacent lymphoma cells due to the radiation cross fire effect. Long t1/2 of iodine means that protecting the patient’s environment is impt to prevent exposure to others Y90 is a pure beta emitter with a much shorter t1/2 meaning that treatment can be given as an outpatient. MINIMISES EXPOSURE TO NON-MALIGNANT CELLS –IMPORTANT IN ELDERLY PATIENTS WITH CO-MORBIDITIES WHO HAVEOFTEN HADSEVERAL LINES OF THERAPY Key Point: Radioimmumotherapy (RIT) provides a synergistic therapeutic effect. Conjugating a monoclonal antibody with a radioactive particle provides a synergistic therapeutic benefit greater than that of each of the separate modalities.1 The continuous targeted delivery of low-dose radiation by RIT to the tumour causes cells to be blocked from progressing past the G2 phase of the cell cycle.2 The accumulation of cells at this stage is thought to increase the cytotoxicity of continuous low doses of radiation by preventing initiation of cellular DNA repair mechanisms. Radiation can be delivered to neighbouring tumour cells that are antigen negative or to which antibody has not bound through a ‘cross-fire’ effect. This effect is particularly useful in the treatment of tumours with heterogeneous antigen expression, as well as bulky or poorly vascularized tumours where some cells are inaccessible to monoclonal antibodies.3,4 1. Witzig TE, White CA, Wiseman GA et al. Phase I/II trial of IDEC-Y2B8 radioimmunotherapy for treatment of relapsed or refractory CD20+ B-cell non-Hodgkin's lymphoma. J Clin Oncol 1999;17(12):3793–3803. 2. Press OW. Physics for practitioners: the use of radiolabeled monoclonal antibodies in B-cell non-Hodgkin’s lymphoma. Semin Hematol 2000;37(4, suppl 7):2–8. 3. Krasner C, Joyce RM. Zevalin™: 90yttrium labelled anti-CD20 (ibritumomab tiuxetan), a new treatment for non-Hodgkin’s lymphoma. Curr Pharma Biotech 2001;2:341–349. 4. Zelenetz AD. Radioimmunotherapy for lymphoma. Curr Opin Oncol 1999;11:375–380.

CHT25 program Challenge of relapsed/refractory lymphomas CD25 expressed in a range of lymphomas Hypothesis: RIT may be beneficial Chimeric antibody CHT25 Labelled with Iodine-131 (Amlot P, et al) Rationale for cd25? expressed in diff lymphomas but few normal cells express CD25 Anti tac for human allograft rejection 9dacluzimab licensed 1997) patients with solid organs experiencing rejection have high sirculating IL2-r levels. Chimeric antibody to alpha chain of ith IL2 receptor- blocks the interaction of this cytokinewith its receptor. Why iodine? Priferation franction Long decay time of Iodine might have theoretical advantage.

Objectives Primary endpoints Toxicity Pharmacokinetics and dosimetry Secondary endpoints Preliminary evidence of response Immunogenicity Royal Free Hospital

Eligibility CD25 positive Hodgkin or T-cell lymphomas Study Information Eligibility CD25 positive Hodgkin or T-cell lymphomas Standard inclusion and exclusion criteria ≥ ≤ 25% bone marrow involved No human anti-CHT25 antibody 50% lymphoma cells to express CD25 Hodgkin in particular: Apart from the fact that hrs ARE cd25+ THE TUMOUR CONTAINS ONLY FEW MALIGNANT CELLS Highly vascular tunours Waldman had produced responses with naked murine anti-Tac

Study details Therapy 10 mg CHT25 escalating 131Iodine activity 14 patients had 26 treatments (range 1-3) 131I activity MBq/m2 370 740 1200 1480 2220 2960 No patients 3 6 1 Better know how MTD was defined

Patients 14 patients (8 M, 6 F) Median age 38 (28-70) 11 Hodgkin; 3 T-cell lymphoma Median number of prior treatments 4 (range 2-8) 9 had an ASCT Stable dose steroids allowed

Toxicity: Non-haematological Infusional reactions Grade 1 elevation liver enzymes - transient Tunneled line infections and chest infection 1 patient with renal failure 1 patient hypothyroid Generally well tolerated

Toxicity - haematological Administered Activity MBq/m2 370 740 1200 1480 ≥ 2220 Platelets: Grade 3 (%)/ duration (days) nil 60% 3-42 83% 27-78 100% 32-176 Neutrophils: Grade 4 (%)/ 50% 2-30+ 25% 36 1 death – Reported as PCP when neutropenic 6 patients had platelet support – at doses ≥ 1200 MBq/m2

Response Data -modified Cheson criteria 2007 Injected single dose level PET / CT combined % < 1200 MBq/m2 1/8 CR 12.5% ≥ 1200 MBq/m2 6/9 ORR -3/6 PR -3/6 CR 66.7% Evidence of the existence of a dose–response relationship can be inferred from several observations. First, the highest CR rate has been reported in the setting of myeloablative RIT 1 of 3 responses in T cell patients 2 went on to transplant with successful engraftment

Conclusions CHT25 Demonstrable activity with a chimeric antibody Well tolerated at a non-myeloablative dose MTD defined as 1200 MBq/m2 Transplantation possible post-treatment Future directions Transplant conditioning regimens in drug resistance Combination therapy Earlier treatment in poor prognosis patients