Different Conditioning Regimens Stephen Mackinnon University College London
Principles of Dose Intensity Standard chemo dosing limited by marrow toxicity Stem cell rescue allows higher doses of chemo or radiotherapy to be given tumour dose response haematological and germ cell cancers Dose escalation limited by toxicity to other organs gut, lungs, skin
What Does the Conditioning Do? Autologous eradicate tumour cells Allogeneic immunosuppress recipient prevent graft rejection eradicate tumour cells regimen intensity control GVHD MTX, ATG, alemtuzumab, cyclophosphamide allow immune reconstitution
How do transplants work? High-dose pretransplant chemoradiotherapy Graft-versus-leukaemia donor immune cells Why do transplants fail? Regimen toxicity Graft rejection recipient T cells Infections neutropenia MTX, cord blood lymphopenia T cell depletion Graft-versus-host disease donor T cells Relapse
Standard Myeloablative Regimens Fractionated TBI 12 15 Gy + high-dose chemo cyclophosphamide, etopside Chemotherapy alone BuCy BEAM Highly active antileukaemic activity Immunosuppressive Toxic
Toxicities Immediate mucositis nausea, vomiting, diarrhoea Alopecia VOD Delayed sicca syndrome hypothyroidism cataracts infertility
Is GVHD prophylaxis part of the conditioning? Sometimes MTX increases mucositis T cell depletion graft rejection, GVHD Cyclophosphamide allodepletion
Regimen Intensity More is more killing more tumour cells results in fewer relapses Less is more a less toxic regimen reduces TRM Can both these statements be true? sometimes
Regimen Intensity AML CR1 12 Gy versus 15.75 Gy TBI Clift et al. Blood 1990, 76:1867
Regimen Intensity AML 12 versus 15.75 Gy TBI Matched Siblings CSA + MTX prophylaxis More severe acute GVHD with 15.75 Gy Clift et al. Blood 1990, 76:1867
Regimen Intensity AML 12 versus 15.75 Gy TBI Clift et al. Blood 1990, 76:1867
AML in CR - T cell Depleted TBI 15 Gy no acute 2-4 GVHD, 3% chronic GVHD Relapse LFS Papadopoulos et al. Blood 91:1083, 1998
Reduced Toxicity Conditioning Less toxic immunosuppressive regimen limits TRM / expands patient eligibility allows allogeneic engraftment Cure mediated by GVL effect of donor T cells Indolent versus rapidly proliferating tumours?
The Conditioning Regimen Dilemma Is There an Alternative? Myeloablative Non Ablative Reduced Intensity High TRM GVHD High Relapse GVHD
Reduced Toxicity Regimens Chemotherapy alone: purine analogue + Flu / Mel, Flu / Bu, Flu / Cy ± ATG / alemtuzumab Chemo + low dose TBI Flu / TBI (2 4 Gy)
The Perfect Transplant Regimen Low toxicity and TRM Low incidence of GVHD High level of tumour control Good immune reconstitution Prevent relapse
Reduced Toxicity Conditioning Allows older patients to have a transplant Most patients are older than 40 yrs Results of standard chemo less good Co-morbidities can be overcome Reduction in TRM GVHD incidence still high Difficult to manage in elderly
Immunosuppressive / engraftment Regimen Intensity Non myeloablative Reduced Intensity Flu / Mel / Campath Ablative Cy / TBI Flu / TBI 2Gy Flu / Cy TBI 2Gy FLAG / Ida Flu / Bu / ATG BEAM Tumour Control / Myelosuppression / Toxicity
Less can be Less Minimally ablative regimen very safe initially e.g. day 100 mortality More reliant on GVL for cure rapid taper of immunosuppression chronic GVHD and late mortality corticosteroids and fungal infections late relapse
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
Nonmyeloablative Transplant for AML Seattle Experience 274 pts median age 60 yrs (5 74) with AML CR1 160, CR2 71, >CR2 28, rel/ref 15 2 Gy TBI ± fludarabine Donors 117 sib, 123 MUD, 34 MMUD Calcineurin inhibitor ± MMF as GVHD prophylaxis 12 pts (4%) had graft rejection Day +100 mortality 4% Less relapse with GVHD Gyurkocza et al. J Clin Oncol 28:2859, 2010
Chronic GVHD Gyurkocza et al. J Clin Oncol 28:2859, 2010
Survival, Relapse, NRM for CR1 Patients Gyurkocza et al. J Clin Oncol 28:2859, 2010
Effect of Age and GVHD on Survival Reduced Intensity Transplantation Corradini et al, J Clin Oncol, 2005, 23:6690
T Cell Depletion Advantages low GVHD unrelated low TRM Disadvantages mixed chimerism immune tolerance lack of GVL
AML in Remission Fludarabine, Melphalan, Alemtuzumab Patients 70 Median age 56 (17 70) Follow up Disease status CR1 43 CR2 27 standard risk 33 high risk 37 41 months High Risk - Poor risk cytogenetics, FLT3-ITD mutated, previous MDS / 2 AML
37% 7%
29% 14%
34% 22%
Chimerism, GVHD and Relapse Acute GVHD II-IV and extensive chronic GVHD reduced relapse agvhd II-IV / extensive GVHD relapse 0% agvhd 0/I / limited or no cgvhd relapse 30% 26 / 41 were full donor chimeras 6 relapses 14 / 15 mixed chimeras remain in CR 8 given pre-emptive DLI 1 relapse
66% 39%
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
What s New? In vivo allo depletion with cyclophosphamide haploidentical transplantation Targeted radiotherapy myeloablative and reduced toxicity
Reduced Intensity Haplo Regimen Marrow infusion Cyclo 15 mg/kg 2 Gy TBI MMF Tacrolimus -6-5 -4-3 -2-1 0 5 10 20 30 40 180 Fludarabine 30 mg/m 2 /d Cyclo 50 mg/kg/d Days 3,4 Luznik et al, BBMT 2008, 14: 641
Myeloablative 2 step Haplo Regimen 2 x 10 8 /kg CD3+ DLI infusion CD34+ infusion MMF Tacrolimus -9-6 -5-4 -3-2 -1 0 10 20 30 40 180 12 Gy TBI Cyclo 60 mg/kg/d Grosso et al, Blood 2011, 118: 4732
Temperature (F) In vivo alloreaction Fever Post DLI 106 105 104 103 102 101 100 99 98 97 CY #1 CY #2 96 0 24 48 72 96 120 144 Hours Post DLI 36
Overall Survival CR at Tx 70% Relapse at Tx 27% 10 20 30 37 40 Months 10 20 30 40
Targeted Radiotherapy Antibodies Radioconjugates CD 45 CD 33 CD 20 CD 66 131 I 188 Re 90 Y 213 Bi 211 At
Targeted Radiotherapy with systemic RIC Reduced Toxicity + Myeloablation 58 patients with advanced AML / MDS 86% not in CR 131 I + Fludarabine + 2 Gy TBI conditioning MTD 24 Gy to liver, 36 Gy to marrow Pagel et al. Blood 114:5444, 2009
131 I labelled anti-cd45 with Flu / 2 Gy TBI Pagel et al. Blood 114:5444, 2009
24 Gy liver 36 Gy marrow CD 45 7 Gy liver 24 Gy marrow CD 66
Conclusions Myeloablative and reduced intensity regimens Different regimens give different benefits / risks There is no perfect regimen More relapse with reduced intensity regimens Targeted radiation / allodepletion GVHD remains a problem in elderly patients