Download Different Conditioning Regimens

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
High TRM
GVHD
Non Ablative
Reduced Intensity
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
Regimen Intensity
Immunosuppressive / engraftment
Non myeloablative
Reduced
Intensity
Ablative
Cy / TBI
Flu / Mel / Campath
Flu / Bu / ATG
Flu / TBI 2Gy
Flu / Cy
TBI 2Gy
FLAG / Ida
Tumour Control / Myelosuppression / Toxicity
BEAM
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
Median age
Follow up
Disease status
–
–
–
–
CR1
CR2
standard risk
high risk
70
56 (17 – 70)
41 months
43
27
33
37
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
-6
-5
2 Gy
TBI
-4
-3
-2
Fludarabine 30 mg/m2/d
-1
MMF
0
5
10
20
Tacrolimus
30 40
180
Cyclo
50 mg/kg/d
Days 3,4
Luznik et al, BBMT 2008, 14: 641
Myeloablative 2 step Haplo Regimen
CD34+
infusion
2 x 108/kg
CD3+ DLI
infusion
MMF
-9
-6
12 Gy
TBI
-5
-4
-3
-2
-1
0
10
20
Tacrolimus
30 40
180
Cyclo
60 mg/kg/d
Grosso et al, Blood 2011, 118: 4732
In vivo alloreaction
Fever Post DLI
106
105
104
Temperature (F)
103
102
101
100
99
98
CY
#1
97
CY
#2
96
0
24
48
72
96
120
144
Hours Post DLI
36
Overall Survival
CR at Tx
Relapse at Tx
Months
10
10
20
20
70%
27%
30
30
37
40
40
Targeted Radiotherapy
Antibodies
Radioconjugates
•
•
•
•
•
•
•
•
•
CD 45
CD 33
CD 20
CD 66
131I
188Re
90Y
213Bi
211At
Targeted Radiotherapy with “systemic RIC”
Reduced Toxicity + Myeloablation
• 58 patients with advanced AML / MDS
– 86% not in CR
• 131I + Fludarabine + 2 Gy TBI conditioning
• MTD 24 Gy to liver, 36 Gy to marrow
Pagel et al. Blood 114:5444, 2009
131I
labelled anti-CD45 with Flu / 2 Gy TBI
Pagel et al. Blood 114:5444, 2009
24 Gy liver
36 Gy marrow
7 Gy liver
24 Gy marrow
CD 45
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