Vikram Mathews M'D

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Role of T cell depleted HLA identical sibling
stem cell transplantation for AML in CR1

• Vikram Mathews M.D

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Patients lt55 years with newly diagnosed acute
myeloid leukemia (AML) treated on ECOG protocols
since 1973.
Appelbaum et al. Hematology 2001
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Risk group stratification based on cytogenetics
at diagnosis (Cooperative group. NEJM
1998) Good Risk group t(1517)
t(821) inv 16 Intermediate Risk
group Normal karyotype Single numerical
abnormality other than those classified as
good or unfavorable Unfavorable Risk
group 5q- / del 5 7q- / del
7 abnormalities of chromosome 9 or
11 three or more clonal abnormalities
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Results of induction therapy in adults with acute
myeloid leukemia according to cytogenetic
prognostic groups
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• Options of consolidation therapy
• High dose non-myeloablative chemotherapy
• Autologous stem cell transplantation
• Allogeneic stem cell transplantation

Good risk group Long term DFS gt70 with
repetitive cycles of HDCT Not candidates for
auto / allo SCT in CR1 Unfavourable risk group
Dismal outcome with either HDCT or auto-SCT 10
20 long term DFS
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Prognosis in acute myeloid leukemia (AML) by
leukemia karyotype
Giles et al. Hematology 2002
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Options of consolidation therapy
Relapse Risk
HDCT Auto Allo TRM lt5 5-15 10-25
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MRC AML 12 Overall survival on a donor versus no
donor basis
Giles et al. Hematology 2002
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To harness anti-leukemia effect of an allogeneic
transplant and improve EFS and OS Need
to reduce TRM Improve supportive
care Decrease Regimen related
toxicity Incidence of GVHD RIC T cell
depletion
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Current approaches to GVHD prophylaxis Blockade
of T cell function Cyclosporine / FK506 - block
calceneurin activity - suppress IL2
secretion Methotrexate - inhibit cellular
proliferation Mycophenolate - inhibit de-novo
purine synthesis Sirolimus - inhibit downstream
signaling pathways Daclizumab - block IL2
receptor In spite of prophylaxis acute GVHD 25
60 matched related 45 70 matched
un-related T cell depletion of the graft most
effective way to reduce incidence of GVHD
Average unmodified bone marrow 1 5 x 107
cells/kg T cells Average unmodified PBSC 3 x 109
cells/kg T cells
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T cell depletion
Soiffer et al. Blood 2001
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T cell depletion - How much? Early murine models
as few as 0.3 (3 x 104) of T lymphocytes
sufficient to cause lethal GVHD (Korngold R
et al. J Exp Med 1978) Early clinical trials
using monoclonal antibodies with rabbit
complement removed 2-3 logs T cells 10-20
incidence of acute GVHD with matched sibling
transplants Wagner et al. 45 incidence of
acute GVHD at T cell dose of 1x106/kg (Blood
1988/1990) 22 when dose reduced to 0.5x106/kg
(counterflow centrifugation) Significant
variability in studies using CD34 positive
selection (function of contaminating T cell
dose) - when T cell dose lt 0.5x106/kg, acute
GVHD 10 (BMT 1998) - immunomagnetic technique
superior to immunoadsorption Aversa et al.
Haploidentical SCT T cell dose 3 x 104/kg, no
GVHD (NEJM 1998) in evaluable patients
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www.miltenyibiotec.com
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Worldwide experience with CliniMacs for CD34
selection/T cell depletion
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T cell depleted transplants

• Advantages
• Reduced incidence of acute and chronic GVHD
• Reduced / no post-transplant immunosupression
• Decreased hepatic and pulmonary toxicity early
  after BMT
• Reduced early TRM

• Disadvantages
• Higher incidence of graft failure
• Loss of GVL
• Delayed immune reconstitution
• Increased risk of EBV-PTLD
• Higher incidence of CMV reactivation
• Overall survival not improved compared to non-TCD
  transplants

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T cell depleted transplants for
AML Retrospective study of the IBMTR data
Bortin et al. Blood 1991 TCD 731 (245) Non
TCD 2480 (909) Variety of T cell depletion
techniques and conditioning regimens Relative
risk of relapse for AML in CR1 - 1.94 with
TCD Also seen significant effect of
Conditioning regimen Lower relapse risk and
graft failure with higher radiation dose
gt11Gy Post transplant immunosuppression with
CSAMTX reduced graft failure and incidence of
GVHD Did not improve leukemia free survival
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• Subsequently a number of single centre studies
  have shown a
• consistent improved DFS and OS with TCD
  transplants for
• AML in CR1
• Available data on T cell depletion and AML in CR1
  under
• Physical methods and non-campath antibody based
• Campath antibody based
• CD34 positive selection
• Selective subset depletion

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Non Campath based T cell depletion Series from
Dana-Farber cancer institute is representative of
this Group March 1984 April 1996 N41 AML in
CR1 28 - All high risk patients In-vitro T
cell depletion using anti CD6 antibody Conditionin
g Cyclo 120/kg, TBI (1300-1560cGy) No post
transplant immunosuppressive therapy Bone marrow
median TNC/kg 5.7 x 107/kg - median CD3
cells 1.5 x 106/kg 40/41 (97.5) engrafted 2
patients late graft failure Acute GVHD grade 2
4 9 (15 of evaluable, 8 grade II) 3 1
TRM by Day 100 2 (lt5)
Soiffer et al. Blood 1997
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Estimated 3 year risk of relapse was
31 Estimated EFS and OS at 4 years was 63 and
71
Soiffer et al. Blood 1997
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Summary of other single institution Non-campath
based studies
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Campath based T cell depletion Advantages of
Campath - Anti CD52 abundantly expressed on
lymphocytes (TB), dendritic cells,
monocytes - Campath 1H - Autologous complement
can lyse cells - Can be used in-vitro and
in-vivo (Campath in bag) - Decreased B cells
reduce incidence of EBV-PTLD - Reduce incidence
of GVHD by additional action on dendritic
cells (host) - Long half life, cytolytic
levels upto 2 3 weeks post infusion
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First report of use of Campath for in-vitro and
in-vivo T cell depletion in AML in CR1 Bunjes
et al. BMT 1995 DFS at 2 years was 80 No
Chronic GVHD Acute GVHD 4 (all Grade
I) Subsequent multi-center trial by same group.
Blood 1998 Royal Free (41), Ulm (16), Riyadh
(13) n70 Campath 1M into bag (bone marrow) 0.1
mg/ml 37C/45 Campath 1G in-vivo 20mg/day x 5
days (-5 to -1) No other GVHD
prophylaxis Conditioning TBI based
(Cy/TBI) Compared to only in-vitro Campath
n50 Historical IBMTR controls n459
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• Results
• - T cell dose lt106/kg at all centres
• - Comparable speed of engraftment
• Risk of rejection 6 vs 2 with
• Probability of relapse comparable
• Only 3/70 developed Grade II acute GVHD
• 2 developed mild/moderate GVHD

Hale et al. Blood 1998
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Summary of two other Campath based studies
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• Data with CD34 positive selection
• Very limited in the setting of AML in CR1
• Majority of the studies in advanced disease and
  in transplants
• from MUD / Haplo
• Limited follow up
• Preliminary data is interesting
• Centre Donor Conditioning N Eng GVHD II-IV
  ChGVHD
• Perugia Haplo TBI/THIO/FLU/ATG 53 98 4 1
• Lisbon Haplo THIO/MEL/FLU/ATG 14 100 5 2
• ULM Matched Bu or TBI/CTXTHIOATG 24 95 0 27
• related

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• Limitations of data
• Majority single centre studies
• Numbers are small
• Limited follow up
• Phase II open clinical trials, no randomized
  clinical trials
• Significant variability in conditioning
  regimens,
• GVHD prophylaxis and T cell depletion tecnhiques
  used
• makes it difficult to compare these studies

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Randomized trial initiated in UK CTC of the Br
Soc of BMT Enrolling patients since Oct
2002 Aims to recruit 300 pts with AML in CR1
Chakrabarti. BMT 2003
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• Selective T cell subset depletion
• Yet to dissect apart mediators of GVHD and GVL
• Animal models both CD4 and CD8 play significant
  role
• but donor CD4 cells can still mediate GVL in the
  absence of
• CD8
• Champlin et al (Transplantation 1994) showed
  that CD8 depletion CSA
• vs CSA alone had less GVHD II-IV (20 vs 80) and
  
• comparable relapse rates
• Further in DLI studies CD8 depletion was shown
  to reduce
• incidence of GVHD but retain GVL and clinical
  response in
• patients relapsed CML (Giralt et al. Blood 1995
• Potential role for T cell add back after T
  cell depleted transplants
• Earlier data using CD6 depleted grafts similar
  rational
• anti CD6 depletes mature T cells sparing
  immature
• thymocytes, NK cells and monocytes. In that
  study CMV