Conditioning Applying Emerging Evidence to Clinical Practice February 4 2012 1215115 pm Marcos J de Lima MD Professor of Medicine Department of Stem Cell Transplantation and Cellular Therapy ID: 808415
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Slide1
Tailoring Reduced-Intensity Conditioning: Applying Emerging Evidence to Clinical Practice
February 4, 2012
12:15-1:15
pm
Slide2Marcos J. de Lima, MDProfessor of MedicineDepartment of Stem Cell Transplantation and Cellular TherapyM.D. Anderson Cancer Center
Houston, TX
Slide3Faculty DisclosuresMarcos J. de Lima, MDProfessor of Medicine
Department of Stem Cell Transplantation and Cellular Therapy
M.D. Anderson Cancer Center
Houston, TX
Research Grant –
Celgene
Kaci
Wilhelm,
PharmD
Clinical Pharmacy Specialist
Blood and Marrow Transplant
M.D. Anderson Cancer Center
Houston, TX
No relevant financial relationships to disclose
Slide4Agenda12:15-12:45 p.m.
Critical Decisions:
Pretransplant
Conditioning
- Marcos J. de Lima, MD
12:45-1:05 p.m.
Putting the Evidence into Practice: Optimized Dosing and Administration of Reduced-Intensity Conditioning Regimens
-
Kaci
Wilhelm,
PharmD
1:05-1:15 p.m.
Faculty Panel: Questions & Answers
Slide5Critical Decisions:
Pretransplant
Conditioning
Marcos J. de Lima, MD
M.D. Anderson Cancer Center
Houston, TX
Slide6Historic perspective and definitions
Donor and recipient-related covariates that influence transplant outcomes and regimen
choice
Myeloablative
versus reduced intensity regimens – can we really compare them ?
Donor – recipient issues that influence regimen
choice
We may not need to reduce dose intensity for all patients in the 6th and 7th decade of life
Conclusions
Discussion Topics
Slide7Goal of Preparative RegimenImmunosuppression - adequate to prevent rejection
Cytoreduction
- eradicate or control malignancy (this element not needed if disease is controlled by prior therapy)
Stem cell space (not
myelosuppression
) - allow donor cells to compete effectively
Slide805/22/11
06/09/11
07/06/11
08/04/11
Slide9How did we get here?1922, Fabricious
-Moeller
Shielding of legs of guinea pigs during TBI decreased
myelosuppression
.
1952, Jacobsen/Lorenz
Protection of TBI aplasia by injection of spleen cells from
syngeneic
mice.
1956, Nowell/van Bekkum/Ford/Tausche
Concept of radiation chimera.
Slide10http://
wpcontent.answers.com
/
wikipedia
/commons/thumb/b/b3/Chimera_Apulia_Louvre_K362.jpg/180px-Chimera_Apulia_Louvre_K362.jpg
Head
of a
Lion
,
the Mid-section of a Goat and the Hindquarters of a Dragon
Slide11BMT Landmarks1955, Barnes and Loutit
Carcinoma bearing mice exposed to lethal TBI with syngeneic spleen cell transplantation had long lived protection, but 50% of mice receiving allogeneic spleen cells died before day 100 without tumors. GVL and GVHD.
1958, Santos
Lymphocytes (T-cells) mediate GVHD, and target organs are lymphoid, skin, gut, and liver.
Slide121996
Slide13TOS00_13.ppt
Two-year Probability of Treatment-related Mortality
After Transplants for CML
, 1992-1997
PROBABILITY, %
0
20
40
60
80
100
HLA-ident Sib
Unrelated
Auto
17%
27%
41%
38%
53%
62%
11%
9%
11%
Leukemia
< 20 years
20 – 40 years
> 40 years
Slide141990’s: How to improve treatment-related mortality and morbidity?Improvements in supportive care, antibiotics, blood support, etc.
Decrease the dose ?
Slide15Graft-vs-Malignancy Allogeneic SCT
Much of the benefit of
alloSCT
is due to immune GVL effect; therefore maximally ablative therapy may not be needed.
Lower dose
nonmyeloablative
preparative regimens may be sufficient to prevent rejection.
It was hypothesized that a reduced intensity,
nonmyeloablative
allogeneic transplant could reduce toxicity and allow successful treatment of older patients and those with major comorbidities.
Slide16ASH-Orlando 1996
Seattle
Hadassah
MDACC
Slide17Graft-Versus-Tumor EffectGraft-Versus-Host Disease
Slide18Graft-versus-Lymphoma Effect
Slide19Graft-versus-Leukemia Effect (GVL)
Intrinsic disease susceptibility is
different.
Some diseases need more chemo / radiation dose intensity than
others.
Slide20Graft-versus-Leukemia Effect (GVL)
+ + + + Low grade lymphomas, chronic myeloid and lymphocytic
leukemias
.
+ +
Myelodysplastic
syndrome and acute
myelogenous
leukemia.
+ Acute lymphocytic
leukemia.
Slide21Histocompatibility
Intensity
Slide22Review Question: Regarding the graft-versus-leukemia effect, it is true that:Donor neutrophils
are the
effector
cells.
Chronic
myelogenous
leukemia is more sensitive to the graft-versus-leukemia effect than acute
lymphoctye
leukemia.
It is not influenced by the use of systemic steroids.It is rarely associated with graft-versus-host disease.
Slide23Review Question: Regarding the graft-versus-leukemia effect, it is true that:Donor
neutrophils
are the
effector
cells.
Chronic
myelogenous
leukemia is more sensitive to the graft-versus-leukemia effect than acute
lymphoctye
leukemia.It is not influenced by the use of systemic steroids.It is rarely associated with graft-versus-host disease.
Slide24Definitions
Bacigalupo
A, et al.
Biol
Blood and Marrow Transplant 2009.
Slide25Myeloablative Dosing Thresholds
CIBMTR Operational Definitions
TBI > 5Gy single dose
TBI > 8Gy fractionated
Busulfan
> 9mg/kg PO
Melphalan
> 150mg/m
2
Thiotepa
> 10mg/kg
Giralt
S, et
al.
Biol
Blood Marrow Transplant
2009; Madden
T, et al.
Biol
Blood Marrow Transplant 2007
.
Total dose per course
Busulfan
equivalent dosing: 7.2mg/kg IV or 288mg/m
2
Slide26Engraftment
Graft
Host
Immunosuppression
Preparative Regimen
Post transplant Rx
Disease effects
Sensitization
Stem cell dose
T-cell dose
Graft-facilitating cells
Stromal stem cells
?
Histocompatibility
Slide27Patient-related VariablesAge
Comorbidities
Performance Status
CMV Status
Other Infections
Slide28Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) for Non-Relapse Mortality (NRM) and Survival after Allogeneic HCT
Sorror
M and
Collaborators
Fred Hutchinson Cancer Research Center, Seattle, WA
and MD Anderson Cancer Center, Houston, TX
Slide29Diagnosis is AML in
First Remission
- Individual
Comorbidities
Lung
Cancer
Liver
Obesity
Infection
Cardiac
% of patients
DM
Psych
Rheum
Slide302-year NRM Stratified by HCT-CI Scores
Years after HCT
Percent NRM
Score 0
Score 1-2
Score
3
FHCRC
MDACC
7
19
37
7
21
27
Slide31Two-year Survival Stratified by HCT-CI Scores
Years after HCT
Percent survival
FHCRC
MDACC
Score
3
Score 1-2
Score
0
Slide32• Genetics• Social economic issues
•
Access to treatment
Race
Slide33Disease-related Variables
Slide34Slide35Disease-related VariablesPrevious treatment(s)Marrow microenvironment
Susceptibility to the GVL effect
Disease tempo
Slide36Donor-related Variables
Slide37- Donor-recipient ABO compatibility- CMV
- Parity
- Age (??)
- Availability
- Co-morbid conditions
Donor-related Variables
Slide38The Graft
Slide39Graft
Several institutional and/or investigator biases.
Donor choice (marrow versus PBPC).
PBPC may be a better choice with reduced intensity preparative regimens.
De novo chronic GVHD with PBPC is a serious problem.
ASH 2011: results of randomized PBPC versus marrow in unrelated donor transplants
.
Slide40Donor TypeMatched Sibling versus Unrelated
Slide41Donor Type Cord Blood versus Unrelated Marrow or Peripheral Blood Stem Cell
Slide42Eapen et al. Lancet Oncol 2010.
Effect of Graft Source on Unrelated Donor
Haemopoietic
Stem-Cell Transplantation in
Adults with Acute Leukemia:
A
Retrospective Analysis
N=1525 - transplanted between 2002 – 2006
UCB = 165
PBPC = 888
Bone marrow = 472
All
myeloablative
Diagnoses: AML and ALL
Slide43Eapen et al. Lancet Oncol 2010.
Probability of Leukemia-Free Survival for Patients
IN REMISSION
NOT IN REMISSION
Slide44Donor-recipient Variables
Slide4565-year Old
P
atient with
AML
Slide46HLA-A*
02:01:01
HLA-A*
03:01:01g
HLA-B*
35:03:01
HLA-B*
51:08
HLA-
Cw
*
04:CXBM
HLA-
Cw
*
16:02
HLA-DRB1*
11:01
HLA-DRB1*
13:02:01
HLA-DRB3*
02:02:01
HLA-DRB3*
03:01
HLA-DQB1*
03:01:01
HLA-DQB1*
06:04:01
HLA-DQB1*
(03:22, 06:39)
HLA-DPB1*
02:01:02
HLA-DPB1*
09:01
Donor
Recipient
01:01:01g
02:01:01
35:03:01
51:08
04:CXBM
16:02
11:01
13:02:01
02:02:01
03:01
03:01:01
06:04:01
(03:22, 06:39)
02:01:02
04:01:01
Slide47Anti HLA
Antibodies
Anti B13, B27, B38, B39, B41, B45, B49, B50,
DR7, DR9, DR53, DQ2, DQ8, DP1, DP11,
DP13, DP15, DP17, DPB1*02:02
The patient's serum has reactivity against
HLA-DPB1*09:01 (827 MFI).
Slide48Slide49Are we transplanting older patients ?
Slide50Unrelated
Donor
T
ransplants
at MDACC
Are we there yet?
NO!!
Median age of AML
Patients: mid 60’s
.
MDS: mid 70
- late 70’s
Slide51Trends in Allogeneic
Transplantation
by Recipient Age,
*
1987-2007
* Transplants for AML, ALL, CML, MM, NHL, CLL, MDS
Transplants,
percent
Slide52Reduced Intensity (RIC) or Non-Myeloablative (NMA) HCT CIBMTR Data
Years 1995-2005
≥ 40 years old or greater
Matched related or unrelated donor
MDS or AML in CR1 1,080 cases
545 AML CR1
535 MDS
Data from 148 centers
McClune
, et al. Blood 2008;112 (11):135a (Abstract #346)
Slide53TRM and
Relapse
of
Patients
40+
Years
R
eceiving Nonmyeloablative
Allogeneic HSCT for AML and MDS, 1995-2005, by AgeTp08_10.ppt
0
1
3
4
100
0
20
40
60
80
90
10
30
50
70
2
Years
TRM
65+ yrs
60-64 yrs
55-59 yrs
40-54 yrs
p=0.66
Years
0
1
3
4
0
100
20
40
60
80
90
10
30
50
70
2
Relapse
40-54 yrs
60-64 yrs
55-59 yrs
p=0.87
65+ yrs
McClune
, et al. Blood 2008;112 (11):135a (Abstract #346)
Slide54Does the intensity of the preparative regimen matter?It does – however, it is not the
same for all diseases.
It depends on the diagnosis
and the sensitivity to the graft
versus malignancy effect
Slide55Are there diseases in which reducing the intensity may be worse than otherwise?
A cautionary tale in AML and MDS.
It is not only the regimen:
stem cell source etc
etc
.
Slide56Effect of Regimen Intensity on Transplant Outcome for AML/MDS
De Lima et al Blood 2004
FAI - relapse
FAI - toxicity
Slide57Comparing RIC vs MA Caveats
Notable absence of prospective RIC
vs
MA conditioning studies….
Level of evidence is not the highest
Retrospective & Registry Studies
Selection Bias
RIC (
vs
MA)
Graft Source
More
likely PBSC
GVHD prophylaxis
More
likely CNI + MMF
Co-morbidity Score Worse
Previous Transplant More
likely
Baseline different when you compare
PARAMESWARAN HARI
Slide58Review Question: Which of the following statements is true?Aging does not influence results of allogeneic stem cell transplantation.
Remission status at transplant influences treatment-related mortality.
There is extensive literature comparing outcomes of
myeloablative
and reduced-intensity preparative regimens in a randomized fashion.
Most patients with
myelodysplastic
syndrome receive
allogeneic
transplants.
Slide59Review Question: Which of the following statements is true?Aging does not influence results of allogeneic stem cell transplantation.
Remission status at transplant influences treatment-related mortality
.
There is extensive literature comparing outcomes of
myeloablative
and reduced-intensity preparative regimens in a randomized fashion.
Most patients with
myelodysplastic
syndrome receive
allogeneic transplants.
Slide60100-day Mortality after Allogeneic Transplantation,
1998-2008
- by conditioning intensity
-
Early mortality has improved for allogeneic transplants in general. Patient selection is key !!
NO
Slide61Adjusted Probability of
Overall Survival
Wsp08_18.ppt
Adjusted Probability, %
Years
0
1
2
5
4
3
100
0
20
40
60
80
90
10
30
50
70
Myeloablative
(N = 3,731)
RIC BM (N = 273)
RIC PB (N = 768)
NST (N = 407)
NST
vs
Myeloablative
, p
<
0.01
NST
vs
RIC PB, p=0.02
Slide62Are there situations in which reduced-intensitytransplants have changed the standard of care
for transplant?
Slide63Ablative
Allo
-BMT in
Indolent Lymphoma
van
Besien
et al.
Blood
. 1998;92:1832-1836.
Years
Probability
, %
5
4
3
2
1
0
0
20
40
60
80
100
6
Survival
DFS
Treatment-related mortality
Relapse
Slide64Rituximab Fludarabine 30 mg/m
2
Rituximab 375 mg/m
2
Cyclophosphamide 750 mg/m
2
1000 mg/m
2
-
13 -6 -5 -4 -3 0 +1 +8
ASCT
Days
NON-MYELOABLATIVE ALLOGENEIC SCT
Conditioning Regimen
ATG 15 mg/kg daily, was given days –5 to –3 for mismatched or unrelated
SCT.
Tacrolimus
and methotrexate were used for GVHD
prophylaxis.
Slide65FCR Allo SCT for Low Grade Lymphoma
Khouri
et al Blood 2008
Slide66Conditioning Regimen Intensity by Histology Allogeneic Transplants for Lymphoma in North America
Transplants
FOLLICULAR
MANTLE
HODGKIN
Graft vs. Lymphoma effect if any , varies by histology
Armand et al.
Biol
BMT 2008;14:418-25
Slide67BMT CTN Clinical Trials of Reduced Intensity Allogeneic Transplantation
Study
#
Disease
Study
Question
BMT CTN 0102
Myeloma
Tandem Auto vs. Auto ->
Allo RIC HCT
BMT CTN 0202
Foll
. NHL
Autologous
vs. Matched Sib
Allo
RIC HCT
BMT CTN 0502
AML CR1
RIC
Allo
HCT in pts 60 – 74 yrs
BMT CTN 0601
Sickle
Cell
RIC URD HCT
BMT CTN 0603
Many
Haplo
identical HCT with RIC
BMT CTN 0604
Many
Double Cord HCT with RIC
BMT CTN 0701
Foll
. NHL
Sibling or URD HCT with RIC
BMT CTN 0901
MDS/AML
Myeloablative
vs. RIC
Allogeneic
HCT
BMT CTN – Bone Marrow Transplant Clinical Trials Network
Slide68Ablative Regimens Are Improving As Well!!
Slide69Intravenous
Busulfan
/
Fludarabine
Day 1 2 3 4 5 6
7
Bu
130 mg/m
2
q d
Flu
* rest* rest*
HSCT
40 mg/m
2
q d
GVHD prophylaxis:
tacrolimus
and “mini” methotrexate
*day of ATG if MUD or one-antigen mismatched related donor
Borje
Andersson
Slide70Al-
Atrash
et al. Blood 2008 112: Abstract 2999.
Years 2002-2008 - n=74
Related or unrelated donors (50% / 50%)
Age
≥ 55
years (median, 58
years; range
, 55-66 years)
Cytogenetics
: poor (27%); intermediate (68%); good (5%)
Complete remission at transplant (54%)
Diagnosis: AML (81%) / MDS (19%)
Myeloablative
IV
Busulfan
and
F
ludarabine
for
Patients
O
lder
T
han
54 years
Al-
Atrash
et al. Blood 2008 112: Abstract 2999
Cumulative Incidence
Treatment-related Mortality Grade II-IV Acute GVHD
Myeloablative
IV
Busulfan
and
Fludarabine
for
P
atients
O
lder
T
han
54
Years
Slide72Al-
Atrash
et al. Blood 2008 112: Abstract 2999
Myeloablative
IV
Busulfan
and
F
ludarabine
for
Patients
O
lder
T
han
54
Years
Slide73Reduced-intensity ConditioningUse has increased over the last decade.
There are no randomized comparisons of regimen intensity - it is a matter of convictions, egos, tradition, careers, and institutional data and experience.
Little controversy: older patients and patients with medical comorbidities.
Slide74Conditioning Regimen Intensity: (some) Take Home Messages
Age does not influence outcomes with RIC/NMA for AML, up to age 65 (+/-!!).
HCT with RIC/NMA offers a possibility to cure AML in the elderly in up to 30-50 % of patients (you can’t
myeloablate
most patients in the late 60’s and early 70’s!!).
Usual prognostic factors do apply (
ie
cytogenetics
etc).
Disease status at transplant is the most important predictor for post transplant outcome.
Slide75Review Question: Given that reduced-intensity regimens are usually associated with lower treatment-related mortality, it is true that: All patients with acute myelogenous leukemia should receive this type of regimen.
All patients with
myelodysplastic
syndrome should receive this type of regimen.
There is frequently a tradeoff between less treatment-related mortality and higher relapse rate.
Disease susceptibility to the graft-versus-leukemia is the same for all hematologic malignancies.
Slide76Review Question: Given that reduced-intensity regimens are usually associated with lower treatment-related mortality, it is true that: All patients with acute
myelogenous
leukemia should receive this type of regimen.
All patients with
myelodysplastic
syndrome should receive this type of regimen.
There is frequently a tradeoff between less treatment-related mortality and higher relapse rate.
Disease susceptibility to the graft-versus-leukemia is the same for all hematologic malignancies.
Slide77Patients with some indolent diseases have more to lose with a high-risk approach upfront (especially now with new medications!):- CML in chronic phase that is refractory to
imatinib
and other TKI but remain in chronic phase.
- Low grade lymphoma.
- CLL.
- Low grade MDS.
- Multiple myeloma
To
Ablate
or
Not
…
Slide78To Ablate or Not…In the absence of controlled trials RIC regimens should be considered standard for:
Hodgkin’s Disease
Myeloma
Older patients
Heavily pretreated patients or those with significant co-morbidities
Most patients with CLL and NHL
Slide79Future Directions
Better definition of risk for treatment-related mortality.
Incorporation of new agents.
Better integration with standard treatment.
Conjugation with graft engineering and post transplant pharmacologic and immunologic manipulations.
Slide80Conclusions The major contribution is the realization that patients in the 7
th
and 8
th
decades of life can have allogeneic transplants.
Major obstacles to cure are delayed or poor immune recovery, graft-versus-host disease and disease relapse.
Relapse rates are higher than in
myeloablative
transplants for certain diseases.
Slide81To ablate or Not, That Is the Question…
Controlled trials are needed to establish whether RIC is superior to conventional
allografting
or standard therapy in most hematologic malignancies.
These trials will need to be performed in single diseases and selected disease stages to be clinically informative.
The issue of preparative regimen of choice is unresolved.
Slide82Acknowledgments
Edwin P.
Alyea
III, MD
Dana Farber Institute
Brenda
Sandmaier
, MD
Fred Hutch – Seattle
Marcelo
Pasquini
, MD
Parameswaran
Hari
, MD
CIBMTR
Sergio
Giralt
, MD - NY
Slide83Image Credit: NASA/JPL/Space Science Institute
Richard Champlin Borje Andersson
Elizabeth Shpall Roy Jones
Stefan Ciurea Simrit Parmar
Jeffrey Molldrem Uday Popat
Paolo Anderlini Partow Kebriaei
Yago Nieto Issa Khouri
Chitra Hosing Martin Korbling
Michael Andreef Qaiser Bashir
Department of Stem Cell Transplantation
M D Anderson Cancer Center