Tailoring Reduced-Intensity - PowerPoint Presentation

Slide1

Tailoring Reduced-Intensity Conditioning: Applying Emerging Evidence to Clinical Practice

February 4, 2012

12:15-1:15

pm

Slide2

Marcos J. de Lima, MDProfessor of MedicineDepartment of Stem Cell Transplantation and Cellular TherapyM.D. Anderson Cancer Center

Houston, TX

Slide3

Faculty 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

Slide4

Agenda12:15-12:45 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

Slide5

Critical Decisions:

Pretransplant

Conditioning

Marcos J. de Lima, MD

M.D. Anderson Cancer Center

Houston, TX

Slide6

Historic 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

Slide7

Goal 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

Slide8

05/22/11

06/09/11

07/06/11

08/04/11

Slide9

How 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.

Slide10

http://

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

Slide11

BMT 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.

Slide12

1996

Slide13

TOS00_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

Slide14

1990’s: How to improve treatment-related mortality and morbidity?Improvements in supportive care, antibiotics, blood support, etc.

Decrease the dose ?

Slide15

Graft-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.

Slide16

ASH-Orlando 1996

Seattle

Hadassah

MDACC

Slide17

Graft-Versus-Tumor EffectGraft-Versus-Host Disease

Slide18

Graft-versus-Lymphoma Effect

Slide19

Graft-versus-Leukemia Effect (GVL)

Intrinsic disease susceptibility is

different.

Some diseases need more chemo / radiation dose intensity than

others.

Slide20

Graft-versus-Leukemia Effect (GVL)

+ + + + Low grade lymphomas, chronic myeloid and lymphocytic

leukemias

.

+ +

Myelodysplastic

syndrome and acute

myelogenous

leukemia.

+ Acute lymphocytic

leukemia.

Slide21

Histocompatibility

Intensity

Slide22

Review 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.

Slide23

Review 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.

Slide24

Definitions

Bacigalupo

A, et al.

Biol

Blood and Marrow Transplant 2009.

Slide25

Myeloablative 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

Slide26

Engraftment

Graft

Host

Immunosuppression

Preparative Regimen

Post transplant Rx

Disease effects

Sensitization

Stem cell dose

T-cell dose

Graft-facilitating cells

Stromal stem cells

?

Histocompatibility

Slide27

Patient-related VariablesAge

Comorbidities

Performance Status

CMV Status

Other Infections

Slide28

Hematopoietic 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

Slide29

Diagnosis is AML in

First Remission

- Individual

Comorbidities

Lung

Cancer

Liver

Obesity

Infection

Cardiac

% of patients

DM

Psych

Rheum

Slide30

2-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

Slide31

Two-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

Slide33

Disease-related Variables

Slide34

Slide35

Disease-related VariablesPrevious treatment(s)Marrow microenvironment

Susceptibility to the GVL effect

Disease tempo

Slide36

Donor-related Variables

Slide37

- Donor-recipient ABO compatibility- CMV

- Parity

- Age (??)

- Availability

- Co-morbid conditions

Donor-related Variables

Slide38

The Graft

Slide39

Graft

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

.

Slide40

Donor TypeMatched Sibling versus Unrelated

Slide41

Donor Type Cord Blood versus Unrelated Marrow or Peripheral Blood Stem Cell

Slide42

Eapen 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

Slide43

Eapen et al. Lancet Oncol 2010.

Probability of Leukemia-Free Survival for Patients

IN REMISSION

NOT IN REMISSION

Slide44

Donor-recipient Variables

Slide45

65-year Old

P

atient with

AML

Slide46

HLA-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

Slide47

Anti 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).

Slide48

Slide49

Are we transplanting older patients ?

Slide50

Unrelated

Donor

T

ransplants

at MDACC

Are we there yet?

NO!!

Median age of AML

Patients: mid 60’s

.

MDS: mid 70

- late 70’s

Slide51

Trends in Allogeneic

Transplantation

by Recipient Age,

*

1987-2007

* Transplants for AML, ALL, CML, MM, NHL, CLL, MDS

Transplants,

percent

Slide52

Reduced 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)

Slide53

TRM 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)

Slide54

Does 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

Slide55

Are 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

.

Slide56

Effect of Regimen Intensity on Transplant Outcome for AML/MDS

De Lima et al Blood 2004

FAI - relapse

FAI - toxicity

Slide57

Comparing 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

Slide58

Review 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.

Slide59

Review 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.

Slide60

100-day Mortality after Allogeneic Transplantation,

1998-2008

- by conditioning intensity

-

Early mortality has improved for allogeneic transplants in general. Patient selection is key !!

NO

Slide61

Adjusted 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

Slide62

Are there situations in which reduced-intensitytransplants have changed the standard of care

for transplant?

Slide63

Ablative

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

Slide64

Rituximab 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.

Slide65

FCR Allo SCT for Low Grade Lymphoma

Khouri

et al Blood 2008

Slide66

Conditioning 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

Slide67

BMT 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

Slide68

Ablative Regimens Are Improving As Well!!

Slide69

Intravenous

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

Slide70

Al-

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

Slide71

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

Slide72

Al-

Atrash

et al. Blood 2008 112: Abstract 2999

Myeloablative

IV

Busulfan

and

F

ludarabine

for

Patients

O

lder

T

han

54

Years

Slide73

Reduced-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.

Slide74

Conditioning 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.

Slide75

Review 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.

Slide76

Review 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.

Slide77

Patients 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

…

Slide78

To 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

Slide79

Future 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.

Slide80

Conclusions 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.

Slide81

To 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.

Slide82

Acknowledgments

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

Slide83

Image 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