Tailoring Reduced-Intensity Conditioning:

Applying Emerging Evidence to Clinical Practice

February 4, 2012

12:15-1:15 pm

Marcos J. de Lima, MDProfessor of Medicine

Department of Stem Cell Transplantation and Cellular Therapy

M.D. Anderson Cancer CenterHouston, TX

Faculty DisclosuresMarcos J. de Lima, MD

Professor of MedicineDepartment of Stem Cell Transplantation and Cellular TherapyM.D. Anderson Cancer CenterHouston, TX

Research Grant – Celgene

Kaci Wilhelm, PharmDClinical Pharmacy SpecialistBlood and Marrow TransplantM.D. Anderson Cancer CenterHouston, TX

No relevant financial relationships to disclose

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

Critical Decisions: Pretransplant Conditioning

Marcos J. de Lima, MDM.D. Anderson Cancer Center

Houston, TX

• 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

Goal of Preparative Regimen

• Immunosuppression - 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

05/22/11 06/09/11 07/06/11

08/04/11

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.

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

BMT Landmarks• 1955, 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.

1996

TOS00_13.ppt

Two-year Probability of Treatment-related Mortality After Transplants for CML, 1992-1997

PRO

BABI

LITY

, %

0

20

40

60

80

100

HLA-ident Sib Unrelated Auto

17%

27%

41%38%

53%

62%

11% 9% 11%

Leukemia

< 20 years20 – 40 years> 40 years

1990’s: How to improve treatment-related mortality

and morbidity?• Improvements in supportive care,

antibiotics, blood support, etc.• Decrease the dose ?

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.

ASH-Orlando 1996

SeattleHadassah

MDACC

Graft-Versus-Tumor Effect

Graft-Versus-Host Disease

Graft-versus-Lymphoma Effect

Graft-versus-Leukemia Effect (GVL)

• Intrinsic disease susceptibility is different.

• Some diseases need more chemo / radiation dose intensity than others.

Graft-versus-Leukemia Effect (GVL)

• + + + + Low grade lymphomas, chronic myeloid and lymphocytic leukemias.

• + + Myelodysplastic syndrome and acute myelogenous leukemia.

• + Acute lymphocytic leukemia.

Histocompatibility

Intensity

Review Question: Regarding the graft-versus-leukemia effect, it is true that:a) Donor neutrophils are the effector cells.b) Chronic myelogenous leukemia is more

sensitive to the graft-versus-leukemia effect than acute lymphoctye leukemia.

c) It is not influenced by the use of systemic steroids.

d) It is rarely associated with graft-versus-host disease.

Review Question: Regarding the graft-versus-leukemia effect, it is true that:a) Donor neutrophils are the effector cells.b) Chronic myelogenous leukemia is

more sensitive to the graft-versus-leukemia effect than acute lymphoctye leukemia.

c) It is not influenced by the use of systemic steroids.

d) It is rarely associated with graft-versus-host disease.

Definitions

Myeloablative

•Profound pancytopenia within 1-3 weeks•Irreversible myelosuppression•Require stem cell support

Reduced-Intensity

•Significant and prolonged cytopenias•Require stem cell support•Reduction in alkylating agent or TBI dose

Non-Myeloablative•Minimal cytopenias•Autologous recovery within 28 days

Bacigalupo A, et al. Biol Blood and Marrow Transplant 2009.

Myeloablative Dosing Thresholds

CIBMTR Operational Definitions

TBI > 5Gy single doseTBI > 8Gy fractionatedBusulfan > 9mg/kg POMelphalan > 150mg/m2

Thiotepa > 10mg/kg

Giralt S, et al. Biol Blood Marrow Transplant 2009; Madden T, et al. Biol Blood Marrow Transplant 2007.

Total dose per courseBusulfan equivalent dosing: 7.2mg/kg IV or 288mg/m2

EngraftmentGraft Host

Immunosuppression Preparative Regimen Post transplant Rx

Disease effects Sensitization

Stem cell doseT-cell dose

Graft-facilitating cellsStromal stem cells?

Histocompatibility

Patient-related Variables

• Age• Comorbidities• Performance Status• CMV Status• Other Infections

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

0

10

20

30

40

50

60 FHCRCMDACC

Diagnosis is AML in First Remission- Individual Comorbidities

Lung CancerLiver Obesity InfectionCardiac

% o

f pat

ient

s

DM Psych Rheum

2-year NRM Stratified by HCT-CI Scores

Years after HCT

Per

cent

NR

M

Score 0 Score 1-2 Score 3

FHCRC MDACC

7

1937

721

27

Two-year Survival Stratified by HCT-CI Scores

Years after HCT

Per

cent

sur

viva

l

FHCRC MDACC

Score 3Score 1-2Score 0

• Genetics

• Social economic issues

• Access to treatment

Race

Disease-related Variables

Disease status and survival

0 20 40 60 80 100 120 140 160

Months

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Cum

ulat

ive

Pro

porti

on S

urvi

ving

n= 433 patients with myeloid leukemias

Disease-related Variables• Previous treatment(s)

• Marrow microenvironment

• Susceptibility to the GVL effect

• Disease tempo

Donor-related Variables

- Donor-recipient ABO compatibility

- CMV

- Parity

- Age (??)

- Availability

- Co-morbid conditions

Donor-related Variables

The Graft

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.

Donor Type

Matched Sibling versus Unrelated

Donor Type

Cord Blood versus Unrelated Marrow or Peripheral Blood Stem Cell

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

Eapen et al. Lancet Oncol 2010.

Probability of Leukemia-Free Survival for Patients

IN REMISSION NOT IN REMISSION

Donor-recipient Variables

65-year Old Patient with AML

HLA-A* 02:01:01HLA-A* 03:01:01gHLA-B* 35:03:01HLA-B* 51:08HLA-Cw* 04:CXBMHLA-Cw* 16:02HLA-DRB1* 11:01HLA-DRB1* 13:02:01HLA-DRB3* 02:02:01HLA-DRB3* 03:01HLA-DQB1* 03:01:01HLA-DQB1* 06:04:01HLA-DQB1* (03:22, 06:39) HLA-DPB1* 02:01:02HLA-DPB1* 09:01

Donor Recipient01:01:01g02:01:0135:03:0151:0804:CXBM16:0211:0113:02:0102:02:0103:0103:01:0106:04:01(03:22, 06:39) 02:01:0204:01:01

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).

Are we transplanting older patients ?

Median age and year of transplantCorrelation: r = .94021

1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010

Year

25

30

35

40

45

50

55

60

Med

ian

age

Unrelated Donor Transplants at MDACC

Are we there yet?

NO!!

Median age of AML Patients: mid 60’s.

MDS: mid 70 - late 70’s

Trends in Allogeneic Transplantationby Recipient Age,* 1987-2007

1987-1993 1994-2000 2001-20070

20

40

60

80

100

<=20 yrs

21-40 yrs

41-50 yrs

51-60 yrs

>60 yrs

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

Tran

spla

nts,

per

cent

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)

TRM and Relapse of Patients 40+ Years Receiving Nonmyeloablative Allogeneic HSCT for AML and MDS,

1995-2005, by Age

Tp08_10.ppt

0 1 3 4

100

0

20

40

60

80

90

10

30

50

70

2Years

TRM

65+ yrs60-64 yrs55-59 yrs40-54 yrs

p=0.66

Years0 1 3 4

0

100

20

40

60

80

90

10

30

50

70

2

Relapse

40-54 yrs

60-64 yrs55-59 yrs

p=0.8765+ yrs

McClune, et al. Blood 2008;112 (11):135a (Abstract #346)

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

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.

Effect of Regimen Intensity on Transplant Outcome for AML/MDS

De Lima et al Blood 2004

FAI - relapse

FAI - toxicity

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 PBSCGVHD prophylaxis More likely CNI + MMFCo-morbidity Score WorsePrevious Transplant More likely

Baseline different when you compare

PARAMESWARAN HARI

Review Question: Which of the following statements is true?

a) Aging does not influence results of allogeneic stem cell transplantation.

b) Remission status at transplant influences treatment-related mortality.

c) There is extensive literature comparing outcomes of myeloablative and reduced-intensity preparative regimens in a randomized fashion.

d) Most patients with myelodysplastic syndrome receive allogeneic transplants.

Review Question: Which of the following statements is true?

a) Aging does not influence results of allogeneic stem cell transplantation.

b) Remission status at transplant influences treatment-related mortality.

c) There is extensive literature comparing outcomes of myeloablative and reduced-intensity preparative regimens in a randomized fashion.

d) Most patients with myelodysplastic syndrome receive allogeneic transplants.

1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 20080

5

10

15

20

25

30

35

40

45

50

Myeloblative RIC

Tran

spla

nts,

%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

Adjusted Probability of Overall Survival

Wsp08_18.ppt

Adju

sted

Pro

babi

lity,

%

Years0 1 2 543

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<0.01NST vs RIC PB, p=0.02

Are there situations in which reduced-intensity

transplants have changed the standard of carefor transplant?

Ablative Allo-BMT in Indolent Lymphoma

van Besien et al. Blood. 1998;92:1832-1836. Years

Prob

abili

ty, %

5432100

20

40

60

80

100

6

SurvivalDFSTreatment-related mortalityRelapse

Rituximab Fludarabine 30 mg/m2 Rituximab 375 mg/m2

Cyclophosphamide 750 mg/m2 1000 mg/m2

-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.

FCR Allo SCT for Low Grade Lymphoma

0 20 40 60 80 100 120

Months Post Transplant

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Cum

ulative Proportion S

urviving

Khouri et al Blood 2008

Burkitt Diffuse Large Cell

Follicular Mantle Cell Peripheral T Cell

Other NHL Hodgkin0

50

100

150

200RICMyeloablative

Conditioning Regimen Intensity by Histology Allogeneic Transplants for

Lymphoma in North America

Tran

spla

nts FOLLICULAR

MANTLE

HODGKIN

Graft vs. Lymphoma effect if any , varies by histologyArmand et al. Biol BMT 2008;14:418-25

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

Ablative Regimens Are Improving As Well!!

Intravenous Busulfan/Fludarabine

Day 1 2 3 4 5 6 7Bu 130 mg/m2 q d

Flu * rest* rest* HSCT 40 mg/m2 q d

GVHD prophylaxis: tacrolimus and “mini” methotrexate

*day of ATG if MUD or one-antigen mismatched related donor

Borje Andersson

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 Fludarabine for Patients Older Than 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 Patients Older Than 54 Years

Al-Atrash et al. Blood 2008 112: Abstract 2999

Myeloablative IV Busulfan and Fludarabine for Patients Older Than 54 Years

Reduced-intensity Conditioning

• Use 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.

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.

Review Question: Given that reduced-intensity regimens are usually associated with lower treatment-related mortality, it is true that:

a) All patients with acute myelogenous leukemia should receive this type of regimen.

b) All patients with myelodysplastic syndrome should receive this type of regimen.

c) There is frequently a tradeoff between less treatment-related mortality and higher relapse rate.

d) Disease susceptibility to the graft-versus-leukemia is the same for all hematologic malignancies.

Review Question: Given that reduced-intensity regimens are usually associated with lower treatment-related mortality, it is true that:

a) All patients with acute myelogenous leukemia should receive this type of regimen.

b) All patients with myelodysplastic syndrome should receive this type of regimen.

c) There is frequently a tradeoff between less treatment-related mortality and higher relapse rate.

d) Disease susceptibility to the graft-versus-leukemia is the same for all hematologic malignancies.

• 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…

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

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.

Conclusions • The major contribution is the realization that

patients in the 7th and 8th 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.

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.

Acknowledgments Edwin P. Alyea III, MDDana Farber Institute

Brenda Sandmaier, MDFred Hutch – Seattle

Marcelo Pasquini, MDParameswaran Hari, MDCIBMTR

Sergio Giralt, MD - NY

Image Credit: NASA/JPL/Space Science Institute

Richard Champlin Borje AnderssonElizabeth Shpall Roy JonesStefan Ciurea Simrit ParmarJeffrey Molldrem Uday Popat Paolo Anderlini Partow Kebriaei Yago Nieto Issa Khouri

Chitra Hosing Martin KorblingMichael Andreef Qaiser Bashir

Department of Stem Cell TransplantationM D Anderson Cancer Center