1. Tailoring Reduced-Intensity Conditioning:
Applying Emerging Evidence to Clinical Practice
February 4, 2012
12:15-1:15 pm

2. Marcos J. de Lima, MD Professor of Medicine
Department of Stem Cell Transplantation and Cellular Therapy
M.D. Anderson Cancer Center
Houston, TX

3. Faculty Disclosures Marcos J. de Lima, MD Research Grant – Celgene
Professor 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
No relevant financial relationships to disclose

4. Agenda 12:15-12:45 p.m. 12:45-1:05 p.m. 1:05-1:15 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

5. Critical Decisions: Pretransplant Conditioning
Marcos J. de Lima, MD
M.D. Anderson Cancer Center
Houston, TX

6. Discussion Topics 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

7. 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

8. 05/22/11
06/09/11
07/06/11
Probability of overall survival after transplantation with acute leukemia in relapse or primary induction failure according to risk score (ie, [A] acute myeloid leukemia score of 0, 1, 2, and ≥ 3; [B] acute lymphoblastic leukemia score of 0 and 1; 2; and ≥ 3).The 3-year survival rates and 95% CIs are indicated.
08/04/11

9. 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.

10. Head of a Lion, the Mid-section of a Goat and
the Hindquarters of a Dragon 10

11. BMT Landmarks 1955, Barnes and Loutit 1958, Santos
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.

12. 1996

13. Two-year Probability of Treatment-related Mortality
After Transplants for CML, 20 40 60 80
100
< 20 years
20 – 40 years
> 40 years
62%
53%
PROBABILITY, %
41%
38%
27%
17%
11%
11% 9%
HLA-ident Sib
Unrelated
Auto
Leukemia
TOS00_13.ppt

14. 1990’s: How to improve treatment-related mortality and morbidity?
Improvements in supportive care, antibiotics, blood support, etc.
Decrease the dose ?

15. 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.

16. ASH-Orlando 1996
MDACC
Hadassah
Seattle

17. Graft-Versus-Tumor Effect Graft-Versus-Host Disease

18. Graft-versus-Lymphoma Effect

19. Graft-versus-Leukemia Effect (GVL)
Intrinsic disease susceptibility is different.
Some diseases need more chemo / radiation dose intensity than others.

20. Graft-versus-Leukemia Effect (GVL)
Low grade lymphomas, chronic myeloid and lymphocytic leukemias.
+ + Myelodysplastic syndrome and acute myelogenous leukemia.
+ Acute lymphocytic leukemia.

21. Histocompatibility
Intensity

22. 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.

23. 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.

24. Definitions
Myeloablative
Profound pancytopenia within 1-3 weeks
Irreversible myelosuppression
Require stem cell support
Reduced-Intensity
Significant and prolonged cytopenias
Reduction in alkylating agent or TBI dose
Non-Myeloablative
Minimal cytopenias
Autologous recovery within 28 days
Reduction is dose by about 30%.
Bacigalupo A, et al. Biol Blood and Marrow Transplant 2009. 24

25. Myeloablative Dosing Thresholds
CIBMTR Operational Definitions
TBI > 5Gy single dose
TBI > 8Gy fractionated
Busulfan > 9mg/kg PO
Melphalan > 150mg/m2
Thiotepa > 10mg/kg
Total dose per course
1mg/kg PO = 0.8mg/kg IV = 32mg/m2 IV
Total dose per course
Busulfan equivalent dosing: 7.2mg/kg IV or 288mg/m2
Giralt S, et al. Biol Blood Marrow Transplant 2009; Madden T, et al. Biol Blood Marrow Transplant 2007. 25

26. Graft-facilitating cells
Engraftment
Graft
Host
Stem cell dose
T-cell dose
Graft-facilitating cells
Stromal stem cells?
Immunosuppression
Preparative Regimen
Post transplant Rx
Disease effects
Sensitization
Histocompatibility

27. Patient-related Variables
Age
Comorbidities
Performance Status
CMV Status
Other Infections

28. 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

29. Diagnosis is AML in First Remission - Individual Comorbidities
% of patients
Lung
Liver
Cancer
Cardiac
Obesity
Infection DM
Psych
Rheum

30. 2-year NRM Stratified by HCT-CI Scores
FHCRC
MDACC
Percent NRM 37 19 27 7 21 7
Years after HCT

31. Two-year Survival Stratified by HCT-CI Scores
FHCRC
MDACC
Percent survival
Years after HCT

32. • Genetics • Social economic issues • Access to treatment
Race
• Genetics • Social economic issues • Access to treatment

33. Disease-related Variables

35. Disease-related Variables
Previous treatment(s)
Marrow microenvironment
Susceptibility to the GVL effect
Disease tempo

36. Donor-related Variables

37. Donor-related Variables
- Donor-recipient ABO compatibility - CMV - Parity - Age (??) - Availability - Co-morbid conditions

38. The Graft

39. 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.

40. Donor Type Matched Sibling versus Unrelated

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

42. Effect of Graft Source on Unrelated Donor
Haemopoietic Stem-Cell Transplantation in
Adults with Acute Leukemia:
A Retrospective Analysis
N= transplanted between 2002 – 2006
UCB = 165
PBPC = 888
Bone marrow = 472
All myeloablative
Diagnoses: AML and ALL
Eapen et al. Lancet Oncol 2010.

43. Probability of Leukemia-Free Survival for Patients
IN REMISSION
NOT IN REMISSION
Eapen et al. Lancet Oncol 2010.

44. Donor-recipient Variables

45. 65-year Old Patient with AML

46. Donor Recipient HLA-A* 02:01:01 03:01:01g HLA-B* 35:03:01 51:08
HLA-Cw*
04:CXBM
16:02
HLA-DRB1*
11:01
13:02:01
HLA-DRB3*
02:02:01
03:01
HLA-DQB1*
03:01:01
06:04:01
(03:22, 06:39)
HLA-DPB1*
02:01:02
09:01
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

47. 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).

49. Are we transplanting older patients ?

50. Unrelated Donor Transplants at MDACC
Are we there yet?
NO!!
Median age of AML
Patients: mid 60’s.
MDS: mid 70
- late 70’s

51. Trends in Allogeneic Transplantation by Recipient Age,* 1987-2007
Transplants, percent
Slides 5 & 6: The numbers of autologous and allogeneic HCTs for treatment of the most common malignant disease indications in patients older than 60 continue to increase. Thirty-two percent of autograft recipients and 10% of allograft recipients in were older than 60 years of age. The majority of autograft recipients (65%) are older than 50 years in this later period.
* Transplants for AML, ALL, CML, MM, NHL, CLL, MDS

52. Reduced Intensity (RIC) or Non-Myeloablative (NMA) HCT CIBMTR Data
Years
≥ 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)

53. TRM and Relapse of Patients 40+ Years Receiving Nonmyeloablative Allogeneic HSCT for AML and MDS, , by Age 1 3 4
100 20 40 60 80 90 10 30 50 70 2
Years 1 3 4
100 20 40 60 80 90 10 30 50 70 2
TRM
Relapse
65+ yrs
60-64 yrs
55-59 yrs
40-54 yrs
60-64 yrs
55-59 yrs
40-54 yrs
65+ yrs
p=0.66
p=0.87
Years
McClune, et al. Blood 2008;112 (11):135a (Abstract #346)
Tp08_10.ppt

54. 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

55. 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.

56. Effect of Regimen Intensity on Transplant Outcome for AML/MDS
FAI - relapse
FAI - toxicity
De Lima et al Blood 2004

57. 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

58. 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.

59. 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.

60. 100-day Mortality after Allogeneic Transplantation, 1998-2008 - by conditioning intensity -NO
Slides 5 & 6: The numbers of autologous and allogeneic HCTs in patients older than 50 continue to increase. Sixty-two percent of autograft recipients and 35% of allograft recipients in were older than 50 years of age.
Early mortality has improved for allogeneic transplants in general. Patient selection is key !!

61. Adjusted Probability of Overall Survival
100 20 40 60 80 90 10 30 50 70
NST vs Myeloablative, p<0.01
NST vs RIC PB, p=0.02
RIC PB (N = 768)
Adjusted Probability, %
Myeloablative (N = 3,731)
NST (N = 407)
RIC BM (N = 273) 1 2 3 4 5
Years
Wsp08_18.ppt 61

62. Are there situations in which reduced-intensity transplants have changed the standard of care for transplant?

63. Ablative Allo-BMT in Indolent Lymphoma
Probability, % 5 4 3 2 1 20 40 60 80
100 6
Survival
DFS
Treatment-related mortality
Relapse
Years
van Besien et al. Blood. 1998;92:

64. NON-MYELOABLATIVE ALLOGENEIC SCT
Conditioning Regimen
Rituximab Fludarabine 30 mg/m2 Rituximab 375 mg/m2 Cyclophosphamide 750 mg/m mg/m2
ASCT
Days
ATG 15 mg/kg daily, was given days –5 to –3 for mismatched or unrelated SCT.
Tacrolimus and methotrexate were used for GVHD prophylaxis.

65. FCR Allo SCT for Low Grade Lymphoma
Khouri et al Blood 2008

66. Conditioning Regimen Intensity by Histology Allogeneic Transplants for Lymphoma in North America
FOLLICULAR
Transplants
MANTLE
HODGKIN
Slides 5 & 6: The numbers of autologous and allogeneic HCTs in patients older than 50 continue to increase. Sixty-two percent of autograft recipients and 35% of allograft recipients in were older than 50 years of age.
Graft vs. Lymphoma effect if any , varies by histology
Armand et al. Biol BMT 2008;14:418-25

67. BMT CTN Clinical Trials of Reduced Intensity Allogeneic Transplantation
BMT CTN – Bone Marrow Transplant Clinical Trials Network
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
Double Cord HCT with RIC
BMT CTN 0701
Sibling or URD HCT with RIC
BMT CTN 0901
MDS/AML
Myeloablative vs. RIC Allogeneic HCT

68. Ablative Regimens Are Improving As Well!!

69. Intravenous Busulfan/Fludarabine
Day
Bu    
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
Fludarabine is given as a 60 min infusion once daily for 4 days, each dose immediately followed by IV Busulfan 130 mg/m2 over 3 hours by pump.
Borje Andersson

70. Myeloablative IV Busulfan and Fludarabine
for Patients Older Than 54 years
Years n=74
Related or unrelated donors (50% / 50%)
Age ≥ 55 years (median, 58 years; range, years)
Cytogenetics : poor (27%); intermediate (68%); good (5%)
Complete remission at transplant (54%)
Diagnosis: AML (81%) / MDS (19%)
Al-Atrash et al. Blood : Abstract 2999.

71. Myeloablative IV Busulfan and Fludarabine for Patients Older Than 54 Years
Cumulative Incidence
Treatment-related Mortality Grade II-IV Acute GVHD
Al-Atrash et al. Blood : Abstract 2999

72. Myeloablative IV Busulfan and Fludarabine
for Patients Older Than 54 Years
Al-Atrash et al. Blood : Abstract 2999

73. 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.

74. 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 % 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.

75. 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.

76. 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.

77. To Ablate or Not…
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

78. 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

79. 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.

80. 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.

81. 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.

82. 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

83. Department of Stem Cell Transplantation M D Anderson Cancer Center
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
Image Credit: NASA/JPL/Space Science Institute