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

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Presentation on theme: "Tailoring Reduced-Intensity Conditioning: Applying Emerging Evidence to Clinical Practice February 4, 2012 12:15-1:15 pm."— Presentation transcript:

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 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 M.D. Anderson Cancer Center Houston, TX No relevant financial relationships to disclose

4 Agenda 12:15-12:45 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

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

6 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

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 05/22/1106/09/11 07/06/11 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 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

11 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.

12 1996

13 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 SibUnrelatedAuto 17% 27% 41% 38% 53% 62% 11% 9% 11% Leukemia < 20 years 20 – 40 years > 40 years

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 Seattle Hadassah MDACC

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: 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.

23 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.

24 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.

25 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

26 Engraftment GraftHost Immunosuppression Preparative Regimen Post transplant Rx Disease effects Sensitization Stem cell dose T-cell dose Graft-facilitating cells Stromal stem cells? 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 LungCancerLiverObesityInfectionCardiac % of patients DMPsychRheum

30 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

31 Two-year Survival Stratified by HCT-CI Scores Years after HCT Percent survival FHCRCMDACC Score  3 Score 1-2 Score 0

32 Genetics Social economic issues Access to treatment Race

33 Disease-related Variables

34

35 Previous treatment(s) Marrow microenvironment Susceptibility to the GVL effect Disease tempo

36 Donor-related Variables

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

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 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

43 Eapen et al. Lancet Oncol 2010. Probability of Leukemia-Free Survival for Patients IN REMISSIONNOT IN REMISSION

44 Donor-recipient Variables

45 65-year Old Patient with AML

46 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

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).

48

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

52 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)

53 TRM and Relapse of Patients 40+ Years Receiving Nonmyeloablative Allogeneic HSCT for AML and MDS, 1995-2005, by Age Tp08_10.ppt 0134 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 0134 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)

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 De Lima et al Blood 2004 FAI - relapse FAI - toxicity

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 SourceMore likely PBSC GVHD prophylaxisMore likely CNI + MMF Co-morbidity ScoreWorse Previous TransplantMore likely Baseline different when you compare PARAMESWARAN HARI

58 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.

59 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.

60 100-day Mortality after Allogeneic Transplantation, 1998-2008 - by conditioning intensity - Early mortality has improved for allogeneic transplants in general. Patient selection is key !! NO

61 Adjusted Probability of Overall Survival Wsp08_18.ppt Adjusted Probability, % Years 012543 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

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

63 Ablative Allo-BMT in Indolent Lymphoma van Besien et al. Blood. 1998;92:1832-1836. Years

64 RituximabFludarabine 30 mg/m 2 Rituximab375 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.

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 Transplants FOLLICULAR MANTLE HODGKIN 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

68 Ablative Regimens Are Improving As Well!!

69 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

70 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

71 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

72 Al-Atrash et al. Blood 2008 112: Abstract 2999 Myeloablative IV Busulfan and Fludarabine for Patients Older Than 54 Years

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 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.

75 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.

76 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.

77 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…

78 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 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.

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 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


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