2 Marcos J. de Lima, MD Professor of Medicine Department of Stem Cell Transplantation and Cellular TherapyM.D. Anderson Cancer CenterHouston, TX
3 Faculty Disclosures Marcos J. de Lima, MD Research Grant – Celgene Professor of MedicineDepartment of Stem Cell Transplantation and Cellular TherapyM.D. Anderson Cancer CenterHouston, TXResearch Grant – CelgeneKaci Wilhelm, PharmDClinical Pharmacy SpecialistBlood and Marrow TransplantNo 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, MD12:45-1:05 p.m.Putting the Evidence into Practice: Optimized Dosing and Administration of Reduced-Intensity Conditioning Regimens- Kaci Wilhelm, PharmD1:05-1:15 p.m.Faculty Panel: Questions & Answers
5 Critical Decisions: Pretransplant Conditioning Marcos J. de Lima, MDM.D. Anderson Cancer CenterHouston, TX
6 Discussion Topics Historic perspective and definitions Donor and recipient-related covariates that influence transplant outcomes and regimen choiceMyeloablative versus reduced intensity regimens – can we really compare them ?Donor – recipient issues that influence regimen choiceWe may not need to reduce dose intensity for all patients in the 6th and 7th decade of lifeConclusions
7 Goal of Preparative Regimen Immunosuppression - adequate to prevent rejectionCytoreduction - 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 05/22/1106/09/1107/06/11Probability 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/LorenzProtection of TBI aplasia by injection of spleen cells from syngeneic mice.1956, Nowell/van Bekkum/Ford/TauscheConcept of radiation chimera.
10 Head of a Lion, the Mid-section of a Goat and the Hindquarters of a Dragon10
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, SantosLymphocytes (T-cells) mediate GVHD, and target organs are lymphoid, skin, gut, and liver.
13 Two-year Probability of Treatment-related Mortality After Transplants for CML,20406080100< 20 years20 – 40 years> 40 years62%53%PROBABILITY, %41%38%27%17%11%11%9%HLA-ident SibUnrelatedAutoLeukemiaTOS00_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.
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 DefinitionsMyeloablativeProfound pancytopenia within 1-3 weeksIrreversible myelosuppressionRequire stem cell supportReduced-IntensitySignificant and prolonged cytopeniasReduction in alkylating agent or TBI doseNon-MyeloablativeMinimal cytopeniasAutologous recovery within 28 daysReduction is dose by about 30%.Bacigalupo A, et al. Biol Blood and Marrow Transplant 2009.24
25 Myeloablative Dosing Thresholds CIBMTR Operational DefinitionsTBI > 5Gy single doseTBI > 8Gy fractionatedBusulfan > 9mg/kg POMelphalan > 150mg/m2Thiotepa > 10mg/kgTotal dose per course1mg/kg PO = 0.8mg/kg IV = 32mg/m2 IVTotal dose per courseBusulfan equivalent dosing: 7.2mg/kg IV or 288mg/m2Giralt S, et al. Biol Blood Marrow Transplant 2009; Madden T, et al. Biol Blood Marrow Transplant 2007.25
28 Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) for Non-Relapse Mortality (NRM) and Survival after Allogeneic HCTSorror M and CollaboratorsFred Hutchinson Cancer Research Center, Seattle, WAand MD Anderson Cancer Center, Houston, TX
29 Diagnosis is AML in First Remission - Individual Comorbidities % of patientsLungLiverCancerCardiacObesityInfectionDMPsychRheum
30 2-year NRM Stratified by HCT-CI Scores FHCRCMDACCPercent NRM3719277217Years after HCT
31 Two-year Survival Stratified by HCT-CI Scores FHCRCMDACCPercent survivalYears after HCT
32 • Genetics • Social economic issues • Access to treatment Race• Genetics • Social economic issues • Access to treatment
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.
50 Unrelated Donor Transplants at MDACC Are we there yet?NO!!Median age of AMLPatients: mid 60’s.MDS: mid 70- late 70’s
51 Trends in Allogeneic Transplantation by Recipient Age,* 1987-2007 Transplants, percentSlides 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 greaterMatched related or unrelated donorMDS or AML in CR1 1,080 cases545 AML CR1535 MDSData from 148 centersMcClune, 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 Age1341002040608090103050702Years1341002040608090103050702TRMRelapse65+ yrs60-64 yrs55-59 yrs40-54 yrs60-64 yrs55-59 yrs40-54 yrs65+ yrsp=0.66p=0.87YearsMcClune, 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 - relapseFAI - toxicityDe 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 highestRetrospective & Registry StudiesSelection BiasRIC (vs MA)Graft Source More likely PBSCGVHD prophylaxis More likely CNI + MMFCo-morbidity Score WorsePrevious Transplant More likelyBaseline different when you comparePARAMESWARAN 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 - NOSlides 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 100204060809010305070NST vs Myeloablative, p<0.01NST vs RIC PB, p=0.02RIC PB (N = 768)Adjusted Probability, %Myeloablative (N = 3,731)NST (N = 407)RIC BM (N = 273)12345YearsWsp08_18.ppt61
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, %54321204060801006SurvivalDFSTreatment-related mortalityRelapseYearsvan Besien et al. Blood. 1998;92:
64 NON-MYELOABLATIVE ALLOGENEIC SCT Conditioning RegimenRituximab Fludarabine 30 mg/m2 Rituximab 375 mg/m2 Cyclophosphamide 750 mg/m mg/m2ASCTDaysATG 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 FOLLICULARTransplantsMANTLEHODGKINSlides 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 histologyArmand 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 NetworkStudy #DiseaseStudy QuestionBMT CTN 0102MyelomaTandem Auto vs. Auto -> Allo RIC HCTBMT CTN 0202Foll. NHLAutologous vs. Matched Sib Allo RIC HCTBMT CTN 0502AML CR1RIC Allo HCT in pts 60 – 74 yrsBMT CTN 0601Sickle CellRIC URD HCTBMT CTN 0603ManyHaplo identical HCT with RICBMT CTN 0604Double Cord HCT with RICBMT CTN 0701Sibling or URD HCT with RICBMT CTN 0901MDS/AMLMyeloablative vs. RIC Allogeneic HCT
69 Intravenous Busulfan/Fludarabine DayBu 130 mg/m2 q dFlu * rest* rest* HSCT40 mg/m2 q dGVHD prophylaxis: tacrolimus and “mini” methotrexate*day of ATG if MUD or one-antigen mismatched related donorFludarabine 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 yearsYears n=74Related 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 IncidenceTreatment-related Mortality Grade II-IV Acute GVHDAl-Atrash et al. Blood : Abstract 2999
72 Myeloablative IV Busulfan and Fludarabine for Patients Older Than 54 YearsAl-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 DiseaseMyelomaOlder patientsHeavily pretreated patients or those with significant co-morbiditiesMost patients with CLL and NHL
79 Future DirectionsBetter 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 ConclusionsThe 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, MDFred Hutch – SeattleMarcelo Pasquini, MDParameswaran Hari, MDCIBMTRSergio Giralt, MD - NY
83 Department of Stem Cell Transplantation M D Anderson Cancer Center Richard Champlin Borje AnderssonElizabeth Shpall Roy JonesStefan Ciurea Simrit ParmarJeffrey Molldrem Uday PopatPaolo Anderlini Partow KebriaeiYago Nieto Issa KhouriChitra Hosing Martin KorblingMichael Andreef Qaiser BashirImage Credit: NASA/JPL/Space Science Institute