allogeneic hematopoietic stem cell transplant for the medical oncologist

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Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist. John Kuruvilla MD FRCPC. Objectives. Understand basic principles of Allogeneic Transplant: Types of Preparative Regimens Stem Cell Source Donor Types. Hematopoietic Stem Cell Transplantation. - PowerPoint PPT Presentation

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  • Allogeneic Hematopoietic Stem Cell Transplant for the Medical OncologistJohn Kuruvilla MD FRCPC

  • ObjectivesUnderstand basic principles of Allogeneic Transplant:Types of Preparative RegimensStem Cell SourceDonor Types

  • Hematopoietic Stem Cell TransplantationPremise a platform to deliver:Dose intensive therapy (chemotherapy and/or radiation) for myeloablation and immune ablationHematopoietic Stem Cells (replacing damaged or abnormal bone marrow)Immunotherapy (graft-versus tumour effect)

  • Stem CellsBy nature have capacity of:Self renewalAbility to differentiate into all mature peripheral blood cellsPractical surrogate marker is CD34Cell surface marker found on immature WBCCounts have been associated with hematopoietic recovery

  • Components of an Allogeneic SCT procedurePre SCT TherapyConditioning Regimen the chemotherapy / radiation regimen that may have anti-cancer properties and that provides bone marrow / immune modulation for the graftDonor stem cell source the person providing stem cells (sibling, MUD, Mismatch MUD, Haploidentical)Type of stem cells bone marrow, peripheral blood, umbilical cord bloodGVHD Prophylaxis agents that may temper the donor immune system in the recipientPost SCT therapy

  • Transplant Conditioning RegimensMyeloablative regimens have been typical approachLimited use of transplant due to high toxicity (upper age limit of 60 and medically fit)Based on drugs that can be dose escalated (typically alkylators) and radiationStandard regimens: CY-TBI and BU-CY

  • Bu-Cy vs Cy-TBI in myeloid diseases Bu-Cy favoured?Survival appears similar in 4 RCTsEasier to give Bu-Cy over Cy-TBI (lack of TBI allows for easier treatment planningMeta-analyses performed:Acute leukemia: CY-TBI had lower relapse and TRM with improved DFSCML: CY-TBI had higher relapse, lower TRM and similar DFSCY-TBI had higher rates of cataracts [odds ratio (OR) 12.69, p = 0.01], interstitial pneumonitis and later growth or development problems [OR 5.04, p = 0.008].BU-Cy associated with higher rates of VOD [OR 0.43, p < 0.00001], hemorrhagic cystitis, and TRM. Shi-Xia Leuk Lymphoma 2010

  • Trade-offs in Traditional BMT Regimens is less better?BMT is a modality that allows the delivery of radiation in disseminated disease (ie. leukemia)Toxicities with both are substantial and limit the delivery of therapyNewer chemotherapy and immunosuppressive agents lead to the development of new regimensLess myeloablationMore immunosuppressive transplant which facilitates engraftment of stem cellsLess direct anti tumour effect

  • Champlin Criteria of a RIC RegimenDefines as reduced intensity:any regimen that does not require stem cell support for hematopoietic recovery andresults in low non-hematologic toxicity andmixed donor recipient chimerism in a substantial proportion of patients in the early post transplant period (around day +30) Champlin in Giralt+Slavin (text)

  • The ultimate non-myeloablative regimen the original Seattle protocol2 Gy TBICsA + MMF

    Tested in AML and CMLProblems with graft failureAdd additional agents (fludarabine) to improve outcomeStorb Mol Ther (Review) 2006

  • Transplant Regimens Non-myeloablative or Reduced IntensityNon-myeloablative transplant autologous marrow and immune recover possibleFludarabine 30 mg/m2 X 3+ 2 Gy TBIReduced Intensity Conditioning (RIC)Concept: less drug = less toxicityRegimens vary agents and doses of drugsFludarabine + Busulfan 3.2 mg/kg X 2 + 2 Gy TBI Fludarabine + Busulfan 3.2 mg/kg X 4 + 4 Gy TBI

  • RIC vs Myeloablative ToxicityInitial studies lead to a variety of possible regimensFludarabine-TBIFludarabine-CyclophosphamideFludarabine-MelphalanFludarabine-BusulfanAll share the RIC concept transplant more as immunotherapy

  • Immunosuppressive and Myelosuppressive Properties of Common Preparative RegimensStorb et al. ASH Education book 2011

  • NMDP Operational Criteria for a RIC RegimenTBI up to 500 cGy single fraction or 800 cGy fractionatedTotal busulfan up to 9 mg/kgTotal melphalan up to 140 mg/m2BEAM regimen (debatable by some)Giralt BBMT 2009

  • Matched Pair Comparison of Flu-Bu-ATG and Bu-Cy (Calgary and CIBMTR)120 cases, 215 controlsTRM ; Flu-Bu 12%, BuCY 34%, p
  • FluBu-ATG and BuCY matched pair comparisonInteresting and suggests trade-offsToxicity vs. efficacyShould this be tested in a phase III trial?Can the platform be improved?

  • Summary Conditioning RegimensWide variety of intensity in regimensSafety and comorbidity typically drives decisionAge and organ function can limit choice (age 50, 55 or 60 is often an arbitrary cutoff to limit myeloablative procedures)RIC or non-myeloablative procedures allows greater availability of transplant procedures

  • Sources of Hematopoietic Stem CellsBone MarrowPeripheral BloodCord Blood

    Stimulated (G-CSF) or not

  • Collection of Stem CellsBone Marrow involves marrow harvestAnaesthesia, OR, procedure timePeripheral Blood requires g-csf to increase peripheral concentration of CD34+ cells and subsequent apheresisUmbilical Cord Blood collected from umbilicus at time of birth and stored

    Trade-off procedures vary substantially for patient but RCTs are available

  • Donor Stem Cell Source AllogeneicRCTs confirmed benefit of PB (g-csf mobilized) over BM (steady state) with improved survivalHigher rate of chronic GVHD in patients receiving PB graftsPilot data of g-csf mobilized BM demonstrates shorter time to engraftment and less C-GVHDRCTs evaluating g-csf mobilized PB vs. BM are ongoingBone marrow still preferred in situation where GVHD is NOT needed (aplastic anemia)

  • Impact of Donor Stem Cell Source on Allo-SCT: Improved SurvivalBensinger NEJM 2001

  • Meta-analysis of G-PB vs. BMCompared to PBSCT, BM had:Lower rates of neutrophil and PLT engraftmentDecrease in the development of grades II-IV A-GVHD (HR, 0.75; 95% CI, 0.63-0.90; p=0.002) Decrease in the rates of overall C-GVHD (HR, 0.70; 95% CI, 0.59-0.83; p
  • Next Generation of TrialsCan benefits of bone marrow (lower GVHD) be combined with benefits of PBSCs (improved engraftment and relapse rates)?Pilot data of g-csf mobilized BM showed promising results and lead to the RCTS:CBMTG 0601 (related donors) and othersNMDP trial in MUD

  • Allogeneic Stem Cell CollectionG-CSF mobilized PBSC became standard of careMobilization failure unlikely as donors are healthy and typically have normal marrow functionMobilize with G-CSF aloneConcerns:Effect of G-CSF (case reports of leukemia)Familial hematologic disorders (ie. finding malignant/pre-malignant disorders during donor workup)

  • Summary Stem Cell SourceOutside of a clinical trial, g-csf mobilized PBSC are typically preferredMore rapid engraftment and lower relapseDonor preference an issue (type of procedure)BM can be considered in transplants where GVHD/GVT effect is less important (ie. Aplastic anemia or benign disorders)

  • Types of DonorAutologousSyngeneic (identical twin)AllogeneicSibling (matched / mismatch)Alternative donorUnrelated Donor (matched / mismatch)HaploidenticalUmbilical Cord Blood

  • Donor Selection and MatchingMost successful results initially with identical twins (fully matched)Siblings more likely to be matched than MUD depending on degree of testingTransplant strategy would require more intensive immunosuppression as quality of match decreasesLarge prospective series limited no RCT of sibling vs. other stem cell source

  • Matching MHC and HLAMajor Histocompatibility Complex (part of immune system)Class 1 found on all nucleated cells and involved in antigen presentationClass 2 found on immune cells (APCs)In humans, the MHC subset that presents APCs on immune cells are called HLA genes (Human Leukocyte Antigens)Class 1 genes: HLA-A, HLA-B, HLA-CClass 2 genes: HLA-DPA, HLA-DP, HLA-DQ, HLA-DRA, HLA-DRB1HLA genes are highly polymorphic

  • Matching and DonorsBeyond the scope of the current discussionBrief summary of NMDP RecommendationsAll should have high resolution testing (4 digit) for HLA-A, HLA-B, HLA-C and HLA-DRB1 (8/8 testing)Mismatches at HLA-DP and HLA-DQ did not affect survivalDRB3, DRB4 and DRB5 have unknown significance

    http://marrow.org/Physicians/Transplant_Advances/HLA_Typing_Advances.aspx#table-1

  • Alternative Donor OptionsMismatched transplants are also an option9 / 10 or 8 / 10Haploidentical transplantation allows almost everyone to have a donor but represents a huge immunologic barrier (high risk)Haploidentical donor can be a parent so most people potentially have a donorDegree of mismatch increases risk of TRM

  • Donor Stem Cell SourceSyngeneic stem cells are lowest risk from TRM standpointConcern of lack of immunologic effect (ie. No GVT)Sibling transplants have traditionally had best outcomes (from NRM and GVHD standpoint)Outcomes for MUD transplants have improved (better regimens and supportive care)Cord blood is appealing as less matching may be necessary but stem cell dose (given size of recipient) is often an issue (solution of 2 cords)

  • Alternative Donor Transplantation Cord vs. HaploidenticalBMT CTN Phase II trial of RIC allo using double UCB (n=50) or Haplo-marrow (n=50)Flu-Cy-200 cGy TBIGVHD prophylaxis with CsA+MMF or FK506+MMFHaplo received CY on Day+3 and +41 year OS: 54 (dUCB) vs 62 (haplo)1 year PFS: 46 (dUCB) vs 48 (haplo)1 year NRM: 24 (dUCB) vs 7 (haplo)1 year relapse: 31 (dUCB) vs 45 (haplo)Based on these results, a phase III trial is planned Brunstein et al. Blood 2011

  • BMT CTN dUCB vs. HaploPrimary Endpoint was OS at 6 months if > 60%, arm was deemed positiveBrunstein et al. Blood 2011

  • Summary Donor SourceClear HierarchySyngeneicMatched

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