Advances in stem cell transplantation
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Advances in stem cell transplantation: The need for better data reporting and outcome measures

Advances in stem cell transplantation: The need for better data reporting and outcome measures
Richard Champlin, MD

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Advances in stem cell transplantation Advances in stem cell transplantation Presentation Transcript

  • Hematopoietic Transplantation and Cellular Therapy 2014: Challenges and Opportunities Richard Champlin, MD
  • Current State of HSCT • HSCT is an effective treatment for a broad range of hematologic, immune, metabolic and neoplastic diseases • For nonmalignant diseases, HSCT replaces defective hematopoietic and immune cells; this offers definitive treatment for hereditary and acquired diseases. • For malignancies, benefit related to high dose therapy and for allogeneic transplants, the immune graft-vs-malignancy effects • HSCT offers a platform for cellular engineering with genetic modification of stem cells, lymphocytes and other hematopoietic cells
  • Cell Lineages after Hematopoietic Transplants • Blood cells (granulocytes, erythrocytes, platelets)- donor • Immune cells (T-cells, B-cells, NK cells)- donor • Tissue macrophages, osteoclasts, antigen presenting cells- slowly become donor • --------------------------------------------- • Connective Tissue- recipient • Epithelial cells- predominantly recipient* – Possibly small population from the donor
  • Indications for Stem Cell Transplants • Bone marrow/Immune failure states – Aplastic anemia, Severe combined immune deficiency – Thalassemia/Hemoglobinapathies • Metabolic diseases – involving hematopoietic and immune cells • Cancer- – Hematologic malignancies and selected solid tumors-support for high dose therapy and induction of graft-vs- tumor immune effects • Tolerance induction for organ transplantation*
  • Donors • Best results with HLA= siblings • Matched unrelated donors comparable results, – available for about half of patients (lower rate for in underrepresented racial ethnic groups); logistical issues coordinating rapid transplants to meet needs of recipients • Recent advance- Cord Blood and Haploidentical transplants for patients who lack HLA identical donor • Virtually all patients have a donor!
  • Mother Father Siblings Patient HLA gene complex is on chromosome 6 and inherited as “haplotypes” and may be completely matched, half matched (haploidentical) or totally mismatched.
  • Effect of HLA Match for Unrelated HSCT
  • Permissible HLA Mismatches Fleschhar et el Lancelt Oncol 2012
  • Unrelated Donors • Tremendous polymorphism of the HLA complex, chance of matching an unrelated person is 1/100,000 • Linkage disequillibrium- frequency of specific HLA alleles vary among racial/ethnic groups • One is most likely to find a match within donors of similar ethnic background. • In each ethnic group, there are common and uncommon HLA haplotypes • It is important to create unrelated donor registries for all major ethnicities • A large fraction of patients have rare alleles and haplotypes, so effective approaches for HLA mismatched “alternative donors“ are needed
  • Need for Unrelated Donor Registries in Asia • Work with existing registries, but Asians are underrepresented • Registries needed in Asian countries – Recruitment of volunteer donors. Costs of typing falling with next generation sequencing (<$50 per donor). – Cultural barriers • Public education regarding safety of bone marrow and peripheral blood progenitor cell donation • Infrastructure- System for collection, transport and transplantation
  • Cord Blood Collection and Cryopreservation 1 Consent Donors – Maternal and Family History 3 Collect umbilical cord blood 5 Overwrap 25 ml PCB unit & place in canister 7 Initiate automatic CRF & archival of PCB unit 6 Insert PCB unit into CRF module 4 Isolate Stem Cells into 20 ml and 5 ml cryoprotectant 2 Separate placenta
  • Cord Blood Transplantation • Rich source of stem cells • ~50,000 units banked, immediately available for transplantation • Immunologically immature- less prone to produce GVHD • Less risk of transmitting infection • Can successfully transplant across HLA mismatch • Major concern- low stem cell dose, longer time to engraftment – Improved with ex vivo expansion – Still prolonged immune recovery in adults • Results comparable to MUD BMTs
  • Haploidentical Transplants • Ultimate challenge in HSCT • High risk of rejection and GVHD; historically high rate of treatment related mortality • Most patients will have a haploidentical donor – Parents – Half of siblings – Children • Progress – T-cell depletion, particularly successful in children – Post transplant cyclophosphamide
  • Post Transplant Cyclophosphamide for Haploidentical Transplantation
  • Autologous SCT for DLBCL Vose J M et al. JCO 2013;31:1662-1668 ©2013 by American Society of Clinical Oncology
  • Tandem auto vs. auto-allo for Multiple Myeloma Krishnan et al Lancet Oncol 2011
  • IV Bu-Flu Overall Survival and Event Free Survival in AML Time(weeks) Survival Probability 0.0 0.2 0.4 0.6 0.8 1.0 In remission, PB.blast=0 Active Disease, PB.blast=0 Active Disease, PB.blast>0 p<0.0001 0 20 40 60 80 100 120 In remission, PB.blast=0 Active Disease, PB.blast=0 Active Disease, PB.blast>0 Time(weeks) Event-free probability 0.0 0.2 0.4 0.6 0.8 1.0 p<0.0001 0 20 40 60 80 100 120
  • Outcomes of allogeneic HSCT stratified by overall disease/status risk group. Armand P et al. Blood 2012;120:905-913 ©2012 by American Society of Hematology
  • Nonmyeloablative Transplant Preparative Regimen HSCT +DLI DT DNK D R R R RL R RL RL DB Dsc DT DNK DT DT DT Dsc D DT DT Dsc D Recipient Donor Mixed Chimera Complete Chimera
  • Age and Reduced Intensity HSCT • HSCT is primarily used for treatment of hematologic malignancies; median age of patients is > 65 years • Myeloablative regimens excessively toxic in elderly patients, most centers limit to patients under age 60 • Reduced intensity and nonmyeloablative regimens allow HSCT to be performed in older and medically infirm patients. Results are generally similar to myeloablative transplants • Age, per se, (at least up to 70 years) is not a barrier to HSCT
  • Nonablative AlloSCT vs Chemo for Elderly AML
  • Figure 3 CALGB and CIBMTR Farag et al Biology of Blood and Marrow Transplantation 2011; 17:1796-1803 (DOI:10.1016/j.bbmt.2011.06.005 )
  • GVHD Prevention • Post-transplant immunosuppression : – Tacrolimus/Mtx – Cyclosporine-mycophenolate mofetil (MMF) – Alemtuzumab (anti CD52, Campath) – Post transplant cyclophosphamide – Maribovir (alters homing) • T-cell depletion of transplant – Removes effector cells causing GVHD • Effectively prevents GVHD, but increased risk of rejection and relapse
  • Chronic GVHD • Most frequent late complication of allogeneic BMT – Occurs in 1/3 to 1/2 of patients – Most frequent in patients with acute GVHD, but 1/3 of cases develop de novo – More frequent with PBSC transplants, may be less common with cord blood transplants, post transplant cyclophosphamide • Treatment- steroids +/- other agents – Trade off immunosuppression improves manifestations of GVHD, but increases risk of infection
  • Limitations of HSCT • Difficult, high risk treatment, patients and caregivers must be totally dedicated to transplant for first 6-12 months. Many patients must leave home for ~4 months to be at transplant center • Slow immune reconstitution • Toxicities and Treatment Related Mortality • GVHD occurs in large fraction of “successful” transplants; chronic disability, steroid toxicities • High Cost; but uniquely effective for some diagnoses. Lifetime cost compares favorably to many new targeted therapies
  • PROBABILITY OF SURVIVAL AFTER HLA-IDENTICAL SIBLING MYELOABLATIVE TRANSPLANTS FOR LEUKEMIA - Registered with the IBMTR, 1975-2002 - 0 1 2 3 4 5 Mln04_3.ppt PROBABILITY, % 100 80 60 40 20 0 YEARS 1995 (N=15,126) 1985-1994 (N=14,755) 1975-1984 (N=2,334) P = 0.0001
  • Professional Standards • Dynamic developing field – Rapidly developing standards of care – Large variability in practice, outcomes – Need to develop standards, treatment guidelines, define evidence based “best practices” • Need to define standards for different regions • Consider financial constraints – Accreditation system to note centers that meet international standards, ensure delivery of high standard of care, objectively identify centers of excellence – Identification of Centers of Excellence which meet professional standards is necessary for public confidence in HSCT. – Public Demand for Center Specific Outcome Reporting • Reporting outcomes to US national SCT Outcomes Database
  • Cellular Therapy Standards FACT-JACIE International Standards for Cellular Therapy Product Collection, Processing, and Administration, • Developed by consensus by experts in the field • FACT standards adopted for European accreditation process (JACIE) • International Committee for extension into Central and South America, Asia • Evidence Based- • Clinical program, Collection, Cell Processing Laboratory • Define minimal standards required for safe, efficacious therapy • Require clinical outcome analysis
  • What Is Needed to Foster the Growth and Development of HSCT • Growth: Worldwide need for transplant professionals, physicians, nurses, technical staff, transplant centers • Professional training- (MD Anderson Cancer Center and other major centers), fellowships – Fundamental principles, “best practices” • FACT Workshops – Standards for accreditation- train inspectors • National/international program for accreditation of centers of excellence world wide, with monitoring of outcomes, and active quality management plans- FACT • Expand unrelated donor registries and cord blood banks- including donors of all major ethnic groups • Public education- safety of donation, importance to cure many blood cancers
  • Future of HSCT • Advances in transplant and tumor immunology are being translated into the clinic – Immunoregulatory cells – Modulation of alloreactivity – Suicide genes • Targeted cellular immune therapy – CARs, antigen specific T-cells – NK cells – May expand the field to include cellular therapies outside of traditional transplant • Incorporation of targeted therapies
  • Ideal Nonablative Hematopoietic Transplant HSCT Vaccine or Immune Effector cells R D D D D RL RL R R R R RL R D D D D D D D D D D D D Recipient Donor Tolerant Complete Chimera Mixed Chimera Preparative Regimen No GVHD, Immune Reconstitution, GVL for malignancy
  • Conclusion • HSCT is a unique effective treatment modality providing normal stem cells for regeneration of hematopoiesis and immunity – Definitive treatment for severe hematopoietic, metabolic and immune diseases (hemoglobinapathies) – Highly effective treatment for hematologic malignancies • Cellular immune therapy with CTL, is evolving into an independent effective treatment modality, given with HSCT or as a stand alone therapy • Continuation and growth of use of HSCT and cellular therapy depends on continued advances in safety, efficacy and cost effectiveness