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Allogeneic Hematopoietic Stem Cell Transplantation: State of the Art in 2014

Allogeneic Hematopoietic Stem Cell Transplantation: State of the Art in 2014 . RICHARD W. CHILDS M.D. NIH, BETHESDA MD. Disclosure Statement.

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Allogeneic Hematopoietic Stem Cell Transplantation: State of the Art in 2014

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  1. Allogeneic Hematopoietic Stem Cell Transplantation: State of the Art in 2014 RICHARD W. CHILDS M.D. NIH, BETHESDA MD

  2. Disclosure Statement • I, Richard W. Childs, MD, DO NOT have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation.

  3. Graft-Vs-Leukemia Effects Critical Are the Component That Cures Hematological Malignancies Following Allogeneic BMT Allograft (PBSC + Lymphs) T-Cells Remission GVL Transplant Day 0 Leukemia cells Pre-transplant intensive therapy 2) Graft-vs-Tumor 1) Conditioning Regimen

  4. AML ALL MDS NHL Multiple Myeloma Most Common Indications for an Allogeneic HCT US 2010

  5. Graft-Vs-Leukemia Effects Can Cure Chemotherapy Resistant Malignancies Nov 2006 7 months post transplant CSA Discontinued May 2011 5 yrs post transplant May 2006 1 month After transplant NHLBI Hematology Branch Transplant Protocol 02-H-0250

  6. GVL Can Cure Treatment Refractory CLL Survival after Allogeneic and HLA-identical Sibling Transplants for Follicular Lymphoma, 2000-2010 100 100 90 90 80 80 Sensitive (N=840) 70 70 60 60 50 50 Probability of Survival, % Resistant (N=212) 40 40 30 30 20 20 10 10 P = 0.002 0 0 1 3 0 2 4 5 6 Years

  7. Allogeneic HCT for AML in CR1 Decreases Relapse Risk and Improves Survival for Select Patients Stelljes et al JCO 2014:32(4)

  8. Allogeneic HCT for AML in CR1 Decreases Relapse Risk and Improves Survival for Select Patients • Methods Cont: • 2 cohorts of AML pts (n=185) in CR1 compared based on whether they went to conventional consolidation vs allogeneic HCT • All pts< 60 with AML in CR1 • Ptsmatched for AML subtype, cytogenetic risk, Age • Results: • - Survival at 7 years superior for allo-group compared to conventional consolidation (58% vs 46% (p=0.037). • Allo • Conv • Allo • Conv Conv Allo Allo Conv • Stelljes et al JCO 2014:32(4)

  9. Allogeneic HCT for AML in CR1 Decreases Relapse Risk and Improves Survival for Select Patients Allo Convent Better Better • Results: • - Survival at 7 years superior for allo-group compared to conventional consolidation (58% vs 46% (p=0.037). • Among subgroups, OS better in older pts (>45 years), 2ndary AML,, high risk cytos • HCT outcome for OS inferior for any groups • Stelljes et al JCO 2014:32(4)

  10. Allogeneic HCT for AML in CR1 Decreases Relapse Risk and Improves Survival for Select Patients Relapse-free Survival Survival • Results: • Outcomes superior for older pts with allogeneic HCT > 45 allo Relapse • >45 conv Non-relapse Mortality >45 conv. >45 conv ≤ 45 conv ≤45 allo • > 45 allo • Stelljes et al JCO 2014:32(4)

  11. GVHD (15%) Relapse (34%) Other (12%) Infection (17%) Organ toxicity (14%) IPn (8%) CAUSES OF DEATH AFTER ALLOGENEIC TRANSPLANTS HLA-ID SIB

  12. Major Improvements in Transplant Outcomes Over the Past 2 Decades Historical Problem Solution • Conditioning regimens too toxic • Older patients ineligible due to prohibitive risk of mortality • Death from invasive fungal process and CMV frequent • Lack of donors precludes the use of the procedure • Development of safer conditioning regimens (IV busulfan)/use of lung shielding • Development of reduced intensity conditioning regimens • Advent of voriconazole, PCR to detect early CMV reactivation with use of empiric gancyclovir • Growth of unrelated registry size, increasing use unrelated donors and mismatched unrelated cord transplants and haploidentical donors

  13. Better Conditioning Regimens and the Use of Reduced Intensity Conditioning to Reduce Transplant Mortality

  14. IV Busulfan Improving Transplant Outcomes

  15. Types of Allogeneic Transplants • Conventional High Dose or Myeloablative Transplant • Conditioning fully eradicates the hosts bone marrow • Reduced Intensity Conditioning (RIC) • Low dose or non-myeloablative transplant • Immunologically eradicates host bone marrow

  16. Reduced Intensity Conditioning (RIC) Allogeneic HCT A less toxic alternative to standard myelo-ablative allo-HCT • Treatment of older patients (e.g. >60 years) feasible • Treatment of patients with co-morbid medical problems or prior history of an auto-transplant feasible • Curative GVL effects inducible in a variety of hematological malignancies

  17. Low intensity conditioning High intensity relapse TRM How does the choice of transplant procedure affect outcome?

  18. Reduced Intensity Conditioning (RIC) Allogeneic HCT • Current indications for RIC Transplants: • - Usually reserved for patients who are not candidates for a MA HCT • 1) older pts (i.e. > 55yrs) • 2) Pts with medical co-morbidity • 3) Heavily pretreated pts (i.e. prior auto HCT) • - Exceptions: • 1) Diseases characterized by extreme sensitivity to a GVL effect • i.e. CLL, indolent lymphoma • 2) Non malignant disease where MA conditioning not required • -i.e. aplastic anemia, sickle cell anemia, thalassemia, etc • 3) In a research setting • - comparing RIC vs MA conditioning High TRM with MA HCT

  19. Percentage of Reduced Intensity Conditioning Allo-HCTs, Registered with CIBMTR, 1998-2010- by Year of Transplant & Disease - CLL Follicular NHL Mantle Cell NHL HD Reduced Intensity Conditioning, %

  20. Data Suggest Outcome Similar For Myelo-ablative Conditioning vs RIC For Myeloid Malignancies • Dec 2004- Dec 2009 • 195 AML pts in Germany randomized 1:1 • to undergo RIC vs MAC • Conditioning: • MAC: TBI 1200 cGy + 120 mg/kg Cytoxan • RIC: Low dose TBI+ Fludarabine 150 mg/m2 • Outcomes: • 94 underwent RIC and 90 MAC • NRM, PFS, and overall survival • not different between cohorts when adjusted • For age/cytogenetics/donor type NRM (all) Relapse Survival Bornhauser M et al. Lancet Oncology 2012: 13:1035-

  21. Transplants Being Performed in Increasing Numbers of Older Patients Due to Safety of RIC Transplant Type and Recipient Age1990-2010 Transplants, % Allogeneic Transplants Autologous Transplants

  22. Increasing Use of Unrelated Donor Transplants U.S. Transplant Activity 1980-2011 Transplants URD Transplants > Related donor Slide 3 SUM12_23.ppt

  23. Survival Unrelated Donors Now Comparable to Sib Donors One Year Survival- Sib vs MUD <50 yrs Sib vs MUD >50 yrs One-Year Survival, % In any remission, Acute Leukemia, CML or MDS-

  24. Good News: Mortality is Decreasing with Allogeneic Stem Cell Transplants 40% reduction in overall mortality 60% reduction in TRM N=1418 N=1148 • Bacterial, viral and fungal infections reduced • Reduction in severe Grade III-IV GVHD • Dramatic reduction in day 200 transplant-related mortality (TRM) and overall TRM Gooley et al; NEJM 2010: 363;22

  25. Chances of Finding a Stem Cell Donor Potential Candidate For a Cord Blood Transplant or A Haploidentical Transplant 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% HLA Matched Unrelated Donor HLA Matched Sibling Availability of a Stem Cell Donor Limits Applicability of Allogeneic Stem Cell Transplantation No Donor

  26. Umbilical Cord Blood Transplantation (UCBT) Placenta Umbilical Cord Cord Blood Unit • Umbilical Cord Blood (UCB) transplants are a transplant option for patients lacking an HLA identical donor: • - Cord blood is a rich source of Hematopoietic progenitor cells- more than human BM Volume 25 mls

  27. Advantages of Cord Blood Lower Graft vs. Host Disease (GvHD) HLA-mismatched Transplants Possible Off the shelf product quickly available Cord Grafts available to Patients with Rare HLA Types And Ethnic Minorities

  28. Increasing World-Wide Use of URD and UCB Transplants Unrelated Cord Blood Transplants URD- Unrelated Donor UCB- Unrelated Cord Blood Pasquini MC, Wang Z. Current use and outcome of hematopoietic stem cell transplantation: CIBMTR Summary Slides, 2010

  29. Adult Cord Match Rates in the Cord Blood Registry, Cell Dose ≥2.5/Kg 29

  30. UCB Transplantation Results in Similar Outcome as Unrelated Donor Transplantation for Lymphomas ASH 2013- Bachanova V et al U. Minn Abstract # 161 • Methods Cont: • 1593 Hodgkin’s and NHL pts • transplanted btw. 2000-2010 • Median age 45 (19-73 yrs) • Outcome analyzed based on • Transplant type • UCB • 8/8 URD • 7/8 URD • Results: • UCB less acute/chronic GVHD • TRM rates comparable • Survival comparable between • UCB and 8/8 and 7/8 URD

  31. Haploidentical BM Transplants • Transplants that utilize stem cells collected from a relative who • only matches for half of the HLA tissue antigens • Advantages; • Virtually every patient will have a haplo-identical relative to serve as a • stem cell donor • Disadvantages: • - Higher incidence of graft versus host disease • - Obligates use of T-cell depleted transplants • - T-cell depletion increases the risk of • - graft rejection • - infection • - disease relapse.

  32. Post Transplant Cyclophosphamide Following T-cell Replete Haploidentical Transplantation of BM or PBSC Fuchs E. et al JHU

  33. 271 patients hematological malignancies – Transplanted single center 2005-2010 • 53 Haploidentical onors • 117 MRDs • 101 MUDS Grade II-IV GVHD NRM Relapse Bashley et al; JCO 2013- ahead of print

  34. Haploidentical transplantation using T-cell replete grafts and post transplant cyclophosphamide Overall Survival Disease free Survival Conclusion: Haploidentical transplantation using T-cell replete grafts and post transplant cyclophosphamide achieves outcomes comparable to transplants using MRDs and MUDS Bashley et al; JCO 2013- ahead of print

  35. ASH Abstract #103: Post-Transplant Cyclophosphamide Following a Myeloablative Conditioning For Hematologic Malignancies Receiving An UnmanipulatedHaploidentical Bone Marrow Transplant • Study of haploidentical BMT followed by Cytoxan • in 95 pts in Genova Italy • Methods/Pts: • - Thiotepa/Busulfan/Flu or • TBI/Flu • - Median age 49yrs(17-74) • - Majority (77%) had AML/ALL/MDS • Results: • - 90% engrafted (median 17 days) • - Acute 2-4 GVHD 14% • - cGVHD 17% • - TRM 7% • - Relapse 17%,30%,37% for CR1, CR2, or active dz Ghiso et al ASH 2013- Abstract 103

  36. ASH Abstract #2091: Outcomes Of Nonmyeloablative (NMA) Haplo-identical • Blood Or Marrow Transplantation (haploBMT) With High Dose • Post transplantation Cyclophosphamide (PT/Cy) For Lymphoma • Study of haplo-identical BMT followed by Cytoxan in 151 lymphoma pts • Methods/Pts: • Cy (14.5 mg/kg IV, days -6 and -5), fludarabine (30 mg/m2 IV, days -6 to -2), and TBI (200 cGy, day -1) • Grafts were T-cell replete (bone marrow in 99%) from haplo-matched relatives • GVHD prophylaxis high-dose Cytoxan post transplant (50 mg/kg days 3 and 4; 150 pts), mycophenolatemofetil, and tacrolimus. • Results: • 88% engrafted (median 17 days) • grade 2-4 acute GVHD 32%, grade 3-4 acute GVHD 5%, • chronic GVHD was 13% • median follow-up of 3.8 (range 0.5 - 8) years in event-free pts • PFS and DFS were 40% (95% CI, 32-48) with a 3-y overall survival (OS) probability of 46 (39-55)% • - non-relapse mortality(16%) and relapse 31% Kasamon Y. et al ASH 2013- Abstract 2091

  37. Transplants Safer- Relapse now is the primary cause of treatment failure after allogeneic HCT New Malignancy (1%) Primary Disease (47%) GVHD (14%) Causes of Death after HCT (matched sibling) • 10-60% of patients experience relapse post-HCT. (NCI Relapse workshop) • Majority of relapse occurs by 1 year post-HCT. (Bajwa R, BMT 2012) Infection (12%) Other (21%) Organ Failure (4%) CIBMTR Summary Slides, 2011

  38. Outcomes after Post-transplant Relapse are Poor 2-yr OS: 16% (ALL) • 2-year overall survival (OS) in adults with post-transplant relapse: • 16% in acute lymphoblastic leukemia (ALL) • 14% in acute myelogenous leukemia (AML) • Treatment options are limited • Malignancy drug resistance • Transplant-related toxicities • Graft-versus-host disease (GVHD) • Limited utility of donor lymphocyte infusion (DLI) 2-yr OS: 14% (AML) Spyridonidis A, et al. Leukemia 2012 Schmid C, et al. Blood 2012

  39. Treatment Options for Post-HCT Relapse Cytotoxic “salvage” therapy • Chemotherapy • Radiation therapy Immune-Based therapy • Withdrawal of immune suppression (i.e. stop CSA) • Donor lymphocyte infusions • Second transplant • CAR T-cell therapy Bajwa R, et al. BMT 2012

  40. Donor Lymphocyte Infusions Have Limited Efficacy For Relapsed Acute Leukemia Overall survival in patients with relapsed hematologic malignancies, post DLI CML ALL AML Collins, JCO 1999

  41. N= 160 relapsed patients • 31% ALL • 31% AML • 23% CML • 17% MDS • Median time to relapse: 7 months Treatment Options for Post-HCT Relapse Bajwa R, et al. BMT 2012

  42. Second Transplant Has Curative Potential but Risky • High-rates of transplant related mortality • Curative potential is biased towards those with late relapse • Overall Survival 5-30% post-second HCT Median time to relapse: 10 months Median time to relapse: 5 months Bajwa R, et al. BMT 2012

  43. Novel Strategies for Treatment of Post-Transplant Relapse • Preemptive therapy upon detection of post transplant MRD • Donor lymphocyte infusion • Abrupt withdrawal of CSA or tacro • Immunomodulatory agents- Interferon alpha • Novel cytotoxic therapies • Immunotoxins • Targeted Immune based Therapies • Vaccination Strategies • Donor Leukemia specific T-cells- • Peptide stimulated ex vivo or transduced to carry a trangenic TCR

  44. Science editors ranked cancer immunotherapy at the top of their list of scientific achievements this past year Chimeric Antigen Receptors • T-cells transduced with a vector to encode a single chain variable region to target a specific antigen • MHC-independent antigen recognition • co-stimulatory signaling allows transduced T-cells to have potent cytotoxicity • CD 19 CAR • CR rates up to 75% in relapsed refractory CLL and ALL • Lee D W et al. Clin Cancer Res 2012;18:2780-2790

  45. Science editors ranked cancer immunotherapy at the top of their list of scientific achievements this past year Chimeric Antigen Receptors • T-cells transduced with a vector to encode a single chain variable region to target a specific antigen • MHC-independent antigen recognition • co-stimulatory signaling allows transduced T-cells to have potent cytotoxicity • CD 19 CAR • CR rates up to 75% in relapsed refractory CLL and ALL • Lee D W et al. Clin Cancer Res 2012;18:2780-2790

  46. CD19 Specific CAR T-cells Can Induce Remission of ALL Relapsing after Allogeneic Transplant ASH 2013- Abstract # 68; Lee et al POB NCI : Anti-CD19 Chimeric Antigen Receptor (CAR) T Cells Produce Complete Responses With Acceptable Toxicity But Without Chronic B-Cell Aplasia In Children With Relapsed Or Refractory Acute Lymphoblastic Leukemia (ALL) Even After Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) • Phase I clinical of anti-CD19-CD28-zeta CAR T cells in children with relapsed and refractory ALL and NHL • T cells expanded from PBMC using anti-CD3/CD28 beads before retroviral transduction of the CAR gene.  • 11-day manufacturing process • CAR T cells infused after pts received fludarabine and cyclophosphamide • 8 patients (7 ALL, 1 NHL; 4 pre-HSCT, 4 post-HSCT) aged 10-23 years.  • Transduction efficiencies of 18-87%. Expansion was insufficient to meet the target dose for 2 patients, but each still received ASH 2013- Abstract # 68; Lee et al POB NCI Lee D W et al. Clin Cancer Res 2012;18:2780-2790

  47. CD19 Specific CAR T-cells Can Induce Remission of ALL Relapsing after Allogeneic Transplant • Response rate: • CR in 5 of 8 (63%) or 5 of 7 ALL patients (71%) • 3 MRD-negative including 1 patient primarily refractory to chemotherapy.  • CAR T cell expansion identified in all responding patientsincluding the CSF of 3 patients. One patient with CNS2 disease cleared all CSF blasts as without additional intrathecal chemotherapy after CAR T cells given. • CAR T cells detectable a median 55 days in any tissue • Toxicity:  • Cytokine storm • Two Gr 2 correlated with high IL6, GM-CSF, IFNg, TNFa, and C-reactive protein.  • One Gr 4 occurred (3 x 10^6 CAR+ T cells/kg) required vasopressors and CPR for hypotension.  • None developed graft versus host (GVH) disease despite administering donor-derived activated T cells harvested from the recipient Lee D W et al. Clin Cancer Res 2012;18:2780-2790 ASH 2013- Abstract # 68; Lee et al POB NCI

  48. Donor-Derived Anti-CD19 Chimeric-Antigen-Receptor Expressing T Cells Cause Regression Of Malignancy Persisting After Allogeneic Hematopoietic Stem Cell Transplantation • ASH Abstract 152; Korfendorfer et al NCI • Phase II study of viral reactive donor lymphocyte infusions transduced to express CD19 CAR in lymphoma and ALL pts with viral infections or relapsing after allo HCT. • Methods: • T-cells from donor were stimulated against donor DCs transduced with AV vector encoding pp65 then donor EBV_LCL cells to generate tri-viral reactive T-cells • Viral reactive T-cells then transduced with a RV vector to express CD19 CAR signaling through CD28 and TCR-zeta • T-cells capable of targeting both virues and CD19 expressing Tumor Cells Results • N=9 pts treated (3months-13 years post HCT) • No infusion related toxicities • CD19 CAR T-cells up to 9 weeks post infusion • Responses seen in 2/6 with relapsed disease (ALL and CML- both had CR followed by relapse at 2 and 3 months • 3/3 receiving T-cells for viral infections in remission remain in remission ASH Abstract 152; Korfendorfer et al

  49. Relative therapeutic potential of cellular therapies for relapse (theoretical) Anti-tumor Activity Off Target Cell Mediated Toxicity De Lima, BBMT 2014

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