Hematopoietic Stem Cell Transplantation: Current Status and Future Directions RICHARD W. CHILDS M.D. NIH, BETHESDA MD

Transcription

1 Hematopoietic Stem Cell Transplantation: Current Status and Future Directions RICHARD W. CHILDS M.D. NIH, BETHESDA MD

2 Stem cell transplantation Autologous Autologous stem cell collection Freeze Stem Cells Thaw + transplant Patient Conditioning regimen First-Line Therapy:Multiple Myeloma Prolongs PFS and survival (Attal et al-nejm-1996) Second-Line Therapy:Relapsed Hodgkin s and NHL Prolongs survival in NHL (Parma Trial-1995) Prolongs DFS in HDz (but not survival)

3 Stem cell transplantation Autologous Autologous stem cell collection Freeze Stem Cells Thaw + transplant Patient Allogeneic Tissue or HLA matched Stem cell donor Allogeneic stem cell collection Conditioning regimen transplant Patient Conditioning regimen

4 How Does Myeloablative Allogeneic BMT Cure? Allograft (PBSC + Lymphs) Remission T-Cells Leukemia cells GVL Pre-transplant intensive therapy Transplant Day 0 1) Conditioning Regimen 2) Graft-vs-Tumor

5 Hematological Malignancies Vary in Their Susceptibility To Graft-Vs-Leukemia (GVL) Effects Malignancy CML chronic phase CLL Low-grade NHL AML/ALL MDS Multiple myeloma Int/high grade NHL Hodgkin s disease Refractory ALL/AML CML blast crisis Susceptibility to GVL (response to DLI) High High High Intermediate Intermediate Intermediate/low Intermediate Intermediate Low Low

6 Most Common Indications for an Allogeneic HCT US 2010 AML ALL MDS NHL Multiple Myeloma 5,500 5,000 4,500 4,000 3,500 3,000 2,500 2,000 1,500 1, Allogeneic (Total N=8,860) Autogeneic (Total N=9,026) 0 Multiple Myeloma NHL AML ALL MDS/MPD HD CML Aplastic Anemia Other Leuk Non- Malig Disease Other Cancer

7 Allogeneic Hematopoietic Stem Cell Transplantation: Can Cure Patients With Chemotherapy Refractory Hematological Malignancies

8 Graft-vs-TumorEffects After Reduced Intensity Allogeneic Hematopoietic Cell Transplantation Can Cure 42 year female: Chemotherapy Refractory Mycosis Fungoides

9 T-cell Mediated Graft-Vs-Leukemia Effects Can Cure Chemotherapy Resistant Malignancies May month After transplant Nov months post transplant CSA Discontinued May yrs post transplant NHLBI Hematology Branch Transplant Protocol 02-H-0250

10 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 - Pts matched for AML subtype, cytogenetic risk, Age Allo Conv Allo Conv Results: - Survival at 7 years superior for allo-group compared to conventional consolidation (58% vs 46% (p=0.037). - Relapse lower for allo-group Conv Allo Allo Conv Stelljes et al JCO 2014:32(4)

11 Allogeneic Transplant For AML in CR1 Decreases Relapse Risk and Improves Survival for Select Patients Results: - Outcomes superior for older pts with allogeneic HCT Survival Relapse >45 conv. > 45 allo > 45 allo >45 conv

12 Complications of an Allogeneic Stem Cell Transplant 1. Toxicities related to the conditioning regimen - Mucosal inflammation (Mucositis) - Liver toxicity (Veno-occlusive disease) - Lung inflammation (pneumonitis) 2. Graft Rejection - occurs rarely with conventional transplants 3. Infection - bacterial/fungal: during neutropenic phase of transplant - Viral: first 100 days of the transplant 4. Graft vs host disease- decreases relapse risk - acute: from engraftment until day Chronic: from day 100 until 2 years post transplant Morbidity and mortality 5. Drug toxicities - many drugs given to prevent infection/gvhd have toxicities

13 Graft-vs-Host Disease (Donor immune Cells attacking patient tissues) Acute GVHD 1. GI Tract: Diarrhea 2. Liver: Jaundice 3. Skin: Rash

14 Improvement in GVHD of the Skin with Time

15 Mortality is Decreasing with Allogeneic Stem Cell Transplants 60% reduction in TRM 40% reduction in overall mortality 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

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

17 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

18 Percentage of Reduced Intensity Conditioning Allo-HCTs, Registered with CIBMTR, Reduced Intensity Conditioning, % by Year of Transplant & Disease - AML ALL CLL HD MDS Follicular LYM Mantle Cell LYM Deffuse Large B-cell LYM CLL Follicular NHL Mantle Cell NHL HD DLCL MDS AML ALL

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

20 Transplants Being Performed in Increasing Numbers of Older Patients Due to Safety of RIC Transplant Type and Recipient Age < 50 years >= 50 years <60 years >=60 years Transplants, % Allogeneic Transplants Autologous Transplants

21 Improving transplant outcome One-Year Survival, percent HLA-matched sibling URD Better supportive care Gentler conditioning 0 Improved mgmt of GVHD Pasquini MC, Wang Z. CIBMTR

22 Long-term Survival after HCT CIBMTR study of 10,632 allogeneic HCT recipients surviving 2 years in remission (median follow-up 9 years) Overall survival Non-relapse mortality J Wingard et al, J Clin Oncol Jun 1;29(16):2230-9

23 Number of Survivors are Increasing Estimated ~110,000 HCT survivors in the US in 2009 >~5X increase by 2030 if transplant rates stay stable Transplants Majhail et al.biol Blood Marrow Transplant Oct;19(10):

24 Special Article HLA Match Likelihoods for Hematopoietic Stem- Cell Grafts in the U.S. Registry Loren Gragert, B.S., B.A., Mary Eapen, M.B., B.S., Eric Williams, Ph.D., John Freeman, B.S., Stephen Spellman, M.B.S., Robert Baitty, M.P.P., Robert Hartzman, M.D., J. Douglas Rizzo, M.D., Mary Horowitz, M.D., Dennis Confer, M.D., and Martin Maiers, B.A. N Engl J Med Volume 371(4): July 24, 2014

25 Likelihood of Finding an 8/8 HLA Match by Year End, Based on Current Donor Availability and with Recruitment Trends Extended to Gragert L et al. N Engl J Med 2014;371:

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

27 Umbilical Cord Blood Transplantation (UCBT) 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 Placenta Umbilical Cord Cord Blood Unit Volume 25 mls

28 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

29 Neutrophil Recovery Cord Cord Eapen 2010 Lancet Oncology

30 LFS Cord Eapen 2010 Lancet Oncology

31 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

32 Adult Cord Match Rates in the Cord Blood Registry, Cell Dose 2.5/Kg NATIONAL MARROW DONOR PROGRAM Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match Registry SM 32

33 Match Likelihoods According to Racial and Ethnic Group and Age. Conclusions Most patients likely to benefit from HSCT will have a donor. Public investment in donor recruitment and cord-blood banks has expanded access to HSCT. Gragert L et al. N Engl J Med 2014;371:

34 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.

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

36 271 patients hematological malignancies Transplanted single center Haploidentical donors 117 MRDs 101 MUDS Grade II-IV GVHD NRM Relapse Bashley et al; JCO 2013-

37 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-

38 RAIOLA-BBMT 2014

39

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

41 Outcomes after Post-transplant Relapse are Poor 2-year overall survival (OS) in adults with posttransplant relapse: 2-yr OS: 16% (ALL) 16% in acute lymphoblastic leukemia 2-yr OS: 14% (AML) (ALL) 14% in acute myelogenous leukemia (AML) Spyridonidis A, et al. Leukemia 2012 Schmid C, et al. Blood 2012

42 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

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

44 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 PD-1 blockade Novel cytotoxic therapies Immunotoxins Targeted Immune based Therapies Vaccination Strategies Donor Leukemia specific T-cells- CAR T-cells (CD19 CAR for relapsed ALL)

45 Eligibility For Allogeneic Transplantation: A Moving Target Several Factors Have Increased Patient Eligibility for Transplants i.e. Age and lack of a donor source no longer prohibitive for most Reduced intensity transplants for the aged Availability of alternative donor transplants for the majority who lack an HLA identical sibs - MUDS, Haplo-transplants, Cord blood transplants Recent Factors have also reduced the application of allogeneic transplantation Break through drugs for diseases where allogeneic transplantation had previously been to established to offer superior results to conventional therapies TKIs for CML BTK/PI3K inhibitors for CML (17p del) Eculizimab for PNH

46