Dr. Joseph McGuirk Professor of Medicine, BMT Medical Director, Interim Director, Division of Hematology/Oncology

Transcription

1 Advances in Autologous and Allogeneic Stem Cell Transplantation Dr. Joseph McGuirk Professor of Medicine, BMT Medical Director, Interim Director, Division of Hematology/Oncology April 12, 2014 Disclosures I do not have any relevant financial relationships with any commercial interests related to the content of my presentation. 2 1

2 3 KUCC BMT Program Annual Volume # of Transplants ( 20.1%) ( 7.0%) ( 9.2%) ( 18.8%) 179 ( 53.3%) ( 91.5%) ( 31.7%) *CY13 Total Auto Allo Year 4 2

3 5 Transplants by Patient Diagnosis Hematologic Malignancies 6 3

4 7 8 4

5 9 10 5

6

7 BMT Program Clinical Trial Accrual ( 112.2%) ( 3.5%) ( 8.3%) ( 20.6%) ( 57.1%) *2013 BMT Volume BMT Volume Trial Accrual Trial Accrual *CY13 volume: CY13 Treatment volume: =100 Supportive Treatment =43 =80 Supportive =19 13 Challenges to Improving Outcomes of Stem Cell Transplantation 1. Relapse 2. Lack of Donors 3. Advanced Age/Co-morbidities 4. Infection 5. Graft-vs-Host Disease 6. Long-term Survival 14 7

8 Causes of Death after Transplants Done in HLA-identical Sibling Primary Disease (49%) New Malignancy (1%) GVHD (16%) Primary Disease (37%) Other (18%) Unrelated Donor Organ Failure (8%) New Malignancy (1%) GVHD (18%) Infection (18%) Infection (13%) Other (16%) Organ Failure (5%) Primary Disease (72%) New Malignancy (1%) Infection (7%) Organ Failure (3%) Autologous Other (17%) Timing Matters Patients transplanted earlier in their disease have better outcomes than patients with advanced disease, regardless of the degree of match Lee SJ et al. Blood. 2007;Vol 110:

9 Advances: Timing and Planning Greater understanding of patient eligibility and timing of the transplant During stable disease During appropriate time in disease process NMDP/ASBMT guidelines for consultation timing Partnering for comprehensive treatment plan Ensures treatments given do not preclude transplant Allows patient to move quickly to transplant, if needed, before disease progresses or complications develop Allows adequate time for unrelated donor/cord blood search, if needed 17 Schematic of the Treatment of a Patient with Chimeric Antigen Receptor (CAR) T Cells Jacobson C A, and Ritz J Blood 2011;118: by American Society of Hematology 18 9

10 19 Myeloma Therapy: Where Are We Now? Biologic therapy has resulted in markedly improved response rates for patients with myeloma Combination of biologic therapy and ASCT Post transplant maintenance therapy Curative outcomes not yet achieved? Cellular immunotherapy to target residual disease

11 Vaccination in Conjunction with HSCT Autologous transplant for myeloma offers a unique opportunity to explore the role of cancer vaccines Patients achieve minimal disease state but reliably relapse Enhanced response to vaccination post transplant in animal models Depletion of regulatory T cells during the period of posttransplant lymphopoietic reconstitution Expansion of tumor reactive clones 21 Source: David Avigan, MD; Beth Israel Deaconess Medical Center 22 11

12 Vaccine Characterization Myeloma Cells CD-38 Dendritic Cells CD86 DC/MM Fusions CD38/CD86 Rosenblatt et al. Blood Jan 13;117(2): Cellular Immune Response CD4 CD8 Rosenblatt et al. Blood Jan 13;117(2):

13 Challenges to Improving Outcomes of Stem Cell Transplantation 1. Relapse 2. Lack of Donors 3. Advanced Age/Co-morbidities 4. Infection 5. Graft-vs-Host Disease 6. Long-term Survival 25 Probability of Having a Donor Match No Donor The only option is an HSCT from a Matched sibling 30% Matched Unrelated Donor Unrelated Cord Blood Unit Mismatched family donor 26 13

14 Reduction in Transplant-Related Mortality 27 Improved Survival in Unrelated Transplant Report year Transplant period One-year survival % % KUCC =64.1% ( ) % % % % % Unadjusted one-year overall survival of NMDP transplant recipients after first allogeneic transplantation at U.S. transplant centers

15 HCT Advances Reasons for improved outcomes: DNA-based HLA typing: better donor-patient matching Better understanding of optimal timing for transplant Advances in clinical practice Advances in conditioning regimens Lower toxicity, reduced-intensity transplants appropriate for older patients New combinations reduce transplant-related mortality 29 Adjusted Probability of OS in adult AML, by Donor Type (n=2,223) HLA-id Sib (n=624) 8/8 MUD (n=1,193) 7/8 MUD (n=406) Saber W et al. Blood 2012;119: by American Society of Hematology 30 15

16 è 4/28/2014 Racial / Ethnic Distribution of Potential Donors in the NMDP Donor registry Lee S J Blood 2013;121: by American Society of Hematology 31 Umbilical Cord Blood Hypothesis 1) Superior proliferative capacity will compensate for low cell dose 2) Naïve immune system reduced GVHD extension of donor pool 3) Unlimited supply, rapid availability 32 16

17 Figure 1 Similar OS Using Sibling, Unrelated Donor, and Cord Blood Grafts after RIC for Older Patients with AML (N =197) R. Peffault de Latour et al. Biol Blood Marrow Transplant. 2013; 19: Unrelated Donor, Cord Blood Grafts extend survival in older AML CR1 patients (N=740) Transplant Outcomes in AML patients in CRI (>50 y.o.) 8/8 Matched 7/8 Matched UCB P-value agvhd 36% 44% 35% n.s. 3-yr cgvhd 53% 59% 28% yr TRM 27% 41% 35% yr relapse 35% 29% 35% n.s. 3-yr survival 43% 37% 30% Weisdorf DJ, Eapen M, Ruggeri A, et al. Blood.2013;122(24): Abs. #

18 Cord Blood Expanding Access in Minority Transplants # of Transplants NMDP Growth in Minority Transplants 73% Growth Year 25% Growth Cord Blood Adult Donors 35 Alternative Donor Availability 100 Related Unrelated /6 4/6 3/6 Genetic Haploidentity All patients Donor found Caucasian Transplant available 6/6 (Serology)* Phenotypic Identity Non-caucasian Transplant available Range 36 18

19 Challenges to Improving Outcomes of Stem Cell Transplantation 1. Relapse 2. Lack of Donors 3. Advanced Age/Co-morbidities 4. Infection 5. Graft-vs-Host Disease 6. Long-term Survival 37 Incidence of Blood Cancers AML ALL CML CLL MDS Rate per 100,000 Population < Ages 38 19

20 AML in Older Patients 1 1 Rowe et al. Blood 103: , Graft-Versus-Tumor Effects Low Sensitivity ALL High-grade NHL Medium Sensitivity High Sensitivity AML Intermediate-grade NHL HL MM CML CLL Low-grade NHL Mantle cell NHL Champlain R. Bone Marrow Transplant. 2001;27 (Suppl 2):S13-S Fundamentals of HCT System Capacity Initiative 20

21 Non-myeloablative Hematopoietic Cell Transplant Preparative Regimen B B B B B B B A B Host Donor HSCT ±DLI A A L A L A A A A L B B A A B B B B B B B Recipient Donor Mixed Chimera Complete Chimera Source: R. Champlain 41 Outcomes of Patients >70 of Age Undergoing Allogeneic SCT for Hematologic Malignancies Patient Characteristics: (n=56) Age (median, range) 71 (70-76) Male (n, %) 37 (66%) HCT-CI score (median, range) 1 (0-5) Disease (n, %) AML 26 (46%) MDS 15 (27%) CLL 5 (9%) NHL 4 (7%) ALL 3 (5%) MPD 2 (4%) CML 1 (2%) Donor Type (n, %) MUD 44 (79%) MRD 10 (18%) Mismatched UD 2 (4%) Conditioning Regimen (n, %) Busulfan/Fludarabine 53 (93%) Melphalan/Fludarabine 2 (4%) Clofarabine/ATG/TLI 1 (2%) GVHD Prophylaxis (n, %) CNI + Siro ± MTX 34 (61%) CNI + MTX 9 (16%) CNI + ATG + MTX 7 (13%) CNI + MMF 3 (5%) Other 3 (5%) Brunner et al. Biol Blood Marrow Transplant. 19 (2013) S114. (ASBMT/CIBMTR Tandem Meeting: Abstract 10) 42 21

22 Outcomes of Patients >70 of Age Undergoing Allogeneic SCT for Hematologic Malignancies Patient Outcomes: (n=56) Median follow-up 15 months (range: 2-86) Max cumulative GVHD (n=46) Acute GVHD (grade II-IV) 13% Acute GVHD (grade III-IV) 7% Chronic 1-year 37% Mortality Died prior to engraftment 2 (3.6%) Graft failure 1 (1.8%) Disease progression 1 (1.8%) Survival Outcomes Overall 1-year 55% Progression-Free 1-year 42% Cum. Incidence of Relapse 34% Non-Relapse 100-day 3.6% Non-Relapse 1-year 5.5% Brunner et al. Biol Blood Marrow Transplant. 19 (2013) S114. (ASBMT/CIBMTR Tandem Meeting: Abstract 10)

23 Challenges to Improving Outcomes of Stem Cell Transplantation 1. Relapse 2. Lack of Donors 3. Advanced Age/Co-morbidities 4. Infection 5. Graft-vs-Host Disease 6. Long-term Survival 45 Phase I, Pre-engraftment, < 30 days Phase II, Post-engraftment, days Phase III, Late phase, > 100 days Host immune system defect Neutropenia, mucositis and agvhd Neutropenia, mucositis and agvhd and cgvhd Impaired cellular and humoral immunity and cgvhd Device risk Allogeneic patients Central line Respiratory and enteric viruses Herpes simplex virus (continuous risk) Cytomegalovirus Varicella-zoster virus Facultative Gram-neg. bacilli Epstein-Barr virus lymphoproliferative ds Staphlococcus epidermidis GI tract Streptococci species All Candida species Encapsulated bacteria (eg., pneumococcus) KEY: Aspergillus species Aspergillus species High incidence Pneumocystis carinii Low incidence Toxoplasma gondii Episodic Strongyloides stercoralis 0 30 Days after transplant

24 Major Viral Problems After HSCT BK Virus CMV EBV Adenoviruses Community Acquired Respiratory Viruses Influenza A & B Rhinovirus RSV A & B Adenovirus Parainfluenza 1 4 Coronavirus Metapneumovirus Source: H. Heslop et al., Baylor University 47 Generation Of CTL Lines For Each Virus Expensive And Time Consuming Single CTL Line for all viruses More time and cost effective Broad spectrum treatment for any patient CTL PBMC PBMC PBMC CTL -VS- PBMC PBMC PBMC CTL CTL CTL Source: H. Heslop et al., Baylor University CTL 48 24

25 Multicenter Study of Third-Party Virus-Specific T Cells to Treat Severe Viral Infections After HSCT Leen et al. Blood. 2013, 121: Characteristics AdV (n = 18) CMV (n = 23) EBV (n = 9) Total (n = 50) Sex (n, %) Male 12 (66.7) 17 (73.9) 4 (44.4) 33 (66.0) Race (n, %) Black 3 (16.7) 4 (17.4) 0 (0.0) 7 (14.0) White 13 (72.2) 16 (69.6) 9 (100.0) 38 (76.0) Age at infusion (y) Mean (SD) 18.0 (17.5) 36.6 (25.6) 34.5 (17.9) 29.5 (23.0) Transplant type (n, %) BM 8 (44.4) 5 (21.7) 1 (11.1) 14 (28.0) PBSC 5 (27.8) 14 (60.9) 2 (22.2) 21 (42.0) CB (single) 3 (16.7) 2 (8.7) 0 (0.0) 5 (10.0) CB (double) 2 (11.1) 2 (8.7) 6 (66.7) 10 (20.0) HLA match (n, %) 1/6 5 (27.8) 4 (17.4) 3 (33.3) 12 (24.0) 2/6 9 (50.0) 12 (52.2) 3 (33.3) 24 (48.0) 3/6 3 (16.7) 6 (26.1) 3 (33.3) 12 (24.0) 4/6 1 (5.6) 1 (4.3) 0 (0.0) 2 (4.0) 49 Cumulative Response Rates at 6-weeks Post-infusion of VSTs Leen A M et al. Blood 2013;121: by American Society of Hematology 50 25

26 ALL, post-cord Blood HSCT - Adenovirus CTL Therapy Patient had progressive adenovirus pneumonia On ventilator (oscillator) Antiviral treatment (Cidofovir) was ineffective BMT Timeline and Adenovirus Plasma PCR Quantities: 07/09/13: Cord Blood HSCT (Flu/Cy/TBI) 07/30/13: <190 copies 08/08/13: 1,300 copies 08/27/13: 666,000 copies 09/19/13: 4x10 7 Trivirus (CMV, EBV & Adenovirus) cytotoxic T-lymphocytes (CTL) 10/14/13: <190 copies 10/21/13: not detected 51 Challenges to Improving Outcomes of Stem Cell Transplantation 1. Relapse 2. Lack of Donors 3. Advanced Age/Co-morbidities 4. Infection 5. Graft-vs-Host Disease 6. Long-term Survival 52 26

27 Causes of Mortality related to Allogeneic BMT ( ) Primary Disease (49%) HLA-identical Sibling New Malignancy (1%) GVHD (16%) Unrelated Donor Primary Disease (37%) Other (16%) New Malignancy (1%) GVHD (18%) Infection (13%) Organ Failure (5%) Infection (18%) Other (18%) Organ Failure (8%) Mechanisms of MSC suppression Rasmusson I, Exp Cell Ther

28 MSCs for GVHD Summary 12 studies used MSCs for GVHD grade 2 4 MSCs have a positive effect (varies between studies) Conditioning varied from myeloablative, nonmyeloablative, RIC, DLI, etc. No apparent difference in response MSCs from HLA identical, haploidentical and unrelated, unmatched have been used No apparent differences in response MSCs from fresh or frozen/thawed 55 Wharton s Jelly Cells the MSCs of the Umbilical Cord Easy isolation, low risk of failure No risk to donor, painlessly collected Superior source to bone marrow: More CFU-F, faster expansion Longer lived in culture Available autologous to cord blood Umbilical cord is not biohazardous waste. It is a gold mine! 56 28

29 Cord Blood and Wharton s Jelly Cells Tissue engineering Local Collaborative Endeavor GvHD Treatment KUMC: Drs. McGuirk & Abhyankar, BMT, Hem/Onc Dr. Weiner, OB/GYN Dr. Detamore, Tissue Engineering Kansas State University: Dr. Weiss, Neurobiology Children s Mercy: Dr. Hopkins, Tissue Engineering 57 Challenges to Improving Outcomes of Stem Cell Transplantation 1. Relapse 2. Lack of Donors 3. Advanced Age/Co-morbidities 4. Infection 5. Graft-vs-Host Disease 6. Long-term Survival 58 29

30 59 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, JCO 2011;29:

31 Long-term Survival after HCT Causes of death, 2 year survivors of allogeneic HCT N = 1,270 deaths Relapse and chronic GVHD most common cause of death Main risk factors for late mortality on multivariate analysis Older age at HCT Chronic GVHD at < 2 yrs Other 4% Second cancers 7% Organ failure 11% Unknown 14% Relapse 41% Prevention and early treatment of late complications are needed Infection 11% GVHD 12% Causes of death (malignant diseases) J Wingard et al, JCO 2011;29: HSCT Guidelines Summary Recommendations include: Adult and pediatric populations Autologous and allogeneic recipients Timing recommendations 6-month post-hct check-up 1-year check-up Annually thereafter Post-HCT vaccination schedule At risk special populations testing recommendations: Chronic GVHD, corticosteroid exposure, TBI, pediatrics 62 31

32 Thank You! 63 32