High dose cyclophosphamide in HLAhaploidentical stem cell transplantation Ephraim J. Fuchs, M.D., M.B.A. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins fuchsep@jhmi.edu
Alternative Donor Transplantation: An Unmet Need HLA-matched related donors are available in only 25-30% of cases Outcomes of MRD and 10/10 matched URD transplantation similar Alternative donor options include cord blood, haploidentical related donor and mismatched URD donor transplantation Studies are underway to compare the risks and benefits of transplantation from these donor sources 25% of allogeneic transplant worldwide are now from haploidentical donors
Cyclophosphamide-induced tolerance Proliferating ALLOREACTIVE cells are killed anti-cmv anti-cmv anti-hsv anti-hsv Non-proliferating non-alloreactive cells are spared
Cyclophosphamide (Cy)-induced tolerance to minor H antigens 50 million CBA spleen cells IV Cy 200 mg/kg IP B10.BR mouse 48-72 hrs. B10.BR (H-2 k ) CBA (H-2 k ) 8 wks 1 year B10.BR tolerant of CBA
Mixed chimerism across full MHC barrier using Fludarabine, 200 cgy TBI, and PTCy 6 months post-bmt MHC-mismatched BMT Conditioned, no BMT
Treatment schema (n=374) Treatment in outpatient department! Median age: 55 (18-75); 132 patients (35%) >60 years Median mismatch: 4/10 (0-5) Disease risk index: Low 19% (n=72); Intermediate 65% (n=242); High 16% (n=60) Disease type: Myeloid 32% (n=120); Lymphoid 67% (n=249)
Mini-haploBMT with PTCy: outcomes
Haplos have caught up to matched *R Szydlo et al. J Clin Oncol 15: 1767-1777, 1997 Personal communication with P. Armand (n=614) S McCurdy et al. Blood 125:3024-31, 2015 3 year progression-free survival, stratified by disease risk index Matched Haplo Disease stage/ risk 1997* (matched sib) 2015 (sib + MUD) 1997* 2015 Early/low risk 66 66 25 63 Intermediate 44 31 20 39 Advanced/high risk 12 15 22 25
Parallel Phase 2 Trials Using Partially HLA-MM Related Bone Marrow or Unrelated ducb Grafts Brunstein CG, Fuchs EJ, Carther SL, et al. Blood 2011; 118: 282-288 CTN Study: 2 Parallel Multicenter Phase 2 Studies 56% AML (cord), 44% AML (haplo) RIC Regimen of FLU/CY/ Low dose TBI for both groups Early TRM higher with UCBT (24% vs 7%) but relapse rate lower (31% vs 45%) UCBT 1 year OS 54%, PFS 46% Haplo-BMT 1 year OS 62%, PFS 48%
A Multi-Center, Phase III, Randomized Trial of Reduced Intensity Conditioning (RIC) and Transplantation of Double Unrelated Umbilical Cord Blood (ducb) versus HLA-Haploidentical Related Bone Marrow (haplo-bm) for Patients with Hematologic Malignancies BMT CTN PROTOCOL 1101 CEA VERSION 4.0 Study Team Scott Ramsey, M.D., Ph.D. Paul O Donnell, M.D., Ph.D. Parent Study Collaborators Ephraim Fuchs, M.D. Paul O Donnell, M.D., Ph.D. Claudio Brunstein, M.D. Mary Eapen, M.D.
Haploidentical Transplantation with Post-Transplantation Cyclophosphamide Compared with HLA-Matched Related or Unrelated Donor Transplantion for Patients 50 years Blaise D, et al. BBMT 2016; 22: 119-124 Age 55 AML + MDS: 48% (haplo) 40% (MRD), 48% (URD) Grades II-IV agvhd higher after URD HCT (44% vs 23% and 21%) No severe cgvhd after haplo vs 16% (MRD) and 14% (URD) PFS NRM 3-fold higher after URD SCT Conclusion: OS, PFS and severe cgvhd same after haplo and MRD HCT but superior to URD HCT Severe cgvhd Free and PFS
Haploidentical Transplantation Using Post-Transplantation Cyclophosphamide Compared With 10/10 Allele-Matched Unrelated and HLA-Identical Sibling Donors Transplanmtion Bashey A, et al. BBMT 2016: 22: 125-133 MDS+AML: Haplo (43%), 10/10 URD (51%) MRD (47%) HCT NRM and relapse same Grades II-IV agvhd same for haplo and MRD but < URD Less moderate-severe cgvhd after haplo compared to URD and MRD HCT DFS same between the three groups, OS similar after haplo and URD HCT but < MRD HCT
RIC Haplo-HCT vs Matched URD HCT for Lymphoma Kanate AS, et al. Blood 2016; 127: 938-947 CIBMTR retrospective comparison N=917 (185 haplo, 241 URD with ATG, 491 URD w/o ATG) agvhd, NRM, relapse, PFS, OS equivalent among the 3 groups URD HCT cgvhd incidence > than haplo HCT Conclusion: Haplo-HCT = URD HCT for lymphoma except for less cgvhd agvhd: NS cgvhd: p<.007
Big increase in number of haplos 2010 2014 % change from 2010 Matched sib 2496 2489 0% Haplo 309 697 126% Matched unrelated 2394 3064 28% Mismatched unrelated 710 723 2% Cord 816 669 18% TOTALS 6725 7642 14%
Ethnic minorities in the US have a hard time finding a matched donor Likelihood of identifying an unrelated donor (%) 8/8 HLA match 7/8 HLA match Likelihood of identifying a cord blood unit for patients >20 years (%) 6/6 HLA match >5/6 HLA match >4/6 HLA match White European 75 97 17 66 96 African-American 19 76 2 24 81 Chinese 41 88 6 44 91 Hispanic South or Central American 34 80 5 43 90
Haplos fill MUD deficit in African-Americans Caucasians Graft source 2010 2014 % of 2014 total African-Americans 2010 2014 % of 2014 total Matched sib 1938 1850 31% 185 239 37% Haplo 160 366 6% 70 147 23% Matched unrelated 2184 2731 46% 56 87 13% Mismatched unrelated 563 553 9% 74 77 12% Unrelated cord blood 547 448 8% 115 98 15% Totals 5392 5948 100% 500 648 100%
HLA-haploidentical BMT plus posttransplantation cyclophopshamide for non-malignant disorders
HaploBMT for non-malignant diseases Summary Disease N Full donor chimerism Graft failure GVHD Death Sickle cell 34 14 (41%) 12 (35%) 4 (12%) 1 (3%) Aplastic anemia 11 11 (100%) 0 (0%) 1 (9%) 0 (0%) Totals 45 25 (56%) 14 (31%) 5 (11%) 1 (2%)
Mini-BMT for sickle cell disease (SCD) Treatment schema 12-28 5 29-34 None 400 cgy TBI prep
HaploBMT for sickle cell disease Overall outcomes Regimen Full donor Mixed chimera Graft failure GVHD Mini-haplo with PT/Cy 1 0 1 0 Add ATG days -9-7 3 1 2 0 ATG, tacro rapamycin 1 0 2 0 ATG, rapa, G-CSF stim donor 5 6 6 3 (1 fatal) ATG, 400 cgy TBI, rapamycin 4 1 1 1 Matched sibs 1 3 0 1 Haplo totals (n=34) 14 8 12 4 Totals (n=38) 15 11 12 5 All complete chimeras are able to discontinue immunosuppression at 1 year post-bmt Overall: 65% cure, 35% graft failure, 10% GVHD, 4% mortality
HaploBMT + PTCy for aplastic anemia ATG ATG ATG Flu Cy Flu Cy Flu Flu Flu GVHD Prophylaxis: Tacrolimus, MMF, & Post-HSCT Cy TBI Cy Cy -9-8 -7-6 -5-4 -3-2 -1 0 1 2 3 4 G-CSF-stimulated bone marrow IV Flu Cy Cy = Fludarabine 30 mg/m 2 IV daily = Cyclophosphamide 14.5 mg/kg IV daily TBI = 200 cgy = Cyclophosphamide 50 mg/kg IV daily ATG = Thymoglobulin 0.5 mg/kg (day-9) & 2 mg/kg (day -8,-7)
Hopkins Haplo BMT for Aplastic Anemia Age/ Sex Pre-BMT Therapy Degree of HLA match Day of engraftm ent (ANC >1000) Last donor chimerism agvhd cghvd Response Follow- Up (mos) 35M ATG/ CsA 5/10 30 100 none none CR 48 52M ATG/ CsA 5/10 24 100 none none CR 25 45F ATG/ CsA 5/10 27 100 Gr 2 skin Gr 2 skin CR 20 27F ATG 5/10 24 100 none none CR 14 33M HiCY 5/10 16 100 none none CR 16 17M HiCY 5/10 17 100 none none CR 8 54M ATG/ CsA 5/10 15 100 none none CR 10 26F ATG/ CsA/TPO 5/10 17 100 none none CR 12 59M ATG/CsA? 23 100 none none CR 7 20F ATG/CsA? 15 100 none none CR 6 11M ATG/CsA? 15 100 none none CR 6 25F HiCY MUD 15 100 none none NE 2 Summary: 12 pts, 12 full donor, 11 CR, 1 GVHD (8%)
New haplo initiatives in the USA
BMT CTN 1502: Aplastic Anemia Haploidentical Cohort ATG ATG ATG Flu Cy Flu Cy Flu Flu Flu GVHD Prophylaxis: Tacrolimus, MMF, & Post-HSCT Cy -9-8 -7-6 -5-4 -3-2 -1 0 1 2 3 4 TBI Cy Cy Flu Cy Cy = Fludarabine 30 mg/m 2 IV daily = Cyclophosphamide 14.5 mg/kg IV daily TBI = 200 cgy = Cyclophosphamide 50 mg/kg IV daily ATG = Thymoglobulin 0.5 mg/kg (day-9) & 2 mg/kg (day -8,-7) 24
Reduced Intensity Conditioning before HLA-Haploidentical Bone Marrow Transplantation in Patients with Symptomatic Sickle Cell Disease BMT CTN protocol development Michael R. DeBaun MD MPH Adetola Kassim, MD Mark Walters, MD Robert Brodsky, MD
Haplo-ID BMT for SCD - Hopkins Conditioning regimen ATG, CPM 14.5 mg/kg x 2, Flu, TBI 200cGy with post-bmt CPM Replaced tacrolimus with sirolimus to avoid posterior reversible encephalopathy syndrome 29 consecutive patients treated First cohort; 8/14 (57%) engrafted Second cohort; 10/15 (67%) engrafted Overall engraftment 62% with 97% survival Bolanos-Meade J et al, Blood 22:4285, 2012 and Brodsky R, et al. Foundation for sickle cell disease research meeting, Miami. April 2014.
Combined HLA-haploidentical bone marrow and kidney transplantation to achieve immunosuppression-free transplantation tolerance Prednisone Patient #1: 29 yo with IgA nephropathy, now 4.3 months out from combined transplant full donor chimerism, gr II skin GVHD, Cr 1.4
Sequential, related donor partial liver transplantation followed by BMT for hepatocellular carcinoma* Patient with HCC confined to liver but outside Milan criteria (single tumor <5 cm or <3 tumors, each <3 cm) *Sponsored by the Fibrolamellar Cancer Foundation
Immunotherapy of HPV-associated cancer Treatment schema Clinical trial objectives Determine maximally tolerated dose of donor lymphocytes Document toxicities of transplantation and post-transplant donor lymphocyte infusions (DLI) Characterize immune and clinical responses to transplantation and to DLI
HaploSCT in the United States Summary Fastest growth in numbers of all graft sources Near universal donor availability, low cost Fills an unmet need for ethnic minorities Post-transplantation cyclophosphamide is the dominant method of GVHD prophylaxis Low rates of acute and chronic GVHD and non-relapse mortality Haplo plus PTCy outcomes are as good as those after cord blood or HLA-matched unrelated donor SCT New national initiatives to treat sickle cell disease and aplastic anemia using haplosct with PTCy PTCy lowers toxicity of haplobmt to enable combined solid organ/ bone marrow transplants, or treatment of solid tumors
Acknowledgements BMT Physicians Rick Jones Leo Luznik Chris Kanakry Shannon McCurdy Yvette Kasamon Javier Bolaños-Meade Lode Swinnen Oncology Biostatistics Gary Rosner Mariana Zahurak Fuchs lab Leo Luznik Heather Symons Han-Hsuan Fu Jie Wang BMT Patients