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The Use of Post-Transplantation Cyclophosphamide after Myeloablative, HLA-Matched Allogeneic Bone Marrow Transplantation Minimizes the Need for Additional Immunosuppression
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Abstracts / Biol Blood Marrow Transplant 22 (2016) S19eS481
Cell Transplantation, Stanford University, Palo Alto, CA; 6 Division of Blood and Marrow Transplantation, Stanford University Medical Center, Stanford, CA Graft-vs-host disease (GVHD) remains a major complication of allogeneic hematopoietic cell transplantation (HCT). Acute (a) GVHD results from direct donor T cell (TC) damage of organs. In contrast, the biology of chronic (c) GVHD with various autoimmune-like manifestations remains poorly understood. We studied the pathophysiology of cGVHD in an MHCmatched mouse model (C57BL/6 à BALB.B) using lethal irradiation and HCT of pure hematopoietic stem cells (HSC; cKIT+Thy1.1loSca1+Lin-) or HSC + TC. Recipients of HSC remained healthy; mice given HSC+TC developed aGVHD with a mortality of w30%. Survivors stabilized around d+45, but developed chronic GVHD after 6-12m with sclerodermatous skin excoriations, cataracts, and liver fibrosis/ cirrhosis. Thymuses were a major target of aGVHD resulting in severe hypocellularity and disrupted organ architecture. During the months of lymphoid reconstitution thymuses of HSC+TCrecipients showed markedly lower expression of cytokeratin 5 (CK5) than HSC recipients. CK5 marks medullary thymic epithelial cells (mTEC) that provide a specialized microenvironment for survival, proliferation, and differentiation of immature TC. Expression of AIRE, a transcription factor in the thymic medulla that controls negative selection during TC maturation was low in all transplanted groups. During aGVHD only TH1-donor TC, but not CD4+IL17+ (TH17)-cells were detectable. Starting at 2m TH17 cells emerged, first in intestines then liver and skin (all typical GVHD target organs) increasing until 6-12 months post-HCT. Of note, TH17 cells originated from donor-HSC, not adaptively transferred mature TC. Even recipients of pure HSC showed increasing proportions of TH17 cells over time, and could manifest discrete signs of cGVHD. From our model we hypothesize the thymus is damaged by conditioning regimen and alloreactive donor TC. Disruption of mTEC may compromise negative selection of nascent HSCderived donor TC, thereby misguide TC maturation and ultimately result in the emergence of TH17 donor-TC in target organs of chronic GVHD.
Figure 1.
Introduction: Post-transplantation cyclophosphamide (PTCy) given on days +3 and +4 is effective single-agent prophylaxis for both acute and chronic graft-versus-host disease (GVHD) for patients receiving myeloablative conditioning (MAC) and 10/10 HLA-matched-related (MRD) or HLA-matched-unrelated (MUD) allogeneic bone marrow transplantation (alloBMT). This approach has the potential benefit of avoiding immunosuppressive therapy after day +4 in patients not experiencing GVHD. Methods: We analyzed the subsequent requirement for systemic immunosuppression in two cohorts of patients treated with this alloBMT platform. Included in these analyses was the use of any pharmacologic or phototherapeutic systemic immunosuppression for the treatment of GVHD or engraftment syndrome, prophylaxis of GVHD after second alloBMT, or treatment of GVHD caused by donor lymphocyte infusion. The first cohort included all 247 adult patients
SESSION E: ALLOGENEIC TRANSPLANTS - GVHD
37 The Use of Post-Transplantation Cyclophosphamide after Myeloablative, HLA-Matched Allogeneic Bone Marrow Transplantation Minimizes the Need for Additional Immunosuppression Christopher G. Kanakry 1, Javier Bolaños-Meade 1, Yvette L. Kasamon 1, Marianna Zahurak 1, Nadira Durakovic 1, Terry Furlong 2, Marta Medeot 1, Marco Mielcarek 2, Ivan M. Borrello 1, Robert A. Brodsky 1, Douglas E. Gladstone 1, Carol Ann Huff 1, William H. Matsui 1, Lode J. Swinnen 1, Richard F. Ambinder 1, Ephraim J. Fuchs 3, Marcos de Lima 4, Borje S. Andersson 4, Ravi Varadhan 1, Paul V. O’Donnell 2, Richard J. Jones 1, Leo Luznik 1. 1 Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD; 2 Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; 3 Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD; 4 Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX
Figure 2.
Abstracts / Biol Blood Marrow Transplant 22 (2016) S19eS481
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Figure 3. Longitudinal burden of systemic immunosuppression (IS) experienced patients treated with myeloablative conditioning and HLA-matched-ralated (MRD) or HLA-matched unrelated (MUD) allogeneic bone marrow transplantation using post transplantation cyclophosphamide (PTCy) as single-agent graft-versus-host disease (GVHD) prophylaxis. Multi-state model probabilities are shown for each of the four cohorts Three states were possible 1) Alive and not on immunosuppression (white area), 2) Alive and on immunosuppression (aqua area), or 3) death from any cause (red area) All patients started in stale 1 on post-transplant day +5 after having received the entirety of the intended GVHD prophylaxis using PTCy on days +3 and +4 The first two stales were transient staites as patients could transition back and forth between the two depending on their need for systemic immunosuppression Death was an absorbing state.
transplanted at the Johns Hopkins Hospital from 2004-2011 using busulfan/cyclophosphamide (BuCy) MAC (median follow-up 4.5 years); data on immunosuppression use by this cohort were collected retrospectively. The second cohort included all 92 patients transplanted on a multi-institutional prospective study (2009-2011) using busulfan/fludarabine (BuFlu) MAC; for this study (median follow-up 2.9 years), data were collected prospectively. Results: With death as the only competing risk, the 3-year cumulative incidences (CIs) of corticosteroid initiation were 46%, 51%, 65%, and 68% for MRD BuCy, MRD BuFlu, MUD BuCy, and MUD BuFlu patients, respectively (Figure 1), while the 3-year CIs of initiation of non-corticosteroid systemic immunosuppression were 40%, 40%, 58%, and 64%, respectively (Figure 2). The higher rates in MUDs were largely reflective of the higher rates of grade II-IV acute GVHD after MUD alloBMT (CIs at 200 days: MRD BuCy 40%, MRD BuFlu 41%, MUD BuCy 54%, MUD BuFlu 60%). Among those requiring corticosteroids, the median durations (interquartile ranges) were 57 (40-98), 74 (41-206), 63 (46-133), and 147 (48-481) days for these four groups, respectively. Among those requiring non-corticosteroid immunosuppression, the median durations (interquartile ranges) were 141 (54-218), 151 (53-354), 162 (64-254), and 232 (87-560) days, respectively. The percentages of patients not requiring any immunosuppression beyond PTCy were 51%, 47%, 31%, and 26%, respectively. A multi-state model of the probability of patients living without systemic immunosuppression is shown in Figure 3. Conclusion: These data confirm in two independent cohorts of patients that the use of PTCy as single-agent GVHD prophylaxis after MAC and bone marrow allografting spares exposure to additional immunosuppression in a significant percentage of patients, while minimizing the duration of immunosuppressive therapy in patients requiring treatment.
38 Prospective, Multicenter Clinical Trial of AtorvastatinBased Acute Graft-Versus-Host-Disease (aGVHD) Prophylaxis in Recipients of HLA-Matched Related Donor (MRD) and Matched Unrelated Donor (MUD) Allogeneic Hematopoietic Cell Transplantation (alloHCT) Mehdi Hamadani 1, Marcelo C. Pasquini 2, Alexis Visotcky 3, Kwang Woo Ahn 4, Mary M. Horowitz 5, Jennifer Boyd6, J. Douglas Rizzo 5, Wael Saber 7, William Drobyski 8, Carlos Arce-lara 9, Anita D’Souza 9, Timothy S. Fenske 10, Aaron Cumpston 11, Pamela Bunner 12, Michael Craig 13, Parameswaran N. Hari 7, Abraham S. Kanate 14. 1 CIBMTR, Medical College of Wisconsin, Milwaukee, WI; 2 CIBMTR, CIBMTR (Center fo, Milwaukee, WI; 3 Medical College of Wisconsin, milwaukee, WI; 4 Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI; 5 Department of Medicine, CIBMTR and Medical College of Wisconsin, Milwaukee, WI; 6 Medical College of Wisconsin, Milwaukee, WI; 7 Department of Medicine, CIBMTR (Center for International Blood and Marrow Transplant Research), Medical College of Wisconsin, Milwaukee, WI; 8 Dept of Medicine, Medical College of Wisconsin, Milwaukee, WI; 9 Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI; 10 Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI; 11 Pharmacy, West Virginia University Medicine, Morgantown, WV; 12 West Virginia University Hospitals - MBRCC, Morgantown, WV; 13 West Virginia University - Health Science Center, Morgantown, WV; 14 Section of Hematology/Oncology, Department of Medicine, West Virginia University, Morgantown, WV Atorvastatin (ATOR) administration to both the donors and recipients of MRD alloHCT as aGVHD prophylaxis is safe and effective (JCO. 2013; 31:4416-23). The efficacy of ATOR as
Abstracts / Biol Blood Marrow Transplant 22 (2016) S19eS481
Cell Transplantation, Stanford University, Palo Alto, CA; 6 Division of Blood and Marrow Transplantation, Stanford University Medical Center, Stanford, CA Graft-vs-host disease (GVHD) remains a major complication of allogeneic hematopoietic cell transplantation (HCT). Acute (a) GVHD results from direct donor T cell (TC) damage of organs. In contrast, the biology of chronic (c) GVHD with various autoimmune-like manifestations remains poorly understood. We studied the pathophysiology of cGVHD in an MHCmatched mouse model (C57BL/6 à BALB.B) using lethal irradiation and HCT of pure hematopoietic stem cells (HSC; cKIT+Thy1.1loSca1+Lin-) or HSC + TC. Recipients of HSC remained healthy; mice given HSC+TC developed aGVHD with a mortality of w30%. Survivors stabilized around d+45, but developed chronic GVHD after 6-12m with sclerodermatous skin excoriations, cataracts, and liver fibrosis/ cirrhosis. Thymuses were a major target of aGVHD resulting in severe hypocellularity and disrupted organ architecture. During the months of lymphoid reconstitution thymuses of HSC+TCrecipients showed markedly lower expression of cytokeratin 5 (CK5) than HSC recipients. CK5 marks medullary thymic epithelial cells (mTEC) that provide a specialized microenvironment for survival, proliferation, and differentiation of immature TC. Expression of AIRE, a transcription factor in the thymic medulla that controls negative selection during TC maturation was low in all transplanted groups. During aGVHD only TH1-donor TC, but not CD4+IL17+ (TH17)-cells were detectable. Starting at 2m TH17 cells emerged, first in intestines then liver and skin (all typical GVHD target organs) increasing until 6-12 months post-HCT. Of note, TH17 cells originated from donor-HSC, not adaptively transferred mature TC. Even recipients of pure HSC showed increasing proportions of TH17 cells over time, and could manifest discrete signs of cGVHD. From our model we hypothesize the thymus is damaged by conditioning regimen and alloreactive donor TC. Disruption of mTEC may compromise negative selection of nascent HSCderived donor TC, thereby misguide TC maturation and ultimately result in the emergence of TH17 donor-TC in target organs of chronic GVHD.
Figure 1.
Introduction: Post-transplantation cyclophosphamide (PTCy) given on days +3 and +4 is effective single-agent prophylaxis for both acute and chronic graft-versus-host disease (GVHD) for patients receiving myeloablative conditioning (MAC) and 10/10 HLA-matched-related (MRD) or HLA-matched-unrelated (MUD) allogeneic bone marrow transplantation (alloBMT). This approach has the potential benefit of avoiding immunosuppressive therapy after day +4 in patients not experiencing GVHD. Methods: We analyzed the subsequent requirement for systemic immunosuppression in two cohorts of patients treated with this alloBMT platform. Included in these analyses was the use of any pharmacologic or phototherapeutic systemic immunosuppression for the treatment of GVHD or engraftment syndrome, prophylaxis of GVHD after second alloBMT, or treatment of GVHD caused by donor lymphocyte infusion. The first cohort included all 247 adult patients
SESSION E: ALLOGENEIC TRANSPLANTS - GVHD
37 The Use of Post-Transplantation Cyclophosphamide after Myeloablative, HLA-Matched Allogeneic Bone Marrow Transplantation Minimizes the Need for Additional Immunosuppression Christopher G. Kanakry 1, Javier Bolaños-Meade 1, Yvette L. Kasamon 1, Marianna Zahurak 1, Nadira Durakovic 1, Terry Furlong 2, Marta Medeot 1, Marco Mielcarek 2, Ivan M. Borrello 1, Robert A. Brodsky 1, Douglas E. Gladstone 1, Carol Ann Huff 1, William H. Matsui 1, Lode J. Swinnen 1, Richard F. Ambinder 1, Ephraim J. Fuchs 3, Marcos de Lima 4, Borje S. Andersson 4, Ravi Varadhan 1, Paul V. O’Donnell 2, Richard J. Jones 1, Leo Luznik 1. 1 Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD; 2 Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; 3 Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD; 4 Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX
Figure 2.
Abstracts / Biol Blood Marrow Transplant 22 (2016) S19eS481
S47
Figure 3. Longitudinal burden of systemic immunosuppression (IS) experienced patients treated with myeloablative conditioning and HLA-matched-ralated (MRD) or HLA-matched unrelated (MUD) allogeneic bone marrow transplantation using post transplantation cyclophosphamide (PTCy) as single-agent graft-versus-host disease (GVHD) prophylaxis. Multi-state model probabilities are shown for each of the four cohorts Three states were possible 1) Alive and not on immunosuppression (white area), 2) Alive and on immunosuppression (aqua area), or 3) death from any cause (red area) All patients started in stale 1 on post-transplant day +5 after having received the entirety of the intended GVHD prophylaxis using PTCy on days +3 and +4 The first two stales were transient staites as patients could transition back and forth between the two depending on their need for systemic immunosuppression Death was an absorbing state.
transplanted at the Johns Hopkins Hospital from 2004-2011 using busulfan/cyclophosphamide (BuCy) MAC (median follow-up 4.5 years); data on immunosuppression use by this cohort were collected retrospectively. The second cohort included all 92 patients transplanted on a multi-institutional prospective study (2009-2011) using busulfan/fludarabine (BuFlu) MAC; for this study (median follow-up 2.9 years), data were collected prospectively. Results: With death as the only competing risk, the 3-year cumulative incidences (CIs) of corticosteroid initiation were 46%, 51%, 65%, and 68% for MRD BuCy, MRD BuFlu, MUD BuCy, and MUD BuFlu patients, respectively (Figure 1), while the 3-year CIs of initiation of non-corticosteroid systemic immunosuppression were 40%, 40%, 58%, and 64%, respectively (Figure 2). The higher rates in MUDs were largely reflective of the higher rates of grade II-IV acute GVHD after MUD alloBMT (CIs at 200 days: MRD BuCy 40%, MRD BuFlu 41%, MUD BuCy 54%, MUD BuFlu 60%). Among those requiring corticosteroids, the median durations (interquartile ranges) were 57 (40-98), 74 (41-206), 63 (46-133), and 147 (48-481) days for these four groups, respectively. Among those requiring non-corticosteroid immunosuppression, the median durations (interquartile ranges) were 141 (54-218), 151 (53-354), 162 (64-254), and 232 (87-560) days, respectively. The percentages of patients not requiring any immunosuppression beyond PTCy were 51%, 47%, 31%, and 26%, respectively. A multi-state model of the probability of patients living without systemic immunosuppression is shown in Figure 3. Conclusion: These data confirm in two independent cohorts of patients that the use of PTCy as single-agent GVHD prophylaxis after MAC and bone marrow allografting spares exposure to additional immunosuppression in a significant percentage of patients, while minimizing the duration of immunosuppressive therapy in patients requiring treatment.
38 Prospective, Multicenter Clinical Trial of AtorvastatinBased Acute Graft-Versus-Host-Disease (aGVHD) Prophylaxis in Recipients of HLA-Matched Related Donor (MRD) and Matched Unrelated Donor (MUD) Allogeneic Hematopoietic Cell Transplantation (alloHCT) Mehdi Hamadani 1, Marcelo C. Pasquini 2, Alexis Visotcky 3, Kwang Woo Ahn 4, Mary M. Horowitz 5, Jennifer Boyd6, J. Douglas Rizzo 5, Wael Saber 7, William Drobyski 8, Carlos Arce-lara 9, Anita D’Souza 9, Timothy S. Fenske 10, Aaron Cumpston 11, Pamela Bunner 12, Michael Craig 13, Parameswaran N. Hari 7, Abraham S. Kanate 14. 1 CIBMTR, Medical College of Wisconsin, Milwaukee, WI; 2 CIBMTR, CIBMTR (Center fo, Milwaukee, WI; 3 Medical College of Wisconsin, milwaukee, WI; 4 Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI; 5 Department of Medicine, CIBMTR and Medical College of Wisconsin, Milwaukee, WI; 6 Medical College of Wisconsin, Milwaukee, WI; 7 Department of Medicine, CIBMTR (Center for International Blood and Marrow Transplant Research), Medical College of Wisconsin, Milwaukee, WI; 8 Dept of Medicine, Medical College of Wisconsin, Milwaukee, WI; 9 Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI; 10 Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI; 11 Pharmacy, West Virginia University Medicine, Morgantown, WV; 12 West Virginia University Hospitals - MBRCC, Morgantown, WV; 13 West Virginia University - Health Science Center, Morgantown, WV; 14 Section of Hematology/Oncology, Department of Medicine, West Virginia University, Morgantown, WV Atorvastatin (ATOR) administration to both the donors and recipients of MRD alloHCT as aGVHD prophylaxis is safe and effective (JCO. 2013; 31:4416-23). The efficacy of ATOR as