Published Ahead of Print on March 16, 2017, as doi:10.3324/haematol.2016.156356. Copyright 2017 Ferrata Storti Foundation.
Improved survival after acute graft vs. host disease diagnosis in the modern era by Hanna J. Khoury, Tao Wang, Michael T. Hemmer, Daniel Couriel, Amin Alousi, Corey Cutler, Mahmoud Aljurf, Joseph H. Antin, Mouhab Ayas, Minoo Battiwalla, Jean-Yves Cahn, Mitchell Cairo, Yi-Bin Chen, Robert Peter Gale, Shahrukh Hashmi, Robert J. Hayashi, Madan Jagasia, Mark Juckett, Rammurti T Kamble, Mohamed Kharfan-Dabaja, Mark Litzow, Navneet Majhail, Alan Miller, Taiga Nishihori, Muna Qayed, Helene Schoemans, Harry C. Schouten, Gérard Socié, Jan Storek, Leo Verdonck, Ravi Vij, William A. Wood, Lolie Yu, Rodrigo Martino, Matthew Carabasi, Christopher Dandoy, Usama Gergis, Peiman Hematti, Melham Solh, Kareem Jamani, Leslie Lehmann, Bipin Savani, Kirk R. Schultz, Baldeep M. Wirk, Stephen Spellman, Mukta Arora, and Joseph Pidala Haematologica 2017 [Epub ahead of print] Citation: Khoury HJ, Wang T, Hemmer MT, Couriel D, Alousi A, Cutler C, Aljurf M, Antin JH, Ayas M, Battiwalla M, Cahn J-Y, Cairo M, Chen Y-B, Gale RP, Hashmi S, Hayashi RJ, Jagasia M, Juckett M, Kamble RT, Kharfan-Dabaja M, Litzow M, Majhail N, Miller A, Nishihori T, Qayed M, Schoemans H, Schouten HC, Socié G, Storek J, Verdonck L, Vij R, Wood WA, Yu L, Martino R, Carabasi M, Dandoy C, Gergis U, Hematti P, Solh M, Jamani K, Lehmann L, Savani B, Schultz KR, Wirk BM, Spellman S, Arora M, and Pidala J. Improved survival after acute graft vs. host disease diagnosis in the modern era. Haematologica. 2017; 102:xxx doi:10.3324/haematol.2016.156356 Publisher's Disclaimer. E-publishing ahead of print is increasingly important for the rapid dissemination of science. Haematologica is, therefore, E-publishing PDF files of an early version of manuscripts that have completed a regular peer review and have been accepted for publication. E-publishing of this PDF file has been approved by the authors. After having E-published Ahead of Print, manuscripts will then undergo technical and English editing, typesetting, proof correction and be presented for the authors' final approval; the final version of the manuscript will then appear in print on a regular issue of the journal. All legal disclaimers that apply to the journal also pertain to this production process.
Improved survival after acute graft vs host disease diagnosis in the modern era Hanna J. Khoury1, Tao Wang2,3, Michael T. Hemmer2, Daniel Couriel4, Amin Alousi5, Corey Cutler6, Mahmoud Aljurf7, Joseph H. Antin6, Mouhab Ayas7, Minoo Battiwalla8, Jean-Yves Cahn9, Mitchell Cairo10, Yi-Bin Chen11, Robert Peter Gale12, Shahrukh Hashmi13,14, Robert J. Hayashi15, Madan Jagasia16, Mark Juckett17, Rammurti T. Kamble18, Mohamed Kharfan-Dabaja19, Mark Litzow13, Navneet Majhail20, Alan Miller18, Taiga Nishihori19, Muna Qayed21, Helene Schoemans22, Harry C. Schouten23, Gerard Socie24, Jan Storek25, Leo Verdonck26, Ravi Vij27, William A. Wood28, Lolie Yu29, Rodrigo Martino30, Matthew Carabasi31, Christopher Dandoy32, Usama Gergis33, Peiman Hematti17, Melham Solh34, Kareem Jamani25, Leslie Lehmann35, Bipin Savani16, Kirk R. Schultz36, Baldeep M. Wirk37, Stephen Spellman38, Mukta Arora39, Joseph Pidala19 1
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA; 2CIBMTR (Center for International Blood and Marrow Transplant Research), Department of Medicine, Medical College of Wisconsin, Milwaukee, WI; 3Division of Biostatistics, Institute for Health and Society, Medical College of Wisconsin, Milwaukee, WI; 4Utah Blood and Marrow Transplant Program-Adults, Salt Lake City, Utah; 5Department of Stem Cell Transplantation, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX; 6Center for Hematologic Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; 7Department of Pediatric Hematology Oncology, King Faisal Specialist Hospital Center & Research, Riyadh, Saudi Arabia; 8Hematology Branch, National Heart, Lung and Blood Institute-NIH, Bethesda, MD; 9Department of Hematology, University Hospital, Grenoble, France; 10Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Department of Pediatrics, New York Medical College, Valhalla, NY; 11 Division of Hematology/Oncology, Massachusetts General Hospital, Boston, MA; 12Hematology Research Centre, Division of Experimental Medicine, Department of Medicine, Imperial College London, London, United Kingdom; 13Department of Internal Medicine, Mayo Clinic Rochester, Rochester, MN; 14 Department of Oncology, King Faisal Specialist Hospital Center & Research, Riyadh, Saudi Arabia; 15 Division of Pediatric Hematology/Oncology, Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO; 16Division of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN; 17Division of Hematology/Oncology/Bone Marrow Transplantation, Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, WI; 18Division of Hematology and Oncology, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX; 19Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; 20Blood & Marrow Transplant Program, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; 21Department of Pediatrics, Emory University School of Medicine, Atlanta, GA; 22 University Hospital of Leuven, Leuven, Belgium; 23Department of Hematology, Academische Ziekenhuis, Maastricht, Netherlands; 24Department of Hematology, Hopital Saint Louis, Paris, France; 25 Department of Medicine, University of Calgary, Calgary, AB, Canada; 26Isala Clinics Zwolle, The Netherlands; 27Division of Hematology and Oncology, Washington University School of Medicine, St. Louis, MO; 28Division of Hematology/Oncology, Department of Medicine, University of North Carolina, Chapel Hill, NC; 29Division of Hematology/Oncology &HSCT, The Center for Cancer and Blood Disorders, Children’s Hospital/Louisiana State University Medical Center, New Orleans, LA; 30Division of Clinical Hematology, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain; 31Thomas Jefferson University Hospital, Philadelphia, PA; 32Cincinnati Children’s Hospital Medical Center, Cincinnati, OH; 33 Hematologic Malignancies & Bone Marrow Transplant, Department of Medical Oncology, New York Presbyterian Hospital/Weill Cornell Medical Center, New York, NY; 34The Blood and Marrow Transplant Group of Georgia, Northside Hospital, Atlanta, GA; 35Dana Farber Cancer Institute/ Boston Children’s Hospital, Boston, MA; 36Department of Pediatric Hematology, Oncology and Bone Marrow Transplant, British Columbia’s Children’s Hospital, The University of British Columbia, Vancouver, BC, Canada; 37Division of Bone Marrow Transplant, Seattle Cancer Care Alliance, Seattle, WA;
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CIBMTR(Center for International Blood and Marrow Transplant Research), National Marrow Donor Program/Be the Match, Minneapolis, MN; 39Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota Medical Center, Minneapolis, MN
Corresponding Author:
Joseph Pidala, MD, PhD Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL 813-745-2556 [email protected] Abstract: 247 words Manuscript: 2,539 words Total figures and tables: 6
Running Head: Outcomes of acute GVHD over time Keywords: outcomes, grades II-IV acute graft-versus-host disease, allogeneic transplantation Key points: 1) Grade III-IV acute GVHD has decreased over time. 2) Overall survival has improved following grade II-IV acute GVHD diagnosis for transplant recipients treated with tacrolimus
Disclaimer: Presented as a poster at the Annual Meeting of the American Society of Hematology in December 2015
2
ABSTRACT Acute graft vs. host disease remains a major threat to successful outcome after allogeneic hematopoietic cell transplantation. While improvements in treatment and supportive care have occurred, it is unknown whether these advances have resulted in improved outcome specifically among those diagnosed with acute graft vs. host disease. We examined outcome following diagnosis of grade II-IV acute graft vs. host disease according to time period, and examine effects according to original graft vs. host disease prophylaxis regimen and maximum overall grade of acute GVHD. Between 1999 and 2012, 2,905 patients with acute myeloid leukemia (56%), acute lymphoblastic leukemia (30%) or myelodysplastic syndromes (14%) received sibling (24%) or unrelated donor (76%) blood (66%) or marrow (34%) transplant and developed grades II-IV acute graft vs. host disease (n=497 for 1999-2001, n=962 for 20022005, n=1,446 for 2006-2010). Median follow-up was 144 (4-174), 97 (4-147) and 60 (8-99) months for 1999-2001, 2002-2005, and 2006-2010, respectively. Among the grade II-IV acute graft vs. host disease cohort, there was a decrease in the proportion of grades III-IV acute graft vs. host disease over time with 56%, 47% , and 37% for 1999-2001, 2002-2005, and 2006-2012, respectively (p99.9% concordance between the 8/8 and well-matched and ≤ 7/8 and partially or mismatched groups.
Study Endpoints The primary endpoint was OS, defined as by death from any cause. Secondary endpoints considered were the following:
DFS, defined as survival in continuous complete remission; TRM,
defined as death in continued remission; malignancy relapse, defined as recurrence of the malignancy for which HCT was performed; and chronic GVHD.(11) All endpoints were estimated from date of acute GVHD onset, as exact date of maximal grade II-IV acute GVHD was not collected.
Statistical Analysis
Included patients were divided into three cohorts based on the year of transplant (1999-
2001, 2002-2005, 2006-2012). Univariate analysis compared the outcomes of OS, DFS, TRM, relapse and chronic GVHD incidence between these three cohorts. Multivariate analyses were performed using the Cox proportional hazards regression models. All the clinical variables were tested for the affirmation of the proportional hazards assumption. Factors violating the proportional hazards assumption were adjusted through stratification. Then a stepwise model selection procedure was used to identify clinical variables that were associated with each particular outcome with a threshold of 0.05 for
6
both entry and stay in the model. Interactions between the main variable ‘Year of transplant’ and the adjusted covariates were tested, and no significant interactions between the ‘Year of transplant’ and the adjusted covariates were detected at the significance level of 0.01 in any of the models. A significant center effect was detected for the outcomes of OS and TRM for those with grade II-IV acute GVHD only among those treated with CsA, and adjustment for this effect was performed. Potential covariates included patient age (by decades), sex and race (Caucasian, African American, Other), Karnofsky performance status (< 90%, ≥ 90%), time from diagnosis to HCT (< 2 weeks, 2 weeks – 1 month, 2 months – 100 days) , disease (AML, ALL, MDS), disease status at time of HCT (early, intermediate, advanced), donor type & donor age (HLA-identical sibling, unrelated well-matched 18-32, unrelated well-matched 33-49, unrelated well-matched 50+, unrelated partially- or mismatched 18-32, unrelated partially- or mismatched 33-49, unrelated partially- or mismatched 50+),(12) donor-recipient sex match, donor-recipient cytomegalovirus (CMV) serological status, use of total body irradiation in the regimen, graft source (bone marrow, peripheral blood mobilized stem cells), and GVHD prophylaxis (cyclosporine +/- others, and tacrolimus +/- others). The product limit estimator proposed by Kaplan-Meier was used to estimate the median and range of the follow-up time. The probabilities of OS and DFS for all patients were calculated using the Kaplan-Meier estimator, with the variance estimated by Greenwood’s formula. Cumulative incidence estimates were calculated for other endpoints to account for competing risks. Nonrelapse death was a competing risk in the estimation of malignancy relapse, death without chronic GVHD was a competing risk for estimation of chronic GVHD, and relapse was a competing risk for estimation of TRM. SAS version 9.4 (SAS Institute, Cary, NC) was used for all the analyses.
RESULTS
7
Patients Between 1999 and 2012, 2,905 un-manipulated blood (66%) or marrow (34%) sibling (24%) or unrelated donor (76%) allograft recipients with AML (56%), ALL (30%) or MDS (14%) developed grade II-IV acute GVHD. Conditioning was myeloablative in all cases. Among the 1,759 patients who received TBIbased conditioning, 1326 (75%) received CY/TBI, 210 (12%) received CY/TBI/others, and 153 (9%) received TBI/Etoposide. Among the 1,146 patients who did not receive TBI as a part of their conditioning regimen, 691 (60%) received BU/CY, 114 (10%) received BU/CY/others, and 295 (26%) received BU/FLU as their regimen. Donor, recipient, and transplant characteristics are summarized in Table 1. Median follow-up for surviving patients was 144 (4-174), 97 (4-147) and 60 (8-99) months for 19992001, 2002-2005, and 2006-2012 periods respectively. Of the 1077 patients receiving cyclosporine-based GVHD prophylaxis, 922 (86%) also received methotrexate (MTX) while 56 (5%) received mycophenolate mofetil (MMF); 28 of these received both MTX and MMF. The remainder mostly received cyclosporine alone +/- steroids (n=87, or 8%). Of the 1,767 patients who received Tacrolimusbased GVHD prophylaxis, 1376 (78%) also received MTX while 229 (13%) received MMF; 63 of these received both MTX and MMF. The remainder mostly received tacrolimus with sirolimus (n=99, or 6%). Other infrequent approaches were seen in both groups on the order of < 1-2% of total each. Trends in GVHD prophylaxis, in this patient population that developed aGVHD, favored predominant use of tacrolimus-based approaches in the later time period. When compared to cyclosporine-based GVHD prophylaxis, recipients of tacrolimus-based GVHD prophylaxis were comparable, but were more likely to have received a well-matched unrelated donor across all time periods (p
Improved survival after acute graft vs. host disease diagnosis in the modern era by Hanna J. Khoury, Tao Wang, Michael T. Hemmer, Daniel Couriel, Amin Alousi, Corey Cutler, Mahmoud Aljurf, Joseph H. Antin, Mouhab Ayas, Minoo Battiwalla, Jean-Yves Cahn, Mitchell Cairo, Yi-Bin Chen, Robert Peter Gale, Shahrukh Hashmi, Robert J. Hayashi, Madan Jagasia, Mark Juckett, Rammurti T Kamble, Mohamed Kharfan-Dabaja, Mark Litzow, Navneet Majhail, Alan Miller, Taiga Nishihori, Muna Qayed, Helene Schoemans, Harry C. Schouten, Gérard Socié, Jan Storek, Leo Verdonck, Ravi Vij, William A. Wood, Lolie Yu, Rodrigo Martino, Matthew Carabasi, Christopher Dandoy, Usama Gergis, Peiman Hematti, Melham Solh, Kareem Jamani, Leslie Lehmann, Bipin Savani, Kirk R. Schultz, Baldeep M. Wirk, Stephen Spellman, Mukta Arora, and Joseph Pidala Haematologica 2017 [Epub ahead of print] Citation: Khoury HJ, Wang T, Hemmer MT, Couriel D, Alousi A, Cutler C, Aljurf M, Antin JH, Ayas M, Battiwalla M, Cahn J-Y, Cairo M, Chen Y-B, Gale RP, Hashmi S, Hayashi RJ, Jagasia M, Juckett M, Kamble RT, Kharfan-Dabaja M, Litzow M, Majhail N, Miller A, Nishihori T, Qayed M, Schoemans H, Schouten HC, Socié G, Storek J, Verdonck L, Vij R, Wood WA, Yu L, Martino R, Carabasi M, Dandoy C, Gergis U, Hematti P, Solh M, Jamani K, Lehmann L, Savani B, Schultz KR, Wirk BM, Spellman S, Arora M, and Pidala J. Improved survival after acute graft vs. host disease diagnosis in the modern era. Haematologica. 2017; 102:xxx doi:10.3324/haematol.2016.156356 Publisher's Disclaimer. E-publishing ahead of print is increasingly important for the rapid dissemination of science. Haematologica is, therefore, E-publishing PDF files of an early version of manuscripts that have completed a regular peer review and have been accepted for publication. E-publishing of this PDF file has been approved by the authors. After having E-published Ahead of Print, manuscripts will then undergo technical and English editing, typesetting, proof correction and be presented for the authors' final approval; the final version of the manuscript will then appear in print on a regular issue of the journal. All legal disclaimers that apply to the journal also pertain to this production process.
Improved survival after acute graft vs host disease diagnosis in the modern era Hanna J. Khoury1, Tao Wang2,3, Michael T. Hemmer2, Daniel Couriel4, Amin Alousi5, Corey Cutler6, Mahmoud Aljurf7, Joseph H. Antin6, Mouhab Ayas7, Minoo Battiwalla8, Jean-Yves Cahn9, Mitchell Cairo10, Yi-Bin Chen11, Robert Peter Gale12, Shahrukh Hashmi13,14, Robert J. Hayashi15, Madan Jagasia16, Mark Juckett17, Rammurti T. Kamble18, Mohamed Kharfan-Dabaja19, Mark Litzow13, Navneet Majhail20, Alan Miller18, Taiga Nishihori19, Muna Qayed21, Helene Schoemans22, Harry C. Schouten23, Gerard Socie24, Jan Storek25, Leo Verdonck26, Ravi Vij27, William A. Wood28, Lolie Yu29, Rodrigo Martino30, Matthew Carabasi31, Christopher Dandoy32, Usama Gergis33, Peiman Hematti17, Melham Solh34, Kareem Jamani25, Leslie Lehmann35, Bipin Savani16, Kirk R. Schultz36, Baldeep M. Wirk37, Stephen Spellman38, Mukta Arora39, Joseph Pidala19 1
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA; 2CIBMTR (Center for International Blood and Marrow Transplant Research), Department of Medicine, Medical College of Wisconsin, Milwaukee, WI; 3Division of Biostatistics, Institute for Health and Society, Medical College of Wisconsin, Milwaukee, WI; 4Utah Blood and Marrow Transplant Program-Adults, Salt Lake City, Utah; 5Department of Stem Cell Transplantation, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX; 6Center for Hematologic Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; 7Department of Pediatric Hematology Oncology, King Faisal Specialist Hospital Center & Research, Riyadh, Saudi Arabia; 8Hematology Branch, National Heart, Lung and Blood Institute-NIH, Bethesda, MD; 9Department of Hematology, University Hospital, Grenoble, France; 10Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Department of Pediatrics, New York Medical College, Valhalla, NY; 11 Division of Hematology/Oncology, Massachusetts General Hospital, Boston, MA; 12Hematology Research Centre, Division of Experimental Medicine, Department of Medicine, Imperial College London, London, United Kingdom; 13Department of Internal Medicine, Mayo Clinic Rochester, Rochester, MN; 14 Department of Oncology, King Faisal Specialist Hospital Center & Research, Riyadh, Saudi Arabia; 15 Division of Pediatric Hematology/Oncology, Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO; 16Division of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN; 17Division of Hematology/Oncology/Bone Marrow Transplantation, Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, WI; 18Division of Hematology and Oncology, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX; 19Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; 20Blood & Marrow Transplant Program, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; 21Department of Pediatrics, Emory University School of Medicine, Atlanta, GA; 22 University Hospital of Leuven, Leuven, Belgium; 23Department of Hematology, Academische Ziekenhuis, Maastricht, Netherlands; 24Department of Hematology, Hopital Saint Louis, Paris, France; 25 Department of Medicine, University of Calgary, Calgary, AB, Canada; 26Isala Clinics Zwolle, The Netherlands; 27Division of Hematology and Oncology, Washington University School of Medicine, St. Louis, MO; 28Division of Hematology/Oncology, Department of Medicine, University of North Carolina, Chapel Hill, NC; 29Division of Hematology/Oncology &HSCT, The Center for Cancer and Blood Disorders, Children’s Hospital/Louisiana State University Medical Center, New Orleans, LA; 30Division of Clinical Hematology, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain; 31Thomas Jefferson University Hospital, Philadelphia, PA; 32Cincinnati Children’s Hospital Medical Center, Cincinnati, OH; 33 Hematologic Malignancies & Bone Marrow Transplant, Department of Medical Oncology, New York Presbyterian Hospital/Weill Cornell Medical Center, New York, NY; 34The Blood and Marrow Transplant Group of Georgia, Northside Hospital, Atlanta, GA; 35Dana Farber Cancer Institute/ Boston Children’s Hospital, Boston, MA; 36Department of Pediatric Hematology, Oncology and Bone Marrow Transplant, British Columbia’s Children’s Hospital, The University of British Columbia, Vancouver, BC, Canada; 37Division of Bone Marrow Transplant, Seattle Cancer Care Alliance, Seattle, WA;
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CIBMTR(Center for International Blood and Marrow Transplant Research), National Marrow Donor Program/Be the Match, Minneapolis, MN; 39Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota Medical Center, Minneapolis, MN
Corresponding Author:
Joseph Pidala, MD, PhD Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL 813-745-2556 [email protected] Abstract: 247 words Manuscript: 2,539 words Total figures and tables: 6
Running Head: Outcomes of acute GVHD over time Keywords: outcomes, grades II-IV acute graft-versus-host disease, allogeneic transplantation Key points: 1) Grade III-IV acute GVHD has decreased over time. 2) Overall survival has improved following grade II-IV acute GVHD diagnosis for transplant recipients treated with tacrolimus
Disclaimer: Presented as a poster at the Annual Meeting of the American Society of Hematology in December 2015
2
ABSTRACT Acute graft vs. host disease remains a major threat to successful outcome after allogeneic hematopoietic cell transplantation. While improvements in treatment and supportive care have occurred, it is unknown whether these advances have resulted in improved outcome specifically among those diagnosed with acute graft vs. host disease. We examined outcome following diagnosis of grade II-IV acute graft vs. host disease according to time period, and examine effects according to original graft vs. host disease prophylaxis regimen and maximum overall grade of acute GVHD. Between 1999 and 2012, 2,905 patients with acute myeloid leukemia (56%), acute lymphoblastic leukemia (30%) or myelodysplastic syndromes (14%) received sibling (24%) or unrelated donor (76%) blood (66%) or marrow (34%) transplant and developed grades II-IV acute graft vs. host disease (n=497 for 1999-2001, n=962 for 20022005, n=1,446 for 2006-2010). Median follow-up was 144 (4-174), 97 (4-147) and 60 (8-99) months for 1999-2001, 2002-2005, and 2006-2010, respectively. Among the grade II-IV acute graft vs. host disease cohort, there was a decrease in the proportion of grades III-IV acute graft vs. host disease over time with 56%, 47% , and 37% for 1999-2001, 2002-2005, and 2006-2012, respectively (p99.9% concordance between the 8/8 and well-matched and ≤ 7/8 and partially or mismatched groups.
Study Endpoints The primary endpoint was OS, defined as by death from any cause. Secondary endpoints considered were the following:
DFS, defined as survival in continuous complete remission; TRM,
defined as death in continued remission; malignancy relapse, defined as recurrence of the malignancy for which HCT was performed; and chronic GVHD.(11) All endpoints were estimated from date of acute GVHD onset, as exact date of maximal grade II-IV acute GVHD was not collected.
Statistical Analysis
Included patients were divided into three cohorts based on the year of transplant (1999-
2001, 2002-2005, 2006-2012). Univariate analysis compared the outcomes of OS, DFS, TRM, relapse and chronic GVHD incidence between these three cohorts. Multivariate analyses were performed using the Cox proportional hazards regression models. All the clinical variables were tested for the affirmation of the proportional hazards assumption. Factors violating the proportional hazards assumption were adjusted through stratification. Then a stepwise model selection procedure was used to identify clinical variables that were associated with each particular outcome with a threshold of 0.05 for
6
both entry and stay in the model. Interactions between the main variable ‘Year of transplant’ and the adjusted covariates were tested, and no significant interactions between the ‘Year of transplant’ and the adjusted covariates were detected at the significance level of 0.01 in any of the models. A significant center effect was detected for the outcomes of OS and TRM for those with grade II-IV acute GVHD only among those treated with CsA, and adjustment for this effect was performed. Potential covariates included patient age (by decades), sex and race (Caucasian, African American, Other), Karnofsky performance status (< 90%, ≥ 90%), time from diagnosis to HCT (< 2 weeks, 2 weeks – 1 month, 2 months – 100 days) , disease (AML, ALL, MDS), disease status at time of HCT (early, intermediate, advanced), donor type & donor age (HLA-identical sibling, unrelated well-matched 18-32, unrelated well-matched 33-49, unrelated well-matched 50+, unrelated partially- or mismatched 18-32, unrelated partially- or mismatched 33-49, unrelated partially- or mismatched 50+),(12) donor-recipient sex match, donor-recipient cytomegalovirus (CMV) serological status, use of total body irradiation in the regimen, graft source (bone marrow, peripheral blood mobilized stem cells), and GVHD prophylaxis (cyclosporine +/- others, and tacrolimus +/- others). The product limit estimator proposed by Kaplan-Meier was used to estimate the median and range of the follow-up time. The probabilities of OS and DFS for all patients were calculated using the Kaplan-Meier estimator, with the variance estimated by Greenwood’s formula. Cumulative incidence estimates were calculated for other endpoints to account for competing risks. Nonrelapse death was a competing risk in the estimation of malignancy relapse, death without chronic GVHD was a competing risk for estimation of chronic GVHD, and relapse was a competing risk for estimation of TRM. SAS version 9.4 (SAS Institute, Cary, NC) was used for all the analyses.
RESULTS
7
Patients Between 1999 and 2012, 2,905 un-manipulated blood (66%) or marrow (34%) sibling (24%) or unrelated donor (76%) allograft recipients with AML (56%), ALL (30%) or MDS (14%) developed grade II-IV acute GVHD. Conditioning was myeloablative in all cases. Among the 1,759 patients who received TBIbased conditioning, 1326 (75%) received CY/TBI, 210 (12%) received CY/TBI/others, and 153 (9%) received TBI/Etoposide. Among the 1,146 patients who did not receive TBI as a part of their conditioning regimen, 691 (60%) received BU/CY, 114 (10%) received BU/CY/others, and 295 (26%) received BU/FLU as their regimen. Donor, recipient, and transplant characteristics are summarized in Table 1. Median follow-up for surviving patients was 144 (4-174), 97 (4-147) and 60 (8-99) months for 19992001, 2002-2005, and 2006-2012 periods respectively. Of the 1077 patients receiving cyclosporine-based GVHD prophylaxis, 922 (86%) also received methotrexate (MTX) while 56 (5%) received mycophenolate mofetil (MMF); 28 of these received both MTX and MMF. The remainder mostly received cyclosporine alone +/- steroids (n=87, or 8%). Of the 1,767 patients who received Tacrolimusbased GVHD prophylaxis, 1376 (78%) also received MTX while 229 (13%) received MMF; 63 of these received both MTX and MMF. The remainder mostly received tacrolimus with sirolimus (n=99, or 6%). Other infrequent approaches were seen in both groups on the order of < 1-2% of total each. Trends in GVHD prophylaxis, in this patient population that developed aGVHD, favored predominant use of tacrolimus-based approaches in the later time period. When compared to cyclosporine-based GVHD prophylaxis, recipients of tacrolimus-based GVHD prophylaxis were comparable, but were more likely to have received a well-matched unrelated donor across all time periods (p
