Biol Blood Marrow Transplant 25 (2019) 23982407 Biology of Blood and Marrow Transplantation journal homepage: www.bbmt.org Comparison of High Doses of Total Body Irradiation in Myeloablative Conditioning before Hematopoietic Cell Transplantation Mitchell Sabloff1, Saurabh Chhabra2,3,*, Tao Wang2,4, Caitrin Fretham5, Natasha Kekre6, Allistair Abraham7, Kehinde Adekola8, Jeffery J. Auletta9, Christopher Barker10, Amer M. Beitinjaneh11, Christopher Bredeson6, Jean-Yves Cahn12, Miguel Angel Diaz13, Cesar Freytes14, Robert Peter Gale15, Siddhartha Ganguly16, Usama Gergis17, Eva Guinan18, Betty K. Hamilton19, Shahrukh Hashmi20,21, Peiman Hematti22, Gerhard Hildebrandt23, Leona Holmberg24, Sanghee Hong25, Hillard M. Lazarus26, Rodrigo Martino27, Lori Muffly28, Taiga Nishihori29, Miguel-Angel Perales30, Jean Yared31, Shin Mineishi32, Edward A. Stadtmauer33, Marcelo C. Pasquini2, Alison W. Loren34 1 Division of Hematology, Department of Medicine, University of Ottawa and Ottawa Hospital Research Institute, Ottawa, Canada 2 Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, Wisconsin 3 Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin 4 Division of Biostatistics, Institute of Health and Equity, Medical College of Wisconsin, Milwaukee, Wisconsin 5 Center for International Blood and Marrow Transplant Research, National Marrow Donor Program/Be the Match, Minneapolis, Minnesota 6 The Ottawa Hospital Blood and Marrow Transplant Program and the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada 7 Division of Blood and Marrow Transplantation, Center for Cancer and Blood Disorders, Children's National Medical Center, Washington, DC 8 Division of Hematology/Oncology, Department of Medicine and Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 9 Blood and Marrow Transplant Program and Host Defense Program, Divisions of Hematology/Oncology/Bone Marrow Transplant and Infectious Diseases, Nationwide Children's Hospital, Columbus, Ohio 10 Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York 11 Division of Hematology/Oncology, University of Miami, Miami, Florida 12 Department of Hematology, CHU Grenoble Alpes, Grenoble, France 13 Department of Hematology/Oncology, Hospital Infantil Universitario Nino Jesus, Madrid, Spain 14 Adult Blood & Marrow Transplant Program, Texas Transplant Institute, San Antonio, Texas 15 Hematology Research Centre, Division of Experimental Medicine, Department of Medicine, Imperial College London, London, United Kingdom 16 Division of Hematological Malignancy and Cellular Therapeutics, University of Kansas Health System, Kansas City, Kansas 17 Hematolgic Malignancies & Bone Marrow Transplant, Department of Medical Oncology, New York Presbyterian Hospital/Weill Cornell Medical Center, New York, New York 18 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 19 Blood & Marrow Transplant Program, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio 20 Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota 21 Oncology Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia 22 Division of Hematology/Oncology/Bone Marrow Transplantation, Department of Medicine, University of Wisconsin, Madison, Wisconsin 23 Markey Cancer Center, University of Kentucky, Lexington, Kentucky 24 Division of Medical Oncology, Fred Hutchinson Cancer Research Center, Seattle, Washington 25 Department of Medicine, Cleveland Clinic Taussig Cancer Center, Cleveland Ohio 26 Case Western Reserve University, Cleveland, Ohio 27 Divison of Clinical Hematology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain 28 Division of Blood and Marrow Transplantation, Stanford University, Stanford, California 29 Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 30 Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 31 Blood & Marrow Transplantation Program, Division of Hematology/Oncology, Department of Medicine, Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, Maryland 32 Division of Hematology and Oncology, Department of Medicine, Penn State Hershey Medical Center, Hershey, Pennsylvania 33 Division of Hematology/Oncology, Department of Medicine, Abramson Cancer Center, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 34 Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania Financial disclosure: See Acknowledgments on page 2406. * Correspondence and reprint requests: Saurabh Chhabra, MD, MS, Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, 9200 W Wisconsin Avenue, Milwaukee, WI 53226 E-mail address: schhabra@mcw.edu (S. Chhabra). https://doi.org/10.1016/j.bbmt.2019.08.012 1083-8791/© 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. M. Sabloff et al. / Biol Blood Marrow Transplant 25 (2019) 23982407 2399 Article history: A B S T R A C T Received 24 May 2019 Malignancy relapse is the most common cause of treatment failure among recipients of hematopoietic cell trans- Accepted 14 August 2019 plantation (HCT). Conditioning dose intensity can reduce disease relapse but is offset by toxicities. Improvements in radiotherapy techniques and supportive care may translate to better outcomes with higher irradiation doses in Keywords: the modern era. This study compares outcomes of recipients of increasing doses of high-dose total body irradia- Total body irradiation tion (TBI) divided into intermediate high dose (IH; 13-13.75 Gy) and high dose (HD; 14 Gy) with standard dose Allogeneic hematopoietic cell (SD; 12 Gy) with cyclophosphamide. A total of 2721 patients ages 18 to 60 years with hematologic malignancies transplantation receiving HCT from 2001 to 2013 were included. Cumulative incidences of nonrelapse mortality (NRM) at 5 years Myeloablative conditioning were 28% (95% confidence interval [CI], 25% to 30%), 32% (95% CI, 29% to 36%), and 34% (95% CI, 28% to 39%) for SD, Hematologic malignancies IH, and HD, respectively (P = .02). Patients receiving IH-TBI had a 25% higher risk of NRM compared with those receiving SD-TBI (12 Gy) (P = .007). Corresponding cumulative incidences of relapse were 36% (95% CI, 34% to 38%), 32% (95% CI, 29% to 36%), and 26% (95% CI, 21% to 31%; P = .001). Hazard ratios for mortality compared with SD were 1.06 (95% CI, .94 to 1.19; P = .36) for IH and .89 (95% CI, .76 to 1.05; P = .17) for HD. The study demon- strates that despite improvements in supportive care, myeloablative conditioning using higher doses of TBI (with cyclophosphamide) leads to worse NRM and offers no survival benefit over SD, despite reducing disease relapse. © 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. INTRODUCTION doses of TBI (>12 Gy) result in improved NRM and lower Relapse of underlying disease is the most frequent cause of relapse rate and therefore improved OS outcomes after alloge- treatment failure after allogeneic hematopoietic cell transplant neic HCT, respectively [28-30]. We queried the Center for (HCT) for hematologic malignancies [1]. Nonrelapse mortality International Blood and Marrow Transplant Research (NRM) accounts for the bulk of the remainder of deaths (20% (CIBMTR) registry to understand whether high-dose TBI would to 30%) [2-5]. One strategy to reduce relapse risk is to intensify translate into improved survival outcomes. We hypothesized the pretransplant conditioning regimen. Several studies have that advances in supportive care and radiation delivery would demonstrated that increasing the intensity of the conditioning reduce toxicity and NRM, thus yielding an OS advantage to regimen can reduce relapse risk [6-9]. Indeed, a prospective higher doses of TBI. randomized trial of myeloablative conditioning (MAC) versus reduced-intensity conditioning for adults with acute myeloid METHODS Data Source leukemia (AML) and myelodysplastic syndrome (MDS) in first The CIBMTR is a research collaboration between the Medical College of remission confirmed that greater conditioning intensity Wisconsin and the National Marrow Donor Program. The CIBMTR comprises resulted in significantly lower relapse risk and improved a network of more than 450 transplant centers worldwide that contribute relapse-free survival [10]. The outcomes after MAC regimens data on allogeneic and autologous HCTs to a centralized statistical center for observational studies [31]. Health information is collected and maintained in of cyclophosphamide (Cy) with total body irradiation (Cy/TBI) the CIBMTR’s capacity as a public health authority under the Health Insurance and busulfan/Cy after allogeneic HCT for acute and chronic leu- Portability and Accountability Act privacy rules. kemia were compared in a prospective study [11] and demon- strated that the adjusted 3-year overall survival (OS) was Patients higher with Cy/TBI (versus busulfan/Cy with oral busulfan), The study included 2721 adults with AML, ALL, MDS, and chronic myeloid leukemia (CML) receiving Cy/TBI, with TBI at varying doses, as conditioning in although there was no difference in relapse-free survival anticipation of a first allogeneic HCT from a well-matched sibling or unre- between the cohorts. More recently, however, a few observa- lated donor between 2001 and 2013. Either matched siblings or well- tional studies have reported that busulfan/Cy (using intrave- matched or partially matched (7/8) unrelated donors were included. Patients nous busulfan) may offer a survival advantage over Cy/TBI in with inherited syndromes predisposing to acute leukemia, those with central nervous system involvement with disease, and those who received prior patients with AML [12-14], whereas for acute lymphoblastic radiation for any reason were excluded. We defined 3 TBI dose groups: leukemia (ALL) patients, TBI was associated with a lower patients receiving standard dose (12 Gy, SD-TBI), intermediate high dose relapse rate and favorable event-free survival, compared with (13-13.75 Gy, IH-TBI), and high dose (14 Gy, HD-TBI). oral busulfan when combined with Cy [15]. Attempts to fur- ther optimize conditioning regimens have not improved out- Study Endpoints The primary endpoint of the study was NRM, defined as death from any comes except in small, single-center studies [16-20]. cause in continuous remission or death within the first 28 days of transplant Radiation is highly lethal to leukemic cells in a dose-depen- from any cause and was summarized by cumulative incidence estimate with dent fashion [21,22]. This observation led investigators, over 3 relapse as competing risk. Secondary endpoints included OS, defined as time decades ago, to attempt to escalate radiation doses given as from transplant to death from any cause, with surviving patients censored at conditioning before transplant. The use of higher doses of TBI time of last contact, and disease-free survival (DFS), in which events were defined as death or relapse. Relapse was summarized by cumulative inci- (>12 Gy), in combination with chemotherapy, has been dence estimate with NRM as the competing risk. We also sought to evaluate reported in small, single-institution studies [23-26]. The upper the incidence of other forms of toxicity and morbidity after allogeneic HCT limit of TBI dose of 16 Gy was established in combination with including acute and chronic graft-versus-host disease (GVHD), veno- Cy and of 14.4 Gy when used in combination with etoposide. A occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS) of the liver [32,33], and idiopathic pneumonia syndrome (IPS) [34], all diagnosed on the study comparing 12 Gy with 15.75 Gy established that the basis of established criteria. Grading of acute and chronic GVHD was based maximum tolerable dose of TBI with Cy was fractionated TBI at on previously defined consensus criteria [35,36]. a dose of 12 Gy [27]. Although higher doses of radiation were indeed associated with lower relapse risk, this benefit was Statistical Analysis negated by increased NRM, and there was no difference in OS. Patient-, disease-, and transplant-related characteristics were compared among the TBI dose groups using the chi-square test for categorical variables However, in the last 2 decades advances in the delivery of radi- and the Kruskal-Wallis test for continuous variables. Outcomes of 3 TBI dose ation therapy and substantial improvements in supportive groups were compared using log-rank and Gray’s test. NRM was described care raise the question of whether, in the current era, higher using the cumulative incidence function, with relapse as a competing risk, 2400 M. Sabloff et al. / Biol Blood Marrow Transplant 25 (2019) 23982407 according to the method of Fine and Gray [37]. Cumulative incidences of SD-TBI and HD-TBI groups, respectively (P < .001). The HD-TBI GVHD, VOD/SOS, and IPS were evaluated by Fine and Gray’s method of com- group received a lower dose of Cy (median 90 mg/kg versus peting risks as well, with death as competing risk. Disease relapse was also 120 mg/kg in the other 2 groups, P < .001). The SD-TBI group reported using the cumulative incidence function, with NRM as the compet- ing risk. Survival probabilities of OS and DFS were calculated using the had a higher proportion of patients with a matched sibling Kaplan-Meier estimator and compared using the log-rank test. Multivariate donor (43% versus 33% in the other 2 groups, P < .001). analysis was performed using Cox proportional hazards regression models Approximately 17% of patients in all 3 groups received alloge- for OS, DFS, acute GVHD, chronic GVHD, VOD/SOS, and IPS, whereas Fine and neic HCT using a 7/8-matched unrelated donor. With respect Gray subdistribution hazards models [37] were used for relapse and NRM. The following variables were included in the analysis: recipient age, dis- to GVHD prophylaxis, most patients (>98%) received a calci- ease, disease status at HCT, donor type, in vivo T cell depletion, GVHD pro- neurin inhibitor, and most did not receive in vivo T cell deple- phylaxis, Karnofsky performance score (KPS), donor-recipient sex match, and tion. Peripheral blood grafts were used more commonly in the year of transplant. All clinical variables were tested first for the affirmation of HD-TBI group (76%) compared with both the SD-TBI (71%) and the proportional hazards assumption. Factors violating the proportional haz- ards assumption were adjusted through stratification. Then, a stepwise, for- IH-TBI (65%) groups. ward-backward procedure was performed to select the adjusted clinical variables (with a threshold of .05 for both entry and stay in the model) and to Impact of Conditioning TBI Dose on Post-Transplant build the multivariate models. To account for multiple comparisons, P < .01 was used as the significance level for the main effect. Analysis was also con- Outcomes ducted to evaluate center effect. All analyses were performed using SAS ver- Nonrelapse mortality sion 9.4 (SAS Institute, Cary, NC). Univariate analysis revealed that at 5 years post-HCT, NRM was 28% (95% confidence interval [CI], 25% to 30%) for the SD- RESULTS TBI group, 32% (95% CI, 29% to 36%) for the IH-TBI group, and Patient and Transplant Characteristics 34% (95% CI, 28% to 39%) for the HD-TBI group (P = .02) Patient characteristics across the 3 TBI groups in the study (Table 3). Multivariate modeling using Fine and Gray’s method cohort (N = 2721) are shown in Table 1. Patients in the 3 accounting for competing risks confirmed that TBI dose was groups received TBI doses of 12 Gy (SD-TBI; n = 1745), 13 to statistically significantly associated with NRM (P = .009) 13.75 Gy (IH-TBI; n = 648), and 14 Gy (HD-TBI; n = 328). The (Table 4, Figure 1). Patients receiving IH-TBI (13 to 13.75 Gy) completeness index at 5 years after allogeneic HCT was excel- had a 25% higher risk of NRM compared with those receiving lent (92% to 96%). The HD-TBI group was older and had lower SD-TBI (12 Gy) (P = .007). The HD-TBI group (14 Gy), however, KPSs. AML was the most common indication for allogeneic did not have a significantly increased NRM risk compared with HCT across the cohort and was a more frequent indication in the SD-TBI (P = .03) or IH-TBI (P = .96) groups. Multivariate the HD-TBI group compared with the SD-TBI group (60% ver- analysis also showed older patients (>30 years versus sus 48%, respectively). ALL, in contrast, was less common in <20 years), those with MDS and ALL (versus AML), those with the HD-TBI group versus SD-TBI group (15% versus 37%, unrelated donor (versus matched sibling donor), and those respectively). HD-TBIbased HCTs were reported from 13 cen- who received calcineurin inhibitor/mycophenolate mofetil ters, compared with SD-TBI recipients from 155 centers and (versus calcineurin inhibitor/methotrexate) had a higher NRM IH-TBI recipients from 49 centers. Median follow-up of survi- risk (Supplemental Table S1). In addition, NRM risk improved vors was similar across the groups at 67 to 73 months after with each time period (2011 to 2013 versus 2001 to 2003; haz- allogeneic HCT. ard ratio [HR], .46; P < .0001) over the years. Transplant characteristics are presented in Table 2. Frac- tionated TBI was administered to patients in all 3 groups. The Overall survival IH-TBI group received a median of 8 fractions with a median OS after allogeneic HCT was similar across the 3 TBI dose dose of 165 cGy per fraction, compared with a median of 6 and groups on univariate analysis: 5-year OS was 42% (95% CI, 39% 7 fractions (with median doses of 200 cGy per fraction) in the to 44%), 40% (95% CI, 36% to 44%), and 45% (95% CI, 39% to 50%) Table 1 Patient Characteristics in the Observational Study of Allogeneic Transplant Patients Receiving MAC Regimen of Cy and TBI with Different Doses of TBI Between 2001 and 2013 Characteristics 12 Gy (n = 1745) 13-13.75 Gy (n = 648) 14 Gy (n = 328) P No. of centers 155 49 13 Age, yr, median (range) 39 (18-60) 39 (18-60) 43 (18-60) <.001 Male sex 959 (55) 344 (53) 169 (52) .436 KPS 90%-100% 1197 (69) 405 (63) 190 (58) <.001 Disease <.001 AML 836 (48) 352 (54) 198 (60) ALL 647 (37) 175 (27) 49 (15) CML 202 (12) 89 (14) 50 (15) MDS 60 (3) 32 (5) 31 (9) Disease status before transplant .50 Early 912 (52) 331 (51) 157 (48) Intermediate 421 (24) 164 (25) 78 (24) Advanced 407 (23) 153 (24) 90 (27) Not reported 5 (<1) 0 3 (<1) BMI, kg/m2, median (range) 25 (16-49) 24 (17-49) 27 (17-49) <.001 Values are n (%) unless otherwise defined. Bold P-values denote statistical significance. M. Sabloff et al. / Biol Blood Marrow Transplant 25 (2019) 23982407 2401 Table 2 Transplant Characteristics in The Observational Study of Allogeneic Transplant Patients Receiving MAC Regimen of Cy and TBI at Different Doses Between 2001 and 2013 Characteristics 12 Gy 13-13.75 Gy 14 Gy P (n = 1745) (n = 648) (n = 328) Time from diagnosis to transplant, mo, median (range) 7 (1-252) 7 (2-310) 6 (1-222) .44 Number of fractions, median (range) 6 (2-12) 8 (3-12) 7 (2-8) <.001 TBI dose per fraction, cGy, median (range) 200 (100-600) 165 (108-440) 200 (175-700) <.001 Cy dose, mg/kg, median (range) 120 (34-240) 120 (36-239) 90 (33-206) <.001 Donor type <.001 HLA-identical sibling 746 (43) 216 (33) 109 (33) Matched unrelated (8/8) 694 (40) 313 (48) 164 (50) Partially matched unrelated (7/8) 305 (17) 119 (18) 55 (17) Graft source <.001 Bone marrow 504 (29) 228 (35) 79 (24) Peripheral blood 1241 (71) 420 (65) 249 (76) Donorrecipient sex match .37 Malemale 606 (35) 218 (34) 114 (35) Malefemale 446 (26) 176 (27) 78 (24) Femalemale 347 (20) 125 (19) 55 (17) Femalefemale 338 (19) 128 (20) 81 (25) Not reported 8 (<1) 1 (<1) 0 Donorrecipient cytomegalovirus status .02 -/- 510 (29) 157 (24) 99 (30) -/+ 429 (25) 183 (28) 96 (29) +/- 193 (11) 63 (10) 38 (12) +/+ 527 (30) 207 (32) 76 (23) Not reported 86 (5) 38 (6) 19 (6) Unrelated donor age, yr, median (range) 33 (19-61) 33 (18-58) 32 (19-60) .95 Year of transplant .005 2001-2005 809 (46) 267 (41) 149 (45) 2006-2010 749 (43) 308 (48) 161 (49) 2011-2013 187 (11) 73 (11) 18 (5) Inpatient days, median (range) 29 (<1-123) 32 (<1-175) 26 (<1-100) Follow-up of survivors, mo, median (range) 72 (3-167) 67 (4-148) 72 (5-144) Values are n (%) unless otherwise defined. Bold P-values denote statistical significance. in the SD-TBI, IH-TBI, and HD-TBI groups, respectively (P = .39) cumulative incidences of relapse were 36% (95% CI, 34% to (Table 3). The multivariate analysis also showed no significant 38%) in the SD-TBI group, 32% (95% CI, 29% to 36%) in the IH- association between the TBI dose and OS (P = .18) (Table 4, TBI group, and 26% (95% CI, 21% to 31%) in the HD-TBI group Figure 2). The analysis also demonstrated that younger (P < .001) (Table 3). Multivariate analysis showed that HD-TBI patients (<20 years versus >40 years), those with CML (versus recipients had a significantly lower relapse risk compared with AML), those with matched sibling donor (versus unrelated SD-TBI recipients (HR, .69; P = .002) (Table 4, Figure 4). Patients donor), those receiving calcineurin inhibitor/methotrexate with MDS (versus AML) and early (versus intermediate or (versus calcineurin inhibitor/mycophenolate mofetil), and advanced) disease and with matched sibling donor (versus those with KPS  90 (versus <90) had significantly improved unrelated) had a lower risk of relapse (Supplemental Table S3). OS (Supplemental Table S2). OS also improved significantly with each time interval (eg, 2011 to 2013 versus 2001 to 2003; Acute GVHD HR, .6; P < .0001) Univariate analysis revealed 1-year cumulative incidence of grades II to IV acute GVHD in the IH-TBI group was 49% (95% CI, Disease-free survival 45% to 53%) compared with 43% in the SD-TBI group (95% CI, Univariate analysis demonstrated that the 5-year probabil- 40% to 45%) and 42% in the HD-TBI group (95% CI, 37% to 47%; ity of DFS did not differ significantly among TBI dose groups P = .02) (Table 3). On multivariate analysis, TBI dose was not and was 37% (95% CI, 34% to 39%), 35% (95% CI, 32% to 39%), associated with grades II to IV acute GVHD (P = .01) or grades and 40% (95% CI, 35% to 46%) in the SD-TBI, IH-TBI, and HD-TBI III to IV acute GVHD (P = .21) (Table 4). groups, respectively (P = .36) (Table 3). There was no signifi- cant difference in DFS among the 3 TBI dose groups on multi- Chronic GVHD variate analysis (Table 4, Figure 3). On univariate analysis, 5-year cumulative incidence of chronic GVHD was not significantly different among the three Relapse groups: 52% (95% CI, 49% to 54%) in the SD-TBI group, 50% (95% The risk of disease relapse post-HCT differed significantly CI, 46% to 54%) in the IH-TBI group, and 53% (95% CI, 48% to among the TBI dose groups on univariate analysis. The 5-year 59%) in the HD-TBI group (P = .68) (Table 3). However, 2402 M. Sabloff et al. / Biol Blood Marrow Transplant 25 (2019) 23982407 Table 3 Unadjusted Clinical Outcomes after MAC Allogeneic Transplant Using Matched Sibling and Unrelated Donor by TBI Dose (2001-2013) Outcomes 12 Gy 13-13.75 Gy 14 Gy P (n = 1745) (n = 648) Probability (95% CI) (n = 328) Probability (95% CI) VOD/SOS 100-day 5 (4-6) 6 (4-7) 9 (6-12) .09 IPS 2-year 8 (6-9) 8 (6-11) 9 (6-13) .57 Grade II-IV acute GVHD 1-year 43 (40-45) 49 (45-53) 42 (37-47) .02 Grade III-IV acute GVHD 1-year 19 (17-21) 23 (20-26) 20 (16-25) .10 Chronic GVHD 5-year 52 (49-54) 50 (46-54) 53 (48-59) .68 Relapse 1-year 27 (25-29) 25 (22-28) 20 (16-24) .01 5-year 36 (34-38) 32 (29-36) 26 (21-31) <.001* NRM 5-year 28 (25-30) 32 (29-36) 34 (28-39) .02 DFS 5-year 37 (34-39) 35 (32-39) 40 (35-46) .29 OS 5-year 42 (39-44) 40 (36-44) 45 (39-50) .39 Values are probability in percents (95% CI). Bold P-values denote statistical significance. * Significant at P < .01 level. multivariate analysis suggested that the risk of chronic GVHD Compared with 12 Gy TBI, we observed increased NRM with among the 3 cohorts was time dependent. TBI was significantly an intermediate TBI dose of 13 to 13.75 Gy and lower relapse associated with chronic GVHD in the first 8 months post-HCT with a high TBI dose (14 Gy). Although the analysis showed (P = .0001) but not beyond 8 months after HCT (P = .02) (Table 4). significant difference in NRM risk between the SD-TBI and IH- HD-TBI conferred a lower risk of chronic GVHD compared with TBI groups, there was no significant difference in the risk of SD-TBI (HR, .64; P = .0001) early on after allogeneic HCT. NRM between the HD-TBI and the other 2 groups. However, the impact on NRM seemed to be equal once the TBI dose TBI-associated post-transplant organ dysfunction increased beyond SD-TBI: Comparing the NRM risk between On univariate analysis, the 100-day cumulative incidences the HD-TBI and SD-TBI groups in the multivariate model of VOD/SOS after allogeneic HCT were 5% (95% CI, 4% to 6%), 6% showed the HR for death was 1.25 (the same as the HR with (95% CI, 4% to 7%), and 9% (95% CI, 6% to 12%) in the SD-TBI, IH- the IH-TBI compared with the SD-TBI group). It is likely that TBI, and HD-TBI groups, respectively (Table 3). Multivariate the statistical significance was not reached given the small analysis showed TBI dose was not significantly associated with sample size of the HD-TBI group, hindering the power to risk of VOD/SOS (P = .03) (Table 4). TBI dose also had no signifi- detect a difference; a larger population may have shown sig- cant association with IPS after allogeneic HCT, which carried a nificant results. With regards to the relapse model, there is a 2-year cumulative incidence of 8% to 9% in the 3 cohorts linear relationship with increments on the TBI dose: HR (for (Tables 3-4). death) of 1.0 for the SD-TBI group, .92 for the IH-TBI group, and .69 for the HD-TBI group (not statistically significant). Causes of Death With the potentially opposing effects of TBI dose on relapse Relapse of primary disease was the most common cause of and NRM, there was no significant difference observed in OS death in all 3 groups (Table 5). However, there were more and DFS among the TBI dose groups in the study. relapse-related deaths with SD-TBI (55%) compared with the There was no statistically significant difference in the risk of other 2 groups (47% in the IH-TBI group and 40% in the HD-TBI grades II to IV or III to IV acute GVHD. Furthermore, no associa- group). The proportion of deaths due to organ failure increased tion of TBI dose with the risk of IPS was found. The risk of with higher doses of TBI (19% in the HD-TBI group and 9% in chronic GVHD (in the early post-HCT period) was lower in the SD-TBI group). Respiratory and multiorgan failure were patients receiving HD-TBI, an unexpected finding, particularly most common, followed by heart failure and hepatic dysfunc- given the absence of significant difference in acute GVHD risk. tion (Table 6). Although there is no good explanation for having an increased risk of chronic GVHD after SD-TBI compared with higher doses, DISCUSSION one possibility is that SD-TBI patients received early interven- This contemporary observational study compared MAC tions to prevent or treat relapse, such as withdrawal of immuno- regimens containing Cy combined with 3 TBI dose groups in suppression or donor leukocyte infusions, which would then be allogeneic HCT recipients with AML, ALL, CML, and MDS. The expected to result in increased risk of early-onset chronic GVHD. HD-TBI group had a more frequent use of peripheral blood However, we did not have access to the post-transplant data to graft and unrelated donors, had fewer patients with KPS > 90, support this hypothesis. There is also a possibility of residual and had a higher median age: All variables were included in confounding by other variables that were not included in the multivariate modeling to account for the baseline differences. analysis such as post-transplant therapeutic interventions. The M. Sabloff et al. / Biol Blood Marrow Transplant 25 (2019) 23982407 2403 Table 4 TBI Dose in Multivariate Models of Treatment with Cy plus TBI as MAC Regimen for Allogeneic Transplant Using Matched Sibling and Unrelated Donor (2001-2013) Outcome n Events HR Upper Lower P OS TBI dose .18 12 Gy 1732 1024 1.0 13-13.75 Gy 647 394 1.06 .94 1.19 .36 14 Gy 325 190 .89 .76 1.05 .17 14 Gy vs. TBI 13-13.75 Gy (Ref.) .85 .71 1.01 .06 DFS TBI dose .04 12 Gy 1727 1098 1.0 13-13.75 Gy 644 423 1.01 .90 1.13 .90 14 Gy 323 199 .83 .71 .97 .02 14 Gy vs. TBI 13-13.75 Gy (Ref.) .82 .69 .97 .02 NRM TBI dose .009* 12 Gy 1734 486 1.0 13-13.75 Gy 645 215 1.25 1.06 1.48 .007 14 Gy 326 117 1.25 1.02 1.53 .03 14 Gy vs. TBI 13-13.75 Gy (Ref.) .99 .79 1.25 .96 Relapse TBI dose .008* 12 Gy 1737 618 1.0 13-13.75 Gy 646 209 .92 .78 1.08 .29 14 Gy 323 84 .69 .55 .88 .002* 14 Gy vs. TBI 13-13.75 Gy (Ref.) .76 .59 .98 .03 Acute GVHD grades II-IV TBI dosey . . . . . .01 12 Gy 1724 739 1.0 . . . 13-13.75 Gy 640 313 1.15 1.00 1.31 .05 14 Gy 326 137 .85 .71 1.03 .09 14 Gy vs. TBI 13-13.75 Gy (Ref.) .74 .61 .91 .004 Acute GVHD grades III-IV TBI dose .21 12 Gy 1728 329 1.0 13-13.75 Gy 641 148 1.18 .97 1.44 .10 14 Gy 324 66 .96 .73 1.27 .79 14 Gy vs. TBI 13-13.75 Gy (Ref.) .82 .61 1.10 .18 Chronic GVHD TBI dose (8 months) .0001z 12 Gy 1127 622 1.0 13-13.75 Gy 401 205 .83 .71 .97 .02 14 Gy 193 96 .64 .52 .80 .0001* 14 Gy vs. TBI 13-13.75 Gy (Ref.) .78 .61 1.00 .05 TBI dose (>8 months) .02 12 Gy 588 217 1.0 13-13.75 Gy 239 102 1.10 .98 1.24 .12 14 Gy 133 75 1.00 .62 1.62 .99 14 Gy vs. TBI 13-13.75 Gy (Ref.) .91 .51 1.63 .75 VOD/SOS TBI dose .03 12 Gy 1737 88 1.0 13-13.75 Gy 648 36 1.16 .78 1.71 .46 14 Gy 322 30 1.77 1.17 2.69 .007 14 Gy vs. TBI 13-13.75 Gy (Ref.) 1.53 .94 2.49 .08 IPS TBI dose .80 12 Gy 1715 131 1.0 13-13.75 Gy 634 53 1.08 .78 1.49 .63 (continued) 2404 M. Sabloff et al. / Biol Blood Marrow Transplant 25 (2019) 23982407 Table 4 (Continued) Outcome n Events HR Upper Lower P 14 Gy 318 30 1.12 .75 1.67 .57 14 Gy vs. TBI 13-13.75 Gy (Ref.) 1.04 .66 1.63 .87 Bold P-values denote statistical significance. * Significant at P < .01 level. y All patients received Cy with TBI. z Significant at P < .01 level. study demonstrated no significant association between the TBI selection bias by clinicians to target a higher risk patient popu- dose and the risk of IPS after allogeneic HCT. Although the inci- lation with increased TBI dose. However, multivariate analysis dence of VOD/SOS of the liver was higher with higher doses of should account for these differences. Similarly, the analysis TBI, this observation did not meet statistical significance. accounted for the higher proportion of AML patients in the Radiation is a potent antitumor therapy that is not depen- HD-TBI group. The analysis demonstrated significantly better dent on cell cycle, growth, or metabolism and is not affected OS in CML patients (versus AML; HR, .8; P = .006); MDS patients by common methods of chemotherapy resistance such as experienced higher NRM (versus AML; HR, 1.82; P = .0001) and P-glycoprotein pumps [38-40], and so chemotherapy-resistant lower relapse risk (versus AML; HR, .45; P < .0001) on multi- clones may still be radiosensitive [41]. Furthermore, radiation variate analysis. With regards to donorrecipient HLA match- is directly toxic to hematopoietic stem cells [21,22] and can ing, because the proportion of 7/8-matched unrelated donors reach potential sanctuary sites such as testis and brain [41], was similar across all 3 groups and our multivariate analysis making TBI an important component of the conditioning regi- adjusted for degree of HLA matching, this small group of mens before allogeneic HCT for treatment of hematologic patients is unlikely to have altered our results. It is worth not- malignancies. TBI has traditionally been a part of MAC regi- ing that we tested for interaction between the TBI dose and mens with the objective of eradicating malignant cells and disease type, disease risk, and all other variables for each end- also providing the immunosuppression needed to prevent point and found none. The study covered a period of 14 years, rejection of donor hematopoietic cells [41]. Dose escalation of and, as expected, patients receiving allogeneic HCT in more TBI in MAC has been investigated and demonstrated to be fea- recent years experienced significantly less NRM (36% better in sible with acceptable NRM in several single-center studies 2008 to 2010 and 54% improvement in 2011 to 2013 as com- [23,24,26]. Myeloablative TBI dose cohorts have been com- pared with 2001 to 2003, respectively) and OS (23% and 40% pared in a few studies and have shown reduced relapse risk of improvement over 2001 to 2003, respectively) (Supplemental AML [27,42], CML [43], and ALL [44] with higher dose TBI in Tables S1 and S2). The lack of significant interaction between the conditioning. A randomized study by Clift et al. [42] pub- the TBI dose and the categorical variable of year of HCT indi- lished in 1990s evaluated a conditioning regimen of Cy cates that the improvement in NRM over time has been 120 mg/kg in combination with TBI 15.75 Gy with 7 consecu- observed in all TBI-based MAC allogeneic HCTs regardless of tive daily fractions of 2.25 Gy (n = 37) and demonstrated a the TBI dose. Stated differently, the results suggest that despite lower relapse risk compared with TBI 12 Gy with 6 consecutive the improvement in supportive care over the years, which daily fractions of 2 Gy (n = 34) in patients with AML in first may allow for a higher dose of TBI, NRM continues to be higher complete remission. The 3-year probabilities of relapse were with HD-TBI. 35% for the 12-Gy group and 12% for the 15.75-Gy group This study has many limitations, including those inherent (P = .06). However, the 3-year NRM was 12% and 32% for the 2 with the retrospective nature of the study arising from non- respective groups (P = .04). In essence, the increased dose of random assignment to the TBI groups, institutional variability TBI significantly reduced the probability of relapse but did not in TBI dosing and fractionation, and variation in Cy dosing (the improve OS because of increased NRM. HD-TBI group had a lower median Cy dose to allow a higher Baseline demographics show the HD-TBI recipients were TBI dose) (Table 2). It is important to point out that the reason older, with poorer KPS: This suggests the possibility of for selecting the doses of TBI is not known; the TBI doses were Figure 1. Cumulative incidence function of NRM by dose of TBI. M. Sabloff et al. / Biol Blood Marrow Transplant 25 (2019) 23982407 2405 Figure 2. Kaplan-Meier curve of OS by dose of TBI. Figure 3. Kaplan-Meier curves of DFS by dose of TBI. Figure 4. Cumulative incidence function of relapse by dose of TBI. most likely decided by the institutions as a matter of prefer- much smaller number of HD-TBI conditioned transplant in the ence and were likely not based on the disease risk category, as recent time periods (6% in 2011 to 2013 versus 12% in 2001 to evident from Table 1. Nonetheless, we cannot exclude poten- 2005 versus 13% in 2006 to 2010) may indicate that this bias is tial selection bias in the higher dose TBI groups and residual present (Table 1). From a radiobiologic perspective, a major confounding that could not be addressed by the analysis. The shortcoming of this analysis is anchoring the analysis on total 2406 M. Sabloff et al. / Biol Blood Marrow Transplant 25 (2019) 23982407 Table 5 HCT. Developing safer methods to deliver radiation, and spar- Causes of Death after MAC Allogeneic Transplant Using Cy and TBI as Condi- ing sensitive organs, continues to be an important area of tioning by TBI Dose (2001-2013) research to maximize the effectiveness of high-dose TBI in Cause of Death 12 Gy 13-13.75 Gy 14 Gy allogeneic HCT recipients. (n = 1034) (n = 395) (n = 192) Primary disease 564 (55) 184 (47) 77 (40) ACKNOWLEDGMENTS New malignancy 9 (1) 4 (1) 3 (2) The authors thank Jennifer Motl for editorial support in GVHD 112 (11) 63 (16) 24 (13) accordance with Good Publication Practice guidelines (http:// Interstitial pneumonitis 52 (5) 15 (4) 9 (5) www.ismpp.org/gpp3). Infection 131 (13) 47 (12) 27 (14) Financial disclosure: The CIBMTR is supported primarily by Organ failure 96 (9) 46 (12) 37 (19) Public Health Service Grant/Cooperative Agreement Other cause 62 (6) 29 (7) 13 (7) 5U24CA076518 from the National Cancer Institute (NCI), the Not reported 8 (1) 7 (2) 2 (1) National Heart, Lung, and Blood Institute (NHLBI), and the Values are n (%). National Institute of Allergy and Infectious Diseases; a grant/ cooperative agreement (1U24HL138660) from the NHLBI and Table 6 NCI; a contract (HHSH250201700006C) with Health Resources Organ Failure as Cause of Death after MAC Allogeneic Transplant Using Cy and and Services Administration; grants N000141712388, TBI as Conditioning by TBI Dose (2001-2013) N000141712850, and N000141812045 from the Organ 12 Gy 13-13.75 Gy 14 Gy Office of Naval Research (HHSH250201700006C); and grants Liver (n = 21) 10 7 4 from Adaptive Biotechnologies; *Amgen, Inc.; Anonymous VOD/SOS (n = 14) 4 4 6 donation to the Medical College of Wisconsin; Astellas Pharma Cardiac (n = 28) 17 8 3 US; Atara Biotherapeutics, Inc.; Be the Match Foundation; Pulmonary (n = 61) 36 10 15 *bluebird bio, Inc.; *Bristol Myers Squibb Oncology; *Celgene Central nervous system (n = 5) 3 2 0 Corporation; *Chimerix, Inc.; *CytoSen Therapeutics, Inc.; Fred Renal (n = 6) 4 0 2 Hutchinson Cancer Research Center; Gamida Cell Ltd.; Gilead Multiple organ (n = 39) 20 13 6 Sciences, Inc.; HistoGenetics, Inc.; Immucor; *Incyte Corpora- Other (n = 4) 1 2 1 tion; Janssen Scientific Affairs, LLC; *Jazz Pharmaceuticals, Inc.; Karius, Inc.; Karyopharm Therapeutics, Inc.; *Kite Pharma, Inc.; Medac, GmbH; *Mediware; The Medical College of Wis- TBI dose; we were unable to incorporate dose rate and/or pro- consin; *Merck & Co, Inc.; *Mesoblast; MesoScale Diagnostics, tractionation. These fundamental variables are known to be Inc.; Millennium, the Takeda Oncology Co.; *Miltenyi Biotec, associated with the biologic consequences of ionizing radiation Inc.; Mundipharma EDO; National Marrow Donor Program; exposure, and interpreting the data in the absence of these Novartis Pharmaceuticals Corporation; PCORI; *Pfizer, Inc; variables can be difficult. This variability in clinical practice *Pharmacyclics, LLC; PIRCHE AG; *Sanofi Genzyme; *Seattle with regards to the use of TBI among centers is exemplified by Genetics; Shire; Spectrum Pharmaceuticals, Inc.; St. Baldrick’s the study by European Society for Blood and Marrow Trans- Foundation; Swedish Orphan Biovitrum, Inc.; *Takeda Oncol- plantation that surveyed 56 centers from 23 countries and ogy; and University of Minnesota. The views expressed in this demonstrated significant differences in the treatment tech- article do not reflect the official policy or position of the nique, dose per fraction, in the organs shielded and the maxi- National Institutes of Health, the Department of the Navy, the mum accepted total delivered dose to those organs [45]. Department of Defense, Health Resources and Services Admin- Furthermore, we did not evaluate TBI dose in combination istration, or any other agency of the US Government. with chemotherapy agents other than Cy such as etoposide, Asterisk indicates corporate members. melphalan, or fludarabine, and this limits the generalizability Conflict of interest statement: There are no conflicts of inter- of the study findings. The question of optimal TBI dose for est to report. other types of allogeneic transplant, such as umbilical cord blood and haploidentical transplants in the myeloablative set- ting, remains unanswered. 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