Biol Blood Marrow Transplant 19 (2013) 123e128 Phase II Trial of 131-Iodine Tositumomab with High-Dose Chemotherapy and Autologous Stem Cell Transplantation for Relapsed Diffuse Large B Cell Lymphoma ASBMT American Society for Blood and Marrow Transplantation Julie M. Vose 1, *, Philip J. Bierman 1, Fausto R. Loberiza 1, Charles Enke 2, Jordan Hankins 3, Robert G. Bociek 1, Wing C. Chan 4, Dennis D. Weisenburger 4, James O. Armitage 1 1 Department of Internal Medicine, Division of Hematology/Oncology, University of Nebraska Medical Center, Omaha, Nebraska 2 Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, Nebraska 3 Department of Radiology, Section of Nuclear Medicine, University of Nebraska Medical Center, Omaha, Nebraska 4 Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska Article history: Received 12 April 2012 Accepted 23 August 2012 Key Words: Radioimmunotherapy Autologous stem cell transplantation Diffuse large B cell lymphoma 131-Iodine tositumomab abstract The purpose of this study was to evaluate the standard outpatient dose of 131-Iodine tositumomab (75 cgy) combined with high-dose carmustine, etoposide, cytarabine, and melphalan (BEAM) followed by autologous stem cell rescue for the treatment of chemotherapy-sensitive relapsed or refractory, or high-risk first complete remission (CR) patients with diffuse large B cell non-hodgkin s lymphoma (DLBCL). Forty patients with chemotherapy-sensitive persistent or relapsed or high/intermediate or high international prognostic index DLCBL were treated in a phase II trial combining 75 cgy 131-Iodine tositumomab with high-dose BEAM followed by autologous stem cell transplantation. The CR rate after transplantation was 78%, and the overall response rate was 80%. Short-term and long-term toxicities were similar to historical control patients treated with BEAM alone. With a median follow-up of 6 years (range, 3-10 years), the 5-year overall survival (OS) was 72% (95% confidence interval [CI], 55%-83%), and the 5-year progression-free survival (PFS) rate was 70% (95% CI, 53%-82%). The PFS and OS were encouraging in this group of chemotherapy-sensitive persistent, relapsed, or high-risk patients with DLBCL. A follow-up phase III trial with 131-Iodine tositumomab/beam vs rituximab/beam was planned based on this information. Ó 2013 American Society for Blood and Marrow Transplantation. INTRODUCTION Standard anthracycline-containing chemotherapy regimens combined with rituximab produce a complete remission (CR) in approximately 60% to 80% of patients with diffuse large B cell lymphoma (DLBCL), which is associated with long-term disease-free survival in approximately 40% to 80% of patients depending on the patient characteristics [1-4]. Patients with persistent or recurrent DLBCL after a standard anthracycline-based regimen, rarely have long-term diseasefree survival with standard salvage chemotherapy [5]. This is particularly true in the rituximab era [6]. High-dose chemotherapy with autologous stem cell transplantation (ASCT) for patients with persistent or recurrent DLBCL can achieve longterm disease-free survival in approximately 30% to 60% of patients [7-9]. Lymphomas also demonstrate radiosensitivity in many cases, and localized radiation can be a useful adjunct to the therapy [10]. In addition, total body irradiation (TBI) has also been used as a part of conditioning regimens for stem cell transplantations [11,12]. However, results with standard high-dose chemotherapy and ASCT have not been optimized, and concerns about the use of TBI for short- and long-term side effects have led to alternative methods for transplantation preparative regimens being developed. Monoclonal Abs such as rituximab have recently been added to the transplantation preparative regimen, used Financial disclosure: See Acknowledgments on page 127. * Correspondence and reprint requests: Julie M. Vose, MD, MBA, Neumann M. and Mildred E. Harris, Section of Hematology/Oncology, 987680 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 68198-7680. E-mail address: jmvose@unmc.edu (J.M. Vose). 1083-8791/$ e see front matter Ó 2013 American Society for Blood and Marrow Transplantation. http://dx.doi.org/10.1016/j.bbmt.2012.08.013 before the collection of autologous stem cells, or in the posttransplantation setting as a consolidative therapy [13,14]. Additionally, several pilot trials using radioimmunotherapy either alone or in combination with highdose chemotherapy followed by ASCT have been published [15-17]. In an initial phase I study, high-dose radioimmunotherapy with 131-Iodine tositumomab followed by ASCT was administered to patients with relapsed B cell non- Hodgkin lymphoma (NHL) [15]. In subsequent studies, highdose 131-Iodine tositumomab was given with dose-intense etoposide and cyclophosphamide followed by ASCT in an attempt to substitute the 131-Iodine tositumomab for TBI in the transplantation regimen [17]. The maximum dose in the combination trial that could be administered with etoposide 60 mg/kg and cyclophosphamide 100 mg/kg was a 131- Iodine tositumomab dose of 25 Gy to critical normal organs. The preliminary results from this study were encouraging with the estimated overall survival (OS) and progression-free survival (PFS) of all treated patients at 2 years to be 83% and 68%, respectively. Because the high doses of 131-Iodine tositumomab used with this approach require specialized facilities for the administration and radiation isolation for the patients, it was difficult to perform at some centers. Subsequently, a phase I trial combining standard outpatient dosing of 131-Iodine tositumomab with high-dose chemotherapy for the treatment of resistant NHL was performed [18]. In this trial, patients with chemoresistant NHL demonstrated an unexpectedly high overall response rate of 65% with a median follow-up of 38 months, a PFS of 39%, and an OS rate of 55% [18]. Based upon the promising results in the phase I trial, this phase II trial in patients who were DLBCL transplantation
124 J.M. Vose et al. / Biol Blood Marrow Transplant 19 (2013) 123e128 131-Iodine Tositumomab Dosimetric Dose 131-Iodine Tositumomab Therapeutic Dose (75 cgy) Total Body Dose BEAM Chemotherapy ASCT Day -19 Day -12 Day -6 to -1 Day 0 Figure 1. Schema for 131-Iodine carmustine, etoposide, cytarabine, and melphalan (BEAM) transplantation program. recipients with chemosensitive persistent or relapsed disease was undertaken. PATIENTS AND METHODS Eligibility Patients who were age 19 to 75 years of age with persistent or relapsed DLBCL or who had high intermediate or high-risk disease by International Prognostic Index [19] were eligible. The patients needed to have a Karnofsky Performance Status of 70 to be eligible. Patients had chemotherapysensitive disease, defined as at least a 50% reduction of persistent or relapsed DLBCL according to the criteria in effect at the time of the protocol. Patients were required to have adequate cardiac and pulmonary function, defined as a left ventricular ejection fraction of 45% and a corrected carbon monoxide diffusing capacity of 50%. Additional eligibility criteria included a calculated creatinine clearance of 50 ml/min. Patients needed <20% bone marrow (BM) involvement with lymphoma. Patients needed to have BM with no evidence of myelodysplastic syndrome before entry into the protocol. In addition, the patients needed to be able to collect >1.5 10 6 CD34þ cell/kg peripheral blood progenitor cells for the transplantation. The protocol was approved by the scientific advisory board, radiation safety, and institutional review boards of the University of Nebraska Medical Center. All patients signed appropriate informed consent forms in effect for the study in accordance with the Declaration of Helsinki. Treatment Protocol: Antibody Dosimetric Dose After >1.5 10 6 CD34þ cells/kg peripheral blood progenitor cells were obtained after filgrastim mobilization, the patients received their dosimetric dose of 131-Iodine tositumomab (Figure 1). This was given on day 19 of the transplantation protocol. Orally administered saturated solution of potassium iodide with 2 drops 3 times daily was given for thyroid blockade starting 1 day before the dosimetric dose and was continued for 14 days after the therapeutic dose of 131-Iodine tositumomab. The murine monoclonal anti-cd20 (tositumomab; GlaxoSmithKline, Philadelphia, PA) was radio iodinated with sodium 131-Iodine (specific activity, 296 GBq/mg; New England Nuclear, Boston, MA) by the Iodogen method, purified, and tested as described previously [20]. Patients were premedicated with acetaminophen 650 mg and diphenhydromine 50 mg orally before the administration. Then patients received 450 mg unlabeled tositumomab i.v. followed by a trace labeled 5 mci (35 mg) 131-Iodineelabeled tositumomab dose. Vital signs were recorded every 15 minutes during the Ab administration. All dosimetric and therapeutic administrations were performed in the outpatient cancer treatment area. Within 1 hour after the dosimetric dose of 131-Iodine tositumomab and before urination, a whole body quantitative gamma camera image was obtained for baseline readings. Additional scans were performed on days 2, 3, or 4, and day 6 or 7 after the dosimetric dose. Using this information, the radioactive clearance from each patient was obtained to determine the radioactive millicurie activity of 131-Iodine tositumomab required to deliver the desired therapeutic dose 1 week later. The methodology for determining the patient-specific millicurie activity was performed in accordance with the Medical Internal Radiation Dose Primer for Absorbed Dose Calculations [21]. Therapeutic Infusions One week later, on day 12 of the transplantation protocol, the therapeutic dose of 131-Iodine tositumomab was administered on an outpatient basis. The patients were again premedicated with acetaminophen 650 mg and diphenhydramine 50 mg orally. Subsequently, 450 mg of unlabeled tositumomab was administered i.v. over 1 hour. This was followed by the patient-specific dose calculated for administration based on the whole body gamma camera images. Patients were treated with 75 cgy total body dose 131-Iodine tositumomab. The millicurie dose for the therapeutic dose was calculated based on the actual body weight for patients weighing 137% of their lean body weight and at 137% of the lean body weight for those patients weighing more than 137% of their lean body weight. Vital signs were taken every 15 minutes during the infusion of the Ab. Outpatient release criteria were used from the Nuclear Regulatory Commission guidelines [22]. These criteria authorize patient release according to a dose-based limit, which is the dose to individuals exposed to the patient (<0.5 rem). The dose-based limit addresses the public safety issue of radioactivity, which is governed by the Nuclear Regulatory Commission. High-Dose Chemotherapy Administration Starting on day 6 of the transplantation protocol, patients received carmustine 300 mg/m 2 i.v. On days 5 to 2, they received etoposide 100 mg/m 2 twice daily (8 doses total) and cytarabine 100 mg/m 2 twice daily (8 doses total) i.v., and on day 1, they received melphalan 140 mg/m 2 once i.v. The following day (day 0), the patients received their previously collected unpurged autologous peripheral blood progenitor cells. The patients received hematopoietic growth factors with filgrastim (neupogen, granulocyte colony-stimulating factor) 5 ug/kg subcutaneously starting on day þ7 after the transplantation and continuing until the absolute neutrophil count was 500/mm 3 for 3 consecutive days. Patients received 2 units of irradiated packed RBCs if their hemoglobin was 8 gm/dl and a singledonor irradiated platelet count if their platelet count was <10,000/uL. In addition, they received standard broad-spectrum antibiotic therapy for associated neutropenic fever and antifungal antibiotics for persistent fevers according to a standard transplantation protocol. Evaluation of Toxicity Toxic effects were assessed by using the National Cancer Institute Common Toxicity Criteria, version 3 [23]. Follow-Up Patients were staged for their extent of lymphoma before the stem cell transplantation, at day þ100 after the transplantation, at yearly intervals posttransplantation, and as clinically appropriate. Patients underwent computed tomography scans of the chest, abdomen, and pelvis, physical examinations, complete blood count, and chemistry profiles at these time points. In addition, if the patients had a positive BM at any point, it was repeated, and optional tests also included a positron emission tomography scan. In addition, the patients had a baseline thyroid-stimulating hormone tested, and it was repeated at day þ100 and yearly thereafter. If the patients had evidence of unexplained cytopenias, a BM biopsy for cytogenetics and analysis was obtained. Statistical Analysis The primary objective included the examination of potential efficacy with evaluation of the complete and overall remission rates (ORRs), PFS, and OS. For these purposes, the CR rate was defined as the complete disappearance of all lymph nodes previously >1.5 cm and BM negativity when previously positive. A partial response (PR) was defined as 50% reduction in the bidimensional sum of the products of all lymph nodes. Responses were evaluated according to the 1999 International Workshop Response Criteria [24]. Both PFS and OS were calculated using the Kaplan-Meier method [25]. PFS was defined as all patients who were alive at last follow-up with no documented relapse or progression of their disease. OS was defined as all patients who were alive at their last follow-up whether their disease had progressed or not. A priori power calculations showed that using PFS as the endpoint, assuming an improvement from 40% to 80% PFS, a sample of 40 patients has power of 93% using a 2-sided alpha of 0.05. RESULTS Patient Information Forty patients were entered in the study between March 2000 and September 2005. The characteristics of the patients are summarized in Table 1. The patients ranged in age from 26 to 75 years of age (median, 54 years). All patients had DLBCL, which was confirmed by central pathology review (W.C.C. and D.D.W.). Thirty-five patients (88%) had received prior rituximab, and 9 (22%) had received prior involved field irradiation. Eleven patients (28%) had received 1 prior chemotherapy regimen, 23 (58%) had received 2 prior
J.M. Vose et al. / Biol Blood Marrow Transplant 19 (2013) 123e128 125 Table 1 Patient Characteristics Variable No. of Patients (%) No. of patients 40 Median age in years (range) 54 (26-75) Male sex 25 (62) White race 38 (95) Prior use of rituxan 35 (88) Prior use of radiation 9 (22) No. of prior chemotherapy treatments One 11 (28) Two 23 (58) Three or more 6 (14) Type of prior chemotherapy CHOP 9 (22) R-CHOP 27 (68) Others 4 (10) Ann Arbor staging before transplantation Stage I-II 11 (28) Stage III-IV 14 (35) CR 13 (33) Unknown 2 (4) LDH > normal at transplantation 13 (32) BM involvement at transplantation 1 (2) Extranodal involvement at transplantation 11 (28) Disease stage at transplantation First CR 13 (33) Primary induction failure - chemosensitive 5 (12) Relapse - chemosensitive 22 (55) Median time from diagnosis to transplantation in 15 (5-200) months (range) Less than 1 year 15 (38) Greater than or equal to 1 year 25 (62) Year of transplantation 2000-2001 9 (22) 2002-2003 14 (35) 2004-2005 17 (43) Median time to follow-up among survivors in 6.89 (3.09-11.04) years (range) CHOP indicates cyclophosphamide, doxorubicin, vincristine, prednisone; R- CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; CR, complete response; LDH, lactic dehydrogenase; BM, bone marrow. regimens, and 6 (14%) had received 3 prior regimens. The status at transplantation included patients in primary induction failure (chemosensitive) (N ¼ 5), high-risk CR1 (N ¼ 13), and chemosensitive relapsed disease (N ¼ 22). Toxicity The grade III and IV toxicities are listed in Table 2. All patients had the expected grade III/IV hematologic toxicities severe myelosuppression (neutrophils <0.5 10 9 /L and platelets <20 10 9 /L) during transplantation. However, all patients engrafted with the median time to neutrophil engraftment (the first of 3 consecutive days of 0.5 10 9 /L) 10 days (range, 8-30 days), the median time to platelet independence (the first of 7 consecutive days with a platelet count 20,000/uL) was 12 days (range, 10-100þ days), and the median time to RBC transfusion independence (the first of 30 consecutive days of a hemoglobin 8 gm/dl) was 9 days (range, 8-100þ days). These were similar to 120 historical control patients receiving carmustine, etoposide, cytarabine, and melphalan (BEAM) alone in which the median time to neutrophil engraftment was 11 days (range, 9-35 days), the median time to platelet independence was 12 days (range, 9-100þ days), and the median time to RBC transfusion independence was 10 days (range, 8-100þ days). Nonhematologic toxicity was similar to controls as well, as 7 patients had a bacteremia, and 1 patient had a sepsis syndrome. Five patients had pneumonia, 4 patients had atrial Table 2 Grade III and IV Nonhematologic Toxicities Toxicity Grade III-IV Events (%) of Patients Gastrointestinal: anorexia 2 (5) Diarrhea 2 (5) Esophagitis 2 (5) Hyperbilirubinemia 1 (3) Ileus 2 (5) Nausea/vomiting 2 (5) Stomatitis 6 (16) Cardiac: atrial fibrillation 4 (10) Congestive heart failure 1 (3) Syncope 1 (3) Pulmonary: pneumonia 4 (10) Pleural effusion 1 (3) Infections: bacteremia/sepsis 8 (20) Clostridium difficile colitis 3 (8) Varicella zoster 3 (8) Renal: renal insufficiency 1 (3) Secondary malignancy - AML 2 (5) AML indicates acute myelogenous leukemia. fibrillation, and 1 patient had renal insufficiency. Three patients had grade I to II, and 6 patients had grade III to IV stomatitis. There were no deaths within the first 100 days after the transplantations. Response to Therapy The response rate was assessed at day þ100 after the transplantation. The patients were restaged with physical examination, computed tomography scans, and BM biopsy (when indicated). The CR rate was 31 of 40 (78%), and the ORR was 32 of 40 (80%). OS and PFS With a median follow-up of 6 years (range, 3-10 years), the 5-year PFS was 70% (95% confidence interval [CI] 53%-82%) (Figure 2A), and the 5-year OS was 72% (95% CI, 55%-83%) (Figure 2B). When evaluating the outcomes by pretransplantation response, the 5-year PFS for patients in CR1 was 85% (95% CI, 51-96), first PR (chemosensitive) was 100%, and for relapsed chemosensitive was 54% (95% CI, 32-72) (Figure 3). The 5-year OS for the patients in CR1 was 85% (95% CI, 52-96), first PR was 100%, and relapsed DLBCL was 63% (95% CI, 40-80). For the 10 patients who relapsed 12 months from diagnosis, the 5-year PFS was 38% compared to 58% for those who relapsed >12 months from diagnosis (P ¼.86). For the patients who relapsed 12 months from diagnosis, the 5-year OS was 58% compared to 80% for those who relapsed >12 months (P ¼.25). The causes of death included progressive lymphoma in 9 patients (69%), secondary malignancy (acute myelogenous leukemia [AML]) in 2 patients (15%), bacterial infection in 1 patient (8%), and thromboembolism in 1 patient (8%). Long-Term Complications Two patients developed myelodysplastic syndrome/aml at 13 and 58 months posttransplantation, respectively. They both died from AML. Both patients had cytogenetics abnormalities at the time of myelodysplastic syndrome development consistent with alkylating agent exposure, cumulative chemotherapy, and/or radiotherapy with monosomy 5 and monosomy 7, respectively. One additional patient developed prostate cancer, 1 patient developed anal cancer, and 1 patient developed squamous cell carcinoma of the skin. Nine
126 J.M. Vose et al. / Biol Blood Marrow Transplant 19 (2013) 123e128 Figure 2. (A) Progression-free survival for patients treated with 131-Iodine tositumomab/carmustine, etoposide, cytarabine, and melphalan (BEAM) and autologous stem cell transplantation (ASCT). (B) Overall survival for patients treated with 131-Iodine tositumomab/beam and ASCT. patients developed subclinical hypothyroidism requiring thyroid hormone replacement. DISCUSSION Although initial rituximab containing anthracycline chemotherapy can produce high response rates and longterm disease-free survival in a majority of patients with DLBCL, between 20% and 50% of patients either fail to go into remission or relapse after an initial response [3,4]. In addition, standard salvage chemotherapy is not felt to be curative for patients with DLBCL [5,6]. High-dose chemotherapy and ASCT has produced approximately 40% to 50% long-term survivors in patients with chemotherapy-sensitive relapsed disease [7,9]. If patients are in primary induction failure, but still have disease that is somewhat chemotherapy sensitive, the results with transplantation may be higher at a 30% PFS [8]. The addition of rituximab to the transplantation program has produced excellent long-term outcomes [13,14]. However, as all of the patients with DLBCL are now receiving rituximab as part of their initial therapy, patients who relapse do not seem to benefit from additional rituximab in the posttransplantation setting [26]. Therefore, optimization of transplantation methods is an important area of research to improve these outcomes. Radiolabeled monoclonal Abs have recently emerged as an effective new treatment for patients with relapsed B cell lymphomas [18,27]. Studies using radioimmunotherapy at nonmyeloablative doses have produced response rates of 60% to 80% for 131-Iodine and 90-Yttriumelabeled anti- CD20 Abs [18,27-29]. The median duration of responses varied from 6 to 18 months in these trials; however, some CRs have been maintained for up to 6 to 8 years [29,30]. Because myelosuppression is the major toxicity associated with radioimmunotherapy, it is an ideal candidate to combine with high-dose chemotherapy and ASCT. The majority of the early studies combining radioimmunotherapy with transplantation have included highdose myeloablative 131-Iodine tositumomab either alone [15,16] or in combination with high-dose etoposide and cyclophosphamide [17]. The single agent myeloablative regimen tested in patients with a variety of relapsed lymphomas produced OS and PFS rates of 68% and 42%, respectively [15,16]. The combination regimen of etoposide, cyclophosphamide with myeloablative 131-Iodine tositumomab, and ASCT produced OS and PFS rates of 83% and 68% in patients with chemotherapy-sensitive relapsed NHL [17]. However, a concern with these high-dose 131-Iodine myeloablative regimens is the radiation safety issues and specialized facilities necessary for the administration of these agents. High-dose 90-Yttrium ibritumomab in doses up to 15 Gy to critical organs combined with BEAM has also recently been used as part of a conditioning regimen for ASCT [31].In this study by Winter et al. [31], 44 patients were treated with this combination. With a median follow-up of 33 months for all patients, the estimated 3-year PFS and OS were 43% and 60%, respectively. In another study, high-dose 90-Yttrium ibritumomab tiuxetan was combined with high-dose etoposide 40-60 mg/kg and cyclophosphamide 100 mg/kg [32]. The 90-Yttrium ibritumomab tiuxetan was delivered to a target dose of 1,000 cgy highest dose to a normal organ. In this study, with a median follow-up of 22 months, the 2-year OS and relapse-free survival rates were 92% and 78%, respectively [32]. Figure 3. (A) Progression-free survival for patients who underwent transplantation in first partial response (N ¼ 5), high-risk CR1 (N ¼ 13), or relapsed diffuse large B cell lymphoma (DLBCL) (N ¼ 22). (B) Overall survival for patients who underwent transplantation in first partial response (N ¼ 5), high-risk CR1 (N ¼ 13), and relapsed DLBCL (N ¼ 22).
J.M. Vose et al. / Biol Blood Marrow Transplant 19 (2013) 123e128 127 Several studies using standard dose 90-Yttrium ibritumomab tiuxetan have also been combined with the BEAM protocol (Z-BEAM) in 2 recent studies. In a study from the Groupe d Etude des Lymphomes de l Adulte group, 77 patients with chemosensitive relapsed or refractory indolent lymphoma received this protocol. The 2-year event-free survival and OS were 63% and 97%, respectively, with a good safety profile [33]. A second recent study of Z-BEAM evaluated 43 patients with relapsed CD20þ NHL. Twentytwo patients were randomized to Z-BEAM and 21 patients to BEAM alone [34]. In this small study, the 2-year OS was 91% in the Z-BEAM and 62% in the BEAM arm, respectively (P ¼.05) [34]. The trial outlined in this article was a phase II trial combining standard dose 131-Iodine tositumomab (75 cgy) with a standard BEAM transplantation protocol. A prior phase I pilot trial was conducted in patients with refractory lymphoma and had promising outcomes with a total CR rate of 57% and an ORR of 65% [18]. In the phase I study, with a follow-up of 38 months, the OS was 55%, and the event-free survival was 39%. With those encouraging results, the larger phase II study adding 75 cgy total body dose 131-Iodine tositumomab to BEAM and autologous transplantation in patients with chemotherapy-sensitive relapsed diffuse large B cell lymphoma was conducted. This preparative regimen was shown to be safe and with a promising 5-year PFS of 70% and OS of 72% in this phase II trial. However, it is difficult to compare all of these trials because of the small numbers of patients, different histologies of lymphoma in the trials, and different patient populations. A subsequent large phase III randomized study to compare 131-Iodine tositumomab/beam to rituximab/beam with standard ASCT has been subsequently performed to compare these techniques [35]. In 224 randomized patients with relapsed chemosensitive DLBCL, the 2-year PFS was 49% in the 131-Iodine tositumomab/beam arm compared to 49% in the rituximab/beam arm (P ¼.65). The 2-year OS was also not different between the 2 arms (60% and 66%, respectively) (P ¼.29). Although a large phase III trial with the use of 90-Yttrim ibritumomab has not been conducted to date, a matched-cohort analysis was done comparing Z-BEAM to TBI-based regimens [36]. In this study, the 4-year OS was better for the Z-BEAM protocol compared to the TBI-based regimens (81% vs 53%; P ¼.01). This seemed to mostly be related to higher nonrelapse mortality in the TBI group (0% compared to 15%, P <.01) [36]. 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