Original Article. Cancer August 15,

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1 High-Dose Chemotherapy With Thiotepa, Busulfan, and Cyclophosphamide and Autologous Stem Cell Transplantation for Patients With Primary Central Nervous System Lymphoma in First Complete Remission Zachariah DeFilipp, MD 1 ; Shuli Li, PhD 2 ; Areej El-Jawahri, MD 1 ; Philippe Armand, MD, PhD 3 ; Lakshmi Nayak, MD 4 ; Nancy Wang, MD 5 ; Tracy T. Batchelor, MD 5 ; and Yi-Bin Chen, MD 1 BACKGROUND: High-dose chemotherapy and autologous stem cell transplantation (HDC-ASCT) is a therapeutic option for patients with primary central nervous system lymphoma (PCNSL). To the authors knowledge, data are limited regarding its use among patients in first complete remission (CR1) with the CNS-directed conditioning regimen of thiotepa, busulfan, and cyclophosphamide (TBC). METHODS: A retrospective analysis of patients with PCNSL in CR1 who underwent transplantation using a TBC-based conditioning regimen at 2 academic institutions was performed. RESULTS: Forty-six consecutive patients who underwent HDC-ASCT while in CR1 were identified. The most common induction regimen was high-dose methotrexate plus temozolomide and rituximab (59%). No patients received whole-brain radiotherapy. A total of 40 patients (87%) received cytarabine before undergoing ASCT as either induction intensification, early consolidation therapy, or mobilization. The median time from diagnosis to transplantation was 6 months (range, 4-15 months). The median age of the patients at the time of transplantation was 59 years (range, years). With a median follow-up of 2.7 years after ASCT (range, 6 months-7.5 years), the Kaplan-Meier estimates of 2-year overall survival and progression-free survival were 95% (95% confidence interval [95% CI], 80%-99%) and 92% (95% CI, 77%-97%), respectively. The most common toxicities were severe mucositis (35%) and bacterial infections occurring within 100 days of transplantation (35%). The estimated 2-year nonrecurrence mortality rate was 2.9% (95% CI, 0.2%-13.4%). CONCLUSIONS: HDC-ASCT with a CNS-directed conditioning regimen such as TBC should be considered for patients with PCNSL who are in CR1 because this approach is associated with encouraging disease control and survival in this select patient population. Cancer 2017;123: VC 2017 American Cancer Society. KEYWORDS: autologous stem cell transplantation (ASCT), busulfan, cyclophosphamide, high-dose chemotherapy, primary central nervous system lymphoma (PCNSL), thiotepa. INTRODUCTION Primary central nervous system lymphoma (PCNSL) is a rare but aggressive subtype of non-hodgkin lymphoma (NHL) that historically has been associated with a poor prognosis. 1,2 Greater than 90% of PCNSL cases consist of the diffuse large B-cell type. However, with the introduction of combined modality treatment regimens that incorporate systemic chemotherapy (most commonly high-dose methotrexate based regimens), targeted therapy (rituximab), and/or whole-brain radiotherapy (WBRT), reproducible improvements in outcomes have been achieved. 3-6 Nevertheless, to the best of our knowledge, the optimal approach to consolidation therapy in patients who achieve a first complete remission (CR1) has yet to be determined. WBRT traditionally has been used as consolidative therapy, but is associated with neurotoxicity, especially in the elderly. 7 High-dose chemotherapy and autologous stem cell transplantation (HDC-ASCT) has emerged as an attractive choice for consolidation therapy because it may obviate the need for WBRT. 8 Ongoing randomized clinical trials are investigating the role of HDC-ASCT consolidation therapy compared with WBRT (ClinicalTrials.gov identifiers NCT and NCT ) and nonmyeloablative chemotherapy (ClinicalTrials.gov identifiers NCT and NCT ), respectively. To our knowledge, many important aspects regarding the role of HDC-ASCT in the management of patients with PCNSL remain unknown, including whether HDC-ASCT should be used in patients in CR1 or used within the setting Corresponding author: Yi-Bin Chen, MD, Blood and Marrow Transplant Program, Massachusetts General Hospital, 55 Fruit St, Yawkey 9E-9052, Boston, MA 02114; Fax: (617) ; ychen6@partners.org 1 Blood and Marrow Transplant Program, Massachusetts General Hospital, Boston, Massachusetts; 2 Department of Biostatistics and Computational Biology, Dana- Farber Cancer Institute, Boston, Massachusetts; 3 Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts; 4 Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; 5 Stephen E. and Catherine Pappas Center for Neuro-Oncology, Massachusetts General Hospital, Boston, Massachusetts. DOI: /cncr.30695, Received: March 1, 2017; Revised: March 7, 2017; Accepted: March 8, 2017, Published online April 3, 2017 in Wiley Online Library (wileyonlinelibrary.com) Cancer August 15,

2 of recurrent disease and whether there is an optimal highdose chemotherapy regimen. Given the limited published experience regarding the use of CNS-directed conditioning for patients with PCNSL in CR1, we reviewed outcomes of patients who received HDC-ASCT as consolidation therapy with the use of thiotepa, busulfan, and cyclophosphamide (TBC) in this select population. MATERIALS AND METHODS The current study was approved by the Institutional Review Board at the Dana-Farber/Harvard Cancer Center. All patients aged 18 years with PCNSL who received HDC-ASCT during CR1 using a TBC-based conditioning regimen between 2008 and 2016 at the cancer center of Massachusetts General Hospital and Dana- Farber/Brigham and Women s Cancer Center were identified through institutional databases and protocol registries. CR was defined as per published consensus criteria. 9 Clinical data were extracted from the institutional database and individual medical record of each patient. It is interesting to note that 9 patients were treated as part of a phase 2 trial of high-dose thiotepa, busulfan, and cyclophosphamide and high-dose rituximab with autologous stem cell transplantation for patients with CNS involvement by NHL or PCNSL. 10 Stem Cell Mobilization and Collection Patients underwent stem cell mobilization with either rituximab with high-dose intravenous (IV) cytarabine and filgrastim (R-HiDAC) or filgrastim alone based on physician discretion. The R-HiDAC schema consisted of cytarabine at a dose of 3 g/m 2 IV every 12 hours on days 1 and 2 and rituximab IV at a dose of 375 mg/m 2 on day 1. The dose of cytarabine was routinely reduced by 33% to 2 g/ m 2 for patients aged 60 years. Those patients being treated on the aforementioned phase 2 clinical trial received high-dose rituximab at a dose of 1000 mg/m 2 IV on days 1 and 8 of R-HiDAC. Filgrastim at a dose of 10 lg/kg subcutaneously daily was initiated 24 hours after HiDAC and continued until the completion of stem cell collection. Patients mobilized without chemotherapy and who were off of treatment with filgrastim alone received a dose of 10 lg/kg daily for 5 days. Conditioning Regimen The TBC conditioning regimen consisted of thiotepa at a dose of 250 mg/m 2 IV on days -9, -8, and -7; busulfan at a dose of 0.67 to 0.8 mg/kg every 6 hours IV on days -6, -5, and -4; and cyclophosphamide at a dose of 60 mg/kg IV on days -3 and -2. Busulfan dosing was not directed by pharmacokinetics. In addition, the busulfan dose was reduced to 0.60 mg/kg IV every 6 hours for patients aged >60 years. For those patients who received rituximab as part of the phase 2 trial, rituximab at a dose of 1000 mg/ m 2 was administered on days -9 and -2. Supportive medications, including mesna, levetiracetam, palifermin, ursodiol, and filgrastim, were administered according to the institutional standard. Patients were discharged from the hospital when engraftment had been achieved and their disease was clinically stable without any evidence of active infection. Prophylaxis against varicella zoster and Pneumocystis jirovecii was used as per the institutional standard. Statistical Analysis Patient characteristics were reported descriptively. Neutrophil engraftment was defined as the first of 2 consecutive days with an absolute neutrophil count 500 cells per mm 2. Platelet recovery was defined as the first of 2 consecutive days with a platelet count 20,000 per mm 2. Clinically significant infections were defined by positive culture data, radiographic evidence, or a high level of clinical suspicion. Febrile neutropenia with negative culture data and no identified source was not recorded as an infectious complication. Transient neurotoxicity was defined as short-term events during or after hospitalization that resolved in <7 days. Persistent or late neurotoxicity was defined as any event persisting or occurring after discharge from the hospitalization for transplantation. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. 11 OS was calculated from the date of transplantation to death or censored at the time of last clinical evaluation. PFS was calculated from the date of transplantation to disease progression or death from any cause. Patients who were alive without disease recurrence or progression were censored at the time of last clinical evaluation. Nonrecurrent mortality (NRM) was estimated with disease recurrence and death from disease recurrence as competing risks. RESULTS Patient and Disease Characteristics Forty-six patients with PCNSL who were treated with HDC-ASCT using a TBC-based conditioning regimen while in CR1 were identified. Characteristics of the patients are shown in Table 1. Of these patients, 25 were women and 21 were men. The median age of the patients at the time of diagnosis was 58 years (range, years). All patients had CD20-positive diffuse large B-cell histology. None of the cases was related to the human 3074 Cancer August 15, 2017

3 ASCT for Primary CNS Lymphoma in CR1/DeFilipp et al TABLE 1. Patient and Disease Characteristics Characteristic Value Total no. of patients 46 Sex, no. (%) Female 25 (54) Male 21 (46) Median age at diagnosis (range), y 58 (27-68) DLBCL histology, no. (%) 46 (100) Surgical resection of CNS mass 7 (15) prior to chemotherapy, no. (%) Induction therapy regimen, no. (%) MT-R 27 (59) MTX 1 R 8 (17) MTX 6 (13) R-MPV 5 (11) Received WBRT, no. (%) 0 (0) Received cytarabine prior to ASCT, no. (%) 40 (87) Median time to diagnosis to 6 (4-15) transplantation (range), mo Y of transplantation (39) (61) Abbreviations: ASCT, autologous stem cell transplantation; CNS, central nervous system; DLBCL, diffuse large B-cell lymphoma; MT-R, methotrexate, temozolomide, and rituximab; MTX, methotrexate; R, rituximab; R- MPV, rituximab, methotrexate, procarbazine, and vincristine; WBRT, wholebrain radiotherapy. immunodeficiency virus/acquired immune deficiency syndrome. Seven patients underwent an initial surgical resection of the CNS mass before chemotherapy was initiated. No patients received WBRT. The most common induction regimen was methotrexate (MTX), temozolomide, and rituximab (59%). Other induction therapies included high-dose systemic MTX alone (13%); MTX and rituximab (17%); and rituximab, MTX, procarbazine, and vincristine (11%). In total, all patients received systemic high-dose IV MTX as part of induction therapy and 87% received IV rituximab. Forty patients (87%) received cytarabine before ASCT either as induction intensification, early consolidation therapy, or mobilization. A total of 36 patients underwent consolidation therapy/stem cell mobilization with R-HiDAC and filgrastim, whereas 10 patients underwent mobilization with filgrastim alone. The median time from diagnosis to transplantation was 6 months (range, 4-15 months). Transplantation Outcomes The median age of the patients at the time of transplantation was 59 years (range, years). The median number of CD34-positive cells/kg infused was (range, ). All patients received a TBCbased conditioning regimen (TBC in 37 patients or TBC plus rituximab in 9 patients). The median times to neutrophil engraftment and platelet recovery were 9 days Figure 1. Kaplan-Meier estimates of overall survival (OS) and progression-free survival (PFS) for patients receiving highdose chemotherapy and autologous stem cell transplantation in first complete remission with the use of a conditioning regimen of thiotepa, busulfan, and cyclophosphamide. (range, 7-10 days) and 12 days (range, 9-22 days), respectively. The median length of hospital admission was 22 days (range, days). The median follow-up for survivors was 2.7 years (range, 6 months-7.5 years) after ASCT. Four patients developed recurrent disease at a median of 1.5 years after ASCT (range, 6 months-3.6 years). At the time of last follow-up, 3 patients had died: 1 from recurrent disease and 2 patients from late (>1 year) NRM. The nature of the late NRMs was sepsis due to pneumonia (1 patient) and progressive neurologic decline with multiorgan failure without evidence of disease on magnetic resonance imaging (1 patient). The estimated 2-year NRM rate was 2.9% (95% confidence interval [95% CI], 0.2%-13.4%). The Kaplan-Meier estimates for 2-year OS and PFS were 95% (95% CI, 80%-99%) and 92% (95% CI, 77%- 97%), respectively (Fig. 1). Transplantation-Related Toxicities The transplantation-related toxicities are shown in Table 2. Sixteen patients (35%) developed a documented infection within 100 days after undergoing ASCT. The most common bacterial infection was Clostridium difficile colitis, which occurred in 13 patients. In addition, patients experienced Escherichia coli bacteremia (2 patients), pneumonia (1 patient), and septic thrombophlebitis (1 patient). Viral and fungal infections were rare, with 1 case of cytomegalovirus colitis and 1 case of Candida dubliniensis fungemia reported. The most common noninfectious toxicity was severe mucositis (35%), which was Cancer August 15,

4 TABLE 2. Transplantation-Related Toxicities Among the 46 Patients in the Current Study Infection within 100 d Bacterial, no. (%) 16 (35) Viral, no. (%) 1 (2) Fungal, no. (%) 1 (2) Severe mucositis, no. (%) 16 (35) Engraftment syndrome, no. (%) 8 (17) Busulfan pulmonary toxicity, no. (%) 1 (2) Veno-occlusive disease, no. (%) 0 (0) Diffuse alveolar hemorrhage, no. (%) 0 (0) Hemorrhagic cystitis, no. (%) 0 (0) Transient neurotoxicity, no. (%) 7 (15) Persistent or late neurotoxicity, no. (%) 7 (15) managed with supportive care according to institutional standards. Eight patients (17%) experienced engraftment syndrome, which was managed with a short course of corticosteroids. There was a single case of suspected busulfan-associated pulmonary toxicity. There were no cases of hemorrhagic cystitis or hepatic veno-occlusive disease reported. Seven patients (15%) experienced transient neurotoxicity, which was described as delirium (5 patients) or vertigo (2 patients). Although patients did not receive formal neuropsychological assessments on a standardized schedule, only 7 patients (15%) experienced persistent or late clinical neurotoxicity, which was described as memory loss (2 patients), cognitive deficits (1 patient), or progressive neurologic decline (4 patients). It is interesting to note that 3 of the late neurotoxicity cases were reported in patients after disease recurrence. DISCUSSION Herein we report encouraging outcomes after HDC- ASCT with TBC conditioning for patients with PCNSL in CR1. The combination of limited acute toxicities and good disease control supports this approach for consolidation therapy. The most common acute toxicities experienced were severe mucositis and bacterial infection within 100 days of undergoing ASCT. However, the NRM rate was low (2-year NRM rate of 2.9%) and the 2-year OS and PFS rates were 95% and 92%, respectively. The favorable survival outcomes in this data set may be influenced by several factors in addition to the use of CNSdirected conditioning. First, this analysis focused on outcomes for patients who underwent transplantation during CR1, selecting for a population with good disease control before undergoing HDC-ASCT. Furthermore, a large percentage of patients (87%) received high-dose cytarabine as induction intensification, early consolidation therapy, or as part of stem cell mobilization. Cytarabine, an agent with known disease activity in patients with PCNSL that is commonly used in nonmyeloablative consolidation approaches, 12 may have contributed in part to the better disease control observed in these patients. Therapeutic strategies for PCNSL traditionally have consisted of combinations of WBRT and high-dose MTX, although long-term disease remission with these approaches is reported to be uncommon. 3,13 Efforts to improve disease outcomes and spare patients from the neurocognitive side effects of WBRT led investigators to pursue alternative approaches to consolidation therapy at the time of CR1 among patients with PCNSL. Initial experiences with HDC-ASCT using the conditioning regimen of carmustine, etoposide, cytarabine, and melphalan (BEAM), which is commonly used for patients with recurrent or high-risk NHL, in patients with PCNSL were disappointing This was believed to be in part due to the limited ability of the chemotherapy agents in BEAM to effectively cross the blood-brain barrier. Busulfan and thiotepa, which have excellent penetration into the CNS, have become the backbone of the TBC regimen, the use of which has been reported in the management of patients with PCNSL and secondary CNS lymphoma Several studies have been published to date that used CNS-directed conditioning regimens as consolidative therapy for patients with PCNSL in CR1 (Table 3). 5,16-18,21-23 A recent phase 2 trial treated patients newly diagnosed with PCNSL with the combination of rituximab, MTX, procarbazine, and vincristine followed by HDC- ASCT using TBC conditioning and found excellent disease control (2-year OS and PFS rates of 81% and 81%, respectively), an acceptable toxicity profile, and minimal neurotoxicity on prospective neuropsychological evaluations. 21 Another CNS-directed conditioning regimen has been the combination of carmustine and thiotepa, which has been investigated in several studies. 5,22-24 Concern does exist that TBC conditioning may be associated with a high rate of septic complications compared with the combination of carmustine and thiotepa. 8,17,20,21 Although approximately 35% of patients in the current study experienced bacterial infections within 100 days of undergoing transplantation, the majority of these cases were Clostridium difficile colitis and the early NRM rate was 0%, suggesting that the severity of TBC-associated acute toxicities was limited in this select population. A history of prior chemotherapy and radiotherapy may contribute to toxicities after ASCT, as one analysis has suggested that patients with a history of >2 prior treatment regimens may be at an increased risk of grade 3 to Cancer August 15, 2017

5 ASCT for Primary CNS Lymphoma in CR1/DeFilipp et al TABLE 3. Published Reports of HDC-ASCT With CNS-Directed Conditioning as Upfront Consolidation Therapy for Patients With PCNSL Median Follow-Up EFS or PFS OS TRM or NRM Patients in CR at Time of Transplantation Conditioning WBRT Patients Who Underwent Transplantation No. of Patients/ Study Type Study Montemurro patients/prospective 69% 19% BU/TT Yes a 15 mo 2-y EFS: 45% 2-y: 48% 9 patients/ 23 patients Illerhaus patients/prospective 77% 65% BCNU/TT Yes 63 mo NA 5-y: 69% 0% b Illerhaus patients/prospective 85% 31% BCNU/TT Yes a 25 mo 3-y DFS: 77% 3-y: 77% 0 patients/ 13 patients Illerhaus patients/prospective 92% 77% R-BCNU/TT Yes a 57 mo 5-y PFS: 65% 5-y: 79% NA Omuro patients/prospective 81% NA TBC No 45 mo 2-y PFS: 81% 2-y: 81% 3 patients/ 33 patients Alimohamed patients/retrospective 100% 24% TBC No 60 mo 5-y PFS: 44% 5-y: 44% 5 patients/ Cheng patients Abbreviations: BCNU/TT, carmustine and thiotepa, BU/TT, busulfan and thiotepa; CNS, central nervous system; CR, complete remission; DFS, disease-free survival; EFS, event-free survival; HDC-ASCT, highdose chemotherapy and autologous stem cell transplantation; NA, not available; NRM, nonrecurrence mortality; OS, overall survival; PCNSL, primary central nervous system lymphoma; PFS, progression-free survival; R-BCNU, rituximab and carmustine; TBC, thiotepa, busulfan, and cyclophosphamide; TRM, treatment-related mortality; TT, thiotepa; WBRT, whole-brain radiotherapy. a WBRT was administered only to patients who did not achieve CR. b For patients who underwent HDC-ASCT. toxicities (National Cancer Institute s Common Terminology Criteria for Adverse Events (CTCAE) 4.0). 25 The favorable toxicity profile observed in the current study may be influenced by the select population of patients who achieved optimal disease control with limited therapy before undergoing ASCT. As treatment outcomes for patients with PCNSL have improved, long-term follow-up has become essential to monitor for disease recurrence, late effects, and overall quality of life. Multiple studies have identified late disease recurrence to be a cause of treatment failure, with up to 26% of disease recurrences occurring after 5 years. 26,27 To the best of our knowledge, it remains unclear whether the incorporation of consolidative ASCT may alter patterns of disease recurrence, although late recurrences have been reported. 26 Furthermore, monitoring for delayed neurotoxicity remains a critical aspect of survivorship care for patients with PCNSL. With the incorporation of rituximab into treatment regimens, the risk of hypogammaglobulinemia and recurrent infections also is important in this population. The disease control and limited toxicities reported for the patients in the data set in the current study are promising, but further long-term follow-up will determine whether these outcomes are durable. Currently, there are 4 ongoing randomized clinical trials investigating the role of HDC-ASCT consolidation therapy compared with WBRT (ClinicalTrials.gov identifiers NCT and NCT ) or nonmyeloablative chemotherapy (ClinicalTrials.gov identifiers NCT and NCT ). International Extranodal Lymphoma Study Group-32 (IELSG32) (ClinicalTrials.gov identifier NCT ) is a phase 2 study that initially randomized patients who were newly diagnosed with PCNSL to 1 of 3 MTX-based induction chemotherapy regimens, and if patients achieved at least stable disease, the authors subsequently randomized responders to consolidation therapy with WBRT (36 grays [Gy] 6 a boost of 9 Gy) or HDC-ASCT with conditioning using carmustine and thiotepa. Results from the initial randomization support the addition of rituximab and thiotepa to induction therapy to achieve a higher CR rate. 28 Preliminary results from the second randomization have suggested that both WBRT and HDC-ASCT are effective consolidation therapies, although specific neurocognitive functions after WBRT remain a concern. 29 The preliminary results of PRECIS (Cranial Radiotherapy or Intensive Chemotherapy With Hematopoietic Stem Cell Rescue for Primary Central Nervous System Lymphoma in Young Patients) (ClinicalTrials.gov identifier NCT ), a phase 2 trial randomizing patients to Cancer August 15,

6 MTX-based chemotherapy followed by either WBRT (40 Gy) or HDC-ASCT with TBC conditioning, have demonstrated favorable outcomes among patients in the transplantation arm (2-year PFS rate of 87%), whereas data regarding outcomes after WBRT and neuropsychological evaluations for all patients currently are undergoing analysis. 30 The final results of these trials are eagerly awaited because they will provide prospective randomized data with regard to disease control, acute toxicities, and longterm neurotoxicities. Overall, in the current study, we report favorable outcomes for patients with PCNSL in CR1 who underwent HDC-ASCT with a TBC-based conditioning regimen. The low rates of NRM and encouraging disease control and OS support the use of HDC-ASCT with CNS-directed conditioning as consolidative therapy. We await the results of currently ongoing randomized clinical trials to better clarify the role of HDC-ASCT in the management of patients with PCNSL. FUNDING SUPPORT No specific funding was disclosed. CONFLICT OF INTEREST DISCLOSURES Philippe Armand has received research funding and consulting fees from Bristol-Myers Squibb and Merck; research funding from Otsuka, Sigma Tau, Sequenta Inc, Pfizer, and Affimed; and consulting fees from Infinity Pharmaceuticals for work performed outside of the current study. Tracy T. Batchelor has received research funding from Pfizer and consulting fees from Merck, Roche, and Accerta for work performed outside of the current study. Yi-Bin Chen has received research funding from Adienne and Otsuka for work performed outside of the current study. AUTHOR CONTRIBUTIONS Zachariah DeFilipp: Conceptualization, methodology, investigation, data curation, writing original draft, and writing review and editing. Shuli Li: Methodology, investigation, resources, and writing review and editing. Areej El-Jawahri: Resources and writing review and editing. Philippe Armand: Resources and writing review and editing. 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