Bone Marrow Transplantation (2020) 55:265–267 https://doi.org/10.1038/s41409-019-0528-y

CORRESPONDENCE

CBeV (, and ) pre-autotransplant conditioning in persons with

1,2 3 2 4 5 Gregorio Jaimovich ● Maria Belen Rosales Ostriz ● Martin Castro ● Leandro Riera ● Cecilia Foncuberta ● 3 1 4 5 1 6 Hector Longoni ● Agustina Cia ● Patricio Duarte ● Adriana Vitriu ● Francisco Lastiri ● Robert Peter Gale

Received: 21 January 2019 / Revised: 26 February 2019 / Accepted: 13 March 2019 / Published online: 23 April 2019 © Springer Nature Limited 2019

To the Editor: December 2014 to April 2018. Subjects must have had adequate heart, lung, and kidney (eGFR > 50 ml/min) Autotransplants are widely-used in persons with lymphoma. function. The study was approved by the Anchorena Hos- There are two common pretransplant conditioning regi- pital Ethics Committee. All subjects provided written mens: CBV (cyclophosphamide, , and etopo- informed consent. CBeV consists of bendamustine (Bend- side); and BEAM (carmustine, etoposide, and avar®), 200 mg/mE+2, on days −6 and −5, cyclopho- ) [1, 2]. Despite many attempts to increase the sphamide, 1.5 g/mE+2, on days −6to−3 and etoposide, efficacy and/or decrease the toxicity of these and other 1 g/mE+9, on days −6to−4. Eleven subjects received conditioning regimens none is proved convincingly safer cyclophosphamide, 4 g/mE+2 total dose, and etoposide, and/or more effective [3–8]. 2.4 g/mE+2 total dose. Hydration of 2 l/ mE+2 was Unavailability of carmustine in Argentina 2012–2017 led employed during conditioning administration. Filgrastim, us to develop a new autotransplant conditioning regimen 5 μg/kg/d, was given post-transplant until granulocytes were resembling CBV but substituting bendamustine for car- ≥4 × 10E + 9/L. mustine (CBeV). Bendamustine is an alkylating drug which To collect blood cells subjects received filgrastim, 10 μg/ in equitoxic doses induces more double-strand DNA breaks kg/d subcutaneously, for 5 days with or without plerixafor than melphalan, cyclophosphamide or carmustine. It also 20 mg subcutaneously 12 h before leukapheresis. Cells were has anti-metabolite activity and a toxicity pattern different collected on a blood cell separator and frozen at −80 °C from carmustine [9, 10]. Bendamustine is active in early in 10% DMSO [14]. Grafts were thawed on day 0 and and advanced including infused numbers of CD34-postitive cells were determined [11, 12] and has been substituted for carmustine in several after collection as recommended [15]. Median numbers BEAM-type autotransplant conditioning regimens [8, 13]. of CD34-postive cells collected was 3.9 × 10E + 6/kg We conducted a prospective multi-centre phase-2 study to (range: 1, 2 – 27 × 10E + 6/kg). evaluate safety and efficacy of CBeV in 115 con- Granulocyte recovery was defined as the first of three secutive subjects with lymphomas at five transplant centres consecutive days of granulocytes ≥0.5 × 10E + 9/L. Platelet recovery was similarly-defined with a threshold of ≥20 × 10E + 9/L without platelet transfusions. Adverse events (AEs) were documented and graded using the National * Gregorio Jaimovich Institute Common Terminology Criteria for Adverse [email protected] Events (CTCAE) Version 4. We collected data on AEs >grade-2 but did not distinguish no AE from AEs ≤grade-2. 1 Favaloro University Hospital, Buenos Aires, Argentina Lymphoma state, first or second complete or partial 2 Anchorena Hospital, Buenos Aires, Argentina remission, was determined immediately pre-transplant. 3 Clinicas University Hospital Jose de San Martin, Buenos Aires, Response was evaluated at 2 mo intervals for the first year Argentina and every 6 mo thereafter by computer tomography (CT) 4 CEMIC, Buenos Aires, Argentina and/or positron emission tomography (PET) using pub- 5 Alexander Fleming Institute, Buenos Aires, Argentina lished criteria [16]. Data are reported as median and range 6 Haematology Research Centre, Imperial College London, or inter-quartile range (IQR) for quantitative variables and London, UK frequencies and percent for qualitative variables. Event-free 266 G. Jaimovich et al. survival (EFS) and survival were estimated using the pericardial effusion, 1, severe hypertension and the third, Kaplan–Meier non-parametric product-limit method and fatal multi-organ failure. Frequency of >grade-3 kidney- time-to-event experiences compared by Log-rank test. failure (<6%) was similar to data reported by others [14]. P-values for pair-wise comparisons were adjusted using Two-year EFS is 65% (95% confidence interval [CI], 56, Bonferroni correction. EFS was the interval from transplant 76%) and survival 85% (77, 92%;). Two-year EFS were to relapse or progression, death from any cause, loss to 76% (61, 95%) for subjects in first and 66% in second (53, follow-up or withdrawal of consent. Survival was the 82%) complete remissions and 51% (35, 74%) for subjects interval from transplant to death from any cause, loss to in partial remission. Difference in EFS between the com- follow-up or withdrawal of consent. P-values were two- plete and partial remission cohorts is significant (P = sided with a significance level set at <0.05. Statistical 0.022). Corresponding 2-year survivals were 94% (87, analyses were performed using R version 3.5.1 (R Core 100%), 82% (70, 96%) and 76% (61, 95%; P = 0.287). Team, 2018). Median follow-up of survivors is 20.4 mo There are several important limitations to our study. (IQR: 13–26 mo). Data was analyzed as of October 2018. First, we lack a comparator cohort and, consequently, All subjects were evaluable for analyses. cannot know if CBeV is comparable, better or worse than Subject- and disease-related variables are displayed in CBV in the contexts of safety and efficacy. Second, we Table 1. Nineteen of 27 subjects transplanted in partial documented AEs ≥grade-3 but did not distinguish subjects remission achieved a complete remission by day 100 post- with no AE from those with AEs grade-1/-2. Other limita- transplant. The 19 subjects were tions include few subjects, diverse lymphomas and remis- transplanted in first complete remission. There was only one sion states and brief follow-up. Nevertheless, based on our death <100 days posttransplant. All subjects but one data we suggest a randomized trial comparing CBeV to recovered bone marrow function. Median interval to gran- CBV should be considered in persons with lymphoma ulocyte recovery was 11 days (range, 8–23 days) and to receiving an autotransplant. platelet recovery, 14 days (range, 7–40 days). The most common >grade-2 AEs were febrile neutropenia (N = 89; Acknowledgements Statistical support was provided, in part, by 77%) (N = 25; 22%), nausea/vomiting (N = 21; Varifarma Argentina. RPG acknowledges support from the National = Institute of Health Research (NIHR) Biomedical Research Centre 18%) and mucositis (N 18; 16%). Other AEs included funding scheme. acute coronary syndrome (N = 3), arrhythmia (N = 1) and congestive heart failure (N = 8). Renal failure occurred in Compliance with ethical standards 5 subjects and respiratory AEs in six. All AEs were transient and reversible except for one subject with multi-organ fail- Conflict of interest The authors had full access to the data and freedom ure. There were mild transient increases in liver transami- in the decision to publish. RPG is apart-time employee of Celgene nase but no sinusoidal obstruction syndrome. Eight subjects Corp. had heart AEs 5 of whom were >60 y. Another had previous Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Table 1 Subject- and disease-related variables N 115 References Age (y; median; range) 47 (18–74) Males 70 1. Zander A, Culbert S, Jagannath S, Spitzer G, Keating M, Larry N, Diagnoses et al. 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