Carmustine Replacement in Intensive Chemotherapy Preceding Reinjection of Autologous Hscs in Hodgkin and Non-Hodgkin Lymphoma: a Review

REVIEW Carmustine replacement in intensive chemotherapy preceding reinjection of autologous HSCs in Hodgkin and non-Hodgkin lymphoma: a review

G Damaj1,2, J Cornillon3, K Bouabdallah4, R Gressin5, S Vigouroux3, T Gastinne6, F Ranchon7, H Ghésquières8, G Salles8, I Yakoub-Agha9 and E Gyan10 for Lymphoma Study Association and the French Society of Bone Marrow Transplantation and Cellular Therapy

High-dose chemotherapy preceding autologous hematopoietic stem cell transplantation (auto-HSCT) is one treatment option for patients with Hodgkin (HL) or non-Hodgkin lymphoma (NHL). The most frequently used intensive chemotherapy is a combination of carmustine (BCNU), etoposide, cytarabine and melphalan (BEAM). However, BCNU is consistently in short supply, and there has been a recent dramatic increase in its cost, necessitating the utilization of conditioning alternatives. The busulfan-based conditioning regimen known as the busulfan–cyclophosphamide–etoposide (BuCyE) combination is the second most-studied conditioning regimen worldwide after BEAM, and it exhibits a beneﬁt/risk ratio that is comparable to that of BEAM. In addition to these two combinations, the present manuscript also summarizes data reported for other conditioning combinations. Owing to the lack of prospective and comparative studies, a comparison of the toxicities and medicoeconomical proﬁles of these treatments is warranted to identify effective replacements for BCNU-based conditioning.

Bone Marrow Transplantation (2017) 52, 941–949; doi:10.1038/bmt.2016.340; published online 23 January 2017

INTRODUCTION prospective study of patients who underwent transplant as a first 10 Intensive chemotherapy followed by autologous hematopoietic response. stem cell transplantation (auto-HSCT) is one therapeutic option for When selecting high-dose therapy, both long-term treatment a subset of eligible patients with Hodgkin lymphoma (HL) or efficacy and potential short- and long-term toxicities must be non-Hodgkin lymphoma (NHL).1 A previous European Blood and considered. The toxicity of TBI in the setting of auto-HSCT has Marrow Transplantation Society survey reported on 1880 patients progressively decreased its use because of the risk of acute leukemia, secondary myelodysplastic syndromes and cumulative with HL and 6000 patients with NHL who received auto-HSCT in 11,12 2013.2 Auto-HSCT has been increasingly performed over the years organ toxicity in the case of previous radiation, primarily in HL. and has become one of the most common treatment approaches The BEAM regimen, which utilizes a combination of for aggressive forms of lymphoma.2 carmustine (BCNU), etoposide, cytarabine and melphalan, fi is the most frequently used conditioning regimen before Auto-HSCT was not widely adopted as a rst-line treatment for 2–4 high-risk patients with diffuse large B-cell lymphoma in the auto-transplantation. However, BCNU is in short supply and fi rituximab era, and this treatment has consequently not been has a high cost, necessitating the identi cation of conditioning recommended outside of clinical trials. However, auto-HSCT alternatives. In the absence of prospective randomized studies has recognized benefits for chemosensitive patients presenting comparing different types of conditioning, we reviewed the data with initially chemotherapy-refractory disease or those who have from the most important and largest published studies to propose relapsed after first-line therapy and are eligible for intensive recommendations for alternative chemotherapies to be used as therapy.3,4 For mantle cell lymphoma, auto-HSCT has demon- conditioning regimens before auto-HSCT. strated benefits associated with response and survival.5 For follicular lymphoma, auto-HSCT is not recommended as a consolidation first-line treatment because of its excessive toxicity METHODOLOGY and lack of benefit for overall survival (OS).6 However, this The French Society of Bone Marrow Transplantation and Cellular therapeutic approach is used in patients with sensitive relapse.7,8 Therapy (SFGMTC) and the Lymphoma Study Association (LYSA) The role of auto-HSCT for the treatment of peripheral T-cell established a collaborative work group. The group met to discuss lymphoma is not clearly established because of the rarity of this BEAM conditioning alternatives for auto-transplantation for disease and the absence of randomized studies.9 Nevertheless, a lymphoma. An extensive literature review was performed focusing Nordic team recently reported a high PFS rate of 44% in a phase II on high-dose therapy in the setting of lymphoma. The group

1Institut d'hématologie de Basse Normandie, Centre Hospitalier Universiatire, Faculté de médecine, Université de Basse-Normandie, Caen, France; 2Microenvironnement Cellulaire et Pathologies, Normandie University, Caen, France; 3Hématologie, Institut de Cancérologie Lucien Neuwirth, Saint-Priest-en-Jarez, France; 4Hématologie et Thérapie Cellulaire, CHU de Bordeaux, Pessac, France; 5Hématologie, CHU de Grenoble, Grenoble, France; 6Hématologie, CHU de Nantes, Nantes, France; 7Unité de Pharmacie Clinique Oncologique, Groupement Hospitalier Sud, Hospices Civils de Lyon, Lyon, France; 8Hématologie, Hospices Civils de Lyon, Lyon, France; 9Maladies du sang, CHRU de Lille, Lille, France and 10Hématologie et Thérapie Cellulaire, CHU de Tours, Tours, France. Correspondence: Professor G Damaj, Institut d’Hématologie de Basse Normandie, Centre Hospitalier Universiatire (CHU), Faculté de médecine, Université de Basse-Normandie, Avenue de la Côte de Nacre, Caen 14033, France. E-mail: [email protected] and [email protected] Received 29 March 2016; revised 8 November 2016; accepted 16 November 2016; published online 23 January 2017 Conditioning regimens for lymphoma G Damaj et al 942

Table 1. Main toxicities related to BCNU-based conditioning regimens

Caballero et al.87 Puig et al.13 Kim et al.82 Sakellari et al.88

Histology NHL, HL NHL, HL NHL NHL, HL No. of patients 148 113 65 137

Disease status at transplant,n(%) First line 49 (33) 61 (54) First relapse = 15 (23) First relapse = 33 (24) More than first line 99 (67) 52 (46) More than first relapse = 50 (77) More than first relapse = 104 (76) Age, median (range) 42 (4–63) CBV = 36 (18–62) BEAM = 46 (15–65) o34 Years = 72 BEAM = 48 (18–70) BuCyE = 46,5 (28–65) 434 Years = 65

Mucositis,n(%) 84% Gr ⩾ 2 G1–2 Not speciﬁed CBV = 47 BEAM = 17 BEAM = 38/BuEM = 25 G3–4 30% BEAM = 13 BuCyE = 9 BEAM = 3/BuEM = 24 P = 0.004 P = NS Po0.001

Gastroenteritis,n(%) 69% Gr ⩾ 2 G1–2 Not speciﬁed CBV = 17; BEAM = 6 BEAM = 17 BEAM = 19/BuEM = 22 G3–4 n = 25 P = NS BuCyE = 4 BEAM = 24/BuEM = 8 P = NS Po0.001

Kidney failure,n(%) — G1–2 8% (Gr 1) CBV = 9; BEAM = 0 BEAM = 7/BuEM = 3 G3–4 P = 0.02 P = NS

PMN recovery time BM = 20 (11–51) CBV = 14 (9–26) BEAM = 11 (8–20) BEAM = 9(6–20) 40.5 G/L; days, (range) CSP = 12 (9–27) BEAM = 12 (9–25) BuCyE = 9(8–17) BuEM = 10 (8–31)

Platelet recovery time BM = 24 (10–250) CBV = 14 (9–58) BEAM = 13.5 (7–31) BEAM = 11 (3–25) 420 G/L, days, (range) CSP = 17 (10–160) BEAM = 12 (8–56) BuCyE = 11 (5–38) BuEM = 11 (6–150) Toxicity-related mortality, n (%) 5.4% CBV = 25% BEAM = 4.1% BEAM = 3.44% BEAM = 7% BuCyE = 9.1% BuEM = 0% P = 0.02 P = NS P = NS Median PFS/DFS DFS = 76% Not specified BEAM = 16.1 Mo BEAM = 63.2% 3 Years BuCyE = 11.3 Mo BuEM = 65.6% EFS; P = NS PFS Median OS 68% Not specified BEAM = 30.6 Mo BEAM = 76.7% 3 Years BuCyE = 22.6 Mo BuEM = 78.8% P = NS P = NS Abbreviations: BEAM = BCNU+etoposide+aracytine+melphalan; BM = bone marrow; BuCyE = busulfan+cyclophosphamide+etoposide; BuEM = busulfan +etoposide+melphalan; CBV = cyclophosphamide+BCNU+VP16 (etoposide); DFS = disease-free survival; EFS = event-free survival; Mo = month; NS = not significant; OS = overall survival; PMN = polymorphonuclear; PSC = peripheral stem cell. Sinusoidal obstruction syndrome was reported in the studies by Kim et al.82 (two for BEAM and one for BuCyE) and Sakellari et al.88 (in one case after BEAM). In the study by Sakellari et al.,88 sepsis was significantly higher following BuEM than BEAM (P = 0.006).

members were responsible for reviewing and synthesizing all the Toxicities data and writing the manuscript. The ﬁnal document was sent to In a 2006 study published by a Spanish team, the toxicities of CBV readers who provided their opinion on the text before submission and BEAM were retrospectively compared in 113 patients.13 The for review by the scientiﬁc boards of the Lymphoma Study results showed comparable hematological toxicities between the Association and the French Society of Bone Marrow Transplanta- two conditioning regimens. However, higher non-hematological tion and Cellular Therapy. toxicities, including mucositis (63% versus 34%, P = 0.004), renal failure (12% versus 0%, P = 0.02), sinusoidal obstruction syndrome (7% versus 0%, P = 0.04) and pulmonary toxicities, were noted in OVERVIEW OF CARMUSTINE-BASED CONDITIONING REGIMENS the CBV group. Treatment-related mortality (TRM) was primarily infection-related, with rates of 5% for BEAM and 24% for CBV Several types of BCNU-based conditioning regimens have been (P = 0.02). The excessive toxicity of CBV was associated with the developed (Supplementary Table 1). Unfortunately, none of these higher total BCNU dose in the CBV regimen (800 mg/m2) versus regimens has been compared in prospective or randomized the BEAM regimen (300 mg/m2). The total etoposide dose was studies. Each regimen involves a combination of two to four comparable between the two regimens (750 versus 800 mg/m2). drugs, including alkylating agents. The CBV (cyclophosphamide Another more recent analysis evaluated 4917 patients (Cy), BCNU and etoposide), BEAM (BCNU, etoposide, aracytine and (NHL = 3905, HL = 1012) who received auto-HSCT after high-dose melphalan) and BEAC regimens (BCNU, etoposide, aracytine and therapy with BEAM (n = 1730), CBV (n = 1853; CBVlow Cy) are the most frequently used. These treatments are generally (BCNU = 300 mg/m2) and CBVhigh (BCNU = 450 mg/m2)), BuCy associated with a post-transplant complete response rate of (busulfan (Bu) and Cy, n = 789) or TBI-based (n = 545) treatment. 60–85% and 2- to 5-year disease-free survival rates that vary from This analysis reported comparable 1-year TRM rates between the 34 to 60% with variable toxicities depending on the types and groups (ranging from 4 to 8%), but pulmonary complications were doses of drugs used. high in the CBVhigh and TBI-based regimens.

Bone Marrow Transplantation (2017) 941 – 949 © 2017 Macmillan Publishers Limited, part of Springer Nature. Conditioning regimens for lymphoma G Damaj et al 943 The BEAC (BCNU, etoposide, aracytine and Cy) combination is Bendamustine-based conditioning regimen: BeAM less frequently used, especially in France, and the toxicity of this Bendamustine is a bifunctional, cytotoxic compound with regimen is higher than that of the BEAM combination. For BEAC, structural similarities to alkylating agents and purine analogs.15 the TRM (infectious, cardiac and pulmonary) is high at ~ 23%.13 The pharmacokinetics of a single dose are equivalent to those of Thus, BEAM remains the most used conditioning regimen with several successive doses.16,17 The maximum dose concentration is acceptable toxicity and low TRM.13 Table 1 summarizes the main attained at the end of a 1-h perfusion. The half-life is estimated at toxicities associated with BEAM (particularly BCNU). 40 min, and there is a low probability of accumulation after repeated daily doses. Renal elimination of the drug is minimal and Efficacy estimated at 3% of the total administered dose. Bendamustine exhibited high antitumor activity in preclinical18 and clinical Interestingly, type of conditioning influences both incidence of 19,20 relapse and survival in certain disease subcategories. studies, and this activity was independent of cellular resistance to typical alkylating agents.15 The limiting toxicities The risk of progression or relapse was lower in patients with reported in phase I monotherapy studies were thrombocytopenia HL who received BuCy (P=0.006) or TBI-based conditioning (320 mg/m2), cardiac arrhythmia (320 mg/m2) and digestive (P = 0.024) compared to BEAM. – complications. Kidney failure was not reported.21 24 Bendamustine The risk of relapse or progression was higher in patients with 25,26 high is effective against indolent lymphomas, chronic lymphocytic mantle cell lymphoma who received CBV compared with 27 28 low leukemia, mantle cell lymphoma, large B-cell lymphomas, CBV (P = 0.005). TBI was associated with a decreased risk of 29,30 31–33 peripheral T-cell lymphomas, HLs and multiple relapse compared to BEAM (P = 0.004), with no impact on survival myelomas.34–36 The doses used are 50–180 mg/m2 on days 1 (P = 0.95). and 2 or a total dose of 100–360 mg/m2 in a single intravenous The OS of patients with follicular lymphoma was significantly – – low high perfusion over 30 60 min every 21 28 days. Digestive disorders higher for those treated with CBV versus BEAM and CBV and increased infectious toxicities were associated with (P=0.006 and P=0.002, respectively). higher doses.19,23,37 In current practice, the recommended Patients with diffuse large B-cell lymphoma treated with high monotherapy doses, or the doses recommended in combination doses of BCNU (CBVhigh) exhibited an inferior survival rate low with rituximab, for lymphomas and multiple myelomas vary from compared with patients treated with BEAM or CBV (P = 0.001 60 to 120 mg/m2.38 and P = 0.003, respectively). A higher conditioning TRM rate and 4 2 notably elevated doses of BCNU ( 350 mg/m ) can explain these Bendamustine use in high-dose chemotherapy. An Italian group differences. recently reported the first use of bendamustine as part of a conditioning regimen. Visani et al. reported that the maximum ALTERNATIVES TO BCNU IN CONDITIONING REGIMENS tolerated dose of bendamustine was not attained in nine patients on day 6 to day 7 when bendamustine was used in combination Lomustine-based conditioning regimen with a fixed dose of aracytine (400 mg/m2/day, day 2 to day 5), Sharme et al.14 proposed the LEAM regimen, which replaces BCNU etoposide (200 mg/m2/day, day 2 to day 5) and melphalan with oral lomustine, as an alternative to BEAM. Data on this (140 mg/m2, day 1).39 The extension phase II study included 34 regimen are scarce, and its toxicity was comparable to BEAM in a patients, to whom bendamustine was administered at a dose of historical, retrospective comparative study. 200 mg/m2/day on day 6 and day 7 (total dose of 400 mg/m2)as

Table 2. Main toxicities of bendamustine-based conditioning regimens

Visani et al.39,40 Garciaz et al.44 Noesslinger et al.41 Martin et al.43 a Martino et al.42

Histology LBCL, HL LBCL, MCL LBCL, MCL, FL, ALCL, HL LBCL, FL, PTCL Myeloma No of patients 43 29 38 60 12

Disease status at transplant,n(%) First line 0 Median prior chemotherapy 11 (18) 0 More than ﬁrst line 43 (100) 2 (1–4) 49 (82) 12 (100) Age, median (range) 47 (18–70) 58 52 (22–71) 54 (27–70) 56 (40–66)

Mucositis,n(%) G1–2 11 (26) 26 (89) 7 (18) 11 (92) G3–4 1 (8)

Digestive toxicity,n(%) 15 (35) G1–2 5 (17) 10 (26) 12 (100) G3–4 0

Kidney failure,n(%) G1–2 NA (17) G3–4 0 4 (14) 5 (8.3)b PMN recovery time 40.5 G/L (days) 10 (8–12) 10 (6–16) 10 (7–13; 41 G/L) 11 (9–72) 12 (11–15) Platelet recovery time 420 G/L (days) 13 (8–39) At day 30 (24 patients) 11 (5–26) 14 (4–53) 14 (11–19) Toxicity-related mortality, n (%) 1 (3) 1 (3) − 2 (3.3) 0 Abbreviations: ALCL = anaplastic large-cell lymphoma; FL = follicular lymphoma; HL = Hodgkin lymphoma; LBCL = large B-cell lymphoma; MCL = mantle cell lymphoma; NA = non-applicable; OS = overall survival; PMN = polymorphonuclear; PTCL = periphery T-cell lymphoma. aMartin reported 39 serious adverse events. Atrial ﬁbrillation was reported in 10 and 8% of patients in the studies by Garciaz and Noesslinger et al.,41,44, respectively. Need for ICU management was reported in 28% of patients in the study by Garciaz et al.44 3-Year PFS and OD were 72% in the study by Visani et al. bResolved in all cases (in Martin, three patients already had a kidney failure episode).

46 an intravenous perfusion for an hour in 500 ml of 0.9% physiological serum.39 64) 64) – – 18)

– The conditioning was well tolerated, and there was no procedure-related mortality. The median times to platelet count ⩾ 20 G/L and polymorphonuclear (PMN) count ⩾ 0.5 G/L were 13 Di Ianni et al. and 10 days, respectively. Non-hematological toxicities were 97 dominated by grade 3/4 mucositis (26%) and grade 2–4 gastroenteritis (35%). No grade 3/4 renal, hepatic, cardiac or 70) 39 (19 39,40 – 12) 39 (19 15) 13 (9 pulmonary toxicity was observed. – – Several reports on the use of a bendamustine-based condition- 3 (18%) 0 46 ing regimen before auto-HSCT were recently published as 41–43

et al. abstracts (Table 2 and Supplementary Table 2) and a journal Montemuro et al. letter.44 Bendamustine was used at 200 mg/m2/day for two 51 60) 55 (18 35) 11 (8 – – successive days in these studies, except for the study reported 30) 8 (7 – by Martino et al.,42 in which bendamustine was used at a dose of 100 mg/m2 in combination with melphalan for patients with Lee et al. multiple myeloma. Toxicities were comparable between the 58 polymorphonuclear. Neurotoxicity was noted at 4 and different studies (Table 2). The most frequent grade 3/4 toxicities = 65) 46 (29 28) 10 (9 – – 53) 20 (11 were sepsis (9–20%), fever (16–100%), mucositis (18–28%), – –– gastrointestinal toxicities (4–26%) and kidney failure (31%). On the basis of its activity in a wide range of hematologic

Zaucha et al. diseases, bendamustine is an attractive drug, and it may have a major role in conditioning regimens. However, data on its usage remain limited and are derived from samples with limited numbers of patients, providing a narrow perspective on toxicities. 60) 51 (35 47 –

26) in the studies by Ganguly and Di Ianni Therefore, its use should remain within the framework of ) 12 (10 )11(8 – – – clinical trials. et al. 33 (14 11 ( 12 (

Guttierez delagado Thiotepa-based conditioning regimens Thiotepa, primarily via its active metabolite TEPA, exhibits alkylating action similar to that of nitrogen mustards. This agent

96 has been used as an alternative to classic conditioning regimens

— based on carmustine to improve the tolerance/effectiveness

primary central nervous system lymphoma; PMN 45–48 49–51 et al. Ganguly

= relationship for patients with NHL or multiple myeloma (Table 3a and Table 3b).52–54 In adults, thiotepa is preferentially indicated for the treatment 45

65) of lymphoid malignancies with central nervous system (CNS) – —— —— localization. This preference is because of its ability to cross the blood–brain barrier and its potential to be combined with

Bains et al. other cytotoxic drugs, such as Bu and Cy (thiotepa, busulfan, 55

52 cyclophosphamide (TBC). A recent meta-analysis highlighted the overall survival; PCNSL

= effectiveness of TBC in patients with primary or secondary CNS lymphoma, and the French reference center for primary 71) 35 (21

– oculocerebral lymphoma group recommends thiotepa-based ) ) 56,57 − − conditioning in these settings. In 2001, Gutierrez-Delgado et al.50 published a comparative study examining thiotepa, Bu and respectively. The median time of hospital stay was 21 days (18 melphalan (TBM) conditioning (n = 130) to TBI/CyE conditioning 97 , (n = 221). There was no signiﬁcant difference in efﬁcacy or toxicity Anagnostopoulos et al.

et al. between the two treatment regimens. Furthermore, OS, event-free 54 survival (EFS) and relapse rates at 5 years were 42%, 34% and 42%, respectively, for TBM and 44%, 32% and 49%, respectively, for 64) 51 (31 non-Hodgkin lymphoma; OS – 14) 10 ( 59) 14 ( = – – TBI/Cy-E. TRM rates were comparable, ranging from 21 and 16%. Zaucha et al.58 observed comparable results. However, this type of 9(7

15 (9 conditioning regimen was not superior to high-dose melphalan and Montemuro alone for multiple myelomas.52 The TBM combination was better Dimopoulos et al. 93 45

(%) than CBV, BEAM or Cyclo-TBI for patients with HL, but these 47 et al. (%) 5 (13%) 6results (6%) were 5 (8%) not conﬁrmed 0 in other studies. 6 (10%) ,n n Thiotepa has also been used in combination with etoposide, cytarabine and melphalan (TEAM; Supplementary Table 3). One study compared the results from TEAM conditioning to those from Hodgkin lymphoma; NHL

= BEAM conditioning in 114 patients with malignant large B-cell rst line Yes Yes 100 100 100 100 100 0 100 ﬁ lymphoma (LBCL), follicular lymphoma or HL. The 3-year PFS,

Main toxicities of thiotepa-based conditioning regimens OS and relapse rates were 64%, 82% and 33%, respectively, for TEAM and 60%, 80% and 40%, respectively, for BEAM. There was no signiﬁcant difference between the two groups in toxicity.59 First lineMore than Yes Yes 0 0 0 0 0 100 0 0.5 G/L (days) 20 G/L (days) Another study evaluated the efﬁcacy and toxicity of the TEAM Age, median (range) 49 (34 HistologyNo of patientsDisease status at transplant Myeloma 40 Myeloma 97 HL HL 60 HL 50 NHL NHL 58 PCNSL 13 HL 58 58 PMN recovery time 4 Platelet recovery time 4 Toxicity-related mortality, Table 3a. Abbreviations: HL 12% in the studies by Omuro protocol in 120 (HL = 51; NHL = 69) patients with relapsed or

Bone Marrow Transplantation (2017) 941 – 949 © 2017 Macmillan Publishers Limited, part of Springer Nature. Conditioning regimens for lymphoma G Damaj et al 945 refractory disease. The overall and complete response rates were 84.8% and 82.3%, respectively, and the TRM rate was 1%.60 67) 53 – 21) 67) The efﬁcacy/tolerance relationship favored BEAM or high-dose – – 52,58 120 melphalan, which appeared less toxic than TBC or TBM. TBM et al. Shimoni 47 10 (7 11 (6 was as toxic as TBI/Cy-E. The TRM rate varied between 0 and 29% for conditioning regimens that combined at least thiotepa 4 49 49 and Bu. Age 60 years was a predictive factor for TRM. Notably,

68) 48 (32 thiotepa-based conditioning without Bu (TC or TECa) was better – 46,61–64 —— — — —— 53 tolerated, with no TRM (Table 3a and Table 3b). Grade 3–4 non-hematological toxicities were mostly gastro-

Gopal et al. intestinal, such as diarrhea (38%) and mucositis (100%). Febrile neutropenia was reported in 14–90% of cases, and infections 95 (bacterial, fungal and viral) were reported in 10–45% of cases, ). 67) 62 (60 38) – – 16) 44) 93 – – which may justify the use of antiviral prophylaxis. Cases of sinusoidal obstruction syndrome (SOS) of the liver were reported et al. 9 (28%) 45,50,51,58

Cote et al. exclusively with TBM, and cutaneous toxicities are the most-reported side effect of thiotepa. Other non-hematological

94 toxicities, including renal, pulmonary, cardiac and hepatic toxicity, ; Omuro 64) 47 (21 35) 24 (20 49,53

58 ⩾ – – – 10) 9 (8 43) 13 (8 are rarer. These toxicities are related to age 55 60 years. – – — Approximately 900 patients, many with diffuse large B-cell et al. lymphoma with CNS involvement, have been treated with TBC Welch et al. (thiotepa (250 mg/m2/day) for 3 days, Bu (3.2 mg/kg/day) for 3 days and Cy (60 mg/kg/day) for 2 days is the most frequently 67) 52 (29 24) 14 (8 90) 26 (20

93 used regimen). – – – 15) 9 (8 – Omuro et al. 12 (27%) 26 (20 BU-BASED CONDITIONING Bu is an alkylating agent that damages DNA65 synergistically with nucleoside analogs in lymphoma cell lineages.66 Developed in the 65) 57 (23

92 62 – 1980s, orally administered Bu was initially widely used in 11 9 (7 18 15 (10 conditioning for allogeneic HSCT and, to a lesser degree, for et al. Soussain auto-HSCT. Intravenous Bu67 has the best bioavailability in vivo68 with few toxicities (for example, mucositis and SOS) and high 69,70 primary central nervous system lymphoma. Mucositis and gastroenteritis were reported between 0 and efﬁcacy in patients with lymphoma. A Bu-based conditioning =

67) 52 (23 regimen was used in double or triple combination with 91 – melphalan-like BuCyM,71 etoposide51 or Cy72 or both, similar to —— — —— – – 73 et al. Bu Cy etoposide (BuCyE) (Table 4, Supplementary Table 4). Soussain Notably, most Bu-based conditioning studies were retrospective, included a low number of patients and exhibited histological heterogeneity with different prognoses, which hinders the drawing of ﬁrm and deﬁnitive conclusions. 69) 52 (23 89) 74 90 – – Copelan et al. evaluated 382 patients with lymphoma who − —— received an auto-transplant after conditioning with BuCyE polymorphonuclear; SCNSL et al.

= (oral Bu) and reported grade 3–4 organ toxicities in 3.7% of the Alimohamed group. The most important side effect was hepatic toxicity, which consisted of SOS in 2.9% of cases. Disease management was more

89 successful for indolent lymphoma (PFS 56.4%) than for aggressive 74) 56 (34 74) 55) 28 (15 – – – 40) forms (PFS 43.7%) of the disease. – Hepatic toxicity has been reported in several studies. One retrospective study of 132 patients (53% LBCL) treated with 11 (37%) 3 (14%) 58 (24 11 (8 Cheng et al. Bu-based conditioning (IV form in 82% of cases) observed SOS in 7.6% of patients. The two predictive factors for SOS occurrence were use of a Bu–Thiotepa combination (odds ratio (OR) 8.8; P = 0.003) and serum ferritin ⩾ 950 μg/mL (OR 8.8; P = 0.003).75 A recent study by Shin et al.76 compared the results of 56 patients with LBCL receiving Bu-based conditioning with those

(%) from patients receiving BEAM or BEAC. The OS was longer for the (%) 0 3 (14%) 6 (8%) 0 3 (11%) 0 1 (3) 24 (29%) 16 (13%)

,n Bu group than the BCNU group, with 2-year OS rates of 70% and n 46%, respectively.77 BuCyE was also evaluated in combination with 90 primary central nervous system lymphoma; PMN Yttrium tiuxetan in 19 patients in relapse or with refractory LBCL. = Three-year OS and EFS rates were 52.6% and 26.3%, respectively, 78

rst line 0in apopulation 0 that 100 previously 100 received two 0 lines of treatment. 100 0 100 0 ﬁ The TBM regimen was also compared with TBI/Cy/E in patients

Main toxicities of thiotepa-based conditioning regimens ﬁ (%) with NHL. Five-year OS and EFS rates were not signi cantly n 2 4 different between TBI/Cy/E and TBM (44% and 32%, respectively; – – 42% and 34%, respectively). The corresponding TRM values were First lineMore than 100 100 0 0 100 0 100 0 100 G1 G3 0.5 G/L (days) 20 G/L (days) 16 and 21% for patients who had already undergone radiotherapy HistologyNo of patients PCNSL 7 PCNSL 21 PCNSL PCNSL 78 PCNSL PCNSL/SCNSL PCNSL/SCNSL Aggressive 44 Myeloma 26 15 32 Indolent 9 Age, median (range) 58 (24 Disease status at transplant Sepsis, PMN recovery time 4 Platelet recovery time 4 Median length of hospital stay in days (range) 23 (18 Toxicity-related mortality, Table 3b. Abbreviations: PCNSL 100% across the studies. Kidney failure was reported in three patients across studies. Skin rash was( reportedN in 8 and=59 12% of patients (Zaucha 50).

© 2017 Macmillan Publishers Limited, part of Springer Nature. Bone Marrow Transplantation (2017) 941 – 949 Conditioning regimens for lymphoma G Damaj et al 946 Thirty-seven patients with indolent follicular lymphoma received ﬂudarabine and Bu-based conditioning regimens 77 prospectively in a phase II study. The PFS was 46%, and the OS 65) 79 –

progressive was 72%. No TRM was reported.

diffuse large 80 = ﬁ HL 80 = Ahn et al. evaluated the ef cacy of BuCyE (Bu 3.2 mg/kg/day NHL 46

Nieto et al. × 3 days IV) in 31 patients with T-cell lymphoma. OS and PFS were both 64.6%. The TRM (mainly SOS) was reported at 9.8%.

mantle cell lymphoma; Bu was also evaluated in tandem with auto-HSCT in high-risk = patients with HL. The ﬁrst conditioning combined Cy/carmustine/

80 etoposide/mitoxantrone followed by a second conditioning that 64) 41 (18 2 –

udarabine; DLBCL included Bu (12 mg/kg), cytarabine (6 g/m ) and melphalan

ﬂ 2 81 overall survival; PML (140 mg/m ; BAM-6). To date, no data regarding the role of = Other 9 PTCL 13 NK/TCL 9

Ahn et al. BAM conditioning in the context of single auto-HSCT have been reported.

busulfan+ Two recent retrospective studies evaluated IV Bu-based = conditioning. The ﬁrst study evaluated 65 patients with NHL 79 who received an autologous transplant between 2002 and 2008.82 66) 47 (18 large B-cell lymphoma; MCL – Forty-three of these patients received BEAM conditioning = (BCNU = 300 mg/m2, etoposide = 800 mg/m2, aracytine = 1,600 mg/m2 FL 25 MCL 6 Other 6 and melphalan = 140 mg/m2), and 22 patients received BuCyE 4 sepsis was reported in 13.6% of patients in the study by Kim 2 – Stewart et al. (Bu = 9.6 mg/kg, Cy = 100 mg/kg and etoposide = 800 mg/m ). Patient characteristics were comparable between the two groups. Hematologic recovery (polymorphonuclear (PMN) 40.5 G/L and

82 4 ﬁ 65) 51 (33 platelets 20 G/L) was signi cantly more rapid in the BEAM group – than in the BuCyE group (P = 0.007 and P = 0.041, respectively). 912129 11 1Gastrointestinal 13 complications, 11 such as nausea, were signiﬁcantly LBCL 4 natural killer T-cell lymphoma (nasal); OS NHTCL 8 NHBCL 10

Kim et al. ﬁ = more common with BuCyE (P = 0.025). TRM was nonsigni cantly Hodgkin lymphoma; LBCL busulfan+etoposide+melphalan; BuFu = higher with BuCyE (9.1%) compared with BEAM (4.3%). EFS and OS = rates were comparable between the two treatments.

69 Another study was conducted after BCNU became scarce in 73) 48,5 (28

– Greece; it compared 87 patients (NHL = 27, HL = 60) who 2 2 — — received BEAM (BCNU = 300 mg/m , etoposide = 800 mg/m , FL 32

LBCL68 2 2

Other 36 aracytine = 800 mg/m and melphalan = 140 mg/m ) with 50 Dean et al. patients (NHL = 22, HL = 28) who received BuEM (Bu = 9.6 mg/kg, sinusoidal obstruction syndrome. Grade 2 2 2 = etoposide = 800 mg/m and melphalan = 140 mg/m ). In contrast to the preceding study on Bu-based conditioning, granulocyte and 88 platelet recovery times were longer with BuEM than BEAM (P = 0.001 and P = 0.025, respectively). Grade 1–2 infectious 34 years 58 (27 complications (P = 0.006), grade 3–4 mucositis (6.8% versus 46%, HL 28 o DLCL 22 Po0.001) and digestive complications were more frequent in the non-Hodgkin T-cell lymphoma; NK/TCL gemcitabine+busulfan+melphalan; HL = Sakellari et al.

= BuEM group than in the BEAM group. Surprisingly, erythrocyte and platelet transfusion rates were lower (Po0.001) in the BuEM 18%, respectively.

– group. In terms of efﬁcacy, the authors reported an improved 2- 76

busulfan+cyclophosphamide+etoposide; BuEM year OS for BuEM compared with BEAM in patients with HL (96.2% =

60 years 54% versus 77.3%; P = 0.05) and a better PFS with BuEM for HL 32 peripheral T-cell lymphoma; SOS LBCL o

= compared with NHL (85.1% versus 41%, P=0.017). 54% and 6 – Shin et al. Using a historical comparison of consecutive studies, MD

68.6% at 2 years 79.8% at 2 years 76% at 12 months 22.6 months 84% at 3 yearsAnderson 64.5% at 3 years 72% at 2 years (HL) evaluated gemcitabine, Bu and melphalan conditioning in patients with refractory or relapsed HL. Despite the higher 74 percentage of patients who were PET-positive at the time of

72) 80% auto-HSCT, the EFS and OS were signiﬁcantly higher than those for – follicular lymphoma; GemBuMel 9 Idem BEAM 10 — — 13 Idem BEAM 13 Bu/M (57% and 82% versus 33% and 52%, respectively). Notably, = (231) Bu administration was based on a single extemporaneous Intermediate non-Hodgkin B-cell lymphoma; NHTCL pharmacokinetic analysis that was not reproducible in all centers. Copelan et al. High grade (56) = polymorphonuclear; PTCL NHL indolent (95) Intravenous Bu in a single daily dose (3.2 mg/kg/day over 3 h) is = approved in France for use in allo-HSCT for reduced-intensity (%) conditioning; this includes the combination of Bu and ﬂudarabine. n (%) 10 (2.6) 4 (15.6)Several 0% recent studies 2.9% have investigated 2 the use of intravenous 3 (9.7%) n Bu as a single daily dose in patients undergoing auto-HSCT, and a event-free survival; FL

BCNU+etoposide+aracytine+melphalan; BuCyE tolerance that seems equivalent to standard fractionated doses = = has been observed. The ﬁrst study evaluated 47 children with Burkitt lymphoma or other solid tumors. Bu was used with rst line 32 (100) 50 (100) 110 (81) 10 (46) 36 (97) 0 (0) ﬁ melphalan and thiotepa or high-dose Cy. The authors of this study reported a 0% TRM rate with no cases of SOS after a median Main toxicities of busulfan-based conditioning regimens follow-up of 18 months.83 Mucositis and gastroenteritis were reported at rates of 6 non-Hodgkin lymphoma; NHBCL 84,85 82 = In 2013, Blanes et al. compared 51 patients with myeloma 20 G/L (days) First lineMore than 0 (0) 0 (0) 26 (19) 12 (54) 1 (3) 31 (100) 133 (100) 0.5 G/L (days) who received Bu and melphalan (n = 140) versus 102 patients who TypeNo of patientsHistology No of patients 382 BuCyE Bu-based 32 BuEM 50 BuCyE 136 BuCyE 22 Flu-Bu BuCyE 37 GemBuMel 31 133 Median PFSMedian OS 46.9% at 3 years 56.3% at 2 years 65.6% at 2 years 74% at 12 months 11.3 months 47% at 5 years in FL 64.5% at 3 years 54% at 2 years (HL) Toxicity-related mortality, Platelet recovery time 4 Age, median (range) 49 (16 Disease status at transplant, PMN recovery time 4 B-cell lymphoma; EFS Table 4. Abbreviations: BEAM NHL multifocal leukoencephalopathy; PMN et al. received melphalan at a dose of 200 mg/m2. Immediate toxicities

Bone Marrow Transplantation (2017) 941 – 949 © 2017 Macmillan Publishers Limited, part of Springer Nature. Conditioning regimens for lymphoma G Damaj et al 947 were equivalent. The TRM rate for the combination was 4% versus marrow transplantation for non-Hodgkin's lymphoma. J Clin Oncol 1999; 17: 2% for melphalan alone. SOS was not reported. Nieto et al.77 used 3128–3135. a single dose of Bu in combination with Gem and melphalan in 12 Fernandez HF, Escalon MP, Pereira D, Lazarus HM. Autotransplant conditioning 133 HL, 47 NHL and 7 myeloma cases. Toxicity appeared regimens for aggressive lymphoma: are we on the right road? Bone Marrow 40 – equivalent to other conditioning treatments, except for cutaneous Transplant 2007; :505 513. 13 Puig N, de la Rubia J, Remigia MJ, Jarque I, Martin G, Cupelli L et al. Morbidity and toxicity, which was related to gemcitabine dose. However, Bu was transplant-related mortality of CBV and BEAM preparative regimens for patients used under the control of daily monitoring and adaptation in with lymphoid malignancies undergoing autologous stem-cell transplantation. 77 accordance with area under the curve analysis. Nieto et al. Leuk Lymphoma 2006; 47: 1488–1494. reported another study comparing GemBuM with BEAM and BuM 14 Sharma A, Kayal S, Iqbal S, Malik PS, Raina V. Comparison of BEAM vs LEAM (Bu administered as a single dose). Toxicity seemed equivalent regimen in autologous transplant for lymphoma at AIIMS. Springerplus 2013; 2: between regimens; however, there were better survival results 489. with GemBuM.86 15 Leoni LM, Bailey B, Reifert J, Bendall HH, Zeller RW, Corbeil J et al. Bendamustine (Treanda) displays a distinct pattern of cytotoxicity and unique mechanistic fea- tures compared with other alkylating agents. Clin Cancer Res 2008; 14:309–317. CONCLUSION 16 Darwish M, Bond M, Hellriegel E, Robertson P Jr, Chovan JP. Pharmacokinetic and pharmacodynamic profile of bendamustine and its metabolites. Cancer In the absence of prospective comparative studies, it is difficult to Chemother Pharmacol 2015; 75: 1143–1154. recommend one conditioning regimen (Supplementary Table 5) 17 Dubbelman AC, Rosing H, Darwish M, D'Andrea D, Bond M, Hellriegel E et al. over another because there is a lack of an acceptable level of Pharmacokinetics and excretion of 14C-bendamustine in patients with relapsed scientific evidence. The choice of a conditioning regimen could or refractory malignancy. Drugs R D 13:17–28. not be evaluated based on efficacy because of the heterogeneity 18 Strumberg D, Harstrick A, Doll K, Hoffmann B, Seeber S. Bendamustine of the studied population and the disease types included in past hydrochloride activity against doxorubicin-resistant human breast carcinoma cell lines. Anticancer Drugs 1996; 7:415–421. cohorts, which have different prognostic factors. 19 Bremer K. High rates of long-lasting remissions after 5-day bendamustine Nevertheless, we propose that choosing a regimen should be chemotherapy cycles in pre-treated low-grade non-Hodgkin's-lymphomas. based on conditioning toxicity, known efficacy of certain drugs, J Cancer Res Clin Oncol 2002; 128:603–609. tumor location, drug approval by competing authorities, such as 20 Cheson BD, Wendtner CM, Pieper A, Dreyling M, Friedberg J, Hoelzer D et al. for thiotepa and Busulfan, and drug cost. Finally, the necessity of Optimal use of bendamustine in chronic lymphocytic leukemia, non-Hodgkin prioritizing participation in ongoing clinical trials should not be lymphomas, and multiple myeloma: treatment recommendations from an overlooked. international consensus panel. Clin Lymphoma Myeloma Leuk 10:21–27. 21 Bergmann MA, Goebeler ME, Herold M, Emmerich B, Wilhelm M, Ruelfs C et al. 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