Univ Fed Juiz de Fora, Div Hematol & Bone Marrow Transplantat, Juiz de Fora, MG, BrazilMed Univ S Carolina, Div Hematol Oncol, Charleston, SC 29425 USAUniv Fed Juiz de Fora, Div Clin Med, Juiz de Fora, MG, BrazilUniversidade Federal de São Paulo, Div Hematol, São Paulo, BrazilUniversidade Federal de São Paulo, Div Hematol, São Paulo, BrazilWeb of Scienc

Atalla, A.

Costa, L. J.

Hallack-Neto, A. E.

Pereira, J. [UNIFESP]

Santos, K. B. dos

Bone Marrow Transplantation

K B dos Santos

L J Costa

A Atalla

J Pereira

A E Hallack-Neto

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Lomustine use in combination with etoposide, cytarabine and melphalan in a brief conditioning regimen for auto-HSCT in patients with lymphoma: the optimal dose

Repositório Institucional UNIFESP

LETTER TO THE EDITORLomustine use in combination with etoposide, cytarabine andmelphalan in a brief conditioning regimen for auto-HSCTin patients with lymphoma: the optimal doseBone Marrow Transplantation (2014) 49, 1239–1240; doi:10.1038/bmt.2014.121; published online 2 June 2014Autologous hematopoietic SCT (auto-HSCT) is widely employed asconsolidation therapy in aggressive Non-Hodgkin lymphoma(NHL) and relapsed or refractory classic Hodgkin's lymphoma.However, there is no evidence regarding the best conditioningregimen to be used. New schemes have therefore been proposedto reduce the toxicity, costs related to the procedure andhospitalization time, without compromising the quality of lifeand survival of patients.1 The maximum recommended dose oflomustine (CCNU) associated with etoposide and cyclophospha-mide has been 600 mg/m2.2,3 However, when it is associated witha combination of etoposide, ara-C and cyclophosphamide, oretoposide, ara-C and melphalan, a dose of 200mg/m2 has beenused.4–6Although the success of auto-HSCT depends on severalvariables, the lower the toxicity and the duration of neutropeniathe smaller the treatment-related mortality.Given that lomustine has low pulmonary toxicity, is easy toadminister, and does not yet have a deﬁned maximum tolerateddose (MTD) when used in combination with melphalan, ara-C andetoposide for conditioning regimens in auto-HSCT in patientswith lymphoma, we proposed to carry out a phase 1 study withdose escalation of lomustine.2 The study was approved by thelocal ethics committee under the number 139-420-2011, CAAE0102.0.420.000-11.To determine the MTD of lomustine we realized a prospectivestudy with a traditional 3:3 dose scaling, with three cohortsinvolving three patients. If a patient presented dose-limitingtoxicity (DLT), three more patients were included in the samecohort. If two patients exhibited DLT, then the dosage used bythat cohort of patients was considered as exceeding MTD andanother intermediate dose to the one previously used was tested.The absence of medullary grafting or platelets after 30 days ofinfusion of HSC, or the presence of grade 4 non-hematologictoxicity, or grade 3 non-hematologic toxicity, such as a fever,infection, skin rash, fatigue, mucositis, electrolyte imbalance,dehydration, pain, glucose intolerance, pulmonary toxicity,acute toxicity related to treatment or death by any cause, wasdeﬁned as DLT.The initial cohort received lomustine (Citostal) at a dose of200mg/m2 (L200), and the subsequent cohort at a dose of400mg/m2 (L400). Because L400 exceeded the MTD, a thirdcohort with lomustine at a dose of 300 mg/m2 (L300) wasanalyzed. The lomustine was administered on day 4 of condition-ing, the other drugs were administered in the following days anddoses: etoposide 1000mg/m2 (day 3), cytarabine 4000mg/m2(day 2) and melphalan 140mg/m2 (day 1). The infusion of HSC wasadministered on day 0 (zero) 24 h after the end of melphalan.We evaluated 14 patients with a mean age of 36 years (16–58).Six patients had PR and eight were in CR at the time of auto-HSCT.The characteristics of the patients are described in Table 1.Six patients participated in the cohort L200, and since one outof six (16.5%) presented DLT (death by sepsis), three more patientshad to be included in this cohort. In the cohort L400, two out ofthe two (100%) patients presented DLT (grade 4 gastrointestinaltoxicity and sinusoidal obstruction syndrome). Given that400mg/m2 of lomustine proved to exceed the MTD, anothercohort with lomustine at a dose of 300 mg/m2 (L300) wasevaluated. From the three patients initially analyzed, one out ofthree (33.3%) presented reversible grade 4 neurological toxicity,which meant that three more patients had to be included in thiscohort. In the end, the dose of 300 mg/m2 was determined to bethe the MTD of lomustine. The main toxicities observed in patientsaccording to the WHO (World Health Organization) criteria aredescribed in Table 2.The patients received an average of 6.91 × 106 (1.37 to18.8 × 106) CD34+ cells per kg. The average length of hospitaliza-tion was 22 days (15–70) and the mean duration of neutropenia(neutrophil count o500/mm3) was 7.8 days (6–18), which wasbelow our historical control of 13 days observed with the CBVprotocol (cyclophosphamide, 1.2 g/m2/day on day -6, -5, -4 and -3;Carmustine, 300 mg/m2 on day -6; Etoposide, 200mg/m2/day,12/12 h on day -6, -5 and -4).7The grafting of neutrophils and platelets occurred on day +10and day +12 after auto-HSCT, respectively. Interestingly, weobserved a signiﬁcant reduction in the need for hemocomponentscompared with our historical series. Only 6/14 (42.8%) patientsneeded RBC transfusion and 4/14 (28.5%) patients did not requireany transfusion support.Table 1. Characterization of patientsCharacteristics N %GenderMale 8 57.1Female 6 42.9Hodgkin lymphomaNodular sclerosis 7 50Mixed cellularity 1 7.1Non-Hodgkin LymphomaDiffuse large B-cell lymphoma 3 21.4Follicular lymphoma 1 7.1Mantle cell lymphoma 1 7.1T-cell lymphoma, NOS 1 7.1BulkyYes 8 57.1No 6 42.9StatusPartial remission 6 42.9Complete remission 8 57.1Abbreviation: NOS= not otherwise speciﬁed.Bone Marrow Transplantation (2014) 49, 1239–1240© 2014 Macmillan Publishers Limited All rights reserved 0268-3369/14www.nature.com/bmtOur results conﬁrm recent study data, which found low toxicityand a medullary grafting time similar to ours using lomustine at adose of 200 mg/m2, also associated with ara-c, etoposide andmelphalan.5 In the same way, higher doses of lomustine havebeen used in other chemotherapy schemes because of its lowerpulmonary toxicity when compared with carmustine. Pulmonarytoxicity usually occurs with lomustine when doses higher than1000mg/m2 are used.2,3In our study we were therefore able to develop a new protocolusing conventional doses of lomustine, which allowed us toreduce the hospitalization time and the days of conditioning, butwithout reducing the number of drugs recommended or theplanned total dose. In addition, we reduced the period ofneutropenia and the hospitalization time compared with theconditioning protocol previously used in our institution.At the same time, we evaluated the MTD of lomustine inassociation with ara-c, etoposide and melphalan. We observed1/14 (7.2%) deaths from pneumonia during the hospitalizationand 3/14 (21.4%) patients presented grade 4 toxicity, one with adose of 300mg/m2 and two with 400mg/m2. We thereforeestablished the MTD to be 300 mg/m2 for lomustine combinedwith high doses of etoposide, Ara-C and melphalan in condition-ing of auto-HSCT in patients with lymphoma.In conclusion, the LEAM protocol (lomustine, 300mg/m2 on day4; etoposide, 1000mg/m2 on day 3; cytarabine, 4000mg/m2 onday 2 and melphalan, 140mg/m2 on day 1), proved to be afeasible conditioning regimen that could be administered rapidly,associated with a short period of neutropenia and acceptabletoxicity. We are currently conducting a phase 2 study with a doseof 300mg/m2 of lomustine.CONFLICT OF INTERESTThe authors declare no conﬂict of interest.KB dos Santos1, LJ Costa2, A Atalla3, J Pereira4 andAE Hallack-Neto31Universidade Federal de Juiz de Fora, Division of Hematology andBone Marrow Transplantation, Minas Gerais, Brazil;2Medical University of South Carolina, Division of Hematology/Oncology, Charleston, SC, USA;3Universidade Federal de Juiz de Fora, Division of Clinical Medical,Minas Gerais, Brazil and4Universidade Federal de São Paulo, Division of Hematology,São Paulo, BrazilE-mail: abrahallack@uol.com.brREFERENCES1 Visani G, Malerba L, Stefani PM, Capria S, Galieni P, Gaudio F et al. BeEAM(bendamustine, etoposide, cytarabine, melphalan) before autologous stem celltransplantation is safe and effective for resistant/relapsed lymphoma patients.Blood 2011; 118: 3419–3425.2 Chao NJ, Kastrissios H, Long GD, Negrin RS, Homing SJ, Wong RM et al. A newpreparatory regimen for autologous bone marrow transplantation for patients withlymphoma. Cancer 1995; 75: 1354–1359.3 Stuart MJ, Chao NS, Horning SJ, Wong RM, Negrin RS, Johnston LJ et al. Efﬁcacy andtoxicity of a CCNU-containing high-dose chemotherapy regimen followed byautologous hematopoietic cell transplantation in relapsed or refractory hodgkin’sdisease. Biol Blood Marrow Transplant 2001; 7: 552–560.4 Perz JB, Giles C, Szydlo R, O’Shea D, Sanz J, Chaidos A et al. LACE-conditionedautologous stem cell transplantation for relapsed or refractory Hodgkin’s lym-phoma: treatment outcome and risk factor analysis in 67 patients from asingle centre. Bone Marrow Transplant 2007; 39: 41–47.5 Ramzi M, Mohamadian M, Vojdani R, Dehghani M, Nourani H, Zakerinia M,Haghighinejad H. Autologous noncryopreserved hematopoietic stem cell trans-plant With CEAM as a modiﬁed conditioning regimen in patients with hodgkinlymphoma: a single-center experience with a new protocol. Exp Clin Transplant2012; 10: 163–167.6 Hallack Neto AE, Santos KB, Atalla A. Modiﬁed BEAM conditioning regimen inpatients with Hodgkin and Non-Hodgkin lymphomas. Exp Clin Transplant 2012;10: 622.7 Santos KB, Hallack Neto AE, Silva GA, Atalla A, Abreu MM, Ribeiro LC. Infectionproﬁle of patients undergoing autologous bone marrow transplantation in aBrazilian institution. Sao Paulo Med J 2012; 130: 10–16.Table 2. Toxicities of the analyzed patientsToxicity N %Temporary alopeciaGrade I 0 0Grade II 2 14.3Grade III 12 85.7Grade IV 0MucositisGrade I 2 14.2Grade II 1 7.1Grade III 1 7.1Grade IV 0 0Gastro-intestinal toxicityGrade I 4 28.5Grade II 2 14.2Grade III 3 21.4Grade IV 0Cutaneous toxicityGrade I 1 7.1Grade II 0 0Grade III 0 0Grade IV 0 0Renal toxicityGrade I 1 7.1Grade II 0 0Grade III 0 0Grade IV 0 0Neurological toxicityGrade I 1 7.1Grade II 0 0Grade III 0 0Grade IV 0 0Sinusoidal obstruction syndrome 2 14.2Infection 7 50Letter to the Editor1240Bone Marrow Transplantation (2014) 1239 – 1240 © 2014 Macmillan Publishers Limited

Lomustine use in combination with etoposide, cytarabine and melphalan in a brief conditioning regimen for auto-HSCT in patients with lymphoma: the optimal dose

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