Letters to the Editor 1233 than the steady state plasmatic concentration. These data 1Pediatric Hematology and Oncology Unit ‘Lalla Sera`gnoli’, University of Bologna, Bologna, Italy; suggest that tipifarnib efficacy could be tested in ETP-ALL 2 patients using well-tolerated dosages. Sensitivity to tipifarnib Interdepartmental Centre for Cancer Research ‘G. Prodi’, University of Bologna, Bologna, Italy and was recently associated with RASGRP1/APTX expression 3 8 Department of Human Anatomical Sciences, University of ratio in acute myeloid leukemia, but we found no significant Bologna, Bologna, Italy correlation between the expression of these predictor signature E-mail: [email protected] and drug sensitivity. Therefore, the mechanism of action of 4These authors contributed equally to this work. farnesyltransferase inhibitors in pediatric T-ALL requires further investigations, as confirmed by early studies that showed no correlation between the presence of Ras mutations and the References response to tipifarnib.6 In fact, even if farnesylation is the dominant class of post-translational modification that activates 1 Coustan-Smith E, Mullighan CG, Onciu M, Behm FG, Raimondi SC, RAS, there are other types of prenylation not inhibited by Pei D et al. Early T-cell precursor leukaemia: a subtype of very high- farnesyltransferase inhibitors that allow RAS attachment to the risk acute lymphoblastic leukaemia. Lancet Oncol 2009; 10: 147–156. cell membrane and its participation in signal transduction.6 2 Bell JJ, Bhandoola A. The earliest thymic progenitors for T cells Indeed, we can suppose that tipifarnib activity in ETP-ALL cells is possess myeloid lineage potential. Nature 2008; 452: 764–767. 3 Balgobind BV, Van Vlierberghe P, van den Ouweland AM, Beverloo at least in part, even if not completely, explained by NF1 HB, Terlouw-Kromosoeto JN, van Wering ER et al. Leukemia- inactivation. More experimental data are needed to clarify the associated NF1 inactivation in patients with pediatric T-ALL and real sensitivity of ETP-ALL cells to tipifarnib. This is the first report AML lacking evidence for neurofibromatosis. Blood 2008; 111: showing a case of pediatric ETP-ALL with high sensitivity to 4322–4328. tipifarnib that could be related to a specific gene (NF1) deletion. 4 Martinelli G, Iacobucci I, Paolini S, Ottaviani E. Farnesyltransferase Thus, additional studies are needed to analyze NF1 role in inhibition in hematologic malignancies: the clinical experience with tipifarnib. Clin Adv Hematol Oncol 2008; 6: 303–310. patients with ETP-ALL and tipifarnib sensitivity to improve the 5 Brandwein JM, Leber BF, Howson-Jan K, Schimmer AD, Schuh AC, outcome of this newly identified high-risk subtype of ALL. Gupta V et al. A phase I study of tipifarnib combined with conventional induction and consolidation therapy for previously untreated patients with acute myeloid leukemia aged 60 years and Conflict of interest over. Leukemia 2009; 23: 631–634. 6 Goemans BF, Zwaan CM, Harlow A, Loonen AH, Gibson BE, The authors declare no conflict of interest. Ha¨hlen K et al. In vitro profiling of the sensitivity of pediatric leukemia cells to tipifarnib: identification of T-cell ALL and FAB M5 AML as the most sensitive subsets. Blood 2005; 106: 3532–3537. 7 Widemann BC, Salzer WL, Arceci RJ, Blaney SM, Fox E, End D et al. Acknowledgements Phase I trial and pharmacokinetic study of the farnesyltransferase inhibitor tipifarnib in children with refractory solid tumors or We thank the Association ‘Morgan di Gianvittorio’ for funding and neurofibromatosis type I and plexiform neurofibromas. J Clin Oncol Ageop for support. 2006; 24: 507–516. 8 Raponi M, Lancet JE, Fan H, Dossey L, Lee G, Gojo I et al. A 2-gene 1,4 2,4 1 1 C Biagi , A Astolfi , R Masetti , S Serravalle , classifier for predicting response to the farnesyltransferase inhibitor M Franzoni1, F Chiarini3, F Melchionda1 and A Pession1 tipifarnib in acute myeloid leukemia. Blood 2008; 111: 2589–2596.

Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

Stem cell collection in patients with de novo treated with the combination of and dexamethasone before autologous stem cell transplantation according to IFM 2005–01 trial

Leukemia (2010) 24, 1233–1235; doi:10.1038/leu.2010.82; Patients were centrally randomized (1:1:1:1) to receive VAD published online 29 April 2010 induction plus no consolidation (arm A1), VAD plus dexa- methasone, , and cis-platinum consolidation (A2), bortezomib–dexamethasone plus no The aim of the IFM2005-01 phase 3 multicenter study (EudraCT consolidation (B1) or bortezomib–dexamethasone plus dexa- 2005–000537–38, Clinicaltrials.gov NCT00200681) was to methasone, cyclophosphamide, etoposide and cis-platinum compare prospectively efficacy and safety of bortezomib and consolidation (B2). VAD comprised four 4-week cycles of dexamethasone with ––dexamethasone vincristine 0.4 mg/day and doxorubicin 9 mg/m2/day by con- (VAD) as induction before autologous stem cell transplantation tinuous infusion, days 1–4, plus dexamethasone 40 mg orally on (ASCT) in patients with previously untreated myeloma less days 1–4 (all cycles) and 9–12 and 17–20 (cycles 1–2). than 66 years of age. The primary end point was post-induction Bortezomib–dexamethasone comprised four 3-week cycles of complete response and near-complete response rate. An bortezomib 1.3 mg/m2 intravenously, days 1, 4, 8 and 11, plus important issue raised by this study was that of stem cell dexamethasone 40 mg on days 1–4 (all cycles) and 9–12 (cycles collection in the bortezomib–dexamethasone arm.1,2 1–2). Dexamethasone, cyclophosphamide, etoposide and

Leukemia Letters to the Editor 1234 Table 1 Stem cell harvest

Patients VAD Arm Bortezomib–dexamethasone arm, P-value A ¼ A1+A2, N ¼ 242 B ¼ B1+B2, N ¼ 240

Evaluable population for stem collection, N 216 225 Median yield after one mobilization with G-CSF, 106 CD34+ cells/kg 8.50 (0–27.9) 6.80 (0–23.3) o0.0001 Mean number of cytaphereses 1.63 2.05 o0.0001 Patients with yields o5 Â 106 cells/kg 11% 23% 0.0005 Patients with yields o2 Â 106 cells/kg 2% 3% 0.10 Patients undergoing second mobilization with cyclophosphamide 13% 25% 0.0009 Patients with yields o5 Â 106 cells/kg after two mobilizations 5% 6% 0.75 Patients with yields o2 Â 106 cells/kg after two mobilizations 0% 0.4% 1 Abbreviations: G-CSF, granulocyte-colony-stimulating factor; VAD, vincristine–doxorubicin–dexamethasone.

Table 2 First ASCT

Patients VAD Arm Bortezomib–dexamethasone arm P-value A ¼ A1+A2, N ¼ 200 B ¼ B1+B2, N ¼ 207

Median 106 CD34+ cells/kg infused 3.77 3.16 0.0003 Duration hospitalization, median (days) 19 18 0.054 Duration G-CSF median (days) 7 6 0.09 Days o500 PMN median 7 7 0.66 Days o20 000 platelets median 1 1 0.43 Nb transfusion red blood cells median 1 0 0.051 Nb transfusion platelets median 1 1 0.63 Nb days i.v. antibiotics median 9 8 0.11 Toxic death 2 1 0.61 Abbreviations: ASCT, autologous stem cell transplantation; G-CSF, granulocyte-colony-stimulating factor; i.v., intravenous; Nb, number; PMN, neutrophils; VAD, vincristine–doxorubicin–dexamethasone.

cis-platinum comprised two 4-week cycles of dexamethasone yields of 8.50 and 6.80 Â 106 CD34 þ cells/kg were obtained 40 mg, days 1–4, plus cyclophosphamide 400 mg/m2, etoposide from patients receiving VAD and bortezomib–dexamethasone, 40 mg/m2 and cis-platinum 15 mg/m2 per day by continuous respectively, with a mean of 1.63 and 2.05 aphereses (Table 1). infusion, on days 1–4. Stem cell mobilization was under- In total, 98 and 97% of patients, respectively, had yields taken with granulocyte-colony-stimulating factor (G-CSF) 42 Â 106 cells/kg, and 11 and 23%, respectively, had 10 mg/kg/day from day 15 of the third induction cycle. If stem yields o5 Â 106 cells/kg. Thirteen and 25% of patients, cell collection was inadequate, a second mobilization was respectively, underwent a second mobilization with cyclo- undertaken with cyclophosphamide 3 g/m2 plus G-CSF 5 mg/kg/ phosphamide þ G-CSF. After this second procedure, no patient day after induction cycle 4. The target yield was 5 Â 106 in arm A and only 1 in arm B had yields o 2 Â 106 cells/kg, and CD34 þ cells/kg allowing a tandem transplant procedure. 5% of patients in arm A and 6 % of patients in arm B had yields Conditioning for the first transplant comprised o5 Â 106 cells/kg precluding a tandem transplant procedure, 200 mg/m2. Response was evaluated 1–3 months later. A if needed. second transplant was not conducted for patients achieving at Of the evaluable population, 200 (82.6%) and 207 (86.2%) least very good partial response. Patients achieving less than patients who had received VAD and bortezomib–dexametha- very good partial response could undergo a second autologous sone induction, respectively, underwent a first ASCT. Thus, procedure. despite adequate stem cell collection, high-dose melphalan and A total of 493 patients were enrolled and 482 were rando- ASCT were not performed in 34 patients, due to progressive mized; 242 received VAD induction (arm A: 121 A1, 121 A2) disease (15 cases), patient’s refusal (3), renal function impair- and 240 received bortezomib–dexamethasone (arm B: 121 B1, ment (2), severe infections (6), poor performance status 119 B2). A better response rate was observed in bortezomib– (4), respiratory failure (2), precluding high-dose therapy or toxic dexamethasone arm. Results for both efficacy and toxicity of deaths after stem cell mobilization (2). A median number of induction therapy will be reported in depth elsewhere.3 3.77 and 3.16 Â 106 CD34 þ cells/kg were infused in patients A total of 441 out of 482 patients were evaluable for stem enrolled in arm A and arm B, respectively, during the first cell collection, 216 in VAD and 225 in bortezomib–dexametha- ASCT procedure (Table 2). There was no difference regarding sone arms, respectively. Overall, 41 randomized patients duration of hospitalization, duration of neutropenia or did not receive G-CSF for stem cell collection due to progressive thrombocytopenia, transfusion requirements, duration of disease (8 cases), toxic deaths (8), severe adverse events G-CSF administration or antibiotic uses in the 2 arms of the (17), patient’s refusal (2), poor performance status (4), diagnosis trial. Two toxic deaths were observed in arm A (1%) versus 1 in of lung cancer during treatment (1), diagnosis of amyloidosis arm B (0.5%). A better response rate following the ASCT was during treatment (1). After one mobilization with G-CSF, median observed in bortezomib–dexamethasone arm, and results for

Leukemia Letters to the Editor 1235 outcome and for the need of a second ASCT will be reported in 9Hematology Department, Centre Paoli-Calmettes, 3 Marseille, France; depth elsewhere. 10 The IFM2005-01 trial showed the superiority of bortezomib– Hematology Department, University Hospital, Bobigny, France; dexamethasone over VAD before ASCT. Other recent studies 11 4–6 Hematology Department, University Hospital, Lyon, France; also indicate that this combination is highly effective and 12Hematology Department, University Hospital, could be considered as the backbone of induction regimens 7–9 Tours, France; before high-dose therapy. 13Hematology Department, University Hospital, We here report that a single mobilization with G-CSF was La Roche-sur-Yon, France; adequate and allowed the harvest of a sufficient number of 14Hematology Department, University Hospital, CD34 þ cells for a single transplant in 97% and for a tandem Louvain, Belgium; 15 transplant in 77% of the patients treated upfront with Hematology Department, University Hospital, Lausanne, Switzerland; bortezomib–dexamethasone. Thus, less than one-fourth of 16 the patients of the bortezomib–dexamethasone arm required Hematology Department, Institut Curie, Paris, France; 17Hematology Laboratory, University Hospital, subsequent potentially toxic chemomobilization with cyclo- 6 Nantes, France; phosphamide plus G-CSF to reach the target yield of 5 Â 10 18Hematology Department, University Hospital, CD34 þ cells/kg. In comparison with VAD, the median Toulouse, France and number of CD34 þ cells harvested in the bortezomib– 19Centre Rene´ Gauducheau, Saint-Herblain, France dexamethasone arm was significantly lower without impairing E-mail: [email protected] the ability of performing ASCT. An identical number of patients in both arms of the study (98 and 97%, respectively) had yields 42 Â 106 CD34 þ cells/kg high enough to perform a single References ACST, but a higher number of patients in the bortezomib– dexamethasone arm required a second mobilization using 1 Giralt S, Stadtmauer EA, Harousseau JL, Palumbo A, Bensinger W, 6 Comenzo RL et al. International myeloma working group (IMWG) cyclophosphamide plus G-CSF to reach the target of 5 Â 10 consensus statement and guidelines regarding the current status of CD34 þ cells/kg. This is not surprising as doxorubicin infused stem cell collection and high-dose therapy for multiple myeloma and with the VAD regimen induces some degree of cytopenia the role of plerixafor (AMD 3100). Leukemia 2009; 23: 1904–1912. improving stem cell harvest after G-SCF priming. The course of 2 Kumar S, Giralt S, Stadtmauer EA, Harousseau JL, Palumbo A, the first ASCT was very similar across the two arms of the study, Bensinger W et al. Mobilization in myeloma revisited: IMWG despite a lower median number of CD34 þ cells infused in the consensus perspectives on stem cell collection following initial therapy with thalidomide-, lenalidomide-, or bortezomib-contain- bortezomib–dexamethasone arm. Hematologic recovery was ing regimens. Blood 2009; 114: 1729–1735. identical as well as transfusion requirements and duration of 3 Harousseau JL, Attal M, Avet-Loiseau H, Marit G, Caillot D, hospitalization. Mohty M, et al. Bortezomib-dexamethasone is superior to vincris- This study, the largest one reporting on stem cell collection tine-doxorubicin-dexamethasone as induction prior to autologous after bortezomib–dexamethasone as induction prior to ASCT, stem cell transplantation in newly diagnosed multiple myeloma: provides important informations for the management of myelo- results of the IFM2005-01 phase 3 trial. J Clin Oncol 2010, in press. 4 Harousseau J-L, Attal M, Leleu X, Troncy J, Pe´gourie´ B, Stoppa AM ma patients treated with high-dose therapy in the era of et al. Bortezomib plus dexamethasone as induction treatment prior novel agents. to autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: results of an IFM phase II study. Haematologica 2006; 91: 1498–1505. 5 Jagannath S, Durie BG, Wolf JL, Camacho ES, Irwin D, Lutzky J et al. Conflict of interest Bortezomib therapy alone and in combination with dexamethasone for previously untreated symptomatic multiple myeloma. The authors declare no conflict of interest. Br J Haematol 2005; 129: 776–783. 6 Rosin˜ol L, Oriol A, Mateos MV, Sureda A, Garcia-Sanchez P, P Moreau1, C Hulin2, G Marit3, D Caillot4, T Facon5, Gutierrez N et al. Phase II PETHEMA trial of alternating bortezomib P Lenain6, C Berthou7,BPe´gourie´8, AM Stoppa9, and dexamethasone as induction regimen before autologous P Casassus10, M Michallet11, L Benboubker12, stem-cell transplantation in younger patients with multiple H Maisonneuve13, C Doyen14, S Leyvraz15, C Mathiot16, myeloma: efficacy and clinical implications of tumor response H Avet-Loiseau17, M Attal18 and JL Harousseau19, on behalf kinetics. J Clin Oncol 2007; 25: 4452–4458. the IFM group 7 Popat R, Oakervee HE, Hallam S, Curry N, Odeh L, Foot N et al. 1Hematology Department, University Hospital, Bortezomib, doxorubicin and dexamethasone (PAD) front-line Nantes, France; treatment of multiple myeloma: updated results after long-term 2Hematology Department, University Hospital, follow-up. Br J Haematol 2008; 141: 512–516. Nancy, France; 8 Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, 3 Galli M et al. A phase III study of double autotransplantation Hematology Department, University Hospital, incorporating bortezomib-thalidomide-dexamethasone (VTD) Bordeaux, France; 4 or thalidomide-dexamethasone (TD) for multiple myeloma: Hematology Department, University Hospital, Dijon, France; superior clinical outcomes with VTD compared to TD. Blood 5Hematology Department, University Hospital, Lille, France; 6 2009; 114: 351a. Hematology Department, Centre Henri Be´cquerel, 9 Richardson P, Lonial S, Jakubowiak A, Jagannath S, Raje NS, Avigan Rouen, France; DE et al. High response rates and encouraging time-to-event data 7 Hematology Department, University Hospital, Brest, France; with lenalidomide, bortezomib, and dexamethasone in newly 8 Hematology Department, University Hospital, diagnosed multiple myeloma: final results of a phase I/II study. Grenoble, France; Blood 2009; 114: 1218a.

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