Letters to the Editor 252 Table 1. Results of multivariate analysis for event-free survival, overall REFERENCES survival and relapse-free survival 1 Hasle H, Clemmensen IH, Mikkelsen M. Risks of leukaemia and solid tumours in individuals with Down’s syndrome. Lancet 2000; 355: 165–169. Outcome Variable HR 95% CI P-value 2 Whitlock JA, Sather HN, Gaynon P, Robison LL, Wells RJ, Trigg M et al. Clinical characteristics and outcome of children with Down syndrome and acute lympho- EFS BTG1 1.97 0.57–6.84 0.29 blastic leukemia: a Children’s Cancer Group study. Blood 2005; 106: 4043–4049. IKZF1 2.45 1.18–5.07 0.02 3 Buitenkamp T, Forestier E, Heerema NA, van den Heuvel MM, Pieters R, de Haas V ETV6–RUNX1 0.22 0.03–1.74 0.15 et al. Acute Lymphoblastic Leukemia in children with Down Syndrome: a report from WBC X50 Â 109 2.55 0.88–7.39 0.08 the Ponti di Legno Study group. ASH: San Diego, 2011. Age X10 years 1.29 0.59–2.85 0.52 4 Forestier E, Izraeli S, Beverloo B, Haas O, Pession A, Michalova K et al. Cytogenetic features of acute lymphoblastic and myeloid leukemias in pediatric patients with OS BTG1 2.24 0.63–7.91 0.21 Down syndrome: an iBFM-SG study. Blood 2008; 111: 1575–1583. IKZF1 2.02 0.95–4.29 0.06 5 Hertzberg L, Vendramini E, Ganmore I, Cazzaniga G, Schmitz M, Chalker J et al. ETV6–RUNX1 0.21 0.03–1.67 0.14 Down syndrome acute lymphoblastic leukemia, a highly heterogeneous disease WBC X50 Â 109 2.49 0.85–7.26 0.09 in which aberrant expression of CRLF2 is associated with mutated JAK2: a report AgeX 10 years 1.20 0.52–2.76 0.66 from the International BFM Study Group. Blood 2010; 115: 1006–1017. 6 Mullighan CG, Collins-Underwood JR, Phillips LA, Loudin MG, Liu W, Zhang J et al. Abbreviations: CI, confidence interval; EFS, event-free survival; HR, hazard Rearrangement of CRLF2 in B-progenitor- and Down syndrome-associated acute ratio; OS, overall survival. lymphoblastic leukemia. Nat Genet 2009; 41: 1243–1246. 7 Mullighan CG, Goorha S, Radtke I, Miller CB, Coustan-Smith E, Dalton JD et al. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature 2007; 446: 758–764. ACKNOWLEDGEMENTS 8 Buitenkamp TD, Pieters R, Gallimore NE, van der Veer A, Meijerink JP, Beverloo HB et al. Outcome in children with Down syndrome and acute lymphoblastic This study was supported by research funding from the foundation Kinderen leukemia: role of IKZF1 deletions and CRLF2 aberrations. Leukemia 2012; e-pub Kankervrij (KIKA) to TDB and CMZ and the Leukemia and Lymphoma Research (LLR) ahead of print 22 March 2012; doi:10.1038/leu.2012.84. to CS, CJH and AVM. 9 Kuiper RP, Schoenmakers EF, van Reijmersdal SV, Hehir-Kwa JY, van Kessel AG, van Leeuwen FN et al. High-resolution genomic profiling of childhood ALL reveals novel recurrent genetic lesions affecting pathways involved in lymphocyte dif- ferentiation and cell cycle progression. Leukemia 2007; 21: 1258–1266. TD Buitenkamp1, R Pieters1,2, M Zimmermann3, V de Haas2, 10 Tsuzuki S, Karnan S, Horibe K, Matsumoto K, Kato K, Inukai T et al. Genetic SM Richards4, AJ Vora5, CD Mitchell6, C Schwab7, CJ Harrison7, abnormalities involved in t(12;21) TEL-AML1 acute lymphoblastic leukemia: AV Moorman7, MM van den Heuvel-Eibrink1 and CM Zwaan1 analysis by means of array-based comparative genomic hybridization. Cancer Sci 1Pediatric Oncology/Hematology, Erasmus MC–Sophia 2007; 98: 698–706. 11 Rouault JP, Rimokh R, Tessa C, Paranhos G, Ffrench M, Duret L et al. BTG1, a Children’s Hospital, Rotterdam, The Netherlands; 2 member of a new family of antiproliferative genes. Embo J 1992; 11: 1663–1670. Dutch Childhood Oncology Group, Den Haag, The Netherlands; 12 Rimokh R, Rouault JP, Wahbi K, Gadoux M, Lafage M, Archimbaud E et al. A 3 Acute Myeloid Leukemia-Berlin-Frankfurt-Mu¨nster Study Group, chromosome 12 coding region is juxtaposed to the MYC protooncogene locus in Pediatric -Hematology/Oncology, Medical School Hannover, a t(8;12)(q24;q22) translocation in a case of B-cell chronic lymphocytic leukemia. Hannover, Germany; Genes Chromosomes Cancer 1991; 3: 24–36. 4Clinical Trial Service Unit, University of Oxford, Oxford, UK; 13 Rouault JP, Samarut C, Duret L, Tessa C, Samarut J, Magaud JP. Sequence analysis 5Department of Haematology, Sheffield Children’s Hospital, reveals that the BTG1 anti-proliferative gene is conserved throughout evolution in Sheffield, UK; its coding and 3’ non-coding regions. Gene 1993; 129: 303–306. 6Department of Paediatric Haematology/Oncology, 14 Lundin C, Hjorth L, Behrendtz M, Nordgren A, Palmqvist L, Andersen MK et al. High frequency of BTG1 deletions in acute lymphoblastic leukemia in children John Radcliffe Hospital, Oxford, UK and 7 with down syndrome. Genes Chromosomes Cancer 2012; 51: 196–206. Leukaemia Research Cytogenetics Group, Northern Institute for 15 van Galen JC, Kuiper RP, van Emst L, Levers M, Tijchon E, Scheijen B et al. BTG1 Cancer Research, Newcastle University, Newcastle, UK regulates glucocorticoid receptor autoinduction in acute lymphoblastic leukemia. E-mail: [email protected] Blood 2010; 115: 4810–4819. Phase 1b study of lenalidomide in combination with rituximab-CHOP (R2-CHOP) in patients with B-cell lymphoma Leukemia (2013) 27, 252–255; doi:10.1038/leu.2012.172 association with standard 21-day R-CHOP (R2-CHOP). Dose of lenalidomide was assessed during the first two cycles. Secondary objectives were to assess the safety and efficacy of R2-CHOP for a We were very interested by the article by Nowakowski et al.1 maximum of six cycles. describing the combination of lenalidomide and R-CHOP Patients from 18 to 70 years of age had documented B-cell in patients with aggressive lymphoma. Our group conducted CD20-positive lymphoma: mantle cell lymphoma, marginal zone a similar phase 1b study of this combination in a lymphoma, lymphocytic lymphoma, follicular lymphoma, diffuse patient population with predominantly indolent B-cell large B-cell lymphoma or histological transformation from low lymphoma. grade to high grade lymphoma. Lenalidomide (5, 10, 15, 20 or The primary objective of the study was to determine the 25 mg once daily) was escalated in serial patient cohorts using a recommended dose of lenalinomide administered for 14 days in standard 3 þ 3 design. Each cycle of R2-CHOP comprised the Accepted article preview online 26 June 2012; advance online publication, 13 July 2012 Leukemia (2013) 233 – 258 & 2013 Macmillan Publishers Limited Letters to the Editor 253 dose of lenalidomide from day 1 to day 14 in combination with episodes occurred despite aspirin prophylaxis. One patient, the 375 mg/m2 of rituximab, 50 mg/m2 of doxorubicin, 750 mg/m2 of one who was 77 years old, had a pulmonary embolism and cyclophosphamide and 1.4 mg/m2 of vincristine (up to a maximal recovered rapidly with anticoagulation therapy and one patient dose of 2 mg, in 50–100 ml normal saline in 10–20 min i.v. infusion had a deep venous thrombosis related to the central catheter. after cyclophosphamide) on day 1 and 60 mg/m2 of prednisone Seven patients had a mild rash attributed to lenalidomide. We did on days 1 through 5. Pegfilgrastim was given at day 4 of each not observe grade 3–4 neuropathy but nine patients experienced cycle at a dose of 6 mg.2 Aspirin prophylaxis (100 mg daily) was grade 1 and four patients had grade 2 sensory neuropathy. mandatory during the study period. A prophylaxis of Two patients had vincristine discontinuation at cycle 4 and 6, Pneumocystic jirovecii pneumonia was recommended during respectively. the study and until 3 months after last cycle administration. Dose escalation was determined by the number of dose limiting toxicities (DLTs) observed during the administration of the two RESPONSE TO TREATMENT first cycles of R2-CHOP. DLTs were defined as any grade 3–4 non- Response according to lenalidomide dose is given in hematological toxicity, grade 3 neutropenia or thombocytopenia Supplemental Table 1. The overall response rate was 96%, with lasting more than 7 days, or grade 4 neutropenia or thombocy- 74% of patients achieving a complete remission (CR/CRu). topenia lasting more than 3 days. Once maximal tolerated dose Only one patient with disseminated follicular lymphoma had was reached, the cohort was expanded to a total of 12 patients. histological transformation with meningeal involvement after the There was no individual dose adjustment of lenalidomide. If a fifth cycle. patient experienced a DLT, lenalidomide treatment was defini- tively stopped and the patient continued on treatment with R-CHOP. There was no dose adjustment of R-CHOP in case DISCUSSION of hematological toxicity or failure to recover neutrophil count of Results of this 1b trial of the combination of R-CHOP and 1.5 Â 109/l or platelet count o100 Â 109/l at day 21, but the next lenalidomide confirm the results from Nowakowski et al.1 The cycle could be postponed for a maximum of 7 additional days toxicity profile was similar in the two studies resulting in (day 28). If grade 1 neurological toxicity was related to vincristine, infrequent discontinuation of lenalidomide and only few delays the dose was reduced to 1 mg. If the neurological toxicity related to slow hematological recovery. Although primary increased despite of dose reduction, vincristine was stopped. prophylaxis with pegfiltrastim was used in both studies, the All patients provided written informed consent. The study was potentially lower incidence of grade 4 neutropenia in our study approved by the Comite´ de Protection des Personnes Sud-Est II, could be due to the administration of this drug on day 4 of the Lyon, France and by the regulatory authorities.