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 : 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 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 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 /, 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 in combination with -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 . Our group conducted CD20-positive lymphoma: , marginal zone a similar phase 1b study of this combination in a lymphoma, lymphocytic 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 , 750 mg/m2 of one who was 77 years old, had a pulmonary embolism and cyclophosphamide and 1.4 mg/m2 of (up to a maximal recovered rapidly with anticoagulation 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. Clinical Trials.gov cycle.2 With this policy, the rate of febrile neutropenia episodes identifier NCT00901615. after R2-CHOP did not appear to be more frequent than after Twenty-eight patients were enrolled in the study from January R-CHOP.3 Mild sensory neuropathy symptoms were observed in 2009 to June 2010. One patient did not receive any treatment and half of our patients leading to discontinuation of vincristine for the was excluded from analysis. Patient characteristics are summar- last cycles of the treatment in two patients. Similarly to ized in Table 1. Although the inclusion criteria limited the age to Nowakowski et al.,1 we observed a thrombosis episode in two 70 years, a patient aged 77 years was included. The majority of patients who were receiving aspirin prophylaxis. Lenalidomide was patients had follicular lymphoma and the majority had dissemi- discontinued in both patients and symptoms resolved with anti- nated disease. coagulation. We agree that ongoing phase 2 trials will help better assessing the risk of thrombosis in patients treated with R2-CHOP. A 14-day treatment with lenalidomide during each 21-day cycle, DOSE ESCALATION in our study, as compared with 10 days in the study from No DLTs occurred at lenalidomide dose of 5, 10 and 15 mg. One Nowakowski et al.,1 results in longer exposure to lenalidomide and neutropenic grade 4 episode lasting more than 3 days occurred at does not appear to increase the toxicity of the combination. the 20 mg level. One of six patients at the 25 mg level experienced Overall, both studies conclude that a daily dose of lenalidomide a transient grade 3 hepatic toxicity in the course of the first cycle. 25 mg appears to be safe in combination with R-CHOP and worth As there was no intent to increase the lenalidomide dose studying in phase 2. above 25 mg, this dose was considered the recommended dose There is a strong rationale to study the combination of and the 25 mg cohort was expanded. lenalidomide and R-CHOP in follicular lymphoma. Although the mechanism of action of lenalidomide appears complex, several of its activities exhibit a potential interest in the treatment of B-cell SAFETY AND TOLERABILITY .4 Lenalidomide has been shown to repair the Lenalidomide was discontinued in six patients, three because of defective immunological synapse between T cells and follicular hematological toxicity (after two cycles in two patients and after lymphoma cells in vitro.5 Results of an early phase II study in four cycles in one patient), two for thrombosis (after three patients with refractory/relapsed indolent lymphoma have shown and four cycles, respectively) and one for hepatic toxicity at the an overall response rate of 27% in the subgroup of patients with first cycle. R2-CHOP was discontinued after the fifth cycle in one follicular lymphoma.6 Furthermore, several studies have shown patient whose disease progressed. Lenalidomide was interrupted that lenalidomide has the potential to enhance natural killer cell during 1–9 days in the course of six of the 143 cycles administered activity, monocyte-mediated antibody-dependent cellular in five patients, mostly because of neutropenia. Six patients had cytotocity and aptoptosis effect of rituximab on lymphoma cycle delays; five resulting from hematological toxicity and one B-cell lines.7,8 Recent clinical results demonstrate a remarkable resulting from bronchitis associated to chronic respiratory efficacy of the combination of lenalidomide and rituximab in insufficiency. the frontline treatment of follicular lymphoma, which confirms this Adverse events are shown in Table 2. Grade 3 and 4 synergy.9 neutropenia occurred in 19% and 41% of patients, respectively. Long-term follow-up of patients with follicular lymphoma has Two neutropenic patients experienced a grade 3 febrile episode. shown that quality of CR could be correlated to an improved Grade 3 and 4 thrombocytopenia occurred in 26% and 4% of survival.10 It is then conceivable that the combination of patients, respectively. One patient had propionibacterium acnes lenalidomide with R-CHOP, currently the most effective septicemia outside of a neutropenic phase. Two thrombosis treatment for follicular lymphoma,11,12 will increase the efficacy

& 2013 Macmillan Publishers Limited Leukemia (2013) 233 – 258 Letters to the Editor 254 Table 1. Patient characteristics Lenalidomide cohort All

5 mg, n ¼ 3 10 mg, n ¼ 3 15 mg, n ¼ 3 20 mg, n ¼ 6 25 mg, n ¼ 12 n ¼ 27 %

Age Median 44 59 56 58.5 58.5 58 Range 43–69 52–67 24–62 57–77 47–67 24–77 460 years 1 1 1 2 6 11

Sex Female 2 1 3 1 4 11 41 Male 1 2 0 5 8 16 59

Performance status 0 1 3 1 2 8 15 56 1 2 0 2 4 4 12 44

Lymphoma type Follicular 3 2 1 4 8 18 67 Mantle cell 0 0 0 1 2 3 11 DLBCL 0 0 1 1 2 4 15 Indolent unclassified 0 1 1 0 0 2 7

Stage I0010014 II 0 0 0 0 1 1 4 III 0 0 0 2 2 4 15 IV 3 3 2 4 9 21 78

LDH Normal 0 2 1 3 7 13 48 4Normal 3 1 2 3 5 14 52

Extranodal sites 0–1 0 1 1 2 6 10 37 41 3 2 2 4 6 17 63

Bone marrow Not involved 0 2 1 4 4 11 41 Involved 3 1 2 2 7 15 56 Not done 0 0 0 0 1 1 4 Abbreviation: DLBCL, diffuse large B-cell lymphoma.

Table 2. Grade 3 and 4 adverse events occurring during the six cycles of R2-CHOP

Grade 5 mg, n ¼ 3 10 mg, n ¼ 3 15 mg, n ¼ 3 20 mg, n ¼ 6 25 mg, n ¼ 12 All, n ¼ 27

343434343 434

Anemia 0 0 0 0 00202 040 Thrombocytopenia 1 0 0 0 00204 171 Neutropenia 1 0 1 1 11032 6511 Febrile neutropenia 1 0 0 0 00010 020 Infection 0 0 0 0 00000 101 Thromboembolism 0 0 0 0 00011 011 AST/ALT elevated 0 0 0 0 10101 020 Pulmonary 0 0 0 0 00100 010 Other 001001202 051 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. Other grade 3 events were: 1 hypokaliemia, 1 lymphopenia, 1 bleeding related to catheter desinsertion, 1 hyponatremia, 1 hyperglycemia. Other grade 4; 1 hyperuricemia.

of immunochemotherapy. Our group is currently conducting a payment for lectures from Celgene. Dr Tilly, Dr Morschhauser, Dr Salles and Dr Coiffier phase 2 trial to test this hypothesis in patients with high tumor have served on advisory boards of Celgene. Dr Casasnovas, Dr Feugier, Dr Molina, burden follicular lymphoma. Dr Jardin and Dr Terriou declare no conflict of interest.

CONFLICT OF INTEREST ACKNOWLEDGEMENTS Dr Tilly, Dr Morschhauser, Dr Salles, Dr Haioun and Dr Coiffier received grant support This trial was supported by a grant from the French Ministry of Health (PHRC 2009 13- from Celgene. Dr Tilly, Dr Morschhauser, Dr Salles, Dr Haioun and Dr Coiffier received 03). Celgene Corporation financially supported the trial and provided the study drug.

Leukemia (2013) 233 – 258 & 2013 Macmillan Publishers Limited Letters to the Editor 255 We thank the staff of the GELA-Recherche Clinique, and especially Yvain Robreau, for 5 Ramsay AG, Clear AJ, Kelly G, Fatah R, Matthews J, Macdougall F et al. Follicular the management of the trial. lymphoma cells induce T-cell immunologic synapse dysfunction that can be repaired with lenalidomide: implications for the tumor microenvironment H Tilly1, F Morschhauser2, G Salles3, R-O Casasnovas4, P Feugier5, and . Blood 2009; 114: 4713–4720. TJ Molina6, F Jardin1, L Terriou2, C Haioun7 and B Coiffier3 6 Witzig TE, Wiernik PH, Moore T, Reeder C, Cole C, Justice G et al. Lenalidomide oral 1 monotherapy produces durable responses in relapsed or refractory indolent Department of Hematology, Centre Henri-Becquerel, UMR918, non-Hodgkin’s Lymphoma. J Clin Oncol 2009; 27: 5404–5409. Universite´ de Rouen, Rouen, France; 7 Wu L, Adams M, Carter T, Chen R, Muller G, Stirling D et al. lenalidomide enhances 2 Centre Hospitalier Universitaire de Lille, Lille, France; natural killer cell and monocyte-mediated antibody-dependent cellular 3 Hospices Civils de Lyon, Universite´ Lyon-1, Lyon, France; cytotoxicity of rituximab-treated CD20 þ tumor cells. Clin Cancer Res 2008; 14: 4Centre Hospitalier Universitaire de Dijon, Dijon, France; 4650–4657. 5Centre Universitaire de Nancy, Nancy, France; 8 Zhang L, Qian Z, Cai Z, Sun L, Wang H, Bartlett JB et al. Synergistic antitumor 6Universite´ Paris Descartes, Hoˆtel-Dieu, AP-HP, Paris, France and effects of lenalidomide and rituximab on mantle cell lymphoma in vitro and 7Hoˆpital Henri Mondor, Cre´teil, France in vivo. Am J Hematol 2009; 84: 553–559. E-mail: [email protected] 9 Fowler N, Hagemeister FB, McLaughlin P, Kwak L, Romaguera J, Fanale M et al. Lenalidomide plus rituximab a highly effective and well-tolerated biologic therapy in untreated indolent B-cell non-. Ann Oncol 2011; 22(Supp 4): iv129. REFERENCES 10 Bachy E, Brice P, Delarue R, Brousse N, Haioun C, Le Gouill S et al. Long-term 1 Nowakowski GS, LaPlant B, Habermann TM, Rivera CE, Macon WR, follow-up of patients with newly diagnosed follicular lymphoma in the pre- Inwards DJ et al. Lenalidomide can be safely combined with R-CHOP (R2CHOP) rituximab era: effect of response quality on survival--A study from the groupe in the initial for aggressive B-cell lymphomas: phase I study. d’etude des lymphomes de l’adulte. J Clin Oncol 2010; 28: 822–829. Leukemia 2011; 25: 1877–1881. 11 Hiddemann W, Kneba M, Dreyling M, Schmitz N, Lengfelder E, Schmits R et al. 2 Zwick C, Hartmann F, Zeynalova S, Poschel V, Nickenig C, Reiser M et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, Randomized comparison of pegfilgrastim day 4 versus day 2 for the prevention of doxorubicin, vincristine, and prednisone (CHOP) significantly improves the out- chemotherapy-induced leukocytopenia. Ann Oncol 2011; 22: 1872–1877. come for patients with advanced-stage follicular lymphoma compared with 3 Pettengell R, Johnson HE, Lugtenburg PJ, Silvestre AS, Duhrsen U, Rossi FG et al. therapy with CHOP alone: results of a prospective randomized study of the Impact of febrile neutropenia on R-CHOP chemotherapy delivery and hospitali- German Low-Grade Lymphoma Study Group. Blood 2005; 106: 3725–3732. zations among patients with diffuse large B-cell lymphoma. Support Care Cancer 12 Salles G, Seymour JF, Offner F, Lopez-Guillermo A, Belada D, Xerri L et al. Ritux- 2012; 20: 647–652. imab maintenance for 2 years in patients with high tumour burden follicular 4 Chanan-Khan AA, Cheson BD. Lenalidomide for the treatment of B-cell lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, malignancies. J Clin Oncol 2008; 26: 1544–1552. randomised controlled trial. Lancet 2011; 377: 42–51.

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

Risk of developing chronic lymphocytic leukemia is influenced by HLA-A class I variation

Leukemia (2013) 27, 255–258; doi:10.1038/leu.2012.173 Infinium HD Human370 Duo BeadChips.3 For controls we made use of genotype data generated by the Wellcome Trust Case Control Consortium on 2930 individuals from the British 1958 Although chronic lymphocytic leukemia (CLL) is characterized by a Birth Cohort (58BC). Collection of samples and information from strong familial risk, the genetic basis of inherited susceptibility to subjects was undertaken with informed consent and ethical review CLL is largely unknown. The increased risk of Hodgkin lymphoma board approval. After imposing rigorous quality control in terms of (HL) and non-Hodgkin lymphoma (NHL) in relatives of CLL patients excluding samples and SNPs with poor call rates and SNPs showing suggests a common etiology to B-cell lymphoproliferative disorders significant departure from Hardy–Weinberg equilibrium, samples (LPDs) through HLA variation.1 Moreover, as B-cell proliferation is showing evidence of relatedness and ancestral differences,3 SNP part of an adaptive immune response, which can be initiated by genotypes were available on 503 cases and 2698 controls. major histocompatibility complex (MHC)-restricted T-cell activation, For single SNP and haplotype analysis we considered the a possible influence of HLA on CLL pathogenesis is plausible. MHC at 6p21 to be defined by a 5-Mb region bordered by the It has recently been demonstrated that single nucleotide RFP and MLN genes (rs4324798 at 28 884 096 bp and rs767896 polymorphism (SNP) variation within the 6p21 region can at 33 899 493 bp; Figure 1). We initially considered the 1149 accurately predict alleles at HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA- SNPs mapping to this 5-Mb region analyzing the association DQA1 and HLA-DQB1 loci.2 Furthermore, HLA alleles can be between SNP and CLL using the Cochran–Armitage trend test. accurately predicted from the SNPs used in a genome-wide Odds ratios (ORs) and associated 95% confidence intervals (CIs) association study (GWAS). To investigate the role of genetic were calculated by unconditional logistic regression. At the 0.05 variation in the MHC region in the etiology of CLL, we have threshold, 88 SNPs showed evidence of an association compared applied this methodology to SNP data from a GWAS of CLL. with an expected of 57.5 (Po0.001). Associations at the 0.01 The 517 CLL cases (364 male) analyzed in the GWAS have been threshold are reported in Supplementary Table 1. The strongest previously documented.3 Briefly, they comprised 155 CLL cases single association was shown by rs6904029, which maps at with a relative affected with CLL or a related B-cell LPD ascertained 30 051 046 bp localizing to the genomic sequence for the non- through the International CLL linkage consortium (ICLLLC) and coding sequence for HLA complex group 9 that is intronic to 362 cases ascertained through the Leukemia Research CLL4 trial. HLA-A (P ¼ 1.38 Â 10 À 4, Figure 1 and Supplementary Table 1). The genome-wide SNP scan was conducted using Illumina To interrogate the relationship between MHC variation and CLL

Accepted article preview online 2 July 2012; advance online publication, 20 July 2012

& 2013 Macmillan Publishers Limited Leukemia (2013) 233 – 258