Correspondence 1682 childhood acute lymphoblastic leukaemia. Br J Cancer 2000; 83: 1617– abnormalities not detected by conventional G-banding. Implications for 1622. treatment stratification of childhood acute lymphoblastic leukaemia: 7 Martinez-Ramirez A, Urioste M, Contra T, Cantalejo A, Tavares A, detailed analysis of 70 cases. Eur J Haematol 2002; 68: 31–41. Portero JA et al. Fluorescence in situ hybridization study of TEL/AML1 9 Sun G, Qin N, Sun N, Close P, Wang S, Yang X et al. Intrachromosomal fusion and other abnormalities involving TEL and AML1 genes. amplification of AML1 gene in a pre-B-ALL in relapse detected Correlation with cytogenetic findings and prognostic value in children predominantly in interphase cells by FISH. 2001; 98(Suppl): with acute lymphocytic . Haematologica 2001; 86: 1245– 448. 1253. 10 Mathew S, Rao PH, Dalton J, Downing JR, Raimondi SC. Multicolor 8 Nordgren A, Heyman M, Sahlen S, Schoumans J, Soderhall S, spectral karyotyping identifies novel translocations in childhood acute Nordenskjold M et al. Spectral karyotyping and interphase FISH reveal lymphoblastic leukemia. Leukemia 2001; 15: 468–472.

Classification of mature T-cell

Leukemia (2003) 17, 1682–1683. doi:10.1038/sj.leu.2403003 between pathologists and clinicians. The very high WBC of case #1, 500 Â 109/l, fits with the aggressive nature of the disease. We are not TO THE EDITOR given any details of follow-up but, in our experience, without 3 We agree with Kussick et al1 that not every case of T-cell leukemia is appropriate treatment, the median survival of T-PLL is 7 months. easily classifiable. However, the only way forward in establishing We feel that there is no need to go back to old classification systems the correct diagnosis and improving the WHO classification is to be in which no clear description of disease entities was given; this will able to define new disease entities. Currently, there are no data in not serve any useful purpose for clinicians dealing with these conditions. In particular, since Campath-1H (Alemtuzumab) ap- the literature, nor in their letter, to support the view that there is a T- 11,12 cell leukemia that should be classified as T-cell chronic lymphocytic pears to be the treatment of choice in T-PLL, the correct leukemia (T-CLL). Historically, the term ‘T-CLL’ was first used by diagnosis of this disease becomes clinically relevant. Brouet et al2 in 1975, when they described patients who would now Although we recognize that there is a degree of morphological be considered largely to be part of T-cell large granular lymphocytic heterogeneity in T-PLL, the data on cytogenetics and molecular genetics are overwhelming, with 90% of patients having inversion (T-LGL) leukemia and a few cases that we now call T-prolympho- 7,9 cytic leukemia (T-PLL). A large number of subsequent reports and 14(q11;q32) and abnormalities of chromosome 8 in 80%. Further data emerging from the literature have allowed us to separate T-LGL advances will, of course, be welcome, but when one undertakes leukemia from T-PLL.3,4 Since then, there has been no clear such studies, there is a need to investigate the patients adequately evidence that a third entity, T-CLL, as proposed by Kussick et al,1 in every aspect – morphology, immunophenotype, cytogenetics indeed exists. We recognize that in T-PLL there is a degree of and clinical manifestations – and then submit the material to morphological heterogeneity, which is already considered in the further molecular analysis, for example, gene profiling. Such ad- WHO classification5 and in our experience.3–6 Therefore, the vances may or may not define new disease entities but will refine classification of T-cell malignancies should not be based purely the diagnostic criteria and point to genes relevant to pathogenesis. on the morphological criteria but substantiated by the underlying In these and other conditions such as B-cell CLL, the way to progress molecular/genetic features as well as clinical manifestations. Not all is to agree on the basic data and then move forward with the new T-PLL cases have circulating cells with the morphology of information.

prolymphocytes as in the classic 1974 description by Galton, which 1 E Matutes 1Academic Department of Haematology & is more applicable to B-cell PLL. Although the term ‘prolymphocyte’ 1 may not be ideal to use in this condition, it has been retained for D Catovsky Cytogenetics, The Royal Marsden Hospital, historical reasons and indeed, provided everybody understands the London, UK disease behavior and what this term defines, this should not be an issue. On reviewing the representative case #1 reported by Kussick References et al,1 it is likely that this represents an example of small-cell variant T-PLL, as defined by the WHO classification and as seen by us in 1 Kussick SJ, Wood BL, Sabath DE. Mature T-cell leukemias which cannot many patients;3–6 the cells in the black and white illustration appear be adequately classified under the new WHO classification of lymphoid typical, with cytoplasmic blebs, although a nucleolus is not neoplasms. Leukemia 2002; 16: 2457–2458. 2 Brouet JC, Sasportes M, Flandrin G, Preud’Homme JL, Seligmann M. prominent, a feature that is common in the small-cell T-PLL variant. Chronic lymphocytic leukaemia of T-cell origin. Immunological and The phenotype CD4+, CD7+, CD8À would fit very well with T-PLL. clinical evaluation in eleven patients. Lancet 1975; 2: 890–893. Unfortunately, the key investigation, chromosome analysis and/or 3 Matutes E, Brito-Babapulle V, Swansbury J, Ellis J, Morilla R, Dearden C overexpression of TCL-1 or mutational analysis for ATM – features et al. Clinical and laboratory features of 78 cases of T-prolymphocytic also characteristic of T-PLL,7–9 – have not been performed. A second leukemia. Blood 1991; 78: 3269–3274. case in which no details are given does not add weight to their 4 Catovsky D, Matutes E. Leukemias of mature T cells. Neoplastic Hematopathol 2001; 43: 1589–1602. argument. 5 Catovsky D, Ralfkiaer E, Muller-Hermelink HK. T-cell prolymphocytic We would also disagree that there is a conflict between the REAL leukaemia. In: Jaffe ES, Harris NL, Stein H, Vardiman JW, WHO and the WHO classifications.5,10 The REAL was an attempt to start Classification of Tumours of Haemopoietic and Lymphoid Tissues. Lyon: grouping cases into disease entities; there was no clear separation of IARC Press, 2001; 195–196. cases within the mature T-cell leukemias, but since that time- 6 Matutes E, Garcia-Talavera J, O’Brien M, Catovsky D. The morpholo- extensive work has been carried out and a consensus reached gical spectrum of T-prolymphocytic leukaemia. Br J Haematol 1986; 64: 111–124. 7 Matutes E, Brito-Babapulle V, Dearden C, Yuille M, Catovsky D. Prolymphocytic leukemia of B and types. Biology and therapy. Correspondence: Dr E Matutes, Academic Department of Haematol- Chronic Lymphoid Leukemias 2000; 24: 525–542. ogy & Cytogenetics, The Royal Marsden Hospital, Fulham Road, 8 Yuille MAR, Coignet LJA, Abraham SM, Yaqub F, Luo L, Matutes E et al. London SW3 6JJ, UK; Fax: +44 20 7351 6420 ATM is usually rearranged in T-cell prolymphocytic leukaemia. Received 14 March 2003; accepted 26 March 2003 Oncogene 1998; 16: 789–796.

Leukemia Correspondence 1683 9 Brito-Babapulle V, Pomfret M, Matutes E, Catovsky D. Cytogenetic 11 Pawson R, Dyer MJS, Barge R, Matutes E, Thornton PD, Emmett E et al. studies on prolymphocytic leukemia. II. T-cell prolymphocytic leuke- Treatment of T-cell prolymphocytic leukemia with human CDw52 mia. Blood 1987; 70: 926–931. antibody. J Clin Oncol 1997; 15: 2667–2672. 10 Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML et al.A 12 Dearden CE, Matutes E, Cazin B, Tjonnfjord GE, Parreira A et al. High revised European–American classification of lymphoid neoplasms: a remission rate in T-cell prolymphocytic leukemia with Campath-1H. proposal from the International Lymphoma Study Group. Blood 1994; Blood 2001; 98: 1721–1726. 84: 1361–1392.

Reply to the letter from Drs Matutes and Catovsky

Leukemia (2003) 17, 1683. doi:10.1038/sj.leu.2403002 morphology and genetic lesions of T-PLL, we are not proposing to move the field back to the T-CLL/T-PLL category of the REAL TO THE EDITOR classification. Rather, we would hope that such an admittedly ill-

1 defined new entity would only represent an interim category, and The point of our letter in the December 2002 issue of Leukemia was would provide the basis for additional research in the field aimed at simply to suggest that there are likely to be mature T-cell leukemias defining the range of mature T-cell leukemias at the molecular level. which do not represent one of the entities recognized by the recent 2 To emphasize that such a disease category reflects uncertainty as to WHO classification of lymphoid neoplasms. These entities include the biology of the cases grouped within it, and to emphasize that this T-cell prolymphocytic leukemia (T-PLL), adult T-cell leukemia/ category should not be viewed as a resurrection of T-CLL, we lymphoma, mycosis fungoides/Sezary syndrome, T-cell large believe that the designation ‘mature T-cell leukemia, not otherwise granular lymphocytic leukemia, and, potentially, peripheral T-cell specified’ might represent an adequate way to describe such lymphoma with a leukemic component. The existence of such neoplasms for the time being. problematic cases is suggested by a recent case report which 3 1 contained both karyotypic information and follow-up data. In that SJ Kussick 1Department of Laboratory Medicine, Box 1 report, Soma and co-workers describe a 73-year-old male with a BL Wood 357110 University of Washington Medical chronic mild which would be best classified as T-PLL DE Sabath1 Center 1959 NE Pacific Street Seattle, WA 98195 under the WHO classification, yet which demonstrated multiple USA cytogenetic abnormalities without the characteristic inv(14) (q11q32) or t(14;14)(q11;q32) of T-PLL, and which showed References remarkably indolent clinical behavior compared to T-PLL. While 2 the median survival in T-PLL is less than 1 year, this patient was 1 Kussick SJ, Wood BL, Sabath DE. Mature T cell leukemias which cannot reportedly asymptomatic without therapy for over 7 years, leading be adequately classified under the new WHO classification of lymphoid the authors to speculate whether this case represented a T-CLL-like neoplasms. Leukemia 2002; 16(12): 2457–2458. entity. Follow-up of this patient will be very useful to determine 2 Jaffe ES, Harris NL, Stein H, Vardiman JW. Pathology and Genetics of whether the acquisition of trisomy 8 in the most recent cytogenetic Tumours of the Hematopoietic and Lymphoid Tissues. IARC Press, 2001, evaluation of this leukemia portends a more aggressive clinical pp 195–196. 2 3 Soma L, Cornfield DB, Prager D et al. Unusually indolent T-cell behavior, as chromosome 8 abnormalities are common in T-PLL. prolymphocytic leukemia associated with a complex karyotype: is By suggesting that an additional entity in the WHO classification this T-cell chronic lymphocytic leukemia?. Am J Hematol 2002; 71(3): may be useful for mature T-cell leukemias without the characteristic 224–226.

Identification of CD14 as a predictor for leukemic dendritic cell differentiation in acute myeloid leukemia

Leukemia (2003) 17, 1683–1684. doi:10.1038/sj.leu.2403014 of CD40+/CD86+ cells at the end of culture (n ¼ 33, Spearman’s r : 0.51, P ¼ 0.002). In contrast to Mohty et al, we were able to culture TO THE EDITOR leukemic DC in 5/19 (26%) of the CD14À AML patients. The Mohty et al1 reported that circulating leukemic myeloid blood discrepancy between these observations could be related to several + aspects. Firstly, in our immunophenotypic analysis we gated dendritic cells (MDCs) and CD14 cells of acute myeloid leukemia dim (AML) patients represent the leukemic compartments that can be specifically on the CD45 blast population, resulting in a well- induced in vitro to acquire the mature dendritic cell (DC) phenotype defined leukemic blast population. Secondly, the culture method used by Mohty et al, is typically used to culture monocyte-derived in the presence of GM-CSF, IL-4 and CD40L. In contrast, culture of 3,4 the CD14À subpopulations did not result in the generation of DC. We observed that it is more effective to use an alternative leukemic DC. In our laboratory, we generate leukemic DC from culture method for the induction of DC differentiation in AML AML blasts by the use of a cytokine cocktail.2 We also observed a samples. We use a combination of various cytokines, namely, GM- a correlation between the percentage of CD14 expression on AML CSF, TNF- , SCF, Flt3-L, IL-3 and IL-4 resulting in functionally active blasts and AML-DC culture outcome, as defined by the percentage (as measured by mixed reaction) leukemic DCs in 14 days. Additionally, a culture method based on the use of calcium ionophores (CI), thereby bypassing receptor-mediated signaling, is able to further increase the percentage of successful AML-DC Correspondence: Dr AA van de Loosdrecht, Department of Hematol- À 2 ogy, VU University Medical Center, De Boelelaan 1117, Amsterdam cultures, even in CD14 AML samples. In a population of 33 AML 1081 HV, The Netherlands; Fax: +31 20 444 2601 patients, blasts of 19 (58%) patients showed less than 15% CD14 Received 29 January 2003; accepted 26 March 2003 expression. In five (26%) AML samples, we were able to generate

Leukemia