Correspondence and intermediate-risk childhood acute lymphoblastic leukemia in the Tokyo Children’s Cancer Study Group L95-14 protocol. Journal of Clinical Oncology, 23, 6489–6498. Kato, M., Koh, K., Manabe, A., Saito, T., Hasegawa, D., Isoyama, K., Kinoshita, A., Maeda, M., Okimoto, Y., Kajiwara, M., Kaneko, T., Sugita, K., Kikuchi, A., Tsuchida, M. & Ohara, A. (2014) No impact of enhanced early intensification with intermediate-risk pediatric acute lymphoblastic leukemia: Results of Randomized Trial TCCSG study L99-15. British Journal of Haematology, 164, 376–383. Kawamata, N., Ogawa, S., Zimmermann, M., Kato, M., Sanada, M., Hemminki, K., Yamatomo, G., Nannya, Y., Koehler, R., Flohr, T., Miller, C.W., Harbott, J., Ludwig, W.D., Stanulla, M., Schrappe, M., Bartram, C.R. & Koeffler, H.P. (2008) Molecular allelokaryotyping of pediatric acute lymphoblastic leukemias by high-resolution sin-

gle nucleotide polymorphism oligonucleotide genomic microarray. Blood, 111, 776–784. Look, A.T., Roberson, P.K., Williams, D.L., Rivera, G., Bowman, W.P., Pui, C.H., Ochs, J., Abromowitch, M., Kalwinsky, D. & Dahl, G.V. (1985) Prognostic importance of blast cell DNA content in childhood acute lymphoblastic leukemia. Blood, 65, 1079–1086. Manabe, A., Ohara, A., Hasegawa, D., Koh, K., Saito, T., Kiyokawa, N., Kikuchi, A., Takahashi, H., Ikuta, K., Hayashi, Y., Hanada, R. & Tsuchida, M. (2008) Significance of the complete clearance of peripheral blasts after 7 days of prednisolone treatment in children with acute lymphoblastic leukemia: the Tokyo Children’s Cancer Study Group Study L99-15. Haematologica, 93, 1155–1160. Sutcliffe, M.J., Shuster, J.J., Sather, H.N., Camitta, B.M., Pullen, J., Schultz, K.R., Borowitz, M.J., Gaynon, P.S., Carroll, A.J. & Heerema, N.A.

(2005) High concordance from independent studies by the Children’s Cancer Group (CCG) and Pediatric Oncology Group (POG) associating favorable prognosis with combined trisomies 4, 10, and 17 in children with NCI StandardRisk B-precursor Acute Lymphoblastic Leukemia: a Children’s Oncology Group (COG) initiative. Leukemia, 19, 734–740. Suzuki, N., Yumura-Yagi, K., Yoshida, M., Hara, J., Nishimura, S., Kudoh, T., Tawa, A., Usami, I., Tanizawa, A., Hori, H., Ito, Y., Miyaji, R., Oda, M., Kato, K., Hamamoto, K., Osugi, Y., Hashii, Y., Nakahata, T. & Horibe, K. & Japan Association of Childhood Leukemia Study (2010) Outcome of childhood acute lymphoblastic leukemia with induction failure treated by the Japan Association of Childhood Leukemia study (JACLS) ALL F-protocol. Pediatric Blood & Cancer, 54, 71–78.

Could a citrus keep the haematologist away?

Anaemia has long been recognized as one of the most important prognostic factors in chronic lymphocytic leukaemia (CLL) (Binet et al, 1981). Many mechanisms can cause anaemia in CLL including bone marrow infiltration, auto-immunity, cytotoxic therapy, hypersplenism, inflammation, iron deficiency and poor nutritional status (Mauro et al, 2002). Among nutritional causes of anaemia, vitamin B9 and vitamin B12 deficiencies are often sought, whereas vitamin C deficiency (hypovitaminosis C) is underestimated (Fain, 2004). Vitamin C, also known as ascorbic acid (AA), is one of the four main antioxidants (AA, vitamin E, selenium and b-carotene) available in human alimentation (Fain, 2004). The pathophysiology of CLL may involve oxidative stress (Sarmento-Ribeiro et al, 2012). Because of its role in preventing anaemia and its ability to degrade free radicals and oxidants, we hypothesized that hypovitaminosis C level could be associated with Binet stage C. Herein, we report a singlecentre study comparing the blood level of vitamin C in patients with Binet stage A and Binet stage C CLL. Between June 2012 and November 2012, we performed a prospective exploratory study of the vitamin C plasma level in patients followed for CLL at the Department of Hematology of University Hospital of Tours. In order to compare vitamin C plasma level between low and high burden of disease, we randomly selected 40 patients with Binet stage A CLL and 40 patients with Binet stage C CLL (Binet et al, 1981). The only exclusion criterion was ongoing vitamin C supplementation. The following baseline demographical and clinical data were recorded for all of the study patients: age, sex, weight, size, performance status and date 298

of CLL diagnosis. The following blood tests were performed in patients who provided an informed consent: complete blood cell count, reticulocytes, aspartate aminotransferase, serum creatinine level, thyroid-stimulating hormone (TSH), C-reactive protein (CRP), serum iron level, transferrin saturation, ferritin, albumin, folic acid, vitamin B12 and vitamin C serum levels. To protect AA from light and air alteration, blood samples were collected in tubes encased in foil. Results are expressed as mean and confidence intervals. Wilcoxon’s test was used to test the comparisons between the two groups. A P value of less than 005 was considered significant. Baseline data and biological test results of the patients are presented in Table I. Stage C patients had lower haemoglobin level than stage A patients (107 g/l, vs. 134 g/l, respectively, P < 000005). Anaemia was mostly normocytic, normochromic and hyporegenerative. Platelet count was also lower in stage C patients than in stage A patients (111 9 109/l, vs. 200 9 109/l, respectively, P < 000005). Thyroid, liver and renal functions, as well as vitamin B9 and serum iron levels, were normal in both groups. CRP and ferritin levels were significantly higher in patients with Stage C (100 mg/l, vs. 30 mg/l, and 431 lg/l, vs. 117 lg/l, respectively, P < 005 for both comparisons). There was no statistical difference in Vitamin B12 level between the two groups. Vitamin C level was significantly higher in stage A patients than in stage C patients (587 lmol/l, vs. 377 lmol/l, P < 000005). In total, 22 CLL patients (275%) had hypovitaminosis C including three stage A patients (75%) and 19 stage C patients (475%). ª 2014 John Wiley & Sons Ltd British Journal of Haematology, 2014, 166, 292–308

Correspondence Table I. Characteristics of Stage A and Stage C CLL patients included in the study.

Characteristic

Stage A N = 40

Stage C N = 40

P

Gender (Male/Female) Age (years) Caucasian Disease duration (years) Body mass index (200–250 kg/m2) Performance Status Haemoglobin (115–160 g/l) Haematocrit (37–47%) Mean corpuscular volume (80–100 fl) Mean corpuscular haemoglobin concentration (320–360 g/l) Platelet count (150–400 9 109/l) White blood cell count (4–10 9 109/l) Lymphocyte count (1-4 9 109/l) Reticulocytes (80–100 9 109/l) Thyroid-stimulating hormone (02–34 miu/l) Folic Acid (6–39 nmol/l) Vitamin B12 (142–725 pmol/l) Serum iron (10–30 lmol/l) Transferrin saturation (25–35%) Ferritin (10–300 lg/l) Creatinine (60–100 lmol/l) Aspartate transaminase (0–30 iu/l) C-reactive protein (0–6 mg/l) Albumin (40–48 g/l) Vitamin C (261–846 lmol/l)

25/15 70  3 40 62 264  099 052  020 134  40 399  11 945  17 333  20 200  17 370  126 303  121 430  64 160  011 161  18 3129  402 150  12 250  23 117  33 1066  77 23  2 30  15 439  07 587  75

25/15 71  3 40 82 254  122 145  027 107  60 32  19 999  29 332  40 111  19 502  314 455  313 614  217 147  036 233  69 4298  787 160  36 315  85 431  199 971  85 27  5 100  55 400  19 377  83

NS NS NS NS NS *** *** *** ** NS *** NS NS NS NS NS NS NS *** * * NS * ** ***

Normal ranges are indicated in parentheses. NS = P > 005; *P < 005; **P < 0005; ***P < 0001.

To our knowledge, this study is the first to measure the frequency of hypovitaminosis C in CLL patients, and to detect an association between stage C and a lower level of Vitamin C. Previous studies of vitamin levels reported low levels of vitamin D in CLL. Two groups reported that vitamin D deficiency is associated with inferior time-to-first-treatment and overall survival (Shanafelt et al, 2011; Molica et al, 2012). Our work highlights the fact that hypovitaminosis C is underestimated in CLL patients. As a known cause of anaemia and fatigue, practitioners should consider screening their patients for vitamin C deficiency. When needed, careful supplementation should be provided together with close surveillance because vitamin C intake may increase markers of haemolysis in patients with sickle cell anaemia or kidney stone formation (Arruda et al, 2013; Thomas et al, 2013). However, the reason for this deficiency remains unclear. Several assumptions can be proposed to explain the low blood levels in CLL: poor nutritional status with low vitamin C intake, reduced vitamin C absorption, or an increased intracellular uptake of vitamin C by tumour cells (Fain, 2004). These results also raise the question of the possible role of vitamin C in the progression and the treatment of the disease. Our work has some limitations that prevent us from drawing the conclusion that a low vitamin C blood level leads to disease progression. First, dietary differences were ª 2014 John Wiley & Sons Ltd British Journal of Haematology, 2014, 166, 292–308

not evaluated. Second, we arbitrarily compared two groups of patients at different stages of the disease, which leads to expected differences in performance status, albumin levels, and inflammatory markers, such as ferritin and CRP. Moreover a low vitamin C blood level could result from disease progression. However, a recent in vitro study found that both arsenic trioxide (ATO) and vitamin C mediated cytotoxicity on CLL B lymphocytes and emphasized the ability of vitamin C to increase the efficacy of ATO (Biswas et al, 2010). Vitamin C derivatives have been recently reported as a ‘promising new class of anti-cancer drugs, either alone or in combination with other molecules’, and vitamin C showed efficiency in a phase I clinical trial in biopsy-proven advanced and/or progressing metastatic solid tumours (Bordignon et al, 2013; Stephenson et al, 2013). Thus, we believe that clinical trials and experimental studies should be performed to determine if vitamin C supplementation could indeed maintain stage A CLL quiescence and/or enhance treatment efficacy in patients needing anticancer therapy.

Acknowledgments BC, CD, LB, MS, FC, SL, ME, HB, PV, FM, PC and EG performed the research. BC, CD, LB, EG, SL, ME designed the research study. BC, CD, FC, MS, FM, HB, PV, PC and EG analysed the data. BC and EG wrote the paper. 299

Correspondence Philippe Colombat1,3 Emmanuel Gyan1,3

Conflict of interest

1

The authors have no competing interests.

Service d’hematologie et therapie cellulaire, Centre hospitalier universi-

taire de Tours, 2Service de medecine interne, Centre hospitalier univers-

Benjamin Chaigne1,2 Caroline Dartigeas1 Lotfi Benboubker1 Francßois Chaumier1,3 Marjan Ertault1 Severine Lissandre1 Marion Stacoffe1 Francßois Maillot2 Helene Blasco4 Patrick Vourc’h4

References Arruda, M.M., Mecabo, G., Rodrigues, C.A., Matsuda, S.S., Rabelo, I.B. & Figueiredo, M.S. (2013) Antioxidant vitamins C and E supplementation increases markers of haemolysis in sickle cell anaemia patients: a randomized, double-blind, placebo-controlled trial. British Journal of Haematology, 160, 688–700. Binet, J.L., Auquier, A., Dighiero, G., Chastang, C., Piguet, H., Goasguen, J., Vaugier, G., Potron, G., Colona, P., Oberling, F., Thomas, M., Tchernia, G., Jacquillat, C., Boivin, P., Lestry, C., Duault, M.T., Monconduit, M., Belabbes, S. & Gremy, F. (1981) A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer, 48, 198–206. Biswas, S., Zhao, X., Mone, A.P., Mo, X., Vargo, M., Jarjoura, D., Byrd, J.C. & Muthusamy, N. (2010) Arsenic trioxide and ascorbic acid demonstrate promising activity against primary

itaire de Tours, 3UMR CNRS 7292, Universite Francßois Rabelais, and Service de biochimie et de biologie moleculaire, Centre hospitalier uni-

4

versitaire de Tours, Tours, France E-mail: [email protected]

Keywords: vitamin C, chronic lymphocytic leukaemia, ascorbic acid, anaemia First published online 20 March 2014 doi: 10.1111/bjh.12840

human CLL cells in vitro. Leukemia Research, 34, 925–931. Bordignon, B., Chiron, J. & Fontes, M. (2013) Ascorbic acid derivatives as a new class of antiproliferative molecules. Cancer Letters, 338, 317– 327. Fain, O. (2004) [Vitamin C deficiency]. La Revue de Medecine Interne, 25, 872–880. Mauro, F.R., Gentile, M. & Foa, R. (2002) Erythropoietin and chronic lymphocytic leukemia. Review of Clinical and Experimental Hematology, S1, 21–31. Molica, S., Digiesi, G., Antenucci, A., Levato, L., Mirabelli, R., Molica, M., Gentile, M., Giannarelli, D., Sperduti, I., Morabito, F. & Conti, L. (2012) Vitamin D insufficiency predicts time to first treatment (TFT) in early chronic lymphocytic leukemia (CLL). Leukemia Research, 36, 443–447. Sarmento-Ribeiro, A.B., Proencßa, M.T., Sousa, I., Pereira, A., Guedes, F., Teixeira, A. & Oliveira, C.R. (2012) A possible role for oxidation stress

in lymphoid leukaemias and therapeutic failure. Leukemia Research, 36, 1041–1048. Shanafelt, T.D., Drake, M.T., Maurer, M.J., Allmer, C., Rabe, K.G., Slager, S.L., Weiner, G.J., Call, T.G., Link, B.K., Zent, C.S., Kay, N.E., Hanson, C.A., Witzig, T.E. & Cerhan, J.R. (2011) Vitamin D insufficiency and prognosis in chronic lymphocytic leukemia. Blood, 117, 1492–1498. Stephenson, C.M., Levin, R.D., Spector, T. & Lis, C.G. (2013) Phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics of high-dose intravenous ascorbic acid in patients with advanced cancer. Cancer Chemotherapy and Pharmacology, 72, 139–146. Thomas, L.D.K., Elinder, C.G., Tiselius, H.G., Wolk, A. & Akesson, A. (2013) Ascorbic acid supplements and kidney stone incidence among men: a prospective study. JAMA Internal Medicine, 173, 386–388.

A novel tri-allelic mutation of TMPRSS6 in iron-refractory iron deficiency anaemia with response to glucocorticoid

Iron-refractory iron deficiency anaemia (IRIDA), a rare autosomal recessive genetic disorder caused by TMPRSS6 mutations (Finberg et al, 2008), is characterized by hypochromic microcytic anaemia, low serum iron (SI) and transferrin saturation (TS), and normal or low serum ferritin (SF). Due to impaired inhibition of hepcidin gene (HAMP) transcription by TMPRSS6 mutations (Du et al, 2008), IRIDA patients exhibit inappropriately elevated levels of hepcidin, are refractory to oral iron and only partially responsive to parenteral iron administration (De Falco et al, 300

2013). The optimal alternative therapy still remains uncertain when the patient is unresponsive to intravenous iron and erythropoietin. To date, 32 IRIDA families with 50 patients of different ethnic origin have been reported, accounting for 40 different mutations in the TMPRSS6 gene (De Falco et al, 2013). Several common single nucleotide polymorphisms (SNPs), including the non-synonymous polymorphisms V736A, K253E, G228D, R446W, V795I and K225E, have been significantly associated with haemoglobin (Hb) levels, iron status and erythrocyte ª 2014 John Wiley & Sons Ltd British Journal of Haematology, 2014, 166, 292–308

Could a citrus keep the haematologist away?

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