DHFR 19‐bp insertion/deletion polymorphism and MTHFR C677T in adult acute lymphoblastic leukaemia: Is the risk reduction due to intracellular folate unbalancing?
Authors: Donato Gemmati, Monica De Mattei, Linda Catozzi, Matteo Della Porta, Maria L. Serino, Cristina Ambrosio, Antonio Cuneo, Simonetta Friso, Mauro Krampera, Elisa Orioli, Giulia Zeri, Alessia Ongaro
Journal: American Journal of Hematology (2009)

Hepcidin is a liver-derived hormone with a central role in iron regulation and in anemia of inflammation.Its correlations with disease variables, anemia response (AR), and responses to treatment have not been investigated in multiple myeloma (MM).A cohort of anemic MM patients undergoing treatment with immunomodulatory drug (IMiDs)based regimens (n 5 18) or conventional chemotherapy (n 5 16) was studied.Overall, hepcidin decreased significantly between baseline and treatment Cycles 2 and 4 (P < 0.05), and this was more profound in the IMiDs group compared with the conventional group.Baseline hepcidin inversely correlated with baseline hemoglobin (Hb) and platelets (PLT) and positively correlated with b2M, ferritin, transferrin saturation (TSAT%), and International Scoring System (ISS) (P < 0.05).Abnormally high baseline hepcidin inversely correlated with duration of response (DOR) in all studied patients and in the conventional group.Abnormally high hepcidin before treatment Cycles 2 and 3 predicted for AR and disease response (DR), respectively, in all studied patients (P < 0.05).These results suggest that serum hepcidin correlates with significant MM variables and may serve as a surrogate marker for MM and as a predictor for response indicators.Anemia is a common complication of MM and has a major impact on patients' quality of life and survival [1,2].The main form of anemia in MM resembles anemia of chronic disease, characterized among others, by impairment in iron metabolism and consequently iron-restricted erythropoiesis, [3,4] induced by the key iron distribution regulatory hormone, hepcidin [5][6][7][8].Studies in humans and animal models suggested that hepcidin overproduction is induced by inflammatory cytokines, such as IL-6, IL-1b, transforming growth factor-b, and bone morphogenic proteins 2, 4, and 9 [9-11].Inflammatory cytokines and particularly IL-6 also play a central role in the biology of MM [12,13].Recently, Sharma et al. [14] indicated that hepcidin is upregulated in MM by both IL-6-dependent and -independent mechanisms, and thus, may play a role in the development of anemia.During the last years, IMiDs (thalidomide and lenalidomide) have been introduced for the treatment of MM exhibiting high response rates, prolonged progression-free survival, and overall survival, in both relapsed or refractory and newly diagnosed patients [15,16].The mechanism of action of IMiDs is complex and includes among others indirect inhibition of several cytokines (e.g., IL-6, IL-1b, TNF, etc) produced by MM and stromal cells [17].Thalidomide may stimulate erythropoiesis by decreasing the expression of TNF-like ligands or receptors on erythroblasts [18], whereas lenalidomide exhibits a 50,000-fold stronger anti-TNF activity and 200-to 1,000-fold stronger regulations of cytokines [19].In this study, we monitored the sequential changes of serum hepcidin at 1month intervals in anemic myeloma patients under conventional or IMiDsbased treatment and explored for possible correlations of hepcidin with disease variables and for any prognostic significance of hepcidin in relation to AR and DR.Patients' characteristics and treatment regimens are shown in Table I.The median follow-up was 48 months (range 7-75).Twenty-seven (79.4%) patients, 16 of 18 (88.8%)patients of the IMiDs group and 11 of 16 of the conventional group (68.7%) responded to myeloma treatment (P 5 0.1).Twentyone patients (61.7%) displayed AR, 12 of 18 (66.6%) in the IMiDs group and 9 of 16 (56%) in the conventional group (P > 0.05).Twenty-seven patients received erythropoiesis-stimulating agents (ESAs) (14 in the IMiDs group and 13 in the conventional group, P > 0.05) and seven did not.ESAs treatments that have recently been questioned in MM [20] did not show any correlation with AR (P 5 0.1).Baseline and sequential hepcidin values for IMiDs and conventional groups are shown in Fig. 1.Overall, hepcidin showed a statistically TABLE I. Patients' Characteristics before Myeloma Treatment Variable IMiDs group Conventional group P-value Patients' number (first-line treatment) 18 (12) 16 (15) NS Age median (range) 63 (41-78) 65.5 (46-80) NS Gender Male 5 5, Female 5 13 Male 5 12, Female 5 4 0.03 Myeloma type IgG 5 10, IgA 5 4, LC 5 3, NSec 5 1 I g G 5 10, IgA 5 3, LC 5 2, NSec 5 1 N S Type of treatment TVAD 5 3, Thal Dex 5 5, Rev Dex 5 5, MPT 5 5 VAD-like 5 10, MP 5 6 ISS I/II/III 3/6/9 3/8/5 NS LDH (U/l) 153 (55-976) 216 (115-899) NS M-component (g/l) 33 (1.84-81.7)38 (1.92-124) NS b2 microglobulin (mg/l) 5.4 (2.6-97) 4.8 (2.2-12) NS Albumin (g/dl) 3.3 (2.5-4.2) 3.3 (2.3-4.4)NS Creatinine (mg/dl) 1 (0.6-8.4) 0.8 (0.6-1.2) 0.03 C-reactive protein (mg/l) 8 (3-123) 7.6 (0.2-22) NS Hb (g/dl) 9.7 (6.1-10.5)10.2 (8.7-11.3)NS Reticulocyte % 0.8 (0.6-1.7) 1.6 (0.5-2.4) NS PLT (Â10 3 /ml) 197 (85-444) 231 (111-342) NS Ferritin (ng/ml) 793 (256-1997) 250 (57-2000) NS TSAT% 18 (14-25) 24 (8-49) NS sTfR (mg/l) 0.8 (0.57-14.9) 0.7 (0.4-11.3)NS Hepcidin 1(ng/ml) 236 (28-1038)