Aurélie Jaspers

Erythropoietin therapy after allogeneic hematopoietic cell transplantation: a prospective, randomized trial

We conducted a prospective randomized trial to assess hemoglobin (Hb) response to recombinant human erythropoietin (rhEPO) therapy after hematopoietic cell transplantation (HCT). Patients (N = 131) were randomized (1:1) between no treatment (control arm) or erythropoietin at 500 U/kg per week (EPO arm). Patients were also stratified into 3 cohorts: patients undergoing myeloablative HCT with rhEPO to start on day (D)28, patients given nonmyeloablative HCT (NMHCT) with rhEPO to start on D28, and patients also given NMHCT but with rhEPO to start on D0. The proportion of complete correctors (ie, Hb ≥13 g/dL) before D126 posttransplant was 8.1% in the control arm (median not reached) and 63.1% in the EPO arm (median, 90 days) (P < .001). Hb levels were higher and transfusion requirements decreased (P < .001) in the EPO arm, but not during the first month in the nonmyeloablative cohort starting rhEPO on D0. There was no difference in rates of thromboembolic events or other complications between the 2 arms. This is the first randomized trial to demonstrate that rhEPO therapy hastens erythroid recovery and decreases transfusion requirements when started one month after allogeneic HCT. There was no benefit to start rhEPO earlier after NMHCT.

Iron sucrose - characteristics, efficacy and regulatory aspects of an established treatment of iron deficiency and iron-deficiency anemia in a broad range of therapeutic areas.

Introduction: Iron is a key element in the transport and utilization of oxygen and a variety of metabolic pathways. Iron deficiency is a major cause of anemia and can be associated with fatigue, impaired physical function and reduced quality of life. Administration of oral or intravenous (i.v.) iron is the recommended treatment for iron-deficiency anemia (IDA) in different therapeutic areas. Areas covered: This article provides an overview of studies that evaluated i.v. iron sucrose for anemia and iron status management, either alone or in combination with erythropoiesis-stimulating agents, across various diseases and conditions. Expert opinion: Iron sucrose is an established, effective and well-tolerated treatment of IDA in patients with acute or chronic conditions such as chronic kidney disease, inflammatory bowel disease, pregnancy (second and third trimester), postpartum period, heavy menstrual bleeding and cancer who need rapid iron supply and in whom oral iron preparations are ineffective or not tolerated. Available data on patient blood management warrant further studies on preoperative iron treatment. First experience with iron sucrose follow-on products raises questions about their therapeutic equivalence without comparative clinical data in newly diagnosed patients or patients on existing chronic treatment.

A novel mutation in the CUB sequence of matriptase-2 (TMPRSS6) is implicated in iron-resistant iron deficiency anaemia (IRIDA)

Monitillo, L., Ghione, P., Barbiero, S., Grasso, M., Rossini, F., Guglielmelli, T., Cangialosi, C., Liberati, A.M., Callea, V., Caravita, T., De Rosa, L., Pisani, F., Falcone, A.P., Pregno, P., Rocci, A., Passera, R., Boccadoro, M. & Palumbo, A. (2011) Long-term results of the GIMEMA VTD Consolidation trial in autografted multiple myeloma patients (VEL-03-096): impact of minimal residual detection by real time quantitative PCR on late recurrences and overall survival. Blood (ASH Annual Meeting Abstracts), 118, Abstract 827. Putkonen, M., Kairisto, V., Juvonen, V., Pelliniemi, T.T., Rauhala, A., Itälä-Remes, M. & Remes, K. (2010) Depth of response assessed by quantitative ASO-PCR predicts the outcome after stem cell transplantation in multiple myeloma. European Journal of Haematology, 85, 416–423. Rajkumar, S.V., Harousseau, J.L., Durie, B., Anderson, K.C., Dimopoulos, M., Kyle, R., Blade, J., Avet-Loiseau, H., Lonial, S., Palumbo, A., Zonder, J., Ludwig, H., Vesole, D., Sezer, O., Munshi, N.C. & San Miguel, J., On behalf of the International Myeloma Workshop Consensus Panel 1. (2011) Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood, 117, 4691–4695. Sarasquete, M.E., Carcı́a-Sanz, R., Gonzáles, D., Martı́nez, J., Mateo, G., Martı́nez, P., Ribera, J.M., Hernándes, J.M., Lahuerta, J.J., Orfáo, A., González, M. & San Miguel, J.F. (2005) Minimal residual disease monitoring in multiple myeloma: a comparison between allelic-specific oligonucleotide real-time quantitative polymerase chain reaction and flow cytometry. Haematologica, 90, 1365–1372. Van de Velde, H.J.K., Liu, X., Chen, G., Cakana, A., Deraedt, W. & Bayssas, M. (2007) Complete response correlates with long-term survival and progression-free survival in high-dose therapy in multiple myeloma. Haematologica, 92, 1399– 1406. Van der Velden, V.H., Cazzaniga, G., Schrauder, A., Hancock, J., Bader, P., Panzer-Grumayer, E.R., Flohr, T., Sutton, R., Cave, H., Madsen, H.O., Cayuela, J.M., Trka, J., Eckert, C., Foroni, L., zur Stadt, U., Beldjord, K., Raff, T., van der Schoot, C.E. & van Dongen, J.J.M., On behalf of the European Study Group on MRD detection in ALL (ESG-MRD-ALL). (2007) Analysis of minimal residual disease by Ig/TCR gene rearrangements: guidelines for interpretation of realtime quantitative PCR data. Leukemia, 21, 604–611.

Long-term safety follow-up of a randomized trial of darbepoetin alpha and intravenous iron following autologous hematopoietic cell transplantation.

To the Editor: Anemia is quite frequent in cancer patients, due to the cancer itself, its treatment, or both. Erythropoiesis-stimulating agents (ESA) have proven effective in increasing hemoglobin levels and improving quality of life. After autologous hematopoietic cell transplantation (auto-HCT), many patients experience prolonged anemia. However, ESA use in this context remains sparse. We recently reported the efficacy of darbepoetin alpha (DA) (AranespVR ) and intravenous (IV) iron (VenoferVR ) on erythroid reconstitution following auto-HCT [1]. Although there was no short-term safety issue, longer follow-up was required as some metaanalyses suggest increased mortality on study and worsened overall survival in cancer patients receiving ESA [2,3], particularly when no concomitant chemotherapy is administered. On the other hand, some in vitro and animal studies raised a possible effect of iron on tumor growth [4], but there are no available data in cancer patients receiving IV iron. In addition, the impact of ESA and/or IV iron on long-term safety, relapse, and survival has never been examined after transplantation. Therefore, we analyzed long-term outcome to verify the safety of DA and IV iron therapy after auto-HCT. We randomized 127 patients with lymphoid malignancies [1] between no erythropoietic therapy (n 5 25), DA from day 28 post-auto-HCT (n 5 52) or DA 1 3 IV iron injections (n 5 50). Median follow-up was 1.4 year (range 89 days–9.5 years). Survival analyses were performed according to the Kaplan–Meier method. More details about patients and methods can be found in the Supporting Information. The incidence of infections between end of study (day 126) and last follow-up remained comparable: three patients in control group (12%), eight in DA group (15%), and six in DA1iron group (12%) experienced at least one infection. Numbers of infections per patient were 0.2 6 0.7, 0.2 6 0.4, and 0.1 6 0.3 in control, DA, and DA1iron groups, respectively (NS). During follow-up, 4/25 (16%) patients in control group, 13/52 (25%) in DA group, and 6/50 (12%) in DA1iron group experienced at least one other complication (NS). While three patients (two in control and one in DA1iron groups) presented a thrombosis on study, no other thrombo-embolic event (TEE) occurred during follow-up. Two patients (one in control and one in DA groups) developed a benign tumor, whereas four (three in DA and one in DA1iron groups) presented a secondary malignancy (NS). Other complications were: hypertension (one in control and one in DA groups), ischemic cardiomyopathy (three in DA group) including one myocardial infarction, four arrhythmias (one in control and three in DA groups), peripheral arteriopathy (one in DA group), diabetes (two in DA and one in DA1iron groups), radiopneumonitis (one in control group), vasculitis (one in DA group), nephritis (one in DA and one in DA1iron groups), thyroiditis (one in DA group), spondylarthritis (one in DA1iron group), osteonecrosis (one in DA and two in DA1iron groups), peripheral neuropathy (one in DA and one in DA1iron groups), sudden transient deafness (one in DA group), and sarcoidosis (one in DA1iron group). One-year overall survival were 100%, 88%, and 100% and 5-year overall survival were 86%, 78%, and 91% in control, DA, and DA1iron groups, respectively (P 5 0.43) (Fig. 1A). One-year and 5-year progression-free survival were 85% and 71% in control group, compared to 86% and 57% in DA group, and 94% and 78% in DA1iron group (P 5 0.30) (Fig. 1B). One year after auto-HCT, 15%, 12%, and 10% of patients in control, DA, and DA1iron groups, respectively, had progressed or relapsed; at five years postHCT, 29%, 42%, and 22% had progressed (P 5 0.35) (Fig. 1C). Disease progression was the major cause of death (three in control group, eight in DA group, and three in DA1iron group). The impact of ESA on survival in untreated cancer patients has been studied in several meta-analyses [2,3,5], but results differed depending on included studies and data and methods used. Glaspy [5] did not find any difference in survival or disease progression, whereas Bohlius [2] and Bennett [3] showed increased mortality in patients receiving ESA. However, there are no data about the effect of ESA on overall or progressionfree survival after transplantation, or about the impact of IV iron in cancer patients, let alone after transplantation. Although our study was not designed to establish an impact on mortality, survival was obviously not different among the groups. The mechanisms responsible for increased mortality with ESA in oncology remain unclear. Whereas some suggested that it was partly explained by TEE [2,3], in our study TEE were no more frequent in the ESA groups on study, and no TEE was observed during long-term follow-up. However, three major non-fatal cardiovascular events occurred in DA group versus none in DA1iron and control groups (NS). Another cause of worsened survival could be an effect of ESA on disease progression [6] as ESA could promote cell growth directly in tumor cells expressing erythropoietin (Epo) receptors and indirectly by stimulating angiogenesis through endothelial cells expressing Epo receptors. We did not observe impaired survival reported in untreated cancer patients receiving ESA, possibly because few patients had active disease. On the other hand, iron could also impact disease progression. In animal models, tumor growth can be favored by iron overload [4] but in these models, iron-replete animals received much larger doses of iron. In our study, iron therapy did not affect disease progression. Whereas patients with pre-transplant iron overload may develop more infections after transplantation, the rates of infection were similar in our three groups, indicating that 900 mg of IV iron post-transplant has no such deleterious effect. The other serious complications were uncommon and hardly attributable to ESA or iron treatment. In conclusion, DA and IV iron therapy following auto-HCT did not affect long-term safety, disease outcome, or survival.

Serum hepcidin following autologous hematopoietic cell transplantation: an illustration of the interplay of iron status, erythropoiesis and inflammation

Hepcidin, the key hormone in iron homeostasis,[1][1] is regulated by erythropoietic activity and hypoxia (negative feedback),[2][2] as well as iron stores (hepcidin induction by iron) and inflammation (upregulation).[1][1],[3][3] Only a few publications have focused on hepcidin in the context of

Erythropoietin therapy after allogeneic hematopoietic cell transplantation has no impact on long-term survival

MAEVE A. O’REILLY, SEÁN R. MILLAR, CLAIRE M. BUCKLEY, JANAS M. HARRINGTON, IVAN J. PERRY, MARY R. CAHILL* Department of Haematology, Cork University Hospital, Cork, Ireland; Department of Epidemiology and Public Health, University College Cork, Cork, Ireland; Contract grant sponsor: Irish Health Research Board; Contract grant number: HRC/2007/13. Additional Supporting Information may be found in the online version of this article. Conflict of interest: All authors declare that no competing interests exist. *Correspondence to: Mary R. Cahill, Cork University Hospital and University College Cork, Cork, Ireland. E-mail: maryr.cahill@hse.ie Received for publication: 3 June 2015; Accepted: 8 June 2015 Published online: 10 June 2015 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ajh.24085