Five-year follow-up of survival and relapse in patients who received cryotherapy during high-dose chemotherapy for stem cell transplantation shows no safety concerns.

We have previously published a randomised controlled study of the efficacy of cryotherapy in preventing acute oral mucositis after high-dose chemotherapy for stem cell transplantation. The present study is a 5-year follow-up safety study of survival in these patients. In the previously published study oral cryotherapy (cooling of the oral cavity) during high-dose chemotherapy significantly reduced mucositis grade and opiate use in the treated group. All patients were followed up for at least 5 years with regard to relapse and death rates. Baseline data, transplant complications and mucositis data were compared. Significantly more patients (25/39) who received oral cryotherapy were alive after 5 years compared to 15/39 in the control group (P= 0.025). Relapse rates were similar. The only baseline difference was a lower proportion of patients in complete remission at transplantation in the control group (6 vs. 13, P= 0.047). This 5-year follow-up study gave no support for safety concerns with cryotherapy.

High incidence of iron depletion and restless leg syndrome (RLS) in regular blood donors: intravenous iron sucrose substitution more effective than oral iron.

BACKGROUND AND OBJECTIVES: Iron depletion is common in regular blood donors. The objective of the study was to investigate the frequency and severity of iron depletion in regular blood donors and whether IV iron is more effective than oral to avoid iron depletion and symptoms thereof, especially restless legs syndrome (RLS). METHOD: One hundred and twenty blood donors with at least five previous whole blood donations were randomized to receive either IV iron sucrose (Venofer(®), RenaPharma/Vifor, Uppsala, Sweden), 200 mg, or to 20×100 mg of oral iron sulphate (Duroferon(®), GlaxoSmithKline, Stockholm, Sweden), after each blood donation during 1 year. Iron status and RLS incidence and severity were investigated. RESULTS: Iron status was generally poor among regular blood donors, especially in women, with a high incidence of iron depletion (>20%) and RLS (18%). The IV iron group increased storage iron to a greater extent than the oral iron group after 12 months (P=0·0043). Female donors were more responsive to IV iron sucrose compared to oral iron sulphate, particularly female donors below 50 years of age. RLS severity scores were significantly lower in the IV iron group. The two treatments were safe. CONCLUSION: Iron status is poor in regular blood donors, restless legs syndrome is common, and the routine iron supplementation is insufficient. IV iron sucrose substitutes iron loss in blood donors more efficiently compared with oral iron sulphate, especially in women. Iron substitution to blood donors should be individualized and based on P-ferritin monitoring.

The role of iron supplementation during epoietin treatment for cancer-related anemia.

UNLABELLED: Cancer-related anemia is common and multifactorial in origin. Functional iron deficiency (FID) is now recognized as a cause of iron-restricted erythropoiesis and may be one of the major reasons for lack of response to treatment with Erythropoietic Stimulating Agents (ESAs). Numerous studies have shown that intravenous (IV), but not oral, iron therapy effectively provides sufficient iron for optimal erythropoiesis in anemic patients with chronic renal disease receiving ESA therapy. The use of IV iron has also been suggested in the cancer setting. Six recent studies have tested this assumption and are summarized in this review. Four formulations of IV iron are available in Europe, with different pharmacokinetics, iron bioavailability, and risk of acute adverse drug reactions. CONCLUSION: Limited iron stores and FID are common causes of response failure during ESA treatment in cancer patients and should be diagnosed. There is now substantial scientific support for the use of IV iron supplementation to improve response and this has been acknowledged in international and national guidelines. Prospective long-term data on the safety of IV iron in this setting are still awaited. Recommendations concerning the optimal formulation, doses, and schedule of iron supplementation to ESA treatment in cancer-related anemia are provisional awaiting data from prospective, randomized trials.

Addition of intravenous iron to epoetin beta increases hemoglobin response and decreases epoetin dose requirement in anemic patients with lymphoproliferative malignancies: a randomized multicenter study.

This randomized study assessed if intravenous iron improves hemoglobin (Hb) response and permits decreased epoetin dose in anemic (Hb 9-11 g/dl), transfusion-independent patients with stainable iron in the bone marrow and lymphoproliferative malignancies not receiving chemotherapy. Patients (n=67) were randomized to subcutaneous epoetin beta 30 000 IU once weekly for 16 weeks with or without concomitant intravenous iron supplementation. There was a significantly (P<0.05) greater increase in mean Hb from week 8 onwards in the iron group and the percentage of patients with Hb increase >or=2 g/dl was significantly higher in the iron group (93%) than in the no-iron group (53%) (per-protocol population; P=0.001). Higher serum ferritin and transferrin saturation in the iron group indicated that iron availability accounted for the Hb response difference. The mean weekly patient epoetin dose was significantly lower after 13 weeks of therapy (P=0.029) and after 15 weeks approximately 10 000 IU (>25%) lower in the iron group, as was the total epoetin dose (P=0.051). In conclusion, the Hb increase and response rate were significantly greater with the addition of intravenous iron to epoetin treatment in iron-replete patients and a lower dose of epoetin was required.

A unified definition of clinical resistance/intolerance to hydroxyurea in essential thrombocythemia: results of a consensus process by an international working group.

A widely accepted definition of resistance or intolerance to hydroxyurea (HU) in patients with essential thrombocythemia (ET) is lacking. An international working group (WG) was convened to develop a consensus formulation of clinically significant criteria for defining resistance/intolerance to HU in ET. To this aim, an analytic hierarchy process (AHP), a multiple-attribute decision-making technique, was used. The steps consisted of selecting the candidate criteria for defining resistance/intolerance; identifying the motivations that could influence the preference of the WG for any individual criterion; comparing the candidate criteria in a pair-wise manner; and grading them according their ability to fulfill the motivations. Every step in the model was derived by questionnaires or group discussion. The WG proposed that the definition of resistance/intolerance should require the fulfillment of at least one of the following criteria: platelet count greater than 600,000/micro l after 3 months of at least 2 g/day of HU (2.5 g/day in patients with a body weight over 80 kg); platelet count greater than 400,000/micro l and WBC less than 2500/micro l or Hb less than 10 g/dl at any dose of HU; presence of leg ulcers or other unacceptable muco-cutaneous manifestations at any dose of HU; HU-related fever.

Which patients with myelofibrosis should receive ruxolitinib therapy? ELN-SIE evidence-based recommendations.

Ruxolitinib is an oral Janus-activated kinase 1 (JAK1)/JAK2 inhibitor approved for the treatment of patients with myelofibrosis based on the results of two randomized clinical trials. However, discordant indications were provided by regulatory agencies and scientific societies for selecting the most appropriate candidates to this drug. The European LeukemiaNet and the Italian Society of Hematology shared the aim of building evidence-based recommendations for the use of ruxolitinib according to the GRADE methodology. Eighteen patient-intervention-comparator-outcome profiles were listed, each of them comparing ruxolitinib to other therapies with the aim of improving one of the three clinical outcomes: (a) splenomegaly, (b) disease-related symptoms, and (c) survival. Ruxolitinib was strongly recommended for improving symptomatic or severe (>15 cm below the costal margin) splenomegaly in patients with an International Prognostic Scoring System (IPSS)/dynamic IPSS risk intermediate 2 or high. Ruxolitinib was also strongly recommended for improving systemic symptoms in patients with an MPN10 score >44, refractory severe itching, unintended weight loss not attributable to other causes or unexplained fever. Because of weak evidence, the panel does not recommend ruxolitinib therapy for improving survival. Also, the recommendations given above do not necessarily apply to patients who are candidates for allogeneic stem cell transplant.

The biogenesis of erythropoietin.

Aerobic living demands a constant supply of oxygen at the cellular mitochondrial level. Numerous interlocking feedback mechanisms insure the constancy of this supply by adapting the supply lines to changes in the intra and extracellular milieu. Among these mechanisms is the feedback circuit which, triggered by an intracellular decrease in oxygen supply, initiates the production of a polypeptide hormone, erythropoietin, which in turn augments the production of an oxygen carrier, the hemoglobin-containing red cell. The biogenesis of this hormone is an important biologic process which is being studied intensively and slowly unravelled.

Clinical end points for drug treatment trials in BCR-ABL1-negative classic myeloproliferative neoplasms: consensus statements from European LeukemiaNET (ELN) and Internation Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT).

The discovery of somatic mutations, primarily JAK2V617F and CALR, in classic BCR-ABL1-negative myeloproliferative neoplasms (MPNs) has generated interest in the development of molecularly targeted therapies, whose accurate assessment requires a standardized framework. A working group, comprised of members from European LeukemiaNet (ELN) and International Working Group for MPN Research and Treatment (IWG-MRT), prepared consensus-based recommendations regarding trial design, patient selection and definition of relevant end points. Accordingly, a response able to capture the long-term effect of the drug should be selected as the end point of phase II trials aimed at developing new drugs for MPNs. A time-to-event, such as overall survival, or progression-free survival or both, as co-primary end points, should measure efficacy in phase III studies. New drugs should be tested for preventing disease progression in myelofibrosis patients with early disease in randomized studies, and a time to event, such as progression-free or event-free survival should be the primary end point. Phase III trials aimed at preventing vascular events in polycythemia vera and essential thrombocythemia should be based on a selection of the target population based on new prognostic factors, including JAK2 mutation. In conclusion, we recommended a format for clinical trials in MPNs that facilitates communication between academic investigators, regulatory agencies and drug companies.

A combination of granulocyte colony-stimulating factor and erythropoietin may synergistically improve the anaemia in patients with myelodysplastic syndromes.

In an attempt to obtain a synergistic effect on the hemoglobin levels in anaemic patients with myelodysplastic syndromes (MDS), granulocyte colony-stimulating factor (G-CSF) and erythropoietin (epo) were combined in a clinical phase II trial. Twenty-two patients with MDS were included in the study. G-CSF was given alone for six weeks and then in combination with epo for the following twelve weeks. Eight (38%) of 21 evaluable patients showed a significant increase in hemoglobin. One patient with a previous response and subsequent failure to epo alone improved after the addition of G-CSF. Responses were more frequent in patients with less advanced pancytopenia, lower endogenous levels of serum-epo and in those with ring sideroblasts in the bone marrow. The response frequency of 38% is higher than in any study of epo as monotherapy. Moreover, patients with ring sideroblasts, who respond poorly to epo alone, showed a response rate of 60%. Our findings suggest a synergistic in vivo effect of granulocyte-CSF and erythropoietin in patients with myelodysplastic syndromes.

Anaemia of pregnancy in Mozambique.

To establish the prevalence of anaemia in pregnant women in Mozambique and to determine the locally most important causes of the disease, 881 pregnant women were examined at nine sites in seven of Mozambique's 10 provinces. In Maputo, the capital city, an additional 91 anaemic gravidae were compared to 207 parturients chosen at random. The study comprised interviews, and clinical and laboratory investigations. Between 5 and 15% of the pregnant women at the different sites had haemoglobin (Hb) values below 90 g/l and 58% had levels below 110 g/l. Inspection of mucosal membranes detected almost all the anaemic women with Hb values below 80 g/l. Nulliparous women were more prone to be anaemic. Iron deficiency and malaria were the main causes of anaemia, with malnutrition also contributing. Occasional cases of folic acid deficiency were found among severely anaemic women but no cases of significant deficiency of vitamin B12 were encountered. Sickle cell disease was not found to contribute significantly to anaemia of pregnancy in Mozambique. The mean corpuscular haemoglobin concentration (MCHC) proved more sensitive, under these conditions, than serum ferritin in detecting iron deficiency in anaemic women. Packed cell volume (PCV) analysis may substitute Hb analysis when screening for pregnancy anaemia in Mozambique.

Serum ferritin: physiological and methodological studies.

Some aspects of normal ferritin physiology have been investigated as well as methodological problems concerning test sample handling etc. No circadian rhythm was found in 11 subjects. The day-to-day variation showed a mean of 9% in 22 subjects, but with considerable individual variation. The ferritin content in erythrocytes was about 0.045 fg/cell, and in leucocytes about 10 fg/cell. Hemolysis of test samples up to a hemoglobin concentration of 3 g/l in the serum did not significantly change the ferritin concentration. This means that hemolysis of test samples is usually no problem in clinical practice. Serum samples could be stored at -20 degrees C for a year or freeze-thawed six times without change in ferritin concentration. Heparin- and sodium citrate plasma gve the same resuls as serum, but EDTA plasma gave 23% (mean) lower values. A moderate amount of alcohol, corresponding to 25 cl of whisky, gave no rise within 56 h in serum ferritin levels in four subjects.

Serum erythropoietin in cross-country skiers.

Serum erythropoietin concentration and hemoglobin concentration were determined during the winter season in 41 male and 31 female well-trained, cross-country skiers. The athletes both lived and trained at low altitude (below 300 m above sea level). No significant differences in serum erythropoietin concentration were seen between male skiers (13.6 +/- 5.0 mU.ml-1), female skiers, (14.9 +/- 5.6 mU.ml-1), and normal controls (12.6 +/- 3.9 mU.ml-1) (mean +/- SD). In 18 of the skiers (12 males and 6 females), a second sample was taken after 2.3 +/- 0.18 months. No significant difference in either serum erythropoietin concentration or hemoglobin concentration was detected between the two samples in this combined group of skiers. The present study indicates that normal serum erythropoietin concentration is to be expected during the winter season at sea level in cross-country skiers living and training at low altitude.

Effects of blood transfusions on some hematological variables in endurance athletes.

Selected hematological variables (blood hemoglobin concentration [Hb], serum (s-) iron, s-bilirubin, s-ferritin, blood lactate, and s-erythropoietin [Epo]) were analyzed before and for 4 wk after autologous blood transfusions. A group of well-trained (8 male and 4 female) former endurance athletes was phlebotomized and 3-4 months later reinfused with the freezer-stored autologous red blood cells (RBC) from 1350 ml of blood. The [Hb] increased significantly (P less than 0.001 for both sexes) from 146.7 +/- 5.31 and 131.7 +/- 11.20 g. l-1 immediately before reinfusion to maximum values of 163.5 +/- 7.47 and 155.9 +/- 11.43 g.l-1 (mean +/- SD) in males and females, respectively, 2 d after reinfusion. S-iron increased transiently 5 h after reinfusion. S-bilirubin remained unchanged throughout the study. S-ferritin increased gradually (P less than 0.02) from 48 +/- 32.91 mmol.l-1 before reinfusion to a maximum of 80.8 +/- 39.52 mmol.l-1 2 wk after reinfusion. S-[Epo] increased transiently (P less than 0.01) from 8.83 +/- 2.51 (mean +/- SD) to 12.36 +/- 5.64 U.l-1, (mean +/- SD) 5 h after reinfusion. Subsequently, there was a significant marked decrease in s-[Epo] to 5.85 +/- 1.32 U.l-1, (mean +/- SD) 1 d after reinfusion (P less than 000.1, as compared to before reinfusion). Thereafter, s-[Epo] remained low throughout the study. Blood lactate was significantly decreased only the first 2 d after reinfusion (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Information to and communication with cancer patients: improvements and psychosocial correlates in a comprehensive care program for patients and their relatives.

Between 1987 and 1989, 177 cancer patients who were to receive intensive chemotherapy with curative intention, participated in a comprehensive care project with the aim of improving their total situation, and that of their relatives (n = 120). A number of steps were taken to improve, among other things, the information to, and communication with, patients and their relatives. Compared with a pre-project evaluation in 54 patients and 24 relatives, significantly lower problem scores were seen in most aspects relating to interaction with medical staff. Strong associations were seen between, on the one hand, various aspects of patient- and relative-staff interaction and, on the other, psychosocial problems, although they were weaker for problems relating to information, than for communication and control problems.

The outcome of allo-HSCT for 92 patients with myelofibrosis in the Nordic countries.

Between 1982 and 2009 a total of 92 patients with myelofibrosis (MF) in chronic phase underwent allo-SCT in nine Nordic transplant centers. Myeloablative conditioning (MAC) was given to 40 patients, and reduced intensity conditioning (RIC) was used in 52 patients. The mean age in the two groups at transplantation was 46±12 and 55±8 years, respectively (P<0.001). When adjustment for age differences was made, the survival of the patients treated with RIC was significantly better (P=0.003). Among the RIC patients, the survival was significantly (P=0.003) better for the patients with age <60 years (a 10-year survival close to 80%) than for the older patients. The type of stem cell donor did not significantly affect the survival. No significant difference was found in TRM at 100 days between the MAC- and the RIC-treated patients. The probability of survival at 5 years was 49% for the MAC-treated patients and 59% in the RIC group (P=0.125). Patients treated with RIC experienced significantly less aGVHD compared with patients treated with MAC (P<0.001). The OS at 5 years was 70, 59 and 41% for patients with Lille score 0, 1 and 2, respectively (P=0.038, when age adjustment was made). Twenty-one percent of the patients in the RIC group were given donor lymphocyte infusion because of incomplete donor chimerism, compared with none of the MAC-treated patients (P<0.002). Nine percent of the patients needed a second transplant because of graft failure, progressive disease or transformation to AML, with no significant difference between the groups. Our conclusions are (1) allo-SCT performed with RIC gives a better survival compared with MAC. (2) age over 60 years is strongly related to a worse outcome and (3) patients with higher Lille score had a shorter survival.