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.

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.

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.

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.

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.

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.

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.

Beta-globin mRNA increases rapidly during erythropoietin treatment.

Recombinant human erythropoietin (r-HuEpo) has an important role in the treatment of anaemic patients. Because of the high cost of r-HuEpo treatment, an early indicator of whether a patient is responding to the therapy would be valuable. Although measurement of gene expression is a promising new tool, it has not yet been established in clinical practice. The response pattern of a possible new marker, beta-globin mRNA, is compared with reticulocyte count, levels of haemoglobin, transferrin receptor and ferritin after r-HuEpo treatment. Eight healthy volunteers were stimulated with erythropoietin three times a week for four weeks and compared with five untreated control subjects. Blood samples were collected before each erythropoietin injection. Quantitative measurement of beta-globin mRNA was performed by poly(A) selection onto a manifold plastic support, coated with oligo(dT). The mRNA was reverse transcribed, followed by quantitative analysis using PCR via the 5' nuclease assay. The individuals treated with rHuEpo showed a more distinct increase in beta-globin mRNA levels than all other laboratory measurements. Beta-globin mRNA levels are therefore promising as a marker for the response to treatment with Epo.

Erythropoetin treatment can increase 2,3-diphosphoglycerate levels in red blood cells.

UNLABELLED: Some patients experience an improved well-being during treatment with recombinant human erythropoietin even with an unchanged Hb level. We have hypothesized that this may not be only a placebo effect. 2,3-diphosphoglycerate (2,3-DPG) in red blood cells increases in response to anaemia/hypoxia and causes a shift of the oxygen dissociation curve, allowing a more effective oxygen delivery. We have investigated red cell 2,3-DPG concentrations during erythropoietin treatment in healthy volunteers as a mediator of a possible physiological explanation. Thirteen healthy subjects with no iron deficiency were recruited and randomly assigned to a treatment group comprising five males and three females and a control group including three males and two females. The treatment group was treated with erythropoietin (Recormon), 20 IE/kg subcutaneously three times/week for 4 weeks. Blood samples were collected at each injection day and 10 days after the last injection and at corresponding times in the control group. B-Hb, red cell 2,3-DPG and P50 were measured by standard techniques and oxygen-releasing capacity was calculated. RESULTS: due to the sampling (26 ml each time, three times/week) the mean Hb level was lowered from 140.5 +/- 5.9 to 128.6 +/- 10.4 g/L in the control group whereas the erythropoietin treatment group maintained a mean Hb level of about 142 g/L (p<0.002). The 2,3-DPG mean level curve as well as that for oxygen releasing capacity also differed significantly between the two groups (p < 0.002), the treatment group showing higher levels. CONCLUSION: treatment with erythropoietin causes an increase in red cell 2,3-DPG levels.

The measurement of venous haematocrit in patients with polycythaemia vera.

OBJECTIVE: In clinical practice, patients with polycythaemia vera (PV) are monitored by measurement of venous packed cell volume (PCV). However, whereas treatment recommendations are still based upon studies in which the results were obtained with the centrifuged microhaematocrit, currently in most instances automated blood cell counters are used to calculate PCV. In a group of patients with polycythaemia we therefore compared the results obtained by the microhaematocrit method with PCV calculated by haematology analysers. DESIGN: The study was carried out on a prospective basis. Duplicate venous blood samples were collected. The centrifuged microhaemotocrit was obtained by using an IEC Micro-MB Centrifuge. Depending on different routine methods used in the participating hospitals, the blood cell counter PCV was calculated using Coulter STKS, Bayer Technicon H2 or H3. SETTING: Patients were included from four Swedish university hospitals: Akademiska (Uppsala), Huddinge and Karolinska (Stockholm) and Sahlgrenska (Göteborg). SUBJECTS: Seventy-four patients with PV and 10 patients with secondary polycythaemia were included and a total of 150 duplicate blood samples were analysed from these subjects. RESULTS: In the 150 measurements the mean blood cell counter calculated PCV was 0.448 +/- 0.037; the mean for centrifuged microhaematocrit was 0.467 +/- 0. 037 and the difference between means was highly significant (P = 6.8 x 10-25). The means for centrifuged haematocrit and calculated PCV differed significantly in the groups of PV patients treated with phlebotomy only, hydroxyurea or radiophosphorous (P < 0.0001, respectively). In PV patients treated with alpha-interferon and in patients with secondary polycythaemia the difference in means did not reach statistical significance (P = 0.07 and P = 0.13, respectively). The groups of patients with MCV <80 fL and >/=80 fL both presented significant differences between means for calculated PCV and centrifuged haematocrit. CONCLUSIONS: If PV patients are monitored with blood cell counter calculated PCV it appears that the therapeutic goal should be to maintain the calculated PCV below 0.43, provided the local differences in calculated PCV and centrifuged haematocrit are of the same magnitude as in this study.

Change in student attitudes to medical school after the introduction of problem-based learning in spite of low ratings.

Students' attitudes to, and opinions of, their studies at medical school were investigated with the help of a questionnaire. They were asked to what extent the medical school encouraged independent, critical thinking, problem-solving skills, decision-making, studying outside the textbook and other behaviours and skills that teachers in higher education usually put forward as important. It was found that students generally had a low opinion of the extent to which their education encouraged such virtues, mean figures ranging between 3.5 and 4.6 on a 10-grade scale. The students felt that their studies to a large extent encouraged focus on details and preparation for examinations. The questionnaire was given to the students after 2 1/2 years of traditional preclinical studies and at the end of the first clinical year. There were significant but numerically small differences for some of the items at the end of the year. However, when problem-based learning (PBL) was introduced during the first clinical year, there was a substantial change: there were now significant and numerically larger differences for seven of the nine items, even though the students were asked to give their opinion of the whole of their time at medical school on both occasions, not only of the last year. There were no other changes in the curriculum or the teaching methods other than the introduction of PBL. The change in attitudes did not depend on the student's appreciation of PBL; students' opinion of PBL was low, indicating that most of them disliked it.

Assessment of erythropoiesis following renal transplantation.

Ten patients, who received cadaveric kidneys, were followed for 24 wk with serial measurements of serum erythropoietin (S-Epo), transferrin receptor (S-TfR) and iron variables. The mean pretransplant creatinine clearance was 8.2 (range 0-22) ml/min and the mean haemoglobin (Hb) level was 99 +/- 18.6 (range 66-124) g/l. Nine patients demonstrated a gradual increase in S-Epo levels, which reached a peak, and was accompanied by a parallel increase in S-TfR levels with a median lag period of 3 wk between both peaks. Hb correction followed the S-TfR peak after a second lag period (median 7 wk). Elevated S-Epo and S-TfR did not result in correction of anaemia in 1 patient due to impaired graft function. Within 4 months, S-Epo levels reached the normal range while TfR levels were higher than normal. Follow-up of iron status demonstrated the development of iron deficiency in 5 patients, which was corrected spontaneously. Improvement in erythropoiesis after renal transplantation seems to occur by means of expansion of the erythroid marrow, as detected by increasing S-TfR levels, subsequent to a S-Epo peak. This expansion precedes Hb normalization. A nonuraemic environment is probably a prerequisite for the correction of anaemia but not for the increase in S-Epo or S-TfR levels. Iron deficiency may occur after transplantation due to an increase in iron utilization.

Preoperative autologous donation of 6 units of blood during rh-EPO treatment.

PURPOSE: To determine if donation of six units of blood in three weeks is possible with self-administered subcutaneous recombinant human erythropoietin (rhEPO) injections and oral iron treatment. METHODS: A prospective trial where a total of 32 otherwise healthy patients were phlebotomised before revision hip arthroplasty during rhEPO and oral iron treatment (ferrofumarate). Adverse events were noted and compliance was controlled. Routine laboratory tests were performed at each visit including reticulocytes and 2,3-DPG. The relative oxygen releasing capacity (RORC) and the oxygen releasing capacity (ORC) were calculated. Blood donation was postponed until the next visit if haemoglobin concentrations was < 115 g.l-1 (men) or < 105 g.l-1 (women). RESULTS: All but two patients were able to donate six units of blood with an acceptable haemoglobin concentration on the day of operation. One serious adverse event occurred when the Hb was 119 g.l-1, compared with 149 g.l-1 before treatment. During the first two weeks before phlebotomy there was no increase in Hb, the mean nadir was reached after six phlebotomies (31 g.l-1 below pre-study level), while at operation it was 19 g.l-1 below pre-study level. There was an increase in 2,3-DPG and oxygen releasing capacity after the initiation of rhEPO therapy, before the first phlebotomy. CONCLUSION: It is possible to donate six units of blood in a three week period before surgery during self-administered subcutaneous rhEPO treatment and oral iron therapy at a rhEPO dose of 60 U.kg-1 BW three times a week. It is suggested that rhEPO per se initiates a right-shift of the oxygen dissociation curve via an increased 2,3-DPG level, which could explain that some patients report subjective benefit of rhEPO in spite of no change in Hb concentration.

Iron absorption in patients with chronic uremia on maintenance hemodialysis and in healthy volunteers measured with a simple oral iron load test.

Gastrointestinal iron absorption was measured by an oral iron load test in patients with uremia on maintenance hemodialysis (n = 19), with iron overload (n = 9), iron deficiency (n = 10) and in healthy volunteers (n = 9). After an overnight fast, serum iron was measured before, and 1, 2, 4 and 6 h after administration of 100 mg ferrous chloride. Bone marrow iron was assessed after staining with Prussian blue. The study shows that iron absorption is impaired in uremic patients. Even uremic subjects with iron deficiency absorbed significantly less than normal subjects. Patients with iron overload and uremia absorbed even less, showing that the iron status of the patient influences absorption also in uremia.

Serum erythropoietin and erythropoiesis during six years after kidney transplantation.

We have studied serum erythropoietin (EPO) levels during 6 years after kidney transplantation in 16 patients. There was a serum EPO peak around 50 mU/ml after 5 weeks. After 3 months the serum EPO level stabilized at around 30 mU/ml. Patients with good transplant function had significantly higher serum EPO levels and normalized their hemoglobin (Hb) after a mean of 3 months. If transplant function was good, Hb was normalized even if the serum EPO was only slightly elevated. Patients with poor transplant function had lower serum EPO and Hb levels. We concluded that a good transplant function is the key to a normal erythropoiesis and that small amounts of EPO are needed to improve Hb.

Treatment of erythropoietin-resistant anaemia with desferrioxamine in patients on haemofiltration.

We studied 5 anaemic patients with Hb 74 +/- 8 g/l on haemofiltration (HF) treatment. They were iron overloaded. Their serum ferritin was 2667 +/- 8 micrograms/l. All patients' haemoglobin (Hb) levels decreased after an initial response to recombinant human erythropoietin (r-HuEPO) treatment. An increase in r-HuEPO dose from 100 to 400 U/kg s.c. thrice weekly with addition of oral and intravenous iron treatment for 8 weeks arrested the fall in Hb level. However, there was no significant increase in Hb during these 8 weeks. Iron was withdrawn at week 24 and desferrioxamine (DFO) treatment (i.v. doses of 2 g thrice weekly) was added to r-HuEPO from week 26 to 36. Two weeks after DFO initiation the Hb level increased to 110 g/l. Thereafter the r-HuEPO doses were reduced from 400 to 25 U/kg within 3 months. The Hb remained stable at a level of 110 g/l during the study, i.e., 17 months after the DFO treatment. Serum ferritin levels fell at a more rapid pace during DFO treatment and continued to decrease after DFO cessation for the following 17 months. In accordance with previous observations we found a positive effect of DFO treatment on erythropoiesis in patients with anaemia and iron overload. DFO treatment should be considered in patients with iron overload and r-HuEPO-resistant anaemia.