Gunnar Birgegård

Philadelphia-Negative Classical Myeloproliferative Neoplasms: Critical Concepts and Management Recommendations From European LeukemiaNet

We present a review of critical concepts and produce recommendations on the management of Philadelphia-negative classical myeloproliferative neoplasms, including monitoring, response definition, first- and second-line therapy, and therapy for special issues. Key questions were selected according the criterion of clinical relevance. Statements were produced using a Delphi process, and two consensus conferences involving a panel of 21 experts appointed by the European LeukemiaNet (ELN) were convened. Patients with polycythemia vera (PV) and essential thrombocythemia (ET) should be defined as high risk if age is greater than 60 years or there is a history of previous thrombosis. Risk stratification in primary myelofibrosis (PMF) should start with the International Prognostic Scoring System (IPSS) for newly diagnosed patients and dynamic IPSS for patients being seen during their disease course, with the addition of cytogenetics evaluation and transfusion status. High-risk patients with PV should be managed with phlebotomy, low-dose aspirin, and cytoreduction, with either hydroxyurea or interferon at any age. High-risk patients with ET should be managed with cytoreduction, using hydroxyurea at any age. Monitoring response in PV and ET should use the ELN clinicohematologic criteria. Corticosteroids, androgens, erythropoiesis-stimulating agents, and immunomodulators are recommended to treat anemia of PMF, whereas hydroxyurea is the first-line treatment of PMF-associated splenomegaly. Indications for splenectomy include symptomatic portal hypertension, drug-refractory painful splenomegaly, and frequent RBC transfusions. The risk of allogeneic stem-cell transplantation-related complications is justified in transplantation-eligible patients whose median survival time is expected to be less than 5 years.

Response criteria for essential thrombocythemia and polycythemia vera: result of a European LeukemiaNet consensus conference

European experts were convened to develop a definition of response to treatment in polycythemia vera (PV) and essential thrombocythemia (ET). Clinicohematologic (CH), molecular, and histologic response categories were selected. In ET, CH complete response (CR) was: platelet count less than or equal to 400 x 10(9)/L, no disease-related symptoms, normal spleen size, and white blood cell count less than or equal to 10 x 10(9)/L. Platelet count less than or equal to 600 x 10(9)/L or a decrease greater than 50% was partial response (PR). In PV, CH-CR was: hematocrit less than 45% without phlebotomy, platelet count less than or equal to 400 x 10(9)/L, white blood cell count less than or equal to 10 x 10(9)/L, and no disease-related symptoms. A hematocrit less than 45% without phlebotomy or response in 3 or more of the other criteria was defined as PR. In both ET and in PV, molecular CR was a reduction of any molecular abnormality to undetectable levels. Molecular PR was defined as a reduction more than or equal to 50% in patients with less than 50% mutant allele burden, or a reduction more than or equal to 25% in patients with more than 50% mutant allele burden. Bone marrow histologic response in ET was judged on megakaryocyte hyperplasia while on cellularity and reticulin fibrosis in PV. The combined use of these response definitions should help standardize the design and reporting of clinical studies.

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 ⩾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.

Myeloproliferative Neoplasm (MPN) Symptom Assessment Form Total Symptom Score: Prospective International Assessment of an Abbreviated Symptom Burden Scoring System Among Patients With MPNs

PURPOSE Myeloproliferative neoplasm (MPN) symptoms are troublesome to patients, and alleviation of this burden represents a paramount treatment objective in the development of MPN-directed therapies. We aimed to assess the utility of an abbreviated symptom score for the most pertinent and representative MPN symptoms for subsequent serial use in assessing response to therapy. PATIENTS AND METHODS The Myeloproliferative Neoplasm Symptom Assessment Form total symptom score (MPN-SAF TSS) was calculated as the mean score for 10 items from two previously validated scoring systems. Questions focus on fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fevers. RESULTS MPN-SAF TSS was calculable for 1,408 of 1,433 patients with MPNs who had a mean score of 21.2 (standard deviation [SD], 16.3). MPN-SAF TSS results significantly differed among MPN disease subtypes (P<.001), with a mean of 18.7 (SD, 15.3), 21.8 (SD, 16.3), and 25.3 (SD, 17.2) for patients with essential thrombocythemia, polycythemia vera, and myelofibrosis, respectively. The MPN-SAF TSS strongly correlated with overall quality of life (QOL; r=0.59; P<.001) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) functional scales (all P<.001 and absolute r≥0.50 except social functioning r=0.48). No significant trends were present when comparing therapy subgroups. The MPN-SAF TSS had excellent internal consistency (Cronbachs α=.83). Factor analysis identified a single underlying construct, indicating that the MPN-SAF TSS is an appropriate, unified scoring method. CONCLUSION The MPN-SAF TSS is a concise, valid, and accurate assessment of MPN symptom burden with demonstrated clinical utility in the largest prospective MPN symptom study to date. This new prospective scoring method may be used to assess MPN symptom burden in both clinical practice and trial settings.

European consensus on the diagnosis and management of iron deficiency and anaemia in inflammatory bowel diseases

European Consensus on the Diagnosis and Management of Iron Deficiency and Anaemia in Inflammatory Bowel Diseases

Treatment-Related Risk Factors for Transformation to Acute Myeloid Leukemia and Myelodysplastic Syndromes in Myeloproliferative Neoplasms

PURPOSE Patients with myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis, have a propensity to develop acute myeloid leukemia (AML) and myelodysplastic syndromes (MDSs). Using population-based data from Sweden, we assessed the role of MPN treatment and subsequent AML/MDS risk with special focus on the leukemogenic potential of hydroxyurea (HU). METHODS On the basis of a nationwide MPN cohort (N = 11,039), we conducted a nested case-control study, including 162 patients (153 and nine with subsequent AML and MDS diagnosis, respectively) and 242 matched controls. We obtained clinical and MPN treatment data for all patients. Using logistic regression, we calculated odds ratios (ORs) as measures of AML/MDS risk. RESULTS Forty-one (25%) of 162 patients with MPNs with AML/MDS development were never exposed to alkylating agents, radioactive phosphorous (P(32)), or HU. Compared with patients with who were not exposed to HU, the ORs for 1 to 499 g, 500 to 999 g, more than 1,000 g of HU were 1.5 (95% CI, 0.6 to 2.4), 1.4 (95% CI, 0.6 to 3.4), and 1.3 (95% CI, 0.5 to 3.3), respectively, for AML/MDS development (not significant). Patients with MPNs who received P(32) greater than 1,000 MBq and alkylators greater than 1 g had a 4.6-fold (95% CI, 2.1 to 9.8; P = .002) and 3.4-fold (95% CI, 1.1 to 10.6; P = .015) increased risk of AML/MDS, respectively. Patients receiving two or more cytoreductive treatments had a 2.9-fold (95% CI, 1.4 to 5.9) increased risk of transformation. CONCLUSION The risk of AML/MDS development after MPN diagnosis was significantly associated with high exposures of P(32) and alkylators but not with HU treatment. Twenty-five percent of patients with MPNs who developed AML/MDS were not exposed to cytotoxic therapy, supporting a major role for nontreatment-related factors.

Cancer-Related Anemia: Pathogenesis, Prevalence and Treatment

Cancer-related anemia is a cytokine-mediated disorder resulting from complex interactions between tumor cells and the immune system. Overexpression of certain inflammatory cytokines results in shortened survival of red blood cells, suppression of erythroid progenitor cells, impaired iron utilization, and inadequate erythropoietin production. Numerous other factors may also contribute to the development of anemia in cancer patients. The European Cancer Anaemia Survey (ECAS) has provided the most current, comprehensive, prospectively collected data on the incidence and prevalence of anemia among cancer patients, as well as important perspectives on anemia treatment and relationship of hemoglobin and performance status. ECAS enrolled over 15,000 treated and untreated patients with various malignancies from cancer centers in 24 European countries and followed them for up to 6 months. The initial analysis of the ECAS data revealed that 39% of the total cancer patient population was anemic (hemoglobin <12.0 g/dl) at enrollment, although the rate varied according to tumor type, disease status, and cancer treatment status. Of the patients who were not anemic at enrollment and started cancer treatment during the survey, those undergoing chemotherapy – either alone or in combination with radiotherapy – had the highest incidence of anemia (63 and 42%, respectively). Low hemoglobin levels correlated with poor performance status and only 40% of patients who were anemic at some time during the survey received treatment for their anemia. These findings are noteworthy, since a growing body of clinical evidence indicates that the treatment of anemia can significantly improve patients’ quality of life and may also improve the clinical outcome.

A unified definition of clinical resistance and intolerance to hydroxycarbamide in polycythaemia vera and primary myelofibrosis : results of a European LeukemiaNet (ELN) consensus process

A unified definition of clinical resistance and intolerance to hydroxycarbamide in polycythaemia vera and primary myelofibrosis : results of a European LeukemiaNet (ELN) consensus process

Marked erythropoietin increase before fall in Hb after treatment with cytostatic drugs suggests mechanism other than anaemia for stimulation

Summary. Serum erythropoietin (Epo) was measured in 23 patients before, during and after intensive cytostatic treatment courses for acute leukaemia or before bone marrow transplantation. A marked increase was seen in all patients, starting 1 or 2 d after initiation of treatment. A peak was reached after about 7 d, at levels as high as 1450 IU/l, after which Epo fell rapidly, even in patients who were anaemic at that time. In 13 of the patients there was no fall in Hb level that could explain the increase in Epo. The increase was too large to be explained by an altered Epo metabolism or marrow utilization. Cytostatic drugs cause an increase in Epo production not mediated through anaemia, possibly initiated by a cytostatic effect on the kidneys or by an unknown stimulatory factor, responsive to bone marrow inhibition.

A Combination of Granulocvte Colonv- Stimulating Factor and Erythiopoietin 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.