Hypersensitivity to intravenous iron: classification, terminology, mechanisms and management.

Intravenous (IV) iron therapy is widely used in iron deficiency anaemias when oral iron is not tolerated or ineffective. Administration of IV-iron is considered a safe procedure, but severe hypersensitivity reactions (HSRs) can occur at a very low frequency. Recently, new guidelines have been published by the European Medicines Agency with the intention of making IV-iron therapy safer; however, the current protocols are still non-specific, non-evidence-based empirical measures which neglect the fact that the majority of IV-iron reactions are not IgE-mediated anaphylactic reactions. The field would benefit from new specific and effective methods for the prevention and treatment of these HSRs, and the main goal of this review was to highlight a possible new approach based on the assumption that IV-iron reactions represent complement activation-related pseudo-allergy (CARPA), at least in part. The review compares the features of IV-iron reactions to those of immune and non-immune HSRs caused by a variety of other infused drugs and thus make indirect inferences on IV-iron reactions. The process of comparison highlights many unresolved issues in allergy research, such as the unsettled terminology, multiple redundant classifications and a lack of validated animal models and lege artis clinical studies. Facts and arguments are listed in support of the involvement of CARPA in IV-iron reactions, and the review addresses the mechanism of low reactogenic administration protocols (LRPs) based on slow infusion. It is suggested that consideration of CARPA and the use of LRPs might lead to useful new additions to the management of high-risk IV-iron patients.

A European patient record study on diagnosis and treatment of chemotherapy-induced anaemia.

PURPOSE: Patients with cancer frequently experience chemotherapy-induced anaemia (CIA) and iron deficiency. Erythropoiesis-stimulating agents (ESAs), iron supplementation and blood transfusions are available therapies. This study evaluated routine practice in CIA management. METHODS: Medical oncologists and/or haematologists from nine European countries (n=375) were surveyed on their last five cancer patients treated for CIA (n=1,730). Information was collected on tests performed at diagnosis of anaemia, levels of haemoglobin (Hb), serum ferritin and transferrin saturation (TSAT), as well as applied anaemia therapies. RESULTS: Diagnostic tests and therapies for CIA varied across Europe. Anaemia and iron status were mainly assessed by Hb (94%) and ferritin (48%) measurements. TSAT was only tested in 14%. At anaemia diagnosis, 74% of patients had Hb ≤ 10 g/dL, including 15% with severe anaemia (Hb <8 g/dL). Low-iron levels (ferritin ≤ 100 ng/mL) were detected in 42% of evaluated patients. ESA was used in 63%of patients, blood transfusions in 52 % and iron supplementation in 31% (74% oral, 26% intravenous iron). Only 30% of ESA-treated patients received a combination of ESA and iron supplementation. Blood transfusions formed part of a regular anaemia treatment regimen in 76% of transfused patients. Management practices were similar in 2009 and 2011. CONCLUSION: Management of anaemia and iron status in patients treated for CIA varies substantially across Europe. Iron status is only assessed in half of the patients. In contrast to clinical evidence, iron treatment is under utilised and mainly based on oral iron supplementation. Implementation of guidelines needs to be increased to minimize the use of blood transfusions.

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.

Economic evaluation in Sweden of epoetin beta with intravenous iron supplementation in anaemic patients with lymphoproliferative malignancies not receiving chemotherapy.

BACKGROUND AND OBJECTIVE: Functional iron deficiency is one reason for lack of response to erythropoietin treatment. Concomitant intravenous (IV) iron supplementation has the potential to improve response to erythropoietin, allowing a decrease in erythropoietin dose requirements. In a recent study of anaemic, iron-replete patients with lymphoproliferative malignancies (Leukemia, 21, 2007, 627), the haemoglobin (Hb) increase and response rate were significantly greater in patients receiving epoetin beta with concomitant IV iron compared with patients receiving epoetin beta without IV iron (P < 0.05). The present analysis aimed to investigate whether a combination of epoetin beta and IV iron is cost-effective compared with epoetin beta without IV iron. METHODS: This analysis was performed from a Swedish societal perspective as a within-trial evaluation of overall costs (based on differences in drug costs and resource use between groups) and effect (differences in Hb increases) during 16 weeks' treatment with epoetin beta with or without concomitant IV iron. RESULTS AND DISCUSSION: There was an improved response to epoetin beta with IV iron therapy and an almost 2-fold greater increase in Hb levels. Overall mean cost per patient in the epoetin beta with IV iron group was euro5558 and in the epoetin beta without IV iron group was euro6228. Thus, treatment with epoetin beta with IV iron resulted in overall cost savings of about 11% compared with epoetin beta without iron, mainly due to reduced erythropoietin dosages. CONCLUSION: Epoetin beta with concomitant IV iron in anaemic patients with lymphoproliferative malignancies not receiving chemotherapy resulted in better outcomes at lower cost compared with epoetin beta without iron. This suggests that epoetin beta with IV iron is a dominant therapy from a Swedish perspective.

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.

More efficient mobilisation of peripheral blood stem cells with HiDAC+AMSA+G-CSF than with mini-ICE+G-CSF in patients with AML.

We have compared the efficacy of two PBSC mobilisation regimens, mini-ICE+filgrastim (second consolidation) and HiDAC+AMSA+filgrastim (third consolidation), in two consecutive cohorts of patients with AML CR1 receiving treatment according to a joint protocol. Group A: 18 patients, aged 41 (21-65) years, were mobilised with mini-ICE (idarubicin 8 mg/m(2)+cytarabine 800 mg/m(2)+etoposide 150 mg/m(2) days 1-3) followed by filgrastim 300-480 microg once daily s.c. from day 11 after start of chemotherapy. Only four patients reached >5 CD34+ cells/microl blood (B-CD34+) and were able to undergo leukaphereses. Two out of 18 (11%) reached the defined target of >/=2.0 x 10(6) CD34+ cells/kg after 1-3 leukaphereses. Group B: 20 patients, aged 50 (29-67) years, received HiDAC+AMSA (cytarabine 3 g/m(2) b.i.d. days 1, 3, 5+amsacrine 150 mg/m(2) q.d. days 2, 4) followed by filgrastim at a similar dose starting on day 7. A total of 18 patients reached B-CD34+ >5/microl and underwent PBSC harvesting, starting on day 23 (14-29) and yielding 4.0 (0.9-21) x 10(6) CD34+ cells/kg. Of 20 patients, 17 (85%) reached the defined target of >/=2.0 x 10(6) CD34+ cells/kg after 1-3 leukaphereses. We conclude that HiDAC+AMSA+G-CSF - in contrast to mini-ICE+G-CSF - is an efficient regimen for mobilising PBSC in patients with AML CR1.

Randomized, double-blind, placebo-controlled trial of recombinant human erythropoietin, epoetin Beta, in hematologic malignancies.

PURPOSE: To investigate the effect of recombinant human erythropoietin (epoetin beta) on anemia, transfusion need, and quality of life (QOL) in severely anemic patients with low-grade non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), or multiple myeloma (MM). PATIENTS AND METHODS: Transfusion-dependent patients with NHL (n = 106), CLL (n = 126), or MM (n = 117) and a low serum erythropoietin concentration were randomized to receive epoetin beta 150 IU/kg or placebo subcutaneously three times a week for 16 weeks. Primary efficacy criteria were transfusion-free and transfusion- and severe anemia-free survival (hemoglobin [Hb] > 8.5 g/dL) between weeks 5 to 16. Response was defined as an increase in Hb > or = 2 g/dL with elimination of transfusion need. QOL was assessed by the Functional Assessment of Cancer Therapy scale. RESULTS: Transfusion-free (P =.0012) survival and transfusion- and severe anemia-free survival (P =.0001) were significantly greater in the epoetin beta group versus placebo (Wald chi(2) test), giving a relative risk reduction of 43% and 51%, respectively. The response rate was 67% and 27% in the epoetin beta versus the placebo group, respectively (P <.0001). After 12 and 16 weeks of treatment, QOL significantly improved in the epoetin beta group compared with placebo (P <.05); this improvement correlated with an increase in Hb concentration (> or = 2 g/dL). A target Hb that could be generally recommended could not be identified. CONCLUSION: Many severely anemic and transfusion-dependent patients with advanced MM, NHL, and CLL and a low performance status benefited from epoetin therapy, with elimination of severe anemia and transfusion need, and improvement in QOL.

Failure of oral pamidronate to reduce skeletal morbidity in multiple myeloma: a double-blind placebo-controlled trial. Danish-Swedish co-operative study group.

In order to study whether oral bisphosphonate therapy might prevent or reduce skeletal-related morbidity in patients with newly diagnosed multiple myeloma who required chemotherapy, 300 patients were included in a randomized multi-centre trial. Patients were given oral pamidronate at a dose of 300 mg daily, or placebo, in addition to conventional intermittent melphalan/prednisolone (and in some cases alpha-interferon) treatment. With a median treatment duration of about 550d, no statistically significant reduction in skeletal-related morbidity (defined as bone fracture, related surgery, vertebral collapse, or increase in number and/or size of bone lesions) could be demonstrated. Pamidronate treatment also did not have any influence on patient survival or on the frequency of hypercalcaemia. However, in patients treated with pamidronate there were fewer episodes of severe pain (P=0.02) and a decreased reduction of body height of 1.5 cm (P= 0.02). The overall negative result of the study is attributed to the very low absorption of orally administered bisphosphonates in general.

Outcome of a multicenter treatment program including autologous or allogeneic bone marrow transplantation for de novo acute myeloid leukemia.

The results of an intensive treatment program for patients 16-60 yr of age with de novo acute myeloid leukemia are presented. The patients were given conventional induction treatment with daunorubicin and cytarabine. Patients not entering complete remission (CR) after 1 course of daunorubicin/cytarabine were given 1 course of amsacrine/etoposide/cytarabine. Those entering complete remission received 3 consolidation courses using mitoxantrone, etoposide, amsacrine and cytarabine. One hundred and eighteen patients were enrolled. Complete remission was attained after 1-2 courses in 90 patients (76%). Another 6 patients reached CR after 3-4 induction courses for a total CR rate of 81%. If feasible, patients were offered either allogeneic or unpurged autologous bone marrow transplantation. Twenty-four patients underwent allogeneic bone marrow transplantation; 15 in first remission, 8 in second remission, 1 in early relapse. Thirty patients below 56 yr of age underwent autologous bone marrow transplantation in first remission. The overall probability of survival at 4 yr was 34%, and for patients below 40 yr of age 50%. Leukemia-free survival was 35% for the whole cohort of patients; 52% for patients below 40 yr of age. Patients undergoing allogeneic or autologous bone marrow transplantation in first remission had an overall survival of 86% and 47%, respectively, while the probability of leukemia-free survival in these groups was 87% vs. 40% at 4 yr. The CR rate and long-term results of this intensive treatment program compare favorably with other recent studies using intensive consolidation with allogeneic or autologous bone marrow transplantation or high dose cytarabine.

Subcutaneous injections of 2-chlorodeoxyadenosine for symptomatic hairy cell leukemia.

PURPOSE: To evaluate the clinical efficacy and safety of 2-chlorodeoxyadenosine (CdA) when administered by subcutaneous injection to patients with symptomatic hairy cell leukemia (HCL), and to evaluate predictive factors for response. PATIENTS AND METHODS: Seventy-three patients were given CdA as a subcutaneous injection once daily for 7 days. Complete remission (CR) required normalized blood counts and the absence of B-ly 7-positive bone marrow cells by flow cytometry. CdA concentrations in plasma following the first injection were analyzed by high-pressure liquid chromatography. RESULTS: Fifty-nine patients (81%) achieved a durable CR after one (n = 55) or two courses, and 10 had a partial remission (PR). With a median follow-up duration of 20 months, no patient had a clinical relapse. Neutropenic fever that required intravenous antibiotics occurred in 28 patients (38%). No toxicity at injection sites was observed. Incomplete response was predicted by an elevated lymphocyte count and serum beta 2-microglobulin level, and by a high percentage of hairy cells in the bone marrow. Plasma CdA levels were similar to those achieved from intravenous administration. CONCLUSION: Subcutaneous injection of CdA is safe and as effective as continuous infusion without problems associated with the mode of administration. Our schedule simplifies CdA treatment and can be generally recommended.

Bolus therapy with mitoxantrone and vincristine in combination with high-dose prednisone (NOP-bolus) in resistant multiple myeloma. Nordic Myeloma Study Group (NMSG).

In a phase II study, 58 patients with resistant multiple myeloma (MM) were treated with a combination chemotherapy (NOP-bolus regimen) consisting of mitoxantrone (16 mg/m2 for the first 25 patients and 12 mg/m2 for the subsequent 33), vincristine (2 mg), both as bolus injections on day 1 and prednisone (250 mg/d on d 1-4 and 17-20). In patients greater than 70 years of age, the mitoxantrone dose was reduced to 12 mg/m2 or 8 mg/m2, respectively. The treatment was repeated every 4 weeks. A response (greater than 50% reduction in M component) was obtained in 26% of the patients and a minor response (clinical improvement but less than 50% reduction in M component) in another 21%. Median response duration was 27 wk and median survival for all patients was 25 wk. There were no differences in response rate or duration between patients receiving the high or low mitoxantrone dose, but patients in the low-dose group had fewer serious infections.

Mitoxantrone and cytarabine versus daunorubicin and cytarabine in previously untreated patients with acute myeloid leukemia.

A total of 44 adults aged 18-78 years were allocated to an open randomized study whose aim was to compare the efficacy and toxicity of mitoxantrone with those of daunorubicin in previously untreated patients presenting with acute myeloid leukemia. In one arm, induction treatment consisted of mitoxantrone plus cytarabine given on a 3- plus 7-day schedule. Post-induction treatment consisted of two courses of mitoxantrone plus cytarabine given on a 2- plus 5-day schedule. In the control arm, mitoxantrone was replaced by daunorubicin. In all, 14 of 21 eligible and evaluable patients in the mitoxantrone arm achieved a complete remission (CR). In the control arm, 14 of 20 subjects attained a CR. The median survival was 365 days for patients randomized to mitoxantrone-cytarabine and 401 days for those given daunorubicin-cytarabine. The efficacy and toxicity of mitoxantrone were similar to those of daunorubicin.

Refractory myelomatosis treated with mitoxantrone in combination with vincristine and prednisone (NOP-regimen): a phase II study. The Nordic Myeloma Study Group (NMSG)

In a phase II study, patients with refractory myelomatosis were treated with a combination chemotherapy (NOP regimen): mitoxantrone (bolus injection of 4 mg/m2 on days 1-4), vincristine (continuous infusion of 0.4 mg/24 h on days 1-4) and prednisone (250 mg/d on days 1-4 and 17-20). The treatment was repeated every 4 weeks. Ninety-two patients were treated after they were found refractory to treatment with melphalan and prednisone (and occasionally vincristine) (n = 50) or more intensive treatment regimens (n = 42) including anthracyclines (n = 18). Response (greater than or equal to 50% reduction of M protein) was obtained in 23 patients and minor response (clinical improvement but less than 50% reduction in M protein) in 22 patients. The median duration of the response was 7.5 months. Equal response rates were observed irrespective of the type of previous treatment. The major toxicity was myelosuppression with severe granulocytopenia and infections. However, the frequency decreased throughout the cycles. The NOP treatment is recommended in refractory myelomatosis, especially in patients refractory to other intensive regimens. Patients in a poor clinical condition or with thrombocytopenia before treatment should have a reduced mitoxantrone dose in the first treatment cycles.

Mitoxantrone in the treatment of patients with non-Hodgkin's Lymphoma.

Thirty-five patients with non-Hodgkin's lymphoma, who had relapsed from or failed prior cytotoxic regimens including doxorubicin, received mitoxantrone at a dose of 14 mg/m2 iv every 3 weeks. According to the working formulation, 18, 15, and two patients had low-, intermediate-, and high-grade malignancy, respectively. Thirty-four patients were evaluable for response and all were evaluable for drug toxicity. Three patients achieved complete response, 12 achieved partial response, eight had stable disease, and 11 had progressive disease. The overall objective response rate was 43% (95% confidence limits, 25%-61%) for all patients. The response durations ranged from 7 to 11+ months. Time to treatment failure was 4.5 months (range, 1-10+). The response achieved were clustered in patients with low-grade malignancy. There was a partial response in a patient who had relapsed from prior anthracyclines. A total of 155 cycles of mitoxantrone therapy were given. The median number of courses per patient was four (range, one to ten). Myelosuppression was the dose-limiting factor. Most nonhematologic toxic effects were mild. The data indicate that mitoxantrone is effective in the treatment of non-Hodgkin's lymphoma with acceptable toxicity.