Martin R. Schipperus

Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial

BACKGROUND Chronic immune thrombocytopenic purpura (ITP) is characterised by accelerated platelet destruction and decreased platelet production. Short-term administration of the thrombopoiesis-stimulating protein, romiplostim, has been shown to increase platelet counts in most patients with chronic ITP. We assessed the long-term administration of romiplostim in splenectomised and non-splenectomised patients with ITP. METHODS In two parallel trials, 63 splenectomised and 62 non-splenectomised patients with ITP and a mean of three platelet counts 30x10(9)/L or less were randomly assigned 2:1 to subcutaneous injections of romiplostim (n=42 in splenectomised study and n=41 in non-splenectomised study) or placebo (n=21 in both studies) every week for 24 weeks. Doses of study drug were adjusted to maintain platelet counts of 50x10(9)/L to 200x10(9)/L. The primary objectives were to assess the efficacy of romiplostim as measured by a durable platelet response (platelet count > or =50x10(9)/L during 6 or more of the last 8 weeks of treatment) and treatment safety. Analysis was per protocol. These studies are registered with ClinicalTrials.gov, numbers NCT00102323 and NCT00102336. FINDINGS A durable platelet response was achieved by 16 of 42 splenectomised patients given romplostim versus none of 21 given placebo (difference in proportion of patients responding 38% [95% CI 23.4-52.8], p=0.0013), and by 25 of 41 non-splenectomised patients given romplostim versus one of 21 given placebo (56% [38.7-73.7], p<0.0001). The overall platelet response rate (either durable or transient platelet response) was noted in 88% (36/41) of non-splenectomised and 79% (33/42) of splenectomised patients given romiplostim compared with 14% (three of 21) of non-splenectomised and no splenectomised patients given placebo (p<0.0001). Patients given romiplostim achieved platelet counts of 50x10(9)/L or more on a mean of 13.8 (SE 0.9) weeks (mean 12.3 [1.2] weeks in splenectomised group vs 15.2 [1.2] weeks in non-splenectomised group) compared with 0.8 (0.4) weeks for those given placebo (0.2 [0.1] weeks vs 1.3 [0.8] weeks). 87% (20/23) of patients given romiplostim (12/12 splenectomised and eight of 11 non-splenectomised patients) reduced or discontinued concurrent therapy compared with 38% (six of 16) of those given placebo (one of six splenectomised and five of ten non-splenectomised patients). Adverse events were much the same in patients given romiplostim and placebo. No antibodies against romiplostim or thrombopoietin were detected. INTERPRETATION Romiplostim was well tolerated, and increased and maintained platelet counts in splenectomised and non-splenectomised patients with ITP. Many patients were able to reduce or discontinue other ITP medications. Stimulation of platelet production by romiplostim may provide a new therapeutic option for patients with ITP.

Efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies: a randomized, double-blind, placebo-controlled study

Summary. This phase 3, randomized, double‐blind, placebo‐controlled study was designed to evaluate the efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies. Patients (n = 344) with lymphoma or myeloma received darbepoetin alfa 2·25 μg/kg or placebo s.c., once weekly for 12 weeks. The percentage of patients achieving a haemoglobin response was significantly higher in the darbepoetin alfa group (60%) than in the placebo group (18%) (P < 0·001), regardless of baseline endogenous erythropoietin level. However, increased responsiveness was observed in patients with lower baseline erythropoietin levels. Darbepoetin alfa also resulted in higher mean changes in haemoglobin than placebo from baseline to the last value during the treatment phase (1·80 g/dl vs 0·19 g/dl) and after 12 weeks of treatment (2·66 g/dl vs 0·69 g/dl). A significantly lower percentage of patients in the darbepoetin alfa group received red blood cell transfusions than in the placebo group (P < 0·001). The efficacy of darbepoetin alfa was consistent for patients with lymphoma or myeloma. Improvements in quality of life were also observed with darbepoetin alfa. The overall safety profile of darbepoetin alfa was consistent with that expected for this patient population. Darbepoetin alfa significantly increased haemoglobin and reduced red blood cell transfusions in patients with lymphoproliferative malignancies receiving chemotherapy.

An open-label, unit dose-finding study of AMG 531, a novel thrombopoiesis-stimulating peptibody, in patients with immune thrombocytopenic purpura.

The objective of this open label, phase 1–2, multicentre trial was to evaluate the safety of AMG 531, a novel thrombopoiesis‐stimulating peptibody, and its effect on platelet counts in adults with immune thrombocytopenic purpura. Four patients were assigned to each of four unit‐dose cohorts: 30, 100, 300 or 500 μg, administered subcutaneously on days 1 and 15 (or day 22 if the day 15 platelet count was >50 × 109/l). Safety was assessed by adverse event (AE) monitoring, clinical laboratory studies and antibody assays. Platelet response was defined as a platelet count double the baseline value and between 50 and 450 × 109/l. Sixteen patients (10 women) were enrolled. The 500‐μg cohort was discontinued because the first patients platelet count became unacceptably high. AEs were generally expected and mild or moderate; the most frequent was headache (eight of 16 patients). Two patients experienced serious AEs related to AMG 531 (severe headache and elevated serum lactic dehydrogenase; thrombocytopenia). Platelet responses occurred with all doses and with a dose equivalent to ≥1 μg/kg in eight of 11 patients. In summary, patients tolerated AMG 531 well at the doses tested. No anti‐AMG or antithrombopoietin antibodies were detected. Doses equivalent to ≥1 μg/kg increased platelet counts.

Clinical effectiveness of leucoreduced, pooled donor platelet concentrates, stored in plasma or additive solution with and without pathogen reduction

Pathogen reduction (PR) of platelet products increases costs and available clinical studies are equivocal with respect to clinical and haemostatic effectiveness. We conducted a multicentre, open‐label, randomized, non‐inferiority trial comparing the clinical effectiveness of buffy‐coat derived leucoreduced platelet concentrates (PC) stored for up to 7 d in plasma with platelets stored in platelet additive solution III (PASIII) without and with treatment with amotosalen‐HCl/ultraviolet‐A (UVA) photochemical pathogen reduction (PR‐PASIII). Primary endpoint of the study was 1‐h corrected count increment (CCI). Secondary endpoints were 24‐h CCI, bleeding, transfusion requirement of red cells and PC, platelet transfusion interval and adverse transfusion reactions. Compared to plasma‐PC, in the intention to treat analysis of 278 evaluable patients the mean difference for the 1‐h CCI of PR‐PASIII‐PC and PASIII‐PC was −31% (P < 0·0001) and −9% (P = n.s.), respectively. Twenty‐seven patients (32%) had bleeding events in the PR‐PASIII arm, as compared to 19 (19%) in the plasma arm and 14 (15%) in the PASIII arm (P = 0·034). Despite the potential advantages of pathogen (and leucocyte) inactivation of amotosalen‐HCl/UVA‐treated platelet products, their clinical efficacy is inferior to platelets stored in plasma, warranting a critical reappraisal of employing this technique for clinical use.

Improved quality of life for romiplostim-treated patients with chronic immune thrombocytopenic purpura: results from two randomized, placebo-controlled trials

Health‐related quality of life (HRQoL) is a major concern for adults with chronic immune thrombocytopenic purpura (ITP) due to the symptoms associated with the disease and its treatment. This study utilized the ITP‐patient assessment questionnaire (ITP‐PAQ), a specialized HRQoL questionnaire for ITP, to investigate the humanistic burden of ITP and the impact of romiplostim therapy on HRQoL in two, placebo‐controlled, phase 3 clinical trials of splenectomized and non‐splenectomized patients. ITP‐PAQ was self‐administered to ITP patients at baseline, and weeks 4, 12 and 24 of treatment. Splenectomized patients had lower baseline HRQoL scores than non‐splenectomized patients in seven of 10 scales (P < 0·05). After 24 weeks of romiplostim therapy, splenectomized patients showed significant improvements over placebo in four of 10 ITP‐PAQ Scales (Symptoms, P = 0·0337; Bother, P = 0·0126; Social Activity, P = 0·0145; and Women’s Reproductive Health, P = 0·0184). Non‐splenectomized patients demonstrated significant improvement over placebo in the Activity Scale (P = 0·0458). Data pooled from the two trials, adjusted for splenectomy status, showed significant improvement for romiplostim‐treated patients in six scales; Symptoms, Bother, Activity, Fear, Social Activity and Women’s Reproductive Health. These results suggest that adult patients with chronic ITP have improved HRQoL following romiplostim therapy.

Quality of life measurement in patients with transfusion-dependent myelodysplastic syndromes.

Summary. The myelodysplastic syndromes (MDS) are clonal disorders characterized by dysplasia in at least two myeloid cell lines. Fatigue is one of the most significant symptoms. MDS patients are treated with blood transfusions to improve their health‐related quality of life (HRQoL). A cross‐sectional pilot study was performed for psychometric evaluation of three internationally established HRQoL measures in MDS patients, and for investigation of the association between the severity of chronic anaemia and HRQoL. Fifty consecutive MDS patients completed the Short Form 36, the Multidimensional Fatigue Inventory and the EuroQoL‐5D Visual Analogue Scale. Hb level was measured during the same visit. Psychometric analysis focused on feasibility, construct validity and reliability. The questionnaires showed a high feasibility, reliability and validity. MDS patients had worse HRQoL scores than the age‐ and sex‐matched general population. We found a positive correlation between haemoglobin (Hb) level and HRQoL. This study provides insights into the suitability of established HRQoL measures for the evaluation of interventions in MDS patients. Hb value and HRQoL are complementary variables for evaluation of the severity of chronic anaemia in patients with MDS.

Feasibility of a restrictive red-cell transfusion policy for patients treated with intensive chemotherapy for acute myeloid leukaemia

Summary.  Red‐cell transfusions are required for symptomatic treatment of severe anaemia caused by intensive chemotherapy. Concerns about the transfusion‐related complications, such as infections (e.g. the very low risk of human immunodeficiency virus (HIV)/hepatitis C virus (HCV) transmission and the risk of postoperative infections), haemolytic transfusion reaction, immunological effects and the costs, prompt a reevaluation of the transfusion practice. Retrospective analysis of prospectively collected data on 84 patients with acute myeloid leukaemia (AML), who were treated with combination chemotherapy between June 1, 1997 and December 7, 2001, was performed. The use of red‐cell transfusions with a restrictive transfusion policy (haemoglobin = 7·2–8·8 g dL−1, dependent on age and symptoms, n = 38) was compared with a more liberal transfusion trigger (haemoglobin = 9·6 g dL−1, n = 46). The number of units transfused was recorded. Signs and symptoms of anaemia, chemotherapy‐related effects and complications were investigated for both transfusion policies. The more restrictive transfusion policy led to a significant decrease of 11% of red blood cell (RBC) transfusions in patients with AML. No significant differences were found in the incidence of infections, number of platelet units transfused, bleeding complications, cardiac symptoms or response to chemotherapy. The more restrictive transfusion policy was feasible in this clinical setting, and it might be concluded that a restrictive transfusion policy is safe in supporting clinical patients treated with intensive chemotherapy for AML.

T-lymphocyte reconstitution following rigorously T-cell-depleted versus unmodified autologous stem cell transplants

We compared the kinetics of T-cell recovery after extensive ex vivo and in vivo T-cell depleted autologous stem cell transplantation (SCT) for multiple sclerosis (MS; n=8) with unmodified SCT for hematological malignancies (HM; n=39). Both patient group showed a very protracted recovery of ‘naive’ CD4+, 45R0− (≈CD45RA+) T-cells. Within the ‘primed’ CD4+, 45R0+ T-cells, the ‘central memory’ cells expressing the CD62L and CD27 markers were the slowest to recover. The repopulating T-cells were highly activated, as shown by increased expression of HLA-DR and the apoptosis marker CD95. The capability of CD4+ and CD8+ T-cells to produce IFN-γ, IL-2 and TNF-α had reached normal ranges from 2 months post SCT onwards. Unexpectedly, the kinetics of T-cell recovery between 3 and 12 months post transplant was similar in T-depleted and unmodified SCT. Before SCT, the HM patients showed lymphopenia of all T-cell subsets, upregulated HLA-DR and CD95 expression and increased cytokine responses. We suggest that the similar kinetics of T-cell recovery in the two patient groups may be explained by the susceptibility to apoptosis of the activated CD4+ T-cells in the autografts of the HM patients. This susceptibility to apoptosis would interfere with a swift and sustained CD4+ T-cell regeneration post SCT.

A novel approach to the evaluation of bleeding-related episodes in patients with chronic immune thrombocytopenia

Abstract Objective: In clinical studies of patients with severe thrombocytopenia, rescue treatments are used to prevent or stop bleeding. Estimating risk reductions of bleeding for clinical study medications can be challenging. This study evaluated a new and possibly more accurate way of assessing the effects of a treatment intervention on bleeding-related outcomes. We developed a composite endpoint, termed bleeding-related episodes (BRE). Research design and methods: BREs were assessed in a post-hoc analysis of patients with chronic immune thrombocytopenia (ITP) who participated in two romiplostim, phase 3, placebo-controlled studies. Patients received romiplostim or placebo once weekly for 24 weeks. A BRE was defined as an actual bleeding event and/or the use of rescue medication. In total, 125 patients (41 placebo, 84 romiplostim) with platelet counts <30 K were enrolled. Clinical trial registration: NCT00102323/NCT00102336. Results: The rate of all BREs across all studies was reduced by 56% in patients receiving romiplostim compared with placebo. The rate of BREs using immunoglobulin (IVIg or anti-D Ig) was reduced by 89% in patients receiving romiplostim compared with placebo. BREs were more frequent in both groups at platelet counts <50 × 109/L. Results were similar between splenectomized and nonsplenectomized patients. We believe that prior to the development of this tool, bleeding events were underdiagnosed. The BRE tool allowed the identification of multiple interventions within bleeding episodes, which may have required separate interventions and were therefore considered to be additional BREs. Conclusions: In this study, the composite endpoint of a bleeding event and the use of rescue medication within close proximity of the bleeding event appears to be feasible and informative. The BRE tool allows for more precise understanding of the effect of rescue therapies in ITP and has broader applications to future clinical trials where assessment of bleeding risk can be complicated or masked by rescue interventions. Limitations: This was a post hoc analysis. The assignment of platelet counts to a BRE was based on the platelet count on the first day of a BRE, which may not reflect the platelet count during the entire episode, and the assignment of platelet counts was based on the estimation required for events that occurred between weekly measurements.

Interleukin-6 and Interleukin-1 enhancement of GM-CSF-dependent proliferation of haematopoietic progenitor cells in myelodysplastic syndromes

Summary. Interleukin‐1 (Il–1) and Interleukin‐6 (Il–6) have been reported to enhance the growth factor dependent colony formation of normal primitive haematopoietic progenitor cells as well as of leukaemic blast‐cell progenitors. We investigated the effects of Il–1β and Il–6 in combination with granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) on the in vitro colony formation of myeloid progenitors from 23 patients with a myelodysplastic syndrome (MDS). Neither Il–1β nor Il–6 were found to have colony stimulating activity on their own. In normal bone marrow cultures, either stimulated with optimal or suboptimal doses of GM‐CSF, no enhancing or antagonistic effect of Il–6 or Il–1β was detected. In a majority of the MDS cases, however, an enhancing effect of Il–6 and Il–1β in combination with GM‐CSF was observed (20/23 and 10/21 cases respectively). In three cases of the Il‐6 and GM‐CSF combination an antagonistic effect was observed as well as in four cases of the Il‐1β and GM‐CSF combination. A delayed addition of Il‐6 to the cultures did not result in an abrogation of the effect, indicating that Il‐6 is not required immediately at the initiation of the culture. These results indicate that co‐stimulation with IL–6 or IL–1β is able to augment the GM‐CSF activity on MDS myeloid progenitor cells.