A phase 3 randomized placebo-controlled trial of darbepoetin alfa in patients with anemia and lower-risk myelodysplastic syndromes.

The use of darbepoetin alfa to treat anemia in patients with lower-risk myelodysplastic syndromes (MDS) was evaluated in a phase 3 trial. Eligible patients had low/intermediate-1 risk MDS, hemoglobin ⩽10 g/dl, low transfusion burden and serum erythropoietin (EPO) ⩽500 mU/ml. Patients were randomized 2:1 to receive 24 weeks of subcutaneous darbepoetin alfa 500 µg or placebo every 3 weeks (Q3W), followed by 48 weeks of open-label darbepoetin alfa. A total of 147 patients were randomized, with median hemoglobin of 9.3 (Q1:8.8, Q3:9.7) g/dl and median baseline serum EPO of 69 (Q1:36, Q3:158) mU/ml. Transfusion incidence from weeks 5-24 was significantly lower with darbepoetin alfa versus placebo (36.1% (35/97) versus 59.2% (29/49), P=0.008) and erythroid response rates increased significantly with darbepoetin alfa (14.7% (11/75 evaluable) versus 0% (0/35 evaluable), P=0.016). In the 48-week open-label period, dose frequency increased from Q3W to Q2W in 81% (102/126) of patients; this was associated with a higher hematologic improvement-erythroid response rate (34.7% (34/98)). Safety results were consistent with a previous darbepoetin alfa phase 2 MDS trial. In conclusion, 24 weeks of darbepoetin alfa Q3W significantly reduced transfusions and increased rates of erythroid response with no new safety signals in lower-risk MDS (registered as EudraCT#2009-016522-14 and NCT#01362140).

Treatment with Hizentra in patients with primary and secondary immunodeficiencies: a real-life, non-interventional trial.

BACKGROUND: Although Hizentra is indicated for immunoglobulin replacement therapy in patients with primary and secondary immunodeficiencies, phase III trials have focused on patients with primary immunodeficiencies. In this 9-month, real-life, prospective, non-interventional, longitudinal, multicenter study of patients with primary and secondary immunodeficiencies in France, treatment modalities (primary endpoint), efficacy, safety, tolerability, quality of life, and treatment satisfaction were evaluated using descriptive statistics. RESULTS: Starting in January 2012, 117 patients were enrolled (99 adults, 18 children). Secondary immunodeficiencies were present in 48.7 % of patients. At follow-up, injections were administered every 7 days in 92.2 % of patients. Nine patients (7.8 %) were taking Hizentra every 10-14 days. The median dose of Hizentra administered was 0.1 g/kg/injection. Fifty-six patients were administered doses <0.1 g/kg/injection and 13 patients were administered doses >0.2 g/kg/injection. Mean trough IgG titers were 9.0 ± 3.3 g/L (median 8.3 g/L). The mean yearly rate of infection was 1.2 ± 1.9. Mean scores on the Short Form-36 physical and mental component summaries were 46.3 ± 10.0 and 46.6 ± 9.3, respectively. Scores on the Treatment Satisfaction Questionnaire for Medication ranged from 69.9 ± 19.9 to 88.3 ± 21.2 depending on the domain. Treatment with Hizentra was well tolerated. No single drug-related systemic reaction occurred in more than one patient and few local reactions were reported (n = 5). CONCLUSIONS: Under real-life conditions and in a cohort that included patients with primary and secondary immunodeficiencies, treatment with Hizentra was effective and well tolerated and patients were generally satisfied with the treatment.

Lenalidomide with or without erythropoietin in transfusion-dependent erythropoiesis-stimulating agent-refractory lower-risk MDS without 5q deletion.

After failure of erythropoiesis-stimulating agents (ESAs), lenalidomide (LEN) yields red blood cell (RBC) transfusion independence (TI) in 20-30% of lower-risk non-del5q myelodysplastic syndrome (MDS). Several observations suggest an additive effect of ESA and LEN in this situation. We performed a randomized phase III study in 131 RBC transfusion-dependent (TD, median transfusion requirement six RBC units per 8 weeks) lower-risk ESA-refractory non-del5q MDS. Patients received LEN alone, 10 mg per day, 21 days per 4 weeks (L arm) or LEN (same schedule) + erythropoietin (EPO) beta, 60,000 U per week (LE arm). In an intent-to-treat (ITT) analysis, erythroid response (HI-E, IWG 2006 criteria) after four treatment cycles (primary end point) was 23.1% (95% CI 13.5-35.2) in the L arm and 39.4% (95% CI 27.6-52.2) in the LE arm (P=0.044), while RBC-TI was reached in 13.8 and 24.2% of the patients in the L and LE arms, respectively (P=0.13). Median response duration was 18.1 and 15.1 months in the L and LE arms, respectively (P=0.47). Side effects were moderate and similar in the two arms. Low baseline serum EPO level and a G polymorphism of CRBN gene predicted HI-E. Combining LEN and EPO significantly improves erythroid response over LEN alone in lower-risk non-del5q MDS patients with anemia resistant to ESA.

Bragg scattering and Brownian motion dynamics in optically induced crystals of submicron particles.

A set of four confocal laser beams of 1064-nm wavelength is used to prepare optically induced crystals of submicron particles in aqueous solution. Thousands of polystyrene spheres of about 200 nm in diameter are trapped in three dimensions. Bragg scattering patterns obtained with a probe beam of 532-nm wavelength are in agreement with the calculated lattice structure and its polarization dependence. The decay and rise of the Bragg scattering intensity upon switching the lattice off and on reveal the Brownian motion dynamics of the particles in the periodic optical trapping potential. Experimental results agree well with results from trajectory simulations based on the Langevin equation. The results exhibit the interplay between Brownian motion and deterministic forces in an inhomogeneous (near-)periodic optical trapping potential.

High response rate and improved exercise capacity and quality of life with a new regimen of darbepoetin alfa with or without filgrastim in lower-risk myelodysplastic syndromes: a phase II study by the GFM.

Darbepoetin (DAR), with or without granulocyte colony-stimulating factor (G-CSF), has proved effective in treating anemia in patients with lower-risk myelodysplastic syndrome (MDS), but its effects on quality of life (QoL) and exercise functioning are less well established. In this phase II study (no. NCT00443339), lower-risk MDS patients with anemia and endogenous erythropoietin (EPO) level <500 IU/L received DAR 500 µg once every 2 weeks for 12 weeks, with G-CSF added at week 12 in non-responders. Physical performance was assessed with the 6-min walking test and, for fit patients, maximal oxygen consumption (VO2max). QoL was evaluated using SF-36 and FACT-An tests. In 99 patients, erythroid response rate according to IWG 2006 criteria was 48 and 56 % at 12 and 24 weeks, respectively. Addition of G-CSF rescued 22 % of non-responders. In 48 % of the responders, interval between darbepoetin injections could be increased for maintenance treatment. Serum EPO level was the only independent predictive factor of response at 12 weeks, and its most discriminant cutoff value was 100 IU/L. QoL and VO2max showed improvement over time in responders, compared with non-responders. With a median follow-up of 52 months, median response duration was not reached, and 3-year cumulative incidence of acute myeloid leukemia and overall survival (OS) was 14.5 and 70 %, respectively. Baseline transfusion dependence, International Prognostic Score System (IPSS), and Revised IPSS accurately predicted OS from treatment onset. Tolerance of darbepoetin was good. In conclusion, this regimen of darbepoetin every 2 weeks yielded high response rates and prolonged response duration. Objective improvement in exercise testing and in patient-reported QoL confirms the clinical relevance of anemia correction with erythropoiesis-stimulating agents.

Weekly paclitaxel as a single agent or in combination with carboplatin or weekly topotecan in patients with resistant ovarian cancer: the CARTAXHY randomized phase II trial from Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens (GINECO).

BACKGROUND: Platinum rechallenge or weekly topotecan in combination have not been evaluated in randomized trials for resistant recurrent ovarian cancer (ROC). METHODS: Patients with ROC after first- or second-line treatment including a platinum and taxane and progression within 6 months were randomized to weekly paclitaxel (wP, 80 mg/m(2)/week) alone or in combination with carboplatin (C, area under the curve of 5 mg/ml/min every 4 weeks) or weekly topotecan (wT, 3 mg/m(2)/week). Primary end point was progression-free survival (PFS) comparing wP and combination therapy. RESULTS: Patients (n = 165) received a median three cycles in each arm. Nonhematologic toxicity was not different, except increased hypersensitivity reactions with wP + C. Grade 3-4 hematologic toxic effects with wP, wP + C, and wP + wT, respectively, were neutropenia in 13%, 54%, and 42%; febrile neutropenia in 0%, 4%, and 5%; and anemia in 6%, 19%, and 29%. Response rates were 35%, 37%, and 39%, and median PFS times were 3.7, 4.8, and 5.4 months, respectively. PFS was not significantly different among the treatment arms [hazard ratio (HR) 0.922; 95% confidence interval (CI) 0.765-1.111; P = 0.46] or between monotherapy and combination therapy (HR 0.951; 95% CI 0.686-1.318; P = 0.76). CONCLUSIONS: Combination chemotherapy in platinum-resistant ROC was more toxic than weekly paclitaxel and did not significantly prolong PFS.

Ferritin level at diagnosis is not correlated with poorer survival in non RBC transfusion dependent lower risk de novo MDS.

We evaluated the prognostic value of serum ferritin (SF) level at diagnosis in 318 newly diagnosed IPSS low and int 1 (lower) risk MDS patients included in the French MDS registry, who did not require RBC transfusions and had baseline SF level determination. Increased baseline SF level (>300 ng/ml) was correlated with male gender, more pronounced anaemia, and diagnosis of RARS but had no negative impact on progression to AML or survival.

Docetaxel and pegylated liposomal doxorubicin combination as first-line therapy for metastatic breast cancer patients: results of the phase II GINECO trial CAPYTTOLE.

BACKGROUND: This phase II study evaluated the clinical benefit of pegylated liposomal doxorubicin (PLD) and docetaxel (Taxotere) as first-line therapy for metastatic breast cancer (MBC). PATIENTS AND METHODS: MBC patients were enrolled to receive six cycles of PLD 35 mg/m2 (day 1) and docetaxel 40 mg/m2 (days 1 and 15), every 28 days (group A). Because of unacceptable toxic effects, doses were modified to PLD 30 mg/m2 (day 1) and docetaxel 75 mg/m2 (day 2), every 3 weeks (group B). The primary end point was clinical benefit. RESULTS: Sixty-seven patients were included (group A, 53; group B, 14). In both groups, the median number of cycles delivered was 4 and the overall dose intensity was 82% for docetaxel and 71% for PLD. In group A, main toxic effects were hematologic, palmar-plantar erythrodysesthesia (PPE), and stomatitis. In group B, higher rates of grade 3-4 PPE, febrile neutropenia, and hematologic toxic effects were reported. The rate of clinical benefit was 47%. Among patients with a measurable disease, 49% achieved a partial response, 27% had a stable disease, and 13% progressed, according to RECIST criteria. CONCLUSION: The combination of PLD and docetaxel delivered at planned doses in this study yields unacceptable toxicity and should not be used routinely in patients with MBC.

Is there a role for all-trans retinoic acid in combination with recombinant erythropoetin in myelodysplastic syndromes? A report on 59 cases.

Erythropoiesis-stimulating agents (ESAs) remain the first-line treatment of anemia in lower risk myelodysplastic syndromes (MDS) without 5q deletion. A preliminary report suggested that adding all-trans retinoic acid (ATRA) to ESAs may improve their erythroid response, particularly in patients with high endogenous erythropoietin (EPO) level, and may improve other cytopenias. We conducted a prospective multicenter study of EPO-beta and ATRA in anemic MDS patients with marrow blasts <10% and either previous ESA failure or relapse, endogenous EPO >500 U/l or other cytopenia(s) (absolute neutrophilic count <1.0 G/l or platelets <50 G/l). A total of 59 patients were evaluable after 12 weeks of treatment. The erythroid response rates according to IWG 2000 and 2006 criteria, respectively, were as follows: overall: 49 and 36%; patients with previous ESA failure (n=28): 43 and 32%; patients with endogenous EPO >500 U/l (n=18): 11 and 19%; patients transfused >2 red blood cells units/month (n=28) 43 and 39%. Only one neutrophil, but no platelet response, and no major side effect were observed. EPO-beta-ATRA combination appears a possible therapeutic option in anemia of MDS having failed an ESA alone, but not in patients with high endogenous EPO level, and does not improve neutropenia and thrombocytopenia.

Widespread granuloma annulare and Hodgkin's disease.

The presence of coexistent disseminated granuloma annulare (GA) and Hodgkin's disease (HD) is rare, with only six reported patients to date. We describe a patient with HD who had limited GA 2 years before the diagnosis of HD; widespread GA appeared after first-line treatment and heralded disease relapse. GA lesions showed hypermetabolic images on positron emission tomography, an interesting finding of unknown significance. We suggest a new pathophysiological mechanism for this association, i.e. that the reactive T-lymphocyte population in HD may contribute to granuloma formation through the secretion of cytokines and the subsequent upregulation of certain metalloproteinases. Diffuse cutaneous GA should raise the possibility of underlying systemic lymphoma or HD.

Transient myocardial perfusion abnormalities during cold provocation test in patients with arterial hyperreactivity.

The effect of peripheral cold provocation on myocardial perfusion was evaluated utilizing thallium-201 perfusion imaging in 13 selected patients with arterial hyperreactivity (Raynaud's phenomenon: n = 8; migraine: n = 6) and angiographically documented coronary artery spasm. Eleven out of 13 subjects with coronary arterial spasm--but none of a group of patients with obstructive coronary artery disease--had transient myocardial perfusion defects during cold provocation. The localization of transient perfusion abnormalities during myocardial scintigraphy correlated with the myocardial areas distal to the spontaneous or ergonovine-induced coronary arterial spasm detected by angiography. Transient reduction of tracer uptake during cold provocation and normalization of myocardial perfusion by redistribution imaging was paralleled by areas of hypokinesia observed during the test by contrast ventriculography (n = 8). The described findings in the coronary system during peripheral cold pressor test occurred independently of the presence of Raynaud's phenomenon, and without achieving the ischemic threshold.