Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 11 de 11
Filter
1.
Br J Haematol ; 185(4): 691-700, 2019 05.
Article in English | MEDLINE | ID: mdl-30919941

ABSTRACT

Anagrelide is an established treatment option for essential thrombocythaemia (ET). A prolonged release formulation was developed with the aim of reducing dosing frequency and improving tolerability, without diminishing efficacy. This multicentre, randomized, double blind, active-controlled, non-inferiority trial investigated the efficacy, safety and tolerability of anagrelide prolonged release (A-PR) over a reference product in high-risk ET patients, either anagrelide-naïve or -experienced. In a 6 to 12-week titration period the individual dose for the consecutive 4-week maintenance period was identified. The primary endpoint was the mean platelet count during the maintenance period (3 consecutive measurements, day 0, 14, 28). Of 112 included patients 106 were randomized. The mean screening platelet counts were 822 × 109 /l (95% confidence interval (CI) 707-936 × 109 /l) and 797 × 109 /l (95% CI 708-883 × 109 /l) for A-PR and the reference product, respectively. Both treatments effectively reduced platelet counts, to mean 281 × 109 /l for A-PR (95% CI 254-311) and 305 × 109 /l (95% CI 276-337) for the reference product (P < 0·0001, for non-inferiority). Safety and tolerability were comparable between both drugs. The novel prolonged-release formulation was equally effective and well tolerated compared to the reference product. A-PR provides a more convenient dosing schedule and will offer an alternative to licensed immediate-release anagrelide formulations.


Subject(s)
Platelet Aggregation Inhibitors/administration & dosage , Quinazolines/administration & dosage , Thrombocythemia, Essential/drug therapy , Delayed-Action Preparations , Dose-Response Relationship, Drug , Double-Blind Method , Drug Compounding , Female , Humans , Male , Middle Aged , Platelet Aggregation Inhibitors/adverse effects , Platelet Aggregation Inhibitors/pharmacokinetics , Platelet Count , Quality of Life , Quinazolines/adverse effects , Quinazolines/pharmacokinetics , Treatment Outcome
3.
Leuk Lymphoma ; 58(7): 1598-1606, 2017 07.
Article in English | MEDLINE | ID: mdl-27830957

ABSTRACT

Chronic lymphocytic leukemia (CLL) is an incurable disease. Quality of life during treatment and periods of subsequent remission is therefore vital. Health-related quality of life (HRQoL) was compared in relapsed CLL during and after treatment with ofatumumab combined with fludarabine and cyclophosphamide versus fludarabine and cyclophosphamide alone. The European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 v3 and QLQ-CLL16 were used to assess HRQoL in this open-label, phase 3 study. Improvements in prespecified domains of patient-reported outcomes (Global Health Status [GHS]/HRQoL and B symptom scores) were recorded in both treatment arms after three cycles and were sustained after 18 months of follow-up. The two treatment arms were not significantly different at the nominal 0.05 level for GHS/HRQoL (p = .7278) or B symptoms (p = .5968). Small improvements in quality of life were maintained after therapy. The addition of ofatumumab was without any adverse impact on HRQoL (NCT00824265).


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Quality of Life , Aged , Aged, 80 and over , Antibodies, Monoclonal , Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cyclophosphamide/administration & dosage , Female , Follow-Up Studies , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Male , Middle Aged , Patient Reported Outcome Measures , Recurrence , Vidarabine/analogs & derivatives
4.
Leuk Lymphoma ; 58(5): 1084-1093, 2017 05.
Article in English | MEDLINE | ID: mdl-27731748

ABSTRACT

In this multicenter, open-label, phase III study, patients with relapsed chronic lymphocytic leukemia (CLL) were randomized (1:1) to receive ofatumumab plus fludarabine and cyclophosphamide (OFA + FC) or FC alone; the primary endpoint being progression-free survival (PFS) assessed by an independent review committee (IRC). Between March 2009 and January 2012, 365 patients were randomized (OFA + FC: n = 183; FC: n = 182). Median IRC-assessed PFS was 28.9 months with OFA + FC versus 18.8 months with FC (hazard ratio = 0.67; 95% confidence interval, 0.51-0.88; p = .0032). Grade ≥3 adverse events (≤60 days after last dose) were reported in 134 (74%) OFA + FC-treated patients compared with 123 (69%) FC-treated patients. Of these, neutropenia was the most common (89 [49%] vs. 64 [36%]). OFA + FC improved PFS with manageable safety for patients with relapsed CLL compared with FC alone, thus providing an alternative treatment option for patients with relapsed CLL. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT00824265).


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cyclophosphamide/administration & dosage , Female , Humans , Kaplan-Meier Estimate , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Male , Middle Aged , Neoplasm Grading , Neoplasm Staging , Recurrence , Treatment Outcome , Vidarabine/administration & dosage , Vidarabine/analogs & derivatives
5.
Lancet Haematol ; 3(12): e581-e591, 2016 Dec.
Article in English | MEDLINE | ID: mdl-27890073

ABSTRACT

BACKGROUND: Optimal management of patients with chronic myeloid leukaemia in chronic phase with suboptimal cytogenetic response remains undetermined. This study aimed to investigate the safety and efficacy of switching to nilotinib vs imatinib dose escalation for patients with suboptimal cytogenetic response on imatinib. METHODS: We did a phase 3, open-label, randomised trial in patients with chronic myeloid leukaemia in chronic phase with suboptimal cytogenetic response to imatinib according to the 2009 European LeukemiaNet criteria, in Latin America, Europe, and Asia (59 hospitals and care centres in 12 countries). Eligible patients were aged 18 years or older with Philadelphia chromosome-positive chronic myeloid leukaemia in chronic phase and Eastern Cooperative Oncology Group performance status of 0-2. Before enrolment, all patients had received 3-18 months of imatinib 400 mg once daily and had a suboptimal cytogenetic response according to 2009 ELN recommendations, established through bone marrow cytogenetics. By use of an interactive response technology using fixed blocks, we randomly assigned patients (1:1) to switch to nilotinib 400 mg twice per day or an escalation of imatinib dose to 600 mg once per day (block size of 4). Investigators and participants were not blinded to study treatment. Crossover was allowed for loss of response or intolerance at any time, or for patients with no complete cytogenetic response at 6 months. The primary endpoint was complete cytogenetic response at 6 months in the intention-to-treat population. Efficacy endpoints were based on the intention-to-treat population, with all patients assessed according to the treatment group to which they were randomised (regardless of crossover); the effect of crossover was assessed in post-hoc analyses, in which responses achieved after crossover were excluded. We present the final results at 24 months' follow-up. This study is registered with ClinicalTrials.gov (NCT00802841). FINDINGS: Between July 7, 2009, and Aug 29, 2012, we enrolled 191 patients. 96 patients were randomly assigned to nilotinib and 95 patients were randomly assigned to imatinib. Complete cytogenetic response at 6 months was achieved by 48 of 96 patients in the nilotinib group (50%, 95·18% CI 40-61) and 40 of 95 in the imatinib group (42%, 32-53%; difference 7·9% in favour of nilotinib; 95% CI -6·2 to 22·0, p=0·31). Excluding responses achieved after crossover, 48 (50%) of 96 patients in the nilotinib group and 34 (36%) of 95 patients in the imatinib group achieved complete cytogenic response at 6 months (nominal p=0·058). Grade 3-4 non-haematological adverse events occurring in more than one patient were headache (nilotinib group, n=2 [2%, including 1 after crossover to imatinib]; imatinib group, n=1 [1%]), blast cell crisis (nilotinib group, n=1 [1%]; imatinib group, n=1 [1%]), and QT prolongation (nilotinib group, n=1 [1%]; imatinib group, n=1 [1%, after crossover to nilotinib]). Serious adverse events on assigned treatment were reported in 11 (11%) of 96 patients in the nilotinib group and nine (10%) of 93 patients in the imatinib group. Seven (7%) of 96 patients died in the nilotinib group and five (5%) of 93 patients died in the imatinib group; no deaths were treatment-related. INTERPRETATION: While longer-term analyses are needed to establish whether the clinical benefits observed with switching to nilotinib are associated with improved long-term survival outcomes, our results suggest that patients with suboptimal cytogenetic response are more likely to achieve improved cytogenetic and molecular responses with switching to nilotinib than with imatinib dose escalation, although the difference was not statistically significant when responses achieved after crossover were included. FUNDING: Novartis Pharmaceuticals.


Subject(s)
Drug-Related Side Effects and Adverse Reactions/epidemiology , Imatinib Mesylate/administration & dosage , Imatinib Mesylate/adverse effects , Imatinib Mesylate/therapeutic use , Leukemia, Myeloid, Chronic-Phase/drug therapy , Philadelphia Chromosome/drug effects , Pyrimidines/adverse effects , Pyrimidines/therapeutic use , Adult , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/therapeutic use , Antineoplastic Protocols/standards , Asia , Biomarkers, Pharmacological/chemistry , Bone Marrow/chemistry , Comparative Effectiveness Research , Cytogenetic Analysis/methods , Disease Progression , Europe , Exanthema/chemically induced , Female , Fever/chemically induced , Follow-Up Studies , Headache/chemically induced , Hematologic Diseases/chemically induced , Humans , Latin America , Leukemia, Myeloid, Chronic-Phase/mortality , Male , Metabolic Diseases/chemically induced , Middle Aged , Random Allocation , Treatment Failure
6.
Br J Haematol ; 165(6): 814-23, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24650009

ABSTRACT

This phase IIa study evaluated the safety and tolerability of sotatercept, and its effects on bone metabolism and haematopoiesis in newly diagnosed and relapsed multiple myeloma (MM) patients. Patients were randomized (4:1) to receive four 28-d cycles of sotatercept (0·1, 0·3, or 0·5 mg/kg) or placebo. Patients also received six cycles of combination oral melphalan, prednisolone, and thalidomide (MPT). Thirty patients were enrolled; six received placebo and 24 received sotatercept. Overall, 25% of patients received all four sotatercept doses; 71% of sotatercept-treated patients had ≥1 dose interruption mainly due to increases in haemoglobin levels. Grade ≥3 adverse events (AEs) were reported in 17% of patients receiving placebo and 58% receiving sotatercept. Grade 4 AEs in sotatercept-treated patients were neutropenia, granulocytopenia, and atrial fibrillation (one patient each). In patients without bisphosphonate use, anabolic improvements in bone mineral density and in bone formation relative to placebo occurred, whereas bone resorption was minimally affected. Increases in haemoglobin levels, versus baseline, and the duration of the increases, were higher in the sotatercept-treated patients, with a trend suggesting a dose-related effect. Multiple doses of sotatercept plus MPT appear to be safe and generally well-tolerated in MM patients.


Subject(s)
Antineoplastic Agents/therapeutic use , Immunologic Factors/therapeutic use , Multiple Myeloma/drug therapy , Multiple Myeloma/pathology , Osteolysis/pathology , Recombinant Fusion Proteins/therapeutic use , Adult , Aged , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers , Bone Density , Female , Humans , Immunologic Factors/administration & dosage , Immunologic Factors/pharmacokinetics , Male , Middle Aged , Multiple Myeloma/complications , Neoplasm Staging , Osteogenesis , Osteolysis/etiology , Recombinant Fusion Proteins/administration & dosage , Recombinant Fusion Proteins/pharmacokinetics , Treatment Outcome
7.
J Clin Oncol ; 31(4): 448-55, 2013 Feb 01.
Article in English | MEDLINE | ID: mdl-23233713

ABSTRACT

PURPOSE: This final analysis of the phase III VISTA trial (Velcade As Initial Standard Therapy in Multiple Myeloma: Assessment With Melphalan and Prednisone) was conducted to determine whether the overall survival (OS) benefit with bortezomib-melphalan-prednisone (VMP) versus melphalan-prednisone (MP) in patients with myeloma who were ineligible for transplantation was maintained after 5 years of follow-up and to explore the risk of second primary malignancies. PATIENTS AND METHODS: In all, 682 patients received up to nine 6-week cycles of VMP or MP and were then observed every 12 weeks or less. Data on second primary malignancies were collected by individual patient inquiries at all sites from 655 patients. RESULTS: After median follow-up of 60.1 months (range, 0 to 74 months), there was a 31% reduced risk of death with VMP versus MP (hazard ratio [HR], 0.695; P < .001; median OS 56.4 v 43.1 months). OS benefit with VMP was seen across prespecified patient subgroups (age ≥ 75 years, stage III myeloma, creatinine clearance < 60 mL/min). Sixty-three percent of VMP patients and 73% of MP patients had received subsequent therapy. Time to next therapy (median, 30.7 v 20.5 months; HR, 0.557; P < .001) was longer with VMP than with MP. Among patients who received subsequent therapies, survival from start of subsequent therapy was similar following VMP (median, 28.1 months) or MP (median, 26.8 months; HR, 0.914). Following VMP/MP, incidence proportions of hematologic malignancies (1%/1%) and solid tumors (5%/3%) and exposure-adjusted incidence rates (0.017/0.013 per patient-year) were similar and were consistent with background rates. CONCLUSION: VMP resulted in a significant reduction in risk of death versus MP that was maintained after 5 years' follow-up and despite substantial use of novel-agent-based salvage therapies. There is no emerging safety signal for second primary malignancies following VMP.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Multiple Myeloma/drug therapy , Multiple Myeloma/mortality , Neoplasms, Second Primary/epidemiology , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Biomarkers, Tumor/blood , Boronic Acids/administration & dosage , Boronic Acids/adverse effects , Bortezomib , Drug Administration Schedule , Female , Follow-Up Studies , Humans , Incidence , Kaplan-Meier Estimate , Male , Melphalan/administration & dosage , Melphalan/adverse effects , Middle Aged , Multiple Myeloma/pathology , Multivariate Analysis , Neoplasm Staging , Neoplasms, Second Primary/chemically induced , Odds Ratio , Prednisone/administration & dosage , Prednisone/adverse effects , Proportional Hazards Models , Pyrazines/administration & dosage , Pyrazines/adverse effects , Risk , Spain/epidemiology , Treatment Outcome , beta 2-Microglobulin/blood
8.
J Clin Oncol ; 28(13): 2259-66, 2010 May 01.
Article in English | MEDLINE | ID: mdl-20368561

ABSTRACT

PURPOSE: The purpose of this study was to confirm overall survival (OS) and other clinical benefits with bortezomib, melphalan, and prednisone (VMP) versus melphalan and prednisone (MP) in the phase III VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma) trial after prolonged follow-up, and evaluate the impact of subsequent therapies. PATIENTS AND METHODS: Previously untreated symptomatic patients with myeloma ineligible for high-dose therapy received up to nine 6-week cycles of VMP (n = 344) or MP (n = 338). RESULTS: With a median follow-up of 36.7 months, there was a 35% reduced risk of death with VMP versus MP (hazard ratio, 0.653; P < .001); median OS was not reached with VMP versus 43 months with MP; 3-year OS rates were 68.5% versus 54.0%. Response rates to subsequent thalidomide- (41% v 53%) and lenalidomide-based therapies (59% v 52%) appeared similar after VMP or MP; response rates to subsequent bortezomib-based therapy were 47% versus 59%. Among patients treated with VMP (n = 178) and MP (n = 233), median survival from start of subsequent therapy was 30.2 and 21.9 months, respectively, and there was no difference in survival from salvage among patients who received subsequent bortezomib, thalidomide, or lenalidomide. Rates of adverse events were higher with VMP versus MP during cycles 1 to 4, but similar during cycles 5 to 9. With VMP, 79% of peripheral neuropathy events improved within a median of 1.9 months; 60% completely resolved within a median of 5.7 months. CONCLUSION: VMP significantly prolongs OS versus MP after lengthy follow-up and extensive subsequent antimyeloma therapy. First-line bortezomib use does not induce more resistant relapse. VMP used upfront appears more beneficial than first treating with conventional agents and saving bortezomib- and other novel agent-based treatment until relapse.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Multiple Myeloma/drug therapy , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Boronic Acids/administration & dosage , Bortezomib , China , Europe , Female , Humans , Israel , Kaplan-Meier Estimate , Male , Melphalan/administration & dosage , Multiple Myeloma/mortality , Prednisone/administration & dosage , Pyrazines/administration & dosage , Recurrence , Risk Assessment , Risk Factors , Time Factors , Treatment Outcome , United States
9.
N Engl J Med ; 359(9): 906-17, 2008 Aug 28.
Article in English | MEDLINE | ID: mdl-18753647

ABSTRACT

BACKGROUND: The standard treatment for patients with multiple myeloma who are not candidates for high-dose therapy is melphalan and prednisone. This phase 3 study compared the use of melphalan and prednisone with or without bortezomib in previously untreated patients with multiple myeloma who were ineligible for high-dose therapy. METHODS: We randomly assigned 682 patients to receive nine 6-week cycles of melphalan (at a dose of 9 mg per square meter of body-surface area) and prednisone (at a dose of 60 mg per square meter) on days 1 to 4, either alone or with bortezomib (at a dose of 1.3 mg per square meter) on days 1, 4, 8, 11, 22, 25, 29, and 32 during cycles 1 to 4 and on days 1, 8, 22, and 29 during cycles 5 to 9. The primary end point was the time to disease progression. RESULTS: The time to progression among patients receiving bortezomib plus melphalan-prednisone (bortezomib group) was 24.0 months, as compared with 16.6 months among those receiving melphalan-prednisone alone (control group) (hazard ratio for the bortezomib group, 0.48; P<0.001). The proportions of patients with a partial response or better were 71% in the bortezomib group and 35% in the control group; complete-response rates were 30% and 4%, respectively (P<0.001). The median duration of the response was 19.9 months in the bortezomib group and 13.1 months in the control group. The hazard ratio for overall survival was 0.61 for the bortezomib group (P=0.008). Adverse events were consistent with established profiles of toxic events associated with bortezomib and melphalan-prednisone. Grade 3 events occurred in a higher proportion of patients in the bortezomib group than in the control group (53% vs. 44%, P=0.02), but there were no significant differences in grade 4 events (28% and 27%, respectively) or treatment-related deaths (1% and 2%). CONCLUSIONS: Bortezomib plus melphalan-prednisone was superior to melphalan-prednisone alone in patients with newly diagnosed myeloma who were ineligible for high-dose therapy. (ClinicalTrials.gov number, NCT00111319.)


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Boronic Acids/administration & dosage , Melphalan/administration & dosage , Multiple Myeloma/drug therapy , Prednisone/administration & dosage , Pyrazines/administration & dosage , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Boronic Acids/adverse effects , Bortezomib , Disease Progression , Female , Follow-Up Studies , Humans , Male , Melphalan/adverse effects , Middle Aged , Pyrazines/adverse effects , Survival Analysis , Time Factors , Treatment Outcome
10.
Leuk Lymphoma ; 48(3): 497-505, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17454589

ABSTRACT

The efficacy and safety of peginterferon-alpha-2a (40 kD) (PEG-IFNalpha-2a), 450 microg once weekly, versus IFNalpha-2a, 9 MIU once daily, for 12 months, was evaluated in a Phase II study in IFN-naïve patients with chronic-phase, Philadelphia-chromosome-positive CML. At the end of the treatment, complete hematological response was observed in 66.2% (47/71) and 45.2% (33/73) of the PEG-IFNalpha-2a group and IFNalpha-2a groups, respectively (p = 0.009), and major cytogenetic response occurred in 35.2% and 17.8%, respectively (p = 0.016). PEG-IFNalpha-2a was at least as effective as IFNalpha-2a overall, including progression-free survival at the end of treatment, and overall survival after 30 months of follow-up. Adverse events necessitated fewer withdrawals but more dose adjustments in the PEG-IFNalpha-2a group compared with the IFNalpha-2a group (11%versus 23%, and 84.5%versus 65.8%, respectively). In conclusion, PEG-IFNalpha-2a (40 kD), 450 microg once weekly, compared with IFNalpha-2a, 9 MIU once daily, resulted in higher rates of hematologic and cytogenetic response and greater overall survival.


Subject(s)
Antiviral Agents/therapeutic use , Interferon-alpha/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Polyethylene Glycols/therapeutic use , Adult , Aged , Drug Carriers , Female , Humans , Interferon alpha-2 , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Male , Maximum Tolerated Dose , Middle Aged , Recombinant Proteins
11.
Pathol Oncol Res ; 3(2): 106-108, 1997.
Article in English | MEDLINE | ID: mdl-11173635

ABSTRACT

The association between severe aplastic anemia (AA) and DR2 antigen seems to be well established. However, since discrimination between two DR2-associated splits, namely DR15 and DR16, rarely was performed, it remains unclear whether one or both of these subvariants are responsible for AA susceptibility. In this study, we have analyzed the HLA-DR allelic distribution in a group of 37 AA patients of slavic origin from North-Western Russia. The experimental design included PCR-based amplification of DRB-specific sequences, followed by reverse dot-blot hybridization of the biotinylated PCR-product with the set of sequence-specific oligonucleotide probes. HLA-DRB alleles were identified by non-radioactive enzymatic reaction, then standard serological specificities of HLA-DR antigen were estimated according to the WHO nomenclature. Whereas DR15 subtype occurred more often in the patients (23.0% vs. 13.3%, p< 0.05), DR16 split did not show the same tendency. The results, show the overall predominance of HLA-DR2 specificity (DR15+DR16) did not reach statistical significance (24.4% vs.17.5%, p<0.2). Thus, we conclude that repeatedly reported DR2 frequency increase in AA patients is mainly attributed to the prevalence of DR15 subtype.

SELECTION OF CITATIONS
SEARCH DETAIL
...