Jerome Zeldis - Academia.edu (original) (raw)
Papers by Jerome Zeldis
Tumor necrosis factor (TNF-) and vas- cular endothelial growth factor (VEGF) play an important ro... more Tumor necrosis factor (TNF-) and vas- cular endothelial growth factor (VEGF) play an important role in the biology of chronic lymphocytic leukemia (CLL) cells. Thalidomide is afirst-generation immuno- modulating agent that down-regulates TNF- and VEGF. We initiated a phase 1/2 clinical trial to determine the safety and efficacy of combining thalidomide with fludarabine in patients with treatment- naive CLL. Patients received 6 months of continuous daily thalidomide with stan- dard monthly doses of fludarabine. Three dose levels of thalidomide (100, 200, and 300 mg) were studied. Results from the phase 1 part of this study are reported here. Thirteen patients were enrolled in the phase 1 component of the study. Dose-limiting toxicity was not reached. The most common toxicities noted were fatigue, constipation, and peripheral sen- sory neuropathy. Overall response rate was 100% with 55% of patients achieving complete remissions. At a median fol- low-up of 15 months none of the pa- tients have had a relapse and the median time to disease progression has not yet been reached. Responses were noted at all dose levels. Thalidomide given up to 300 mg/day concurrently with fludarabine in patients with previously untreated CLL shows encouraging clinical efficacy and acceptable toxicity. An ongoing phase 2 part of this study will help validate the clinical efficacy of this regimen. (Blood. 2005;106:3348-3352)
British journal of cancer, Jan 8, 2004
We assessed the safety, tolerability and efficacy of the immunomodulatory drug, CC-5013 (REVIMID ... more We assessed the safety, tolerability and efficacy of the immunomodulatory drug, CC-5013 (REVIMID trade mark ), in the treatment of patients with metastatic malignant melanoma and other advanced cancers. A total of 20 heavily pretreated patients received a dose-escalating regimen of oral CC-5013. Maximal tolerated dose, toxicity and clinical responses were evaluated and analysis of peripheral T-cell surface markers and serum for cytokines and proangiogenic factors were performed. CC-5013 was well tolerated. In all, 87% of adverse effects were classified as grade 1 or grade 2 according to Common Toxicity Criteria and there were no serious adverse events attributable to CC-5013 treatment. Six patients failed to complete the study, three because of disease progression, two withdrew consent and one was entered inappropriately and withdrawn from the study. The remaining 14 patients completed treatment without dose reduction, with one patient achieving partial remission. Evidence of T-cell...
New England Journal of Medicine, 2009
New England Journal of Medicine, 2005
Ineffective erythropoiesis is the hallmark of myelodysplastic syndromes. Management of the anemia... more Ineffective erythropoiesis is the hallmark of myelodysplastic syndromes. Management of the anemia caused by ineffective erythropoiesis is difficult. In patients with myelodysplastic syndromes and symptomatic anemia, we evaluated the safety and hematologic activity of lenalidomide, a novel analogue of thalidomide. Forty-three patients with transfusion-dependent or symptomatic anemia received lenalidomide at doses of 25 or 10 mg per day or of 10 mg per day for 21 days of every 28-day cycle. All patients either had had no response to recombinant erythropoietin or had a high endogenous erythropoietin level with a low probability of benefit from such therapy. The response to treatment was assessed after 16 weeks. Neutropenia and thrombocytopenia, the most common adverse events, with respective frequencies of 65 percent and 74 percent, necessitated the interruption of treatment or a dose reduction in 25 patients (58 percent). Other adverse events were mild and infrequent. Twenty-four patients had a response (56 percent): 20 had sustained independence from transfusion, 1 had an increase in the hemoglobin level of more than 2 g per deciliter, and 3 had more than a 50 percent reduction in the need for transfusions. The response rate was highest among patients with a clonal interstitial deletion involving chromosome 5q31.1 (83 percent, as compared with 57 percent among those with a normal karyotype and 12 percent among those with other karyotypic abnormalities; P=0.007) and patients with lower prognostic risk. Of 20 patients with karyotypic abnormalities, 11 had at least a 50 percent reduction in abnormal cells in metaphase, including 10 (50 percent) with a complete cytogenetic remission. After a median follow-up of 81 weeks, the median duration of transfusion independence had not been reached and the median hemoglobin level was 13.2 g per deciliter (range, 11.5 to 15.8). Lenalidomide has hematologic activity in patients with low-risk myelodysplastic syndromes who have no response to erythropoietin or who are unlikely to benefit from conventional therapy.
New England Journal of Medicine, 2006
Myelodysplastic syndrome (MDS) associated with chromosome 5q31 deletion is characterized by sever... more Myelodysplastic syndrome (MDS) associated with chromosome 5q31 deletion is characterized by severe anemia that is often refractory to cytokine therapy. We investigated whether lenalidomide (CC5013; Revlimid™) would restore erythropoiesis in red blood cell (RBC) transfusion-dependent patients and suppress the abnormal clone.
Mayo Clinic Proceedings, 2005
OBJECTIVE: To study the efficacy of daily low-dose aspirin (81 mg orally) in decreasing the incid... more OBJECTIVE: To study the efficacy of daily low-dose aspirin (81 mg orally) in decreasing the incidence of venous thromboembolic events (VTEs) in patients with multiple myeloma receiving pegylated doxorubicin, vincristine, and decreased-frequency dexamethasone, plus thalidomide (DVd-T).
Leukemia, 2009
We present a pooled update of two large, multicenter MM-009 and MM-010 placebo-controlled randomi... more We present a pooled update of two large, multicenter MM-009 and MM-010 placebo-controlled randomized phase III trials that included 704 patients and assessed lenalidomide plus dexamethasone versus dexamethasone plus placebo in patients with relapsed/refractory multiple myeloma (MM). Patients in both studies were randomized to receive 25 mg daily oral lenalidomide or identical placebo, plus 40 mg oral dexamethasone. In this pooled analysis, using data up to unblinding (June 2005 for MM-009 and August 2005 for MM-010), treatment with lenalidomide plus dexamethasone significantly improved overall response (60.6 vs 21.9%, Po0.001), complete response rate (15.0 vs 2.0%, Po0.001), time to progression (median of 13.4 vs 4.6 months, Po0.001) and duration of response (median of 15.8 months vs 7 months, Po0.001) compared with dexamethasoneplacebo. At a median follow-up of 48 months for surviving patients, using data up to July 2008, a significant benefit in overall survival (median of 38.0 vs 31.6 months, P ¼ 0.045) was retained despite 47.6% of patients who were randomized to dexamethasone-placebo receiving lenalidomide-based treatment after disease progression or study unblinding. Low b 2 -microglobulin and low bone marrow plasmacytosis were associated with longer survival. In conclusion, these data confirm the significant response and survival benefit with lenalidomide and dexamethasone.
Journal of Thrombosis and Haemostasis, 2006
... doi: 10.1111/j.1538-7836.2006.02059.x. Author Information. 1 Divisione di Ematologia dell&... more ... doi: 10.1111/j.1538-7836.2006.02059.x. Author Information. 1 Divisione di Ematologia dell'Università di Torino, Azienda Ospedaliera S. Giovanni Battista, Torino, Italy. 2 Celgene Corporation, Warren, NJ, USA. 3 Divisione di Ematologia, Ospedale San Bortolo, Vicenza, Italy. ...
Journal of Clinical Oncology, 2009
Lenalidomide is a novel immunomodulatory agent with antiproliferative activities. Given its effic... more Lenalidomide is a novel immunomodulatory agent with antiproliferative activities. Given its efficacy in a wide range of hematologic malignancies, we conducted a phase II trial (NHL-001) of single-agent lenalidomide in indolent non-Hodgkin's lymphoma (NHL). Patients with relapsed/refractory indolent NHL were eligible, with no limit on the number of previous therapies. Oral lenalidomide 25 mg was self-administered once daily on days 1 to 21 of every 28-day cycle for up to 52 weeks as tolerated, or until disease progression. The primary end point was objective response rate (ORR), with secondary end points of duration of response (DR), progression-free survival (PFS), and safety. Forty-three enrolled patients were assessable for response and safety. Patients received a median of three prior systemic therapies (range, 1 to 17) and half were refractory to last therapy. ORR was 23% (10 of 43), including a 7% complete response (CR) or unconfirmed CR rate. Twenty-seven percent (six of 22) of patients with follicular lymphoma grade 1 or 2, and 22% (four of 18) with small lymphocytic lymphoma responded to therapy. Median DR was not reached, but was longer than 16.5 months with seven of 10 responses ongoing at 15 to 28 months. Median PFS for the whole group was 4.4 months (95% CI, 2.5 to 10.4 months). Adverse events were predictable and manageable; the most common grade 3 or 4 adverse events were neutropenia (30% and 16%, respectively) and thrombocytopenia (14% and 5%, respectively). Oral lenalidomide monotherapy produces durable responses with manageable adverse events in patients with relapsed/refractory indolent NHL, warranting further investigation of treatment for indolent NHL.
Journal of Clinical Oncology, 2007
Lenalidomide has shown significant antimyeloma activity in clinical studies. Oral melphalan, pred... more Lenalidomide has shown significant antimyeloma activity in clinical studies. Oral melphalan, prednisone, and thalidomide have been regarded as the standard of care in elderly multiple myeloma patients. We assessed dosing, efficacy, and safety of melphalan, prednisone, and lenalidomide (MPR) in newly diagnosed elderly myeloma patients. Oral melphalan was administered in doses ranging from 0.18 to 0.25 mg/kg on days 1 to 4, prednisone at a 2-mg/kg dose on days 1 to 4, and lenalidomide at doses ranging from 5 to 10 mg on days 1 to 21, every 28 days for nine cycles, followed by maintenance therapy with lenalidomide alone. Aspirin was given as a prophylaxis for thrombosis. Fifty-four patients were enrolled and evaluated after completing the assigned treatment schedule. The maximum tolerated dose was defined as 0.18 mg/kg melphalan and 10 mg lenalidomide. With these doses, 81% of patients achieved at least a partial response, 47.6% achieved a very good partial response, and 23.8% achieved a complete immunofixation-negative response. In all patients, 1-year event-free and overall survival rates were 92% and 100%, respectively. At the maximum tolerated dose, grade 3 adverse events included neutropenia (38.1%), thrombocytopenia (14.2%), febrile neutropenia (9.5%), vasculitis (9.5%), and thromboembolism (4.8%); grade 4 adverse events were neutropenia (14.2%) and thrombocytopenia (9.5%). Oral MPR therapy is a promising first-line treatment for elderly myeloma patients. Hematologic adverse events were frequent but manageable. A low incidence of nonhematologic adverse events was noted. Aspirin appears to provide adequate antithrombosis prophylaxis.
Journal of Clinical Oncology, 2008
The major cause of death in aggressive lymphoma is relapse or nonresponse to initial therapy. Len... more The major cause of death in aggressive lymphoma is relapse or nonresponse to initial therapy. Lenalidomide has activity in a variety of hematologic malignancies, including non-Hodgkin's lymphoma (NHL). We report the results of a phase II, single-arm, multicenter trial evaluating the safety and efficacy of lenalidomide oral monotherapy in patients with relapsed or refractory aggressive NHL. Patients were treated with oral lenalidomide 25 mg once daily on days 1 to 21, every 28 days, for 52 weeks, until disease progression or intolerance. The primary end point was response; secondary end points included duration of response, progression-free survival (PFS), and safety. Forty-nine patients with a median age of 65 years received lenalidomide in this study. The most common histology was diffuse large B-cell lymphoma (53%), and patients had received a median of four prior treatment regimens for NHL. An objective response rate of 35% was observed in 49 treated patients, including a 12% rate of complete response/unconfirmed complete response. Responses were observed in each aggressive histologic subtype tested (diffuse large B-cell, follicular center grade 3, mantle cell, and transformed lymphomas). Of patients with stable disease or partial response at first assessment, 25% improved with continued treatment. Estimated median duration of response was 6.2 months, and median PFS was 4.0 months. The most common grade 4 adverse events were neutropenia (8.2%) and thrombocytopenia (8.2%); the most common grade 3 adverse events were neutropenia (24.5%), leukopenia (14.3%), and thrombocytopenia (12.2%). Oral lenalidomide monotherapy is active in relapsed or refractory aggressive NHL, with manageable side effects.
Journal of Adolescent Health, 1995
A prospective, two-armed, open-label, randomized trial was performed to compare the geometric mea... more A prospective, two-armed, open-label, randomized trial was performed to compare the geometric mean titers (GMT), seroprotection (SP) and seroconversion (SC) rates found after administration of two doses of recombinant hepatitis B vaccine. Recombinant hepatitis B vaccine 10 or 20 micrograms was administered IM at 0, 1, and 6 months in healthy adolescents. Volunteers who received either dose of the vaccine had similarly high seroconversion and seroprotection rates at all visits. At Month 8, both doses of the vaccine were highly immunogenic with GMTs of 1989 mIU/mL (10 micrograms dose) and 7672 mIU/mL (20 micrograms dose) and nearly equivalent SP rates (97% and 99% in the 10 and 20 micrograms dose groups, respectively). The geometric mean titers of seroconverters at Months 3, 6 and 8 were significantly greater in the 20 micrograms group as compared to the 10 micrograms group (p < or = 0.003). Both doses were well-tolerated, with injection site pain the most common reported adverse event. Injection site pain was reported significantly (p = 0.004) more by volunteers who received the 20 micrograms dose (10.7%) compared with volunteers who received the 10 micrograms dose (3.8%). Vaccination with 10 micrograms of recombinant hepatitis B vaccine may provide a clinically effective and economical alternative to the use of the 20 micrograms dose in healthy adolescents.
Journal of Clinical Oncology, 2008
Haematologica, 2007
In vitro studies suggest that thalidomide has an immunoregulatory role and alters the marrow micr... more In vitro studies suggest that thalidomide has an immunoregulatory role and alters the marrow microenvironment. We assessed laboratory and clinical parameters in patients with myeloma treated with thalidomide as potential prognostic markers and looked for changes with therapy.
Haematologica, 2010
This retrospective pooled analysis of two phase III trials (MM-009/MM-010) compared clinical outc... more This retrospective pooled analysis of two phase III trials (MM-009/MM-010) compared clinical outcomes of patients who achieved a complete response or very good partial response to treatment with lenalidomide plus dexamethasone with the outcomes of those who only achieved a partial response.
Current Medical Research and Opinion, 2008
To evaluate the clinical and biological activity of apremilast in patients with severe plaque-typ... more To evaluate the clinical and biological activity of apremilast in patients with severe plaque-type psoriasis. Apremilast, a phosphodiesterase-4 inhibitor, inhibits in vitro activity of multiple inflammatory factors implicated in the pathogenesis of psoriasis. Patients received 20 mg apremilast orally for 29 days. Immunohistological analysis was conducted on lesional-skin biopsies for psoriasis-associated inflammatory markers. Lipopolysaccharide-stimulated tumor necrosis factor-alpha levels were evaluated in blood. Psoriasis Area and Severity Index (PASI), static Physician's Global Assessment, and Body Surface Area were used to monitor disease severity. There were 19 patients enrolled in this study, of whom 17 completed the study. Epidermal thickness was reduced by a mean of 20.5% from baseline to day 29. Among the responders, T cells were reduced by 28.8% and 42.6% in the dermis and epidermis, respectively. Similarly, CD11c cells were reduced by 18.5% and 40.2% in the dermis and epidermis, respectively. Fourteen of the 19 (73.7%) patients demonstrated an improvement in their PASI scores. This was a small, single-arm, open-label pilot study; therefore there was neither a placebo nor a comparison group. Apremilast demonstrated biological activity and improved psoriasis clinical efficacy scores in patients with severe plaque-type psoriasis. The majority of adverse events were mild in nature. Two adverse events (fatigue and dizziness) were judged by the investigator to be moderate and related to apremilast. In addition, there were no clinically-relevant abnormal laboratory test results in subjects treated with apremilast for 29 days.
Clinical Lymphoma and Myeloma, 2009
Lenalidomide is an oral immunomodulatory structural derivative of thalidomide with more potent ac... more Lenalidomide is an oral immunomodulatory structural derivative of thalidomide with more potent activity and a more predictable and manageable toxicity profile than its parent compound. It possesses pleiotropic activities (immunomodulatory, antiangiogenic, and antineoplastic), as well as anti-inflammatory effects. 1,2 Lenalidomide induces apoptosis, decreases the binding of myeloma cells to bone marrow stromal cells, and inhibits the production of cytokines. It has direct antiproliferative activity, enhances dexamethasone cytotoxicity, and stimulates host antimyeloma natural killer-cell immunity via T-cell activation. In patients with newly diagnosed multiple myeloma (MM), the effectiveness of lenalidomide has been explored in combination with dexamethasone, or dexamethasone plus clarithromycin, leading to response rates (RRs) between 86% and 91% and grade 3/4 hematologic toxicity rates from 12% to 22%. Background: Initial analysis of the combination melphalan, prednisone, plus lenalidomide (MPR) showed significant antimyeloma activity in patients with untreated multiple myeloma, with neutropenia and thrombocytopenia as the most frequent side effects. This updated analysis reassessed the kinetics of neutropenia and thrombocytopenia as well as the safety and efficacy of MPR. Patients and Methods: A total of 21 patients with newly diagnosed myeloma received melphalan 0.18 mg/kg on days 1-4, prednisone 2 mg/kg on days 1-4, and lenalidomide 10 mg daily on days 1-21 for nine 28-day cycles, followed by maintenance therapy with lenalidomide 10 mg daily on days 1-21. Results: Grade 3/4 neutropenia occurred in 52% of the patients, and granulocyte colonystimulating factor was administered in 43%. The mean neutrophil counts at the start of each MPR cycle, during nadir, and after 6 months of maintenance were 2.69 × 10 9 /L, 1.43 × 10 9 /L, and 2.11 × 10 9 /L, respectively. Grade 3/4 thrombocytopenia occurred in 24% of the patients. Platelet transfusions were required by 1 patient (5%) with a platelet count of 16 × 10 9 /L; however, no thrombocytopenia-associated bleeding was reported. The mean platelet counts at the start of each cycle, during nadir, and after 6 months of maintenance were 174 ×
Clinical Drug Investigation, 2009
Background and objectives: Multiple myeloma treatment with lenalidomidebased regimens is associat... more Background and objectives: Multiple myeloma treatment with lenalidomidebased regimens is associated with risk of venous thromboembolism (VTE), particularly during concomitant use with erythropoiesis-stimulating agents (ESAs). The risk of VTE in myelodysplastic syndrome (MDS) patients treated with lenalidomide is not well characterized and the background risk in untreated patients is not known. This study set out to determine the reporting rate of VTE in MDS patients on lenalidomide in the two years of postmarketing experience in the US, and to investigate whether there is a disproportional signal of VTE in MDS patients on lenalidomide by screening the US FDA Adverse Event Reporting System (AERS) safety database. Methods: The MDS population exposed to lenalidomide was obtained from RevAssist Ò , the company's proprietary restrictive distribution programme. VTE reports were identified from the company's postmarketing surveillance safety database. The FDA AERS database was used for disproportionality analysis, and signal scores computed using three algorithms: multi-item gamma Poisson shrinker (MGPS), proportional reporting ratio (PRR), and reporting odds ratios (ROR). Results: A total of 7764 MDS patients were prescribed lenalidomide during the first two years of commercial use in the US. VTE representing deep vein thrombosis and pulmonary embolism was reported in 41 patients, a reporting rate of 0.53%. The computed signal scores did not exceed the statistical threshold for identification of a significant disproportional signal for VTE in MDS reports involving use of lenalidomide without concomitant use of ORIGINAL RESEARCH ARTICLE
Tumor necrosis factor (TNF-) and vas- cular endothelial growth factor (VEGF) play an important ro... more Tumor necrosis factor (TNF-) and vas- cular endothelial growth factor (VEGF) play an important role in the biology of chronic lymphocytic leukemia (CLL) cells. Thalidomide is afirst-generation immuno- modulating agent that down-regulates TNF- and VEGF. We initiated a phase 1/2 clinical trial to determine the safety and efficacy of combining thalidomide with fludarabine in patients with treatment- naive CLL. Patients received 6 months of continuous daily thalidomide with stan- dard monthly doses of fludarabine. Three dose levels of thalidomide (100, 200, and 300 mg) were studied. Results from the phase 1 part of this study are reported here. Thirteen patients were enrolled in the phase 1 component of the study. Dose-limiting toxicity was not reached. The most common toxicities noted were fatigue, constipation, and peripheral sen- sory neuropathy. Overall response rate was 100% with 55% of patients achieving complete remissions. At a median fol- low-up of 15 months none of the pa- tients have had a relapse and the median time to disease progression has not yet been reached. Responses were noted at all dose levels. Thalidomide given up to 300 mg/day concurrently with fludarabine in patients with previously untreated CLL shows encouraging clinical efficacy and acceptable toxicity. An ongoing phase 2 part of this study will help validate the clinical efficacy of this regimen. (Blood. 2005;106:3348-3352)
British journal of cancer, Jan 8, 2004
We assessed the safety, tolerability and efficacy of the immunomodulatory drug, CC-5013 (REVIMID ... more We assessed the safety, tolerability and efficacy of the immunomodulatory drug, CC-5013 (REVIMID trade mark ), in the treatment of patients with metastatic malignant melanoma and other advanced cancers. A total of 20 heavily pretreated patients received a dose-escalating regimen of oral CC-5013. Maximal tolerated dose, toxicity and clinical responses were evaluated and analysis of peripheral T-cell surface markers and serum for cytokines and proangiogenic factors were performed. CC-5013 was well tolerated. In all, 87% of adverse effects were classified as grade 1 or grade 2 according to Common Toxicity Criteria and there were no serious adverse events attributable to CC-5013 treatment. Six patients failed to complete the study, three because of disease progression, two withdrew consent and one was entered inappropriately and withdrawn from the study. The remaining 14 patients completed treatment without dose reduction, with one patient achieving partial remission. Evidence of T-cell...
New England Journal of Medicine, 2009
New England Journal of Medicine, 2005
Ineffective erythropoiesis is the hallmark of myelodysplastic syndromes. Management of the anemia... more Ineffective erythropoiesis is the hallmark of myelodysplastic syndromes. Management of the anemia caused by ineffective erythropoiesis is difficult. In patients with myelodysplastic syndromes and symptomatic anemia, we evaluated the safety and hematologic activity of lenalidomide, a novel analogue of thalidomide. Forty-three patients with transfusion-dependent or symptomatic anemia received lenalidomide at doses of 25 or 10 mg per day or of 10 mg per day for 21 days of every 28-day cycle. All patients either had had no response to recombinant erythropoietin or had a high endogenous erythropoietin level with a low probability of benefit from such therapy. The response to treatment was assessed after 16 weeks. Neutropenia and thrombocytopenia, the most common adverse events, with respective frequencies of 65 percent and 74 percent, necessitated the interruption of treatment or a dose reduction in 25 patients (58 percent). Other adverse events were mild and infrequent. Twenty-four patients had a response (56 percent): 20 had sustained independence from transfusion, 1 had an increase in the hemoglobin level of more than 2 g per deciliter, and 3 had more than a 50 percent reduction in the need for transfusions. The response rate was highest among patients with a clonal interstitial deletion involving chromosome 5q31.1 (83 percent, as compared with 57 percent among those with a normal karyotype and 12 percent among those with other karyotypic abnormalities; P=0.007) and patients with lower prognostic risk. Of 20 patients with karyotypic abnormalities, 11 had at least a 50 percent reduction in abnormal cells in metaphase, including 10 (50 percent) with a complete cytogenetic remission. After a median follow-up of 81 weeks, the median duration of transfusion independence had not been reached and the median hemoglobin level was 13.2 g per deciliter (range, 11.5 to 15.8). Lenalidomide has hematologic activity in patients with low-risk myelodysplastic syndromes who have no response to erythropoietin or who are unlikely to benefit from conventional therapy.
New England Journal of Medicine, 2006
Myelodysplastic syndrome (MDS) associated with chromosome 5q31 deletion is characterized by sever... more Myelodysplastic syndrome (MDS) associated with chromosome 5q31 deletion is characterized by severe anemia that is often refractory to cytokine therapy. We investigated whether lenalidomide (CC5013; Revlimid™) would restore erythropoiesis in red blood cell (RBC) transfusion-dependent patients and suppress the abnormal clone.
Mayo Clinic Proceedings, 2005
OBJECTIVE: To study the efficacy of daily low-dose aspirin (81 mg orally) in decreasing the incid... more OBJECTIVE: To study the efficacy of daily low-dose aspirin (81 mg orally) in decreasing the incidence of venous thromboembolic events (VTEs) in patients with multiple myeloma receiving pegylated doxorubicin, vincristine, and decreased-frequency dexamethasone, plus thalidomide (DVd-T).
Leukemia, 2009
We present a pooled update of two large, multicenter MM-009 and MM-010 placebo-controlled randomi... more We present a pooled update of two large, multicenter MM-009 and MM-010 placebo-controlled randomized phase III trials that included 704 patients and assessed lenalidomide plus dexamethasone versus dexamethasone plus placebo in patients with relapsed/refractory multiple myeloma (MM). Patients in both studies were randomized to receive 25 mg daily oral lenalidomide or identical placebo, plus 40 mg oral dexamethasone. In this pooled analysis, using data up to unblinding (June 2005 for MM-009 and August 2005 for MM-010), treatment with lenalidomide plus dexamethasone significantly improved overall response (60.6 vs 21.9%, Po0.001), complete response rate (15.0 vs 2.0%, Po0.001), time to progression (median of 13.4 vs 4.6 months, Po0.001) and duration of response (median of 15.8 months vs 7 months, Po0.001) compared with dexamethasoneplacebo. At a median follow-up of 48 months for surviving patients, using data up to July 2008, a significant benefit in overall survival (median of 38.0 vs 31.6 months, P ¼ 0.045) was retained despite 47.6% of patients who were randomized to dexamethasone-placebo receiving lenalidomide-based treatment after disease progression or study unblinding. Low b 2 -microglobulin and low bone marrow plasmacytosis were associated with longer survival. In conclusion, these data confirm the significant response and survival benefit with lenalidomide and dexamethasone.
Journal of Thrombosis and Haemostasis, 2006
... doi: 10.1111/j.1538-7836.2006.02059.x. Author Information. 1 Divisione di Ematologia dell&... more ... doi: 10.1111/j.1538-7836.2006.02059.x. Author Information. 1 Divisione di Ematologia dell'Università di Torino, Azienda Ospedaliera S. Giovanni Battista, Torino, Italy. 2 Celgene Corporation, Warren, NJ, USA. 3 Divisione di Ematologia, Ospedale San Bortolo, Vicenza, Italy. ...
Journal of Clinical Oncology, 2009
Lenalidomide is a novel immunomodulatory agent with antiproliferative activities. Given its effic... more Lenalidomide is a novel immunomodulatory agent with antiproliferative activities. Given its efficacy in a wide range of hematologic malignancies, we conducted a phase II trial (NHL-001) of single-agent lenalidomide in indolent non-Hodgkin's lymphoma (NHL). Patients with relapsed/refractory indolent NHL were eligible, with no limit on the number of previous therapies. Oral lenalidomide 25 mg was self-administered once daily on days 1 to 21 of every 28-day cycle for up to 52 weeks as tolerated, or until disease progression. The primary end point was objective response rate (ORR), with secondary end points of duration of response (DR), progression-free survival (PFS), and safety. Forty-three enrolled patients were assessable for response and safety. Patients received a median of three prior systemic therapies (range, 1 to 17) and half were refractory to last therapy. ORR was 23% (10 of 43), including a 7% complete response (CR) or unconfirmed CR rate. Twenty-seven percent (six of 22) of patients with follicular lymphoma grade 1 or 2, and 22% (four of 18) with small lymphocytic lymphoma responded to therapy. Median DR was not reached, but was longer than 16.5 months with seven of 10 responses ongoing at 15 to 28 months. Median PFS for the whole group was 4.4 months (95% CI, 2.5 to 10.4 months). Adverse events were predictable and manageable; the most common grade 3 or 4 adverse events were neutropenia (30% and 16%, respectively) and thrombocytopenia (14% and 5%, respectively). Oral lenalidomide monotherapy produces durable responses with manageable adverse events in patients with relapsed/refractory indolent NHL, warranting further investigation of treatment for indolent NHL.
Journal of Clinical Oncology, 2007
Lenalidomide has shown significant antimyeloma activity in clinical studies. Oral melphalan, pred... more Lenalidomide has shown significant antimyeloma activity in clinical studies. Oral melphalan, prednisone, and thalidomide have been regarded as the standard of care in elderly multiple myeloma patients. We assessed dosing, efficacy, and safety of melphalan, prednisone, and lenalidomide (MPR) in newly diagnosed elderly myeloma patients. Oral melphalan was administered in doses ranging from 0.18 to 0.25 mg/kg on days 1 to 4, prednisone at a 2-mg/kg dose on days 1 to 4, and lenalidomide at doses ranging from 5 to 10 mg on days 1 to 21, every 28 days for nine cycles, followed by maintenance therapy with lenalidomide alone. Aspirin was given as a prophylaxis for thrombosis. Fifty-four patients were enrolled and evaluated after completing the assigned treatment schedule. The maximum tolerated dose was defined as 0.18 mg/kg melphalan and 10 mg lenalidomide. With these doses, 81% of patients achieved at least a partial response, 47.6% achieved a very good partial response, and 23.8% achieved a complete immunofixation-negative response. In all patients, 1-year event-free and overall survival rates were 92% and 100%, respectively. At the maximum tolerated dose, grade 3 adverse events included neutropenia (38.1%), thrombocytopenia (14.2%), febrile neutropenia (9.5%), vasculitis (9.5%), and thromboembolism (4.8%); grade 4 adverse events were neutropenia (14.2%) and thrombocytopenia (9.5%). Oral MPR therapy is a promising first-line treatment for elderly myeloma patients. Hematologic adverse events were frequent but manageable. A low incidence of nonhematologic adverse events was noted. Aspirin appears to provide adequate antithrombosis prophylaxis.
Journal of Clinical Oncology, 2008
The major cause of death in aggressive lymphoma is relapse or nonresponse to initial therapy. Len... more The major cause of death in aggressive lymphoma is relapse or nonresponse to initial therapy. Lenalidomide has activity in a variety of hematologic malignancies, including non-Hodgkin's lymphoma (NHL). We report the results of a phase II, single-arm, multicenter trial evaluating the safety and efficacy of lenalidomide oral monotherapy in patients with relapsed or refractory aggressive NHL. Patients were treated with oral lenalidomide 25 mg once daily on days 1 to 21, every 28 days, for 52 weeks, until disease progression or intolerance. The primary end point was response; secondary end points included duration of response, progression-free survival (PFS), and safety. Forty-nine patients with a median age of 65 years received lenalidomide in this study. The most common histology was diffuse large B-cell lymphoma (53%), and patients had received a median of four prior treatment regimens for NHL. An objective response rate of 35% was observed in 49 treated patients, including a 12% rate of complete response/unconfirmed complete response. Responses were observed in each aggressive histologic subtype tested (diffuse large B-cell, follicular center grade 3, mantle cell, and transformed lymphomas). Of patients with stable disease or partial response at first assessment, 25% improved with continued treatment. Estimated median duration of response was 6.2 months, and median PFS was 4.0 months. The most common grade 4 adverse events were neutropenia (8.2%) and thrombocytopenia (8.2%); the most common grade 3 adverse events were neutropenia (24.5%), leukopenia (14.3%), and thrombocytopenia (12.2%). Oral lenalidomide monotherapy is active in relapsed or refractory aggressive NHL, with manageable side effects.
Journal of Adolescent Health, 1995
A prospective, two-armed, open-label, randomized trial was performed to compare the geometric mea... more A prospective, two-armed, open-label, randomized trial was performed to compare the geometric mean titers (GMT), seroprotection (SP) and seroconversion (SC) rates found after administration of two doses of recombinant hepatitis B vaccine. Recombinant hepatitis B vaccine 10 or 20 micrograms was administered IM at 0, 1, and 6 months in healthy adolescents. Volunteers who received either dose of the vaccine had similarly high seroconversion and seroprotection rates at all visits. At Month 8, both doses of the vaccine were highly immunogenic with GMTs of 1989 mIU/mL (10 micrograms dose) and 7672 mIU/mL (20 micrograms dose) and nearly equivalent SP rates (97% and 99% in the 10 and 20 micrograms dose groups, respectively). The geometric mean titers of seroconverters at Months 3, 6 and 8 were significantly greater in the 20 micrograms group as compared to the 10 micrograms group (p < or = 0.003). Both doses were well-tolerated, with injection site pain the most common reported adverse event. Injection site pain was reported significantly (p = 0.004) more by volunteers who received the 20 micrograms dose (10.7%) compared with volunteers who received the 10 micrograms dose (3.8%). Vaccination with 10 micrograms of recombinant hepatitis B vaccine may provide a clinically effective and economical alternative to the use of the 20 micrograms dose in healthy adolescents.
Journal of Clinical Oncology, 2008
Haematologica, 2007
In vitro studies suggest that thalidomide has an immunoregulatory role and alters the marrow micr... more In vitro studies suggest that thalidomide has an immunoregulatory role and alters the marrow microenvironment. We assessed laboratory and clinical parameters in patients with myeloma treated with thalidomide as potential prognostic markers and looked for changes with therapy.
Haematologica, 2010
This retrospective pooled analysis of two phase III trials (MM-009/MM-010) compared clinical outc... more This retrospective pooled analysis of two phase III trials (MM-009/MM-010) compared clinical outcomes of patients who achieved a complete response or very good partial response to treatment with lenalidomide plus dexamethasone with the outcomes of those who only achieved a partial response.
Current Medical Research and Opinion, 2008
To evaluate the clinical and biological activity of apremilast in patients with severe plaque-typ... more To evaluate the clinical and biological activity of apremilast in patients with severe plaque-type psoriasis. Apremilast, a phosphodiesterase-4 inhibitor, inhibits in vitro activity of multiple inflammatory factors implicated in the pathogenesis of psoriasis. Patients received 20 mg apremilast orally for 29 days. Immunohistological analysis was conducted on lesional-skin biopsies for psoriasis-associated inflammatory markers. Lipopolysaccharide-stimulated tumor necrosis factor-alpha levels were evaluated in blood. Psoriasis Area and Severity Index (PASI), static Physician's Global Assessment, and Body Surface Area were used to monitor disease severity. There were 19 patients enrolled in this study, of whom 17 completed the study. Epidermal thickness was reduced by a mean of 20.5% from baseline to day 29. Among the responders, T cells were reduced by 28.8% and 42.6% in the dermis and epidermis, respectively. Similarly, CD11c cells were reduced by 18.5% and 40.2% in the dermis and epidermis, respectively. Fourteen of the 19 (73.7%) patients demonstrated an improvement in their PASI scores. This was a small, single-arm, open-label pilot study; therefore there was neither a placebo nor a comparison group. Apremilast demonstrated biological activity and improved psoriasis clinical efficacy scores in patients with severe plaque-type psoriasis. The majority of adverse events were mild in nature. Two adverse events (fatigue and dizziness) were judged by the investigator to be moderate and related to apremilast. In addition, there were no clinically-relevant abnormal laboratory test results in subjects treated with apremilast for 29 days.
Clinical Lymphoma and Myeloma, 2009
Lenalidomide is an oral immunomodulatory structural derivative of thalidomide with more potent ac... more Lenalidomide is an oral immunomodulatory structural derivative of thalidomide with more potent activity and a more predictable and manageable toxicity profile than its parent compound. It possesses pleiotropic activities (immunomodulatory, antiangiogenic, and antineoplastic), as well as anti-inflammatory effects. 1,2 Lenalidomide induces apoptosis, decreases the binding of myeloma cells to bone marrow stromal cells, and inhibits the production of cytokines. It has direct antiproliferative activity, enhances dexamethasone cytotoxicity, and stimulates host antimyeloma natural killer-cell immunity via T-cell activation. In patients with newly diagnosed multiple myeloma (MM), the effectiveness of lenalidomide has been explored in combination with dexamethasone, or dexamethasone plus clarithromycin, leading to response rates (RRs) between 86% and 91% and grade 3/4 hematologic toxicity rates from 12% to 22%. Background: Initial analysis of the combination melphalan, prednisone, plus lenalidomide (MPR) showed significant antimyeloma activity in patients with untreated multiple myeloma, with neutropenia and thrombocytopenia as the most frequent side effects. This updated analysis reassessed the kinetics of neutropenia and thrombocytopenia as well as the safety and efficacy of MPR. Patients and Methods: A total of 21 patients with newly diagnosed myeloma received melphalan 0.18 mg/kg on days 1-4, prednisone 2 mg/kg on days 1-4, and lenalidomide 10 mg daily on days 1-21 for nine 28-day cycles, followed by maintenance therapy with lenalidomide 10 mg daily on days 1-21. Results: Grade 3/4 neutropenia occurred in 52% of the patients, and granulocyte colonystimulating factor was administered in 43%. The mean neutrophil counts at the start of each MPR cycle, during nadir, and after 6 months of maintenance were 2.69 × 10 9 /L, 1.43 × 10 9 /L, and 2.11 × 10 9 /L, respectively. Grade 3/4 thrombocytopenia occurred in 24% of the patients. Platelet transfusions were required by 1 patient (5%) with a platelet count of 16 × 10 9 /L; however, no thrombocytopenia-associated bleeding was reported. The mean platelet counts at the start of each cycle, during nadir, and after 6 months of maintenance were 174 ×
Clinical Drug Investigation, 2009
Background and objectives: Multiple myeloma treatment with lenalidomidebased regimens is associat... more Background and objectives: Multiple myeloma treatment with lenalidomidebased regimens is associated with risk of venous thromboembolism (VTE), particularly during concomitant use with erythropoiesis-stimulating agents (ESAs). The risk of VTE in myelodysplastic syndrome (MDS) patients treated with lenalidomide is not well characterized and the background risk in untreated patients is not known. This study set out to determine the reporting rate of VTE in MDS patients on lenalidomide in the two years of postmarketing experience in the US, and to investigate whether there is a disproportional signal of VTE in MDS patients on lenalidomide by screening the US FDA Adverse Event Reporting System (AERS) safety database. Methods: The MDS population exposed to lenalidomide was obtained from RevAssist Ò , the company's proprietary restrictive distribution programme. VTE reports were identified from the company's postmarketing surveillance safety database. The FDA AERS database was used for disproportionality analysis, and signal scores computed using three algorithms: multi-item gamma Poisson shrinker (MGPS), proportional reporting ratio (PRR), and reporting odds ratios (ROR). Results: A total of 7764 MDS patients were prescribed lenalidomide during the first two years of commercial use in the US. VTE representing deep vein thrombosis and pulmonary embolism was reported in 41 patients, a reporting rate of 0.53%. The computed signal scores did not exceed the statistical threshold for identification of a significant disproportional signal for VTE in MDS reports involving use of lenalidomide without concomitant use of ORIGINAL RESEARCH ARTICLE