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Dan T Vogl,
Edward A Stadtmauer,
Paul G Richardson,
Pieter Sonneveld, Michael W Schuster,
David Irwin,
Thierry Facon,
Jean-Luc Harousseau,
Anthony Boral,
Rachel Neuwirth,
Kenneth C Anderson
[show abstract]
[hide abstract]
ABSTRACT: This subgroup analysis of the phase III APEX (Assessment of Proteasome Inhibition for Extending Remissions) trial examined whether prior exposure to specific therapies affected the relative efficacy of bortezomib versus dexamethasone in relapsed/refractory myeloma. Time to progression and overall survival were superior with bortezomib in all subgroups, with no evidence of interaction between any prior therapies and assignment to study therapy. Patients with prior thalidomide exposure had worse outcomes overall, but neither prior thalidomide nor prior autologous stem cell transplantation affected the relative efficacy of bortezomib versus dexamethasone. These results confirm the superiority of bortezomib over dexamethasone, regardless of prior exposure to specific therapies (clinicaltrials.gov: NCT00048230).
British Journal of Haematology 10/2009; 147(4):531-4. · 4.94 Impact Factor
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Lawrence B Marks,
Constance Cirrincione,
Thomas J Fitzgerald,
Frances Laurie,
Arvin S Glicksman,
James Vredenburgh,
Leonard R Prosnitz,
Elizabeth J Shpall,
Michael Crump,
Paul G Richardson, Michael W Schuster,
Jinli Ma,
Bercedis L Peterson,
Larry Norton,
Steven Seagren,
I Craig Henderson,
David D Hurd,
William P Peters
[show abstract]
[hide abstract]
ABSTRACT: To report, from Cancer and Leukemia Group B Protocol 9082, the impact of high-dose cyclophosphamide, cisplatin, and BCNU (HD-CPB) vs. intermediate-dose CPB (ID-CPB) on the ability to start and complete the planned course of local-regional radiotherapy (RT) for women with breast cancer involving >or=10 axillary nodes.
From 1991 to 1998, 785 patients were randomized. The HD-CPB and ID-CPB arms were balanced regarding patient characteristics. The HD-CPB and ID-CPB arms were compared on the probability of RT initiation, interruption, modification, or incompleteness. The impact of clinical variables and interactions between variables were also assessed.
Radiotherapy was initiated in 82% (325 of 394) of HD-CPB vs. 92% (360 of 391) of ID-CPB patients (p = 0.001). On multivariate analyses, RT was less likely given to patients who were randomized to HD treatment (odds ratio [OR] = 0 .38, p < 0.001), older (p = 0.005), African American (p = 0.003), postmastectomy (p = 0.02), or estrogen receptor positive (p = 0.03). High-dose treatment had a higher rate of RT interruption (21% vs. 12%, p = 0.001, OR = 2.05), modification (29% vs. 14%, p = 0.001, OR = 2.46), and early termination of RT (9% vs. 2%, p = 0.0001, OR = 5.35), compared with ID.
Treatment arm significantly related to initiation, interruption, modification, and early termination of RT. Patients randomized to HD-CPB were less likely to initiate RT, and of those who did, they were more likely to have RT interrupted, modified, and terminated earlier than those randomized to ID-CPB. The observed lower incidence of RT usage in African Americans vs. non-African Americans warrants further study.
International journal of radiation oncology, biology, physics 09/2009; 76(5):1305-13. · 4.59 Impact Factor
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Paul G Richardson,
Pieter Sonneveld, Michael W Schuster,
Edward A Stadtmauer,
Thierry Facon,
Jean-Luc Harousseau,
Dina Ben-Yehuda,
Sagar Lonial,
Hartmut Goldschmidt,
Donna Reece,
Joan Bladé,
Mario Boccadoro,
Jamie D Cavenagh,
Anthony L Boral,
Dixie-Lee Esseltine,
Patrick Y Wen,
Anthony A Amato,
Kenneth C Anderson,
Jesus San Miguel
[show abstract]
[hide abstract]
ABSTRACT: The frequency, characteristics and reversibility of bortezomib-associated peripheral neuropathy were evaluated in the phase III APEX (Assessment of Proteasome Inhibition for Extending Remissions) trial in patients with relapsed myeloma, and the impact of a dose-modification guideline on peripheral neuropathy severity and reversibility was assessed. Patients received bortezomib 1.3 mg/m(2) (days 1, 4, 8, 11, eight 21-d cycles, then days 1, 8, 15, 22, three 35-d cycles); bortezomib was held, dose-reduced or discontinued depending on peripheral neuropathy severity, according to a protocol-specified dose-modification guideline. Overall, 124/331 patients (37%) had treatment-emergent peripheral neuropathy, including 30 (9%) with grade >or=3; incidence and severity were not affected by age, number/type of prior therapies, baseline glycosylated haemoglobin level, or diabetes history. Grade >or=3 incidence appeared lower versus phase II trials (13%) that did not specifically provide dose-modification guidelines. Of patients with grade >or=2 peripheral neuropathy, 58/91 (64%) experienced improvement or resolution to baseline at a median of 110 d, including 49/72 (68%) who had dose modification versus 9/19 (47%) who did not. Efficacy did not appear adversely affected by dose modification for grade >or=2 peripheral neuropathy. Bortezomib-associated peripheral neuropathy is manageable and reversible in most patients with relapsed myeloma. Dose modification using a specific guideline improves peripheral neuropathy management without adversely affecting outcome.
British Journal of Haematology 01/2009; 144(6):895-903. · 4.94 Impact Factor
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Stephanie J Lee,
Paul G Richardson,
Pieter Sonneveld, Michael W Schuster,
David Irwin,
Jesús-F San Miguel,
Bruce Crawford,
Joseph Massaro,
Ravinder Dhawan,
Sanjay Gupta,
Kenneth C Anderson
[show abstract]
[hide abstract]
ABSTRACT: Health-related quality of life (HRQL) was prospectively measured during the phase III APEX trial of bortezomib versus dexamethasone in relapsed multiple myeloma patients. The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core (QLQ-C30) and Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (NTX) side-effects questionnaires were administered at baseline and every 6 weeks up to 42 weeks. Patients receiving bortezomib (1.3 mg/m(2), days 1, 4, 8 and 11 for eight 3-week cycles, then days 1, 8, 15 and 22 for three 5-week cycles; n = 296) demonstrated significantly better mean Global Health Status over the study versus patients receiving dexamethasone (40 mg/d, days 1-4, 9-12, and 17-20 for four 5-week cycles, then days 1-4 only for five 4-week cycles; n = 302), plus significantly better physical health, role, cognitive, and emotional functioning scores, lower dyspnoea and sleep symptom scores, and better NTX questionnaire score, using multiple imputation to account for missing data. Results were similar using available-data analyses. Sensitivity analyses suggested that improved HRQL with bortezomib is at least partially explained by improved survival. These results show that bortezomib was associated with significantly better multidimensional HRQL compared with dexamethasone, consistent with the better clinical outcomes seen with bortezomib.
British Journal of Haematology 12/2008; 143(4):511-9. · 4.94 Impact Factor
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Asher Chanan-Khan,
Pieter Sonneveld, Michael W Schuster,
Edward A Stadtmauer,
Thierry Facon,
Jean-Luc Harousseau,
Dina Ben-Yehuda,
Sagar Lonial,
Hartmut Goldschmidt,
Donna Reece,
Rachel Neuwirth,
Kenneth C Anderson,
Paul G Richardson
[show abstract]
[hide abstract]
ABSTRACT: The aim of this subset analysis was to determine if bortezomib treatment is associated with increased incidence of varicella-zoster virus (VZV) reactivation in patients with relapsed multiple myeloma (MM).
Incidence of herpes zoster was evaluated in 663 patients with relapsed MM from the phase III APEX trial comparing single-agent bortezomib with high-dose dexamethasone.
Bortezomib was associated with a significantly higher incidence of herpes zoster compared with dexamethasone treatment (13%, 42 of 331 v 5%, 15 of 332; P = .0002). Most herpes zoster infections were grade 1/2; incidences of grade 3/4 events (1.8% v 1.5%) and infections considered serious adverse events (1.5% v 0.9%) were similar between treatment arms, and no herpes zoster-related deaths occurred. Neither the time to onset of the herpes event nor the patients' absolute lymphocyte counts at baseline differed significantly between arms. VZV reactivation was the only herpes viral event noted to be significantly elevated in the bortezomib treatment group compared with the dexamethasone treatment group (P = .0002). The incidence of non-VZV-related herpes viral infections was comparable between arms. No additional risk factors for herpes zoster reactivation were identified.
Further studies are needed to explain these observations and their implications; however, for patients treated with bortezomib or bortezomib-containing regimens, the risk of VZV reactivation should be monitored and routine use of antiviral prophylaxis considered.
Journal of Clinical Oncology 09/2008; 26(29):4784-90. · 18.37 Impact Factor
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Sagar Lonial,
Paul G Richardson,
Jesús San Miguel,
Pieter Sonneveld, Michael W Schuster,
Joan Bladé,
Jamie Cavenagh,
S Vincent Rajkumar,
Andrzej J Jakubowiak,
Dixie-Lee Esseltine,
Kenneth C Anderson,
Jean-Luc Harousseau
[show abstract]
[hide abstract]
ABSTRACT: Haematological toxicities and thromboembolic (TE) events are common complications of myeloma therapy. TE risk may be elevated with combination regimens, notably thalidomide/lenalidomide plus high-dose dexamethasone; concomitant erythropoietin appears to further increase the risk with lenalidomide-dexamethasone. We characterised thrombocytopenia and neutropenia in the phase 3 APEX (Assessment of Proteasome Inhibition for Extending Remissions) study of bortezomib versus high-dose dexamethasone in relapsed myeloma, and calculated the incidences of deep-vein thrombosis (DVT)/pulmonary embolism (PE) with: bortezomib or dexamethasone +/- erythropoietin in APEX; bortezomib +/- dexamethasone +/- erythropoietin in two phase 2 studies of relapsed/refractory myeloma. Bortezomib-associated thrombocytopenia and neutropenia were transient, predictable and manageable; mean platelet and neutrophil counts followed a cyclical pattern, and improved over the treatment course. Grade 3/4 thrombocytopenia incidence was higher with bortezomib versus dexamethasone (26%/4% vs. 5%/1%), but significant bleeding events were comparable (4% vs. 5%). DVT/PE incidence was low (< or =3.1%) in all analyses; addition of dexamethasone/erythropoietin did not affect TE risk. In APEX, TE risk appeared lower with bortezomib versus dexamethasone. Bortezomib caused transient and cyclical thrombocytopenia and was not associated with elevated TE risk, alone or with dexamethasone +/- erythropoietin. Preliminary data suggest bortezomib may reduce the thrombogenic potential of combination regimens via inhibition of platelet function or other mechanism-specific effects on coagulation.
British Journal of Haematology 08/2008; 143(2):222-9. · 4.94 Impact Factor
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Ruben Niesvizky,
Paul G Richardson,
S Vincent Rajkumar,
Morton Coleman,
Laura Rosiñol,
Pieter Sonneveld, Michael W Schuster,
David Irwin,
Edward A Stadtmauer,
Thierry Facon,
Jean-Luc Harousseau,
Anthony L Boral,
Dixie-Lee Esseltine,
Kenneth C Anderson,
Joan Bladé
[show abstract]
[hide abstract]
ABSTRACT: Quality of response is associated with prolonged overall survival (OS) in newly diagnosed multiple myeloma patients. This cohort study within the phase 3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial of bortezomib versus dexamethasone in relapsed myeloma assessed the relationship between quality of response to bortezomib (n = 315) and clinical benefit. Treatment-free interval (TFI), time to alternative therapy (TTAT), time to progression (TTP) and OS were assessed in response-evaluable patients in the bortezomib arm in cohorts defined by achievement of complete response (CR; n = 27), very good partial response (VGPR; n = 31), partial response (PR; n = 77), minimal response (MR; n = 21) or non-response (NR, including stable and progressive disease; n = 159). CR was associated with significantly longer median TFI (24.1 vs. 6.9/6.4 months) and TTAT (27.1 vs. 13.6/14 months) versus VGPR/PR. Median TTP was similar in CR, VGPR and PR cohorts; median OS was not reached. Patients achieving MR appeared to have prolonged median TFI (3.8 vs. 2.3 months), TTAT (8.7 vs. 6.2 months), TTP (4.9 vs. 2.8 months) and OS (24.9 vs. 18.7 months) versus NR. In conclusion, bortezomib had substantial activity in relapsed myeloma patients; CR may be a surrogate marker for significant clinical benefit with bortezomib. MR appeared to be valid as a separate response category in this setting.
British Journal of Haematology 08/2008; 143(1):46-53. · 4.94 Impact Factor
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Tomer Mark,
Jessica Stern,
Jessica R Furst,
David Jayabalan,
Faiza Zafar,
April LaRow,
Roger N Pearse,
John Harpel,
Tsiporah Shore, Michael W Schuster,
John P Leonard,
Paul J Christos,
Morton Coleman,
Ruben Niesvizky
[show abstract]
[hide abstract]
ABSTRACT: A total of 28 treatment-naïve patients with stage II or III multiple myeloma (MM) were treated with the combination of clarithromycin, lenalidomide, and dexamethasone (BiRD). Stem cells were collected following granulocyte-colony stimulating factor (G-CSF) or cyclophosphamide (Cy) plus G-CSF mobilization at maximum response. Sufficient stem cells for 2 autologous stem cell transplants were collected from all patients mobilized with Cy plus G-CSF, versus 33% mobilized with G-CSF alone (P < .0001). The duration of prior lenalidomide therapy did not correlate with success of stem cell harvests (P = .91). In conclusion, Cy can be added to G-CSF for stem cell mobilization to successfully overcome the suppressive effect of prior treatment with lenalidomide.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 08/2008; 14(7):795-8. · 3.15 Impact Factor
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[show abstract]
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ABSTRACT: The objective of this study was to evaluate the safety and tolerability of velafermin in patients at risk of developing severe oral mucositis (OM) from chemotherapy.
This study was a single-center, open-label, single-dose escalation, phase I trial in patients undergoing high-dose chemotherapy (HDCT) and autologous peripheral blood stem cell transplant (PBSCT). Velafermin was administered 24 h after stem cell infusion as a single intravenous dose infused over 15 min. Clinical safety variables were assessed and OM status scored daily for 30 days using the World Health Organization (WHO) grading scale.
Thirty patients were treated with velafermin at doses of 0.03 (n = 10), 0.1 (n = 10), 0.2 (n = 8), or 0.33 mg/kg (n = 2). Patients were diagnosed with multiple myeloma (n = 16), non-Hodgkin's lymphoma (n = 12), acute myelogenous leukemia (n = 1), or desmoplasmic round cell tumor (n = 1). Velafermin was well tolerated at doses up to 0.2 mg/kg. There were no drug-related serious adverse events. No patient discontinued because of adverse events; however, two patients administered 0.33 mg/kg developed adverse reactions immediately after infusion of the study drug. No other patients were treated at this dose level. The most frequent (>35% of patients) treatment-emergent adverse events were diarrhea, fatigue, pyrexia, vomiting, and nausea. Most adverse events were mild or moderate and resolved the same day without sequelae. Eight (27%) patients developed WHO grade 3 or 4 OM during the study; seven of these patients received high-dose melphalan as a conditioning regimen.
Velafermin was well tolerated by autologous PBSCT patients at doses up to 0.2 mg/kg.
Supportive Care Cancer 06/2008; 16(5):477-83. · 2.60 Impact Factor
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Ruben Niesvizky,
David S Jayabalan,
Paul J Christos,
Jessica R Furst,
Tara Naib,
Scott Ely,
Jessica Jalbrzikowski,
Roger N Pearse,
Faiza Zafar,
Karen Pekle, [......],
Hearn J Cho,
Tsiporah Shore,
Jeffrey Tepler,
John Harpel, Michael W Schuster,
Susan Mathew,
John P Leonard,
Madhu Mazumdar,
Selina Chen-Kiang,
Morton Coleman
[show abstract]
[hide abstract]
ABSTRACT: This trial determined the safety and efficacy of the combination regimen clarithromycin (Biaxin), lenalidomide (Revlimid), and dexamethasone (BiRD) as first-line therapy for multiple myeloma. Patients received BiRD in 28-day cycles. Dexamethasone (40 mg) was given orally once weekly, clarithromycin (500 mg) was given orally twice daily, and lenalidomide (25 mg) was given orally daily on days 1 to 21. Objective response was defined by standard criteria (ie, decrease in serum monoclonal protein [M-protein] by at least 50%, and a decrease in urine M-protein by at least 90%). Of the 72 patients enrolled, 65 had an objective response (90.3%). A combined stringent and conventional complete response rate of 38.9% was achieved, and 73.6% of the patients achieved at least a 90% decrease in M-protein levels. This regimen did not interfere with hematopoietic stem-cell harvest. Fifty-two patients who did not go on to receive transplants received continued therapy (complete response, 37%; very good partial response, 33%). The major adverse events were thromboembolic events, corticosteroid-related morbidity, and cytopenias. BiRD is an effective regimen with manageable side effects in the treatment of symptomatic, newly diagnosed multiple myeloma. This trial was registered at www.clinicaltrials.gov as #NCT00151203.
Blood 03/2008; 111(3):1101-9. · 9.90 Impact Factor
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Paul G Richardson,
Pieter Sonneveld, Michael W Schuster,
David Irwin,
Edward A Stadtmauer,
Thierry Facon,
Jean-Luc Harousseau,
Dina Ben-Yehuda,
Sagar Lonial,
Jesús-F San Miguel,
Jamie D Cavenagh,
Kenneth C Anderson
[show abstract]
[hide abstract]
ABSTRACT: Adverse prognostic factors in multiple myeloma include advanced age, number of prior therapies, and higher International Staging System (ISS) disease stage. In the international, randomised, phase-3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) study, bortezomib demonstrated significantly longer time to progression (TTP), higher response rates and improved survival compared with high-dose dexamethasone in patients with relapsed multiple myeloma following one to three prior therapies. In this APEX subgroup analysis, efficacy of bortezomib and dexamethasone was compared in elderly (age > or =65 years) and high-risk (>1 prior line of therapy; ISS stage II/III; refractory to prior therapy) patients. Bortezomib demonstrated substantial clinical activity in these patients. Response rate (34-40% vs. 13-19%), including complete response rate (5-8% vs. 0-1%), was significantly higher with bortezomib versus dexamethasone in all four subgroups. Similarly, median TTP was significantly longer with bortezomib versus dexamethasone, and 1-year survival probability was significantly higher in all subgroups. As in the total APEX population, rates of grade 3/4 adverse events were higher in bortezomib- versus dexamethasone-treated patients aged > or =65 years and with >1 prior line, while rates of serious adverse events were similar; toxicities generally proved manageable. Bortezomib should be considered an appropriate treatment for elderly and high-risk patients with relapsed multiple myeloma.
British Journal of Haematology 06/2007; 137(5):429-35. · 4.94 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Nonmyeloablative transplantation (NMT) is intended to be less toxic than traditional allografts, but such regimens as fludarabine/melphalan still pose a significant risk of graft-versus-host disease (GVHD). We used Campath-1H in an attempt to reduce the risk of GVHD in NMT. Patients with hematologic malignancies suitable for allogeneic transplantation underwent transplantation using a regimen of fludarabine 30 mg/m(2) on days -5 to -2 (total, 120 mg/m(2)), total body irradiation of 200 cGy on day -1, and Campath-1H 20 mg/day on days -7 to -3 (total dose, 100 mg). After loss of graft in 5 of the first 6 patients, the protocol was amended by decreasing the Campath-1H dose to 20 mg on days -4 and -3 and 10 mg on day -2 (total dose, 50 mg) for all subsequent patients. GVHD prophylaxis consisted of only cyclosporine, due to the immunosuppressive effect of Campath-1H. Patients received prophylactic acyclovir, fluconazole, and a quinolone. Other requirements included creatinine clearance > or = 25 mL/min, diffusing capacity > or = 45% of predicted, and cardiac ejection fraction > or = 40%. Twenty-five patients with hematologic malignancies entered the study. The median age was 40 years (range, 26-71 years). Median time to engraftment (defined as a neutrophil count of 500 mm(3) and a platelet count of 20,000 mm(3) without platelet support on at least 2 days) was 19 days (range, 9-32 days). All patients who were treated after the amendment engrafted with 90%-100% donor cells by day 100 except for 2 early deaths. Acute GVHD developed in 40% of the patients. Patients who underwent related transplants developed GVHD after donor lymphocyte infusions for poor engraftment or relapse whereas those undergoing unrelated transplants developed GVHD de novo. Two patients (8%) developed chronic GVHD, and 48% had cytomegalovirus reactivation, which was easily managed medically. Nonrelapse mortality within the first 12 months was 12%; 32% of the patients survived at a median of 269 days. We conclude that Campath-1H, fludarabine, and melphalan is a reasonable preparative regimen for reduced-intensity transplantation with a low nonrelapse mortality, but that issues of GVHD remain problematic, due to either the use of donor lymphocyte infusions or the use of volunteer unrelated donors.
Biology of Blood and Marrow Transplantation 09/2006; 12(8):868-75. · 3.87 Impact Factor
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Alan D Dosik,
Morton Coleman,
Lale Kostakoglu,
Richard R Furman,
Jennifer M Fiore,
Daniel Muss,
Ruben Niesvizky,
Tsiporah Shore, Michael W Schuster,
Patricia Stewart,
Shankar Vallabhajosula,
Stanley J Goldsmith,
John P Leonard
[show abstract]
[hide abstract]
ABSTRACT: Iodine I-131 tositumomab is a well tolerated and effective therapy for recurrent low-grade and transformed low-grade non-Hodgkin lymphoma (NHL). Hematologic reserve after radioimmunotherapy (RIT) is an important consideration when subsequent therapy is required.
One hundred fifty-five patients who received treatment with I-131 tositumomab were assessed, and 68 patients had progressive disease after RIT. The median age (n=68 patients) was 59 years (range,18-82 yrs), and patients received a median of 2 pre-RIT regimens (range,1-8 regimens), including 66% who received anthracycline, 19% who received platinum, and 50% who received fludarabine.
The median time to disease progression (among progressors) was 168 days (range, 19-771 days). At the time they developed recurrent disease, patients had median white blood cell count (WBC) of 4.9 K cells/microL (range, 1.1-21.4 K cells/microL), a median absolute neutrophil count (ANC) of 3.25 K cells/microL (range, 0.59-8.20 K cells/microL), a median platelet count of 130 K cells/microL (range, 9-440 K cells/microL), and there was no significant difference between pre-RIT and recurrence values except for the platelet count (P<0.05). No patient demonstrated a WBC<1.0 K cells/microL or an ANC<0.5 K cells/microL, although 1 patient had a platelet count<10 K cells/microL. Twenty-four patients subsequently received no further chemotherapy; and, in 21 patients (88%), hematologic parameters appeared to allow subsequent chemotherapy if necessary (blood counts: National Cancer Institute Grade 0-2). Among 44 patients (65%) who received further chemotherapy (median, 2 regimens; range, 1-4 regimens), 19 patients (43%) were treated with anthracyclines, 17 patients (39%) were treated with platinum, 10 patients (23%) were treated with fludarabine, and 13 patients (30%) underwent stem cell transplantation. Disease improvement occurred in most patients, although 18 patients died (40%) after further chemotherapy, predominantly from refractory lymphoma.
Most patients with progressive disease after treatment with iodine I-131 tositumomab were able to receive subsequent therapy, including cytotoxic chemotherapy and stem cell transplantation.
Cancer 03/2006; 106(3):616-22. · 4.77 Impact Factor
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John P Leonard,
Morton Coleman,
Lale Kostakoglu,
Amy Chadburn,
Ethel Cesarman,
Richard R Furman, Michael W Schuster,
Ruben Niesvizky,
Daniel Muss,
Jennifer Fiore,
Stewart Kroll,
George Tidmarsh,
Shankar Vallabhajosula,
Stanley J Goldsmith
[show abstract]
[hide abstract]
ABSTRACT: To evaluate the safety and efficacy of a sequential chemotherapy plus radioimmunotherapy (RIT) regimen in previously untreated follicular non-Hodgkin's lymphoma.
Thirty-five patients received an abbreviated course (three cycles) of fludarabine followed 6 to 8 weeks later by tositumomab and iodine I 131 tositumomab.
After fludarabine, 31 (89%) of 35 patients responded, with three (9%) of 31 patients achieving a complete response (CR). After the full regimen of fludarabine and iodine I 131 tositumomab, all 35 patients responded; 30 (86%) of 35 patients achieved CR, and five (14%) of 35 achieved partial response. After a median follow-up of 58 months, the median progression-free survival (PFS) had not been reached (95% CI, 27 months to not reached), but it will be at least 48 months. The 5-year estimated PFS rate is 60%. Baseline Follicular Lymphoma International Prognostic Index (FLIPI) was significantly associated (P = .003) with PFS. Five of six patients with more than 25% bone marrow involvement at baseline achieved adequate bone marrow cytoreduction to receive standard-dose iodine I 131 tositumomab. Ten (77%) of 13 patients with baseline bone marrow Bcl-2 positivity demonstrated molecular remissions at month 12. Toxicities were manageable and principally hematologic. Two (6%) of 35 patients developed human antimurine antibodies (HAMA) after RIT.
Use of abbreviated fludarabine before iodine I 131 tositumomab can reduce bone marrow involvement, when needed, to allow the use of RIT and can suppress HAMA responses. This sequential treatment regimen is highly effective as front-line therapy for follicular lymphoma, particularly for low- or intermediate-risk FLIPI patients.
Journal of Clinical Oncology 09/2005; 23(24):5696-704. · 18.37 Impact Factor
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Paul G Richardson,
Pieter Sonneveld, Michael W Schuster,
David Irwin,
Edward A Stadtmauer,
Thierry Facon,
Jean-Luc Harousseau,
Dina Ben-Yehuda,
Sagar Lonial,
Hartmut Goldschmidt, [......],
Jesus F San-Miguel,
Joan Bladé,
Mario Boccadoro,
Jamie Cavenagh,
William S Dalton,
Anthony L Boral,
Dixie L Esseltine,
Jane B Porter,
David Schenkein,
Kenneth C Anderson
[show abstract]
[hide abstract]
ABSTRACT: This study compared bortezomib with high-dose dexamethasone in patients with relapsed multiple myeloma who had received one to three previous therapies.
We randomly assigned 669 patients with relapsed myeloma to receive either an intravenous bolus of bortezomib (1.3 mg per square meter of body-surface area) on days 1, 4, 8, and 11 for eight three-week cycles, followed by treatment on days 1, 8, 15, and 22 for three five-week cycles, or high-dose dexamethasone (40 mg orally) on days 1 through 4, 9 through 12, and 17 through 20 for four five-week cycles, followed by treatment on days 1 through 4 for five four-week cycles. Patients who were assigned to receive dexamethasone were permitted to cross over to receive bortezomib in a companion study after disease progression.
Patients treated with bortezomib had higher response rates, a longer time to progression (the primary end point), and a longer survival than patients treated with dexamethasone. The combined complete and partial response rates were 38 percent for bortezomib and 18 percent for dexamethasone (P<0.001), and the complete response rates were 6 percent and less than 1 percent, respectively (P<0.001). Median times to progression in the bortezomib and dexamethasone groups were 6.22 months (189 days) and 3.49 months (106 days), respectively (hazard ratio, 0.55; P<0.001). The one-year survival rate was 80 percent among patients taking bortezomib and 66 percent among patients taking dexamethasone (P=0.003), and the hazard ratio for overall survival with bortezomib was 0.57 (P=0.001). Grade 3 or 4 adverse events were reported in 75 percent of patients treated with bortezomib and in 60 percent of those treated with dexamethasone.
Bortezomib is superior to high-dose dexamethasone for the treatment of patients with multiple myeloma who have had a relapse after one to three previous therapies.
New England Journal of Medicine 06/2005; 352(24):2487-98. · 53.30 Impact Factor
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William P Peters,
Gary L Rosner,
James J Vredenburgh,
Elizabeth J Shpall,
Michael Crump,
Paul G Richardson, Michael W Schuster,
Lawrence B Marks,
Constance Cirrincione,
Larry Norton,
I C Henderson,
Richard L Schilsky,
David D Hurd
[show abstract]
[hide abstract]
ABSTRACT: The prognosis for women with primary breast cancer involving multiple axillary nodes remains poor. High-dose chemotherapy with stem-cell support produced promising results in initial clinical trials conducted at single institutions.
Seven hundred eighty-five women aged 22 to 66 years with stage IIA, IIB, or IIIA breast cancer involving 10 or more axillary lymph nodes were randomized after surgery and standard adjuvant chemotherapy to either high-dose cyclophosphamide, cisplatin, and carmustine (HD-CPB) with stem-cell support or intermediate-dose cyclophosphamide, cisplatin, and carmustine (ID-CPB) with G-CSF support but without stem cells. Planned treatment for all patients included locoregional radiation therapy. Hormone-receptor-positive patients were to receive 5 years of tamoxifen. Event-free survival (EFS) was the primary end point.
Median follow-up was 7.3 years. Event-free survival was not significantly different between the two treatment groups (P = .24). The probability of being free of an event at 5 years with HD-CPB was 61% (95% CI, 56% to 65%), and was 58% (95% CI, 53% to 63%) for ID-CPB. Thirty-three patients died of causes attributed to HD-CPB, compared with no therapy-related deaths among women treated with ID-CPB. Overall survival for the two arms was identical at 71% at 5 years (P = .75).
HD-CPB with stem-cell support was not superior to ID-CPB for event-free or overall survival among all randomized women with high-risk primary breast cancer.
Journal of Clinical Oncology 05/2005; 23(10):2191-200. · 18.37 Impact Factor
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John P Leonard,
Morton Coleman,
Jamie C Ketas,
Amy Chadburn,
Richard Furman, Michael W Schuster,
Eric J Feldman,
Michelle Ashe,
Stephen J Schuster,
William A Wegener,
Hans J Hansen,
Heather Ziccardi,
Michael Eschenberg,
Urte Gayko,
Scott Z Fields,
Alessandra Cesano,
David M Goldenberg
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ABSTRACT: We conducted a single-center, dose-escalation study evaluating the safety, pharmacokinetics, and efficacy of epratuzumab, an anti-CD22 humanized monoclonal antibody, in patients with aggressive non-Hodgkin's lymphoma.
Epratuzumab was administered once weekly for 4 weeks at 120-1000-mg/m2 doses to 56 patients [most (n = 35) with diffuse large B-cell lymphoma].
Patients were heavily pretreated (median, 4 prior therapies), 25% received prior high-dose chemotherapy with stem cell transplant, and 84% had bulky disease (> or =5 cm). Epratuzumab was well tolerated, with no dose-limiting toxicity. Most (95%) infusions were completed within 1 h. The mean serum half-life was 23.9 days. Across all dose levels and histologies, objective responses (ORs) were observed in five patients (10%; 95% confidence interval, 3-21%), including three complete responses. In patients with diffuse large B-cell lymphoma, 15% had ORs. Overall, 11 (20%) patients experienced some tumor mass reduction. Median duration of OR was 26.3 weeks, and median time to progression for responders was 35 weeks. Two responses are ongoing at > or =34 months, including one rituximab-refractory patient.
These data demonstrate that epratuzumab has a good safety profile and exerts antitumor activity in aggressive non-Hodgkin's lymphoma at doses of > or =240 mg/m2, thus warranting further evaluation in this clinical setting.
Clinical Cancer Research 08/2004; 10(16):5327-34. · 7.74 Impact Factor
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Michael W Schuster
Oncology (Williston Park, N.Y.) 11/2003; 17(10):1333-5. · 1.03 Impact Factor
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ABSTRACT: Hematopoietic growth factors are commonly used in allogeneic and autologous stem cell transplantation. The growth factors most frequently used are human recombinant erythropoietin, filgrastim, and sargramostim, and a number of trials have been done using them either singly or in various combinations for mobilization, post-transplant, and for delayed engraftment. Filgrastim and sargramostim can shorten the neutropenic period and decrease infectious complications post-transplant, thus lowering the cost of both autologous and allogeneic transplants. Erythropoietin has not been particularly effective for mobilization, and studies have not shown its efficacy in reducing red blood cell transfusions in autologous transplants. However, they have been clinically beneficial in allogeneic transplantation and in delayed erythropoiesis post-transplantation. Stem cell factor remains investigational at this time but seems promising. The new long-acting erythropoietin and filgrastim are also introduced here and briefly discussed.
Current hematology reports 12/2002; 1(2):103-9.
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ABSTRACT: To assess the safety and efficacy of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) administered after autologous bone marrow transplantation (ABMT).
Two randomized, double-blind, placebo-controlled studies were done. In the phase 1/2 study, 75 breast cancer patients underwent a bone marrow harvest and myeloablative STAMP V chemotherapy and were randomized to receive placebo or one of three doses of PEG-rHuMGDF. In the phase 3 study, 64 patients were randomized to receive placebo or the minimally effective dose of PEG-rHuMGDF. The study drug was administered daily starting on the day of bone marrow infusion until the platelet count was greater than or equal to 50 x 10(9)/L (without transfusion) or for a maximum of 28 days. All patients received 10 microg/kg/day filgrastim starting on day 2 until neutrophil count recovery.
PEG-rHuMGDF appeared to be safe and well tolerated. No significant differences were noted in mortality or disease progression rates. Antibodies to MGDF were not observed. In the phase 1/2 study, the time to platelet recovery to greater than or equal to 20 x 10(9)/L and platelet transfusion requirements were significantly reduced for patients treated with PEG-rHuMGDF compared with placebo (p < 0.05). In the phase 3 study, no significant differences in the kinetics of early thrombopoiesis or platelet transfusions after ABMT were observed.
PEG-rHuMGDF was not consistently efficacious in reducing the duration of severe thrombocytopenia. The maximum platelet counts for PEG-rHuMGDF-treated patients occurred a median of 2 weeks after the last dose of drug, suggesting that the biologic effects of this hematopoietic cytokine are delayed compared with other hematopoietic cytokines.
Experimental Hematology 09/2002; 30(9):1044-50. · 2.90 Impact Factor
