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Ranjit Banwait,
Kevin O'Regan,
Federico Campigotto,
Brianna Harris,
Dilek Yarar,
Meghan Bagshaw,
Xavier Leleu, Renee Leduc,
Nikhil Ramaiya,
Edie Weller,
Irene M Ghobrial
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ABSTRACT: Disease assessment in WM is dependent on the quantification of the IgM monoclonal protein and percent involvement of the bone marrow. There is a need for imaging studies that objectively measure tumor load in these patients. In this study, we sought to examine the role of combined FDG-PET/CT imaging in the detection of tumor load and in the assessment of response to therapy. Thirty-five patients were enrolled on a prospective study using bortezomib and rituximab therapy and were included in this study because they completed a pre- and post-treatment FDG-PET/CT imaging at one facility (12 newly diagnosed and 23 relapsed/refractory). The use of combined FDG-PET/CT imaging showed positive findings in 83% of patients with WM, unlike prior studies using conventional imaging that indicate that only 20% of patients have lymphadenopathy or hepatosplenomegaly. Moreover, 43% of patients had abnormal bone marrow uptake on FDG-PET imaging that can potentially help in the assessment of their tumor load, especially with heterogenous sampling of the bone marrow. There was no statistical correlation between EORTC response criteria for FDG-PET/CT and response by monoclonal protein. This is the first study to examine the role of FDG-PET/CT imaging in WM. Future studies should examine the role of FDG-PET/CT in conjunction with monoclonal protein response in the assessment of progression-free survival in patients with WM.
American Journal of Hematology 07/2011; 86(7):567-72. · 4.67 Impact Factor
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ABSTRACT: The serum free light chain (sFLC) has been widely used in the assessment of response in patients with multiple myeloma and other plasma cell dyscrasias. However, its use in Waldenstrom macroglobulinemia (WM) has not been previously assessed. We sought to examine the role of sFLC in response and progression of patients with WM.
This study was conducted in a cohort of 48 patients with a diagnosis of WM, untreated (n = 20) or relapsed/refractory (n = 28), prospectively treated on a bortezomib and rituximab trial.
Involved FLC (iFLC) response occurred in 79% patients versus 60% by M-spike protocol criteria. The median time to response was shorter with iFLC than per protocol (2.1 and 3.7 months; P = 0.05). Progression defined using iFLC also correlated well to progression in the protocol (κ = 0.63). However, the median time to progression (TTP) was more rapid by iFLC than per protocol (13.7 and 18.9 months). We also confirmed that a flare in iFLC in post-rituximab therapy did not correlate with lack of response or shorter TTP.
Involved sFLC may be a useful marker of tumor measurement, showing earlier response and progression compared with IgM or M-spike measurements.
Clinical Cancer Research 03/2011; 17(9):3013-8. · 7.74 Impact Factor
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Irene M Ghobrial,
Edie Weller,
Ravi Vij,
Nikhil C Munshi,
Ranjit Banwait,
Meghan Bagshaw,
Robert Schlossman, Renee Leduc,
Stacey Chuma,
Janet Kunsman, [......],
Aldo Roccaro,
Philippe Armand,
Akari Dollard,
Diane Warren,
Brianna Harris,
Tiffany Poon,
Amy Sam,
Scott Rodig,
Kenneth C Anderson,
Paul G Richardson
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ABSTRACT: Multiple myeloma is the second most prevalent haematological malignancy and is incurable. Our aim was to assess the response and safety of the combination of temsirolimus (an mTOR inhibitor) and bortezomib in patients with relapsed or refractory multiple myeloma.
We did an open-label, dose-escalation study in three centres in the USA. Patients were enrolled from June, 2007, to December, 2009. Eligible patients were aged 18 years or older with relapsed or relapsed and refractory multiple myeloma after one or more treatment (including lenalidomide, bortezomib, or thalidomide), with an Eastern Cooperative Oncology Group performance status of 0-2. Patients were assigned a dose level in the order of their entry into the study. Phase 1 was to assess the safety and establish the maximum tolerated dose (MTD) of the combination and phase 2 was to assess overall response rate at the MTD. Intravenous temsirolimus was given at 15 or 25 mg and intravenous bortezomib at 1·3 or 1·6 mg/m(2) once a week, with dose escalation until dose-limiting adverse events were recorded in two of the three people in the dose cohort. Use of steroids were not permitted. The primary endpoint was the proportion of patients with a partial response or better. Analyses were done on an intention-to-treat basis, with all patients who had been enrolled included. The study is registered with ClinicalTrials.gov, number NCT00483262.
20 patients were enrolled into the phase 1 study and 43 into phase 2. All patients were heavily pretreated (median five lines in the phase 1 cohort, and four lines in the phase 2 cohort). The MTD was determined to be 1·6 mg/m(2) bortezomib on days 1, 8, 15, and 22 in combination with 25 mg temsirolimus on days 1, 8, 15, 22, and 29, for a cycle of 35 days. In the phase 2 study, the proportion of patients with a partial response or better was 33% (14 of 43; 90% CI 21-47). Long-term follow-up of patients is ongoing. There were three deaths during treatment in the phase 1 and 2 studies: one patient died of septic shock in the phase 1 study; one patient died with H1N1 influenza infection and one died with cardiac amyloid and ventricular arrhythmia unrelated to treatment in the phase 2 study. In the phase 1 study, the most common treatment-related grade 3-4 adverse events were thrombocytopenia (13 patients), lymphopenia (ten), neutropenia (nine), leucopenia (seven), and anaemia (five). In the phase 2 study, the most common treatment-related grade 3-4 adverse events were thrombocytopenia (25 patients), lymphopenia (24), neutropenia (17), leucopenia (ten), anaemia (seven), and diarrhoea (five). Four patients in the phase 1 study had sensory peripheral neuropathy (grade 2 or less); in the phase 2 study, 11 had sensory peripheral neuropathy (all grade 2 or less) and seven motor peripheral neuropathy (one grade 3, six grade 2 or less).
mTOR inhibitors could have a role in combination with weekly bortezomib for the treatment of patients with relapsed and refractory multiple myeloma without the addition of steroids.
Millennium Inc, Pfizer Inc, Multiple Myeloma Research Foundation, and the Leukemia and Lymphoma Society.
The lancet oncology 02/2011; 12(3):263-72. · 14.47 Impact Factor
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Irene M Ghobrial,
Wanling Xie,
Swaminathan Padmanabhan,
Ashraf Badros,
Meghan Rourke, Renee Leduc,
Stacey Chuma,
Janet Kunsman,
Diane Warren,
Tiffany Poon,
Brianna Harris,
Amy Sam,
Kenneth C Anderson,
Paul G Richardson,
Steven P Treon,
Edie Weller,
Jeffrey Matous
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ABSTRACT: This study aimed to determine the activity and safety of weekly bortezomib and rituximab in patients with untreated Waldenström Macroglobulinemia (WM). Patients with no prior therapy and symptomatic disease were eligible. Patients received bortezomib IV weekly at 1.6 mg/m(2) on days 1, 8, 15, q 28 days × 6 cycles, and rituximab 375 mg/m(2) weekly on cycles 1 and 4. Primary endpoint was the percent of patients with at least a minor response (MR). Twenty-six patients were treated. At least MR was observed in 23/26 patients (88%) (95% CI: 70-98%) with 1 complete response (4%), 1 near-complete response (4%), 15 partial remission (58%), and 6 MR (23%). Using IgM response evaluated by nephlometry, all 26 patients (100%) achieved at least MR or better. The median time to progression has not been reached, with an estimated 1-year event free rate of 79% (95% CI: 53, 91%). Common grade 3 and 4 therapy related adverse events included reversible neutropenia in 12%, anemia in 8%, and thrombocytopenia in 8%. No grade 3 or 4 neuropathy occurred. The combination of weekly bortezomib and rituximab exhibited significant activity and minimal neurological toxicity in patients with untreated WM.
American Journal of Hematology 09/2010; 85(9):670-4. · 4.67 Impact Factor
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Irene M Ghobrial,
Fangxin Hong,
Swaminathan Padmanabhan,
Ashraf Badros,
Meghan Rourke, Renee Leduc,
Stacey Chuma,
Janet Kunsman,
Diane Warren,
Brianna Harris,
Amy Sam,
Kenneth C Anderson,
Paul G Richardson,
Steven P Treon,
Edie Weller,
Jeffrey Matous
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ABSTRACT: This study aimed to determine activity and safety of weekly bortezomib and rituximab in patients with relapsed/refractory Waldenström macroglobulinemia (WM).
Patients who had at least one previous therapy were eligible. All patients received bortezomib intravenously weekly at 1.6 mg/m(2) on days 1, 8, and 15, every 28 days for six cycles and rituximab 375 mg/m(2) weekly on cycles 1 and 4. The primary end point was the percentage of patients with at least a minor response.
Thirty-seven patients were treated. The majority of patients (78%) completed treatment per protocol. At least minimal response (MR) or better was observed in 81% (95% CI, 65% to 92%), with two patients (5%) in complete remission (CR)/near CR, 17 patients (46%) in partial response, and 11 patients (30%) in MR. The median time to progression was 16.4 months (95% CI, 11.4 to 21.1 months). Death occurred in one patient due to viral pneumonia. The most common grade 3 and 4 therapy-related adverse events included reversible neutropenia in 16%, anemia in 11%, and thrombocytopenia in 14%. Grade 3 peripheral neuropathy occurred in only two patients (5%). The median progression-free (PFS) is 15.6 months (95% CI, 11 to 21 months), with estimated 12-month and 18-month PFS of 57% (95% CI, 39% to 75%) and 45% (95% CI, 27% to 63%), respectively. The median overall survival has not been reached.
The combination of weekly bortezomib and rituximab showed significant activity and minimal neurologic toxicity in patients with relapsed WM.
Journal of Clinical Oncology 02/2010; 28(8):1422-8. · 18.37 Impact Factor
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Irene M Ghobrial,
Morie Gertz,
Betsy Laplant,
John Camoriano,
Suzanne Hayman,
Martha Lacy,
Stacey Chuma,
Brianna Harris, Renee Leduc,
Meghan Rourke,
Stephen M Ansell,
Daniel Deangelo,
Angela Dispenzieri,
Leif Bergsagel,
Craig Reeder,
Kenneth C Anderson,
Paul G Richardson,
Steven P Treon,
Thomas E Witzig
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ABSTRACT: PURPOSE The phosphatidylinositol 3-kinase/mammalian target of rapamycin (mTOR) signal transduction pathway controls cell proliferation and survival. Everolimus is an oral agent targeting raptor mTOR (mTORC1). The trial's goal was to determine the antitumor activity and safety of single-agent everolimus in patients with relapsed/refractory Waldenström macroglobulinemia (WM). PATIENTS AND METHODS Eligible patients had measurable disease (immunoglobulin M monoclonal protein > 1,000 mg/dL with > 10% marrow involvement or nodal masses > 2 cm), a platelet count more than 75,000 x 10(6)/L, a neutrophil count more than 1,000 x 10(6)/L, and a creatinine and bilirubin less than 2 x the laboratory upper limit of normal. Patients received everolimus 10 mg orally daily and were evaluated monthly. Tumor response was assessed after cycles 2 and 6 and then every three cycles until progression. Results Fifty patients were treated. The median age was 63 years (range, 43 to 85 years). The overall response rate (complete response plus partial remission [PR] plus minimal response [MR]) was 70% (95% CI, 55% to 82%), with a PR of 42% and 28% MR. The median duration of response and median progression-free survival (PFS) have not been reached. The estimated PFS at 6 and 12 months is 75% (95% CI, 64% to 89%) and 62% (95% CI, 48% to 80%), respectively. Grade 3 or higher related toxicities were observed in 56% of patients. The most common were hematologic toxicities with cytopenias. Pulmonary toxicity occurred in 10% of patients. Dose reductions due to toxicity occurred in 52% of patients. CONCLUSION Everolimus has high single-agent activity with an overall response rate of 70% and manageable toxicity in patients with relapsed WM and offers a potential new therapeutic strategy for this patient group.
Journal of Clinical Oncology 02/2010; 28(8):1408-14. · 18.37 Impact Factor
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Irene M Ghobrial,
Aldo Roccaro,
Fangxin Hong,
Edie Weller,
Nancy Rubin, Renee Leduc,
Meghan Rourke,
Stacey Chuma,
Antonio Sacco,
Xiaoying Jia,
Feda Azab,
Abdel Kareem Azab,
Scott Rodig,
Diane Warren,
Brianna Harris,
Lyuba Varticovski,
Peter Sportelli,
Xavier Leleu,
Kenneth C Anderson,
Paul G Richardson
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ABSTRACT: Waldenström's macroglobulinemia (WM) is a rare, low-grade lymphoproliferative disorder. Based on preclinical studies, we conducted a phase II clinical trial testing the efficacy and safety of the Akt inhibitor perifosine in patients with relapsed/refractory WM.
Thirty-seven patients were treated with oral perifosine (150 mg daily) for six cycles. Stable or responding patients were allowed to continue therapy until progression.
The median age was 65 years (range, 44-82). The median number of prior therapy lines was two (range, one to five). Of the 37 patients, 4 achieved partial response (11%), 9 minimal response (24%), and 20 showed stable disease (54%). The median progression-free survival was 12.6 months. Additionally, beta2 microglobulin of >3.5 mg/dL was associated with poor event-free survival (P = 0.002). Perifosine was generally well tolerated; adverse events related to therapy were cytopenias (grade 3-4, 13%), gastrointestinal symptoms (grade 1-2, 81%), and arthritis flare (all grades, 11%). Translational studies using gene expression profiling and immunohistochemistry showed that perifosine inhibited pGSK activity downstream of Akt, and inhibited nuclear factor kappaB activity.
Perifosine resulted in at least a minimal response in 35% of patients and a median progression-free survival of 12.6 months in patients with relapsed or relapsed/refractory WM, as well as in vivo inhibition of pGSK activity. The results of this study warrant further evaluation of perifosine in combination with rituximab or other active agents in patients with WM.
Clinical Cancer Research 02/2010; 16(3):1033-41. · 7.74 Impact Factor
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Xavier Leleu,
Anne-Sophie Moreau,
Edie Weller,
Aldo M Roccaro,
ValéRie Coiteux,
Robert Manning,
Marybeth Nelson, Renee Leduc,
Daniela Robu,
Sophie Dupire,
Evdoxia Hatjiharissi,
Nicholas Burwick,
Stéphane Darre,
Bernadette Hennache,
Steven P Treon,
Thierry Facon,
Morie A Gertz,
Irene M Ghobrial
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ABSTRACT: The serum IgM level has been utilised as a marker of tumor progression and to assess response to therapy in patients with Waldenstrom macroglobulinemia (WM). However, there are many limitations to the IgM protein level. The objective of this study was to evaluate the association of known tumor burden markers and prognostic factors with serum free light chain (sFLC) in 98 patients with WM. We demonstrated that sFLC measurement accurately differentiated IgM-MGUS compared with WM reflecting a measurement of tumor burden. In univariate and multivariate analysis, median sFLC at the cut-off at 60 mg/L was higher for WM patients with low hemoglobin and high beta2M, when we applied the WM-IPSS cut-offs, but showed no association with IgM level. This study demonstrates that sFLC is a new marker in WM disease. Further analysis is required to prospectively study the role of sFLC in monitoring response to therapy and as a prognostic marker in WM patients.
Leukemia & lymphoma 05/2008; 49(6):1104-7. · 2.40 Impact Factor
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Steven P Treon,
Evdoxia Hatjiharissi,
Xavier Leleu,
Anne-Sophie Moreau,
Aldo Roccaro,
Zachary R Hunter,
Jacob D Soumerai,
Bryan Ciccarelli,
Lian Xu,
Antonio Sacco, [......],
Andrew R Branagan,
Allen W Ho,
Daniel D Santos,
Olivier Tournilhac,
Robert J Manning, Renee Leduc,
Kelly O'Connor,
Marybeth Nelson,
Christopher J Patterson,
Irene Ghobrial
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ABSTRACT: Waldenström's macroglobulinemia is a B-cell disorder characterized by bone marrow infiltration with lymphoplasmacytic cells and demonstration of an immunoglobulin M monoclonal gammopathy. Despite advances in therapy, Waldenström's macroglobulinemia remains incurable. As such, novel therapeutic agents are needed for the treatment of Waldenström's macroglobulinemia. In ongoing efforts, we and others have sought to exploit advances made in the understanding of the biology of Waldenström's macroglobulinemia so as to better target therapeutics for this malignancy. Importantly, as part of these efforts, we have prioritized the development of stem cell-sparing drugs because autologous stem cell transplantation remains a viable salvage option in Waldenström's macroglobulinemia. These efforts have led to the development of several novel agents for treating Waldenström's macroglobulinemia, including bortezomib; monoclonal antibodies and/or blocking protein targeting CD40, CD52, or CD70, a proliferation-inducing ligand and B-lymphocyte stimulator; the immunomodulator thalidomide as an enhancer of rituximab activity, as well as agents interfering with stem cell factor, phosphatidylinositol 3-kinase/Akt, phosphodiesterase, cholesterol, and protein kinase C beta signaling. This report provides an update on biologic studies and clinical efforts for the development of these novel agents in the treatment of Waldenström's macroglobulinemia.
Clinical Lymphoma & Myeloma 09/2007; 7 Suppl 5:S199-206. · 1.13 Impact Factor
