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Yasuhiro Oki,
Anas Younes, Amanda Copeland,
Fredrick Hagemeister,
Luis E Fayad,
Peter McLaughlin,
Jatin Shah,
Nathan Fowler,
Jorge Romaguera,
Larry W Kwak,
Barbara Pro
British Journal of Haematology 04/2013; · 4.94 Impact Factor
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Anas Younes,
Jorge Romaguera,
Michelle Fanale,
Peter McLaughlin,
Frederick Hagemeister, Amanda Copeland,
Sattva Neelapu,
Larry Kwak,
Jatin Shah,
Silvana de Castro Faria,
Stefan Hart,
Jeanette Wood,
Ramesh Jayaraman,
Kantharaj Ethirajulu,
Joy Zhu
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ABSTRACT: PURPOSEThe Janus kinase 2/signal transducers and activators of transcription (JAK2/STAT) pathway plays an important role in the pathogenesis of hematologic malignancies. We conducted a phase I dose-finding and pharmacokinetic/pharmacodynamic study of SB1518, a potent JAK2 inhibitor, in patients with relapsed lymphoma.Patients And methodsPatients with relapsed or refractory Hodgkin or non-Hodgkin lymphoma of any type except Burkitt's or CNS lymphoma were enrolled. Patient cohorts received escalating doses of SB1518 orally once daily for 28-day cycles. Response was evaluated after 8 weeks.ResultsThirty-four patients received doses of 100 to 600 mg/d. The maximum tolerated dose was not reached. Treatment was well tolerated, with mostly grade 1 and 2 toxicities. Gastrointestinal toxicities were the most common treatment-related events. Cytopenias were infrequent and modest. Pharmacologically active concentrations were achieved at all doses. Dose-related linear increases in area under the concentration-time curve were seen on day 1, with no significant accumulation on day 15. Mean terminal half-life was 1 to 4 days, and mean time to peak concentration ranged from 5 to 9 hours. SB1518 inhibited JAK2 signaling at 4 hours postdose at all levels. Increases in fms-like tyrosine kinase-3 (FLT-3) ligand, reflecting FLT-3 inhibition, were seen in most patients. There were three partial responses (≥ 300 mg/d) and 15 patients with stable disease (SD), with most responses lasting longer than 2 months. Seven of 13 SDs had tumor reductions of 4% to 46%. CONCLUSIONSB1518 has encouraging activity in relapsed lymphoma, providing the first proof-of-principle of the potential therapeutic value of targeting the JAK/STAT pathway in lymphoma in the clinical setting.
Journal of Clinical Oncology 09/2012; · 18.37 Impact Factor
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ABSTRACT: This review will focus on monoclonal antibodies and small molecule inhibitors used in the treatment of newly diagnosed and relapsed/refractory classical Hodgkin lymphoma.
Development of novel therapies is highly needed to improve treatment outcome of relapsed patients. New agents have shown to be effective and safe suggesting their use in combination with conventional therapy or with other targeted therapies in frontline and salvage regimens.
Approximately 9000 new cases of Hodgkin lymphoma will be diagnosed in 2012, representing 11% of all lymphomas in the USA. Although considered a highly curable malignancy, a third of patients will not respond to or relapse after initial therapy. Second-line therapy typically includes multiagent chemotherapy regimens followed by autologous stem cell transplantation. Patients whose disease relapses after autologous stem cell transplantation have poor prognosis, with a median survival of less than 3 years.
Current opinion in oncology 08/2012; 24(5):466-74. · 4.09 Impact Factor
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Anas Younes,
Stella Kim,
Jorge Romaguera, Amanda Copeland,
Silvana de Castro Farial,
Larry W Kwak,
Luis Fayad,
Frederick Hagemeister,
Michelle Fanale,
Sattva Neelapu,
John M Lambert,
Rodica Morariu-Zamfir,
Sandrine Payrard,
Leo I Gordon
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ABSTRACT: We determine the maximum-tolerated dose (MTD), pharmacokinetics, safety, and preliminary efficacy of SAR3419, an antibody-drug conjugate targeting CD19, in a first-in-man phase I clinical trial in patients with relapsed lymphoma.
Patients with relapsed CD19+ B-cell lymphoma were treated with escalating doses of SAR3419 given by intravenous infusion once every 21 days.
Thirty-nine patients were treated on seven dose levels ranging from 10 to 270 mg/m(2). The median number of prior treatment regimens was four (range, 1 to 9), and 11 patients had prior autologous or allogeneic stem-cell transplantation. The dose-limiting toxicities were reversible severe blurred vision associated with microcystic epithelial corneal changes reported in six patients and neuropathy in one patient. The MTD was 160 mg/m(2) once every 21 days. Hematologic and hepatic toxicities were predominantly grade 1 or 2 in severity. A total of 35 patients have completed at least two cycles of treatment and were evaluable for tumor response. Twenty-six patients (74%) demonstrated reduction in their tumor size; six of those patients achieved partial or complete remissions. Seven (47%) of 15 patients with rituximab-refractory disease demonstrated reduction in their tumor sizes. The pharmacokinetic profile of SAR3419 is characterized by linear kinetics, low clearance from 0.2 to 0.6 L/d/m(2), and an elimination half-life in the range of 3 to 7 days.
Using an every 3-week-schedule of SAR3419 for six cycles, the MTD is 160 mg/m(2). SAR3419 can be safely administered to patients with relapsed B-cell lymphoma and demonstrates promising clinical activity, including patients who were refractory to rituximab.
Journal of Clinical Oncology 07/2012; 30(22):2776-82. · 18.37 Impact Factor
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Blood 03/2012; 119(9):2171-2. · 9.90 Impact Factor
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ABSTRACT: Previous studies have shown that interferon-α (IFN-α) and chemotherapy is an effective treatment for patients with newly diagnosed follicular lymphoma. Therefore, we performed a phase II trial to determine the safety and effectiveness of IFN-α and standard doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) chemotherapy (IABVD) in these patients. Patients with newly diagnosed advanced stage classic Hodgkin lymphoma (HL) were enrolled between July 1997 and March 2000 on IABVD as initial therapy. This consisted of six cycles of ABVD with concurrent IFN-α followed by radiation therapy if indicated. IFN-α 6 million IU/m(2) was administered subcutaneously daily for 3 days and on day 4 patients received IFN-α with ABVD. Courses were repeated every 2 weeks for a maximum of 12 courses. IFN-α dose reduction was allowed for cytopenia. Outcome and baseline characteristics were reported. Thirty patients (median age, 30 years [range, 18-62 years]) were evaluable. Patients had Ann Arbor stage II (7%), III (30%) or IV (63%) disease, and 47% were at intermediate or high risk, as defined by the International Prognostic Score (≤ 2 vs. > 2). The 3-year event-free survival rate was 71% (95% confidence interval [CI], 56-90%), and the 3-year overall survival rate was 96% (95% CI, 89-100%). Treatment was well tolerated, with only three patients requiring IFN-α dose reduction or discontinuation because of cytopenia. IABVD is an effective regimen against advanced HL and is well tolerated. However, because of the emergence of effective new biologic agents, further development of this regimen is not warranted.
Leukemia & lymphoma 01/2012; 53(5):801-6. · 2.40 Impact Factor
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Anas Younes,
Yasuhiro Oki,
R Gregory Bociek,
John Kuruvilla,
Michelle Fanale,
Sattva Neelapu, Amanda Copeland,
Daniela Buglio,
Ahmed Galal,
Jeffrey Besterman,
Zuomei Li,
Michel Drouin,
Tracy Patterson,
M Renee Ward,
Jessica K Paulus,
Yuan Ji,
L Jeffrey Medeiros,
Robert E Martell
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ABSTRACT: The prognosis of patients with relapsed Hodgkin's lymphoma, especially those who relapse after stem-cell transplantation, is poor, and the development of new agents for this patient population is an unmet medical need. We tested the safety and efficacy of mocetinostat, an oral isotype-selective histone deacetylase inhibitor, in patients with relapsed classical Hodgkin's lymphoma.
Patients with relapsed or refractory classical Hodgkin's lymphoma aged 18 years or older were treated with mocetinostat administered orally three times per week, in 28-day cycles. Two doses were assessed (85 mg and 110 mg). Patients were treated until disease progression or prohibitive toxicity. The primary outcome was disease control rate, defined as complete response, partial response, or stable disease (for at least six cycles), analysed by intention to treat. This trial has been completed and is registered with ClinicalTrials.gov, number NCT00358982.
51 patients were enrolled. Initially, 23 patients were enrolled in the 110 mg cohort. Subsequently, because toxicity-related dose reductions were necessary in the 110 mg cohort, we treated 28 additional patients with a dose of 85 mg. On the basis of intent-to-treat analysis, the disease control rate was 35% (eight of 23 patients) in the 110 mg group and 25% (seven of 28) in the 85 mg group. 12 patients (24%) discontinued treatment because of adverse events, nine (32%) in the 85 mg cohort and three (13%) in the 110 mg cohort. The most frequent treatment-related grade 3 and 4 adverse events were neutropenia (four patients [17%] in the 110 mg group, three [11%] in the 85 mg group); fatigue (five patients [22%] in the 110 mg group, three [11%] in the 85 mg group); and pneumonia (four patients [17%] in the 110 mg group, two [7%] in the 85 mg group). Four patients, all in the 110 mg cohort, died during the study, of which two might have been related to treatment.
Mocetinostat, 85 mg three times per week, has promising single-agent clinical activity with manageable toxicity in patients with relapsed classical Hodgkin's lymphoma.
MethylGene Inc, Montreal, Canada; Celgene Corporation, Summit, NJ, USA; Tufts Medical Center, Boston, MA, USA.
The lancet oncology 12/2011; 12(13):1222-8. · 14.47 Impact Factor
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Leukemia & lymphoma 10/2011; 53(5):990-2. · 2.40 Impact Factor
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Conrad R Cruz,
Ulrike Gerdemann,
Ann M Leen,
Jessica A Shafer,
Stephanie Ku,
Benjamin Tzou,
Terzah M Horton,
Andrea Sheehan, Amanda Copeland,
Anas Younes,
Cliona M Rooney,
Helen E Heslop,
Catherine M Bollard
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ABSTRACT: Patients with Hodgkin lymphoma (HL) relapsing after hematopoietic stem cell transplant have limited options for long-term cure. We have shown that infused cytotoxic T cells (CTL) targeting Epstein Barr virus (EBV)-derived proteins induced complete remissions in EBV(+) HL patients. A limitation of this approach is that up to 70% of relapsed HL tumors are EBV-negative. For these patients, an alternative is to target the cancer/testis antigen MAGE-A4 present in EBV antigen-negative HL tumors. Furthermore, epigenetic modification by clinically available demethylating agents can enhance MAGE-A4 expression in previously MAGE-negative tumors.
We explored the feasibility of combining adoptive T cell therapy with epigenetic modification of tumor antigen expression. We further characterized MAGE-A4-specific T-cell phenotype and function, and examined the effects of the epigenetic modifying drug decitabine on these T cells.
Cytotoxic T cells were generated specifically recognizing MAGE-A4 expressed by autologous HL targets and tumor cell lines. Decitabine-previously shown to increase tumor antigen expression in HL-did not compromise MAGE-A4-specific T-cell phenotype and function. In patients treated with decitabine, expanded MAGE-A4-specific T cells had a broader antitumor T cell repertoire, consistent with increased antigen stimulation in vivo.
Adoptive transfer of MAGE-A4-specific T cells, combined with epigenetic modifying drugs to increase expression of the protein, may improve treatment of relapsed HL.
Clinical Cancer Research 09/2011; 17(22):7058-66. · 7.74 Impact Factor
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ABSTRACT: Deacetylase (DAC) inhibitors are promising new anticancer drugs that have complex mechanisms of action, including induction of cell-cycle arrest and apoptosis, inhibition of angiogenesis and induction of a favorable anti-tumor immune response. Panobinostat, a potent inhibitor of DAC 1-11 enzymatic activity, has demonstrated a significant in vitro antiproliferative activity against classical Hodgkin's lymphoma (cHL) cell lines in addition to a promising clinical activity in early Phase I studies in patients with relapsed cHL. In a recently completed large Phase II study in patients with relapsed cHL, panobinostat reduced tumor measurements in 74% of patients, including 23% partial and 4% complete remissions. In this article, we review the status of panobinostat drug development and compare its activity to those of other DAC inhibitors in patients with relapsed cHL. Future investigations should focus on designing rational combination regimens and identifying predictive markers that will assist in selecting patients who are likely to benefit from this novel therapy.
Expert Review of Hematology 06/2011; 4(3):245-52. · 1.16 Impact Factor
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ABSTRACT: Although many advances have been made in the treatment of lymphoma in the past decade, the treatment of patients with relapsed and refractory disease remains challenging. Only a fraction of patients will be cured with salvage therapy and transplantation. For those patients that are either ineligible or relapse after transplant, the treatment options are limited. This illustrates the need for new drugs and novel treatment strategies. This review will focus on the emerging role of histone deacetylase inhibitors (HDACis) in patients with relapsed lymphoma.
Several HDACis have been evaluated in relapsed and refractory Hodgkin and non-Hodgkin lymphoma showing promising activity in both. Specifically, vorinostat and romidepsin have been approved by the US Food and Drug Administration for patients with relapsed or refractory cutaneous T-cell lymphoma. Several other HDACis have shown very promising activity in Hodgkin lymphoma including panobinostat, entinostat and mocetinostat.
With the limited options available for lymphoma patients in the relapsed and refractory setting, the efficacy demonstrated by HDACis in this patient population is exciting and much needed and will hopefully prompt further investigation into additional agents and into the combination with HDACis.
Current opinion in oncology 09/2010; 22(5):431-6. · 4.09 Impact Factor
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Michael Wang,
Yasuhiro Oki,
Barbara Pro,
Jorge Enrique Romaguera,
Maria Alma Rodriguez,
Felipe Samaniego,
Peter McLaughlin,
Frederick Hagemeister,
Sattva Neelapu, Amanda Copeland,
Barry I Samuels,
Evelyne M Loyer,
Yuan Ji,
Anas Younes
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ABSTRACT: This phase II trial evaluated the safety and efficacy of yttrium-90 ((90)Y)-ibritumomab tiuxetan in patients with relapsed or refractory mantle cell lymphoma (MCL).
Patients with relapsed or refractory MCL were eligible for the study if they had adequate major organ function and performance status. Those with CNS disease, pleural effusion, circulating lymphoma cells > or = 5,000/microL, or history of stem-cell transplant were ineligible. Patients with a platelet count > or = 150,000/microL received a dose of 0.4 mCi/kg of (90)Y-ibritumomab tiuxetan, whereas those with a platelet count less than 150,000/microL received a dose of 0.3 mCi/kg.
Thirty-four patients with a median age of 68 years (range, 52 to 79 years) received the therapeutic dose. The patients had received a median of three prior treatment regimens (range, one to six treatment regimens), including those that contained rituximab (n = 32) and bortezomib (n = 7). Of the 32 patients with measurable disease, 10 (31%) achieved complete or partial remission. After a median follow-up of 22 months (range, 2 to 72+ months), an intent-to-treat analysis revealed a median event-free survival (EFS) duration of 6 months and an overall survival duration of 21 months. The median EFS for those who achieved partial or complete remission was 28 months, while it was 3 months for those whose disease did not respond (P < .0001); it was 9 months for patients whose tumor measured less than 5 cm in the largest diameter before treatment and 3 months for those whose tumor measured > or = 5 cm (P = .015).
The single-agent activity of (90)Y-ibritumomab tiuxetan and its favorable safety profile warrant its further development for the treatment of MCL.
Journal of Clinical Oncology 09/2009; 27(31):5213-8. · 18.37 Impact Factor
