Publications by authors named "Michael E Williams"

47 Publications

Risk of Major Bleeding with Ibrutinib.

Clin Lymphoma Myeloma Leuk 2018 11 1;18(11):755-761. Epub 2018 Aug 1.

Division of Hematology-Oncology, Department of Medicine and Cancer Center, University of Virginia Health System, Charlottesville, VA.

Background: The Bruton tyrosine kinase inhibitor, ibrutinib, is an effective therapy against mature B-cell malignancies. Although generally well tolerated, serious bleeding emerged during developmental clinical trials as an unexpected, although uncommon, adverse event. As the use of ibrutinib increases outside of the clinical trial setting and in patients with more comorbidities, the rate of major bleeding could be greater.

Materials And Methods: A retrospective analysis the data from all patients at our center and its regional clinics who had been prescribed ibrutinib from January 2012 to May 2016 were reviewed for demographic data, comorbid illnesses, bleeding events, and concurrent medications.

Results: We identified 70 patients. Bleeding of any grade occurred in 56% of patients, mostly grade 1 to 2 bruising and epistaxis. Major bleeding, defined as grade ≥ 3, occurred in 19% of patients, greater than previously reported. Anemia (hemoglobin < 12 g/dL; hazard ratio [HR], 5.0; 95% confidence interval [CI], 1.4-18.2; P = .02) and an elevated international normalized ratio (> 1.5; HR, 9.5; 95% CI, 2.7-33.5; P < .01) at ibrutinib initiation were associated with an increased risk of major bleeding. Of those with major bleeding, most patients were also taking an antiplatelet agent (70%), an anticoagulant (17%), or a CYP 3A4 inhibitor (7%), with 13% taking both antiplatelet and anticoagulant medications. The use of both antiplatelet and anticoagulant therapy significantly increased the risk of a major bleed event (HR, 19.2; 95% CI, 2.3-166.7; P < .01).

Conclusion: The results of the present study have demonstrated a greater rate of major bleeding with ibrutinib use in a standard clinical setting than previously reported. Patients with anemia or an elevated international normalized ratio or requiring anticoagulant and/or antiplatelet medications during ibrutinib therapy have a significantly increased risk of major bleeding. Careful consideration of the risks and benefits for this population is needed. The combination of antiplatelet and anticoagulation medications with ibrutinib therapy is of particular concern.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clml.2018.07.287DOI Listing
November 2018

Outcomes of adults and children with primary mediastinal B-cell lymphoma treated with dose-adjusted EPOCH-R.

Br J Haematol 2017 12 29;179(5):739-747. Epub 2017 Oct 29.

Department of Medicine, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY, USA.

Treatment with dose-adjusted EPOCH (etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone) chemotherapy and rituximab (DA-EPOCH-R) has become the standard of care for primary mediastinal B-cell lymphoma (PMBCL) at many institutions despite limited data in the multi-centre setting. We report a large, multi-centre retrospective analysis of children and adults with PMBCL treated with DA-EPOCH-R to characterize outcomes and evaluate prognostic factors. We assessed 156 patients with PMBCL treated with DA-EPOCH-R across 24 academic centres, including 38 children and 118 adults. All patients received at least one cycle of DA-EPOCH-R. Radiation therapy was administered in 14·9% of patients. With median follow-up of 22·6 months, the estimated 3-year event-free survival (EFS) was 85·9% [95% confidence interval (CI) 80·3-91·5] and overall survival was 95·4% (95% CI 91·8-99·0). Outcomes were not statistically different between paediatric and adult patients. Thrombotic complications were reported in 28·2% of patients and were more common in paediatric patients (45·9% vs. 22·9%, P = 0·011). Seventy-five per cent of patients had a negative fluorodeoxyglucose positron emission tomography (FDG-PET) scan at the completion of DA-EPOCH-R, defined as Deauville score 1-3. Negative FDG-PET at end-of-therapy was associated with improved EFS (95·4% vs. 54·9%, P < 0·001). Our data support the use of DA-EPOCH-R for the treatment of PMBCL in children and adults. Patients with a positive end-of-therapy FDG-PET scan have an inferior outcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.14951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6650639PMC
December 2017

Microenvironmental agonists generate phenotypic resistance to combined ibrutinib plus venetoclax in CLL and MCL.

Blood Adv 2017 Jun;1(14):933-946

Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA, United States.

resistance and rapid recurrence often characterize responses of B-cell malignancies to ibrutinib (IBR), indicating a need to develop drug combinations that block compensatory survival signaling and give deeper, more durable responses. To identify such combinations, we previously performed a combinatorial drug screen and identified the Bcl-2 inhibitor venetoclax (VEN) as a promising partner for combination with IBR in Mantle Cell Lymphoma (MCL). We have opened a multi-institutional clinical trial to test this combination. However, analysis of primary samples from patients with MCL as well as chronic lymphocytic leukemia (CLL) revealed unexpected heterogeneous resistance even to the IBR+VEN combination. In the current study, we demonstrate that resistance to the combination can be generated by microenvironmental agonists: IL-10, CD40L and, most potently, CpG-oligodeoxynucleotides (CpG-ODN), which is a surrogate for unmethylated DNA and a specific agonist for TLR9 signaling. Incubation with these agonists caused robust activation of NF-κB signaling, especially alternative NF-κB, which led to enhanced expression of the anti-apoptotic proteins Mcl-1, Bcl-xL, and survivin, thus decreasing dependence on Bcl-2. Inhibitors of NF-κB signaling blocked overexpression of these anti-apoptotic proteins and overcame resistance. Inhibitors of Mcl-1, Bcl-xL, or survivin also overcame this resistance, and showed synergistic benefit with the IBR+VEN combination. We conclude that microenvironmental factors, particularly the TLR9 agonist, can generate resistance to the IBR+VEN combination in CLL and MCL cells. This signaling pathway presents targets for overcoming drug resistance induced by extrinsic microenvironmental factors in diverse B-cell malignancies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5637393PMC
http://dx.doi.org/10.1182/bloodadvances.2016004176DOI Listing
June 2017

Implementation of a Model-Based Design in a Phase Ib Study of Combined Targeted Agents.

Clin Cancer Res 2017 Dec 21;23(23):7158-7164. Epub 2017 Jul 21.

Division of Translational Research & Applied Statistics, Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia.

In recent years, investigators have recognized the rigidity of single-agent, safety-only, traditional designs, rendering them ineffective for conducting contemporary early-phase clinical trials, such as those involving combinations and/or biological agents. Novel approaches are required to address these research questions, such as those posed in trials involving targeted therapies. We describe the implementation of a model-based design for identifying an optimal treatment combination, defined by low toxicity and high efficacy, in an early-phase trial evaluating a combination of two oral targeted inhibitors in relapsed/refractory mantle cell lymphoma. Operating characteristics demonstrate the ability of the method to effectively recommend optimal combinations in a high percentage of trials with reasonable sample sizes. The proposed design is a practical, early-phase, adaptive method for use with combined targeted therapies. This design can be applied more broadly to early-phase combination studies, as it was used in an ongoing study of a melanoma helper peptide vaccine plus novel adjuvant combinations. .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-17-1069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5712236PMC
December 2017

Beyond RCHOP: A Blueprint for Diffuse Large B Cell Lymphoma Research.

J Natl Cancer Inst 2016 12 16;108(12). Epub 2016 Dec 16.

Department of Medicine, Mayo Clinic, Rochester, MN (GSN); Department of Internal Medicine, Ohio State University, Columbus, OH (KAB); Department of Medicine, Oncology Division, Washington University, St. Louis, MO (BSK); Wilmot Cancer Center and Division of Hematology/Oncology, University of Rochester, Rochester, NY (JWF); Coordinating Center for Clinical Trials (LB), Division of Cancer Treatment and Diagnosis (RFL), and Center for Cancer Research (WHW), National Cancer Institute, National Institute of Health, Bethesda, MD; Division of Oncology, University of Washington, Seattle WA (DGM); British Colombia Cancer Agency, Vancouver, BC (LHS); Department of Medicine, University of Virginia, Charlottesville, VA (MEW); Department of Medicine, Weil Cornell University, New York, NY (JPL); Department of Medicine, University of Chicago, Chicago, IL (SMS).

Diffuse large B cell lymphoma (DLBCL) comprises multiple molecular and biological subtypes, resulting in a broad range of clinical outcomes. With standard chemoimmunotherapy, there remains an unacceptably high treatment failure rate in certain DLBCL subsets: activated B cell (ABC) DLBCL, double-hit lymphoma defined by the dual translocation of MYC and BCL2, dual protein-expressing lymphomas defined by the overexpression of MYC and BCL2, and older patients and those with central nervous system involvement. The main research challenges for DLBCL are to accurately identify molecular subsets and to determine if specific chemotherapy platforms and targeted agents offer differential benefit. The ultimate goal should be to maximize initial cure rates to improve long-term survival while minimizing toxicity. In particular, a frontline trial should focus on biologically defined risk groups not likely to be cured with cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab (R-CHOP). An additional challenge is to develop effective and personalized strategies in the relapsed setting, for which there is no current standard other than autologous stem cell transplantation, which benefits a progressively smaller proportion of patients. Relapsed/refractory DLBCL is the ideal setting for testing novel agents and new biomarker tools and will require a national call for biopsies to optimize discovery in this setting. Accordingly, the development of tools with both prognostic and predictive utility and the individualized application of new therapies should be the main priorities. This report identifies clinical research priorities for critical areas of unmet need in this disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jnci/djw257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6080361PMC
December 2016

Rituximab extended schedule or retreatment trial for low tumour burden non-follicular indolent B-cell non-Hodgkin lymphomas: Eastern Cooperative Oncology Group Protocol E4402.

Br J Haematol 2016 06 11;173(6):867-75. Epub 2016 Mar 11.

Washington University School of Medicine, St. Louis, MO, USA.

The rituximab extended schedule or retreatment trial (RESORT; E4402) was a phase 3 randomized prospective trial comparing maintenance rituximab (MR) versus a retreatment (RR) dosing strategy in asymptomatic, low tumour burden indolent lymphoma. A planned exploratory sub-study compared the two strategies for small lymphocytic (SLL) and marginal zone lymphomas (MZL). Patients responding to rituximab weekly × 4 were randomized to MR (single dose rituximab every 3 months until treatment failure) or RR (rituximab weekly × 4) at the time of each progression until treatment failure. The primary endpoint was time to treatment failure (TTTF). Patients with SLL (n = 57), MZL (n = 71) and unclassifiable small B-cell lymphoma (n = 3) received induction rituximab. The overall response rate (ORR) was 40% [95% confidence interval (CI) 31-49%; SLL ORR 22·8%; MZL ORR 52·1%]; all 52 responders were randomized. At a median of 4·3 years from randomization, treatment failure occurred in 18/23 RR and 15/29 MR. The median TTTF was 1·4 years for RR and 4·8 years for MR (P = 0·012); median time to first cytotoxic therapy was 6·3 years for RR and not reached for MR (P = 0·0002). Survival did not differ (P = 0·72). In low tumour burden SLL and MZL patients responding to rituximab induction, MR significantly improved TTTF as compared with RR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.14007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4900920PMC
June 2016

Postibrutinib outcomes in patients with mantle cell lymphoma.

Blood 2016 Mar 13;127(12):1559-63. Epub 2016 Jan 13.

Ohio State University Comprehensive Cancer Center, Columbus, OH;

Despite unprecedented clinical activity in mantle cell lymphoma (MCL), primary and acquired resistance to ibrutinib is common. The outcomes and ideal management of patients who experience ibrutinib failure are unclear. We performed a retrospective cohort study of all patients with MCL who experienced disease progression while receiving ibrutinib across 15 international sites. Medical records were evaluated for clinical characteristics, pathological and radiological data, and therapies used pre- and postibrutinib. A total of 114 subjects met eligibility criteria. The median number of prior therapies was 3 (range, 0-10). The Mantle Cell Lymphoma International Prognostic Index (MIPI) scores at the start of ibrutinib were low, intermediate, and high in 46%, 31%, and 23% of patients, respectively. Of patients with available data prior to ibrutinib and postibrutinib, 34 of 47 and 11 of 12 had a Ki67 >30%. The median time on ibrutinib was 4.7 months (range 0.7-43.6). The median overall survival (OS) following cessation of ibrutinib was 2.9 months (95% confidence interval [CI], 1.6-4.9). Of the 104 patients with data available, 73 underwent subsequent treatment an average of 0.3 months after stopping ibrutinib with a median OS of 5.8 months (95% CI, 3.7-10.4). Multivariate Cox regression analysis of MIPI before postibrutinib treatment, and subsequent treatment with bendamustine, cytarabine, or lenalidomide failed to reveal any association with OS. Poor clinical outcomes were noted in the majority of patients with primary or secondary ibrutinib resistance. We could not identify treatments that clearly improved outcomes. Future trials should focus on understanding the mechanisms of ibrutinib resistance and on treatment after ibrutinib.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2015-10-673145DOI Listing
March 2016

Fc Gamma Receptor 3A and 2A Polymorphisms Do Not Predict Response to Rituximab in Follicular Lymphoma.

Clin Cancer Res 2016 Feb 28;22(4):821-6. Epub 2015 Oct 28.

Washington University School of Medicine, St. Louis, Missouri.

Purpose: Preclinical studies suggest that SNPs in the Fc gamma receptor (FCGR) genes influence response to rituximab, but the clinical relevance of this is uncertain.

Experimental Design: We prospectively obtained specimens for genotyping in the rituximab extended schedule or re-treatment trial (RESORT) study, in which 408 previously untreated, low tumor burden follicular lymphoma (FL) patients were treated with single agent rituximab. Patients received rituximab in 4 weekly doses and responders were randomized to rituximab re-treatment (RR) upon progression versus maintenance rituximab (MR). SNP genotyping was performed in 321 consenting patients.

Results: Response rates to initial therapy and response duration were correlated with the FCGR3A SNP at position 158 (rs396991) and the FCGR2A SNP at position 131 (rs1801274). The response rate to initial rituximab was 71%. No FCGR genotypes or grouping of genotypes were predictive of initial response. A total of 289 patients were randomized to RR (n = 143) or to MR (n = 146). With a median follow-up of 5.5 years, the 3-year response duration in the RR arm and the MR arm was 50% and 78%, respectively. Genotyping was available in 235 of 289 randomized patients. In patients receiving RR (n = 115) or MR (n = 120), response duration was not associated with any FCGR genotypes or genotype combinations.

Conclusions: Based on this analysis of treatment-naïve, low tumor burden FL, we conclude that the FCGR3A and FCGR2A SNPs do not confer differential responsiveness to rituximab.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-15-1848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4755793PMC
February 2016

Long-term follow-up of MCL patients treated with single-agent ibrutinib: updated safety and efficacy results.

Blood 2015 Aug 9;126(6):739-45. Epub 2015 Jun 9.

Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, United Kingdom.

Ibrutinib, an oral inhibitor of Bruton tyrosine kinase, is approved for patients with mantle cell lymphoma (MCL) who have received one prior therapy. We report the updated safety and efficacy results from the multicenter, open-label phase 2 registration trial of ibrutinib (median 26.7-month follow-up). Patients (N = 111) received oral ibrutinib 560 mg once daily, and those with stable disease or better could enter a long-term extension study. The primary end point was overall response rate (ORR). The median patient age was 68 years (range, 40-84), with a median of 3 prior therapies (range, 1-5). The median treatment duration was 8.3 months; 46% of patients were treated for >12 months, and 22% were treated for ≥2 years. The ORR was 67% (23% complete response), with a median duration of response of 17.5 months. The 24-month progression-free survival and overall survival rates were 31% (95% confidence interval [CI], 22.3-40.4) and 47% (95% CI, 37.1-56.9), respectively. The most common adverse events (AEs) in >30% of patients included diarrhea (54%), fatigue (50%), nausea (33%), and dyspnea (32%). The most frequent grade ≥3 infections included pneumonia (8%), urinary tract infection (4%), and cellulitis (3%). Grade ≥3 bleeding events in ≥2% of patients were hematuria (2%) and subdural hematoma (2%). Common all-grade hematologic AEs were thrombocytopenia (22%), neutropenia (19%), and anemia (18%). The prevalence of infection, diarrhea, and bleeding was highest for the first 6 months of therapy and less thereafter. With longer follow-up, ibrutinib continues to demonstrate durable responses and favorable safety in relapsed/refractory MCL. The trial is registered to www.ClinicalTrials.gov as #NCT01236391.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2015-03-635326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4528064PMC
August 2015

Anxiety and health-related quality of life among patients with low-tumor burden non-Hodgkin lymphoma randomly assigned to two different rituximab dosing regimens: results from ECOG trial E4402 (RESORT).

J Clin Oncol 2015 Mar 20;33(7):740-8. Epub 2015 Jan 20.

Lynne I. Wagner and David Cella, Northwestern University Feinberg School of Medicine, Chicago, IL; Fengmin Zhao, Fangxin Hong, Dana-Farber Cancer Institute, Boston, MA; Michael E. Williams, University of Virginia, Charlottesville, VA; John C. Krauss, University of Michigan, Ann Arbor, MI; Ranjana H. Advani, Stanford University, Stanford; Sandra J. Horning, Genentech, South San Francisco, CA; Ronald S. Go, Gunderson Health System, La Crosse; Brad S. Kahl, University of Wisconsin, Madison, WI; Thomas M. Habermann, Mayo Clinic, Rochester; Joseph W. Leach, Metro Minnesota Community Clinical Oncology Program, Minneapolis, MN; Brian O'Connor, Frederick Memorial Health System, Frederick, MD; Stephen J. Schuster, University of Pennsylvania, Philadelphia, PA; and Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, BC, Canada.

Purpose: The purpose of this study was to compare illness-related anxiety among participants in the Rituximab Extended Schedule or Retreatment Trial (RESORT) randomly assigned to maintenance rituximab (MR) versus rituximab re-treatment (RR). A secondary objective was to examine whether the superiority of MR versus RR on anxiety depended on illness-related coping style.

Patients And Methods: Patients (N = 253) completed patient-reported outcome (PRO) measures at random assignment to MR or RR (baseline); at 3, 6, 12, 24, 36, and 48 months after random assignment; and at rituximab failure. PRO measures assessed illness-related anxiety and coping style, and secondary end points including general anxiety, worry and interference with emotional well-being, depression, and health-related quality of life (HRQoL). Patients were classified as using an active or avoidant illness-related coping style. Independent sample t tests and linear mixed-effects models were used to identify treatment arm differences on PRO end points and differences based on coping style.

Results: Illness-related anxiety was comparable between treatment arms at all time points (P > .05), regardless of coping style (active or avoidant). Illness-related anxiety and general anxiety significantly decreased over time on both arms. HRQoL scores were relatively stable and did not change significantly from baseline for both arms. An avoidant coping style was associated with significantly higher anxiety (18% and 13% exceeded clinical cutoff points at baseline and 6 months, respectively) and poorer HRQoL compared with an active coping style (P < .001), regardless of treatment arm assignment.

Conclusion: Surveillance until RR at progression was not associated with increased anxiety compared with MR, regardless of coping style. Avoidant coping was associated with higher anxiety and poorer HRQoL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.2014.57.6801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4334777PMC
March 2015

Development and characterization of a Mantle Cell Lymphoma Cell Bank in the American Type Culture Collection.

Leuk Lymphoma 2015 Jul 11;56(7):2114-22. Epub 2015 Feb 11.

Department of Pathology, NYU School of Medicine , New York, NY , USA.

Mantle cell lymphoma (MCL) is a rare B-cell malignancy that carries a relatively poor prognosis compared to other forms of non-Hodgkin lymphoma. Standardized preclinical tools are desperately required to hasten the discovery and translation of promising new treatments for MCL. Via an initiative organized through the Mantle Cell Lymphoma Consortium and the Lymphoma Research Foundation, we gathered MCL cell lines from laboratories around the world to create a characterized MCL Cell Bank at the American Type Culture Collection (ATCC). Initiated in 2006, this collection now contains eight cell lines, all of which have been rigorously characterized and are now stored and available for distribution to the general scientific community. We believe the awareness and use of these standardized cell lines will decrease variability between investigators, harmonize international research efforts, improve our understanding of the pathogenesis of the disease and hasten the development of novel treatment strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/10428194.2014.970548DOI Listing
July 2015

Rituximab extended schedule or re-treatment trial for low-tumor burden follicular lymphoma: eastern cooperative oncology group protocol e4402.

J Clin Oncol 2014 Oct 25;32(28):3096-102. Epub 2014 Aug 25.

Brad S. Kahl, University of Wisconsin, Madison; Christopher G. Peterson, Aspirus Regional Cancer Center, Wausau; Matthias Weiss, Marshfield Clinic, Marshfield, WI; Fangxin Hong, Dana-Farber Cancer Institute, Boston, MA; Michael E. Williams, University of Virginia, Charlottesville, VA; Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; Lynne I. Wagner, Northwestern University, Chicago, IL; John C. Krauss, University of Michigan, Ann Arbor, MI; Thomas M. Habermann, Mayo Clinic, Rochester; Mark D. Sborov, Fairview-Southdale Hospital, St Louis Park, MN; Lode J. Swinnen, Johns Hopkins University, Baltimore, MD; Stephen J. Schuster, University of Pennsylvania, Philadelphia; W. Christopher Ehmann, Penn State Cancer Institute, Hershey, PA; S. Eric Martin, Christiana Care Community Clinical Oncology Program and Helen F. Graham Cancer Network, Newark, DE; and Sandra J. Horning, Genentech, South San Francisco, CA.

Purpose: In low-tumor burden follicular lymphoma (FL), maintenance rituximab (MR) has been shown to improve progression-free survival when compared with observation. It is not known whether MR provides superior long-term disease control compared with re-treatment rituximab (RR) administered on an as-needed basis. E4402 (RESORT) was a randomized clinical trial designed to compare MR against RR.

Patients And Methods: Eligible patients with previously untreated low-tumor burden FL received four doses of rituximab, and responding patients were randomly assigned to either RR or MR. Patients receiving RR were eligible for re-treatment at each disease progression until treatment failure. Patients assigned to MR received a single dose of rituximab every 3 months until treatment failure. The primary end point was time to treatment failure. Secondary end points included time to first cytotoxic therapy, toxicity, and health-related quality of life (HRQOL).

Results: A total of 289 patients were randomly assigned to RR or MR. With a median follow-up of 4.5 years, the estimated median time to treatment failure was 3.9 years for patients receiving RR and 4.3 years for those receiving MR (P = .54). Three-year freedom from cytotoxic therapy was 84% for those receiving RR and 95% for those receiving MR (P = .03). The median number of rituximab doses was four patients receiving RR and 18 for those receiving MR. There was no difference in HRQOL. Grade 3 to 4 toxicities were infrequent in both arms.

Conclusion: In low-tumor burden FL, a re-treatment strategy uses less rituximab while providing disease control comparable to that achieved with a maintenance strategy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.2014.56.5853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4171355PMC
October 2014

Transplantation for mantle cell lymphoma: is it the right thing to do?

Hematology Am Soc Hematol Educ Program 2013 ;2013:568-74

1Hematology/Oncology Division and Cancer Center, University of Virginia Health System, Charlottesville, VA.

Mantle cell lymphoma (MCL) is a unique subtype of non-Hodgkin lymphoma that is both biologically and clinically heterogeneous. A variety of biomarkers, the achievement of minimal residual disease negativity after initial therapy, and the MCL International Prognostic Index (MIPI) are associated with patient outcome, although none has as yet been used for routine treatment stratification. Given the lack of widely accepted and standardized treatment approaches, clinical trial enrollment should always be considered for the initial therapy of MCL. Outside of the trial setting, younger and transplantation-eligible patients with newly diagnosed MCL who require treatment should first be considered for a rituximab+a high-dose cytarabine-containing regimen, followed by autologous stem cell transplantation consolidation in first remission. Symptomatic elderly and nontransplantation-eligible individuals typically receive rituximab+bendamustine, or R-CHOP (rituximab+cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone/prednisolone) followed by maintenance rituximab, the latter a treatment plan that has demonstrated extended response duration and survival. Promising early results for consolidation approaches with proteasome inhibitors and immunomodulatory drugs are now being tested in randomized clinical trials. The availability of highly active BCR signaling pathway inhibitors and cell death pathway modulation via BH3 mimetics, among other novel agents, promise to rapidly expand treatment options, change existing treatment paradigms, and further improve outcomes for MCL patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/asheducation-2013.1.568DOI Listing
July 2014

MHC class I-associated phosphopeptides are the targets of memory-like immunity in leukemia.

Sci Transl Med 2013 Sep;5(203):203ra125

Carter Immunology Center and Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA.

Deregulation of signaling pathways is a hallmark of malignant transformation. Signaling-associated phosphoproteins can be degraded to generate cancer-specific phosphopeptides that are presented by major histocompatibility complex (MHC) class I and II molecules and recognized by T cells; however, the contribution of these phosphoprotein-specific T cells to immune surveillance is unclear. We identified 95 phosphopeptides presented on the surface of primary hematological tumors and normal tissues, including 61 that were tumor-specific. Phosphopeptides were more prevalent on more aggressive and malignant samples. CD8(+) T cell lines specific for these phosphopeptides recognized and killed both leukemia cell lines and human leukocyte antigen-matched primary leukemia cells ex vivo. Notably, healthy individuals showed robust CD8(+) T cell responses against many of these phosphopeptides within the circulating memory compartment. This immunity was significantly reduced or absent in some leukemia patients. This reduction correlated with clinical outcome; however, immunity was restored after allogeneic stem cell transplantation. These results suggest that phosphopeptides may be targets of cancer immune surveillance in humans, and point to their importance for development of vaccine-based and T cell adoptive transfer immunotherapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/scitranslmed.3006061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4071620PMC
September 2013

Single-agent lenalidomide in patients with mantle-cell lymphoma who relapsed or progressed after or were refractory to bortezomib: phase II MCL-001 (EMERGE) study.

J Clin Oncol 2013 Oct 3;31(29):3688-95. Epub 2013 Sep 3.

Andre Goy, John Theurer Cancer Center at Hackensack University Medical Center, Hackensack; Lei Zhang, Sherri Cicero, and Tommy Fu, Celgene, Summit, NJ; Rajni Sinha, Emory University Winship Cancer Institute, Atlanta, GA; Michael E. Williams, University of Virginia Health System, Charlottesville, VA; Sevgi Kalayoglu Besisik, Istanbul University Faculty of Medicine, Istanbul, Turkey; Johannes Drach, Medical University of Vienna, Vienna, Austria; Radhakrishnan Ramchandren, Karmanos Cancer Institute, Detroit, MI; and Thomas E. Witzig, Mayo Clinic, Rochester, MN.

Purpose: Although dose-intensive strategies or high-dose therapy induction followed by autologous stem-cell transplantation have improved the outcome for patients with mantle-cell lymphoma (MCL), most eventually relapse and subsequently respond poorly to additional therapy. Bortezomib (in the United States) and temsirolimus (in Europe) are currently the only two treatments approved for relapsed disease. Lenalidomide is an immunomodulatory agent with proven tumoricidal and antiproliferative activity in MCL. The MCL-001 (EMERGE) trial is a global, multicenter phase II study examining the safety and efficacy of lenalidomide in patients who had relapsed or were refractory to bortezomib.

Patients And Methods: Lenalidomide 25 mg orally was administered on days 1 through 21 every 28 days until disease progression or intolerance. Primary end points were overall response rate (ORR) and duration of response (DOR); secondary end points included complete response (CR) rate, progression-free survival (PFS), overall survival (OS), and safety.

Results: In all, 134 patients were enrolled with a median age of 67 years and a median of four prior therapies (range, two to 10 prior therapies). The ORR was 28% (7.5% CR/CR unconfirmed) with rapid time to response (median, 2.2 months) and a median DOR of 16.6 months (95% CI, 7.7 to 26.7 months). Median PFS was 4.0 months (95% CI, 3.6 to 5.6 months), and median OS was 19.0 months (95% CI, 12.5 to 23.9 months). The most common grade 3 to 4 adverse events were neutropenia (43%), thrombocytopenia (28%), anemia (11%), pneumonia (8%), and fatigue (7%).

Conclusion: The MCL-001 study demonstrated durable efficacy of lenalidomide with a predictable safety profile in heavily pretreated patients with MCL who had all relapsed or progressed after or were refractory to bortezomib.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.2013.49.2835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879693PMC
October 2013

Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma.

N Engl J Med 2013 Aug 19;369(6):507-16. Epub 2013 Jun 19.

Department of Lymphoma and Myeloma, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.

Background: Bruton's tyrosine kinase (BTK) is a mediator of the B-cell-receptor signaling pathway implicated in the pathogenesis of B-cell cancers. In a phase 1 study, ibrutinib, a BTK inhibitor, showed antitumor activity in several types of non-Hodgkin's lymphoma, including mantle-cell lymphoma.

Methods: In this phase 2 study, we investigated oral ibrutinib, at a daily dose of 560 mg, in 111 patients with relapsed or refractory mantle-cell lymphoma. Patients were enrolled into two groups: those who had previously received at least 2 cycles of bortezomib therapy and those who had received less than 2 complete cycles of bortezomib or had received no prior bortezomib therapy. The primary end point was the overall response rate. Secondary end points were duration of response, progression-free survival, overall survival, and safety.

Results: The median age was 68 years, and 86% of patients had intermediate-risk or high-risk mantle-cell lymphoma according to clinical prognostic factors. Patients had received a median of three prior therapies. The most common treatment-related adverse events were mild or moderate diarrhea, fatigue, and nausea. Grade 3 or higher hematologic events were infrequent and included neutropenia (in 16% of patients), thrombocytopenia (in 11%), and anemia (in 10%). A response rate of 68% (75 patients) was observed, with a complete response rate of 21% and a partial response rate of 47%; prior treatment with bortezomib had no effect on the response rate. With an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months (95% confidence interval [CI], 15.8 to not reached), the estimated median progression-free survival was 13.9 months (95% CI, 7.0 to not reached), and the median overall survival was not reached. The estimated rate of overall survival was 58% at 18 months.

Conclusions: Ibrutinib shows durable single-agent efficacy in relapsed or refractory mantle-cell lymphoma. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01236391.)
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa1306220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4513941PMC
August 2013

Current and emerging therapies in mantle cell lymphoma.

Curr Treat Options Oncol 2013 Jun;14(2):198-211

Hematology/Oncology Division, University of Virginia Health System, Hospital West, Room 6023, Jefferson Park Avenue, Charlottesville, VA 22908, USA.

Mantle Cell Lymphoma, characterized by the t(11;14)(q13; q32) chromosomal translocation and cyclin D1 expression, remains one of the most challenging lymphoma subtypes to treat. Therapy can be divided into treatment modalities for younger, stem cell transplant (SCT)-eligible patients vs older, SCT-ineligible patients. For clinically fit patients younger than 60-65 years of age we recommend cytarabine-containing induction and conditioning regimens such as Rituximab (R)-CHOP alternating with R-DHAP followed by autologous SCT consolidation. Elderly patients benefit from R-bendamustine or R-CHOP with maintenance rituximab following induction therapy, especially after R-CHOP. While standard chemoimmunotherapy provides high overall response rates, the responses are not durable and sequential therapies are thus necessary. MCL is proving to be sensitive to novel therapies that may in the near future become useful adjuncts to standard regimens. For example, bortezomib, lenalidomide, and temsirolimus each have single-agent efficacy in relapsed and refractory disease. Several targeted agents are emerging that likewise may transform management of MCL. The B-cell receptor pathway appears to be critical in the pathogenesis of MCL, and novel agents such as ibrutinib and idelalisib that target this signaling pathway are highly active in relapsed and refractory MCL. Similarly, cell cycle inhibitors targeting cyclin dependent kinases as well as HDAC inhibitors have shown promise in early studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11864-013-0230-zDOI Listing
June 2013

Recent advances in mantle cell lymphoma: report of the 2012 Mantle Cell Lymphoma Consortium Workshop.

Leuk Lymphoma 2013 Sep 4;54(9):1882-90. Epub 2013 Mar 4.

University of Virginia Health System, Charlottesville, VA, USA.

Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma characterized by overexpression of cyclin D1 and the t(11;14)(q13;q32) chromosomal translocation. MCL is biologically and clinically heterogeneous and frequently disseminates to extranodal areas. While a subset of patients have an indolent clinical course, the overall outcome for patients with MCL remains poor. There is no proven curative therapy, and no standard of care has been established for initial or subsequent lines of therapy. Several regimens are highly active in previously untreated patients, and recent research has led to improvements in currently available therapy. Moreover, investigational agents have recently demonstrated promising activity in clinical trials. A workshop was held to review recent data on MCL pathogenesis, novel molecular targets and alternative approaches to immunotherapy, and to discuss recent and ongoing clinical trials in MCL. The presentations are summarized in this article, which is intended to highlight areas of active investigation and identify important avenues for future research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/10428194.2013.771400DOI Listing
September 2013

Impact of high-risk classification by FISH: an eastern cooperative oncology group (ECOG) study E4A03.

Br J Haematol 2011 Nov 9;155(3):340-8. Epub 2011 Sep 9.

Dana-Farber Cancer Institute, Boston, MA, USA.

Lenalidomide with dexamethasone is a standard induction treatment regimen for newly diagnosed myeloma (although a Federal Drug Administration indication is still absent). In the context of the Phase 3 clinical trial E4A03 (lenalidomide plus dexamethasone in low or high doses), we queried whether a fluorescence in situ hybridization (FISH)-based genetic classification into high risk (HR) and standard risk (SR) multiple myeloma (MM) would remain clinically significant. Of 445 E4A03 patients, 126 had FISH analysis; 21 were classified HR with t(4;14), t(14;16), or 17p13 deletions. Median survival follow-up approached 3 years. Patients with FISH data tended to be younger and healthier compared to the rest of the study population and, consequently, had superior overall survival (OS) results. Within the FISH cohort, shorter OS in the HR versus SR group (P = 0·004) corresponded to a hazard ratio of 3·48 [95% confidence interval: (1·42-8·53)], an effect also observed in multivariate analysis. Two-year OS rates were 91% for SR MM and 76% for HR MM. There was also evidence of interaction between risk status and treatment (P = 0·026). HR patients were less likely to attain good partial response (SR 46% and HR 30%, Odds Ratio = 2·0 [0·7-5·6]), but overall response rates were not different. FISH-based risk classification retained prognostic significance in patients receiving lenalidomide-based induction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1365-2141.2011.08849.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3192237PMC
November 2011

Bortezomib, bendamustine, and rituximab in patients with relapsed or refractory follicular lymphoma: the phase II VERTICAL study.

J Clin Oncol 2011 Sep 1;29(25):3389-95. Epub 2011 Aug 1.

MD Anderson Cancer Center, 1515 Holcombe Blvd #429, Houston, TX 77030-4009, USA.

Purpose: The aims of this multicenter study were to evaluate the response rate, progression-free survival, and toxicity of the combination of bortezomib, bendamustine, and rituximab in patients with follicular lymphoma whose disease was relapsed or refractory to prior treatment.

Patients And Methods: Patients received five 35-day cycles of bortezomib, bendamustine, and rituximab: bortezomib administered intravenously (IV) at a dose of 1.6 mg/m(2) on days 1, 8, 15, and 22, cycles one to five; bendamustine 50, 70, or 90 mg/m(2) IV over a 60-minute infusion on days 1 and 2, cycles one to five; and rituximab 375 mg/m(2) on days 1, 8, 15, and 22 of cycle one and day 1 of subsequent cycles. Patients were assessed using the International Workshop Response Criteria, with the primary end point of 60% complete response rate.

Results: Seventy-three patients were enrolled. During the dose-escalation phase, the maximum-tolerated dose for bendamustine was not reached; the 90 mg/m(2) dose level was expanded for the efficacy assessment, and a total of 63 patients received bendamustine 90 mg/m(2). In these 63 patients, the overall response rate was 88% (including 53% complete response). Median duration of response was 11.7 months (95% CI, 9.2 to 13.3). Median progression-free survival was 14.9 months (95% CI, 11.1 to 23.7). Toxicities were manageable; myelosuppression was the main toxicity (25% and 14% of patients experienced grade 3 to 4 neutropenia and grade 3 to 4 thrombocytopenia, respectively). Transient grade 3 to 4 neuropathy occurred in 11% of patients.

Conclusion: The combination of bortezomib, bendamustine, and rituximab is highly active in patients with follicular lymphoma who have received previous treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.2010.32.1844DOI Listing
September 2011

Clinical roundtable monograph: Recent advances in the treatment of mantle cell lymphoma: a post-ASH 2009 discussion.

Clin Adv Hematol Oncol 2010 Apr;8(4 Suppl 8):1-14; quiz 2p following page 14

Lymphoma/Myeloma Service, Lymphoma Translational Research Laboratory, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.

Mantle cell lymphoma (MCL) is a rare subtype of non-Hodgkin lymphoma characterized by CD5 expression and a t(11;14) cytogenetic translocation that results in overexpression of the cyclin D1 gene. Currently, there is no standard of care for the treatment of MCL, and patient prognosis is poor. Traditional treatments for MCL rely on conventional chemotherapy agents, including cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). The addition of the immunotherapeutic agent rituximab to this regimen (CHOP-R) has helped to improve patient response to treatment. These treatments often provide good initial responses that are difficult to sustain. Therefore, a number of newer agents and combinations have been investigated to produce more durable benefit. Several of these advances were reported at the 51st American Society of Hematology (ASH) Annual Meeting and Exposition, held December 5-8, 2009 in New Orleans, Louisiana. In this clinical roundtable monograph, new strategies in the treatment of MCL are discussed. Some of the drug classes examined here are proteasome inhibitors, inhibitors of the protein mammalian target of rapamycin (mTOR), the unique alkylating agent bendamustine, and immunomodulatory agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
April 2010

Two patients with Hailey-Hailey disease, multiple primary melanomas, and other cancers.

Arch Dermatol 2011 Feb;147(2):211-5

Department of Dermatology, Eastern Virginia Medical School, Norfolk, VA 23507, USA.

Background: Hailey-Hailey Disease (HHD) is an autosomal dominant skin disorder that is characterized by erythematous and sometimes vesicular, weeping plaques of intertriginous regions. Squamous cell carcinoma and basal cell carcinoma arising in lesions of HHD have been described in the literature. To our knowledge, there are no reports of melanoma or noncutaneous malignant neoplasms associated with HHD.

Observations: We discuss the mechanisms of oncogenicity, including genetic, environmental, and iatrogenic factors, in 2 patients with HHD, multiple primary melanomas, and other cancers. Patient 1 had a mucoepidermoid carcinoma of the parotid gland. Patient 2 had a history of acute monoblastic leukemia and malignant peripheral nerve sheath tumor as well as radiologic evidence of an acoustic neurilemmoma.

Conclusions: The cause of the cancers in these 2 patients is likely multifactorial. We describe the patients to draw attention to the possible association between HHD and cancer. Additional research should be performed to determine whether patients with HHD have an increased incidence of cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/archdermatol.2010.445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010426PMC
February 2011

Mantle cell lymphoma: report of the 2010 Mantle Cell Lymphoma Consortium Workshop.

Leuk Lymphoma 2011 Jan 6;52(1):24-33. Epub 2010 Dec 6.

University of Virginia School of Medicine, Charlottesville, VA, USA.

Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma typically characterized by cyclin D1 overexpression as result of the t(11;14) translocation. MCL is biologically and clinically heterogeneous and frequently involves extranodal dissemination. Although MCL is incurable with current therapies, with the exception of allogeneic stem cell transplant, recent advances are improving long-term outcomes in MCL. Intensive research has continued to focus on elucidating biological mechanisms of MCL, identifying new molecular targets, and optimizing existing therapies. Most recently, researchers have begun focusing on new areas such as epigenetics and microRNAs and their potential applications to MCL therapy. Advances across a broad spectrum of MCL research were presented at a recent MCL Workshop. This report provides an overview of the scientific highlights from the meeting and a framework for future research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/10428194.2010.532893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357185PMC
January 2011

Exposure assessment among US workers employed in semiconductor wafer fabrication.

J Occup Environ Med 2010 Nov;52(11):1075-81

Vanderbilt University Department of Medicine and Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.

Objective: To classify 100,081 semiconductor workers employed during 1983-2002, and some as early as 1968, regarding potential for chemical exposures in cleanrooms during silicon wafer fabrication.

Methods: This study involved site visits to 10 cities with fabrication facilities, evaluation of 12,300 personal air samples for >60 chemicals, and examination of >37,000 departments and >8600 job codes to develop exposure groupings.

Results: Each worker was classified into one of five exposure groups on the basis of job-department combinations: 1) fabrication process equipment operators or process equipment service technicians working in cleanrooms (n = 28,583); 2) professionals such as supervisors working in fabrication areas (n = 8642); 3) professionals and office workers in nonfabrication areas (n = 53,512); 4) back-end workers (n = 5256); or 5) other nonfabrication workers (n = 4088). More than 98% of the personal air samples were below current occupational exposure limits.

Conclusions: Although specific chemical exposures at the level of the individual could not be quantified, semiconductor workers were classified into broad exposure groups for assessment of cancer mortality in an epidemiologic study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/JOM.0b013e3181f6ee1dDOI Listing
November 2010

Management of mantle cell lymphoma: key challenges and next steps.

Clin Lymphoma Myeloma Leuk 2010 Oct;10(5):336-46

University of Virginia School of Medicine, Charlottesville, VA, USA.

Mantle cell lymphoma (MCL) is regarded as an aggressive lymphoid malignancy that exhibits varied clinical behavior and prognoses, reflecting the biologic heterogeneity of the disease. In most cases, patients with MCL achieve a shorter median survival compared with more common B-cell lymphomas, such as follicular lymphoma, and are less likely to achieve a durable response with chemotherapy. Currently, there is no defined standard of care for patients with MCL. Rituximab-containing immunochemotherapy strategies are commonly used, but the addition of rituximab to conventional induction chemotherapy has produced suboptimal responses that are relatively short-lived and have not resulted in a survival advantage. Further intensification of the chemotherapy component, including autologous stem cell transplantation, has increased response and survival rates but has not proven to be curative while being associated with higher toxicity. Clearly, there is a need for developing novel agents and strategies that will improve clinical outcomes for patients with MCL. Targeted therapies and new cytotoxic agents are showing great promise and may have a role in maintenance and/or initial therapy. This summary highlights current challenges in the management of MCL, and outlines expert perspectives, key questions, and future directions. For the third consecutive year, a panel of global experts in MCL assembled to deliberate on topical issues in MCL including advances in pathobiology, strategies for risk-adapted therapy, front-line treatment options, consolidation approaches, and novel therapeutic strategies. The proceedings of this workshop, held December 3, 2009 in New Orleans, LA, are summarized here. It must be emphasized that this synopsis is not meant to serve as an exhaustive review of MCL biology and management, but is a distillation of the expert discussions, highlighting key questions and future directions identified.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3816/CLML.2010.n.066DOI Listing
October 2010

Recent advances in the treatment of mantle cell lymphoma: a post-ASH 2009 discussion.

Clin Adv Hematol Oncol 2010 Apr;8(4):A1-14; quiz A15

Lymphoma/Myeloma Service and Lymphoma Translational Research Laboratory, Roswell Park Cancer Institute, Buffalo, New York, USA.

Mantle cell lymphoma (MCL) is a rare subtype of non-Hodgkin lymphoma characterized by CD5 expression and a t(11;14) cytogenetic translocation that results in overexpression of the cyclin D1 gene. Currently, there is no standard of care for the treatment of MCL, and patient prognosis is poor. Traditional treatments for MCLrely on conventional chemotherapy agents, including cyclophosphamide, doxorubicin, vincristine, and prednisone(CHOP). The addition of the immunotherapeutic agent rituximab to this regimen (CHOP-R) has helped to improve patient response to treatment. These treatments often provide good initial responses that are difficult to sustain. Therefore, a number of newer agents and combinations have been investigated to produce more durable benefit. Several of these advances were reported at the 51st American Society of Hematology (ASH)Annual Meeting and Exposition, held December 5-8, 2009 in New Orleans, Louisiana. In this clinical roundtable monograph, new strategies in the treatment of MCL are discussed. Some of the drug classes examined here are proteasome inhibitors, inhibitors of the protein mammalian target of rapamycin (mTOR), the unique alkylating agent bendamustine, and immunomodulatory agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
April 2010

Mantle cell lymphoma: report of the 2009 Mantle Cell Lymphoma Consortium Workshop.

Leuk Lymphoma 2010 Mar;51(3):390-8

Hematology/Oncology Division and Cancer Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.

Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma characterized by cyclin D1 overexpression as a result of the t(11;14) chromosomal translocation, and by biological and clinical heterogeneity with frequent extranodal dissemination. There is no consensus or standard for initial therapy or for treatment of relapsed disease, and no proven curative therapy exists. Nonetheless, considerable progress in treatment response and survival has been realized over the past several years, and the disease remains an important focus of preclinical and clinical research. Advances in the biologic understanding of MCL, new molecular targets and therapeutic strategies, and the applications of biomarkers for risk stratification and molecular targeting were reviewed at a recent MCL Workshop. These are summarized herein, and are intended as both a status report on areas of active investigation and to serve as a template for future research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/10428190903503453DOI Listing
March 2010

Bendamustine is effective therapy in patients with rituximab-refractory, indolent B-cell non-Hodgkin lymphoma: results from a Multicenter Study.

Cancer 2010 Jan;116(1):106-14

Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA.

Background: Bendamustine hydrochloride is a novel alkylating agent. In this multicenter study, the authors evaluated the efficacy and toxicity of single-agent bendamustine in patients with rituximab-refractory, indolent B-cell lymphoma.

Methods: Eligible patients (N = 100, ages 31-84 years) received bendamustine at a dose of 120 mg/m(2) by intravenous infusion on Days 1 and 2 every 21 days for 6 to 8 cycles. Histologies included follicular (62%), small lymphocytic (21%), and marginal zone (16%) lymphomas. Patients had received a median of 2 previous regimens (range, 0-6 previous regimens), and 36%were refractory to their most recent chemotherapy regimen. Primary endpoints included overall response rate (ORR) and duration of response (DOR). Secondary endpoints were safety and progression-free survival (PFS).

Results: An ORR of 75% (a 14% complete response rate, a 3% unconfirmed complete response rate, and a 58% partial response rate) was observed. The median DOR was 9.2 months, and median PFS was 9.3 months. Six deaths were considered to be possibly treatment related. Grade 3 or 4 (determined using National Cancer Institute Common Toxicity Criteria [version 3.0.19]. reversible hematologic toxicities included neutropenia (61%), thrombocytopenia (25%), and anemia (10%). The most frequent nonhematologic adverse events (any grade) included nausea (77%), infection (69%), fatigue (64%), diarrhea (42%), vomiting (40%), pyrexia (36%), constipation (31%), and anorexia (24%).

Conclusions: Single-agent bendamustine produced a high rate of objective responses with acceptable toxicity in patients with recurrent, rituximab-refractory indolent B-cell lymphoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.24714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2916680PMC
January 2010

Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial.

Lancet Oncol 2010 Jan 21;11(1):29-37. Epub 2009 Oct 21.

Mayo Clinic, Rochester, Minnesota, USA.

Background: High-dose dexamethasone is a mainstay of therapy for multiple myeloma. We studied whether low-dose dexamethasone in combination with lenalidomide is non-inferior to and has lower toxicity than high-dose dexamethasone plus lenalidomide.

Methods: Patients with untreated symptomatic myeloma were randomly assigned in this open-label non-inferiority trial to lenalidomide 25 mg on days 1-21 plus dexamethasone 40 mg on days 1-4, 9-12, and 17-20 of a 28-day cycle (high dose), or lenalidomide given on the same schedule with dexamethasone 40 mg on days 1, 8, 15, and 22 of a 28-day cycle (low dose). After four cycles, patients could discontinue therapy to pursue stem-cell transplantation or continue treatment until disease progression. The primary endpoint was response rate after four cycles assessed with European Group for Blood and Bone Marrow Transplant criteria. The non-inferiority margin was an absolute difference of 15% in response rate. Analysis was by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00098475.

Findings: 445 patients were randomly assigned: 223 to high-dose and 222 to low-dose regimens. 169 (79%) of 214 patients receiving high-dose therapy and 142 (68%) of 205 patients on low-dose therapy had complete or partial response within four cycles (odds ratio 1.75, 80% CI 1.30-2.32; p=0.008). However, at the second interim analysis at 1 year, overall survival was 96% (95% CI 94-99) in the low-dose dexamethasone group compared with 87% (82-92) in the high-dose group (p=0.0002). As a result, the trial was stopped and patients on high-dose therapy were crossed over to low-dose therapy. 117 patients (52%) on the high-dose regimen had grade three or worse toxic effects in the first 4 months, compared with 76 (35%) of the 220 on the low-dose regimen for whom toxicity data were available (p=0.0001), 12 of 222 on high dose and one of 220 on low-dose dexamethasone died in the first 4 months (p=0.003). The three most common grade three or higher toxicities were deep-vein thrombosis, 57 (26%) of 223 versus 27 (12%) of 220 (p=0.0003); infections including pneumonia, 35 (16%) of 223 versus 20 (9%) of 220 (p=0.04), and fatigue 33 (15%) of 223 versus 20 (9%) of 220 (p=0.08), respectively.

Interpretation: Lenalidomide plus low-dose dexamethasone is associated with better short-term overall survival and with lower toxicity than lenalidomide plus high-dose dexamethasone in patients with newly diagnosed myeloma.

Funding: National Cancer Institute, Rockville, MD, USA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(09)70284-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3042271PMC
January 2010

Mantle cell lymphoma: biological insights and treatment advances.

Clin Lymphoma Myeloma 2009 Aug;9(4):267-77

Center for Lymphoma and Myeloma, Clinical Research, Division of Hematology/Oncology, New York Weill Cornell Medical Center, New York, NY, USA.

Mantle cell lymphoma (MCL) exhibits considerable molecular heterogeneity and complexity, and is regarded as one of the most challenging lymphomas to treat. With increased understanding of the pathobiology of MCL, it is proposed that MCL is the result of 3 major converging factors, namely, deregulated cell cycle pathways, defects in DNA damage responses, and dysregulation of cell survival pathways. In the present era of targeted therapies, these biologic insights have resulted in the identification of several novel rational targets for therapeutic intervention in MCL that are undergoing active clinical testing. To date, there is no standard of care in MCL. Several approaches including conventional anthracycline-based therapies and intensive high-dose strategies with and without stem cell transplantation have failed to produce durable remissions for most patients. Moreover, considering the heterogeneity of MCL, it is increasingly being recognized that risk-adapted therapy might be a relevant therapeutic approach in this disease. At the first and second Global Workshops on Mantle Cell Lymphoma, questions addressing advances in the pathobiology of MCL, optimization of existing therapies, assessment of current data with novel therapeutic strategies, and the identification of molecular or phenotypic risk factors for utilization in risk-adapted therapies were discussed and will be summarized herein.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3816/CLM.2009.n.055DOI Listing
August 2009