Publications by authors named "Anne W Beaven"

34 Publications

Belinostat in combination with standard cyclophosphamide, doxorubicin, vincristine and prednisone as first-line treatment for patients with newly diagnosed peripheral T-cell lymphoma.

Exp Hematol Oncol 2021 Feb 18;10(1):15. Epub 2021 Feb 18.

Medical Oncology, Yale Cancer Center, 333 Cedar St, TMP 3, PO Box 208028, New Haven, CT, 06510, USA.

Background: Belinostat is a histone deacetylase inhibitor approved for relapsed refractory peripheral T-cell lymphoma (PTCL). The primary objective of this study was to determine the maximum tolerated dose (MTD) of belinostat combined with CHOP (Bel-CHOP). Secondary objectives included safety/tolerability, overall response rate (ORR), and belinostat pharmacokinetics (PK).

Methods: Patients were ≥ 18 years with histologically confirmed, previously untreated PTCL. Patients received belinostat (1000 mg/m once daily) + standard CHOP for 6 cycles with varying schedules using a 3 + 3 design in Part A. Part B enrolled patients at MTD dose.

Results: Twenty-three patients were treated. One patient experienced DLT (Grade 3 non-hematologic toxicity) on Day 1-3 schedule, resulting in escalation to Day 1-5 schedule (n = 3). No DLTs were observed and Day 1-5 schedule with 1000 mg/m was declared as MTD. Twelve additional patients were enrolled in Part B using MTD. Median relative dose intensity was 98%. All patients experienced adverse events (AEs), including nausea (78%), fatigue (61%), and vomiting (57%). Serious AEs occurred in 43%, with febrile neutropenia (17%) and pyrexia (13%). Overall ORR was 86% with 71% reported CR at MTD. Belinostat PK parameters were similar to single-agent.

Conclusions: Bel-CHOP was well tolerated and MTD in CHOP combination was the same dose and schedule as single agent dosing.

Trial Registration: ClinicalTrials.gov Identifier: NCT01839097.
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http://dx.doi.org/10.1186/s40164-021-00203-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893947PMC
February 2021

Therapeutic Updates for Relapsed and Refractory Classical Hodgkin Lymphoma.

Cancers (Basel) 2020 Oct 8;12(10). Epub 2020 Oct 8.

Department of Internal Medicine, Division of Hematology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27514, USA.

Hodgkin lymphoma (HL) is a B-cell malignancy representing approximately one in ten lymphomas diagnosed in the United States annually. The majority of patients with HL can be cured with chemotherapy; however, 5-10% will have refractory disease to front-line therapy and 10-30% will relapse. For those with relapsed or refractory (r/r) HL, salvage chemotherapy followed by autologous stem cell transplant (ASCT) is standard of care, but half of patients will subsequently have disease progression. Relapse following ASCT has been associated with exceedingly poor prognosis with a median survival of only 26 months. However, in recent years, novel agents including brentuximab vedotin (BV) and programmed cell death protein 1 monoclonal antibodies (anti-PD-1, nivolumab and pembrolizumab) have been shown to extend overall survival in r/r HL. With the success of novel agents in relapsed disease after ASCT, these therapies are beginning to show clinically meaningful response rates prior to ASCT. Finally, a new investigation in r/r HL continues to produce promising treatment options even after ASCT including CD30 directed chimeric antigen receptor T-cell therapy. In this review, we will discuss the recent advances of BV and anti-PD-1 therapy prior to ASCT, novel approaches in r/r HL after ASCT, and review active clinical trials.
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http://dx.doi.org/10.3390/cancers12102887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601361PMC
October 2020

Consolidative or palliative whole brain radiation for secondary CNS diffuse large B-Cell lymphoma.

Leuk Lymphoma 2021 01 16;62(1):68-75. Epub 2020 Sep 16.

Department of Radiation Oncology, University of North Carolina Hospitals, Chapel Hill, NC, USA.

We analyzed 25 patients receiving whole brain radiation (WBRT) for secondary CNS lymphoma (SCNSL), grouped by consolidative intent (after complete/partial response,  = 13) vs. palliative intent (initial CNS treatment, primary refractory disease, or CNS progression,  = 12). Median WBRT dose for the consolidative and palliative cohorts were 24 Gy and 30 Gy, respectively. For 13 patients receiving consolidative WBRT, median OS was 24 months from WBRT and 2-year OS was 64%. Three patients had CNS relapse at 2, 9, and 24 months after consolidative WBRT. For 12 patients receiving palliative WBRT, median OS was 3 months from WBRT and two-year OS was 8%. All 10 patients with neurologic symptoms had documented improvement. In conclusion, consolidative WBRT after chemotherapy response led to reasonable long-term survival and may be an effective strategy for SCNSL, especially transplant-ineligible patients and/or isolated CNS recurrence. Palliative WBRT effectively improved neurologic symptoms, but survival was usually only months.
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http://dx.doi.org/10.1080/10428194.2020.1821014DOI Listing
January 2021

Identification of high-risk monomorphic post-transplant lymphoproliferative disorder following solid organ transplantation.

Leuk Lymphoma 2021 01 16;62(1):86-94. Epub 2020 Sep 16.

Division of Hematology and Oncology, Department of Internal Medicine, University of North Carolina, Chapel Hill, NC, USA.

Monomorphic post-transplant lymphoproliferative disorder (M-PTLD) occurring after solid organ transplant histologically resembles aggressive non-Hodgkin lymphomas, with diffuse large B-cell lymphoma being the most common. In a cohort of 40 patients with DLBCL-type M-PTLD, inferior progression free survival (PFS) was observed for Revised International Prognostic Index (R-IPI) >2 ( = 0.01) and high-risk pathologic features ( = 0.02), defined by double expressor lymphoma, rearrangement, or increased copy number of either or . Overall survival (OS) was inferior in R-IPI >2 ( = 0.002) and high-risk pathologic features ( = 0.003). Combining both R-IPI >2 and high-risk pathologic features resulted in well-delineated good, intermediate, and poor risk groups of DLBCL-type M-PTLD with respect to both PFS and OS ( < 0.001). Our results demonstrate a prognostic role for both the R-IPI score and presence of high-risk pathologic features in DLBCL-type M-PTLD.
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http://dx.doi.org/10.1080/10428194.2020.1821006DOI Listing
January 2021

Anti-CD30 CAR-T Cell Therapy in Relapsed and Refractory Hodgkin Lymphoma.

J Clin Oncol 2020 11 23;38(32):3794-3804. Epub 2020 Jul 23.

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC.

Purpose: Chimeric antigen receptor (CAR) T-cell therapy of B-cell malignancies has proved to be effective. We show how the same approach of CAR T cells specific for CD30 (CD30.CAR-Ts) can be used to treat Hodgkin lymphoma (HL).

Methods: We conducted 2 parallel phase I/II studies (ClinicalTrials.gov identifiers: NCT02690545 and NCT02917083) at 2 independent centers involving patients with relapsed or refractory HL and administered CD30.CAR-Ts after lymphodepletion with either bendamustine alone, bendamustine and fludarabine, or cyclophosphamide and fludarabine. The primary end point was safety.

Results: Forty-one patients received CD30.CAR-Ts. Treated patients had a median of 7 prior lines of therapy (range, 2-23), including brentuximab vedotin, checkpoint inhibitors, and autologous or allogeneic stem cell transplantation. The most common toxicities were grade 3 or higher hematologic adverse events. Cytokine release syndrome was observed in 10 patients, all of which were grade 1. No neurologic toxicity was observed. The overall response rate in the 32 patients with active disease who received fludarabine-based lymphodepletion was 72%, including 19 patients (59%) with complete response. With a median follow-up of 533 days, the 1-year progression-free survival and overall survival for all evaluable patients were 36% (95% CI, 21% to 51%) and 94% (95% CI, 79% to 99%), respectively. CAR-T cell expansion in vivo was cell dose dependent.

Conclusion: Heavily pretreated patients with relapsed or refractory HL who received fludarabine-based lymphodepletion followed by CD30.CAR-Ts had a high rate of durable responses with an excellent safety profile, highlighting the feasibility of extending CAR-T cell therapies beyond canonical B-cell malignancies.
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http://dx.doi.org/10.1200/JCO.20.01342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655020PMC
November 2020

Multicenter, Open-Label, Phase II Study of Bendamustine and Rituximab Followed by 90-Yttrium (Y) Ibritumomab Tiuxetan for Untreated Follicular Lymphoma (Fol-BRITe).

Clin Cancer Res 2019 10 26;25(20):6073-6079. Epub 2019 Jun 26.

Division of Hematology/Oncology UNC Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina.

Purpose: Bendamustine and rituximab (BR) has been established as a superior frontline therapy over R-CHOP in the treatment of follicular lymphoma (FL). Yttrium-90 Ibritumomab tiuxetan (YIT) is an effective consolidation strategy after chemotherapy induction. This prospective, single-arm, multicenter, phase II trial evaluated the response rate, progression-free survival (PFS), and tolerability of BR followed by consolidation with YIT in patients with untreated FL.

Patients And Methods: The study included grade 1 to 3a FL patients aged ≥18 years, chemotherapy-naïve, and requiring treatment for stage II-IV disease. Study treatment included an initial rituximab treatment, followed by four cycles of BR. Patients were eligible for consolidation with YIT, 6 to 12 weeks after BR, if they obtained at least a partial response after induction had adequate count recovery and bone marrow infiltration < 25%.

Results: Thirty-nine patients were treated. Eighty-two percent had an intermediate or high-risk Follicular Lymphoma International Prognostic Index score, and 6 of 39 (15%) were grade 3a. The response rate was 94.8%, and the complete response(CR)/CR unconfirmed (CRu) rate was 77% in the intention-to-treat analysis. The conversion rate from PR to CR/Cru after YIT was 81%. After median follow-up of 45 months, the PFS was 0.71 (95% confidence interval, 0.57-0.89).

Conclusions: This report demonstrates that four cycles of BR followed by consolidation with YIT achieve high response rates that are durable. In addition, consolidation with YIT results in a high conversion rate of PR to CR/CRu. A short course of BR followed by YIT is a safe and effective regimen for frontline treatment of FL.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3755DOI Listing
October 2019

Relapsed and Refractory Classical Hodgkin Lymphoma: Keeping Pace With Novel Agents and New Options for Salvage Therapy.

Am Soc Clin Oncol Educ Book 2019 Jan 17;39:477-486. Epub 2019 May 17.

3 Lineberger Comprehensive Cancer Center, University of North Carolina - Chapel Hill, Chapel Hill, NC.

The management of relapsed and refractory classic Hodgkin lymphoma (HL) has changed substantially since the approval of brentuximab vedotin (BV) and the checkpoint inhibitors nivolumab and pembrolizumab. For patients progressing after frontline treatment, second-line therapy followed by consolidation with autologous stem cell transplant (ASCT) remains the standard of care; however, although traditional combination chemotherapy regimens previously represented the only options for salvage, BV is now routinely incorporated into second-line therapy, and studies are evaluating checkpoint inhibitors in this setting as well. After ASCT, BV maintenance improves progression-free survival for patients at higher-risk, and studies are evaluating the role of post-ASCT maintenance with checkpoint inhibitors. Management of HL that progresses after ASCT remains a challenge. Although many patients achieve prolonged disease control with checkpoint inhibitors, the majority eventually progress and require additional therapy. Newer approaches, including CD30-directed chimeric antigen receptor-T-cell therapy, appear promising. Furthermore, allogeneic stem cell transplant remains an important consideration. Altogether, BV and checkpoint inhibitors have improved survival for patients with relapsed and refractory HL. However, the ideal place for these drugs in the treatment course of HL is still under investigation. Ongoing studies testing novel combinations and assessing for prognostic and predictive markers will ultimately define the optimal setting for these drugs in the treatment of relapsed and refractory HL.
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http://dx.doi.org/10.1200/EDBK_238799DOI Listing
January 2019

Phase 2 Study of Dose-Reduced Consolidation Radiation Therapy in Diffuse Large B-Cell Lymphoma.

Int J Radiat Oncol Biol Phys 2019 09 8;105(1):96-101. Epub 2019 Mar 8.

Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.

Purpose: To evaluate the feasibility of reducing the dose of consolidation radiation therapy (RT) in diffuse large B-cell lymphoma.

Methods And Materials: This phase 2 study enrolled patients with diffuse large B-cell lymphoma, not otherwise specified and primary mediastinal (thymic) large B-cell lymphoma in complete response on positron emission tomography-computed tomography imaging after ≥4 cycles of a rituximab/anthracycline-containing combination chemotherapy regimen. Consolidation RT used a dose of 19.5 to 20 Gy. The primary endpoint was 5-year freedom from local recurrence.

Results: Sixty-two patients were enrolled between 2010 and 2016. Stage distribution was as follows: I to II (n = 49, 79%) and III to IV (n = 13, 21%). Bulky disease (defined as ≥7.5 cm or ≥10 cm) was present in 23 (40%) and 16 (28%) patients, respectively. Chemotherapy was R-CHOP (then list the drugs) in 58 (94%) and R-EPOCH (then list the drugs) in 4 (6%) with a median of 6 cycles. With a median follow-up of 51 months, 7 patients developed disease progression (6 outside the RT field, 1 within the RT field). Freedom from local recurrence at 5 years was 98% (90% lower confidence bound, 88%). Progression-free and overall survival at 5 years were 83% and 90%, respectively.

Conclusions: With more effective systemic therapy (e.g., addition of rituximab) and more refined chemotherapy response assessment (e.g., positron emission tomography-computed tomography), the dose of RT in combined modality treatment programs may potentially be reduced to 20 Gy. This achieves excellent local control with the potential to decrease acute and long-term side effects.
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http://dx.doi.org/10.1016/j.ijrobp.2019.02.055DOI Listing
September 2019

Chemotherapy or Combined Modality Therapy for Early-stage Hodgkin Lymphoma.

Anticancer Res 2018 05;38(5):2875-2881

Department of Radiation Oncology, Duke University, Durham, NC, U.S.A.

Background/aim: Optimizing treatment of early-stage Hodgkin lymphoma (HL) requires balancing cure with potential acute and late toxicities from treatment. We reviewed our institutional experience with chemotherapy alone (ChT) versus combined modality therapy (CMT).

Materials And Methods: Patients with stage I-II classical HL in a complete response (CR) by functional imaging after chemotherapy were included. Progression-free survival (PFS) and overall survival (OS) were calculated and a multivariate analysis (MVA) was performed.

Results: A total of 136 patients with a CR to chemotherapy were identified. Consolidation radiation therapy (RT) was administered to 117 while 19 received no further therapy. PFS (5 years) was 97% with CMT and 84% with chemotherapy alone (p=0.02). Long-term (10 year) survival was no different (96 vs. 94%, p=0.8). On MVA, CMT improved PFS. Secondary malignancies were rare and no cardiac events were observed.

Conclusion: Consolidation RT results in superior PFS in early-stage Hodgkin lymphoma with minimal added toxicity.
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http://dx.doi.org/10.21873/anticanres.12533DOI Listing
May 2018

Consolidation Radiation Therapy for Patients With Advanced Hodgkin Lymphoma in Complete Metabolic Response According to PET-CT or Gallium Imaging.

Clin Lymphoma Myeloma Leuk 2018 02 30;18(2):145-151. Epub 2017 Dec 30.

Department of Radiation Oncology, Duke University Medical Center, Durham, NC. Electronic address:

Introduction: The purpose of this study was to evaluate the role of consolidation radiation therapy (RT) in advanced Hodgkin lymphoma (HL) in the setting of a complete metabolic response (CR) to chemotherapy (ChT).

Patients And Methods: Patients with stage III/IV HL treated with ChT alone or combined modality therapy (CMT) between 1992 and 2012 were reviewed. Only patients in a CR according to positron emission tomography-computed tomography (PET-CT) or gallium imaging were included. Clinical end points were estimated using the Kaplan-Meier method and a multivariate analysis using the Cox proportional hazards model was performed.

Results: Ninety patients were identified (46 CMT; 44 ChT alone). Median follow-up was 50 months. ChT (median 6 cycles) consisted primarily of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine; 74%) or an ABVD hybrid (10%). Post-ChT imaging consisted of PET-CT (71%) or gallium (29%). RT plans primarily included all initially involved sites of disease with a median dose of 21 Gy (range, 13-31 Gy). CMT was associated with improved 5-year progression-free survival (PFS; 88% vs. 65%, respectively; P < .001) and overall survival (97% vs. 78%, respectively; P = .002) compared with ChT alone. In multivariate analysis, age younger than 45 years (hazard ratio [HR], 0.23; 95% confidence interval [CI], 0.07-0.74; P = .013) and CMT (HR, 0.32; 95% CI, 0.11-0.96; P = .04) were independently associated with improved PFS. Secondary malignancies were comparable in both cohorts (5 with CMT, 4 with ChT), whereas cardiac events were slightly more frequent with CMT (5 vs. 2).

Conclusion: Low-dose RT, administered to all sites of original involvement, was associated with improved PFS, even in the setting of a metabolic CR after ABVD.
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http://dx.doi.org/10.1016/j.clml.2017.12.007DOI Listing
February 2018

The Genetic Basis of Hepatosplenic T-cell Lymphoma.

Cancer Discov 2017 04 25;7(4):369-379. Epub 2017 Jan 25.

Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.

Hepatosplenic T-cell lymphoma (HSTL) is a rare and lethal lymphoma; the genetic drivers of this disease are unknown. Through whole-exome sequencing of 68 HSTLs, we define recurrently mutated driver genes and copy-number alterations in the disease. Chromatin-modifying genes, including , and , were commonly mutated in HSTL, affecting 62% of cases. HSTLs manifest frequent mutations in (31%), (9%), and (9%), for which there currently exist potential targeted therapies. In addition, we noted less frequent events in , and was the most frequently silenced gene in HSTL. We experimentally demonstrated that acts as a tumor suppressor gene. In addition, we found that mutations in and activate critical signaling pathways important to cell survival in HSTL. Our work thus defines the genetic landscape of HSTL and implicates gene mutations linked to HSTL pathogenesis and potential treatment targets. We report the first systematic application of whole-exome sequencing to define the genetic basis of HSTL, a rare but lethal disease. Our work defines as a tumor suppressor gene in HSTL and implicates genes including and in the disease. .
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http://dx.doi.org/10.1158/2159-8290.CD-16-0330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5402251PMC
April 2017

Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study.

Lancet Oncol 2017 Feb 13;18(2):230-240. Epub 2017 Jan 13.

Victorian Comprehensive Cancer Centre, Parkville, Melbourne, VIC, Australia; Faculty of Medicine, University of Melbourne, Parkville, Melbourne, VIC, Australia; Department of Clinical Haematology and BMT, The Royal Melbourne Hospital, Parkville, Melbourne, VIC, Australia; Division of Cancer and Haematology, The Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, VIC, Australia.

Background: Selective BCL2 inhibition with venetoclax has substantial activity in patients with relapsed or refractory chronic lymphocytic leukaemia. Combination therapy with rituximab enhanced activity in preclinical models. The aim of this study was to assess the safety, pharmacokinetics, and activity of venetoclax in combination with rituximab.

Methods: Adult patients with relapsed or refractory chronic lymphocytic leukaemia (according to the 2008 Modified International Workshop on CLL guidelines) or small lymphocytic lymphoma were eligible for this phase 1b, dose-escalation trial. The primary outcomes were to assess the safety profile, to determine the maximum tolerated dose, and to establish the recommended phase 2 dose of venetoclax when given in combination with rituximab. Secondary outcomes were to assess the pharmacokinetic profile and analyse efficacy, including overall response, duration of response, and time to tumour progression. Minimal residual disease was a protocol-specified exploratory objective. Central review of the endpoints was not done. Venetoclax was dosed daily using a stepwise escalation to target doses (200-600 mg) and then monthly rituximab commenced (375 mg/m in month 1 and 500 mg/m in months 2-6). Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for adverse events version 4.0. Protocol-guided drug cessation was allowed for patients who achieved complete response (including complete response with incomplete marrow recovery) or negative bone marrow minimal residual disease. Analyses were done per protocol for all patients who commenced drug and included all patients who received at least one dose of venetoclax. Data were pooled across dose cohorts. Patients are still receiving therapy and follow-up is ongoing. The trial is registered at ClinicalTrials.gov, number NCT01682616.

Findings: Between Aug 6, 2012, and May 28, 2014, we enrolled 49 patients. Common grade 1-2 toxicities included upper respiratory tract infections (in 28 [57%] of 49 patients), diarrhoea (27 [55%]), and nausea (25 [51%]). Grade 3-4 adverse events occurred in 37 (76%) of 49 patients; most common were neutropenia (26 [53%]), thrombocytopenia (eight [16%]), anaemia (seven [14%]), febrile neutropenia (six [12%]), and leucopenia (six [12%]). The most common serious adverse events were pyrexia (six [12%]), febrile neutropenia (five [10%]), lower respiratory tract infection, and pneumonia (each three [6%]). Clinical tumour lysis syndrome occurred in two patients (resulting in one death) who initiated venetoclax at 50 mg. After enhancing tumour lysis syndrome prophylaxis measures and commencing venetoclax at 20 mg, clinical tumour lysis syndrome did not occur. The maximum tolerated dose was not identified; the recommended phase 2 dose of venetoclax in combination with rituximab was 400 mg. Overall, 42 (86%) of 49 patients achieved a response, including a complete response in 25 (51%) of 49 patients. 2 year estimates for progression-free survival and ongoing response were 82% (95% CI 66-91) and 89% (95% CI 72-96), respectively. Negative marrow minimal residual disease was attained in 20 (80%) of 25 complete responders and 28 (57%) of 49 patients overall. 13 responders ceased all therapy; among these all 11 minimal residual disease-negative responders remain progression-free off therapy. Two with minimal residual disease-positive complete response progressed after 24 months off therapy and re-attained response after re-initiation of venetoclax.

Interpretation: A substantial proportion of patients achieved an overall response with the combination of venetoclax and rituximab including 25 (51%) of 49 patients who achieved a complete response and 28 (57%) of 49 patients who achieved negative marrow minimal residual disease with acceptable safety. The depth and durability of responses observed with the combination offers an attractive potential treatment option for patients with relapsed or refractory chronic lymphocytic leukaemia and could allow some patients to maintain response after discontinuing therapy, a strategy that warrants further investigation in randomised studies.

Funding: AbbVie Inc and Genentech Inc.
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http://dx.doi.org/10.1016/S1470-2045(17)30012-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5316338PMC
February 2017

Quality of Life is Similar between Long-term Survivors of Indolent and Aggressive Non-Hodgkin Lymphoma.

Cancer Invest 2016 Jul 5;34(6):279-85. Epub 2016 Jul 5.

d Duke University School of Nursing , Durham , NC , USA.

Differences in quality of life (QOL) of long-term survivors of aggressive or indolent subtypes of non-Hodgkin lymphoma (NHL) have not been frequently evaluated. We assessed these differences by analyzing results of a large QOL survey of long-term NHL survivors. We hypothesized that the incurable nature of indolent NHL would relate to worse QOL in long-term survivors while the potentially cured long-term survivors of aggressive lymphoma would have better QOL. We found that QOL was similar between the two groups. Results suggest that patients with indolent NHL are coping well with their disease, yet experience some overall feelings of life threat.
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http://dx.doi.org/10.1080/07357907.2016.1194427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5025868PMC
July 2016

Ascertainment, classification, and impact of neoplasm detection during prolonged treatment with dual antiplatelet therapy with prasugrel vs. clopidogrel following acute coronary syndrome.

Eur Heart J 2016 Jan 5;37(4):412-22. Epub 2015 Dec 5.

Duke Clinical Research Institute, 2400 Pratt Street, Rm 7035, Durham, NC 27705, USA Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA.

Aims: Studies have suggested increased cancer incidence associated with long-term dual antiplatelet therapy (DAPT) for acute coronary syndrome (ACS). We evaluated cancer incidence and treatment-related differences in an analysis of DAPT for ACS.

Methods And Results: The Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes trial enrolled 9326 participants with ACS, who received aspirin plus clopidogrel or prasugrel. Median treatment exposure was 15 months. Cancer history and screening procedures were collected. Suspected non-benign neoplasm events were reported and adjudicated. The primary outcome was detection of new, non-benign neoplasm. Factors associated with neoplasm events, the relationship of these events to cardiovascular and bleeding endpoints, and treatment-related differences in neoplasm detection were studied. Among 9240 participants who received ≥1 dose of study drug, 1.8% had a confirmed neoplasm event. The efficacy composite of cardiovascular death, myocardial infarction, or stroke occurred more frequently among those with a neoplasm event vs. those without (18.2 vs. 13.5%) as did Global Use of Strategies to Open Occluded Coronary Arteries severe/moderate bleeding (11.2 vs. 1.5%). Screening rates were substantially higher in North America and Western Europe/Scandinavia vs. other regions. Factors most strongly associated with detection of neoplasm events were older age, region, male sex, and current/recent smoking. Among the pre-specified population without a history of neoplasm or previous curative treatment for neoplasm (n = 9105), the incidence of neoplasm events was similar with prasugrel vs. clopidogrel (1.8 vs. 1.7%; HR = 1.04; 95% CI 0.77-1.42; P = 0.79).

Conclusions: Neoplasm events were infrequent during long-term DAPT after ACS, were associated with differential cancer-screening practices across regions, and the frequency of neoplasm detection was similar with prasugrel vs. clopidogrel.

Trial Registration: ClinicalTrials.gov identifier: NCT00699998.
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http://dx.doi.org/10.1093/eurheartj/ehv611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4720838PMC
January 2016

Peripheral T-cell lymphoma, NOS, and anaplastic large cell lymphoma.

Hematology Am Soc Hematol Educ Program 2015 ;2015:550-8

Duke University Medical Center, Durham, NC.

Peripheral T-cell lymphomas (PTCL), with the exception of anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL), have a very poor prognosis. Although current first line chemotherapy continues to be a CHOP-like (cyclophosphamide, doxorubicin, vincristine, prednisone) regimen there is now data suggesting that the addition of etoposide in younger patients improves outcomes. Even for those patients who do have a response to therapy, the risk of relapse remains quite high. Although autologous transplant in first remission is often used, its role as consolidation therapy in first remission remains unclear and may preferentially benefit low-risk patients. In the relapsed setting, major advances have occurred with Food and Drug Administration (FDA) approval of 4 new agents (pralatrexate, romidepsin, belinostat, brentuximab vedotin) for relapsed/refractory PTCL since 2009. These 4 drugs represent the first agents ever approved specifically for this indication. Unfortunately, with the exception of ALCL for which brentuximab vedotin will likely substantially change our approach to treatment, there are still many patients for whom available drugs will not be effective, and it is for these patients that further advances are urgently needed.
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http://dx.doi.org/10.1182/asheducation-2015.1.550DOI Listing
October 2016

A phase II study of cyclophosphamide, etoposide, vincristine and prednisone (CEOP) Alternating with Pralatrexate (P) as front line therapy for patients with peripheral T-cell lymphoma (PTCL): final results from the T- cell consortium trial.

Br J Haematol 2016 Feb 2;172(4):535-44. Epub 2015 Dec 2.

Division of Hematology/Oncology, University of Nebraska Medical Center, Omaha, NE, USA.

Peripheral T-cell lymphomas (PTCL) have suboptimal outcomes using conventional CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy. The anti-folate pralatrexate, the first drug approved for patients with relapsed/refractory PTCL, provided a rationale to incorporate it into the front-line setting. This phase 2 study evaluated a novel front-line combination whereby cyclophosphamide, etoposide, vincristine and prednisone (CEOP) alternated with pralatrexate (CEOP-P) in PTCL. Patients achieving a complete or partial remission (CR/PR) were eligible for consolidative stem cell transplantation (SCT) after 4 cycles. Thirty-three stage II-IV PTCL patients were treated: 21 PTCL-not otherwise specified (64%), 8 angioimmunoblastic T cell lymphoma (24%) and 4 anaplastic large cell lymphoma (12%). The majority (61%) had stage IV disease and 46% were International Prognostic Index high/intermediate or high risk. Grade 3-4 toxicities included anaemia (27%), thrombocytopenia (12%), febrile neutropenia (18%), mucositis (18%), sepsis (15%), increased creatinine (12%) and liver transaminases (12%). Seventeen patients (52%) achieved a CR. The 2-year progression-free survival and overall survival, were 39% (95% confidence interval 21-57) and 60% (95% confidence interval 39-76), respectively. Fifteen patients (45%) (12 CR) received SCT and all remained in CR at a median follow-up of 21·5 months. CEOP-P did not improve outcomes compared to historical data using CHOP. Defining optimal front line therapy in PTCL continues to be a challenge and an unmet need.
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http://dx.doi.org/10.1111/bjh.13855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642048PMC
February 2016

Low-dose consolidation radiation therapy for early stage unfavorable Hodgkin lymphoma.

Int J Radiat Oncol Biol Phys 2015 May;92(1):54-9

Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.

Purpose: The German Hodgkin Study Group (GHSG) trial HD11 established 4 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and 30 Gy of radiation therapy (RT) as a standard for early stage (I, II), unfavorable Hodgkin lymphoma (HL). Additional cycles of ABVD may allow for a reduction in RT dose and improved toxicity profile.

Methods And Materials: Patients treated with combined modality therapy at the Duke Cancer Institute for early stage, unfavorable HL by GHSG criteria from 1994 to 2012 were included. Patients who did not undergo post-chemotherapy functional imaging (positron emission tomography or gallium imaging) or who failed to achieve a complete response were excluded. Clinical outcomes were estimated using the Kaplan-Meier method. Late effects were also evaluated.

Results: A total of 90 patients met inclusion criteria for analysis. Median follow-up was 5 years. Chemotherapy consisted primarily of ABVD (88%) with a median number of 6 cycles. The median dose of consolidation RT was 23.4 Gy. Four patients had relapses, 2 of which were in-field. Ten-year progression-free survival (PFS) and overall survival (OS) were 93% (95% confidence interval [CI]: 0.82-0.97) and 98% (95% CI: 0.92-0.99), respectively. For the subset of patients (n=46) who received 5 to 6 cycles of chemotherapy and ≤ 24 Gy, the 10-year PFS and OS values were 88% (95% CI: 70%-96%) and 98% (95% CI: 85% - 99%), respectively. The most common late effect was hypothyroidism (20%) with no cardiac complications. Seven secondary malignancies were diagnosed, with only 1 arising within the RT field.

Conclusions: Lower doses of RT may be sufficient when combined with more than 4 cycles of ABVD for early stage, unfavorable HL and may result in a more favorable toxicity profile than 4 cycles of ABVD and 30 Gy of RT.
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http://dx.doi.org/10.1016/j.ijrobp.2015.02.003DOI Listing
May 2015

Improving outcomes in advanced DLBCL: systemic approaches and radiotherapy.

Oncology (Williston Park) 2014 Dec;28(12):1074-81, 1084

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. Approximately half of patients will present with advanced (stage III/IV) disease. The cornerstone of treatment is a combination of chemotherapy and immunotherapy, most commonly R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). Efforts to improve upon R-CHOP-including more chemotherapy cycles, dose-dense chemotherapy, alternative drug combinations, high-dose chemotherapy with autologous stem cell transplant, and maintenance rituximab-have generally proved unsuccessful. There is a growing body of retrospective and prospective data, however, suggesting a benefit for consolidation radiation therapy (RT) in select patients with advanced DLBCL. Consolidation RT has been shown to improve outcomes for patients with advanced DLBCL generally, and in specific instances including initially bulky disease, bone involvement, or in the setting of a partial response to systemic therapy. In these settings consolidation RT is highly efficacious at achieving local disease control and improving overall outcomes.
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December 2014

Addition of lenalidomide to rituximab, ifosfamide, carboplatin, etoposide (RICER) in first-relapse/primary refractory diffuse large B-cell lymphoma.

Br J Haematol 2014 Jul 25;166(1):77-83. Epub 2014 Mar 25.

John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ, USA.

Relapsed/refractory diffuse large B-cell lymphoma (DLBCL) is associated with a poor prognosis. Outcomes are particularly poor following immunochemotherapy failure or relapse within 12 months of induction. We conducted a Phase I/II trial of lenalidomide plus RICE (rituximab, ifosfamide, carboplatin, and etoposide) (RICER) as a salvage regimen for first-relapse or primary refractory DLBCL. Dose-escalated lenalidomide was combined with RICE every 14 d. After three cycles of RICER, patients with chemosensitive disease underwent stem cell collection and consolidation with BEAM [BCNU (carmustine), etoposide, cytarabine, melphalan] followed by autologous stem cell transplantation (autoSCT). Patients who recovered from autoSCT toxicities within 90 d initiated maintenance treatment with lenalidomide 25 mg daily for 21 d every 28 d for 12 months. No dose-limiting or unexpected toxicities occurred with lenalidomide 25 mg plus RICE. Grade 3/4 haematological toxicities resolved appropriately, and planned dose density and dose intensity of RICER were preserved. No lenalidomide or RICE dose reductions were required in any of the three cycles. After two cycles of RICER, nine of 15 patients (60%) achieved a complete response, and two achieved a partial response (13%). Combining lenalidomide with RICE is feasible, and results in promising response rates (particularly complete response rates) in high-risk DLBCL patients.
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http://dx.doi.org/10.1111/bjh.12846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4283736PMC
July 2014

Ofatumumab-based chemoimmunotherapy is effective and well tolerated in patients with previously untreated chronic lymphocytic leukemia (CLL).

Cancer 2013 Nov 6;119(21):3788-96. Epub 2013 Aug 6.

Mayo Clinic, Rochester, Minnesota.

Background: Although rituximab-based chemoimmunotherapy (CIT) has substantially improved clinical outcomes in chronic lymphocytic leukemia (CLL), only 40% to 50% of patients achieve a complete remission (CR). There remains interest in identifying new approaches to improve the effectiveness of CIT. Ofatumumab is a fully human anti-CD20 monoclonal antibody with greater apparent single-agent activity than rituximab in CLL patients.

Methods: Previously untreated CLL patients in need of therapy received 6 cycles of CIT induction with pentostatin, cyclophosphamide, and ofatumumab (PCO) followed by response assessment.

Results: Of the 48 patients enrolled, 77% completed PCO induction. Adverse events during induction included grade 3+ hematologic toxicity (27%) and grade 3+ nonhematologic toxicity (23%). Median CD4 count after induction and 6 months later were 186 × 10(6)/L and 272 × 10(6) /L. The overall response rate was 96% (46 of 48 patients), and the CR rate was 46% (22 of 48 patients). Among the 38 patients who underwent minimal residual disease evaluation, 7 (18%) were negative for minimal residual disease. After median follow-up of 24 months, 10 (21%) patients have progressed and 8 (17%) have required retreatment. The efficacy and toxicity of ofatumumab-based CIT compare favorably to our historical trials of rituximab-based CIT using an identical chemotherapy backbone (n = 64). Time to retreatment also appeared longer for ofatumumab-based CIT (free of retreatment at 24 months: 86% [95% confidence interval = 75-99] versus 68% [95% confidence interval = 56-81] for rituximab-based CIT).

Conclusions: Ofatumumab-based CIT is well tolerated in patients with previously untreated CLL. The efficacy of ofatumumab-based CIT compares favorably to historical trials of rituximab-based CIT, suggesting randomized trials comparing ofatumumab-based CIT and rituximab-based CIT should be considered.
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http://dx.doi.org/10.1002/cncr.28292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3894149PMC
November 2013

Combined-modality therapy for early-stage Hodgkin lymphoma: maintaining high cure rates while minimizing risks.

Oncology (Williston Park) 2012 Dec;26(12):1182-9, 1193

Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, USA.

Multiple randomized studies have demonstrated that chemotherapy, most commonly ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, dacarbazine), followed by consolidation radiation therapy is the most effective treatment program for early-stage Hodgkin lymphoma. With a combined-modality approach, the great majority of patients are cured of their disease. It is also apparent that both chemotherapy and radiation therapy can increase the risk of complications in the decades following treatment, with second cancers and cardiac disease being the most common. Most studies,evaluating such risks primarily include patients treated in decades past with what are now considered outdated approaches, including high-dose, wide-field radiation therapy. The treatment of Hodgkin lymphoma has evolved significantly, particularly in regard to radiation therapy. In combination with chemotherapy, much lower doses and smaller fields are employed, with success equivalent to that achieved using older methods. Many studies have shown a significant decline in both the rates of second cancers and the risk of cardiac disease with low-dose radiation confined to the original extent of disease. In favorable patients, as few as 2 cycles of ABVD have been shown to be effective. The current combined-modality approach seeks to maintain high cure rates but minimize risks by optimizing both chemotherapy and radiation therapy
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December 2012

Radiotherapy dose-response analysis for diffuse large B-cell lymphoma with a complete response to chemotherapy.

Radiat Oncol 2012 Jun 21;7:100. Epub 2012 Jun 21.

Department of Radiation Oncology, University Hospitals Seidman Cancer Center and Case Western Reserve University, 11100 Euclid Avenue, Cleveland, OH 44106, USA.

Objective: To examine the efficacy of different radiation doses after achievement of a complete response to chemotherapy in diffuse large B-cell lymphoma (DLBCL).

Methods: Patients with stage I-IV DLBCL treated from 1995-2009 at Duke Cancer Institute who achieved a complete response to chemotherapy were reviewed. In-field control, event-free survival, and overall survival were calculated using the Kaplan-Meier method. Dose response was evaluated by grouping treated sites by delivered radiation dose.

Results: 105 patients were treated with RT to 214 disease sites. Chemotherapy (median 6 cycles) was R-CHOP (65%), CHOP (26%), R-CNOP (2%), or other (7%). Post-chemotherapy imaging was PET/CT (88%), gallium with CT (1%), or CT only (11%). The median RT dose was 30 Gy (range, 12-40 Gy). The median radiation dose was higher for patients with stage I-II disease compared with patients with stage III-IV disease (30 versus 24.5 Gy, p < 0.001). Five-year in-field control, event-free survival, and overall survival for all patients was 94% (95% CI: 89-99%), 84% (95% CI: 77-92%), and 91% (95% CI: 85-97%), respectively. Six patients developed an in-field recurrence at 10 sites, without a clear dose response. In-field failure was higher at sites ≥ 10 cm (14% versus 4%, p = 0.06).

Conclusion: In-field control was excellent with a combined modality approach when a complete response was achieved after chemotherapy without a clear radiation dose response.
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http://dx.doi.org/10.1186/1748-717X-7-100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3464871PMC
June 2012

Update on treatment of follicular non-Hodgkin's lymphoma: focus on potential of bortezomib.

Patient Prefer Adherence 2012 23;6:239-51. Epub 2012 Mar 23.

Duke University Medical Center, Durham, NC, USA.

Follicular lymphoma is predominantly managed as a chronic disease, with intermittent chemo/immunotherapy reserved for symptomatic progression. It is considered incurable with conventional treatments, and current therapeutic options are associated with significant toxicities that are especially limiting in older patients. Bortezomib (PS-341; Velcade(®)), a first-in-class drug targeting the proteolytic core subunit of the 26S proteasome, has emerged as a therapeutic alternative in follicular lymphoma, with promising preclinical data and efficacy in patients with other hematological malignancies. Several clinical trials were conducted with bortezomib for the treatment of non-Hodgkin's lymphoma. As a single agent, overall responses in follicular lymphoma varied greatly (16%-41%), with weekly bortezomib showing less neurotoxicity than twice-weekly regimens, but with concern about decreased responses. Combination with rituximab was projected to improve the efficacy of bortezomib, but this resulted in increased toxicities and questionable added benefit. Although the largest Phase III study in follicular lymphoma of bortezomib plus rituximab versus rituximab alone demonstrated a significant progression-free survival difference, the absolute difference was small (12.8 months versus 11 months). Combining bortezomib with established regimens, such as rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP), or rituximab-bendamustine also did not show definite benefit, and many of these studies did not meet their primary endpoint when bortezomib failed to improve responses or survival to the degree anticipated. In a disease where the goal of treatment is palliative and affected patients often have other medical and treatment-related comorbidities, decisions regarding therapies which carry risks of additional toxicities must be considered carefully. Conclusive evidence of the ability of bortezomib to improve patient outcomes meaningfully and to justify the added toxicity is lacking, but limitations in cross-trial comparisons are recognized. Large randomized trials and investigations of combinations with promising novel targeted agents will aid in determining the role of bortezomib, if any, in the future treatment of follicular lymphoma.
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http://dx.doi.org/10.2147/PPA.S23241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3333814PMC
October 2012

Impact of consolidation radiation therapy in stage III-IV diffuse large B-cell lymphoma with negative post-chemotherapy radiologic imaging.

Int J Radiat Oncol Biol Phys 2012 Nov 13;84(3):762-7. Epub 2012 Mar 13.

Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.

Purpose: While consolidation radiation therapy (i.e., RT administered after chemotherapy) is routine treatment for patients with early-stage diffuse large B-cell lymphoma (DLBCL), the role of consolidation RT in stage III-IV DLBCL is controversial.

Methods And Materials: Cases of patients with stage III-IV DLBCL treated from 1991 to 2009 at Duke University, who achieved a complete response to chemotherapy were reviewed. Clinical outcomes were calculated using the Kaplan-Meier method and were compared between patients who did and did not receive RT, using the log-rank test. A multivariate analysis was performed using Cox proportional hazards model.

Results: Seventy-nine patients were identified. Chemotherapy (median, 6 cycles) consisted of anti-CD20 antibody rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; 65%); cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP; 22%); or other (13%). Post-chemotherapy imaging consisted of positron emission tomography (PET)/computed tomography (CT) (73%); gallium with CT (14%); or CT only (13%). Consolidation RT (median, 25 Gy) was given to involved sites of disease in 38 (48%) patients. Receipt of consolidation RT was associated with improved in-field control (92% vs. 69%, respectively, p = 0.028) and event-free survival (85% vs. 65%, respectively, p = 0.014) but no difference in overall survival (85% vs. 78%, respectively, p = 0.15) when compared to patients who did not receive consolidation RT. On multivariate analysis, no RT was predictive of increased risk of in-field failure (hazard ratio [HR], 8.01, p = 0.014) and worse event-free survival (HR, 4.3, p = 0.014).

Conclusions: Patients with stage III-IV DLBCL who achieve negative post-chemotherapy imaging have improved in-field control and event-free survival with low-dose consolidation RT.
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http://dx.doi.org/10.1016/j.ijrobp.2011.12.067DOI Listing
November 2012

A phase I study evaluating ibritumomab tiuxetan (Zevalin®) in combination with bortezomib (Velcade®) in relapsed/refractory mantle cell and low grade B-cell non-Hodgkin lymphoma.

Leuk Lymphoma 2012 Feb 19;53(2):254-8. Epub 2011 Sep 19.

Duke University Medical Center, Durham, NC 27710, USA.

Proteasome inhibitors may inhibit DNA repair of radiation-induced strand breaks and adducts thereby making the combination of radioimmunotherapy and bortezomib a promising approach. Preclinical models demonstrate additive/synergistic effects from combining DNA damaging agents with proteasome inhibitors. This phase I trial combines ibritumomab tiuxetan with bortezomib. Twelve patients with relapsed/refractory mantle cell and low grade B-cell non-Hodgkin lymphoma were enrolled. Patients with prior radioimmunotherapy were prohibited. The maximum tolerated dose (MTD) was not reached. No dose limiting toxicities (DLTs) occurred in cohort 1 or 2. One of six patients on cohort 3 had DLTs of asthenia, dizziness and neuropathy. Grade 3/4 thrombocytopenia occurred in two patients (16%) and grade 3/4 neutropenia in three patients (25%). Five subjects (41.7%) had complete responses (CRs) and one patient had a partial response (8.3%) for an overall response rate (ORR) of 50%. The combination of standard dose ibritumomab tiuxetan and bortezomib at 1.5 mg/m(2) is well tolerated with a promising response rate.
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http://dx.doi.org/10.3109/10428194.2011.608445DOI Listing
February 2012

Infusional mitoxantrone plus bolus melphalan as a stem cell transplant conditioning regimen for multiple myeloma.

Cancer Invest 2011 Mar;29(3):214-9

Division of Oncology, Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.

This study combined infusional mitoxantrone with bolus melphalan as a transplant preparative regimen for multiple myeloma. Mitoxantrone was infused over 6 hr on days 6 and 5. Melphalan was given as a 15 min bolus on day 1 followed by autologous transplant on day 0. Thirty-five patients were enrolled; 57% of enrollees had received ≥ 2 prior treatments. The median overall survival was 5 years and 8 months, with 37% of the subjects alive >7 years posttransplantation. Myelosuppression and mucositis were the most frequent adverse events. This regimen is well tolerated and the survival compares well to other transplant trials.
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http://dx.doi.org/10.3109/07357907.2010.550663DOI Listing
March 2011

Radiation therapy in the management of diffuse large B-cell lymphoma: still relevant?

Oncology (Williston Park) 2010 Nov;24(13):1204-12

Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma in the United States. Historically, radiation therapy (RT) was the primary treatment for patients with localized disease. Several randomized trials have demonstrated that the addition of systemic therapy improves outcomes. Additional randomized trials have shown that the combination of RT and systemic therapy is superior to systemic therapy alone. The role of RT in advanced-stage DLBCL has not been firmly established, but some prospective phase III trials, as well as retrospective studies, suggest a benefit for advanced disease also. For patients with relapsed or primary refractory disease, autologous stem cell transplantation is the treatment of choice. Here too, consolidation RT appears to improve outcomes compared with autologous stem cell transplant alone. Finally, for patients with advanced DLBCL who are no longer responsive to systemic therapy, RT may provide rapid and durable palliation of local lymphoma-related symptoms.
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November 2010

Sequential high-dose ifosfamide, carboplatin and etoposide with rituximab for relapsed Hodgkin and large B-cell non-Hodgkin lymphoma: increased toxicity without improvement in progression-free survival.

Leuk Lymphoma 2009 May;50(5):741-8

Division of Hematology/Oncology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.

Non-cross resistant drugs given at high-dose intensity may maximise tumor cell kill leading to improved patient outcomes. We investigated the feasibility and efficacy of administering ifosfamide, carboplatin and etoposide +/- rituximab as sequential high-dose single agents. Twenty-two patients with relapsed/refractory Hodgkin lymphoma (n = 9) or non-Hodgkin (n = 13) lymphoma (NHL) were included. Therapy included: cycle 1 ifosfamide (15 g/m(2)), cycle 2 etoposide (900 mg/m(2)) and cycle 3 carboplatin (area under the curve 15). Patients with NHL received rituximab (375 mg/m(2)) with cycles 1 and 2. Blood stem cell collection was performed after etoposide. Primary endpoints were overall response (complete response (CR) + PR) and ability to mobilise stem cells after etoposide. Secondary endpoints were to assess the toxicity of the regimen and to evaluate the ability of patients to proceed to stem cell transplant (SCT). Overall response rate was 54% with CR in 4/22 (18%) subjects and PR in 8/22 (36%). Median progression-free survival was 15 months and overall survival has not been reached at 40 months. Thirteen participants proceeded to SCT. Grade 3/4 thrombocytopenia and neutropenia occurred in 58% of cycles and 91% of subjects respectively. Forty-five percent of patients required hospitalisation for toxicity and two patients died from complications of therapy. Sequential dose intense ifosfamide, etoposide, carboplatin +/- rituximab was more toxic and no more effective than the same drugs given in a conventional fashion.
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http://dx.doi.org/10.1080/10428190902853136DOI Listing
May 2009