The OSUCCC – James has a strong experimental therapeutics and clinical research focus on B- and T-cell lymphomas, including rare lymphomas such as adult T-Cell lymphoma. A particularly exciting and promising area of research investigates vaccine and immunotherapies for Epstein-Barr-virus-related post-transplant lymphoma.

The Clinical Lymphoma Research Program also benefits from National Cancer Institute (NCI) funding to the OSUCCC – James that supports the cost of conducting phase I and phase II clinical trials, and that facilitates the movement of promising phase II studies into phase III national trials.

Research Strengths

  • Follicular Lymphoma
  • Diffuse large B-cell lymphoma 
  • Mantle Cell Lymphoma
  • Hodgkin’s lymphoma 
  • Burkitt’s lymphoma
  • T-cell and NK-cell lymphomas 
  • Cutaneous T-cell lymphoma
  • Adult T-cell lymphoma
  • AIDS-related lymphoma
  • Experimental therapeutics for (epigenetic, antibodies, vaccine/immunotherapy)
  • Epstein-Barr virus (EBV)-positive lymphomas and mechanisms of EBV-driven B-cell transformation
  • New treatment methods for immune-deficient patients (HIV/AIDS and post-transplantation) who develop cancer
  • Experimental therapeutics for Non-Hodgkin, Hodgkin and cutaneous T-cell lymphomas
  • Non-Hodgkin and Hodgkin’s lymphomas
  • Mycosis fungoides and Sezary syndrome
  • Blood and Marrow Transplantation
  • Graft-vs-host disease

Affiliated and Collaborating Programs 

  • Alliance for Clinical Trials in Oncology
  • NCI, CTEP cancer therapy evaluation program
  • Cancer Trials Support Unit (CTSU) and trials through the Southwest Oncology Group (SWOG) and the Eastern Cooperative Oncology Group (ECOG)
  • Lymphoma Research Consortium
  • Leukemia and Lymphoma Society
  • NCI AIDS Malignancy Consortium 
  • Blood and Bone Marrow Transplantation Clinical Trials Network (BMT CTN)
  • College of Veterinary Medicine Clinical Trials Office
  • NCCN, national comprehensive cancer network

Lymphoma Clinical Trials


A few interesting examples of clinical lymphoma trials available at the OSUCCC – James.

OSU-13027: A Phase I Study of BKM120 and Rituximab in Patients with Relapsed or Refractory Indolent B-Cell Lymphoma

PI: Kami Maddocks, MD
NCT ID: NCT02049541

Key Objectives:

  • Maximum tolerated dose
  • Incidence of grade 3 or greater adverse events
  • Overall response rate
  • Change in correlative markers in blood, bone marrow and tumor tissue

OSU-13190: A Study of the Bruton's Tyrosine Kinase Inhibitor, PCI-32765 (Ibrutinib), in Combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Patients with Newly Diagnosed Non-Germinal Center B-Cell Subtype of Diffuse Large B-Cell Lymphoma

PI: Beth Christian,
NCT ID: NCT01855750

Key Objectives:

  • Event-free survival, 
  • Progression-free and overall survival
  • Complete response rate

OSU-13016: A Randomized, Open-label, Phase 3 Trial of A+AVD Versus ABVD as Frontline Therapy in Patients With Advanced Classical Hodgkin Lymphoma

PI: Kristie Blum, MD
NCT ID: NCT01712490

This trial compares the modified progression-free survival (mPFS) obtained with brentuximab vedotin (ADCETRIS®) plus AVD (doxorubicin [Adriamycin], vinblastine, and dacarbazine; abbreviated A+AVD) versus that obtained with ABVD (doxorubicin [Adriamycin],bleomycin, vinblastine, and dacarbazine) for the frontline treatment of advanced classical Hodgkin lymphoma.

Key Objectives:

  • Modified progression free survival rate
  • Overall survival rate

ACP-196, a Btk Inhibitor, for Treatment of Novo Activated B-cell (ABC) Subtype of Diffuse Large B-Cell Lymphoma

PI: Kami Maddocks, MD
NCT ID: NCT02112526

Objective:

To characterize the safety profile of ACP-196 in subjects with relapsed or refractory de Novo Activated B-cell (ABC) Subtype of Diffuse Large B-Cell Lymphoma (DLBCL).

Lymphoma Research Grants


Novel Biomarkers in Cutaneous T Cell Lymphoma (5R21CA164911)

PI: Henry Keung Wong, MD, PhD

Mycosis fungoides and Sezary syndrome are two related types of cutaneous T cell lymphoma that are often difficult to distinguish from benign chronic skin disorders due to the lack of sensitive and specific markers.

Objectives:

  • Determine the prevalence of several potential genetic blood biomarkers of mycosis fungoides and of Sezary syndrome. 
  • Determine whether these genes are differentially expressed in advanced stage versus early stage mycosis fungoides. 
  • Identify a progression signature by detecting longitudinal changes in the gene signature in individual patients as they progress from early to advanced stage. 

If successful, this work could help to:
  • Stratify patients with mycosis fungoides/Sezary syndrome
  • Determine the biological function of these genes in malignant T-cells, 
  • Develop new methods to identify and purify malignant T-cells for study.

Computer-Based Assessment of the Tumor Microenvironment in Follicular Lymphoma (2R01CA134451)

PI: Metin Nafi Gurcan

This research aims to develop a pathology-based prognostic index for follicular lymphoma and ultimately to better treatment options to follicular lymphoma patients. This research could improve the prognosis of patients with follicular lymphoma, the second most common lymphoma subtype the Western World.

Objectives:

  • Measure the prognostic impact of histologic grade of follicular lymphoma cases by comparing it with outcome measures; 
  • Develop a computer-assisted image analysis system to quantitatively assess the follicular lymphoma tumor microenvironment; 
  • Compare the effectiveness of combined prognostic measure incorporating grade (without and with computer assistance), tumor microenvironment parameters and existing FLIPI score. 

Lymphoma Clinical Research Accomplishments


Ibrutinib shows potential as safe and effective for mantle cell lymphoma. Results of a phase II trial suggests that the novel agent ibrutinib showed an overall response rate of 68 percent, with 21 percent of patient achieving a complete response and 47 percent achieving a partial response. Estimated overall survival was 58 percent at 18 months.
Published in the New England Journal of Medicine with accompanying editorial.

A phase 2 multi-center study of lenalidomide in relapse or refractory classical Hodgkin lymphoma.
Abstract: Relapsed or refractory (rel/ref) classical Hodgkin lymphoma (cHL) remains a clinical challenge, with limited effective treatment options available after stem cell transplantation. In a multicenter phase 2 study, the efficacy of lenalidomide in rel/ref cHL patients was evaluated at a dose of 25 mg/d on days 1-21 of a 28-day cycle. Patients remained on lenalidomide until disease progression or an unacceptable adverse event (AE) occurred. Thirty-eight cHL patients were enrolled with a median of 4 (range, 2-9) prior therapies; 87% had undergone prior stem cell transplantation and 55% of patients did not respond to their last prior therapy. Of 36 evaluable patients, responses were 1 complete remission (CR), 6 partial remissions (PRs), and 5 patients with stable disease (SD) for ≥ 6 months resulting in an International Working Committee (IWC) objective overall response rate (ORR) of 19% and a cytostatic ORR of 33%. Decreased chemokine (CCL17 and CCL22) plasma levels at 2 weeks were associated with a subsequent response. The treatment was well tolerated, and the most common grade 3/4 AEs were neutropenia (47%), anemia (29%), and thrombocytopenia (18%). Four patients discontinued lenalidomide because of rash, elevated transaminases/bilirubin, and cytopenias. We provide preliminary evidence of lenalidomide's activity in patients with rel/ref cHL, and therefore exploration of lenalidomide in combination with other active agents is warranted.
Published in Blood.

Hodgkin Lymphoma, version 2.2012 Featured Updates to NCCN guidelines.
Abstract: The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Hodgkin Lymphoma (HL) include the clinical management of classical HL and lymphocyte-predominant HL (LPHL). Major changes have been incorporated into these guidelines since their inception. In the 2012 NCCN Guidelines for HL, PET scans are not recommended for interim restaging of patients with stage I to II favorable disease. After reevaluating the available evidence on the use of interim PET imaging, the panel recommends the use of diagnostic CT scan of involved sites for interim restaging after completion of chemotherapy for this group of patients. Maintenance rituximab for 2 years is included as an option for patients with stage IB to IIB or stage III to IV LPHL treated with rituximab alone in the first-line setting. Brentuximab vedotin is included as an option for patients with progressive disease or relapsed disease after second-line chemotherapy or high-dose therapy with autologous stem cell rescue.
Published in the Journal of the National Comprehensive Cancer Network.

Randomized phase III trial of ABVD versus Stanford V with or without radiation therapy in locally extensive and advanced-stage Hodgkin Lymphoma: An Intergroup study coordinated by the Eastern Cooperative Oncology Group (E2496).
Abstract:
Purpose: Although ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) has been established as the standard of care in patients with advanced Hodgkin lymphoma, newer regimens have been investigated, which have appeared superior in early phase II studies. Our aim was to determine if failure-free survival was superior in patients treated with the Stanford V regimen compared with ABVD.
Patients and Methods: The Eastern Cooperative Oncology Group, along with the Cancer and Leukemia Group B, the Southwest Oncology Group, and the Canadian NCIC Clinical Trials Group, conducted this randomized phase III trial in patients with advanced Hodgkin lymphoma. Stratification factors included extent of disease (localized v extensive) and International Prognostic Factors Project Score (0 to 2 v 3 to 7). The primary end point was failure-free survival (FFS), defined as the time from random assignment to progression, relapse, or death, whichever occurred first. Overall survival, a secondary end point, was measured from random assignment to death as a result of any cause. This design provided 87% power to detect a 33% reduction in FFS hazard rate, or a difference in 5-year FFS of 64% versus 74% at two-sided .05 significance level.
Results: There was no significant difference in the overall response rate between the two arms, with complete remission and clinical complete remission rates of 73% for ABVD and 69% for Stanford V. At a median follow-up of 6.4 years, there was no difference in FFS: 74% for ABVD and 71% for Stanford V at 5 years (P = .32).
Conclusion: ABVD remains the standard of care for patients with advanced Hodgkin lymphoma.
Published in the Journal of Clinical Oncology.

Association of pre-transplantation PET/CT and outcome in mantle cell lymphoma.
Abstract: Positron emission tomography/computed tomography (PET/CT)-positive findings before autologous SCT (auto-SCT) are associated with inferior PFS and OS in patients with relapsed Hodgkin's and diffuse large B-cell lymphoma. We classified pre-transplant PET/CT performed before auto-SCT as positive or negative to evaluate the impact of pre-transplant PET/CT in mantle cell lymphoma (MCL). In 29 patients, 17 were PET/CT(-) and 12 were PET/CT(+). PET/CT(+) patients were younger (P=0.04), had lower MCL International Prognostic Index (MIPI, P=0.04) scores, but increased bulky adenopathy >5 cm (45% vs 13%, P=0.09). With a median follow-up of 27 months (range: 5-55 months), 7 patients relapsed (4 in the PET/CT(-) group and 3 in the PET/CT(+) group) with 2 deaths in the PET/CT(+) group without a documented relapse. The estimated 2-year PFS was 64% (95% confidence interval (CI): 0.30-0.85) vs 87% (95% CI: 0.57-0.97) in PET/CT(+) and PET/CT(-) patients, respectively (P=0.054). OS was significantly decreased in PET/CT(+) patients (P=0.007), with 2-year estimates of 60% (95% CI: 0.23-0.84) vs 100% in PET/CT(-) patients. A positive pre-transplant PET/CT is associated with a poor prognosis in patients with MCL. Additional factors may impact the prognostic value of PET/CT, as several PET/CT(+) patients remain in remission.
Published in Bone Marrow Transplantation – Nature.

Targeting Bruton’s Tyrosine Kinase with Ibrutinib in relapsed/refractory mantle cell lymphoma.
Abstract: Ibrutinib is a novel oral tyrosine kinase inhibitor that irreversibly binds and inhibits tyrosine-protein kinase BTK (Bruton tyrosine kinase). BTK has been found to be important in the function of B-cell receptor signaling and therefore in the maintenance and expansion of various B-cell malignancies including chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). Targeting BTK with ibrutinib has been found to be an effective strategy in treating these malignancies. Phase I clinical testing in non-Hodgkin's lymphomas and CLL showed that the drug was extremely well tolerated with no major dose-limiting toxicities and a 54% overall response rate. Subsequently, two phase Ib/II studies were performed on patients with CLL, one in relapsed/refractory CLL and one in previously untreated elderly patients with CLL. Both of these studies continued to show good tolerability of the drug and an overall response rate of about 71% with extended duration of response. Another phase II study using ibrutinib in relapsed/refractory MCL was conducted and also showed that it was well tolerated with an overall response rate of 68% and extended duration of response. Due to these results, the U.S. Food and Drug Administration granted accelerated approval for ibrutinib in November 2013 for patients with MCL who had received at least one prior therapy and in February 2014 for patients with CLL who had received at least one prior therapy. This review will discuss the preclinical pharmacology, pharmacokinetics and clinical efficacy to date of ibrutinib in the treatment of CLL and MCL.
Published in Drugs of Today.

Lymphoma occurring during pregnancy: antenatal therapy, preterm complications, and maternal survival in a multicenter analysis.
Abstract:
Purpose: Lymphoma is the fourth most frequent cancer in pregnancy; however, current clinical practice is based largely on small series and case reports.
Patients and Methods: In a multicenter retrospective analysis, we examined treatment, complications, and outcomes for Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) occurring during pregnancy.
Results: Among 90 patients (NHL, n = 50; HL, n = 40), median age was 30 years (range, 18 to 44 years) and median diagnosis occurred at 24 weeks gestation. Of patients with NHL, 52% had advanced-stage versus 25% of patients with HL (P = .01). Pregnancy was terminated in six patients. Among the other 84 patients, 28 (33%) had therapy deferred to postpartum; these patients were diagnosed at a median 30 weeks gestation. This compared with 56 patients (67%) who received antenatal therapy with median lymphoma diagnosis at 21 weeks (P < .001); 89% of these patients received combination chemotherapy. The most common preterm complication was induction of labor (33%). Gestation went to full term in 56% of patients with delivery occurring at a median of 37 weeks. There were no differences in maternal complications, perinatal events, or median infant birth weight based on deferred versus antenatal therapy. At 41 months, 3-year progression-free survival (PFS) and overall survival (OS) for NHL were 53% and 82%, respectively, and 85% and 97%, respectively, for HL. On univariate analysis for NHL, radiotherapy predicted inferior PFS, and increased lactate dehydrogenase and poor Eastern Cooperative Oncology Group performance status (ECOG PS) portended worse OS. For HL patients, nulliparous status and “B” symptoms predicted inferior PFS.
Conclusion: Standard (non-antimetabolite) combination chemotherapy administered past the first trimester, as early as 13 weeks gestation, was associated with few complications and expected maternal survival with lymphoma occurring during pregnancy.
Published in the Journal of Clinical Oncology.

Improved efficacy using rituximab and brief duration, high intensity chemotherapy with filgrastim support for Burkitt or aggressive lymphomas: Cancer and Leukemia Group B study 1002.
Abstract: To improve long-term outcomes for Burkitt leukaemia/lymphoma (BL) or aggressive lymphomas in adults, we assessed the benefit of adding rituximab and filgrastim support to a dose-dense modified chemotherapy regimen from the Cancer and Leukemia Group B (CALGB) 9251 trial. One hundred and five patients (aged 19-79 years) were enrolled; 27% were >60 years old; 47% had high or high-intermediate risk by International Prognostic Index (IPI) criteria. Common severe toxicities included stomatitis/upper gastrointestinal toxicity (69%), renal insufficiency (10%), neurological events (25%) and pulmonary events (18%). Seven died from treatment-related causes (one central nervous system bleed, four infections, two respiratory failure); five were >60 years old. Results in this adult population are encouraging as complete response (CR) was observed in 83% and 4-year event-free (EFS) and overall survivals (OS) were 74% and 78%, respectively. Results compare favourably to our prior chemotherapy alone study (CALGB 9251) but despite this, high-risk patients still had worse outcomes. In conclusion, short duration, intensive chemo-immunotherapy is feasible and should be considered in adults with BL as it results in high remission rates and durable remissions.
Published in the British Journal of Haematology

PI3Kdelta inhibition by idelalisib in patients with relapsed indolent lymphoma.
Abstract:
Background: Phosphatidylinositol-3-kinase delta (PI3Kδ) mediates B-cell receptor signaling and microenvironmental support signals that promote the growth and survival of malignant B lymphocytes. In a phase 1 study, idelalisib, an orally active selective PI3Kδ inhibitor, showed antitumor activity in patients with previously treated indolent non-Hodgkin's lymphomas.
Methods: In this single-group, open-label, phase 2 study, 125 patients with indolent non-Hodgkin's lymphomas who had not had a response to rituximab and an alkylating agent or had had a relapse within 6 months after receipt of those therapies were administered idelalisib, 150 mg twice daily, until the disease progressed or the patient withdrew from the study. The primary end point was the overall rate of response; secondary end points included the duration of response, progression-free survival, and safety.
Results: The median age of the patients was 64 years (range, 33 to 87); patients had received a median of four prior therapies (range, 2 to 12). Subtypes of indolent non-Hodgkin's lymphoma included follicular lymphoma (72 patients), small lymphocytic lymphoma (28), marginal-zone lymphoma (15), and lymphoplasmacytic lymphoma with or without Waldenström's macroglobulinemia (10). The response rate was 57% (71 of 125 patients), with 6% meeting the criteria for a complete response. The median time to a response was 1.9 months, the median duration of response was 12.5 months, and the median progression-free survival was 11 months. Similar response rates were observed across all subtypes of indolent non-Hodgkin's lymphoma, though the numbers were small for some categories. The most common adverse events of grade 3 or higher were neutropenia (in 27% of the patients), elevations in aminotransferase levels (in 13%), diarrhea (in 13%), and pneumonia (in 7%).
Conclusions: In this single-group study, idelalisib showed antitumor activity with an acceptable safety profile in patients with indolent non-Hodgkin's lymphoma who had received extensive prior treatment.
Published in the New England Journal of Medicine.

Complete response (CR) to induction therapy in patients (pts) with myc-positive and double hit non-Hodgkin’s lymphoma is associated with prolonged progression-free survival (PFS).
Abstract:
Background: Myc-positive B-cell non-Hodgkin lymphoma (NHL) with or without a B-cell chronic lymphocytic leukemia/lymphoma 2 (BCL2) rearrangement is associated with inferior progression-free survival (PFS) and overall survival (OS). In this study, the authors reviewed the outcomes of patients with myc-positive and double-hit NHL at The Ohio State University.
Methods: All patients who had non-Burkitt, aggressive B-cell NHL from 2008 to 2011 were assessed for the t(14;18) translocation and for v-myc avian myelocytomatosis viral oncogene homolog (CMYC) rearrangements at diagnosis, and all myc-positive patients were included in the current analysis. Associations with clinical characteristics were described, and univariable and multivariable models were used to assess correlations between clinical variables and outcomes.
Results: Of 49 myc-positive patients, 29 patients also had BCL2 rearrangements (double-hit NHL). No patients underwent autologous stem cell transplantation in first remission. For all myc-positive patients, the median PFS was 16.6 months, and the median OS was 37.7 months. For patients who had double-hit NHL, the median PFS was 8 months, and the median OS was 12.5 months; whereas the median PFS and OS were not reached for myc-positive patients. A complete response (CR) after front-line therapy, the presence of t(14;18), International Prognostic Index (IPI) group, and age were associated with PFS; whereas only the achievement of a CR and age >60 years were associated with OS in the multivariable setting. The median PFS was 3.3 months, and the median and OS was 7.0 months for patients who did not attain a CR; and the medians were not reached for patients who achieved a CR (P < .00001).
Conclusions: The achievement of a CR with front-line therapy is associated with a prolonged PFS and OS in patients with myc-positive NHL, even after adjusting for type of initial therapy, histology, age, IPI, or the presence of a concurrent BCL2 translocation.
Published in Cancer.


Combined rituximab, bendamustine and ibrutinib in patients with previously untreated and relapsed/refractory non-Hodgkin’s lymphoma.
Abstract: Ibrutinib has single agent activity of 22-68% in relapsed B-cell non-Hodgkin's lymphoma (NHL). This study evaluated the safety and efficacy of ibrutinib combined with rituximab (R) and bendamustine. Patients received R 375 mg/m2 day 1, bendamustine 90 mg/m2 days 1 and 2, and ibrutinib (280 or 560 mg) days 1-28 every 28 days for 6 cycles followed by ibrutinib alone until progression. Forty-eight patients enrolled, including 12 patients with follicular lymphoma (FL), 16 with diffuse large cell lymphoma (DLCL), and 17 with mantle cell lymphoma (MCL). No dose limiting toxicities were observed. Patients received a median of 8 cycles, with 26 completing 6 cycles and continuing ibrutinib alone in cycles 7-34. The overall response rate (ORR) was 72%, with 52% complete responses (CR). By histology, the ORR was 94% (76% CR) in MCL, 37% (31% CR) in DLCL, and 90% (50% CR) in FL. Grade 3-4 toxicities included lymphopenia (77%), neutropenia (33%), thrombocytopenia (19%), and rash (25%). Median progression-free survival has not been reached (95% CI, 8.7 months - not reached). The recommended phase 2 dose of ibrutinib in combination with R-bendamustine in patients with NHL is 560 mg. The combination has promising efficacy, particularly in MCL and FL.
Published in Blood.

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