Jesus G. Berdeja

Allogeneic bone marrow transplantation in patients with sensitive low-grade lymphoma or mantle cell lymphoma.

PURPOSE To report survival outcomes of allogeneic BMT in patients with low-grade lymphoma or mantle cell lymphoma (MCL). PATIENTS AND METHODS Thirty-five patients with low-grade lymphoma (48%), chronic lymphocytic leukemia (26%), or MCL (26%) underwent myeloablative allogeneic BMT from HLA-identical siblings at the Johns Hopkins Oncology Center. Patients had a median age of 46 years, a median of 2 prior treatments, and 31% were in complete remission at the time of transplantation. The preparative regimen was cyclophosphamide/total body irradiation for most patients. All grafts were T-cell depleted by counter flow centrifugal elutriation with CD34+ augmentation. RESULTS The incidence of acute GVHD grade >2 was 6% and of grades 1 to 2 was 37%. The incidence of chronic GVHD was 6%. The median follow-up time was 25 months. The rate of event-free survival (EFS) was 50% (95% confidence interval [CI], 33%-66%). Only 1 patient relapsed. The transplantation-related mortality (TRM) was 46% for all patients. The TRM was 86% for patients with resistant disease and 14% for patients with sensitive disease and <2 prior treatments; rates of EFS were 0% (95% CI, 0%-0%) and 79% (95% CI, 47%-93%), respectively. CONCLUSION These data show that, with T-cell depletion, the TRM and relapse rates are modest for patients with sensitive disease and <2 prior treatment courses. Thus, if there is a role for allogeneic BMT in the management of patients with these tumors, it is early in the course of the disease.

New approaches to blood and marrow transplantation for patients with low-grade lymphomas.

Low-grade lymphomas are generally considered incurable diseases with current standard therapies. Blood or marrow transplantation may be the exception. Nevertheless, the role of bone marrow transplantation in low-grade lymphomas has been limited by the usual indolent course of this heterogeneous group of diseases and the historically high rates of transplant-related mortality associated with most transplant procedures. This review discusses the current issues pertaining to bone marrow transplantation and comments on investigational approaches such as the use of monoclonal antibodies as in vivo purging mechanisms and nonmyeloablative and radioimmunoconjugated antibodies as alternate preparative regimens.

Abstract 1879: Dual function HDAC and PI3K inhibitor, CUDC-907 affects cancer cells and the tumor microenvironment in hematological malignancies

Histone deacetylases (HDACs) and the phosphatidylinositol 3-kinase (PI3K)/AKT pathway are promising therapeutic targets in hematologic cancers and evidence of synergistic anti-cancer activity has recently emerged. CUDC-907, a small molecule drug candidate that is designed to target HDACs and PI3Ks in a single chemical entity, is currently in Phase 1 clinical testing for the treatment of patients with lymphoma or multiple myeloma. Preclinically, CUDC-907 has been shown to inhibit activation of PI3K/AKT, JAK/STAT and MAPK pathways in hematologic cancer cell lines such as Hodgkin9s lymphoma, diffuse large B-cell lymphoma, and multiple myeloma. In this study, we report that in the setting of hematological malignancies, CUDC-907 targets not only the cancer cells but also the tumor microenvironment. Cytotoxicity against primary CLL cells was independent of the protective effects provided by stromal cells when primary CLL cells were co-cultured with nurse-like cells. CUDC-907 was shown in vitro to impair cytokine and chemokine production by immune cells in the tumor microenvironment and by Hodgkin9s lymphoma cells. The ongoing first-in-human Phase 1 clinical study of CUDC-907 has yielded preliminary evidence of anti-cancer activity and impact on the tumor microenvironment as measured by cytokine and chemokine levels (e.g., thymus and activation regulated chemokine [TARC]). Ongoing analyses are probing the potential utility of selected cytokine and chemokine as predictive markers of CUDC-907 activity. Citation Format: Anna W. Ma, Ruzanna Atoyan, Anas Younes, Ian W. Flinn, Yasuhiro Oki, Amanda Copeland, Jesus G. Berdeja, Robert Laliberte, Jaye Viner, Maria Elena S. Samson, Steven Dellarocca, Ling Yi, Mylissa Borek, Brian Zifcak, Guangxin Xu, Jing Wang. Dual function HDAC and PI3K inhibitor, CUDC-907 affects cancer cells and the tumor microenvironment in hematological malignancies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1879. doi:10.1158/1538-7445.AM2014-1879

Immunotherapy of lymphoma: update and review of the literature

Purpose The therapeutic options for treating patients with lymphoma have dramatically expanded with the advent of immune-based treatments. While monoclonal antibodies have quickly become incorporated into the therapeutic armamentarium in the treatment of lymphoma, others have struggled to find a niche. This review will summarize the state of the art of this burgeoning therapy. Recent findings The optimal use and timing of existing immunotherapies such as rituximab and radioimmunoconjugates has generated much data in the past few years. Other research has concentrated on the development of newer generation antibodies with alternate binding sites, such as epratuzumab and HU1D10, and bispecific antibodies that can directly interact with cellular immunity. Furthermore, the role of therapeutic vaccines continued to be an important ongoing research question. Summary This review will enumerate the available and most promising developments in immunotherapy as well as provide a working framework to incorporate them into the treatment paradigm for patients with lymphoma.

Blood and Bone Marrow Transplantation for Patients with Hodgkin’s and Non-Hodgkin’s Lymphoma

Most lymphomas are initially sensitive to chemotherapy and radiation. Unfortunately, many patients will relapse with their disease. Dose escalation of chemotherapy is often limited by hematopoetic toxicity. The realization that a significantly higher dose of chemotherapy or chemoradiotherapy could be delivered to a patient by reconstituting their marrow with hematopoetic stem cells paved the way to autologous blood or marrow transplantation (ABMT) for patients with lymphoma. Initial studies were performed in refractory patients. These studies demonstrated the feasibility of this approach and ushered in more definitive trials in patients with homogenous histologies.

A Phase II Trial Evaluating the Safety of Rapid Infusion of Ofatumumab in Patients with Previously Treated Chronic Lymphocytic Leukemia

Lessons Learned. Ofatumumab infusion reactions can be diminished by escalating the dose rate in individual patients in sequential infusions. Background. Ofatumumab (OFA) is a fully humanized, anti‐CD20 antibody approved for use in chronic lymphocytic leukemia (CLL). The recommended administration requires long infusion times. We evaluated an accelerated infusion regimen of 2 hours. Methods. The first dose of OFA (300 mg) was given on week 1 day 1 starting at 3.6 mg/hour and doubling every 30 minutes until a rate of 240 mg/hour was reached. If tolerated, the second dose (1,000 mg) was given on week 1 day 3 starting at 50 mg/hour and doubling every 30 minutes until a rate of 800 mg/hour was reached. If tolerated, the third dose (2,000 mg) was given on week 2 day 1 at 800 mg/hour over the first 30 minutes and, if tolerated, at 1,068 mg/hour over the next 90 minutes (goal infusion time: 120 minutes). Subsequent OFA infusions were administered weekly in the same manner for 8 weeks, and then monthly for 4 months. Results. Thirty‐four patients were treated. Most infusion‐related reactions occurred during the first and second infusion. Eighty‐seven percent (87%) of patients finished the third infusion within 15 minutes of the planned 2 hours and only one had an infusion reaction. Conclusion. Using this stepped‐up dosing regimen, a rapid infusion of OFA is safe and well tolerated.