Safety and Efficacy of the Immunomodulatory Drug (IMiD) Lenalidomide in Patients with Lymphoma: Development of RU051417I - Phase I/II Open-Label Study of R-ICE (Rituximab-Ifosfamide-Carboplatin-Etoposide) with Lenalidomide [R2-ICE] in Patients with First-Relapse/Primary Refractory Diffuse Large B-Cell Lymphoma (DLBCL).

摘要

Lenalidomide (CC-5013; REVLIMID, Celgene Corp., NJ, USA) belongs to a new immunomodulatory class of drugs called IMiDs. It is an oral thalidomide analogue drug that belongs to the second generation of IMiDs. Its parent compound thalidomide's initial descriptions of its teratogenicity are attributed to its anti-angiogenic properties. The drug has other mechanisms of action beyond just cytotoxicity and immune modulation. It includes effects on both the tumor and the tumor microenvironment.;Within hematological malignancies, lenalidomide is being used in a number of conditions. Lenalidomide is being used to treat myelodysplastic syndrome patients with 5q deletion resulting in improvement in their transfusion requirements. Lenalidomide in combination with steroids is used in patients with multiple myeloma.;Recently there has been increased interest to use lenalidomide to treat patients due to its immunomodulatory effect. According to the Surveillance, Epidemiology, and End Results Program (SEER), Non-Hodgkin Lymphoma (NHL) represents 4.3% of all new patients with cancer in United States, with an estimated 71,850 cases in 2015. Within NHL, diffuse large B-cell lymphoma (DLBCL) is most frequently seen constituting approximately 40% of these cases.;Therapies upfront (at the time of diagnosis) for DLBCL include chemotherapeutic options in combination with biologics/monoclonal antibodies (mAbs), which are curative in intent. In the relapsed or refractory settings , the intent treatment for patients with DLBCL is to achieve cure; however, these have to be consolidated with a stem cell transplant (autologous in most instances). The number of treatment options is increasing, and newer regimens and classes of drugs are being developed and tested for patients with DLBCL. These go beyond mAbs and traditional chemotherapeutic agents, and include novel targeted therapies, immunotherapies and immunomodulatory agents. Immune modulation, as noted, has been a focus of increasing interest particularly for patients with DBLCL. With lenalidomide, responses were seen in up to half of the patients treated with lenalidomide, with about a quarter achieving complete responses. Even as single agent, these responses appeared to be relatively durable (PFS 6.2 months), given the highly aggressive nature of disease. The side effect profile was noted to be manageable without any untoward adverse events.;This led to the development of clinical trials for patients incorporating lenalidomide. These were both in frontline as well as the relapsed/refractory setting. Lenalidomide (Revlimid) was added to the frontline regimen R-CHOP [referred to as R2CHOP] and showed significant activity and manageable safety profile. The focus of my thesis is the development of the clinical trial of incorporating lenalidomide (Revlimid) in the relapsed/refractory setting to one of the most commonly employed chemoimmunotherapy regimens called the R-ICE (rituximab-ifosfamide-carboplatin-etoposide) regimen. The regimen developed therefore, is called R2ICE.;The patients that we studied, who have refractory disease or relapse with lymphoma, constitute at least a quarter of all patients with DLBCL. The majority of these are patients who relapse within the first 1.5 years of upfront curative treatment. For patients with first-relapse/primary-refractory DLBCL, the response rate achieved prior to proceeding with a stem cell transplant (SCT) is a key variable. Usually this is an autologous stem cell transplant (ASCT). ASCT can be potentially curative for these patients who tend to show chemosensitivity by achieving either a complete response (CR) or partial response (PR) with their salvage chemotherapy prior to the transplant. Patients with CR tend to do better than patients who achieved PR after salvage chemotherapy. To achieve this, patients with relapsed/refractory disease are currently treated with a variety of treatment regimens prior to them going for a transplant. Currently the most commonly used regimen is the chemotherapy regimen of ICE (ifosfamide-carboplatin-etoposide). Historically, when rituximab was added to this regimen (R-ICE), the number of patients responding increased. This increase was clinically significant. However, this could further be increased, since at present, this is estimated to be around 40% for patients who receive 2 cycles of therapy prior to them getting a transplant.;The goals of my master's program and thesis were, therefore, to (a) develop rationale for a clinical trial incorporating the novel drug lenalidomide into regimens treating patients with lymphoma (Chapter 1); (b) review literature on paradigm changes on how to treat patients with DLBCL in a molecular era (Chapter 2); (c) secure funding and develop a clinical trial protocol of the addition of lenalidomide to treat patients with DLBCL to the standard R-ICE regimen [R2ICE](Chapter 3); (d) to report the early results of the safety from the completed Phase-1 study and ongoing phase-2 study for our R2ICE regimen, and for its potential to become a new regimen for patients with relapsed/refractory lymphoma (Chapter 4).