Recent statistics estimate that 15,000 cases of follicular lymphoma, a somewhat common type of slow-growing non-Hodgkin lymphoma (NHL), are diagnosed each year in the U.S. (Hematology Am Soc Hematol Educ Program 2012;2012:417-425).
This form of carcinoma can be effectively managed with first-line chemotherapy; however, the clinical course of follicular lymphoma prior to, during, and after treatment varies. Many patients experience frequent relapses, and disease can often become refractory to standard therapy (Rev Bras Hematol Hemoter 2012;34(1):54-59, Am J Hematol 2009;84(12):826-829).
Approaches to Treatment
Advances in research and treatment protocols have resulted in a substantial improvement in survival among patients with follicular lymphoma. These improvements are likely due to the greater utilization of anti-CD20 monoclonal antibody therapies, such as rituximab (Blood 2016;127(17):2055-2063). Depending upon the patient, an anti-CD20 monoclonal antibody can be used as either a monotherapy approach or in addition to standard chemotherapy.
Treatment for follicular lymphoma varies and depends upon the stage the patient is in at presentation. Early stage follicular lymphoma can often be managed effectively with radiation. In fact, radiation therapy provides curative potential in stages I-II of the disease (Med Oncol 1994;11(1):19-25, Cancer 2010;116(16):3843-3851, Cancer 1983;52(1):1-7). When the disease is found in its late stages, however, an immunotherapy regimen, usually consisting of rituximab in addition to chemotherapy, is often initiated.
According to a review by Auayporn Nademanee, MD, a Hematologist/Oncologist at City of Hope, Duarte, Calif., “In 5 years, more patients with B-cell NHL may be cured or live longer with the addition of rituximab to induction chemotherapy, salvage chemotherapy, and stem cell transplant.”
Despite the use of this therapeutic regimen, Nademanee believes HSCT “will continue to be a curative treatment for patients with relapsed or high-risk NHL.”
Patients with high-risk follicular lymphoma who experience early chemoimmunotherapy failure, characterized by disease relapse within a 2-year period of front-line chemoimmunotherapy, have an average overall survival rate of 50 percent (J Clin Oncol 2015;33(23):2516-2522).
For patients who have follicular lymphoma that has transformed into diffuse large B-cell lymphoma (DLBCL), the use of high-dose therapy as well as autologous hematopoietic stem cell transplantation (auto-HSCT) represents current standard treatment. Specifically, auto-HSCT is used most frequently in patients with refractory and/or relapsed DLBCL.
The prospective, phase III PARMA trial, which included 215 patients who had relapsed lymphoma, demonstrated a favorable survival benefit of high-dose therapy and auto-HSCT compared with salvage therapy. In these patients, the event-free survival rate was 46 percent for auto-HSCT and high-dose therapy versus 12 percent for salvage therapy (P=0.001). This study essentially helped establish autologous HSCT and high-dose therapy as a standard therapeutic approach for refractory or relapsed lymphoma (N Engl J Med 1995;333(23):1540-1545).
Autologous vs. Allogeneic HSCT
Currently undergoing rigorous clinical trials, autologous or allogeneic HSCT remains a controversial treatment approach for lymphoma patients.
Using an autologous transplant approach, blood-generating stem cells (peripheral blood stem cells) are obtained from the patient prior to treatment and frozen. Prior to collection, patients are assessed for HSCT to make sure their stem cells are healthy and the candidate is appropriate for transplantation. Apheresis is the typical method for collecting qualified stem cells. Medications such as G-CSF or filgrastim are given to stimulate stem cells to divide. These stem cells are then filtered out of circulation and then frozen for post-therapy utilization.
Indications for autologous HSCT include both Hodgkin lymphoma and NHL. High-dose chemotherapy or a combined chemotherapy-radiation approach is then implemented in attempt to put the carcinoma in remission. Since the treatment kills blood-generating cells in the bone marrow (in addition to carcinogenic cells), the stem cells obtained from the patient prior to treatment are transplanted back to the patient. This facilitates the production of new blood cells. Once the stem cells are infused back into the treated patient, the patient can usually be discharged within 7-10 days once blood counts return to normal. Patients undergoing autologous HSCT have a low risk for graft versus host disease or graft rejection. Despite this low risk, it may take 1 year or more for the patient's immune system to recover from this therapy.
Previous research has suggested that the average overall survival in lymphoma patients undergoing autologous HSCT is around 52 percent at 10 years (Leukemia 2007;21(11):2324-2331). Additionally, this patient population features a low mortality rate related to treatment.
In comparison to autologous HSCT, allogeneic HSCT provides curative potential in patients with follicular lymphoma and other indolent NHLs, but this strategy carries with it a higher treatment-related mortality rate. Additionally, there is substantial clinical difficulty in identifying high-risk patients for receiving this transplant. Limited data exist to determine the efficacy and safety of allogeneic HSCT in high-risk patients, further limiting its use in clinical practice.
In addition, optimal timing for this approach as well as appropriate indications for performance have yet to be established by wide-scale data (Curr Opin Hematol 2013;20(6):509-514). According to some research, allogeneic HSCT-related mortality has been decreasing with the increasing use of nonmyeloablative preparative strategies (Rambam Maimonides Med J 2014;5(4):e0028).
The curative effect of allogeneic HSCT is mostly driven by the graft versus lymphoma effect. Essentially, the immune system from the donor detects and eliminates any residual lymphoma in the HSCT patient. This effect is demonstrated at a high rate in indolent NHL and has been verified on numerous occasions in the published literature (Bone Marrow Transplant 2003;32(12):1159-1163, Biol Blood Marrow Transplant 2008;14(1):50-58).
Although it can be highly beneficial, the donor's immune cells may attack normal, healthy host tissues, resulting in graft versus host disease. This results in significant morbidity and potential subsequent mortality. Chronic graft versus host disease, which can last for a number of years, can impede long-term quality of life in transplant survivors (Blood 2011;117(17):4651-4657).
A study led by investigator James K. Godfrey, MD, from the University of Chicago, sought to determine outcomes among patients undergoing autologous HSCT (n = 240) versus matched sibling donor (n = 105) or matched unrelated donor (n = 95) allogeneic HSCT.
Patient data were obtained from the CIBMTR (Center for International Blood and Marrow Transplant Research) database. Researchers included patients with follicular lymphoma who experienced early chemoimmunotherapy failure (N = 440).
According to the investigators, the use of autologous HSCT resulted in a significantly lower 5-year adjusted probability for non-relapse mortality compared with matched sibling donor and matched unrelated donor HSCT (5% vs. 17% and 33%, respectively; P<0.0001).
Conversely, the 5-year adjusted probably of relapse was greater in the autologous HSCT arm versus those undergoing matched sibling or matched unrelated donor HSCT (58% vs. 31% and 23%, respectively; P<0.0001). Researchers also found adjusted probably rates of progression-free survival in 38 percent versus 43 percent and 52 percent of autologous HSCT versus matched unrelated donor and matched sibling donor HSCT, respectively (P=0.006).
Overall, the survival rate at 5 years was found to be significantly higher for patients undergoing autologous HSCT or matched sibling donor HSCT (70% and 73%, respectively) compared with those undergoing matched unrelated donor HSCT (49%; P=0.004).
The limitations of this study are its retrospective design, prompting the researchers to suggest future performance of a prospective trial in this patient population.
According to Godfrey, the use of autologous HSCT for patients with follicular lymphoma who also experience early chemotherapy failure is associated with a “low non-relapse mortality and 5-year overall survival rates that are provocatively higher than historical data.”
Brandon May is a contributing writer.