Dec. 6, 2010 The next generation of drug therapies and enhanced treatment approaches for various forms of lymphoma are evolving as researchers continue to better understand how these cancers progress. Research recently presented at the 52nd Annual Meeting of the American Society of Hematology introducing promising new options for the standard treatment of advanced asymptomatic follicular lymphoma, mantle cell lymphoma, and early, unfavorable (referring to patients with clinical stage I or II disease and one or more risk factors) Hodgkin disease. Other research highlights the efficacy of an innovative investigational agent that has the potential to become a new treatment option for patients with relapsed or refractory Hodgkin disease, which currently has no available treatment options.
"Results of these studies underscore the continued progress we are making in improving the survival and quality of life of our patients with various forms of lymphoma," said Ginna G. Laport, MD, moderator of the press conference and Associate Professor of Medicine, Stanford University Medical Center. "Furthermore, these results represent another important step forward in finding a way to eradicate these particular forms of blood cancer."
An Intergroup Randomized Trial of Rituximab Versus a Watch and Wait Strategy in Patients With Stage II, III, IV, Asymptomatic, Non-Bulky Follicular Lymphoma (Grades 1, 2 and 3a). A Preliminary Analysis
For the past three decades, the standard treatment for patients with asymptomatic, advanced-stage follicular lymphoma has been a watchful-waiting approach in which the use of chemotherapy is delayed until the cancer progresses, as this type of cancer is often slow growing before it becomes symptomatic. This strategy has been based on research showing that there is no overall survival benefit in treating these asymptomatic patients with chemotherapy immediately after diagnosis. A watchful-waiting approach can, on average, defer chemotherapy for 2.5 years, and this strategy is often preferred as it results in a better quality of life for patients by sparing them from the debilitating side effects of chemotherapy at a time when they are feeling well.
Follicular lymphoma develops when a type of white blood cell called a "B" cell becomes cancerous. Rituximab is a monoclonal antibody that selectively depletes cancerous B cells, and it has a more favorable side effect profile than chemotherapy. Researchers wanted to determine whether treating patients with follicular lymphoma with the drug immediately after diagnosis would further delay the time until chemotherapy is needed.
Researchers funded by Cancer Research UK and sponsored by the University College London randomized a total of 462 patients with asymptomatic stage 2, 3, or 4 follicular lymphoma to one of three treatment arms. In the first arm, 186 patients underwent a watchful-waiting approach. In the second arm, 84 patients received 375 mg/m2 of rituximab once a week for four weeks. In the third arm, 192 patients received 375 mg/m2 of rituximab once a week for four weeks followed by maintenance therapy with rituximab that was given every two months for two years. The primary endpoints of the study were time to initiation of new therapy (chemotherapy or radiotherapy) and overall effect on quality of life. The study was originally designed to show an improvement of 18 months in the median time to the start of therapy in each of the rituximab arms (i.e., from 30 months to 48 months). A total of 600 patients were set to be enrolled into this study in order to identify 230 patients who required chemotherapy or radiotherapy treatment. However, three years into the trial, a decision was made to discontinue the second arm of the study as evidence of the efficacy of rituximab as a maintenance therapy became apparent. At that point in time, the study became a two-arm comparison study, and a total of 360 patients were enrolled into the two remaining arms. It was estimated that 192 patients would be required to show the 18-month improvement in the two-arm study.
With a median follow up of 34 months, the study found that far fewer patients required a new therapy in both of the rituximab-containing arms compared with the watchful-waiting arm. At three years from randomization, 49 percent of patients in the watchful-waiting arm had not required new therapy, whereas 80 percent of patients in the rituximab induction arm and 91 percent of patients in the rituximab induction and maintenance arm had not required new therapy. At this time, 96 percent of patients in the study remain alive, and there is no difference in overall survival between the three arms.
"This study demonstrates that treating asymptomatic patients with rituximab can significantly prolong the time until a patient may require chemotherapy" said lead study author Kirit M. Ardeshna, MD, Consultant Hematologist, University College London Hospitals in London. "These results will increase the options for the management of newly diagnosed patients with advanced asymptomatic follicular lymphoma, and it is likely that upfront rituximab therapy will prove popular with patients when compared with a watchful-waiting approach."
Alternating Courses of 3x CHOP and 3x DHAP Plus Rituximab Followed by a High Dose ARA-C Containing Myeloablative Regimen and Autologous Stem Cell Transplantation (ASCT) Is Superior to 6 Courses CHOP Plus Rituximab Followed by Myeloablative Radiochemotherapy and ASCT in Mantle Cell Lymphoma: Results of the MCL Younger Trial of the European Mantle Cell Lymphoma Network (MCL net)
While recent treatment advances have improved outcomes over the last several decades for patients with mantle cell lymphoma (a fast-growing form of B-cell non-Hodgkin lymphoma found in the lymph nodes, bone marrow, blood, spleen, and gastrointestinal system), it is still associated with an overall poor prognosis and a median survival of three to four years. A previous study conducted by the European Mantle Cell Lymphoma Network (MCL net) found that high-dose chemotherapy followed by an autologous stem cell transplant resulted in a significant increase in progression-free survival in patients with advanced stage mantle cell lymphoma. Additionally, other studies have found that the addition of rituximab to CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone) with or without high dose ARA-C (cytarabine) prior to an autologous stem cell transplant may significantly improve remission rates and progression-free survival. One specific study from the GELA (Groupe d'Etude des Lymphomes de I'Adulte) that evaluated a regimen of rituximab and CHOP chemotherapy followed by rituximab and DHAP chemotherapy (dexamethasone, cytarabine, and cisplatin) prior to an autologous stem cell transplant resulted in an overall response rate of 95 percent and a complete response rate of 61 percent, which translated into a median event-free survival rate of 83 months (6.9 years) and an overall survival rate of 75 percent at five years.
In order to confirm the hypothesis that a high-dose ARA-C (cytarabine)-based chemotherapy induction regimen prior to an autologous stem cell transplant provides superior outcomes, researchers from MCL Net initiated a randomized study, led by Professors Olivier Hermine and Martin Dreyling, in which patients younger than 65 years with previously untreated stage 2, 3, or 4 mantle cell lymphoma were randomized to one of two treatment arms. In the control arm of the study, patients received six courses of rituximab and CHOP chemotherapy followed by high-dose myeloablative radiochemotherapy and an autologous stem cell transplant, a procedure in which patients receive an infusion of their own stem cells. In the experimental arm of the study, patients received alternating courses of CHOP chemotherapy and DHAP chemotherapy three times plus rituximab followed by a high-dose ARA-C myeloablative chemotherapy regimen and an autologous stem cell transplant.
The primary endpoint of the study was time to treatment failure (TTF). Stable disease after induction therapy as well as progression or death from any causes were considered treatment failures. Randomization in the study was stopped as soon as a significant difference was observed between the two study arms.
After a median follow up of 27 months, TTF had not yet been reached in the ARA-C arm as compared with 49 months in the control arm. At three years, the survival rate was 79 percent in the control arm and 80 percent in the ARA-C arm. Overall survival was found to be similar in both treatment arms with median overall survival not yet reached.
"Results of this study confirm that there is a new standard of care for the treatment of younger patients with previously untreated mantle cell lymphoma," said lead study author Olivier Hermine, MD, PhD, Professor, Head of the Hematological Department, Necker Hospital in Paris. "High-dose ARA-C chemotherapy should be part of the induction therapy along with rituximab and CHOP chemotherapy prior to an autologous stem cell transplant in order to improve outcomes without an increase in toxicity in these patients."
Dose-Escalation With BEACOPP Escalated Is Superior to ABVD in the Combined-Modality Treatment of Early Unfavorable Hodgkin Lymphoma: Final Analysis of the German Hodgkin Study Group (GHSG) HD14 Trial
Hodgkin lymphoma, a form of lymphoma characterized by the presence of Reed-Sternberg cells (a type of B cell), is estimated to represent 11.5 percent of all types of lymphoma diagnosed this year, including approximately 8,500 new cases in the United States alone.1,2 This type of cancer is also one of the most curable. Previous research of the HD8 trial by the German Hodgkin Study Group demonstrated that the standard treatment for early, unfavorable Hodgkin lymphoma is combination chemotherapy along with involved field radiation therapy (IF-RT) -- four cycles of ABVD chemotherapy (adriamycin, bleomycin, vinblastine, and dacarbazine) followed by IF-RT, a treatment in which radiation is delivered only to areas of the body affected by the lymphoma. Results from this study have shown that overall survival and freedom from treatment failure (time from random assignment to the occurrence of a Hodgkin lymphoma-specific event) at five years in patients treated with this particular regimen reached 91 percent and 83 percent, respectively.
In order to further improve the overall survival and freedom from treatment failure results, researchers from the German Hodgkin Study Group initiated a new study (HD14 trial) to determine whether an escalated dose of the BEACOPP chemotherapy regimen (cyclophosphamide, doxorubicin, etopodise, procarbazine, prednisone, bleomycin, and vincristine) added to standard ABVB chemotherapy would improve freedom from treatment failure in patients with early, unfavorable Hodgkin lymphoma.
In this study, a total of 1,655 patients with early, unfavorable stages of Hodgkin lymphoma were randomized to one of two treatment arms. In the control arm, 818 patients received four cycles of ABVD chemotherapy. In the experimental arm, 805 patients received two cycles of an escalated dose of BEACOPP chemotherapy followed by two cycles of ABVD chemotherapy. Following the chemotherapy regimens, all patients received 30 Gy IF-RT.
After a median follow-up of 42.4 months (about 3.5 years), the estimated four-year freedom from treatment failure rate was significantly higher in the BEACOPP arm as compared with the control arm (94.7 percent and 89.3 percent, respectively). The overall response rate to treatment was 95 percent in each arm of the study. No significant difference in overall survival has been seen yet.
"Results from this study demonstrate that an early intensification treatment approach with an escalated regimen of BEACOPP chemotherapy results in better overall tumor control in patients with early, unfavorable Hodgkin lymphoma," said lead study author Andreas Engert, MD, Chairman, German Hodgkin Study Group, University Hospital Cologne in Germany. "The treatment regimen of two cycles of escalated BEACOPP followed by AVBD chemotherapy and involved-field radiation has become the new standard of care in a follow-up study we are currently conducting, and this approach continues to improve tumor control rates in these patients."
Results of a Pivotal Phase 2 Study of Brentuximab Vedotin (SGN-35) in Patients With Relapsed or Refractory Hodgkin Lymphoma
While 70-80 percent of all newly diagnosed patients with adult Hodgkin lymphoma are typically cured with combination chemotherapy of three or four agents together, there still is a significant number of patients whose disease progresses after initial induction chemotherapy. For these patients, treatment options include additional courses of the same or different chemotherapy regimens followed by an autologous stem cell transplant. However, for patients whose disease returns after an autologous stem cell transplant, there currently are no approved treatment options.
A phase I study in 45 relapsed or refractory Hodgkin lymphoma patients (NEJM, Nov. 4 issue) found that more than half of the 28 patients treated at doses ranging from 1.2 mg/kg to 2.7 mg/kg of brentuximab vedotin achieved an objective (measurable) response. Brentuximab vedotin is an investigational antibody-drug conjugate that delivers a highly potent chemotherapy agent -- monomethyl auristatin E -- directly to Hodgkin lymphoma cells and induces cell death via an anti-CD-30 antibody.
Based on these phase I results, researchers led by the City of Hope National Cancer Center in California and The University of Texas M. D. Anderson Cancer Center enrolled patients into a phase II, single-arm, multicenter study that was designed to evaluate the efficacy and safety of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma who had already undergone an autologous stem cell transplant.
A total of 102 patients at 26 study centers across the United States received brentuximab vedotin (1.8 mg/kg) every three weeks as a 30-minute outpatient IV infusion for up to 16 cycles of treatment. The primary endpoint of the study was the overall objective response rate. Secondary endpoints included complete response rate, duration of response, progression-free survival, overall survival, and tolerability.
Similar to findings from the phase I study, tumor reduction was demonstrated in 96 patients (94 percent), and objective response rate was 75 percent. These findings were validated by an independent review committee. Thirty-four percent of patients achieved a complete remission, and median duration has not yet been reached. Brentuximab vedotin was generally well-tolerated in this patient population, with the majority of adverse events, including peripheral neuropathy, fatigue, and nausea, being grade 1 or 2.
"The responses seen in these heavily pre-treated and refractory patients suggest that, if approved by the Food and Drug Administration, brentuximab vedotin may become an important treatment option for patients with relapsed or refractory Hodgkin lymphoma," said Robert Chen, MD, Assistant Professor, City of Hope National Medical Center in California. "Additionally, other studies are currently underway to determine if brentuximab vedotin, when used in combination with standard chemotherapy, will also improve outcomes in newly diagnosed patients, potentially changing the treatment paradigm for Hodgkin lymphoma."
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