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Ofatumumab plus salvage chemotherapy fails to improve outcomes in relapsed, refractory DLBCL
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Ofatumumab combined with salvage chemotherapy yielded no additional survival benefits compared with rituximab in the treatment of relapsed or refractory diffuse large B-cell lymphoma, according to results from the ORCHARD study.
The addition of rituximab (Rituxan; Genentech, Biogen) to salvage chemotherapy in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who were rituximab-naive has improved autologous stem cell transplantation (ASCT) outcomes; however, resistance to rituximab lessens the efficacy of rituximab-containing salvage therapy.
Ofatumumab (Arzerra, Novartis) — a human IgG1k anti-CD20 monoclonal antibody that targets a different epitope than rituximab — has demonstrated efficacy in studies of rituximab-resistant chronic lymphocytic leukemia and follicular lymphoma.
Preliminary results of a phase 2 study of ofatumumab in combination with DHAP chemotherapy (cisplatin, cytarabine and dexamethasone) or ifosfamide, carboplatin and etoposide chemotherapy demonstrated a 55% response rate in patients with early relapsing or refractory DLBCL after treatment with R-CHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone).
Therefore, Gustaaf W. van Imhoff, MD, PhD, from the department of hematology at University Medical Center Groningen in the Netherlands, and colleagues compared ofatumumab vs. rituximab in combination with DHAP as salvage treatment, followed by high-dose chemotherapy and ASCT in 447 patients (median age, 57 years) with relapsed or refractory DLBCL.
Sixty-three percent of patients had stage III or stage IV disease, and 71% did not achieve complete response or experienced a response for less than 1 year on first-line R-CHOP therapy.
The researchers randomly assigned patients to receive 1,000 mg of ofatumumab or 375 mg/m² of rituximab — administered on days 1 and 8 of cycle 1, followed by day 1 of cycles 2 and 3 — in combination with three cycles of DHAP salvage chemotherapy, each for 21 days. Patients who experienced a response after two cycles of treatment received the third cycle, followed by high-dose chemotherapy and ASCT.
PFS served as the primary outcome. Median follow-up was 10.9 months.
Of 445 patients who started salvage therapy, 35% completed high-dose chemotherapy plus ASCT on protocol — including 83 patients in the rituximab arm and 74 patients in the ofatumumab arm (OR = 0.84; 95% CI, 0.56-1.27).
After completion of salvage therapy, patients treated with rituximab had insignificantly higher rates of overall response (42% vs. 38%; OR = 0.84; 95% CI, 0.56-1.24) and complete response (22% vs. 15%; OR = 1.66; 95% CI, 0.39-1.1).
Survival rates also were not significantly different between arms, in terms of 2-year PFS (rituximab vs. ofatumumab, 26% vs. 24%; HR = 1.12; 95% CI, 0.89-1.42), 2-year EFS (18% vs. 16%; HR = 1.1; 95% CI, 0.9-1.36) and 2-year OS rate (38% vs. 41%; HR = 0.9; 95% CI, 0.7-1.15).
PET negativity before ASCT was highly predictive for superior outcome. Patients with PET–positive outcomes after cycle 3 had inferior rates of 2-year PFS (32% vs. 70%; P = .001) and 2-year OS (43% vs. 78%; P = .0018) compared with patients with PET–negative disease.
Mobilization of stem cells was successful for 96% of the 125 patients in the ofatumumab group and 90% of 134 patients in the rituximab group in whom treatment commenced.
The most frequently reported severe adverse event was febrile neutropenia (13%), followed by acute renal failure, thrombocytopenia and vomiting (5% for each).
Patients in the ofatumumab arm experienced an increase in rash (22% vs. 9%) and raised serum creatinine (23% vs. 16%) compared with the rituximab group.
Adverse events resulted in dose interruption or delay of either anti-CD20 therapy or chemotherapy in 49% of patients in the ofatumumab group compared with 30% of the rituximab group.
“Results of this study showed that use of ofatumumab instead of rituximab in conjunction with standard salvage chemotherapy was not able to overcome treatment resistance in early relapsed or refractory DLBCL,” van Imhoff and colleagues wrote. “Clearly, for these patients, other treatment approaches are eagerly awaited.” – by Kristie L. Kahl
Disclosure: Please see the full study for a list of all other researchers’ relevant financial disclosures.
Perspective
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Craig H. Moskowitz
For the past 15 years, R-CHOP (rituximab [Rituxan; Genentech, Biogen] cyclophosphamide, doxorubicin, vincristine and prednisone) has become the standard treatment for diffuse large B-cell lymphoma (DLBCL), and the cure rate after first-line therapy has improved by about 10% to 15%. Unfortunately, this is not the case for patients with relapsed or primary refractory disease where outcome has worsened. This is secondary to a suboptimal response to pre-autologous stem cell transplantation rituximab-based salvage chemotherapy in patients who received R-CHOP, as well as an unfavorable second-line international prognostic index in the majority of patients.
There are a number of negative phase 3 studies in this setting comparing rituximab-based salvage chemotherapy programs, leaving no standard regimen to choose. The current study, ORCHARRD, was an attempt to overcome rituximab resistance by substituting ofatumumab for rituximab in the DHAP regimen (cisplatin, cytarabine and dexamethasone). Phase 2 data suggested that the regimen was safe and efficacious with a favorable complete response rate. The ORCHARRD study was a phase 3 comparison of DHAP with ofatumumab (O-DHAP) or rituximab (R-DHAP) evaluating the overall and complete response rate to salvage chemotherapy. In addition, PFS and OS were analyzed by intent to treat and for the transplanted cohorts.
This was typical patient population that was well balanced for prognostic factors. In total, 447 patients were randomly assigned to one of the two regimens; however, only 157 patients were transplanted. The major reason for the disparity was progression of disease during salvage chemotherapy.
The overall and complete response rates to the regimens were poor; the ORR was 38% and complete response rate was 15% for O-DHAP, and the ORR was 42% and complete response rate was 22% for R-DHAP. As analyzed by intent to treat, the 2-year PFS for the two regimens were 24% for O-DHAP and 26% for R-DHAP.
Based upon these data it is very clear that substituting another anti-CD20 agent into the salvage chemotherapy platform makes little sense. Increasing the complete response rate by adding novel drugs with significant single agent activity to the salvage chemotherapy backbone are desperately needed and is a major unmet need in the management of DLBCL.
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