Chlorambucil/Rituximab Combination Delayed Progression in MALT Lymphoma

Patients with mucosa-associated lymphoid tissue (MALT) lymphoma had improved event-free survival (EFS) when treated with chlorambucil plus rituximab compared with either therapy alone, according to the results of the International Extranodal Lymphoma Study Group 19 (IELSG-19) phase III study published in the Journal of Clinical Oncology. However, improvements seen in EFS and progression-free survival (PFS) did not result in improvements in overall survival (OS) for patients’ treatment with the combination.

“Improved EFS and PFS with little added toxicity justifies the first-line use of this regimen, and the results of this controlled clinical study may define a standard regimen for treatment of patients MALT lymphoma who are in need of systemic therapy,” wrote Emanuele Zucca, MD, Oncology Institute of Southern Switzerland, and colleagues. “The lack of OS benefit, however, leaves room to consider the use of chlorambucil alone when treatment cost is a relevant issue, but also provides evidence for the use of single-agent rituximab to avoid the toxicity of chemotherapy.”

According to the researchers there is currently no consensus on the best therapy for patients with MALT lymphoma and few trials have tested the use of single agents or combination regimens.

The IELSG-19 study included 252 patients who were randomly assigned to receive chlorambucil monotherapy or chlorambucil plus rituximab. Later, the study protocol was amended to a three-arm design with patients randomly assigned 1:1:6 with the addition of a third rituximab monotherapy arm. The final sample was 454 patients. The primary endpoint was EFS.

About 80% of patients completed the treatment program according to the study protocol. Objective response occurred in 345 (86%) of patients with 66% achieving complete response and 20% achieving partial response. Treatment with the combination regimen resulted in better responses with significantly higher rates of overall response and complete response than either drug alone.

With a median follow-up of 7.4 years, the median EFS was 8.6 years. Patients assigned to combination therapy with chlorambucil plus rituximab had significantly longer EFS compared with monotherapy treatment with chlorambucil or rituximab alone (not reached vs. 5.1 years vs 5.6 years; P = .0009). The addition of rituximab resulted in significantly fewer EFS events (hazard ratio [HR], 0.54; 95% CI, 0.38–0.77). Five-year EFS was 68% for combination treatment and about 50% for either monotherapy regimens.

Patients assigned to combination treatment also had significantly improved PFS (HR, 0.62; 95% CI, 0.42–0.93). The median PFS was not reached for combination treatment compared with 8.3 years for chlorambucil and 6.9 years for rituximab.

No differences in OS were noted among the three study arms. According to the researchers, this is “likely as a result of effective second treatment options in indolent disease.”

All treatments were well-tolerated with no unexpected adverse events.

“As the only randomized study that has specifically addressed MALT lymphoma, these results can be considered a benchmark for future trials in this entity,” the researchers wrote. “Lack of OS difference between arms has also provided evidence for the use of rituximab alone as initial therapy to delay or avoid the long-term risks of chemotherapy and radiotherapy.”