The effects of chemotherapy-free treatment for advanced indolent lymphoma

On 4 October 2018, Sandra Lockmer from Karolinska Institute, Stockholm, SE, and colleagues, published in the Journal of Clinical Oncology, results from two Nordic Lymphoma Group(NLG) clinical trials on the effects of chemotherapy-free treatment for advanced indolent lymphoma.

Indolent B-cell lymphoma is mainly treated with rituximab-based regimens in combination with chemotherapy. Nevertheless, the ideal timing, sequence, and choice of those treatments are still undetermined. The purpose of this study was to evaluate the long- and short-term effects of rituximab-based regimen without chemotherapy, on the survival of patients with advanced indolent B-cell lymphoma. For this, the NLG investigators collected data from cross-sectional studies with 10.6-year follow-up, involving two randomized clinical trials (M39035; 1998−1999 and ML16865; 2002−2008) mainly on patients with follicular lymphoma (FL; 84%). The primary endpoint of this analysis was overall survival (OS), while secondary endpoints included time-to-treatment failure, time-to-new anti-lymphoma therapy (TTNT), lymphoma-specific survival (LSS), and time-to-transformation.

Study design

• N = 439 patients randomized to either of the two trials: M39035 (n = 126) and ML16865 (n = 313)
• Eligible participants for this analysis were previously untreated patients with FL, marginal zone lymphoma (MZL), small lymphocytic lymphoma (SLL), or indolent lymphoma not otherwise specified (NOS)
• Both trials had a similar design, with four weekly doses of rituximab (375 mg/m²) or in the applicable combination treatment cases with 3 million Units/day of interferon (IFN)-a2a, subcutaneously on week 1 followed by 4.5 million Units/day subcutaneously on weeks 2 to 5. Total treatment duration for two cycles, each containing four rituximab doses, was a maximum of 6 months
• Overall, median follow-up (range) = 9.8 (0.1−8) years from randomization

Key findings

• At the median follow-up, n = 234 patients (73%) were still alive
• Ten-year OS rate from random assignment = 75% and LSS rate = 81%
• Fifteen-year OS rate from random assignment = 66% and LSS rate = 77%
• Ten-year OS rate from diagnosis = 78% and LSS rate = 84%
• Fifteen-year OS rate from diagnosis = 66% and LSS rate = 77%
• For patients who responded to the first treatment cycle (n = 256):
  • Ten-year OS rate = 79% and LSS rate = 85%
  • Fifteen-year OS = 68% and LSS rate = 81%
• For patients who did not respond to the first treatment cycle (n = 65):
  • Ten-year OS rate = 58%
  • Fifteen-year OS = 54%
• The adjusted HR for deaths between responders and non-responders was 0.6 (95% CI, 0.34−94; P =0.03)
• Totally, n = 117 patients (36%) never requires chemotherapy during follow-up but n =24 of them were treated with antibodies and/or radiation
• Treatment failure occurred in n = 237 patients (74%), with a median time to failure (range) = 1.5 (0.1−16) years
• Transformation to aggressive lymphoma occurred in n = 63 patients, with a median time to transformation of 4.2 years. The overall transformation rate was 2.4% per person-year
• In the event where transformation was the first event after the trial treatment, median survival for patients in the single rituximab arm (n = 14) was 4.1 years, and when occurring after chemotherapy (n = 21), median survival was 3.4 years

FL patient subgroup analysis

• With median follow-up of 10.6 years, n = 197 FL patients (73%) were still alive
• Ten-year OS rate after randomization = 75% and LSS rate 82%
• Fifteen-year OS rate after randomization = 65% and LSS rate 77%
• Ten-year OS rate from diagnosis = 78% and LSS rate = 85%
• Fifteen-year OS rate from diagnosis = 65% and LSS rate = 77%
• For patients who responded to the first treatment cycle (n = 219):
  • Ten-year OS rate = 80%
  • Fifteen-year OS = 68%
• For patients who did not respond to the first treatment cycle (n = 50):
  • Ten-year OS rate = 56%
  • Fifteen-year OS = 51%
• The adjusted HR for responders versus non-responders was 0.5 (95% CI, 0.29−88; P =0.02)
• In total, n = 103 patients (38%) never required chemotherapy but n = 22 of them received antibodies and/or radiation
• Transformation occurred in n = 49 patients and overall transformation rate was 2.1% per person-year
• With a median follow-up time after transformation of 2.2 years, the five- and ten-year survival rate was 41%

Safety

• At least one second primary malignancy was reported in 12% of patients who received chemotherapy and in 10% of patients who were chemotherapy-free (P = 0.74)
• Patients receiving chemotherapy, experienced more episodes of bacterial pneumonia, sepsis, or herpes simplex/zoster, and were more often in need of immunoglobulin substitution, as compared to chemotherapy-free patients
• The occurrence and complications of long-term infections were not significantly different between patients who received trial combination therapy from those in the rituximab arm

The NLG investigators concluded that the follow-up data from these two clinical trials indicate that an initial chemotherapy-free regimen in patients with indolent B-cell lymphoma leads to acceptable OS and low toxicity. The authors pinpointed that a substantial amount of patients did not need chemotherapy even after a 10.6-year follow-up and that this finding should be taken into consideration in future treatment planning.