In Lymphoma, Best Partner With Rituximab Still in Question

Alexander M. Castellino, PhD

June 15, 2017

Results from the long-term follow-up of frontline therapy for patients with indolent non-Hodgkin's lymphoma (iNHL) show the long-term benefits of chemotherapy in combination with rituximab (Rituxan, Roche/Genentech).

However, there is still a question as to which is the best chemotherapy partner, the combinations of CVP (cyclophosphamide/vincristine/prednisone), CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone), or bendamustine.

The issue was discussed recently at the American Society of Clinical Oncology (ASCO) 2017 Annual Meeting, when the results from two long-term studies, StiL and BRIGHT, that used frontline therapy with the combination of rituximab and chemotherapy in the treatment of iNHL were discussed at a Highlights of the Day session.

"Rituximab chemotherapy with or without rituximab maintenance is the only treatment that has demonstrated a significant improvement of OS [overall survival] in patients with follicular lymphoma and other indolent lymphomas," commented Gilles Salles, MD, of the Hospices Civils de Lyon, Université Claude Bernard de Lyon, France.

"For mantle cell lymphoma, the combination of bendamustine and rituximab [BR] may be better than CHOP-rituximab [R-CHOP], but for iNHL, I believe the benefit of BR remains undetermined," Dr Salles commented. "In iNHL, there is no OS and there is a trend towards higher toxicity," he noted.

Commenting further on the toxicity, Dr Salles said, "The field was shaken at the ASH 2006 meeting with data from the registration GALLIUM study.

"What GALLIUM has shown was there was an excess of adverse event–related fatalities in patients receiving bendamustine with either rituximab or the newer CD-20 antibody obinutuzumab [Gazyva, Genentech/Roche]," he added.

Excess Toxicity With Bendamustine

GALLIUM was a phase 3 head-to-head comparison of frontline obinutuzumab vs rituximab. The strategy was to use induction therapy with a CD-20 antibody (obinutuzumab or rituximab) and chemotherapy (bendamustine, CHOP, or CVP) for 6 months followed by maintenance therapy with the CD-20 antibody for 2 years.

Results presented at the ASH meeting and reported by Medscape Medical News showed that progression-free survival (PFS) was significantly improved in patients in the obinutuzumab arm compared to those in the rituximab arm, but there was no difference in OS, and there was more toxicity in the obinutuzumab arm.

A further analysis of the toxicity data showed an excess of deaths in the patients who received bendamustine for induction in comparison with patients who received the other chemotherapy regimens. Bendamustine induction regimens were associated with the highest rates of death: 5.6% (19 patients) for obinutuzumab-bendamustine (G-bendamustine) and 4.4% (15 patients) for BR. In contrast, deaths occurred in nine patients across all other arms.

GALLIUM lead investigator Robert E. Marcus, MD, of King's College Hospital, London, United Kingdom, told Medscape Medical News at the time that the fatal toxicities were mainly infections, but that there were also some fatalities from cardiac, neurologic, and respiratory toxicities.

The rate of death from infection was also higher for bendamustine-containing regimens — 2.7% (nine patients) for G-bendamustine and 0.6% (two patients) for BR. Death from infection was reported in one patient across all other arms.

Rituximab With Chemo Improves Survival

In his talk, Dr Salles highlighted the latest long-term data that had been reported at the meeting from the BRIGHT and Stil studies.

The BRIGHT study (abstract 7500) provided a 5-year follow-up of treatment-naive patients with iNHL or mantle cell lymphoma who received BR or R-CHOP, or BR or CVP-rituximab (R-CVP).

Among iNHL patients, PFS was similar for those who received BR or R-CHOP-R/R-CVP (hazard ratio [HR], 0.70). However, PFS was significantly longer in patients with mantle cell lymphoma who received BR (HR, 0.40; P = .0035).

Duration of response followed a similar pattern as PFS by treatment group.

However, OS was not significant for either lymphoma type.

Although not significant, there was an imbalance in the deaths that occurred with BR. Excess of non-lymphoma-related deaths (eg, infections, second malignancies, and cardiac events) were reported for more patients who received BR (24 vs 15 for R-CHOP/R-CVP), and there was an increase (but not significant) in secondary malignancies (10% for BR vs 6% for R-CHOP/R-CVP), such as transformation to high-grade NHL or nonmelanoma skin cancers.

In the StiL study (abstract 7501), 420 patients with follicular lymphoma (66%), Waldenström's macroglobulinemia (10%), marginal zone lymphoma (16%), and small lymphocytic leukemia (5%) were randomly allocated to receive either the combination of BR (n = 215) or R-CHOP (n = 205) as frontline therapy.

An earlier 45-month follow-up had shown that PFS was significantly longer with BR than CHOP-R, and time-to-next treatment (TTNT) followed a similar trend. In the 10-year follow-up, a significant delay in TTNT, used as a surrogate for PFS, was reported for patients on BR (not reached vs 56 months for R-CHOP; P < .001).

However, OS was similar with both regimens (10-year OS: 70.3% for BR vs 66.3% for CHOP-R).

Contrary to the BRIGHT study, 37 patients who received BR experienced a second malignancy vs 40 patients who received CHOP-R. However, Dr Salles noted that this was an academic study in which investigators were given questionnaires regarding these events.

Caution Required, but Long-term Outcomes Improve

"Based on these data, caution should be exercised with respect to the short- and long-term toxicities of each R-chemotherapy regimen [R-CHOP, BR, R-CVP] with or without R-maintenance," Dr Salles said.

"We need long-term data regarding the benefits and risks of the different chemotherapy regimens," he said.

However, the main message remains that the outcome of patients with iNHL continues to improve, he noted. "A substantial proportion of patients have not experienced disease progression or received a new treatment after 10 years," he added.

Dr Salle receives honoraria from Amgen, Bristol-Myers Squibb, Celgene, Gilead, Janssen, Novartis, Roche/Genentech, and Servier. He also consults for or is on the advisory board of Celgene, Gilead, Janssen, Merck, Novartis, Novimmune, and Roche/Genentech.

American Society of Clinical Oncology (ASCO) 2017 Annual Meeting. Abstracts 7500 and 7501, both presented June 3, 2017.

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