Three studies on chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma were discussed at the ASH in New Orleans: One was an update on the stage 1 analysis of the CLL11 trial. This investigated the benefit of adding GA101 or rituximab to chlorambucil in the first-line treatment of patients with CLL and comorbidities. Furthermore, results of a gender-specific analysis on rituximab in maintenance therapy in patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) were presented. Finally, they discussed the six-year follow-up to the PRIMA trial, which evaluated rituximab in two-year maintenance therapy in patients with FL.
(ag) Valentin Goede, MD, University Hospital Cologne, Germany, presented results from the CLL11 study, a large phase III trial evaluating first-line chemoimmunotherapy in patients with chronic lymphocytic leukemia (CLL) and comorbidities [1]. Among them was an update on the stage 1 analysis comparing GA101 (obinutuzumab) plus chlorambucil (GClb) with Clb and rituximab plus Clb (RClb) with Clb. At that time, GClb and RClb were shown to be superior to Clb chemotherapy alone in terms of efficacy. As part of the update, the observation period has now been extended.
The study group consisted of CLL patients with no prior treatment and a total Cumulative Illness Rating Scale (CIRS) score of >6 and/or an estimated creatinine clearance (CrCl) of <70 mL/min. They received either Clb alone (6 cycles of 0.5 mg/kgKG orally on day 1, 15 and every 28 days), GClb (100 mg i.v. on day 1, 900 mg i.v. on day 2, 1000 mg on days 8 and 15 in the first cycle; 1000 mg on day 1 in cycles 2-6) or RClb (375 mg/m2 i.v. on day 1 in the first cycle; 500 mg/m2 on day 1 in cycles 2-6).
Results: The update covered a median observation period of 23 months. “First, we can say that the primary stage 1 results were confirmed: Compared with Clb alone, the combinations of GClb and RClb produced a statistically significant improvement in progression-free survival (primary endpoint). Both GClb and RClb reached a significance of p<0.0001. The updated progression-free survival periods were 26.7 months under GClb, 16.3 under RClb, and 11.1 under Clb,” Dr. Goede said. Overall survival (one of the secondary endpoints) showed a significant benefit of GClb over Clb (p=0.002), but not of RClb over Clb (p=0.113). By the end of data collection, 9% of patients under GClb, 15% under RClb, and 20% under Clb had died.
NHL13 study
Prof. Dr. med. Ulrich Jäger, Arbeitsgemeinschaft Medikamentöse Tumortherapie (AGMT), Salzburg, Austria, spoke about the advantages of maintenance therapy with rituximab in patients with aggressive B-cell lymphoma [2].
A 2012 study showed that female patients with diffuse large B-cell lymphoma (DLBCL) benefited more from rituximab than male patients in the first-line setting [3]. The same is true for maintenance therapy of relapsed DLBCL [4] and for induction and maintenance therapy with rituximab in follicular lymphoma (FL) [5]. “So why did women respond differently to the drug than men? Lower body weight or lower volume of drug distribution in women have been discussed as possible causes.”
In its NHL13 study, the AGMT investigated rituximab as maintenance therapy in patients with DLBCL and FL grade 3 in complete remission or unconfirmed complete remission after treatment according to the R-CHOP regimen (rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone/prednisolone). It concluded that maintenance therapy with rituximab did not significantly prolong either event- or progression-free survival. Only a trend in event-free survival and a reduced incidence of recurrence could be observed. In the second interim analysis, different toxicities were also observed for women and men. “This prompted us to examine the results on a gender-specific basis in the final analysis,” Prof. Jäger explained.
Study Design: 683 patients were studied in the NHL13 trial, 662 DLBCL and 21 FL patients (grade 3). They either received rituximab 375 mg/m2 every two months for two years in maintenance therapy (n=338) or were monitored only (n=345). They had previously completed a four- to eight-cycle R-CHOP regimen and were in complete remission or unconfirmed complete remission. The median observation period was 45 months. The primary endpoint was event-free survival, and one of the secondary endpoints was progression-free survival.
Gender-specific results of the final analysis: while event-free survival was prolonged in men receiving rituximab compared with those receiving observation (84.1 vs. 74.4% at three years, p=0.0267), this was not the case in women (76.8 vs. 78.7%). The effect was particularly pronounced in male patients with an IPI <1 (“International Prognostic Index”). There was also a significant effect of rituximab on progression-free survival in men only compared to the control group (89 vs. 77.6% at three years, p=0.0058). In contrast, no significant differences were observed in overall survival. “Regarding side effects, more women experienced at least one grade 3 or 4 side effect than men (21.7 vs. 12.3%, p=0.0297),” Prof. Jäger said. “Consequently, this unplanned, gender-specific subanalysis yielded surprising results: Bi-monthly rituximab maintenance therapy provides significant benefits for men with DLBCL and FL grade 3, suggesting the importance of proper dosing of rituximab. It may need to be prolonged and taken at increased doses in men with aggressive B-cell lymphomas, particularly those in the low IPI subset.”
Update PRIMA Study
An update on the six-year follow-up of the PRIMA trial was provided by Gilles Andre Salles, MD, of Hospices Civils de Lyon [6]: “PRIMA evaluated rituximab in two-year maintenance therapy in 1018 patients with FL who had previously responded to one of three non-randomized first-line immunochemotherapies. The results of the final analysis with a follow-up of 36 months showed a significant risk reduction for progression or death in patients receiving rituximab (n=505) [7]. We have now extended the observation period by three additional years.”
Results: There was sustained and consistent benefit of two-year maintenance therapy with rituximab after immunochemotherapy even after this period.
The progression-free survival value at six years was 42.7% in the observation group and 59.2% in the rituximab group (p<0.0001).
The effect of rituximab was consistent across different subgroups (age, sex, “Follicular Lymphoma International Prognostic Index-“[FLIPI-]score category, type of induction chemotherapy, and response to it).
No additional or unexpected long-term toxicities were observed with rituximab. The most common side effects in the original study were infections. At that time, grade 3 and 4 adverse events occurred in 24% of patients under rituximab and 17% in the observation group (p=0.0026).
Overall survival results were comparable in the two groups (11.3% died in the observation arm, 11.7% in the rituximab arm). Reasons for death were mainly lymphoma, other malignant tumors and infections.
The extent of histologic transformation did not differ in the two treatment arms.
“So we found that even after a significantly prolonged follow-up, progression-free survival remained constant and significantly better after two-year maintenance therapy with rituximab than without such treatment,” Dr. Salles concluded his presentation.
Source: 55th ASH Annual Meeting, December 7-10, 2013, New Orleans.
The results of the stage 2 analysis, also discussed at ASH, will be presented in the next InFo ONKOLOGIE & HÄMATOLOGIE.
Literature:
- Goede V, et al: Head-To-Head Comparison Of Obinutuzumab (GA101) Plus Chlorambucil (Clb) Versus Rituximab Plus Clb In Patients With Chronic Lymphocytic Leukemia (CLL) And Co-Existing Medical Conditions (Comorbidities): Final Stage 2 Results Of The CLL11 Trial. ASH Abstract #6.
- Jäger U, et al: Rituximab Maintenance Significantly Prolongs Event Free (EFS) and Progression Free Survival (PFS) In Male Patients With Aggressive B-Cell Lymphoma In The NHL13 Study. ASH Abstract #851.
- Müller C, et al: The role of sex and weight on rituximab clearance and serum elimination half-life in elderly patients with DLBCL. Blood 2012 Apr 5; 119(14): 3276-3284. doi: 10.1182/blood-2011-09-380949. epub 2012 Feb 15.
- Gisselbrecht C, et al: Rituximab maintenance therapy after autologous stem-cell transplantation in patients with relapsed CD20(+) diffuse large B-cell lymphoma: final analysis of the collaborative trial in relapsed aggressive lymphoma. J Clin Oncol 2012 Dec 20; 30(36): 4462-4469. doi: 10.1200/JCO.2012.41.9416. epub 2012 Oct 22.
- Jäger U, et al: Rituximab serum concentrations during immuno-chemotherapy of follicular lymphoma correlate with patient gender, bone marrow infiltration and clinical response. Haematologica 2012 Sep; 97(9): 1431-1438. epub 2012 Apr 17.
- Salles GA, et al: Updated 6 Year Follow-Up Of The PRIMA Study Confirms The Benefit Of 2-Year Rituximab Maintenance In Follicular Lymphoma Patients Responding To Frontline Immunochemotherapy. ASH Abstract #509.
- Salles G, et al: Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet 2011 Jan 1; 377(9759): 42-51. doi: 10.1016/S0140-6736(10)62175-7. epub 2010 Dec 20.
InFo Oncology & Hematology 2014; 2(1): 26-27.
