Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent and mantle cell lymphomas (MCL): Updated results from the StiL NHL1 study
Reporter: Annemarie Fernandes
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 3, 2012
Presenter: Mathias J. Rummel MD, PhD
Presenter's Affiliation: Universitaetsklinik, Giessen, Germany
- There are about 25,000 new cases of indolent B-cell lymphoma and mantle cell lymphoma per year, with a median overall survival of about 5 years for mantle cell lymphoma and about 10 years for the more indolent histologies.
- Patients often have a chronic, relapsing course, requiring multiple chemotherapy agents and other treatment modalities.
- First-line therapy has typically involved R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone).
- Bendamustine is a DNA alkylating agent that has been studied in CLL, Hodgkins disease and multiple myeloma. Bendamustine has also been studied in refractory or relapsed indolent Non-Hodgkin's lymphoma and mantle cell lymphoma with favorable outcomes and toxicity profiles (Robinson JCO 2008).
- The preliminary data from the StiL NHL1 study was presented at ASH 2009 including a comprehensive safety analysis that demonstrated a favorable toxicity profile with Bendamustine-Rituximab.
- This presentation reveals an updated analysis with a cut-off date for 31 Oct 2011.
Materials and Methods
- This is a multicenter (involving 81 centres in Germany), randomized, phase III study comparing Bendamustine-Rituximab (B-R) and CHOP-R as first-line treatment in indolent lymphoma and mantle cell lymphoma (MCL). Patients were enrolled between September 2003 and August 2008
- Inclusion Criteria
- Lymphomas included follicular lymphoma (FL, 54%), Waldenstrom's (8%), Marginal Zone Lymphoma (MZL, 13%), small lymphocytic lymphoma (SLL, 4%), or MCL (elderly, 18%).
- Histology could not be older than 6 months
- No pretreatment with chemotherapeutics, Interferon or Rituximab
- Stage III or IV
- Age>18 years, no upper age limit, WHO 0-2
- Defined indications for treatment: B-symptoms, hematopoietic failure, large tumor burden, rapid progression, complications due to disease
- Treatment: A maximum of 6 cycles of chemotherapy were delivered using one of the following regimens:
- B-R: Bendamustine (90 mg/m2, day 1+2); Rituximab (375 mg/m2, day 1)
- CHOP-R: Cyclophosphamide (750 mg/m2, day 1), Doxorubicin (50 mg/m2, day 1), Vincristine (1.4 mg/m2, day 1), Prednisone (100 mg, days 1-5), Rituximab (375 mg/m2, day 1)
- The primary endpoint was PFS.
- Primary Objective: Prove a non-inferiority of B-R vs. CHOP-R, defined as a decrease of less than 10% in PFS after 3 years
- Secondary Objectives: response rates, time to next treatment, event-free survival (EFS), overall survival (OS), acute and late toxicity, stem cell mobilization capacity.
- 549 patients were randomized. 514 randomized patients were evaluable (261 B-R; 253 CHOP-R).
- Patient characteristics were well-balanced between arms; median age was 64 years. There was a higher percentage of patients with B-symptoms in the B-R arm (38% vs. 29%, p=0.0322). The majority of patients had Stage IV disease (77%), bone marrow involvement (67 and 68%, respectively); 28% had bulky disease.
- Median follow-up was 45 months
- Progression-Free Survival (PFS):
- PFS was significantly prolonged with B-R compared with CHOP-R (HR 0.58, 95% CI 0.44–0.74; P<0.001). Median PFS was 69.5 versus 31.2 months, respectively.
- Histology: Marginal zone lymphoma was the only histology that did not demonstrate an improvement in PFS with B-R.
- Age: The PFS benefit with B-R was independent of age; HR 0.52 (P=0.002) in pts ?60 years (n=199), and HR 0.62 (P=0.002) in pts >60 years (n=315).
- LDH: In pts with normal LDH (62%), PFS was significantly prolonged with B-R compared with CHOP-R (P<0.001), while in the elevated LDH group (38%) PFS was not significantly increased with B-R compared with CHOP-R (P=0.118).
- FLIPI subgroups: In patients with follicular lymphoma, FLIPI subgroups defined by 0–2 factors (favorable) and 3–5 factors (unfavorable) had a longer PFS with B-R than with CHOP-R (P=0.043 and P=0.068 for the favorable and unfavorable FLIPI subgroups, respectively).
- Overall survival did not differ between the treatment arms.
- Similar overall response rates (ORR) were seen in the 2 arms: 92.7% (B-R) vs. 91.3% (CHOP-R), however, the B-R arm was associated with a higher complete response rate (39 vs. 30%, p=0.021)
- Choice of salvage regimens after failure was left up to physician discretion. Of those in the CHOP-R group, 52 (37%) patients received B-R as salvage regimen. Additionally more patients in the CHOP-R arm went on to autologous stem cell transplant (13% vs. 5%).
- There was no significant anemia or thrombocytopenia
- Patients treated with B-R had less neutropenia, infectious complications, alopecia, neuropathy and stomatitis.
- Patients treated with CHOP-R had less lymphopenia and skin toxicity
- Twenty secondary malignancies were observed in the B-R group compared with 23 in the CHOP-R group, with 1 hematological malignancy in each group (1 MDS in B-R, 1 AML in CHOP-R).
- <2% of the total patient population experienced transformation to a more aggressive histology
- Compared with CHOP-R, B-R demonstrates a PFS benefit, increased complete response rate and improved tolerability in patients with previously untreated indolent lymphoma, and elderly patients with MCL.
- The authors conclude that B-R is not only less toxic, but also more effective than the most often used first-line treatment approach, CHOP-R. Therefore, B-R can be considered as a preferred first-line treatment for patients with indolent lymphoma and elderly patients with MCL.
- The authors demonstrate a significant benefit with treatment of indolent and mantle cell lymphoma with Bendamustine-Rituximab, as this treatment regimen demonstrated improved progression-free survival in patients with all histologic subtypes except marginal-zone lymphoma, and a more favorable toxicity profile with less neutropenia, less infectious complications, less alopecia, less neuropathy and less stomatitis when compared to the standard first-line therapy of CHOP-R.
- Interestingly, the 2-year PFS rate in the CHOP-R arm of 60% is slightly lower than some recent studies with 3-year PFS rates of 60% (Morschhauser et al, ICML, 2011). This slightly lower PFS rate in the CHOP-R arm may have inflated the difference in PFS between the two arms. Regardless, the difference in PFS between B-R and CHOP-R is still statistically significant and robust.
- There was no overall survival benefit seen with B-R, probably because longer follow-up is required to detect a difference in overall survival in indolent lymphoma.
- Additionally, longer follow-up is required to further understand the long-term toxicities associated with B-R, such as the risk of MDS and secondary malignancies.
- Since many patients with relapsing and remitting disease undergo multiple treatment regimens, it is important to understand the how first-line therapy with B-R impacts the use of other treatment regimens in the course of a patients overall therapy course. For example, the impact of B-R on salvage chemotherapy regimens, radiation therapy and autologous stem cell transplant needs to be further defined.
- Further studies: Currently, the authors are conducting a StiL NHL 7-2008 study evaluating the optimal duration of maintenance Rituximab (2 years vs. 4 years) after initial first-line therapy with B-R in patients with Follicular Lymphoma
- Additionally, understanding the activity of B-R in other lymphomas, such as DLBCL and transformed lymphoma will be interesting and potentially useful in improving outcomes in these more aggressive histologies.
ASCO Endorses Guideline for Radiation After Prostatectomy
Nov 6, 2014 - The American Society for Clinical Oncology has endorsed a recent guideline for adjuvant and salvage radiotherapy after prostatectomy. The endorsement was published online Nov. 3 in the Journal of Clinical Oncology.
Frequently Asked Questions
I Wish You Knew
How cancer patients have changed my life
Blogs and Web Chats
OncoLink Blogs give our readers a chance to react to and comment on key cancer news topics and provides a forum for OncoLink Experts and readers to share opinions and learn from each other.
Facing a new cancer diagnosis or changing the course of your current treatment? Let our cancer nurses help you through!