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
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.
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