StiL

Published

Rummel MJ, et al. "Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial". The Lancet. 2013. 381(9873):1203-10.
PubMed • Full text • PDF

Clinical Question

Among patients with advanced indolent lymphomas, how does first-line therapy with rituximab-bendamustine (BR) compare to rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) in terms of progression-free survival (PFS), overall survival (OS), and toxicity profile?

Bottom Line

Among patients with advanced indolent lymphomas, first-line therapy with bendamustine-rituximab (BR) is superior to R-CHOP in terms of PFS and toxicity profile, with similar OS benefit, and should therefore supplant R-CHOP in many patients with indolent lymphomas.

Major Points

Although head-to-head comparisons with other regimens are lacking, R-CHOP forms the backbone of treatment for many types of lymphomas in the US, including the indolent lymphomas. Bendamustine has been used widely in Germany since the 1970s for patients with lymphoid malignancies, with a favorable efficacy and toxicity profile. Bendamustine has pharmacologic properties of an alkylator and purine analog, and this dual function may enhance its efficacy as a single agent. Bendamustine's FDA approval for relapsed or refractory rituximab-resistant indolent lymphomas was based on a study published in 2010 that demonstrated an overall response rate (ORR) of 75% and median progression-free survival (PFS) of 9.3 months with single-agent bendamustine. Combination therapy with bendamustine-rituximab (BR) appeared superior to single-agent bendamustine based on a single-arm, phase II study in which combination BR demonstrated an ORR of 92% and median PFS of 23 months. As in the German experience, both efficacy and tolerability were excellent. Efforts were therefore focused on bringing BR into front-line therapy, and a phase III study comparing BR to R-CHOP was necessary.

Published in 2013, the Study Group Indolent Lymphomas (StiL) trial enrolled 549 patients with untreated mantle cell, grade 1-2 follicular, marginal zone, lymphoplasmacytic, or small lymphocytic lymphomas, and randomized patients to either combination BR or R-CHOP for up to six cycles. The primary outcome was progression-free survival performed as a noninferiority analysis. A total of 514 patients in 81 German centers were included in the final analysis. Although the study was designed as a non inferiority study, median PFS was superior with BR compared to R-CHOP at a median follow-up of 3.8 years (69.5 vs. 31.2 months). Overall survival (16.4% vs. 17.8%) and overall response rate (93% vs. 91%) were similar between groups, although complete response (CR) rate favored BR (40% vs. 30%). The toxicity profiles favored BR as well; patients in the BR group received fewer growth factors (4% vs. 20%), had less grade 3-4 neutropenia (29% vs. 69%), less neuropathy (7% vs. 29%), and fewer infections (37% vs. 50%). The rate of secondary malignancies was comparable (8% vs. 9%).

Similar results were seen in an interim analysis of the BRIGHT trial, which studied 419 patients with indolent lymphomas or MCL in North and South America, Australia, and New Zealand. For the primary outcome of CR rate, BR was noninferior to R-CHOP/R-CVP (31% vs. 25%; P=0.0225). Follow-up is ongoing to ascertain differences in PFS and OS.

The role of maintenance rituximab after BR induction therapy is unknown. Maintenance rituximab after R-CHOP gained popularity based on results of the PRIMA study which randomized patients with grade 1-2 follicular lymphoma to 2 years of rituximab maintenance or no maintenance following induction chemoimmunotherapy with R-CHOP, R-CVP, or R-FCM. To date, studies of maintenance rituximab after induction BR are lacking. As of December 2014, the MAINTAIN trial is currently recruiting and well help answer the question of maintenance rituximab after BR; in MAINTAIN, patients with indolent lymphomas or MCL are randomized to either 2 or 4 years of rituximab maintenance following induction with 6 cycles of BR. Similarly, the ECOG 2408 study will evaluate the role of rituximab maintenance or rituximab-lenalidomide maintenance following BR or BR-like induction therapy.

Guidelines

NCCN Guidelines for Non-Hodgkin Lymphoma (2014, adapted)

• BR for grade 1-2 follicular lymphoma in the front line (category 1)
• BR a reasonable less aggressive choice in MCL front-line therapy
• BR is a reasonable choice for CLL/SLL in the front line

Design

• Randomized, open-label, multicenter, phase III noninferiority trial
• N=514 patients with mantle cell or indolent lymphoma were analyzed
  • BR (n=261)
  • R-CHOP (n=253)
• Setting: 81 German centers
• Enrollment: 2003-2008
• Median follow-up: 3.8 years
• Analysis: Per-protocol
• Primary outcome: PFS

Population

Inclusion Criteria

• Age ≥18 years
• WHO performance status ≤2
• Histologically confirmed mantle cell lymphoma or indolent non-Hodgkin lymphoma (grade 1-2 follicular, lymphplasmacytic, small lymphocytic, and marginal zone lymphoma)
• Previously untreated stage III or IV disease
• At least one indication to treat
  • Impaired hematopoiesis (hemoglobin <100g/L, granulocyte count <1.5/L, or platelets <100/L)
  • B symptoms
  • Large tumor burden
  • Bulky disease with impingement on internal organs
  • Progressive disease (>50% in tumor mass in prior 6 months)
  • Hyperviscosity syndrome

Exclusion Criteria

• History of severe cardiac disease
• History of prior malignancy
• Inadequate hepatic, renal, or cardiac function
• HIV or HBV infection
• Patients <65yo with MCL were recommended to participate in other clinical trials incorporating ASCT

Baseline Characteristics

From the BR group, which was similar to the R-CHOP group.

• Mean age: 64 years (36% <60, 23% >70)
• 3% stage II, 19% stage III, 77% stage IV
• 53% follicular, 18% mantle cell, 14% marginal zone, 8% lymphaplasmacytic, 4% SLL, 3% unclassifiable
• B symptoms 38%
• Bone marrow involved 68%
• ≥1 extranodal site involved 81%
• LDH >240 U/L 38%
• Median beta-2 microglobulin 2.6 mg/L
• IPI >2 37%
• 12% FLIPI 0-1, 41% FLIPI 2, 46% FLIPI 3-5

Interventions

• 1:1 randomization to either
  • BR

    Bendamustine 90 mg/m² IV over 30-60 minutes on days 1 and 2

    Rituximab 375 mg/m² IV on day 1

    Repeat every 28 days

  • R-CHOP

    Rituximab 375 mg/m² IV on day 1

    Cyclophosphamide 750 mg/m² IV on day 1

    Doxorubicin 50 mg/m² IV on day 1

    Vincristine 1.4 mg/m² (maximum dose of 2 mg) IV on day 1

    Prednisone 100 mg PO on days 1-5

    Repeat every 21 days

• Patients received up to 6 cycles; no maintenance or consolidation was allowed.
• Supportive medications, G-CSF, treatment delays, and dose reductions per standard guidelines.
• Scans, labs, clinic visits every 3-6 months.

Outcomes

Comparisons are BR vs. R-CHOP.

Primary Outcome

Progression-free survival (median)

69.5 vs. 31.2 months (HR 0.58; 95% CI 0.44-0.74; P<0.0001)

Secondary Outcomes

PFS in FL (median)

Not reached vs. 40.9 months (HR 0.61; 95% CI 0.42-0.87; P=0.0072)

PFS in MCL (median)

35.4 vs. 22.1 months (HR 0.49; 95% CI 0.28-0.79; P=0.0044)

PFS in MZL (median)

57.2 vs. 47.2 months (HR 0.70; 95% CI 0.34-1.43; P=0.3249)

PFS in LPL (median)

69.5 vs. 28.1 months (HR 0.33; 95% CI 0.11-0.64; P=0.0033)

Overall survival

16.4% vs. 17.8%

Treatment Details

Cycles per person

5.58 vs. 5.63

Full treatment doses given

95.9% vs. 88.8%

Cycles requiring G-CSF

4% vs. 20%

Overall response rate

93% vs. 91%

Complete response rate

40% vs. 30% (P=0.021)

Adverse Events

Any toxicity

19% vs. 29%

Neutropenia, grade 3-4

29% vs. 69% (P<0.0001)

Lymphocytopenia, grade 3-4

74% vs. 43% (P not specified)

Alopecia

0% vs. 100% (P<0.0001)

Paresthesia

7% vs. 29% (P<0.0001)

Stomatitis

6% vs. 19% (P<0.0001)

Infection

37% vs. 50% (P=0.0025)

Sepsis

<1% vs. 3% (P=0.019)

Secondary malignancies

8% vs. 9%

Criticisms

• Longer-term follow-up will be necessary to ascertain the long-term complication rate of bendaumstine-containing chemotherapy (eg, secondary MDS, AML).

Funding

Industry (Roche and Ribosepharm)