Effectiveness of Treatment with VR-CAP Versus R-CHOP for Patients with Non-GCB DLBCL

Clinical outcomes differ considerably between the germinal center B-cell-like (GCB) and non-GCB subtypes of diffuse large B-cell lymphoma (DLBCL), with overall survival inferior in non-GCB patients. While R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) is the standard frontline treatment for DLBCL, outcomes with R-CHOP are not as good in non-GCB DLBCL compared with GCB, and new approaches are needed for the non-GCB group.

The proteasome inhibitor bortezomib has clinical activity in patients with DLBCL, and earlier studies suggested that bortezomib may have specific utility in non-GCB DLBCL subtype. However, according to results from the phase II LYM-2034 trial, substituting bortezomib for vincristine in the standard frontline treatment of R-CHOP did not improve response or survival rates for patients with non-GCB DLBCL.

“More efficacious therapies targeting the molecular basis of non-GCB DLBCL are required,” wrote Prof. Fritz Offner, from the University Hospital Ghent in Belgium, and colleagues in their report recently published in Blood. “[The results from] this study highlight the need for better identification of markers of poor prognosis in DLBCL and of markers for patients who could achieve better outcomes with bortezomib-based therapy versus standard R-CHOP.”

LYM-2034 was a phase II, open-label, multinational, randomized study to determine if bortezomib plus R-CHOP produces a clinical benefit in patients with previously untreated non-GCB DLBCL. The study was conducted at 57 centers in 18 countries between January 2010 and December 2011. All 164 study participants had immunohistochemistry-confirmed stage 2-4 disease or stage 1 primary mediastinal DLBCL.

Patients were excluded from the study if they had a diagnosis of transformed lymphoma (follicular, T-cell, or Hodgkin lymphoma) or central nervous system lymphoma; previous chemotherapy or extended radiotherapy for lymphoma; grade ≥2 peripheral neuropathy; and uncontrolled or severe cardiovascular disease.

All study participants received six 21-day cycles of R-CHOP (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and doxorubicin 50 mg/m2 all delivered intravenously on day one, followed by prednisone 100 mg/m2 on days one through five), and then were randomized 1:1 to receive either:

  • bortezomib 1.3 mg/m2 IV on days one, four, eight, and 11 (VR-CAP treatment; n=84)
  • vincristine 1.4 mg/m2 IV on day one (R-CHOP treatment; n=80)

Treatment was discontinued for progressive disease (PD) or relapse, unacceptable toxicity, patient withdrawal, and a delay in treatment due to insufficient recovery from toxicity of longer than three weeks. Response and PD were assessed at the end of treatment cycles three and six, and thereafter as clinically indicated.

Over a median follow-up of 24.9 months (range, 0-40 months), the researchers found no significant difference in complete response rate (CRR; the study’s primary endpoint) between the two groups: 64.5 percent for VR-CAP and 66.2 percent for R-CHOP (odds ratio [OR] = 0.91; p=0.80). Similarly, no difference was recorded for the secondary endpoints of overall response rate (93.4% for VR-CAP and 48.6% for R-CHOP; OR = 0.21; p=0.11), progression-free survival (HR=1.12; p=0.76), or overall survival (HR=0.89; p=0.75) (TABLE).

Twenty-three (27%) patients in the VR-CAP arm and 19 (24%) in the R-CHOP arm received subsequent treatment; nine patients in the VR-CAP arm and four in the R-CHOP arm went on to receive high-dose therapy and autologous stem cell transplantation (HDT-ASCT) as subsequent therapy.

“At the time of this final analysis, PFS and OS data had not reached full maturity,” Prof. Offner and colleagues wrote, “however, findings from a recent report indicate that two-year PFS is a good surrogate marker for long-term outcomes in DLBCL, and therefore more extended follow-up is unlikely to reveal a survival benefit for VR-CAP.”

On the safety side, the rates of adverse events (AEs) were similar between the VR-CAP and R-CHOP cohorts:

  • Grade ≥3 AEs: 88% and 89%
  • Serious AEs: 38% and 34%
  • Discontinuations due to AEs: 7% and 3%
  • Deaths due to AEs: 2% and 5%

However, grade ≥3 febrile neutropenia rates were lower, and grade ≥3 thrombocytopenia rates were higher, with VR-CAP – likely reflecting the different regimen components, the authors added.

Prof. Offner and co-authors note that the delay in treatment caused by the central pathology review procedure (albeit only 5 days on average) may have excluded patients with the worst disease prognosis from being considered for participation in the trial, “which may explain the relatively good outcomes in both arms of the study.”


Reference

Offner F, Samoilova O, Osmanov E, et al. Frontline rituximab, cyclophosphamide, doxorubicin, and prednisone with bortezomib (VR-CAP) or vincristine (R-CHOP) for non-GCB DLBCL. Blood. 2015 July 31. [Epub ahead of print]

TABLE. Rates of PFS, OS, and Patients Remaining Treatment-Free

Outcome, %

(95% CI)

VR-CAP(n=84) R-CHOP(n=80) Hazard Ratio(95% CI)

p Value

PFS Rate
One-year rate

80%

(69.0-87.5)

82.%

(71.4-89.3)

1.12

(0.57-2.20)

0.76

Two-year rate

76.2

(64.2-84.7)

77.1%

(65.1-85.4)

OS Rate
One-year rate

91.2%

(82.3-95.7)

85.9%

(76.0-92.0)

0.89

(0.44-1.81)

0.75

Two-year rate

80.1%

(69.0-87.5)

79.0%

(67.9-86.6)

Treatment-Free Rate
One-year rate

70.6%

(59.2-79.4)

78.4%(67.2-86.2) 1.25

(0.69-2.24)

0.49

Two-year rate

69.3%(57.8-78.3)

71.8%

(59.6-80.9)

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