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PRIORITY PRESS - 54th Annual Meeting of the American Society of Hematology

Atlanta, Georgia / December 8-11, 2012

Atlanta - Decades of laboratory and clinical research have yet to determine the optimal therapy for indolent non-Hodgkin lymphoma and mantle-cell lymphoma. The combination of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) remains a therapeutic standard. Some clinicians have found that omission of doxorubicin from the regimen (CVP) improves tolerability without sacrificing efficacy. The addition of rituximab (R-CHOP or R-CVP) has demonstrated better results in some studies and has become a favoured regimen among some lymphoma specialists. Evaluation of alternatives to CHOP and CVP remain a focal point of clinical investigation, as reflected in presentations at the recent American Society of Hematology conference.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

Several recent clinical investigations have examined the therapeutic potential of the alkylating agent bendamustine in the treatment of indolent non-Hodgkin lymphoma (NHL) and mantle-cell lymphoma (MCL). Distinct from other agents in the class, it has a multifaceted mechanism of action, stated Dr. Ian Flinn, Vanderbilt University, Nashville, Tennessee.

Recently, the combination of bendamustine and rituximab (B-R) was compared with R-CHOP in a randomized clinical trial (Abstract 902).The results showed a higher rate of complete response with B-R (40% vs. 30%) and more than a twofold increase in progression-free survival (PFS) at 70 months vs. 31 months, P<0.0001), although overall survival (OS) was similar. The B-R regimen was associated with lower rates of neutropenia and leucopenia but more skin reactions as compared with R-CHOP, noted Dr. Flinn.

Continuing clinical evaluation of the B-R regimen, investigators in a multicentre trial compared the 2-drug combination with R-CHOP/R-CVP in patients with untreated indolent NHL or MCL. After preassignment of R-CHOP and R-CVP to investigators, 447 patients were randomized to 6 cycles of one of the standard regimens or to B-R. At physician discretion, patients could receive 8 cycles of therapy.

Follow-up in the trial continued for 5 years and the primary objective was to determine the noninferiority of B-R to standard therapy with respect to achievement of complete response. Secondary outcomes of interest were overall response rate, safety and tolerability, quality of life (QOL) and time-to-event analyses.

The final analysis comprised 419 evaluable patients, 213 treated with B-R and 206 who received R-CHOP/R-CVP.

Key Results

For the primary analysis, rates of complete response (CR) were 31% with B-R and 25% with R-CHOP/R-CVP, a difference that resulted in a ratio of 1.26 in favour of the former. The results met statistical criteria for noninferiority (P=0.0225). Comparison for superiority showed no difference between treatment groups (P=0.1269). An additional 65% of patients in the B-R arm achieved partial responses (PRs), as did 66% of patients randomized to R-CHOP/R-CVP.

The regimens differed somewhat with respect to adverse events. Patients treated with B-R had higher rates of nausea, vomiting, pyrexia, chills, drug hypersensitivity, decreased appetite, rash and pruritus. The R-CHOP/R-CVP regimens were associated with more constipation, paresthesia, peripheral neuropathy and alopecia.

Summarizing the findings, Dr. Flinn stated, “The CR rate of the B-R regimen is statistically noninferior to R-CHOP and R-CVP in patients with previously untreated indolent NHL and MCL. The objective response rate was high for both treatment groups. B-R and R-CHOP/R-CVP have distinct toxicity profiles.”

Quality of Life

A separate presentation of study data focused on QOL associated with the different regimens. Patients completed the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire after completion of chemotherapy cycles 1, 3, 6 and 8. The QLQ-C30 has 30 items that can be organized into 3 scales: function, symptom and global health status, explained Dr. John Burke, University of Colorado, Aurora.

Compilation of the results showed advantages for the B-R regimen at various points in time during treatment. Analyses favoured B-R for cognitive function after cycles 1 and 3; physical functioning after cycle 6; social functioning after cycle 1; emotional functioning after cycle 6; constipation after cycle 3; dyspnea after cycle 3; fatigue after cycles 1, 3 and 6.

The results showed that the R-CHOP/R-CVP regimens were associated with less nausea and vomiting after cycle 3 among patients who had low baseline levels of nausea and vomiting. Results for other QOL outcomes and other time points were similar for the regimens.

“Patients with indolent NHL or MCL treated with B-R experienced improvements in various aspects of QOL compared with patients treated with R-CHOP/R-CVP,” remarked Dr. Burke.

Ongoing follow-up in another clinical evaluation of the B-R regimen focused on the emerging issue of CR as a prognostic marker.

“An important question in the management of patients with indolent lymphomas surrounds the depth of response and whether the achievement of a high-quality response is associated with an improved outcome,” Prof. Mathias J. Rummel, University Hospital Giessen, Germany, stated in a poster presentation. “The demonstration of such an effect may have implications for the choice of treatment, particularly for newly diagnosed disease. In addition, the finding of a prognostic impact may also aid the discussion of suitable end points in clinical trials.”

CR as a Prognostic Marker

Prof. Rummel and colleagues evaluated the association between CR and subsequent outcome in 514 patients randomized to B-R or R-CHOP for treatment of indolent NHL or MCL. Overall response rates were 92.7% with B-R and 91.3% with R-CHOP, including CRs in 39.8% patients treated with B-R and 30% of those randomized to R-CHOP (P=0.021).

Evaluation of PFS and OS showed that patients who achieved CR had a median PFS of 57.5 months, whereas PR was associated with a median PFS of 43.5 months (P=0.0037). The 5-year OS was 90.3% among patients who achieved a CR and 77.5% in those who had PRs (P=0.0008).

Continuing the evaluation to the separate treatment arms, Prof. Rummel reported that median PFS had not been reached in patients who had CRs with the B-R arm, whereas those who had PRs had a median PFS of 57.2 months (P=0.1912). The 5-year OS in the arm was 91.0% among patients who achieved CRs and 80.1% among those who had PRs (P=0.0044).

Median PFS also differed significantly (P=0.0215) in the R-CHOP arm when patients achieved CR (53.7 months) vs. PR (30.9 months). OS at 5 years did not differ significantly between patients who had CRs or PRs (89.6% vs. 75.4%, P=0.0737).

“Patients in complete remission following first-line treatment had a significantly longer PFS and OS compared to those achieving a PR,” Prof. Rummel concluded. “Therefore, our results strongly suggest an association between the quality of response and outcome, indicating that the achievement of a deep response should be an important goal in follicular lymphoma (FL).”

Striving for Better Outcomes

Other studies reported at the ASH conference reflected the ongoing search for effective alternatives to conventional CHOP and CVP regimens for indolent NHL, MCL and FL.

Clinical researchers from Italy retrospectively examined medical records of 548 patients with FL in first relapse treated at 25 different centres. The data showed that 22% of patients received alkylating agent-based therapy, 61% received anthracycline-based regimens and 17% received nucleoside analog therapy. Half of the patients received regimens that included rituximab.

The primary end point was time to next treatment after relapse. Overall, both the median follow-up after first relapse and the median time to next treatment after relapse was 41 months. The analysis showed that anthracycline-based therapy ±rituximab led to prolonged time to next therapy compared with alkylating agent-based therapy (HR 0.71, P=0.007) and treatment with nucleoside analog regimens (HR 0.73, P=0.021). The addition or omission of rituximab did not significantly alter the results, reported Dr. Giuseppe Rossi, Spedali Public Hospital, Brescia, Italy.

The investigators also evaluated outcomes with various strategies for salvage therapy. They found that autologous stem cell transplantation (SCT) led to the best results.

“Considering the combinations of first-line and salvage treatments received, using multiple Cox regression, the time to next therapy after relapse was significantly better in patients receiving first-line anthracycline chemotherapy ±rituximab, followed by autologous hematopoietic SCT as salvage,” Dr. Rossi concluded. “Other factors independently influencing time to next therapy after hematopoietic SCT were rituximab maintenance, duration of first remission >12 months and stage III-IV at diagnosis.

PFS after relapse was 35% at 5 years, virtually identical to time to next treatment, Dr. Rossi added. Treatment sequences had the same effect on PFS as on time to next treatment after relapse. The 5-year OS was 89%. The best results occurred when chemotherapy was followed by SCT or additional chemotherapy plus rituximab.    

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