In the JournalsPerspective

Maintenance rituximab prolongs survival for certain patients with mantle cell lymphoma

Rituximab maintenance therapy after autologous hematopoietic stem cell transplantation prolonged EFS, PFS and OS among patients aged younger than 66 years at mantle cell lymphoma diagnosis, according to results from a phase 3 clinical trial.

“These results show the efficacy of a cytarabine-based induction regimen free of anthracycline or alkylating agents in patients with this condition,” Steven Le Gouill, MD, PhD, from the department of hematology at CHU de Nantes in France, and colleagues wrote.

Most patients with mantle cell lymphoma respond to initial therapy; however, residual tumor cells may persist after treatment and lead to relapse. Le Gouill and colleagues hypothesized that maintenance therapy could prolong the duration of complete response and reduce the risk for relapse.

The initial analysis — results from which were presented in part at the ASH Annual Meeting and Exposition — included 299 patients (median age, 57 years) with stage II to stage IV mantle cell lymphoma and an ECOG performance status score of less than 3. Of these, 279 received induction therapy with four courses of rituximab (Rituxan; Genentech, Biogen), dexamethasone, high-dose cytarabine and salt platinum — also known as R-DHAP — every 21 days. Patients who achieved a partial response and tumor mass reduction less than 75% received rescue induction therapy with four courses of rituximab plus CHOP chemotherapy once every 14 days prior to autologous HSCT. A total of 257 patients underwent autologous HSCT.

Researchers randomly assigned 240 patients who achieved response after autologous HSCT to rituximab maintenance therapy (n = 120) or observation (n = 120). The rituximab group received one 375 mg/m2 infusion every 2 months for 3 years.

EFS — defined as disease progression, relapse, death, severe infection or allergy to the study drug — served as the primary endpoint. Secondary endpoints included PFS and OS.

Median follow-up was 54.4 months from inclusion and 50.2 months from the time of randomization.

Median PFS and OS were not reached among low-risk and intermediate-risk patients. Among high-risk patients, median PFS was 47.4 months and OS was 56.2 months (P < .001 compared with the low-risk groups).

Four-year EFS was 79% (95% CI, 70-86) in the rituximab group compared with 61% (95% CI, 51-70) in the observation group (P = .001). Researchers calculated an HR for disease progression, relapse, death, allergy or severe infection of 0.46 (95% CI, 0.28-0.74).

A greater proportion of patients in the rituximab group also achieved 4-year PFS (83% vs. 64%; HR for disease progression, relapse or death = 0.4; 95% CI, 0.23-0.68) and OS (89% vs. 80%; HR for mortality = 0.5; 95% CI, 0.26-0.99).

Neutropenia was the most frequent grade 3 or grade 4 adverse event. Three patients in the rituximab group and one in the observation group died of a second cancer.

Researchers noted no late effects of rituximab have been observed. – by Melinda Stevens

Disclosures: Roche and Amgen funded the study. Le Gouill reports personal fees and nonfinancial support from Roche, grant support and personal fees from Janssen-Cilag and personal fees from Celgene outside the submitted work. Please see the study for a list of all other authors’ relevant financial disclosures.

Rituximab maintenance therapy after autologous hematopoietic stem cell transplantation prolonged EFS, PFS and OS among patients aged younger than 66 years at mantle cell lymphoma diagnosis, according to results from a phase 3 clinical trial.

“These results show the efficacy of a cytarabine-based induction regimen free of anthracycline or alkylating agents in patients with this condition,” Steven Le Gouill, MD, PhD, from the department of hematology at CHU de Nantes in France, and colleagues wrote.

Most patients with mantle cell lymphoma respond to initial therapy; however, residual tumor cells may persist after treatment and lead to relapse. Le Gouill and colleagues hypothesized that maintenance therapy could prolong the duration of complete response and reduce the risk for relapse.

The initial analysis — results from which were presented in part at the ASH Annual Meeting and Exposition — included 299 patients (median age, 57 years) with stage II to stage IV mantle cell lymphoma and an ECOG performance status score of less than 3. Of these, 279 received induction therapy with four courses of rituximab (Rituxan; Genentech, Biogen), dexamethasone, high-dose cytarabine and salt platinum — also known as R-DHAP — every 21 days. Patients who achieved a partial response and tumor mass reduction less than 75% received rescue induction therapy with four courses of rituximab plus CHOP chemotherapy once every 14 days prior to autologous HSCT. A total of 257 patients underwent autologous HSCT.

Researchers randomly assigned 240 patients who achieved response after autologous HSCT to rituximab maintenance therapy (n = 120) or observation (n = 120). The rituximab group received one 375 mg/m2 infusion every 2 months for 3 years.

EFS — defined as disease progression, relapse, death, severe infection or allergy to the study drug — served as the primary endpoint. Secondary endpoints included PFS and OS.

Median follow-up was 54.4 months from inclusion and 50.2 months from the time of randomization.

Median PFS and OS were not reached among low-risk and intermediate-risk patients. Among high-risk patients, median PFS was 47.4 months and OS was 56.2 months (P < .001 compared with the low-risk groups).

Four-year EFS was 79% (95% CI, 70-86) in the rituximab group compared with 61% (95% CI, 51-70) in the observation group (P = .001). Researchers calculated an HR for disease progression, relapse, death, allergy or severe infection of 0.46 (95% CI, 0.28-0.74).

A greater proportion of patients in the rituximab group also achieved 4-year PFS (83% vs. 64%; HR for disease progression, relapse or death = 0.4; 95% CI, 0.23-0.68) and OS (89% vs. 80%; HR for mortality = 0.5; 95% CI, 0.26-0.99).

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Neutropenia was the most frequent grade 3 or grade 4 adverse event. Three patients in the rituximab group and one in the observation group died of a second cancer.

Researchers noted no late effects of rituximab have been observed. – by Melinda Stevens

Disclosures: Roche and Amgen funded the study. Le Gouill reports personal fees and nonfinancial support from Roche, grant support and personal fees from Janssen-Cilag and personal fees from Celgene outside the submitted work. Please see the study for a list of all other authors’ relevant financial disclosures.

    Perspective

    Brad S. Kahl, MD

    The impact of this study is anticipated to be large. Prior to this report, there were no data that suggested benefit for maintenance rituximab after autologous stem cell transplantation in mantle cell lymphoma. Any data supporting maintenance rituximab had been generated from older patients who had received less intensive therapies. In addition, most lymphoma trials that tested maintenance rituximab have been unable to demonstrate an OS benefit.

    This trial clearly demonstrates the substantial impact of maintenance rituximab as a therapeutic intervention in mantle cell lymphoma. I would expect that this trial will result in a change in the standard of care worldwide. I also would anticipate that these results will be extrapolated to patients who undergo autologous transplantation no matter what type of induction regimen they received and no matter what type of stem cell transplant conditioning regimen they received.

    The 3-year duration of maintenance therapy is a bit unusual. Most studies in follicular lymphoma have limited the duration of maintenance exposure to 2 years. It is not entirely clear why the authors selected 3 years in this particular trial, but certainly the results speak for themselves, and 3 years of maintenance should become the standard of care for younger patients with mantle cell lymphoma.

    Brad S. Kahl, MD

    HemOnc Today Editorial Board Member

    Washington University School of Medicine in St. Louis

    Disclosure: Kahl reports no relevant financial disclosures.