Cytarabine in Conditioning Regimen for Younger Patients with MCL 


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High-dose cytarabine should be incorporated into the induction regimen of younger patients with mantle cell lymphoma (MCL) before autologous stem cell transplantation, according to final results of the MCL Younger Trial of the European Mantle Cell Lymphoma Network, presented at the ASH Annual Meeting.1

The study demonstrated that three alternating courses of R-CHOP (rituximab [Rituxan] plus cyclophosphamide, doxorubicin, vincristine, prednisone) and R-DHAP (rituximab plus dexamethasone, cytarabine, cisplatin), compared to R-CHOP, increased clinical complete response rate in MCL patients following induction as well as molecular response, according to polymerase chain reaction analysis (ie, minimal residual disease).

“This regimen also improved time to treatment failure in all risk groups and was related to increased [minimal residual disease]–negative status, which is the best prognosis factor, and showed a trend toward improved overall survival with a good safety profile,” stated lead author Olivier
Hermine, MD, PhD, University of Paris Descartes and Hopital Necker, Paris. “Regimens that include high-dose [cytarabine] should become the new gold standard,” he said.

The study compared three alternating courses of R-CHOP and R-DHAP followed by a myeloablative regimen and autologous stem cell transplantation vs six courses of R-CHOP followed by myeloablative radiochemotherapy and autologous stem cell transplantation in younger patients with MCL. The study randomly assigned 497 patients aged 65 or younger with stage II to IV MCL to the two arms. A total of 233 in the R-CHOP arm and 232 in the R-CHOP/R-DHAP arm were evaluable.

At baseline, median age was 55 years, 79% were male, and about 82% had stage IV disease. Approximately 62% were low risk, 24% were intermediate risk, and 14% were high risk.

Following induction, responses were significantly better in the cytarabine-containing arm: The complete response rate was 25% in the R-CHOP arm vs 36% in the R-CHOP/R-DHAP arm (P = .0077); the complete response/unconfirmed complete response rate was 39% vs 55%, respectively (P = .0013). Overall response (complete response, unconfirmed complete response, or partial response) was not significantly different: 90% and 95%, respectively.

A similar percentage of patients in both arms underwent autologous stem cell transplantation: 83% vs 80%. Response rate was high in both arms following stem cell transplant: 97% vs 98%.

Key Findings

At a median follow-up of 53 months, time to treatment failure was a median of 46 months in the R-CHOP arm vs 88 months in the R-CHOP/R-DHAP arm (P = .0382). Patients in the R-CHOP arm had almost twice the number of events related to treatment failure: 122 vs 69. The relapse rate following complete response/unconfirmed complete response/partial response was twice as high in the R-CHOP arm: 88 vs 44, respectively. Significant differences in time to treatment failure favoring the R-DHAP/R-CHOP arm were present in the low-risk (P = .0004) and intermediate-risk (P = .053) groups.

The investigators found that achievement of minimal residual disease postinduction was the strongest independent prognostic factor of outcome (P = .001), even stronger than Mantle Cell Lymphoma International Prognostic Index (MIPI) risk status (P = .008), treatment arm, or complete response. In pooled trials of the European Mantle Cell Lymphoma Network, minimal residual disease was significantly associated with longer duration of remission.

Compared with R-CHOP, R-CHOP/R-DHAP was associated with higher rates of grade 3 or 4 myelosuppression and similar rates of other grade 3 and 4 toxicities during induction. During autologous stem cell transplantation, both treatment arms had similar rates of grade 3 and 4 toxicities. At the time of the ASH meeting, median survival had not yet been reached in either arm. The best survival rates were in the low-risk group of younger MCL patients, with a strong trend in the R-CHOP/R-DHAP arm. Most importantly, at the time of analysis, overall survival in the cytarabine arm was also superior to the control arm (not reached vs 82 months, P = .045).

“No matter which conditioning regimen is used, high-dose [cytarabine] should be used in the induction regimen of younger patients with MCL. This study sets the standard and confirms the addition of [cytarabine] worldwide,” stated Martin Dreyling, MD, University of Munich, Germany. ■

Disclosure: Drs. Hermine and Dreyling reported no potential conflicts of interest.

Reference

1. Hermine O, et al: Alternating courses of 3x CHOP and 3x DHAP + rituximab followed by a high dose Ara-C containing myeloablative regimen and ASCT increases overall survival when compared to 6 courses of CHOP + rituximab followed by radioimmunotherapy and ASCT in mantle cell lymphoma. 2012 ASH Annual Meeting. Abstract 151. Presented December 9, 2012.



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