R-DHAP Regimen Produces Favorable Efficacy in Younger MCL Patients

Olivier Hermine, MD, PhD

R-DHAP (rituximab [Rituxan], dexamethasone, cytarabine, and cisplatin) plus high-dose cytarabine-containing myeloablative radiochemotherapy conditioning and autologous stem cell transplant (ASCT) demonstrated sustained time to treatment failure (TTF) and overall survival (OS) benefits vs R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) plus standard myeloablative radiochemotherapy and ASCT in patients with mantle cell lymphoma (MCL) aged 65 years and younger, according to long-term follow-up data from the phase 3 MCL Younger trial (NCT00209222).

After a median follow-up of 10.6 years, the primary analysis confirmed that the patients who received R-CHOP/R-DHAP induction plus high-dose cytarabine and ASCT (R-DHAP arm) continued to experience an improved median TTF compared with those who received R-CHOP plus standard myeloablative radiochemotherapy and ASCT (R-CHOP arm), at 8.4 years vs 3.9 years (HR, 0.59; P = .038). The 5-year TTF rates were 64% (95% CI, 58%-71%) and 41% (95% CI, 35%-49%) and the 10-year TTF rates were 46% (95% CI, 39%-54%) and 25% (95% CI, 19%-32%) in the R-DHAP and R-CHOP arms, respectively (HR, .059; P = .038).

“This update of the MCL Younger trial confirms our first primary results on TTF overall and in all subgroups, particularly in those of poor prognosis,” lead study author, Olivier Hermine, MD, PhD, of Paris Descartes University in France, and colleagues, wrote. “In addition, we were able to show a significant OS improvement when adjusted for prognostic factors.”

The multicenter, open-label, parallel-group MCL Younger trial, initiated in 2004, investigated R-CHOP/R-DHAP induction plus high-dose cytarabine and ASCT vs R-CHOP plus standard myeloablative radiochemotherapy and ASCT in patients with advanced MCL under the age of 66 years. With 6.1 years of median follow-up, patients in the R-DHAP arm experienced a significantly longer TTF than those in the R-CHOP arm (HR, 0.56; P = .038).

This long-term report aimed to confirm the initial efficacy findings of the R-DHAP combination, evaluate the long-term efficacy and safety of the investigative regimen, and assess biological subgroups and second-line therapies.

MCL Younger was conducted in 128 centers across France, Poland, Germany, and Belgium. Patients were eligible if they were under 66 years of age, had previously untreated stages II to IV MCL, and were suitable for ASCT.

Between July 20, 2004, and March 18, 2010, 497 patients were randomized to the R-DHAP (n = 248) or R-CHOP (n = 249) arms. Of these patients, 466 were included in the primary analysis, 232 from the R-DHAP arm and 234 from the R-CHOP arm.

The primary end point of this trial was TTF, defined as the time from randomization to stable disease, progressive disease, or death from any cause. The secondary end points were progression-free survival (PFS) and OS. Exploratory outcomes included secondary malignancies and OS from first treatment failure.

The R-DHAP and R-CHOP arms had respective median ages of 56 (range, 32-66) and 55 (range, 30-67), and 79% of each arm was male. The median Mantle Cell Lymphoma International Prognostic Index (MIPI) scores were 5.56 (range, 4.07-8.68) and 5.60 (range, 4.21-7.98), and the median Ki-67 indexes were 21 (range, 2-95; n = 141) and 20 (range, 2-97; n = 143) in the R-DHAP and R-CHOP arms, respectively. Additionally, 6 patients in the R-DHAP arm and 9 patients in the R-CHOP arm had high-risk MCL based on their combined MIPI score and Ki-67 index. A total of 14 patients in each arm had blastoid cytology, and 10 and 8 patients in the R-DHAP and R-CHOP arms, respectively, had p53 expression over 50%.

A secondary intent-to-treat analysis of the R-DHAP and R-CHOP arms revealed 5-year TTF rates of 63% (95% CI, 57%-70%) and 43% (95% CI, 37%-50%) and 10-year TTF rates of 43% (95% CI, 37%-51%) and 27% (95% CI, 21%-34%) in the R-DHAP and R-CHOP arms, respectively, with a MIPI score–adjusted HR of 0.56 (95% CI, 0.44-0.71; P < .0001) and a HR of 0.52 (95% CI, 0.38-0.70; P < .0001; n = 297) when additionally adjusted for Ki-67 index.

In the R-DHAP arm, the 5-year PFS rates calculated from randomization, from the end of successful induction, and from ASCT were 64% (95% CI, 58%-70%), 67% (95% CI, 61%-73%), and 74% (95% CI, 68%-81%), respectively, and the respective 10-year PFS rates were 44% (95% CI, 37%-51%), 45% (95% CI, 38%-53%), and 51% (95% CI, 44%-61%). In the R-CHOP arm, the 5-year PFS rates calculated from randomization, from the end of successful induction, and from ASCT were 45% (95% CI, 39%-52%), 46% (95% CI, 39%-53%), and 47% (95% CI, 40%-56%), respectively, and the respective 10-year PFS rates were 27% (95% CI, 21%-34%), 30% (95% CI, 24%-37%), and 32% (95% CI, 25%-40%).

The median OS in the R-DHAP arm was NR vs 11.3 years in the R-CHOP arm, with 5-year rates of 76% (95% CI, 71%-82%) vs 69% (95% CI, 63%-75%) and 10-year rates of 60% (95% CI, 53%-67%) vs 55% (95% CI, 48%-62%), respectively. These OS data were not significant in the unadjusted analysis (HR, 0.80; 95% CI, 0.61-1.06; P = .12). The MIPI score–adjusted HR and HR and additionally adjusted for Ki-67 index were 0.74 (95% CI, 0.56-0.98; P = .038) and 0.60 (95% CI, 0.41-0.87; P = .0066), respectively.

Subgroup analyses for sex, MIPI score, Ki-67 index, MIPI score plus Ki-67 index, and cytology revealed no heterogeneity of treatment effects. However, cytarabine efficacy was stronger in patients with p53 expression over 50% and in those with high-risk MCL.

Of the 95 and 148 patients in the R-DHAP and R-CHOP arms who received second-line treatment, 24% and 36% received cytarabine. The R-DHAP arm experienced a slightly shorter median OS from first treatment failure, at 1.7 years (95% CI, 1.2-4.4) vs 2.9 years (95% CI, 1.8-4.9) in the R-CHOP arm.

In both arms, patients who received second-line cytarabine did not experience superior OS from first treatment failure vs standard chemotherapy. The MIPI-adjusted HRs were 0.95 (95% CI, 0.45-2.00; P = .90) and 1.34 (95% CI, 0.73-2.47; P = .34) in the R-DHAP and R-CHOP arms, respectively.

Although investigators observed no major differences in causes of death, the cumulative incidence of death without treatment failure was slightly higher in the R-DHAP arm, with respective 5- and 10-year rates of 7% and 12% vs 5% and 7% in the R-CHOP arm.

In both arms, the frequency and severity of toxicities decreased over time, except for grade 1-2 renal toxicities, which remained stable. Toxicities in hemoglobin, granulocytes, leukocytes, creatinine, and platelets, as well as infection, were more common in the R-DHAP arm than the R-CHOP arm during the first 3 years post treatment. Additionally, the R-DHAP arm experienced higher rates of grade 3 or 4 cardiac function below 5%.

The R-DHAP arm experienced a trend toward a higher incidence of secondary hematologic malignancies. In the R-DHAP and R-CHOP arms, respectively, 4 and 9 patients each developed a secondary myelodysplastic syndrome or acute myelogenous leukemia, with 10-year cumulative incidences of 1.4% and 4.5% (P = .14).

Regarding secondary nonhematologic malignancies, 19 and 25 patients in the R-DHAP and R-CHOP arms, respectively, were diagnosed with secondary solid tumors, with 10-year cumulative incidences of 9.0% and 7.4% (P = .42).

“On the basis of these excellent long-term results, high-dose cytarabine-containing regimens should remain the standard of care in younger patients,” the study authors concluded. “Considering the relatively small difference and a lack of correction for multiple end points, the finding of OS improvement warrants further confirmation in future studies.”

Reference

Hermine O, Jiang L, Walewski J, et al. High-dose cytarabine and autologous stem-cell transplantation in mantle cell lymphoma: long-term follow-up of the randomized mantle cell lymphoma younger trial of the European Mantle Cell Lymphoma Network. J Clin Oncol. Published online December 5, 2022. doi:10.1200/JCO.22.01780