Study Reaffirms the Use of Cytarabine in Younger Patients with Mantle Cell Lymphoma

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Long-term follow up of a phase 3 European Mantle Cell Lymphoma (MCL) Network trial confirmed the previous observation of significantly prolonged time to treatment failure (TTF) and longer overall survival (OS) with the addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation (ASCT) in patients with MCL aged 65 years or younger.1 These results were presented at the 2021 American Society of Hematology (ASH) Annual Meeting.

“The high-dose cytarabine containing induction and ASCT achieves 60% survival at 10 years with acceptable toxicity,” said Olivier Hermine, MD, PhD, of the University of Paris in France on behalf of the European MCL Network investigators.

In the initial analysis after a median follow-up of 6.1 years, patients who received high-dose cytarabine had a significantly longer time to treatment failure (median 9.1 years; 5- year rate, 65%) compared with the control group (median 3.9 years; 5-year rate, 40%) (hazard ratio [HR], 0.56; P =.038).2


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With extended follow-up of an additional 5 years, Dr Hermine and colleagues observed significant prolongation of the median OS and the benefit of high-dose cytarabine was seen in both high- and low-risk patients.

In the randomized, open-label, phase 3 European MCL network trial (ClinicalTrials.gov Identifier: NCT00209222), researchers sought to determine whether the introduction of high-dose cytarabine to immunochemotherapy before ASCT improved clinical outcomes.

The study included 466 evaluable patients aged 65 years or younger with untreated stage II-IV MCL at 128 sites across 4 European countries.

The participants received either 6 cycles of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by myeloablative radiochemotherapy and ASCT (control group, 234 patients) or 6 cycles of alternating R-CHOP or R-DHAP induction (rituximab plus dexamethasone, high-dose cytarabine, and cisplatin) followed by a high-dose cytarabine-containing conditioning regimen and ASCT (cytarabine group. 232 patients).

The median age of the patients was 55 years (range, 30-67), with similar MCL International Prognostic Index (MIPI) and Ki-67 in both arms.

The median TTF was 4.1 years in the R-CHOP arm compared with 7.7 years in the R-DHAP arm (P <.0001). The 10-year TTF in the R-CHOP arm was 27% (95% CI, 21-34) compared with 43% in the R-DHAP arm (95% CI, 37-51) (unadjusted HR, 0.60; 95% CI, 0.47-0.76; MIPI-adjusted HR, 0.56; 95% CI, 0.44-0.71; Ki67-adjusted HR, 0.52; 95% CI, 0.38-0.70; all P <.0001).

The median PFS from randomization was 4.3 years in the R-CHOP arm compared with 8.0 years in the R-DHAP arm (HR, 0.61; 95% CI, 0.48-0.78; P <.0001). The median PFS from the end of induction was 4.2 years in the R-CHOP arm compared with 8.5 years in the R-DHAP arm (HR, 0.60; 95% CI, 0.47-0.78; P <.0001).  The median PFS from ASCT in the R-CHOP arm was 4.7 years compared with 10.8 years in the R-DHAP arm (HR, 0.53; 95% CI, 0.40-0.71; P <.0001).

At a median follow-up of 11.0 years, the median OS was not reached in the R-DHAP arm compared with 11.3 years in the R-CHOP arm (P =.12). The 10-year OS in the R-CHOP arm was 55% (95% CI, 48-62) compared with 60% (95% CI, 53-67) in the R-DHAP arm (unadjusted HR, 0.80; 95% CI, 0.61-1.06; P =.12).

The OS was found to be significantly superior in the R-DHAP arm after adjusting for MIPI score without Ki-67 (HR, 0.74; 95% CI, 0.56-0.98; P =.038) and with Ki67 (HR, 0.60; 95% CI, 0.41-0.87; P =.0066).

In high-risk patients with high intermediate or high MIPI, the median OS was significantly better in the R-DHAP arm (10.4 years) than in the R-CHOP arm (5.0 years; HR, 0.55; 95% CI, 0.35-0.88; P =.013). In low-risk patients with low-intermediate or low MIPI, the median OS was not reached in the R-DHAP arm compared with 14.4 years in the R-CHOP arm (HR, 0.37; 95% CI, 0.13-1.06, P =.064).

In high-risk patients, the median TTF was 2.8 years in the R-CHOP arm compared with 7.6 years in the R-DHAP arm (HR, 0.49; 95% CI, 0.32-0.74; P <.00078). In low-risk patients, the median TTF was not reached in the R-DHAP arm compared with 5.3 years in the R-CHOP arm (HR, 0.56; 95% CI, 0.27-1.15; P =.11), which was not statistically significant.

Although not statistically significant, the cumulative incidence of secondary hematological malignancies was higher in the R-DHAP arm (9 events) compared with the R-CHOP arm (4 events). The 10-year probability was 4.5% in the R-DHAP arm and 1.4% in the R-CHOP arm (P =.14).

Dr Hermine commented that in the future, the question remains whether to avoid total-body irradiation to reduce the rate of secondary malignancies after R-CHOP/R-DHAP. He indicated that this chemotherapy regimen might cure some patients and this therapy may challenge future chemotherapy-free strategies in MCL.

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.

Read more of Cancer Therapy Advisor’s coverage of the ASH 2021 meeting by visiting the conference page.

References

  1. Hermine O, Jiang L, Walewski J, et al. Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL younger): A long-term follow-up of the randomized, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network. Presented at ASH 2021; December 11-14, 2021. Abstract 380.
  2. Hermine O, Hoster E, Walewski J, et al. Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network. Lancet. Published August 6, 2016. doi:10.1016/S0140-6736(16)00739-X



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