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

Abstract

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. In 2004, the European Mantle Cell Lymphoma (MCL) Network initiated the randomized open-label, phase III MCL Younger trial for first-line treatment of patients with advanced-stage MCL, age < 66 years, comparing an alternating rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone/rituximab plus dexamethasone, high-dose cytarabine, and cisplatin (R-CHOP/R-DHAP) induction followed by high-dose cytarabine-containing myeloablative radiochemotherapy conditioning and autologous peripheral blood stem-cell transplantation (R-DHAP arm) to R-CHOP with standard myeloablative radiochemotherapy and autologous stem-cell transplantation (R-CHOP arm). After a median follow-up of 10.6 years, the time to treatment failure was still significantly improved in the R-DHAP versus R-CHOP arms (medians 8.4 v 3.9 years, 5-/10-year rates 64%/46% v 41%/25%, P = .038, hazard ratio, 0.59). Median overall survival (OS) was not reached in the R-DHAP arm versus 11.3 years in R-CHOP arm (5-/10-year rates, 76%/60% v 69%/55%, P = .12). The unadjusted OS hazard ratios (0.80 [95% CI, 0.61 to 1.06], P = .12) reached significance when adjusted for Mantle Cell Lymphoma International Prognostic Index (MIPI) and MIPI + Ki-67 (MIPI-c) (0.74; 95% CI, 0.56 to 0.98; P = .038 and .60; 95% CI, 0.41 to 0.87; P = .0066). The incidence of secondary hematologic malignancies tended to be higher in the R-DHAP arm (4.5% v 1.4% at 10 years). With mature long-term data, we confirm the previously observed substantially prolonged time to treatment failure and, for the first time to our knowledge, show an improvement of OS. Some patients with MCL may be cured.

Mantle cell lymphoma—Update on molecular biology, prognostication and treatment approaches

“…7 Furthermore, lack of molecular remission after end of currently recommended standard treatment was shown to be strongly predictive for early clinical relapse within 1-2 years. 7,21 However, use of MRD analysis in clinical routine is still limited. Furthermore, the impact of MRD monitoring in the context of the new targeted treatments, such as the BTK inhibitor ibrutinib, remains unclear.…”

“…Concerning the prognostic impact of minimal residual disease (MRD) status, several studies have been published, providing evidence of the strong prognostic potential of MRD status predicting improved subsequent progression‐free survival (PFS) for MRD‐negative patients at the end of induction and before high‐dose consolidation 7 . Furthermore, lack of molecular remission after end of currently recommended standard treatment was shown to be strongly predictive for early clinical relapse within 1–2 years 7,21 . However, use of MRD analysis in clinical routine is still limited.…”

“…1,7,23 The administration of the R-CHOP/ DHAP regimen compared to administration of R-CHOP alone prior to myelo-ablative consolidation with ASCT more than doubled Time to Treatment Failure (TTF) (109 vs. 47 months). 7 Yet, in the era of targeted therapies, the phase III TRIANGLE trial recently evaluated the remaining value of ASCT for first-line therapy: 870 patients <65 years were treated with either the current standard of care including ASCT (arm A), the additional application of ibrutinib (arm A + I) or an ibrutinib-combination without ASCT (arm I). As recently reported, 3-year-disease-free survival was higher in both ibrutinibcontaining arms compared to intensive high-dose consolidation followed by ASCT (86% respectively 88% vs. 72%; p = 0,0008; HR 0,52).…”

“…Traditionally, MCL was associated with a poor prognosis with a median overall survival (OS) of 3–5 years. However, major advances in the treatment of MCL patients have been achieved over the last years, especially by the development of an immunochemotherapy induction implementing cytarabine and anti‐CD20 antibodies and addition of a consolidative high‐dose therapy with autologous stem cell transplantation (ASCT) 7 . Moreover, introduction of rituximab maintenance, especially for those patients not eligible for high‐dose therapy, significantly improved survival rates in this group of patients 8 .…”

“…However, major advances in the treatment of MCL patients have been achieved over the last years, especially by the development of an immunochemotherapy induction implementing cytarabine and anti-CD20 antibodies and addition of a consolidative high-dose therapy with autologous stem cell transplantation (ASCT). 7 Moreover, introduction of rituximab maintenance, especially for those patients not eligible for high-dose therapy, significantly improved survival rates in this group of patients. 8 The implementation of targeted therapies into the relapsed setting including the BTK-inhibitor ibrutinib has further improved outcomes for patients with relapsed or refractory disease.…”