Molecular remission is an independent predictor of clinical outcome in patients with mantle cell lymphoma after combined immunochemotherapy: a European MCL intergroup study

Abstract

The prognostic impact of minimal residual disease (MRD) was analyzed in 259 patients with mantle cell lymphoma (MCL) treated within 2 randomized trials of the European MCL Network (MCL Younger and MCL Elderly trial). After rituximab-based induction treatment, 106 of 190 evaluable patients (56%) achieved a molecular remission (MR) based on blood and/or bone marrow (BM) analysis. MR resulted in a significantly improved response duration (RD; 87% vs 61% patients in remission at 2 years, P = .004) and emerged to be an independent prognostic factor for RD (hazard ratio = 0.4, 95% confidence interval, 0.1-0.9, P = .028). MR was highly predictive for prolonged RD independent of clinical response (complete response [CR], complete response unconfirmed [CRu], partial response [PR]; RD at 2 years: 94% in BM MRD-negative CR/CRu and 100% in BM MRD-negative PR, compared with 71% in BM MRD-positive CR/CRu and 51% in BM MRD-positive PR, P = .002). Sustained MR during the postinduction period was predictive for outcome in MCL Younger after autologous stem cell transplantation (ASCT; RD at 2 years 100% vs 65%, P = .001) and during maintenance in MCL Elderly (RD at 2 years: 76% vs 36%, P = .015). ASCT increased the proportion of patients in MR from 55% before high-dose therapy to 72% thereafter. Sequential MRD monitoring is a powerful predictor for treatment outcome in MCL. These trials are registered at www.clinicaltrials.gov as #NCT00209222 and #NCT00209209.

Keywords: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cell Separation; Combined Modality Therapy; Female; Flow Cytometry; Humans; Immunohistochemistry; Immunotherapy; Lymphoma, Mantle-Cell; MRD; Male; Middle Aged; Neoplasm Staging; Neoplasm, Residual; Polymerase Chain Reaction; Prognosis; RQ-PCR; Radiotherapy; Treatment Outcome; autologous stem cell transplantation; immunochemotherapy; mantle cell lymphoma; methods; minimal residual disease; pathology; therapeutic use; therapy.

Figure 1. Diagram of the two randomized EU-MCL network trials

(A) MCL Younger and (B) MCL Elderly with the respective MRD sampling time points. MRD is assessed until clinical relapse or death. Maintenance treatment in both arms of the elderly protocol is given until progression or death.

Figure 2. MRD quantification by RQ-PCR of 190 patients prior to, during and after induction

Combined immunochemotherapy resulted in a significant 3 log reduction of lymphoma cells in PB and BM from 6.2×10⁻² in PB and 7.0×10⁻² in BM prior treatment to 1.0×10⁻⁴ in PB and 1.2×10⁻⁴ in BM at midterm staging (p<0.0001) and to MRD negativity after end of induction (prior to DexaBEAM/ASCT or maintenance). Filled black symbols for MRD positive samples, empty symbols for MRD negative samples.

Figure 3

Figure 3a. Response duration according to MRD status after combined immunochemotherapy. MRD was assessed in PB and/or BM after end of induction in MCL Younger and MCL Elderly patients. Figure 3b: Response duration according to MRD status assessed in the peripheral blood after induction with combined immunochemotherapy. MRD was assessed in MCL Younger and MCL Elderly patients. Figure 3c: Response duration according to MRD status assessed in the bone marrow after induction with combined immunochemotherapy. MRD was assessed in MCL Younger and MCL Elderly patients.

Figure 3

Figure 3a. Response duration according to MRD status after combined immunochemotherapy. MRD was assessed in PB and/or BM after end of induction in MCL Younger and MCL Elderly patients. Figure 3b: Response duration according to MRD status assessed in the peripheral blood after induction with combined immunochemotherapy. MRD was assessed in MCL Younger and MCL Elderly patients. Figure 3c: Response duration according to MRD status assessed in the bone marrow after induction with combined immunochemotherapy. MRD was assessed in MCL Younger and MCL Elderly patients.

Figure 3

Figure 3a. Response duration according to MRD status after combined immunochemotherapy. MRD was assessed in PB and/or BM after end of induction in MCL Younger and MCL Elderly patients. Figure 3b: Response duration according to MRD status assessed in the peripheral blood after induction with combined immunochemotherapy. MRD was assessed in MCL Younger and MCL Elderly patients. Figure 3c: Response duration according to MRD status assessed in the bone marrow after induction with combined immunochemotherapy. MRD was assessed in MCL Younger and MCL Elderly patients.

Figure 4. Response duration according to MRD status and clinical remission (CR/Cru/PR)

MRD was assessed in the bone marrow after induction with combined immunochemotherapy in MCL Younger and MCL Elderly patients.

Figure 5

Response duration according to MRD status assessed in PB and/or BM after induction with combined immunochemotherapy in MCL Younger patients.

Figure 6

Response duration according to MRD status assessed in PB and/or BM after induction with combined immunochemotherapy in MCL Elderly patients.

Figure 7. Response duration according to MRD status assessed in PB and/or BM within the first 12 months after ASCT in MCL Younger patients

MRD status was judged as MRD positive if at least one sample of in median 3 was positive.

Figure 8

Response duration according to MRD status assessed in PB and/or BM during the first year of maintenance in MCL Elderly patients.