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Mantle Cell Lymphoma | Image Credit: © Tatiana Shepeleva – stock.adobe.com Induction therapy with continuous R-DA-EDOCH (a dose-adjusted regimen of rituximab [Rituxan], etoposide, dexamethasone, doxorubicin, cyclophosphamide, and vincristine) alternated with R-DHAP (rituximab, dexamethasone, high-dose cytarabine, and cisplatin) followed by autologous stem cell transplant (ASCT) produced high complete response (CR) rates and was well tolerated in young patients with newly diagnosed mantle cell lymphoma (MCL) with high-risk factors.
1 Findings from the phase 3 BDH-MCL01 trial (NCT02858804), which were published in Cancer Biology & Medicine , showed that among 55 enrolled patients, the CR rate at end of induction (EOI) was 89.1% (95% CI, 78%-96%), and the overall response rate (ORR) was 98.1% (95% CI, 90%-100%).
Investigators observed no significant differences in CR rate or ORR across most subgroups of patients with various prognostic characteristics. Across most prespecified subgroups, the CR rates exceeded 80%; across all prespecified subgroups, the ORRs met or exceeded 95%. However, notably, patients with blastoid or pleomorphic MCL had a relatively unfavorable response to the study treatment, with a CR rate of 75% (95% CI, 35%-97%), although the partial response (PR) rate in this subgroup was 25% (95% CI, 3%-65%), translating to an ORR of 100% (95% CI, 63%-100%).
“Intensive therapy based on a high dose of cytarabine and continuously administered EDOCH may partially overcome the adverse prognostic effects of high-risk factors, such as high MCL International Prognostic Index risk, high Ki-67 [proliferation], and MYC abnormalities,” the study authors wrote in the paper. “However, this treatment cannot fully overcome the negative effects of blastoid pathological subtypes and TP53 mutations. Combination therapy with targeted drugs is necessary to provide patients with additional survival benefits.
” Treatment with the immunochemotherapy regimen of R-DA-EDOCH has elicited favorable outcomes across populations of patients with high-risk aggressive B-cell lymphomas. Based on these findings, investigators designed an induction therapy regimen consisting of R-DA-EPOCH and R-DHAP as an enhanced version of the R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)/R-DHAP regimen that is frequently used in clinical trials. The open-label, nonrandomized BDH-MCL01 trial enrolled patients 18 to 65 years of age with a confirmed diagnosis of MCL with translocation breakpoints at t(11;14) or CD1 expression.
Patients needed to have Ann Arbor stage II to IV disease and an ECOG performance status of 1 or 0. During the induction phase, patients received alternating doses of R-DA-EPOCH and R-DHAP for 2 cycles, for a total of 4 courses of therapy, after which patients who achieved less than a PR discontinued the trial, and responders received another cycle of treatment. After 3 total cycles of induction therapy, those patients decided whether to receive consolidation therapy with ASCT or 1 cycle of R-EDOCH/R-DHAP.
Maintenance therapy with rituximab at 375 mg/m 2 every 3 months for up to 8 additional doses was recommended for all patients. Supportive care—including the use of prophylactic anti-infective agents and polyethylene glycol recombinant human granulocyte stimulating factor—was provided at investigator discretion. The primary end point was CR rate at EOI.
Secondary end points included ORR at EOI, progression-free survival (PFS), overall survival (OS), and safety and tolerability. Minimal residual disease (MRD) status served as an exploratory efficacy end point. MRD negativity was defined as a clonal malignant cell count of less than 10 –4 (0.
01%). Patients had a median age of 53 years (range, 37-65). Most patients were male (69.
1%) and had advanced-stage (Ann Arbor stage III-IV) disease (94.6%). In total, 38.
2% of patients had B symptoms. Pathological disease types among 52 evaluable patients included classic (84.7%), blastoid (11.
5%), and pleomorphic (3.8%). Immunohistochemistry studies among evaluable patients showed that 43.
6% of patients had a Ki-67 score of at least 30% (n = 17/39), and 50.0% of patients (n = 18/36) had p53 expression of at least 50%. Fluorescence in situ hybridization detection in evaluable patients revealed 17 deletions in 18.
9% (n = 10/53), 9p deletions in 34.1% (n = 14/41), both 17p deletions and 9p deletions in 12.2% (n = 5/41), and MYC translocations/amplifications in 30.
0% (n = 9/30). Additionally, among 42 evaluable patients, TP53 mutations were present in 26.2%, and both TP53 mutations and 17p deletions were detected in 16.
7%. Among 33 patients who underwent IGHV somatic hypermutation analysis, 66.7% had unmutated IGHV genes.
A total of 61.8% of all enrolled patients had at least 1 high-risk factor. All patients received at least 2 cycles of alternating R-DA-EDOCH and R-DHAP.
One patient discontinued the trial because of disease progression during induction. In total, 28 patients underwent ASCT consolidation, and 25 patients received R-EDOCH/R-DHAP consolidation. “Crucially, this regimen did not impair the successful collection of stem cells for ASCT and was suitable for patients eligible for transplantation,” the authors explained.
At a median follow-up of 48 months (range, 6-112), the 3-year PFS rate was 66.3%. The 3-year OS rate was 83.
2%. During this time, 23 patients had disease progression, and 15 patients died due to disease progression (n = 11), treatment-related secondary leukemia (MCL still in CR; n = 2), cerebral infarction (n = 1), and Pneumocystis carinii pneumonia during post-ASCT maintenance therapy (n = 1). Notably, the 1- and 5-year PFS rates were 89.
0% and 53.6%, respectively. The OS rates at these respective time points were 98.
1% and 72.9%. Patients who received sequential ASCT consolidation and/or rituximab maintenance achieved a slightly higher CR rate compared with patients who did not receive these therapies; however, the 3-year PFS rate was significantly improved among those who received ASCT and/or rituximab (ASCT + rituximab, 83.
6%; rituximab alone, 61.5%; no ASCT/rituximab, 50.0%; P = .
009). OS outcomes did not vary significantly across these subgroups. Moreover, investigators did not observe significant PFS or OS differences between patients with or without high-risk features (PFS, P = .
735; OS, P = .612). A univariate analysis showed TP53 mutations ( P = .
038), blastoid/pleomorphic pathologic morphology ( P = .003), and TP53 double-allele events ( P = .020) to be risk factors for PFS with R-DA-EPOCH/R-DHAP therapy.
However, this analysis also demonstrated that factors including Ki-67 score of at least 30%, MYC abnormalities, 17p deletions, and 9p deletions were not significantly adversely prognostic. A subgroup analysis of high-risk patients (those with blastoid morphology and/or TP53 abnormalities) revealed that those who completed ASCT and maintenance therapy had improved prognosis compared with those who did not undergo ASCT or receive maintenance therapy. However, the investigators cautioned that this post hoc analysis included subgroups with small sample sizes, limiting statistical validity.
In total, 48 patients had bone marrow involvement at initial diagnosis, 68.8%, 93.8%, and 95.
8% of whom underwent bone marrow evaluation after 2 cycles of treatment, after 4 cycles of treatment, and at EOI, respectively. Notably, most patients with bone marrow involvement achieved MRD negativity early in the treatment course; the MRD negativity rates after 2 treatment cycles, after 4 treatment cycles, and at EOI were 51.5%, 93.
3%, and 95.7%, respectively. By EOI, no patients with a CR had detectable MRD.
Furthermore, among the 5 patients who achieved a best response of PR, 3 had undetectable MRD in the bone marrow. The low proportion of patients with MRD positivity in the bone marrow at EOI may explain why bone marrow MRD status was not significant for prognosis ( P = .347), the authors emphasized.
At least 1 hematologic adverse effect (AE) was reported in 85.5% of patients. No grade 4 nonhematologic AEs were observed.
The most common any-grade AEs were grade 1/2 nausea/vomiting (25.4%), fatigue (17.9%), and peripheral neuritis (14.
5%). The most common high-grade AEs included leukocytopenia (grade 3, 25.5%; grade 4, 23.
6%), neutrocytopenia (23.6%; 34.6%), pulmonary infection (23.
6%; 0.0%), febrile neutropenia (14.5%; 0.
0%), thrombocytopenia (9.1%; 16.4%), anemia (7.
3%, 0.0%), hyperglycemia (3.6%; 0.
0%), upper respiratory infection (1.8%; 0.0%), urinary system infection (1.
8%; 0.0%), and gingivitis (1.8%; 0.
0%). Other notable AEs included grade 2 arrythmias during treatment (n = 2), grade 2 thrombosis (n = 2), and grade 1 bleeding (n = 1). No patients discontinued treatment due to AEs.
“The alternating R-DA-EDOCH/R-DHAP regimen presents a compelling induction choice for young patients with MCL, particularly for those with high tumor proliferative activity,” the authors concluded. Wang Y, Yan Y, Shan D, et al. Continuous R-DA-EDOCH alternated with high-dose Ara-C induces deep remission and overcomes high-risk factors in young patients with newly diagnosed mantle cell lymphoma.
Cancer Biol Med . 2025;22(2):177–89. doi:10.
20892/j.issn.2095-3941.
2024.0200.
