Abstract
To the editor,
Mantle cell lymphoma (MCL), about 3–6% of non-Hodgkin’s lymphoma (NHL), is a rare form of a generally aggressive B-cell malignancy, resulting in a malignant transformation of the B cells in the mantle zone region of the lymph node. 1 The cytogenetic abnormality of MCL is the t(11;14)(q13;q32) translocation, resulting in an over-expression of the cyclin D1. 2 The disease is also characterized by the expression of the SOX11 transcription factor, the mutational status of IGHV, genetic alternations such as TP53 mutations, C-Myc, and variable expressions of the Ki-67 biomarkers.2,3 The various combinations of these elements express the aggressiveness of the disease.
Although the majority of patients require therapy at diagnosis because of disease-related symptoms, involved sites, or rapid progression, deferring treatment is appropriate in about 20% of patients with indolent disease behavior. 3 There is no defined treatment for this lymphoma. However, for younger and fit patients who require treatment, immunochemotherapy induction followed by autologous hematopoietic stem cell transplantation (Auto-HSCT) consolidation remains the current standard of care,4,5 although patients with TP53 mutation do not appear responsive to intensive treatment and should be considered for treatments with novel agents and clinical trials. 6 The induction treatment in Europe is generally based on Rituximab associated with CHOP chemotherapy (R-CHOP), followed or alternated with DHAP regimens (R-DHAP).3,4 Only R-DHAP alone can be employed in view of the great efficacy demonstrated by a high dose of Aracytin against MCL. 7 Carmustine, etoposide, cytarabine, and melphalan (BEAM) is one of the conditioning regimens more commonly used before Auto-HSCT for lymphomas. 4 In 2018, a letter from our group was published in Bone Marrow Transplantation in which the result of 44 patients with Hodgkin’s and NHL who had undergone an Auto-HSCT conditioned by a modified BEAM protocol was reported. 8 Following are the results of a study conducted on patients with MCL transplanted using the same conditioning regimen. Maintaining the BEAM protocol scheme, the dose of Ara-C was increased to 2.0 g/m2/day in combination with a standard dose of etoposide for 3 days instead of 4 to reduce the toxicity of the changed conditioning regimen combination (mBEAM). The mBEAM conditioning regimen is effective and without increased toxicity compared to classical BEAM. 8 As the case study following transplantation was not extensive and included different histological types of lymphoma, it was not possible to establish its real effectiveness. Among the patients included in the study, two were MCL. They were treated with three cycles of R-CHOP followed by three cycles of R-DHAP, in complete remission (CR) after the induction regimen, and transplanted with mBEAM, both in CR 2.5 and 4 years after transplantation. It was therefore collectively decided to use the mBEAM conditioning regimen before Auto-HSCT only for patients with MCL, due to the high sensitivity of MCL to high doses of Aracytin. In this retrospective analysis, we report the data from our single center of young and/or fit patients with MCL consecutively transplanted after the mBEAM conditioning regimen. The study was undertaken in compliance with the Declaration of Helsinki. All patients provided written informed consent before starting treatment. Between June 2011 and August 2022, 14 patients with MCL were treated with three cycles of R-CHOP followed by three cycles of R-DHAP and the collection of hematopoietic stem cells (HSC) after the second or third R-DHAP if in CR of the disease. This was followed by a high-dose therapy with mBEAM without rituximab and an auto HSC infusion. Follow-up of patients was conducted until November 2023. The clinical and biological characteristics of the patients are reported in Table 1. The mutation of TP53 and hyper-expression of C-Myc were not detected in any patient. The lymphoma showed blastoid morphology in 5 out of 14 patients without a direct correlation with a high Ki-67. The evaluation of TP53, C-Myc, and Ki-67 was carried out by immunohistochemistry. The MIPI-C prognostic score (9) was on average low or high-intermediate, except for only one case with a high score.
Clinical and biological characteristics of transplanted patients.
A, alive; AD, active disease; CR, complete remission; F, female; H, high risk; H-I, high-intermediate risk; L, low risk; L-I, low-intermediate risk; M, male; N, no; NE, not evaluated; Neg, negative; Pos, positive; WT, wild type; Y, yes.
As already reported, 8 the mBEAM regimen consisted of BCNU 300 mg/m2 on day -5, cytarabine 2000 mg/m2 and vepesid 200 mg/m2 on days −4, −3, −2, and melphalan 140 mg/m2 on day −1. Patients received antimicrobial prophylaxis and treatment as per our center guidelines, consisting in from day +1 of mycostatin suspension 500,000 U swish and swallow three times a day, fluconazole 200 mg daily, and levofloxacin 500 mg daily. Filgrastim at the dose of 300 or 480 µg/day was administered to all patients starting on day +6 after transplantation until the neutrophil count was >2000 × 109/L. Antimicrobial therapy for febrile neutropenic episodes consisted of broad-spectrum intravenous antibiotics or based on antibiograms whenever possible. Intravenous antifungal therapy was added if the fever persisted for more than 7 days notwithstanding intravenous antibacterial therapy. Red blood cells were infused for hemoglobin level <8.5 g/dl and random donor or single donor apheresis platelets for platelet count <10 × 109/L or clinical indication. Prophylaxis for pneumocystis jiroveci and herpes virus infections was administered for 2 months after discharge from the hospital. All patients maintained after transplantation the CR obtained with induction therapy, regardless of MIPI-C and other prognostic factors. Overall mBEAM conditioning was well tolerated and non-hematological side effects were found to overlap with those reported in the previous treatment evaluation which included a larger number of patients, all of whom were not above grade 2, along with a myelotoxicity resulting as expected.8,9 In our study, no patient received maintenance therapy. Four patients (27%) relapsed, after 6 (high-intermediate risk), 23 (low risk), 42 (low risk), and 59 (high risk) months from transplant. Disease-free survival (DFS) at 3 years was 85%, and 57% at 5 and 11 years (median DFS was not reached). To date, no patients have died.
There is no clearly established best Auto-HSCT conditioning regimen for MCL because it is difficult to separate the beneficial effects of intensive induction from those of consolidation as the high dose of aracytin was introduced into the induction therapy before autotransplantation. In addition, the different number of patients involved in other studies, as well as the small number of patients in our study, makes for a difficult comparison. The studies that evaluated the Auto-HSCT in MCL showed a PFS at 4–5 years of about 55–70% and OS of 60–80%. 4 Our results, therefore, can be considered satisfactory compared to those obtained from other studies that include a small number of cases and subjected to different conditioning regimens. In fact, Huwyler et al., 10 using bortezomib, bendamustin, etoposide, aracytin, and melphalan (Bortezomib-BeEAM) as a conditioning therapy in 11 patients, obtained a rate of CR of 54.5% and an OS at 22 months from transplantation of 64%, but with a conditioning regimen that showed significant toxicity. Kroger et al. 11 treated 19 patients using a different conditioning regimen, all including TBI, and altogether showed a relapse rate of 52.6% and overall survival of 50% at 11 years from transplantation. 11
Thanks to proven efficacy, through the increase in dosage of aracytin from 400 to 2000 mg/m2, and the low toxicity profile, by reducing the number of administration days from 4 to 3, albeit in a small number of patients, the mBEAM conditioning therapy is to be considered in cases where Auto-HSCT is indicated for MCL.
