TY - JOUR
T1 - Rituximab, bendamustine, and low-dose cytarabine as induction therapy in elderly patients with mantle cell lymphoma: a multicentre, phase 2 trial from Fondazione Italiana Linfomi
AU - Visco, Carlo
AU - Chiappella, Annalisa
AU - Nassi, L.
AU - Patti, C.
AU - Ferrero, S.
AU - Barbero, Daniela
AU - Evangelista, A.
AU - Spina, M.
AU - Molinari, A.
AU - Rigacci, Luigi
AU - Tani, M.
AU - Di Rocco, Alice
AU - Pinotti, G.
AU - Fabbri, A.
AU - Zambello, R.
AU - Finotto, S.
AU - Gotti, M.
AU - Carella, Angelo Michele
AU - Salvi, F.
AU - Pileri, S.A.
AU - Ladetto, Marco
AU - Ciccone, G.
AU - Gaidano, G.
AU - Ruggeri, M.
AU - Martelli, M.
AU - Vitolo, U.
N1 - Export Date: 20 March 2017
Correspondence Address: Visco, C.; Department of Cell Therapy and Hematology, San Bortolo Hospital, Via Rodolfi 37, Italy; email: carlovisco@hotmail.com
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Romaguera, J.E., Fayad, L., Rodriguez, M.A., High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine (2005) J Clin Oncol, 23, pp. 7013-7023; Geisler, C.H., Kolstad, A., Laurell, A., Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo-purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group (2008) Blood, 112, pp. 2687-2693; Visco, C., Castegnaro, S., Chieregato, K., The cytotoxic effects of bendamustine in combination with cytarabine in mantle cell lymphoma (2012) Blood Cells Mol Dis, 48, pp. 68-75; Castegnaro, S., Visco, C., Chieregato, K., Cytosine arabinoside potentiates the apoptotic effect of bendamustine on several B- and T-cell leukemia/lymphoma cells and cell lines (2012) Leuk Lymphoma, 53, pp. 2262-2268; Visco, C., Finotto, S., Zambello, R., Combination of rituximab, bendamustine, and cytarabine for patients with mantle-cell non-Hodgkin lymphoma ineligible for intensive regimens or autologous transplantation (2013) J Clin Oncol, 31, pp. 1442-1449; Swerdlow, S.H., Campo, E., Harris, N.L., (2008) WHO classification of tumours of haematopoietic and lymphoid tissues, , IARC Press Lyon, France; Ferrero, S., Monitillo, L., Mantoan, B., Rituximab-based pre-emptive treatment of molecular relapse in follicular and mantle cell lymphoma (2013) Ann Hematol, 92, pp. 1503-1511; Voena, C., Ladetto, M., Astolfi, M., A novel nested-PCR strategy for the detection of rearranged immunoglobulin heavy-chain genes in B cell tumors (1997) Leukemia, 11, pp. 1793-1798; Cheson, B.D., Pfistner, B., Juweid, M.E., Revised response criteria for malignant lymphoma (2007) J Clin Oncol, 25, pp. 579-586; Bryant, J., Day, R., Incorporating toxicity considerations into the design of two-stage phase 2 clinical trials (1995) Biometrics, 51, pp. 1372-1383; Tournoux, C., De Rycke, Y., Médioni, J., Asselain, B., Methods of joint evaluation of efficacy and toxicity in phase II clinical trials (2007) Contemp Clin Trials, 28, pp. 514-524; Albertsson-Lindblad, A., Kolstad, A., Laurell, A., Lenalidomide-bendamustine-rituximab in patients older than 65 years with untreated mantle cell lymphoma (2016) Blood, 128, pp. 1814-1820; Armand, P., Redd, R., Bsat, J., A phase 2 study of rituximab–bendamustine and rituximab–cytarabine for transplant-eligible patients with mantle cell lymphoma (2016) Br J Haematol, 173, pp. 89-95; Chang, J.E., Li, H., Smith, M.R., Phase 2 study of VcR-CVAD with maintenance rituximab for untreated mantle cell lymphoma: an Eastern Cooperative Oncology Group study (E1405) (2014) Blood, 123, pp. 1665-1673; Till, B.G., Li, H., Bernstein, S.H., Phase II trial of R-CHOP plus bortezomib induction therapy followed by bortezomib maintenance for newly diagnosed mantle cell lymphoma: SWOG S0601 (2016) Br J Haematol, 172, pp. 208-218; Hoster, E., Rosenwald, A., Berger, F., Prognostic value of Ki-67 index, cytology, and growth pattern in mantle-cell lymphoma: results from randomized trials of the European Mantle Cell Lymphoma Network (2016) J Clin Oncol, 34, pp. 1386-1394; Salek, D., Vesela, P., Boudova, L., Retrospective analysis of 235 unselected patients with mantle cell lymphoma confirms prognostic relevance of Mantle Cell Lymphoma International Prognostic Index and Ki-67 in the era of rituximab: long-term data from the Czech Lymphoma Project Database (2014) Leuk Lymphoma, 55, pp. 802-810; Wang, M.L., Lee, H., Chuang, H., Ibrutinib in combination with rituximab in relapsed or refractory mantle cell lymphoma: a single-centre, open-label, phase 2 trial (2016) Lancet Oncol, 17, pp. 48-56; Pott, C., Hoster, E., Delfau-Larue, M.H., Molecular remission is an independent predictor of clinical outcome in patients with mantle cell lymphoma after combined immunochemotherapy: a European MCL intergroup study (2010) Blood, 115, pp. 3215-3223; Gressin, R., Callanan, M., Daguindau, N., Frontline therapy with the RiBVD regimen elicits high clinical and molecular response rates and long PFS in elderly patients mantle cell lymphoma (MCL); final results of a prospective phase II trial by the LYSA group (2014) Blood, 124. , abstr 148; Ruan, J., Martin, P., Shah, B., Lenalidomide plus rituximab as initial treatment for mantle-cell lymphoma (2015) N Engl J Med, 373, pp. 1835-1844
PY - 2016
Y1 - 2016
N2 - Background The combination of rituximab, bendamustine, and cytarabine (R-BAC) was highly active in a pilot trial of mantle cell lymphoma, but its use was restricted by high haematological toxicity. We aimed to assess the efficacy and safety of an R-BAC regimen with low-dose cytarabine (RBAC500). Methods In this multicentre, phase 2 trial, we recruited previously untreated patients with an established histological diagnosis of mantle cell lymphoma from 29 Fondazione Italiana Linfomi centres in Italy. Patients had to be older than 65 years and fit according to the comprehensive geriatric assessment, or aged 60–65 years if they were ineligible for high-dose chemotherapy plus autologous stem-cell transplantation and were fit or unfit. All patients received RBAC500 (rituximab 375 mg/m2 on day 1, bendamustine 70 mg/m2 on days 2 and 3, and cytarabine 500 mg/m2 on days 2–4; all administered intravenously) every 4 weeks for up to six cycles. Primary endpoints were the proportion of patients achieving complete response at the end of treatment and toxicity, defined as the occurrence of any of the stop treatment criteria or of any episode of relevant toxicity. All patients who started at least one cycle of RBAC500 were included in the primary and safety analyses. Using efficacy and toxicity as a composite primary endpoint, we considered the final conclusion positive if more than 28 of 57 patients achieve complete response and fewer than 18 of 57 patients report toxicities. This study is registered with EudraCT, number 2011-005739-23, and ClinicalTrials.gov, number NCT01662050, and is completed. Findings Between May 2, 2012, and Feb 25, 2014, we enrolled 57 patients (median age 71 years, IQR 67–75). 54 (95%) patients received at least four RBAC500 cycles (three discontinued because of toxicity), and 38 (67%) completed six cycles. Two (4%) had disease progression (one after the fourth cycle and one after the sixth cycle). All 52 (91%, lower limit of one-sided 95% CI 85%) remaining patients achieved complete response at the end of treatment. 23 (40%, upper limit of one-sided 95% CI 53%) of 57 patients had at least one episode of relevant toxicity. The most frequent grade 3–4 haematological toxicities were neutropenia (149 [49%] of 304 cycles) and thrombocytopenia (158 [52%]). Most treatment-related non-haematological adverse events were of grade 1–2, with the most frequent ones being fatigue (14 [25%] patients), nausea or vomiting (12 [21%]), and infusion-related reactions or tumour lysis syndrome (12 [21%]). 41 (72%) patients required a dose reduction. 12 patients died during the study, but no deaths were related to treatment. Interpretation RBAC500 is an effective treatment for elderly patients with mantle cell lymphoma and, despite not meeting our prespecified safety boundary, haematological toxicity was manageable with appropriate supportive care and dose reduction. Since maintenance therapy is not required, RBAC500 could be considered an option and should be studied in phase 3 trials. Funding Fondazione Italiana Linfomi and Mundipharma. © 2017 Elsevier Ltd
AB - Background The combination of rituximab, bendamustine, and cytarabine (R-BAC) was highly active in a pilot trial of mantle cell lymphoma, but its use was restricted by high haematological toxicity. We aimed to assess the efficacy and safety of an R-BAC regimen with low-dose cytarabine (RBAC500). Methods In this multicentre, phase 2 trial, we recruited previously untreated patients with an established histological diagnosis of mantle cell lymphoma from 29 Fondazione Italiana Linfomi centres in Italy. Patients had to be older than 65 years and fit according to the comprehensive geriatric assessment, or aged 60–65 years if they were ineligible for high-dose chemotherapy plus autologous stem-cell transplantation and were fit or unfit. All patients received RBAC500 (rituximab 375 mg/m2 on day 1, bendamustine 70 mg/m2 on days 2 and 3, and cytarabine 500 mg/m2 on days 2–4; all administered intravenously) every 4 weeks for up to six cycles. Primary endpoints were the proportion of patients achieving complete response at the end of treatment and toxicity, defined as the occurrence of any of the stop treatment criteria or of any episode of relevant toxicity. All patients who started at least one cycle of RBAC500 were included in the primary and safety analyses. Using efficacy and toxicity as a composite primary endpoint, we considered the final conclusion positive if more than 28 of 57 patients achieve complete response and fewer than 18 of 57 patients report toxicities. This study is registered with EudraCT, number 2011-005739-23, and ClinicalTrials.gov, number NCT01662050, and is completed. Findings Between May 2, 2012, and Feb 25, 2014, we enrolled 57 patients (median age 71 years, IQR 67–75). 54 (95%) patients received at least four RBAC500 cycles (three discontinued because of toxicity), and 38 (67%) completed six cycles. Two (4%) had disease progression (one after the fourth cycle and one after the sixth cycle). All 52 (91%, lower limit of one-sided 95% CI 85%) remaining patients achieved complete response at the end of treatment. 23 (40%, upper limit of one-sided 95% CI 53%) of 57 patients had at least one episode of relevant toxicity. The most frequent grade 3–4 haematological toxicities were neutropenia (149 [49%] of 304 cycles) and thrombocytopenia (158 [52%]). Most treatment-related non-haematological adverse events were of grade 1–2, with the most frequent ones being fatigue (14 [25%] patients), nausea or vomiting (12 [21%]), and infusion-related reactions or tumour lysis syndrome (12 [21%]). 41 (72%) patients required a dose reduction. 12 patients died during the study, but no deaths were related to treatment. Interpretation RBAC500 is an effective treatment for elderly patients with mantle cell lymphoma and, despite not meeting our prespecified safety boundary, haematological toxicity was manageable with appropriate supportive care and dose reduction. Since maintenance therapy is not required, RBAC500 could be considered an option and should be studied in phase 3 trials. Funding Fondazione Italiana Linfomi and Mundipharma. © 2017 Elsevier Ltd
U2 - 10.1016/S2352-3026(16)30185-5
DO - 10.1016/S2352-3026(16)30185-5
M3 - Article
JO - The Lancet Haematology
JF - The Lancet Haematology
SN - 2352-3026
ER -