Combination of rituximab, bortezomib, doxorubicin, dexamethasone and chlorambucil (RiPAD+C) as first-line therapy for elderly mantle cell lymphoma patients: results of a phase II trial from the GOELAMS

Houot, Roch; Gouill, Steven Le; Ojeda-Uribe, Mario; Mounier, Christiane; Courby, Stéphane; Dartigeas, Caroline; Bouabdallah, Krimo; Vigier, Magda; Moles, Marie Pierre; Tournilhac, Olivier; Arakelyan, Nina; Rodon, Philippe; Yamani, Abderrazak El; Sutton, Laurent; Fornecker, L.; Assouline, David; Harousseau, Jean‐Luc; Maisonneuve, Hervé; Caulet‐Maugendre, Sylvie; Gressin, Rémy

doi:10.1093/annonc/mdr450

Cited by 42 publications

(23 citation statements)

References 17 publications

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“…Bortezomib was also combined with rituximab, vincristine, doxorubicin, dexamethasone, and chlorambucil as part of a frontline strategy for older MCL patients (ages 65-80). 31 This phase 2 study from the Groupe Ouest Est d'Etude des Leucémies et Autres Maladies du Sang also generated high CR rates (59%).…”

Section: Discussionmentioning

confidence: 95%

Phase 2 study of VcR-CVAD with maintenance rituximab for untreated mantle cell lymphoma: an Eastern Cooperative Oncology Group study (E1405)

Chang

Smith

et al. 2014

Blood

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• VcR-CVAD produced high overall and CR rates in previously untreated MCL patients.• No substantial difference in 3-year PFS or OS was observed in patients receiving ASCT compared with patients receiving maintenance rituximab.Rituximab, bortezomib, modified hyper-cyclophosphamide, doxorubicin, vincristine, dexamethasone (VcR-CVAD) induction chemoimmunotherapy and maintenance rituximab (MR) were evaluated for efficacy and safety in Eastern Cooperative Oncology Group protocol E1405. Patients with previously untreated mantle cell lymphoma received VcR-CVAD chemotherapy every 21 days for 6 cycles, followed by MR for 2 years. Transplant-eligible patients had the option of autologous stem cell transplantation (ASCT) consolidation instead of MR. The primary end point was the complete response (CR) rate to VcR-CVAD. The secondary end points were overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and toxicities. Seventy-five eligible patients with a median age of 62 (range 40-76) were enrolled. The ORR was 95% and a CR was achieved in 68% of patients. After a median follow-up of 4.5 years, 3-year PFS and OS were 72% and 88%, respectively. No substantial difference in PFS or OS was observed between patients treated with MR (n 5 44) vs ASCT (n 5 22). There were no unexpected toxicities. VcR-CVAD produced high ORR and CR rates in mantle cell lymphoma. MR after VcR-CVAD induction performed similarly to ASCT and may improve response duration. Randomized clinical trials comparing MR against ASCT should be considered and randomized clinical trials evaluating bortezomib's contribution to conventional therapy are under way. This study was registered at www.clinicaltrials.gov as #NCT00433537. (Blood. 2014;123(11):1665-1673

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Section: Discussionmentioning

confidence: 95%

Phase 2 study of VcR-CVAD with maintenance rituximab for untreated mantle cell lymphoma: an Eastern Cooperative Oncology Group study (E1405)

Chang

Smith

et al. 2014

Blood

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“…In an age-stratified phase I trial, a combination of bortezomib, gemcitabine, and liposomal doxorubicin in patients with advanced malignancies is well tolerated and demonstrated effective antitumor activity in T-cell lymphoma and small cell carcinoma 23 . Recently, a phase II trial demonstrated that the botezomib-containing combination treatment in elderly mantle cell lymphoma patients results in high complete responses and prolonged progression-free survival with predictable and manageable toxic effect 24 . We also found a synergistic inhibitory activity when using a combination of botezomib and topoisomerase inhibitors in human chordoma cell lines and primary cell cultures, suggesting that this combination drug treatment might be a future direction for chordoma therapy.…”

Section: Discussionmentioning

confidence: 99%

Identification of repurposed small molecule drugs for chordoma therapy

Xia

Huang

Sakamuru

et al. 2013

Cancer Biology & Therapy

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Chordoma is a rare, slow growing malignant tumor arising from remnants of the fetal notochord. Surgery is the first choice for chordoma treatment, followed by radiotherapy, although postoperative complications remain significant. Recurrence of the disease occurs frequently due to the anatomy of the tumor location and violation of the tumor margins at the initial surgery. Currently, there are no effective drugs available for patients with chordoma. Due to the rarity of the disease, there is limited opportunity to test agents in clinical trials and no concerted effort to develop agents for chordoma in the pharmaceutical industry. To rapidly and efficiently identify small molecules that inhibit chordoma cell growth, we screened the NCGC Pharmaceutical Collection (NPC) containing approximately 2800 clinically approved and investigational drugs at 15 different concentrations in chordoma cell lines, U-CH1 and U-CH2. We identified a group of drugs including bortezomib, 17-AAG, digitoxin, staurosporine, digoxin, rubitecan, and trimetrexate that inhibited chordoma cell growth, with potencies from 10 to 370 nM in U-CH1 cells, but less potently in U-CH2 cells. Most of these drugs also induced caspase 3/7 activity with a similar rank order as the cytotoxic effect on U-CH1 cells. Cantharidin, digoxin, digitoxin, staurosporine, and bortezomib showed similar inhibitory effect on cell lines and 3 primary chordoma cell cultures. The combination treatment of bortezomib with topoisomerase I and II inhibitors increased the therapeutic potency in U-CH2 and patient-derived primary cultures. Our results provide information useful for repurposing currently approved drugs for chordoma and potential approach of combination therapy.

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“…A phase III clinical trial is currently ongoing, randomizing MCL relapsed patients to receive either R-HAD AE bortezomib (NCT01449344). Other studies tested bortezomib combinations in first-line treatment, too [32][33][34].…”

Section: Proteasome Inhibitorsmentioning

confidence: 99%

The current therapeutic scenario for relapsed mantle cell lymphoma

Ferrero

Dreyling

2013

Current Opinion in Oncology

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Purpose of reviewPatients with relapsing mantle cell lymphoma (MCL) still represent a demanding challenge for the hematooncologist. The dismal prognosis and the absence of generally accepted therapeutic standards hamper the clinical management of such cases. Moreover, the availability of many targeted approaches, in a field so far missing efficient salvage regimens, challenges current therapeutic algorithms in these patients. Recent findingsMolecular targeted drugs provide unprecedented response rates in relapsed and even chemorefractory MCL. Many phase II studies demonstrated impressive antilymphoma activity of compounds such as bortezomib, lenalidomide and temsirolimus, whereas ongoing phase III trials currently assess the 'real world' benefit and the impact on survival, both alone and in combination with chemotherapy or monoclonal antibodies. Recently, the Bruton's tyrosine kinase inhibitor ibrutinib, targeting the B-cell receptor cascade, showed impressive response rates and will be soon available in phase III trials. SummaryIn the present review we focus on the major therapeutic discoveries of the last few years to offer a practical algorithm to select the appropriate treatment in patients with relapsed MCL.

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Combination of rituximab, bortezomib, doxorubicin, dexamethasone and chlorambucil (RiPAD+C) as first-line therapy for elderly mantle cell lymphoma patients: results of a phase II trial from the GOELAMS

Abstract: The bortezomib-containing RiPAD+C regimen results in high CR rates and prolonged PFS with predictable and manageable toxic effects in elderly patients with MCL.

Cited by 42 publications

References 17 publications

Phase 2 study of VcR-CVAD with maintenance rituximab for untreated mantle cell lymphoma: an Eastern Cooperative Oncology Group study (E1405)

Phase 2 study of VcR-CVAD with maintenance rituximab for untreated mantle cell lymphoma: an Eastern Cooperative Oncology Group study (E1405)

Identification of repurposed small molecule drugs for chordoma therapy

The current therapeutic scenario for relapsed mantle cell lymphoma

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