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Aggressive lymphomas of the elderly: the DEVEC metronomic chemotherapy schedule fits the unfit

2017; Wiley; Volume: 183; Issue: 5 Linguagem: Inglês

10.1111/bjh.15039

1365-2141

Maria Christina Cox, Gerardo Musuraca, Roberta Battistini, Ivana Casaroli, Valerio Zoli, Paola Anticoli‐Borza, Annalisa Arcari, Virginia Naso, Francesca Di Landro, Francesca Fabbri, Agostino Tafuri, Guido Bocci, Francesco Merli,

Acute Lymphoblastic Leukemia research

Elderly patients with aggressive lymphomas have less benefit than younger subjects from standard maximum-tolerated-dose chemotherapies (Chihara et al, 2016). Metronomic chemotherapy (MC) has been recently defined as the frequent, regular administration of chemotherapeutic drug doses that maintain a low, prolonged and active range of plasma concentrations with a favourable toxicity profile (Bocci & Kerbel, 2016). As MC is poorly studied in lymphomas (Buckstein et al, 2006; Coleman et al, 2008; Zeng et al, 2016), in 2011, we formulated a new oral MC regimen termed DEVEC (Deltacortene®, etoposide, vinorelbine, cyclophosphamide), which was adopted in six Italian clinical centres. DEVEC foresees an induction and a deescalated maintenance phase both consisting of six cycles. In CD20+ lymphomas, rituximab was administered weekly for a maximum of four doses (excluding patients who relapsed 80 years (Fig S2E) and for patients with performance status ≥2 (Fig S3). In B-cell lymphomas DEVEC was active even without rituximab (Fig S2F). This study shows that the all-oral DEVEC schedule was active in both naïve and relapsed/refractory aggressive lymphomas and quite well tolerated also in very elderly non-FIT patients. Overall, haematological toxicity was mild and manageable. Infections were the most frequent extra-haematological toxicities. Very few studies have investigated the activity of MC in aggressive lymphomas (Mandelli et al, 1980; Buckstein et al, 2006; Coleman et al, 2008; Zeng et al, 2016). PROVECIP (procarbazine, vinblastine, cyclophosphamide, prednisone) was an ante-litteram MC schedule (Mandelli et al, 1980) In the first study reporting on MC, PEP-C (prednisone, etoposide, procarbazine, cyclophosphamide) was investigated in a heterogeneous series of lymphoma patients. However, the majority of the enrolled subjects had an indolent subtype (Coleman et al, 2008). Recently, Zeng et al (2016), prospectively compared MC to standard-chemotherapy in a small series of refractory/relapsed lymphomas, reporting better PFS in the MC arm. These schedules (Buckstein et al, 2006; Coleman et al, 2008; Zeng et al, 2016), foresaw continuous administration of MC. Conversely, DEVEC was devised with short chemo-free breaks within subsequent cycles in order to allow haematological recovery and to maintain a continuous exposure to different drugs during the cycle, thus reducing the possibility of drug resistance (Bocci & Kerbel, 2016). We acknowledge that our data are retrospective and the series is heterogeneous. Despite these limitations, given that the majority of patients were >75 years old, relapsed/refractory and frail, these preliminary results look promising. Furthermore, the ORR seems at least not inferior to that of previous studies on relapsed/refractory series treated with standard in fusional schedules (Arcari et al, 2016) and/or new expensive drugs (Czuczman et al, 2017). In the exciting era of targeted therapies, there is still an unmet need for suitable treatments for elderly non-FIT patients. The Italian Lymphoma Foundation is assessing DEVEC in a prospective trial (EUDRACT 2016-003703-62). As the potential of MC, and its combination with biological drugs, still awaits to be fully exploited in lymphomas (Pasquier et al, 2010) we hope this report will further stimulate the search for more active, less toxic and financially sustainable treatments. M Christina Cox: designed and performed the research, analysed data and wrote the paper. Gerardo Musuraca: designed and performed the research, wrote the paper. Roberta Battistini: performed research, analysed data and wrote the paper. Annalisa Arcari, Guido Bocci, Francesco Merli: designed research and wrote the paper. Valerio Zoli: performed research and wrote the paper. Ivana Casaroli, Paola Anticoli Borza, Francesca di Landro, Francesca Fabbri: analysed data, and wrote the paper. Virginia Naso: wrote the paper. Agostino Tafuri: critically revised the paper. None of the above Authors have any relevant conflict of interest. Fig S1. DEVEC schedule. Fig S2. Overall survival and progression free survival of 45 patients treated with DEVEC. Fig. S3. Overall survival and progression free survival in patients with performance status 2< or ≥2. Table SI. Management of neutropenia during first cycle* Table SII. Management of neutropenia in subsequent induction cycles Table SIII. Management of neutropenia in maintenance phase Table SIV. Patients disposition Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.