Oxaliplatin as Single Agent or in Combination in Chronic Lymphocytic Leukaemia (CLL).
Authors: Montillo Marco , Miqueleiz Sara , Tedeschi Alessandra , Ricci Francesca , Molteni Alfredo , Morra Enrica 
Published: April 2020

Abstract
Patients who failed fludarabine (FLU) or showing a relapse after several lines of chemo or immuno therapy have poor chance to obtain further response to treatment. Oxaliplatin (OX) is a third generation platinum compound with a 1,2 diaminocyclohexamine carrier ligand, it has a different activity and side effect profile from cisplatin. In order to test the activity of OX in CLL we administered first this agent as monotherapy in relapsed patients. OX covalently binds DNA, inducing DNA intra and inter-strand cross-links. FLU has been shown to have a biochemical modulating effect on others antineoplastic agents. Moreover, FLU and Ara-C act synergistically to inhibit excision repair of DNA cross-links. This evidence provides a rationale to test the combination of OX, FLU and Ara-C in patients with advanced CLL. The first cohort of patients received OX 140 mg/m2, as single agent. The second cohort of patients received OX, at increasing dose 17.5 (1st course), 25 (2nd course), 35 mg/m2 (from 3rd course up to the 6th course), days 1–4; Fludarabine 25 mg/m2, days 2 and 3; Ara-C 1 g/m2, days 2 and 3. Courses were given every 4 weeks for a total of 6 courses; all patients received G-CSF 5μcg/m2. Prophylaxis against tumor lysis syndrome, PCP and DNA virus were provided. Seven patients (M=4;F=3; Median age = 62 years; Binet stage B =3, Binet stage C= 4) who received a median of 3 previous (range 2–5) lines of treatment, two of them resistant to FLU, have been treated with OX as single agent. Patients receiving at least 1 course were evaluable for toxicity. Four patients completed the entire program of treatment, 2 patients received 4 courses of OX and they didn’t continued treatment because of persistant neutropenia from the previous course. The last patient stopped OX after the second course because of disease progression. The major toxicity was hematologic. Grade 3–4 neutropenia and thrombocytopenia were experienced in 5 and 6 patients respectively. There were no treatment related deaths. One patient showed a disease progression, 2 patients showed PR while 4 remained with stable disease. No response was observed in patients who had failed FLU. In the second cohort 4 patients (M=3: F=1; Median age=61 years) have been treated with the combination of FLU, OX and Ara-C. Three patients presented abdominal bulky disease resistant to the last treatment. Three patients were FLU resistant. Three patients received the entire program while the fourth patient stopped treatment after three courses because of a hepatic toxicity while on partial response. The major toxicity was hematologic and appeared OX-dose dependent. Grade 3/4 neutropenia was experienced by 1/4, 2/4 and 4/4 patients treated at 17.5, 25 and 35 mg/m2 OX levels respectively. Grade 3–4 thrombocytopenia was experienced by 2/4, 3/4 and 4/4 patients treated at 17.5, 25 and 35 mg/m2 OX levels respectively. No treatment related deaths were observed. One patient reached CR, and 3 patients a PR. Considering the three patients with bulky disease, disappearance of the abdominal involvement in one patient and reduction &gt; 50% in the other two patients were recorded. The usefulness of OX given as single agent is limited in patients with advanced CLL, at the contrary these preliminary results of the combination OX, FLU and Ara-C appeared very promising. Further accrual of patients to be treated with the combination using OX at 35 mg/m2, days 1–4, is warranted.