Phase I/II Study of Escalating Doses of Idarubicin Orally Given with Oral Cyclophosphamide, Etoposide, Prednisolone and Intravenous Rituximab in Elderly Patients with Disseminated High Grade Non Hodgkin Lymphoma.

This study was performed to determine the maximum-tolerated dose (MTD) of oral idarubicin in combination with oral cyclophosphamide (CY), etoposide (ET), prednisolone (PRED) and intravenous (IV) rituximab (RI) administrated to previously untreated patients (pts) (60-80 years-old) with high grade stage III or IV non Hodgkin lymphoma. Secondary objectives were evaluation of toxicity and efficacy.

Idarubicin was administrated per os on day 1 with doses starting at 20 mg/m2 and escalated by 10 mg/m² increments. Each idarubicin dose level included 3 to 6 pts. No intrapatient dose escalatation was allowed. Dose-limiting toxicity (DLT) was defined as grade 4 neutropenia lasting at least 4 days or grade 4 thrombopenia or more than grade 2 extra haematological toxicity. The MTD was defined as the dose level at which at least 2 of 3 or 3 of 6 pts experienced a DLT. CY and ET were given per os on day 1 to 3 at the fixed dose of 150 mg/m² and 100 mg/m² respectively. PRED was given at the fixed dose of 50 mg/m² per os on day 1 to 5. RI was administrated IV on day 1 at the fixed dose of 375 mg/m². G-CSF was systematically used from day 6 to haematological reconstitution. Eight cycles were planned at 3 week-intervals.

Between October 2003 and August 2008, 19 immunocompetent pts [median age 70 (range 62-80)] with a new diagnosis of high grade non Hodgkin lymphoma received 128 cycles at 3 different idarubicin dose levels. No DLT was observed at dose level 1 (20 mg/m2), whereas 2 of 6 patients developed a DLT at dose level 2 (30 mg/m2). All 3 pts developed a DLT at level 3 (40 mg/m2) which was considered as MTD. Seven pts were enrolled at level 2 to confirm the results. Main toxicity results are summarized in the table below. No toxicity related mortality was observed. Two pts stopped treatment because of toxicity and 8 pts received a decreased dose. Overall response rate and complete response rate were 79% and 68% respectively. With a median follow-up of 22 months, the 2-year survival rates were 75% (95% CI: 45-90) for all pts and 58 % (95% CI: 21-83) for dose level 2 pts.

This first analysis clearly shows that the MTD of oral idarubicin administrated with CY, ET, PRED and RI, is 40 mg/ m² on day 1 every 21-day cycle. The recommended dose study is ongoing. Overall survival data seems to be similar to previous publications. (Coiffier et al, NEJM 2002). Future development of subcutaneous anti-CD20 antibody could represent a special interest for this new oral chemotherapeutic protocol in order to improve the quality of life of elderly pts.

No relevant conflicts of interest to declare.