The Length of Treatment of Aggressive Non Hodgkin’s Lymphomas According to the International Prognostic Index Score. Some Lessons from the GISL LA03 Study.

In 1993 the Gruppo Italiano per lo Studio dei Linfomi (GISL) started a randomized 2x2 factorial study comparing a flexible versus fixed dosing schedule of two different antracycline-containing ProMACE-CytaBOM regimens, where the length of the treatment was modulated according to the IPI. Patients were randomly assigned to receive one of the following treatments: fixed ProME(Epidoxorubicin)CE-CytaBOM (PE-C); fixed ProMI(Idarubicin)CE-CytaBOM (PI-C); flexible PE-C; flexible PI-C. Epidoxorubicin (EPI) was used at the dose of 40 mg/sm IV and Idarubicin (IDA) at 8 mg/sm IV. In the flexible arms the doses of EPI or IDA were modified according to the following criteria: in absence of haematologic toxicity (i.e.WBC>4,000 and platelets>150,000) during the previous cycle increase the dose by 20%, in case of grade 1 toxicity, was increased the dose by 10%, in case of grade 2 toxicity administer the same dose, in case of grade 3-4 toxicity decrease the dose by 10%.After four courses of ProMACE-CytaBOM, remitters patients with low or low-intermediate IPI (low risk) were planned to receive 2 additional courses whereas those with intermediate-high or high IPI(high risk)were planned to receive 4 additional courses of chemotherapy. Between July 1993 and June 1997, 356 patients with advanced aggressive NHL were registered for the study. After randomization 11 patients were excluded for lacking inclusion criteria. Five out of remaining 345 patients withdrawn from the study before the first assessment of response. The remaining 340 patients, 246 at low and 94 at high risk, were assessed for response. The relative dose intensity of EPI and IDA was 0.91 and 0.88 in the fixed and 1.00 and 1.01 in flexible arms, respectively. At the end of induction chemotherapy 208 patients(61%)achieved a CR, and 59(17%)a PR. The CR rate was 70% and 48% for patients at low and high risk(P = 0.000), whereas no differences emerged between patients treated with fixed or flexible PC(P = 0.894) and EPI or IDA containing PC(P = 0.144). With radiotherapy(10 patients) or other different salvage treatments(11 patients), 21 additional patients reached a CR. In conclusion 229 patients (65% of all eligible and 67% of assessable patients) enrolled in the trial achieved a CR.During follow-up 77 relapses(34%) were recorded, with a 5-year relapse-free survival rate of 65%. The relapse rate was similar in patients treated with fixed or flexible PC(P=0.339), EPI or IDA containing PC(P=0.335), and in patients at low or high risk (P=0.507). After a median follow-up of 57 months (84 months for patients alive), 59% patients were estimated to be alive at 5 years. The 5-year estimated survival rates were 60% and 58% for flexible and fixed P-C (P=0.915), 61% and 57% for EPI and IDA (P=0,325), and 66% and 40% for patients at low and high risk (P = 0.000) respectively.The mature results of our study suggest that 6 courses of fixed or flexible PE-C or PI-C can determine a promising success rate in patients with advanced aggressive NHL and low or low intermediate IPI, whereas the same regimens are less effective in patients with intermediate or high IPI, even if 2 additional courses are delivered. Moreover, given that in the latter group of patients most failures were observed during the first 4 courses of therapy, we suggest that innovative approaches should be considered up-front.