A PROSPECTIVE, RANDOMIZED, PHASE II STUDY OFGISL COMPARING TWO MITOXANTRONE-BASED SALVAGEPROGRAM (MIPE VS MJMA) IN AGGRESSIVE NON-HODGKIN’SLYMPHOMA (ANHL) FAILING AN ANTHRACYCLINECONTAININGFRONT-LINE TREATMENT

Background: Patients (pts) never achieving or failing after initial completeresponse (CR) have a poor prognosis when treated with conventionalsalvage regimens. The Parma study has shown significantly better eventfree(EFS) and overall survival (OS) with high-dose therapy and stem-cellsupport in pts with first or subsequent chemosensitive relapsing aNHL.However, many pts prove to be ineligible because of age or associatedmorbidity for this potentially curing approach. Although, newer combinationsincluding agents with proven efficacy, without cross-resistance,and not included in the front-line regimens have been developed is notstill clear which of them is able to give higher response rates and longlastingCR. Aim of study was to compare in a prospective, randomizedstudy two mitoxantrone-based regimens in order to evaluate their efficacyand toxicity in patients with relapsed-refractory aNHL after anthracyclinecontainingup-front therapy.Patients and methods: Between April 1991 and October 1996, 87 ptsentered in the study; 44 pts were randomized to receive MJMA (mitoxantrone10 mg/m2 d1, carboplatin 100 mg/m2 d1-4, methyl-prednisolone500 mg td d1-4 and Ara-C 2000 mg/m2 d5) and 43 MIPE (mitoxantrone12 mg/m2 d1, ifosfamide 1660 mg/m2 d1-3, VP-16 120 mg/m2 d1-3, prednisone60 mg/m2 PO d1-5, MESNA 600 mg/m2 h 0, + 4, + 8 d1-3) every4 weeks for maximum six courses. To be eligible pts had to have histologicallyconfirmed aNHL, age older 15 years and at least one measurablelesion. There were no significant differences between the two arm ofstudy concerning the median age (51.9 vs 52.8 yr), B-symptoms (37 vs44%), bulky disease (27 vs 21%), bone marrow involvement (43 vs 44%),abnormal LDH level (50 vs 53%), and IPI score 0-1(34 vs30%) whilethere were more pts with advanced stage in the MIPE arm (82 vs 98%;P = 0.015). Thirty-seven pts (42.5%) had relapsed and 50 refractorydisease.Results: On intent to treat analysis, the ORR was 50% in the MJMA and42% in the MIPE arm including 38.6% and 27.9% of CRs respectively(P = 0.33). After a median observation time of 36 months (range: 1 to 85months), the actuarial 5-year RFS, EFS, and OS rates were 42.8% vs66.6% (P = 0.27), 14.6% vs 16.2%, and 31.8% vs 30.2% (P = 0.29) forMJMA and MIPE respectively. For CR pts the median TTF was 8 months(95% CI, 6 to 10), and 6 months (95% CI, 5 to 7)[P = 0.3], and the mediansurvival time 14 (range: 1 to 91; 95% CI, 1.93 to 26.07) and 7 months(range: 1 to 90; 95% CI, 3.26 to 10.74) [P = 0.4] for MJMA and MIPErespectively. In multivariate analysis pts with IPI score 0-1 had significantlybetter 5-yr OS than those with score 2-5 (57 vs 16.6%; p = 0.0002).The WHO grade III-IV hematologic toxicity was comparable in the twoarm (59 vs 67%) while the mucositis occurred more frequently in theMIPE arm (37 vs 7%; P = 0.0001). Twenty patients in the MJMA and 22in the MIPE arm died of progressive disease while 1 and 3 patientsrespectively died of treatment-related toxicity.Conclusion: the results of this randomized study show that both regimensare effective and safe in patients with refractory/relapsed aNHL; the5-year EFS and OS rates achieved in both arm are comparable with thosereported by other series in patients with only chemosensitive relapsed disease.In the future studies including monoclonal antibodies should be conducted.