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Phase I dose-escalation trial of total lymphoid irradiation and high-dose chemotherapy with cyclophosphamide, carboplatin and etoposide and autologous peripheral blood stem cell transplantation in patients with relapsed/refractory Hodgkins disease The Northwestern University/Robert H Lurie Comprehensive Cancer Center experience



Phase I dose-escalation trial of total lymphoid irradiation and high-dose chemotherapy with cyclophosphamide, carboplatin and etoposide and autologous peripheral blood stem cell transplantation in patients with relapsed/refractory Hodgkins disease The Northwestern University/Robert H Lurie Comprehensive Cancer Center experience



Blood 98(11 Part 1): 680a-681a



To investigate novel therapeutic approaches to relapsed/refractory Hodgkins disease (HD), we treated 26 patients; 25 were evaluable for response and toxicity, and of these 15 had relapsed and 10 had primary refractory disease. The regimen included TLI to a dose of 1500 cGy to uninvolved sites (150 cGy/fraction in the AM for 10 days to uninvolved sites), 3000 cGy to involved sites (150 cGy/fraction boost in the PM to involved sites) and 3540 cGy (3 additional fractions at 180 cGy/fraction, maximum 13 days) to bulk (>5 cm) sites followed immediately (between 6-14 days) by high-dose chemotherapy and AuPBSCT. The minimal interfraction interval was 6 hours for BID radiation. The chemotherapy was delivered in a Phase I design in cohorts of 3 patients with dose escalation of VP-16 starting from 400 mg/m2/day for 3 days by continuous infusion (CI) (total 1200 mg/m2) and escalating by 50 mg/m2 increments/day in subsequent cohorts to dose limiting toxicity (DLT); cyclophosphamide (Cy) 60 mg/kg daily for 2 days (total 120 mg/kg) and carboplatin (C) 450 mg/m2 by CI for 3 days (total 1350 mg/m2). Peripheral blood stem cells (PBSC) were reinfused 48 hours after completion of chemotherapy. Patients with prior radiation received the chemotherapy alone (n=9) while those with no or limited (<2000 cGy) prior radiation received TLI and chemotherapy (n=16). DLT was defined as any grade 5 toxicity or unexpected grade 4 toxicity. If the DLT was reached in any patient in any cohort, an additional 3 patients entered the trial at the same dose level of VP-16. If there was further DLT (2/6), that dose was chosen as the maximum tolerated dose (MTD). Of the 26 patients, there were 15 men and 11 women. The median age was 35 years (range 18-55). The MTD for VP-16 was 700 mg/m2/day (total=2100 mg/m2) by CI. There was 1 grade 5 infection, and no other treatment-related deaths (total treatment-related mortality 4%). There was 1 grade 4 cardiac (heart failure) toxicity (4%) and 1 grade 4 pulmonary (acute interstitial pneumonia requiring ventilation) toxicity (4%). There were 14 complete remissions (CR=56%), 6 partial remissions (PR= 24%) and 5 patients without response (NR=20%). With a median follow up of 26 months (mos) (range 2-76 mos), overall survival by Kaplan-Meier analysis at 1 year was 87%, at 2 years 71%, at 3 years 71% and at 4 years 61%. Disease free survival (DFS) among the 14 patients with CR was 79% (11/14) with median follow-up of 33 mos (range 4-76 mos). Overall DFS among the 25 evaluable patients was 54% at 1 year, and 45% at 2, 3 and 4 years. No differences in response or survival could be seen among the dose cohorts. We conclude that this combined modality TLI/CyCE and AuPBSCT regimen for relapsed/refractory HD is tolerated at a dose up to 2100 mg/m2 VP-16 given by CI over 3 days, and is associated with durable CR, with DFS among CRs of 79% and overall DFS of 45% at 4 years.

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