ALBERT

Description: Objective: In this pilot study we evaluated the clinical activity, toxicity and mobilizing capacity of a new short-course (bi-weekly), dose intensive, cytoreductive/mobilizing salvage regimen (R-GIFOX) combining the cross-synergistic agents Gemcitabine (G), Ifosfamide (Ifo), Oxaliplatin (Ox) and Rituximab (R), in patients with relapsed and refractory CD20+ NHL. Based on the predicted clinical activity, tolerability and synergy among drugs, the R-GIFOX regimen may offer an effective and less toxic alternative to Cisplatin/ARA-C-based salvage regimens, also for patients aged or unfit for high-dose procedures. Patients and methods: Patients were scheduled to receive three courses of therapy followed by mobilization and ASCT or three more courses if ineligible for ASCT. Therapy was delivered on a compassionate basis after written informed consent. R-GIFOX consisted of R (375 mg/m2, d 1), G (1000 mg/m2, d 2), Ox (130 mg/m2, d 3) and Ifo (5 g/m2, d 3), as a 24-hour single infusion in patients aged ≤ 65 years, or fractionated over 3 days (dd 3–5) in older patients. Treatment was given every two weeks with G-CSF support (5 mcg/kg/day, dd 6–11; 10 mcg/kg/day at the 3rd course for stem cells mobilization). Responses were evaluated after three courses by the integrated FDG-PET/IWC criteria, and reassessed at the end of the entire program. Results: Fourteen patients (median age 63 years, range 37–78 years) with relapsed (n = 9) or primary progressive (n = 5) aggressive [diffuse large cell (n=7), mantle cell (n=4), follicular G3b (n=3)], advanced (stage IV = 71%), poor risk (IPI 3–5 = 50%; median number of previous therapy=2, r 1–4) NHL, were accrued. Forty-nine total courses were delivered (median 4, range 1–6); thirteen patients completed at least 3 courses of therapy and were evaluable for response. Actual dose intensity of the first 3 courses was 81%, 83.5%, and 86.5% for G, Ifo and Ox, respectively. CTCAE v3.0 G3/G4 thrombocytopenia was present in 26 % of courses, G3/G4 neutropenia in 22%; febrile neutropenia and infections in 8% and 6% of cycles, respectively. The ORR assessed after three courses of R-GIFOX was 77%, with 7 complete responses (54%; CR=5; CRu=2) and 3 partial; CRu converted to CR at BM biopsy after 6 courses. According to age, the ORR was 67% (4 CR, 2 PR) and 80% (3 CR, 1 PR) for patients aged ≤ 65 years and those older, respectively. According to disease status, the ORR was 40% (1 CR, 1 PR) and 89% (6 CR, 2 PR) for primary refractory and relapsed patients, respectively. Among CRs no patient has relapsed at a median time of 5 months (range, 2+ − 10+). Effective CD34+ cell mobilization was obtained in 4 out of 6 eligible patients and 2 already received ASCT. Failure free survival was 79.6%. In mantle cell lymphoma 2 CRs and 1 PR were obtained, including 2 molecular remissions (BM, PB). Conclusions: Based on the results of this pilot study, R-GIFOX was feasible, tolerable, effective and able to mobilize peripheral stem cells in patients with reccurrent aggressive NHL. It enabled the achievement of effective dose-intensities and high response rates also in the older patients. Finally, the R-GIFOX regimen showed clinical activity also in ’difficult’ histotypes such as mantle cell lymphomas.

Description: Abstract 2829 Background: Peripheral T/NK cell lymphomas (PTCL) have a dismal prognosis with an overall 5yr survival 〈 30% and of 21% and 6% for intermediate-high and high IPI scores, respectively. The incorporation of new agents and transplant procedures in upfront strategies is a present challenge to investigators, due to the advanced age of the patient population and to the unsatisfactory results achieved with anthracyclines- based standard or intensified regimens. The nucleoside analog gemcitabine has shown high single agent activity in recurrent disease, but very little data are available on the upfront efficacy of gemcitabine-based combinations. We assessed activity, toxicity and stem cells (SCs) mobilizing capacity of a dose-dense combination of gemcitabine (G) with ifosfamide (Ifo) and oxaliplatin (Ox) (GIFOX regimen) for front-line therapy of PTCL other than anaplastic large cell subtypes and with 3–5 IPI scores. Methods: Patients had to receive 6 GIFOX courses at biweekly intervals; SCs mobilization and consolidation of chemosensitive response with autologous transplantation (ASCT) were planned after the 3rd and the 6th course, respectively. GIFOX consisted of G 1200 mg/m2 D1, Ox 120 mg/m2 D2 and Ifo 5 g/m2 D2, as a 24h single infusion in pts aged ≤ 65 years, or fractionated over days 2, 3 and 4 in pts aged 〉 65 years, G-CSF 5 mcg/kg/d DD 7–11 (10 mcg/kg/d, 3rd course until SCs mobilization). No dose reductions were planned in case of inadequate bone marrow recovery, and treatment was delayed until the absolute neutrophil count was more than 1000/μL and the platelet count more than 50000/μL. For patients 〉 65 years the agents dosing was determined according to the nadir neutrophil or platelet counts with reduction to 75% of the planned dose for gemcitabine in case of CTCAE v.3 grade 3 toxicity, and for all the three drugs in case of grade 4 toxicity. A strict monitoring of Clcr was required and Ifo doses were reduced according to Kintzel (Cancer Treat Rev, 1995, 21(1):33-64). Results: Twenty-one pts (M/F=15/6; median age 63 yrs, r 42–80) with PTCL [angioimmunoblastic (n=6), PTCL,nos (n=8), extranasal NK (n=2), Sezary syndrome (n=5)] were prospectively accrued. Fifteen pts (71%) had stage IV disease, nine (43%) had 〉1 extranodal site, 71% had abnormal LDH, 29% had ECOG PS 〉1, 43% B-symptoms. A total of 105 courses were delivered (median 6, r 2–6) with only three patients receiving less than 4 courses due to disease progression (n=2) and early death (n=1). This latter event occurred in a 76 yr-old man succumbing to septic shock after the 2nd cycle of treatment. In two elderly patients Ifo was omitted from the 4th course onward due to signs of encephalopathy. Grade 4 thrombocytopenia occurred in 8 pts (38%), grade 4 anemia and grade 3 infection were found in 24% and 33%, respectively. The ORR according to FDG-PET/IWC criteria after the first 3 courses was 86% (95%CI: +/− 15), with 4 partial and 14 complete responses (8CR+6 CRu= 67%; 95%CI: 47–87). Bone marrow tumor clearance after full completion of GIFOX eventually converted 6 CRu in full CR. Among the eight pts eligible for ASCT, 6 had effective CD34+ cells harvest and 4 proceeded to transplant. The 5-year Event-Free Survival was 49%, median survival 30.5 months. For complete responders the probability of relapse was 36.5 % at a median follow-up of 24 months (Figure). Conclusions: GIFOX retains an attractive therapeutic potential as upfront strategy in PTCL, enabling cytoreduction and SCs mobilization for ASCT consolidation, and allows the safe delivery of a full induction program also to patients aged or unfit for high dose therapy. Disclosures: No relevant conflicts of interest to declare.

Description: Background: Multiple extranodal localizations, nodal spreading and bone marrow (BM) involvement have been associated with shorter overall and event-free survival in Extranodal Marginal Zone Lymphoma (EMZL). No optimal treatment has yet been defined and, in this setting, Rituximab has demonstrated only moderate single agent activity while the role of purine analogs is still controversial, although promising in terms of objective response rate. In order to verify a potential synergy of these agents we conducted a prospective phase II trial evaluating a sequential treatment with 2-CDA, a purine nucleoside analog with proapoptotic and cytotoxic activity on both proliferating and quiescent lymphoid cells, and Rituximab in patients (pts) with untreated disseminated EMZL. Patients and methods: Pts with histologically confirmed MZL, ECOG 〈 2 and Stage IV disease were enrolled. 2-CDA was administered at a dose of 0.12 mg/kg on 5 consecutive days as a 2-hour infusion, every 4 weeks for 6 courses on outpatient basis. Thereafter, 4 doses of Rituximab (375 mg/m2, i.v., every 2 weeks) were delivered. Prophylaxis with TMP-SMX was required and filgrastim introduced if grade 3–4 neutropenia had occurred. Responses were evaluated after the 4th course of 2-CDA and at the end of the entire program. Results: Twenty-three pts (median age 67 yrs; r 34–81) with advanced [multiple extranodal site (n=16), BM (n=15), distant/diffuse nodal involvement (n=14), orbit (n=8), multicentric skin (n=3), gastric (n=4), leukemic (n=2), lung and pleura (n=3), salivary glands (n=3), Waldeyer’s ring (n= 1), breast (n=1)] EMZL were accrued. B symptoms were present in 4 pts, abnormal LDH in 6. No pts had been irradiated and only 2 had received surgical resection due to emergency (ileum) and diagnostic (lung) procedures. All pts completed treatment program and were evaluable for response. The median number of delivered courses of 2-CDA was 6 (r 3–6). The overall response rate was 91 % [after the 4th course: CR=4, CRu=11, PR=6; at the end of treatment (i.e. including Rituximab): CR= 18 (78%), PR=3 (13%)]. Interestingly, a histological CR was achieved in 13 out of 15 pts with BM involvement (81%). Only 2 pts, with B symptoms at presentation, had a therapeutical diversion at the 3rd and 4th course due to minor response and persisting symptomatic disease. Extrahematological toxicity was negligible. CTCAE Grade 3 and 4 neutropenia occurred in 9 and 5 (22%) pts, respectively and febrile neutropenia occurred in 6 pts (26%). Grade 4 Thrombocytopenia and lymphocytopenia developed in 4 (17%) and 3 (13%) patients, respectively. Delayed grade 3 leuko- and thrombocytopenia occurred two months after 2-CDA withdrawal in three pts and slowly recovered in the following 6–8 weeks. No late opportunistic infection, nor disease recurrence have to date occurred. Failure free survival was 86 % at median follow up of 18 months (range, 4–34). Conclusions: Our prospective study shows that 2-CDA plus sequential Rituximab represents an effective strategy for the upfront treatment of disseminated EMZL. It is feasible in outpatient setting, and associated with favorable early and late toxicity profiles. While a longer follow-up will assess its impact on disease natural history, our results show for the first time that 2-CDA plus sequential rituximab may achieve very high CR rates even in poor prognosis pts with extragastric and widespread EMZL.

Description: Despite the mature results of the new intensive treatments, ABVD is still considered the standard therapy of the HL. Here we report the 2-year results of a phase 2 study which explore the possibility to ameliorate the performance of this (g)old schedule. Primary End-Points: CR and early cardio-toxicity. Secondary End-Points: survival (FFP,OS) and late cardio-toxicity. 23/25 CR (CI 90%) to validate the study (80% standard vs 90% DD-DI ABVD, CI +/− 10% one tail test, 5% sig stat level). Modifications of the standard (st) ABVD and strategy concepts are summarized as follow: Each patient received a total of 6 cycles without RT Adryamicin (ADM) was escalated from 50 to 70 mg/m2 in the cycles 1,2,3,4. The cumulative dose of ADM was 380 mg/m2. The intercycle period was shortened from 28 to 21 days for all 6 cycles; the 4 drugs were delivered at day 1 and 11 of each cycle G-CSF was given from d4 to d8, and from d14 to d18 of each cycle The therapy program was driven by dynamic indicators such as interim-PET and CT fusion images. Normalisation of PET images at the end of 2nd cycles was indicator of early CR, while the persistence of PET+ lesion(s) at the end of the 4th cycle was indicator of failure and consequently the treatment was shift to a high-dose CT/CD34+ rescue program. RT was eliminated. At the end of 6th cycle, PET- residual masses were monitored by PET/TC fusion images. An historical group of 94 HL pts treated with 6–8 cycles of st-ABVD +/− RT was used to compare response, survival and toxicity data. Compared to st-ABVD the theoretical relative dose-intensity (RDI) values of drugs were 1.86 for ADM, 1.33 for DTIC, Bleomycin and Vinblastine, and 1.46 for the entire schedule. Administered RDIs of the schedule (delivered cycles = 184) ranged between 1.10 to 1.55 (median value 1.39). Results: from June 2004 to August 2006 thirty-nine pts were enrolled (tab1). As the 8th August 2006 thirty-five out of 39 pts have performed the interim-PET-TC fusion images and thirty-two completed the treatment: 100% of valuable pts obtained the early CR (35/35) and CR (32/32). All pts are alive and free of disease (tab2 and fig.1). Cardiac functions were monitored by ECG, Ecography, MUGA scan, pro-BNP, and troponin T. Toxicity was mild and similar to standard ABVD. Dose-dense and dose-intense ABVD is feasible, well tolerated and highly active in newly diagnosed patients with advanced/intermediated Hodgkin’s lymphoma: six cycles without RT seem superior to 6–8 cycles of ABVD +/− RT (fig 1) and may be a promising program for optimal long-term results. tab1 presentation features Features total 39 100% Early unfavourable 9 23% Advanced 30 77% Age 〉 45 –yr 4 10% Bulky 19 44% Stage IV 13 33% B symptoms 25 64% Extranodal 9 23% VES 〉 50 mm 20 51% LDH Ratio 〉 1 15 38% IPS ≥ 3 10 26% N. Sites〉3 28 72% Male 13 33% tab.2 Response and Survival N. of patients percent *n°. of valuable pts as 8 August 2006 Early CR 35/35* 100% CR 32/32* 100% FFP-2yr 32/32* 100% OS-2yr 32/32* 100% Freedom From Progression Freedom From Progression