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In the course of investigations on the complex phenomenon of bee decline, Aspergillus flavus was isolated from the haemocoel of worker bees. Observations on the metabolomic profile of this strain showed kojic acid to be the dominant product in cultures on Czapek-Dox broth. However, an accurate review of papers documenting secondary metabolite production in A. flavus also showed that an isomer of kojic acid, identified as 5-(hydroxymethyl)-furan-3-carboxylic acid and named flufuran is reported from this species. The spectroscopic data of kojic acid were almost identical to those reported in the literature for flufuran. This motivated a comparative study of commercial kojic acid and 5-(hydroxymethyl)-furan-3-carboxylic acid, highlighting some differences, for example in the 13C-NMR and UV spectra for the two compounds, indicating that misidentification of the kojic acid as 5-(hydroxymethyl)-furan-3-carboxylic acid has occurred in the past.

Summary We explored activity and safety of a dose-dense/dose-intense adriamycin, bleomycin, vinblastine and dacarbazine regimen (ABVDDD-DI) in 82 patients with advanced Hodgkin Lymphoma. Patients entered a two-stage Bryant-Day Phase II study to receive six cycles of ABVDDD-DI without consolidation radiotherapy. Cycles were supported with granulocyte colony-stimulating factor and delivered every 21 d; drugs were administered on days 1 and 11 at the same doses of standard ABVD except for doxorubicin (35 mg/m2; first four cycles only). Co-primary endpoints were complete response (CR) rate and severe acute cardiopulmonary toxicity; secondary endpoints were event-free (EFS) and disease-free survival (DFS). All patients received the four doxorubicin-intensified courses and 96% concluded all six cycles (82·3% within the intended 18 weeks). This translated into a 66·9% increase of received dose-intensity for doxorubicin and 31·8% for the other agents over standard ABVD. The CR rate was 95·1% (78/82) and 87·8% (72/82) achieved a metabolic CR after two cycles. Cardiopulmonary toxicity never exceeded grade 2 and affected 14·6% of patients. Most frequent toxicities were grade 4 neutropenia (10%) and anaemia (9%), grade 3 infection (17%) and grade 2 mucocutaneous changes (30%). Five-year EFS and DFS was 88·3% and 93·7%, respectively. ABVDDD-DI regimen was well-tolerated and ensured substantial CR and EFS rates without radiotherapy.

This Phase II study assessed feasibility and efficacy of a biweekly R-COMP-14 regimen (rituximab, cyclophosphamide, non-pegylated liposome-encapsulated doxorubicin, vincristine and prednisone) in untreated elderly patients with poor-risk diffuse large B-cell lymphoma (DLBCL) and moderate to high ‘life threat’ impact NIA/NCI cardiac comorbidity. A total of 208 courses were delivered, with close cardiac monitoring, to 41 patients (median age: 73 years, range: 62–82; 37% >75 years) at a median interval of 15·6 (range, 13–29) days; 67% completed all six scheduled courses. Response rate was 73%, with 68% complete responses (CR); 4-year disease-free survival (DFS) and time to treatment failure (TTF) were 72% and 49%, respectively. Failures were due to early death (n = 3), therapy discontinuations (no-response n = 2; toxicity n = 6), relapse (n = 6) and death in CR (n = 3). Incidence of cardiac grade 3–5 adverse events was 7/41 (17%; 95% confidence interval: 8–31%). Time to progression and overall survival at 4-years were 77% and 67%, respectively. The Age-adjusted Charlson Comorbidity Index (aaCCI) correlated with failures (P = 0·007) with patients scoring ≤7 having a longer TTF (66% vs. 29%; P = 0·009). R-COMP-14 is feasible and ensures a substantial DFS to poor-risk DLBCL patients who would have been denied anthracycline-based treatment due to cardiac morbidity. The aaCCI predicted both treatment discontinuation rate and TTF.

Objective: To investigate the possible role and tolerability of high-dose (>160 mg/day) oxycodone controlled release (CR) for the treatment of cancer and non-cancer pain. Design: 227 patients with cancer or non-cancer pain were enrolled in an open-label, multi-center, Italian study in order to assess the adequacy of their existing pain management (using a numerical rating scale [NRS]) and the possible benefit high-dose oxycodone CR may offer patients experiencing uncontrolled pain. Results: Pain was poorly controlled at baseline, with only 18.1% of patients reporting adequate pain relief (NRS

Paroxysmal nocturnal haemoglobin- uria (PNH) is a haematopoieis disorder character- ized by the expansion of a stem cell bearing a somatic mutation in the phosphatidylinositol gly- can-A (PIG-A) gene, which is involved in the bio- synthesis of the glycosylphosphatidylinositol (GPI) anchor. A number of data suggest the inability of the PIG-A mutation to account alone for the clonal dominance of the GPI-defective clone and for the development of PNH. In this context, additional immune-mediated mechanisms have been hypoth- esized. We focused on the analysis of T lympho- cytes in three PNH patients bearing a mixed GPI and GPI - T cell population and showing a marked cytopenia. To analyze the biological mechanisms underlying the control of T cell homeostasis in PNH, we addressed the study of CD40-dependent pathways, suggested to be of crucial relevance for the control of autoreactive T cell clones. Our data revealed significant, functional alterations in GPI and GPI - T cell compartments. In the GPI - T cells, severe defects in T cell receptor-dependent prolif- eration, interferon- production, CD25, CD54, and human leukocyte antigen-DR surface expres- sion were observed. By contrast, GPI T lympho- cytes showed a significant increase of all these pa- rameters, and the analysis of CD40-dependent pathways revealed a functional persistence of CD154 expression on the CD48CD4 lympho- cytes. The alterations of the GPI T cell subset could be involved in the biological mechanisms underlying PNH pathogenesis. J. Leukoc. Biol. 78: 000-000; 2005.

Specific trials on adult Burkitt lymphoma (BL) and 'unclassifiable' lymphomas with features intermediate between BL and diffuse large B-cell lymphoma (BL/DLBCL) are advocated which include substantial numbers of older patients, to improve treatment feasibility, while countering risks of systemic and central nervous system (CNS) recurrences. We prospectively evaluated a modified CODOX-M/IVAC (CODOX-M: cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate; IVAC: ifosfamide, etoposide and high-dose cytarabine) regimen by the addition of rituximab (R) and liposome-encapsulated cytarabine (D) to increase antitumour activity and halve the number of intrathecal treatments. Thirty adults (40% >60years) with BL (n=15) and BL/DLBCL (n=15) were accrued. Primary endpoints were progression-free survival (PFS), CNS recurrence, and liposomal cytarabine-associated toxicity. Eighty percent of patients received the whole treatment programme, the remaining cases received at least three full courses. Application of the RD-CODOX-M/IVAC regimen resulted in remarkable 4-year PFS (78%) and complete remission (CR) rates (93%). However, PFS was significantly lower in patients older than 60years as compared to younger ones (49%vs 93%, P=0·03; median, 36months), despite high actual dose-intensity, CR rate and tolerability. Reduced-intensity intratechal prophylaxis through liposomal cytarabine was effective because the CNS failure rate was low (3·4%) and without severe neurological toxicities. The RD-CODOX-M/IVAC strategy is feasible and highly effective, but improving outcomes in elderly patients remains a priority.

Non-Hodgkin lymphomas arising from mature post-thymic T cells (T-NHL) encompass biologically heterogeneous malignancies with a dismal prognosis (1, 2). Patients with histotypes such as peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), kinase-negative anaplastic large cell lymphoma (ALK-negative ALCL), angioimmunoblastic T-cell lymphoma, and Sezary syndrome (SS) experience early disease recurrence with 5-yr overall survival rates rarely exceeding 40%, also because of the lack of effective salvage strategies (1–3). While the biologic basis of T-NHL aggressiveness is under extensive research, investigation into novel active agents remains a critical need, especially in the setting of stem cell transplantation ineligibility/failure and end-stage disease (2, 4). Fotemustine is a third-generation chloroethylnitrosourea displaying a significant clinical efficacy in highly chemoresistant cancers such as disseminated melanoma and primary or metastatic brain tumors (5–9). While second-generation nitrosoureas have been incorporated into standard and high-dose salvage regimens for NHL, including T-cell subtypes (10–13), the activity of fotemustine in lymphoma has been poorly explored, despite its lower hepatic and renal toxicity, as compared to congener agents, and several more favorable pharmacodynamic properties (14, 15). First, the presence of a phosphoalanine carrier group renders fotemustine more lipophilic because its octanol/water partition coefficient results within the optimal lipophilicity interval, differently from both carmustine and lomustine (16, 17). Second, preclinical studies on rat and human tissues have shown that intracellular penetration of fotemustine is superior to that of carmustine (18, 19). Third, studies have documented that fotemustine is cleared 2–5 times more slowly than carmustine from tumor tissues (17–19). The higher lipophilic properties, the more efficient tissue distribution, and slower elimination of fotemustine from tumor tissues, as compared to other nitrosoureas, might provide a preclinical rationale for testing this drug in chemorefractory lymphomas. Because normal and malignant T cells express a low level of O6-alkylguanine-DNA alkyltransferase (AGT) and of O6-methylguanine-DNA methyltransferase (MGMT) (20, 21), two DNA repair enzymes implicated in cellular resistance to nitrosureas, and specifically to fotemustine (22–25), we speculated that alkylator-refractory T-NHL could represent a proper setting to explore the potential clinical activity of this newer nitrosourea derivative. Here, we report the first evidence ever that fotemustine is able to induce substantial clinical responses in patients with post-thymic T-cell malignancies.

To determine the efficacy and safety of the combination of gemcitabine plus oxaliplatin, with and without rituximab, in patients with relapsed/refractory B-cell lymphoma unsuitable for high dose therapy.Patients were prospectively enrolled in two subsequent trials, GEMOX [gemcitabine (1200 mg/m(2), days 1 and 8) and oxaliplatin (120 mg/m(2), day 2), three-weekly] and R-GEMOX [rituximab (375 mg/m(2), day 1), gemcitabine (1200 mg/m(2), day 1) and oxaliplatin (120 mg/m(2), day 2), bi-weekly], up to six courses.Sixty-two patients were enrolled: GEMOX [n = 30; median age, 66 years (range, 46-85); previous chemotherapyor =2, 70%; PS ECOGor = 2, 57%]; R-GEMOX [n = 32; median age, 65 years (range 32-79); previous chemotherapyor =2, 75%; PS ECOGor = 2, 47%]. Overall and complete response rates were 57 and 30% (95% CI, 15-49) for GEMOX and 78 and 50% (95% CI, 32-68) in R-GEMOX, respectively. Grade 3/4 neutropenia occurred in 57 and 47% of cycles and grade 3/4 thrombocytopenia in 26 and 17% of courses for GEMOX and R-GEMOX, respectively. At 42 months, the failure-free survival (FFS) was 7% (95% CI, 0-16) for GEMOX and 28% (95% CI, 9-47) for R-GEMOX (P = 0.014), with overall survivals of 7 (95% CI, 0-16) and 37% (95% CI, 20-55), respectively (P = 0.016).Both regimes showed good tolerability and appealing response rates. FFS was more prolonged in R-GEMOX, but patients continuously relapsed without a clear plateau on survival curves.

Tumor necrosis factor receptor-associated factor 1 (TRAF1) is unique among the members of the TRAF family, as it lacks the N-terminal RING/zinc-finger domain. Also the function of TRAF1 is not clearly established, with many papers reporting contradictory results. Here we show that TRAF1 interacts with BAFF receptor, a member of the TNF receptor family, and positively regulates activation of the alternative NF-kappaB pathway. Ectopic expression of TRAF1 causes degradation of TRAF3, stabilization of NIK, and processing of p100 to produce the mature form p52. In addition, we show that knocking-down expression of TRAF1 in the Hodgkin's disease derived cell line L1236, interfere with p100 processing and with p52 mediate gene transcription. Collectively these results support a role for TRAF1 as a positive regulator of the NF-kappaB alternative pathway.

Patients with Hodgkin lymphoma (HL) failing salvage stem cell transplantation are candidates to investigational strategies. Lenalidomide represents an attractive option as it targets several signaling pathways, which regulate survival of HL cells and their microenvironmental interactions. We report the occurrence of Grades 2 and 3 tumor flare reactions in the first three patients entered a lenalidomide-based compassionate program for treatment-refractory HL. Flares occurred in concomitance of the scheduled week-off lenalidomide and upon withdrawal of symptomatic steroid treatment, and were associated with changes in B-cell regulatory cytokines and the concurrent expansion of polyclonal B-cells. Flares mimicked tumor progression but were effectively managed with anti-inflammatory treatment and followed by a clinical response, suggesting that they may mirror the pleiotropic actions of lenalidomide on HL microenvironment.

8564 Background: Patients (pts) with peripheral T/NK cell lymphomas (PTCL) and intermediate-high/high IPI risk have a 5-yr overall survival < 20%. Current chemotherapy is unsatisfactory while benefit of upfront autologous transplantation (ASCT) is limited by high pre-transplant progression rates and pts advanced age. We evaluated efficacy and stem cells (SCs)-mobilizing activity of a biweekly regimen of gemcitabine (G), ifosfamide (Ifo) and oxaliplatin (Ox) (GIFOX), as an upfront strategy ensuring fast cytoreduction and early ASCT access or an effective alternative to CHOP-like programs in transplant-inelegible pts. Methods: Six biweekly courses of GIFOX [G 1000 mg/m2 D1, Ox 130 mg/m2 D2, Ifo 5 g/m2 D2 as 24h infusion (fractionated over days 2-4 in pts>65 yrs), G-CSF DD 7-11] were planned for all pts, with SCs mobilization at course 3 in ASCT-eligible pts. Simon's minimax two-stage design was adopted with the primary and secondary endpoints of response rate (RR) and progression-free survival (PFS), respectively. Results: Thirty-four pts (median age 63 yrs, r 42-80) [PTCL, nos (n=16), AITL (n=7), extranodal NK/T-cell (n=5), SS (n=6)], with IPI score intermediate-high (62%) or high (38%) were accrued [stage IV: 71%; BM involvement: 38%; E-site >1: 47%; hi LDH: 71%; ECOG>1: 38%; B-symptoms: 44%]. A total of 172 courses was delivered (median 6, r 2-6). Only 5 pts received + cells harvest: 4.36x106/kg) and 8 (7CRs,1PR) underwent ASCT, 6 to 13 weeks after the 6th course. Estimated 5-yr PFS was 48% (95%CI: 28-65); median PFS for non-transplanted pts was 15 mo.s. Estimated 4-yr disease-free survival was 58%. Relevant toxicities were G4 thrombocytopenia (13%), G4 anemia (23%), G3/G4 infection (29%/6%), G3 encephalopathy (6%). Conclusions: Response and survival rates of GIFOX in high-risk PTCL compared more than favorably to CHOP-based regimens. Effective cytoreduction and prompt access to ASCT were ensured, together with safe delivery of a full induction program to transplant-ineligible pts.

8066 Background: The role of consolidation RT on MBD after upfront chemotheraphy for advanced HL is debated, also given the supradditive iatrogenic risk. We present the results achieved in the subset of patients (pts) with MBD (max width > 1/3 of thoracic diameter) accrued in a phase II study of an intensified ABVD program without RT. Methods: The current analysis derives from the final evaluation of our trial for advanced HL (stage IIXB-IV) conducted from 06/2004 to 03/2010 (Russo et al, ASH 2009 abst 715). Pts were scheduled to 6 cycles of a ‘time-densified’ ABVD (3-week intercycle, drugs on days 1 and 11) with the first 4 cycles being also ‘dose-intensified’: doxorubicin (ADM) 35 mg/m2, days 1 and 11 and G-CSF on days 6-8 and 17-19. Results: Of 82 accrued pts, 39 had BMD at presentation. Median age was 29yrs (r 16-58); male 46%; stage IIB 48%, III 8%, IV 43%; B-sympt 87%, E-disease 53%; IP Score ≥3 51%. All pts completed the intensified program. Median actual dose intensities for ADM, bleomycin, vinblastine and dacarbazine were 23.12, 6.69, 3.96 and 245 mg/week, respectively; the increase over conventional ABVD was 85% for ADM and averaged 32% for the other agents. PET2 negativity was achieved in 36/39 (92%; 95% CI 79-98), complete responses (CR) in 37/39 [94%; 95% CI 82-99]. At a median f.u. of 54 mo.s (r 20-91) all pts are alive with an event-free survival of 89% (95% CI, 80-98). Events were: 1, DLCO,FEF25-75) were seen. Conclusions: Intensified ABVD can achieve PET2 negativity in a very high proportion of pts with MBD and ensure a long-term disease-free status even without RT. While results need confirmation on a randomized basis, the low mediastinal failure rate seems in line with recent suggestions that RT could be omitted in MBD when CR is achieved upon intensified chemotheraphy.

Abstract 715 We previously reported interim results (Blood-ASH Annual Meeting Abstracts-2007 110: abstract 2324) of a prospective study evaluating dose-dense and dose-intense variants of ABVD regimen. Seventy pts with a newly diagnosis of cHL were enrolled from 06/04 to 03/08. Pts had intermediate-(INT) or advanced-stage (ADV) according to GHLSG criteria (Tab.1). INT (n=24) were treated with dd ABVD, and ADV (n=46) with dd-di ABVD. Briefly, the strategy concepts of treatment were: 6 cycles of chemotherapy; the inter-cycle period shortened from 28 to 21 days; drugs delivered at day 1 and 11 of each cycle; In the dd-di-ABVD, adriamycin was escalated from 50 to 70 mg/m2 in cycles 1-4; primary G-CSF was given; the therapy was driven by interim-FDG-PET; radiotherapy was planned with very stringent criteria. TOXICITY: On a total of 838 courses of chemo we had 18 events which needed red cell transfusion; 5 of severe thrombocytopenia completely reversed within one week; 25 of severe neutropenia ( DOSE INTENSITY STUDY: Median duration of chemotherapy (planned 18-wk) was 19.7-wk (range 17.6-21.7). Planned and delivered RDIs of drugs were significantly higher as compared with the most used regimens (Tab.2). RESPONSE: Early-CR (PETneg > 2 cycles) was obtained in 65/70 pts (95%). No statistical differences was noted between INT and ADV subsets. At the end of 6thcycle 69/70 pts (98,6%) were in CR. Three out of 69 complete responders (4.3%) had a biopsy-proven relapse: a 33-yr old man ( IVEA), a 27-yr old girl (IIB) and 29-yr old girl ( IVXEB). Relapsed occurred at 3, 10 and 14 months from the end of Tx, respectively. SURVIVAL: Data with a minimum follow up of 12-mo from the end of Tx were available in all 70 pts. Fig.1 shows the EFS rates of 24 INT-stage (95.8%), and 46 ADV-stage (91.3%) pts, respectively. A comparative analysis (Fig.2) between this series of 70 pts treated with dd ABVD or dd-di ABVD and the last 70 historical INT-stage (n=25) and ADV-stage (N=45) pts treated with baseline ABVD shows a statistically significant increment in EFS rate in pts receiving intensified ABVDs (93.0% vs 73.2% p=0.0041). CONCLUSIONS: The final results of this study shows that the activity of intensified ABVD is significantly higher than baseline ABVD in terms of response (CR) and survival (EFS) rates, still maintaining a low-toxicity profile. Based on these results a randomised comparison of intensified versus baseline ABVD seems justified. Disclosures: No relevant conflicts of interest to declare.

Abstract 3716 Poster Board III-652 Introduction Intrathecal (IT) chemotherapy is an integral component of treatment for Burkitt lymphoma (BL), together with intensive systemic chemotherapy including blood brain barrier crossing agents such as high dose cytarabine (Ara-C) and methotrexate (MTX). However, the optimal IT treatment is yet to be established. Since cytotoxic concentrations of conventional IT agents (Ara-C and MTX), are maintained in the cerebrospinal fluid (CSF) for only a few hours, repeated lumbar punctures are necessary which may turn cumbersome for patients (pts) and pose technical difficulties in some instances. The availability of a sustained-release formulation of Ara-C (liposome-encapsulated Ara-C; Depocyte®) may offer the opportunity of reducing the total number of IT administrations by maintaining/enhancing, the efficacy of CNS prophylaxis. In this regard, a single 50 mg IT injection of Depocyte is able to achieve cytoxic concentrations of free-Ara-C in the CSF for 10-14 days. We report the results of a prospective phase II study aimed at evaluating the safety/activity profile of IT Depocyte in pts with BL and atypical (a)BL. Patients and Methods The study was designed to assess, in untreated pts with BL and aBL, the safety and feasibility of a 50% reduction (from 8 to 4) of the number of IT injections required by substituting IT Ara-C (4 doses) and MTX (4 doses) with 4 administrations (50 mg) of IT Depocyte. IT injections were planned on days (d) 1 or 2 of each rituximab (R)-CODOX-M courses and on d 8 of each R-IVAC course. Pts with aBL received 2 additional R-CODOX courses without any further IT therapy. Primary study endpoints were safety, Depocyte-related extra-hematologic adverse events ≥G3, and CNS failure, i.e. progression/relapse at leptomeningeal and/or parenchymal sites; secondary endpoints included event- and disease-free survival (EFS, DFS). Results A total of 30 HIV negative pts (15 BL and 15 aBL) were enrolled and treated with a dose-modified Magrath regimen (Lacasce, 2004). The median age of pts (M/F: 22/8) was 53 years (r, 25-78), 10 pts (33%) were considered as a low risk (LR) category by displaying ≥ 3 of the following factors: normal LDH, WHO PS 0-1, Ann Arbor stage I-II, and ≤ 1 extra nodal sites. All remaining cases (67%) were considered as high-risk (HR). At diagnosis, 3 pts (10%) had a positive CSF for lymphoma, 6 (20%) had bone marrow involvement and 12 (40%) bulky (>10 cm) disease. Each pt received a median of 4 (r, 1-6) IT injections of Depocyte at the a median day of 0.5 (r, -1 to 1) for R-CODOX-M1 (course1), 4.0 (r, -2 to 17) for R-IVAC1 (course 2), 1 (r, -1 to 1) for R-CODOX-M2 (course 3) and 6.5 (r, -3 to 14) for R-IVAC2 (course 4). On a total of 111 applications, the following IT injection-related adverse events (NCI-CTCAE v 3.0) of G1-G2 severity were recorded (pts experiencing toxicity): headache 26.6%, nausea 6.6%, vomiting 3.3%, fever 10%, lumbar pain 10%, fatigue 26.6%, somnolence 6.6% and sinus bradycardia 3.3%. A G3 headache episode, accompanied by a transient loss in visual acuity, led to refusal of further IT Depocyte by a single pt. At 51 mo.s, the EFS was 70% with a DFS of 90% at a median observation of 24 mo.s (r, 1-49). Among the 27 complete responders, no isolated leptomeningeal relapses occurred. In particular, none of the 3 responders with CSF involvement at presentation, displayed any form of CNS progression (leptomenigeal and/or parenchymal). In contrast, a parenchymal CNS involvement, with a negative CSF, was observed, at 4.0 mo.s, as a part of the systemic progression in a single pt (3.3%) with chemorefractory aBL. This pt presented with unfavorable features (hi-LDH, stage IVB, PS 2, bulky retroperitoneal adenopathy and 4 extra nodal sites including liver, pancreas, kidney and spleen) and skipped both the first IT and systemic MTX administrations. Conclusions Within the limits of a single arm study, our results show that substitution of 8 IT injections (Ara-C/MTX) with 4 IT administrations of Depocyte within the R-CODOX-M/IVAC regimen is feasible and devoid of severe and/or life-threatening/invalidating neurotoxicity. The CNS progression/recurrence rate was at least super imposable to historical results (CNS relapse rate: 6% to 11%) achieved by the Magrath regimen including double-agent IT treatment. Based on these results, it appears that Depocyte can be safely incorporated into the Magrath regimen to provide adequate single-agent CNS prophylaxis with a reduced burden of IT applications. Disclosures: Off Label Use: Liposome-encapsulated Ara-C for CNS prophylaxis. Vitolo:Mundipharma: Lecture fees. Pinto:Mundipharma: Lecture fees.

8579 Background: Gemcitabine (G), ifosfamide (Ifo), oxaliplatin (Ox) and rituximab (R) have been accounted of cross-synergy in preclinical and early clinical studies in Hodgkin lymphoma (HL). We assessed activity, toxicity and stem cells (SCs) mobilizing capacity of a bi-weekly salvage combination with these agents in HL recurring after conventional or high dose therapy (HDT). Methods: Patients were scheduled to receive 3 R-GIFOX courses followed by SCs mobilization and HDT if elegible for autologous transplantation (ASCT) or 3 more courses if not. R-GIFOX consisted of R 375 mg/m2 D1, G 1000 mg/m2 D2, Ox 130 mg/m2 D3 and Ifo 5 g/m2 D3, as a 24-h single infusion, G-CSF 5 mcg/kg/d DD 7–11 (10 mcg/kg/d, 3rd course until SCs mobilization). Results: Twenty-one patients (median age 33 yrs, r 22–64) with relapsed (n = 16) [post-ASCT (n=6), 12 mo.s (n=3)] or primary progressive (n = 5) HL, were prospectively accrued. Ten patients (48%) had received ≥ 2 previous CHT lines and 15 (78%) had GHLSG recurring HL prognostic score ≥ 2. Eighty-three total courses were delivered (median 3, r 3–6). CTCAE v3.0 G4 thrombocytopenia occurred in 18% of courses, G4 infection in 11%. Ifosfamide was withdrawn at the 4th course in 2 patients, both aged 64 yrs, due to tachyarrhythmia and encephalopathy. Actual dose intensity of the first 3 courses was 82%, 86%, 92 % for G, Ifo and Ox, respectively. The overall response according to FDG-PET/IWC criteria after 3 courses was 86%, with 2 partial and 16 complete responses (CRs) (76%; CR=10, CRu=6). Four CRs were achieved among the 6 patients with post-ASCT relapses. Eight of 14 eligible patients had effective CD34+ cells harvest [median 4,35 × 106/kg (r 2,91–11.45)] and proceeded to subsequent ASCT. Five ’bad mobilizers’ had previously undergone radiation therapy (n=3) and radioimmunotherapy (n=2). At 42 mo.s. Failure Free Survival was 57%. At a median f.u. of 12 mo.s for CRs, Disease Free Survival was 79% in patients eligible for ASCT and 41% in those unfit treated with additional R-GIFOX. Conclusions: R-GIFOX retains an attractive therapeutic potential in recurring HL, enabling pre-ABMT cytoreduction and mobilization, and also a safe delivery of a full salvage program to patients unfit for HDT. No significant financial relationships to disclose.

Background: We evaluated the clinical activity, toxicity, and stem cells mobilizing capacity of a short-course (bi-weekly), dose intensive, salvage regimen (R-GIFOX) in patients with relapsed and refractory Hodgkin Lymphoma. The agents Gemcitabine, Ifosfamide, Oxaliplatin and Rituximab employed in this combination have been all accounted of cross-synergistic activity in both preclinical and early clinical studies in Hodgkin lymphoma. 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. R-GIFOX consisted of Rituximab (375 mg/m2 on day 1), Gemcitabine (1000 mg/m2 on day 2), Oxaliplatin (130 mg/m2 on day 3) and Ifosfamide (5 g/m2 on day 3), as a 24-hour single infusion. Treatment was given every two weeks with G-CSF support (5 mcg/kg/day or 10 mcg/kg/day at the end of the third course for stem cells mobilization). Responses were evaluated by the integrated FDG-PET/IWC criteria, after the third course and at the end of the entire program. Results: Fifteen patients (median age 36 years, range 24–64 years) with relapsed (n = 12) [post-ABMT (n=4), < 12 mo.s (n=6), > 12 mo.s (n=2)] or primary progressive (n = 3) Hodgkin Lymphoma, were accrued in this prospective study. Forty percent of them had received 2 or more previous treatment lines. Stage IV at recurrence was found in 9 patients (60%), B symptoms in 7 (46%). Sixty-two total courses were delivered (median 3, range, 3–6). Hematologic toxicity was tolerable, but CTCAE v3.0 G4 thrombocytopenia was found in 15% of courses and infection occurred in 9% of cycles. Ifosfamide was withdrawn in two patients; both aged 64 years, at the fourth course due to the occurrence of tachyarrhythmia and encephalopathy, respectively. Actual dose intensity of the first 3 courses was 84%, 87%, and 91% for Gemcitabine, Ifosfamide, and Oxaliplatin, respectively. All the patients completed at least 3 courses of therapy and were valuable for response. The overall response rate assessed after three courses of R-GIFOX was 87%, with 12 complete responses (CRs) (80%; CR=8, CRu=4) and 1 partial response. Interestingly 3 CRs were achieved among the four patients with post-ABMT relapses. Effective CD34+ cell mobilization was obtained in 6 out of 11 eligible patients and all of them proceeded to subsequent ASCT. The median number of collected CD34+ cells was 4,16 × 106/kg body weight (range, 3.52–10.95) In all instances a single leukapheresis was performed. Among the five ‘bad mobilizers’, two patients had previously undergone radiation therapy and one had received immunoradiotherapy with Ibritumomab Tiuxetan. Failure Free Survival was 46% at 32 mo.s and Disease Free Survival 53% at 30 mo.s. with a median follow-up of complete responders of 11 mo.s. Conclusions: The present study confirms the attractive therapeutic potential of Gemcitabine/Ifosfamide-based combination in the setting of recurrent Hodgkin Lymphoma and further suggests additional contribution from Rituximab and Oxaliplatin. R-GIFOX may represent a less toxic, cytoreductive, and stem cell mobilizing alternative to toxic cisplatin-based salvage regimes, useful for pre-ABMT cytoreduction but also for a full salvage treatment program to be safely delivered to patients unfit for high-dose procedures.