A recent case of iatrogenic Cushing's syndrome and complete suppression of the pituitary-adrenal-axis in a patient with cystic fibrosis (CF) and allergic bronchopulmonary aspergillosis treated with itraconazole as an antifungal agent, and budesonide as an anti-inflammatory agent led to a systematic assessment of this axis and gonadal function in all patients treated with itraconazole in the authors' CF centre. Itraconazole can inhibit CYP3A, thus interfering with synthesis of gluco- and mineralocorticoids, androgens and oestradiol as well as the metabolism of budesonide. The aim of this study was to evaluate adrenal and gonadal function in patients treated with itraconazole with or without budesonide.An adrenocorticotrophic hormone (ACTH) test (250 µg tetracosactid) was performed in 25 CF patients treated with both itraconazole and budesonide, and in 12 patients treated with itraconazole alone (six patients with CF and six with chronic granulomateous disease). Mineralocorticoid and gonadal steroid function were evaluated by measurements of plasma-renin, follicle stimulating hormone, luteinising hormone, progesterone, oestradiol, testosterone, serum-inhibin A and B. ACTH tests performed as part of a pretransplantation programme in an additional 30 CF patients were used as controls.Eleven of the 25 patients treated with both itraconazole and budesonide had adrenal insufficiency. None of the patients on itraconazole therapy alone nor the control CF patients had a pathological ACTH test. Mineralocorticoid and gonadal insufficiency was not observed in any of the patients. Only one patient with an initial pathological ACTH-test subsequently normalised, the other 10 patients improved but had not achieved normalised adrenal function 2–10 months after itraconazole treatment had been discontinued.Suppression of the adrenal glucocorticoid synthesis was observed in 11 of 25 cystic fibrosis patients treated with both itraconazole and budesonide. The pathogenesis is most likely an itraconazole caused increase in systemic budesonide concentration through a reduced/inhibited metabolism leading to inhibition of adrenocorticotrophic hormone secretion along with a direct inhibition of steroidogenesis. In patients treated with this combination, screening for adrenal insufficiency at regular intervals is suggested.

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Background: Aggressive non-Hodgkin lymphoma (aNHL) relapsing after high-dose therapy or, in not transplant-eligible patients, after 1st-line chemotherapy represents an unmet clinical need. Therefore, we aimed at evaluating a salvage combination regimen based on pixantrone, an aza-anthracenadione recently approved in Europe for patients with multiply relapsed aNHL. Etoposide and bendamustine were chosen as companion compounds due to available feasibility data in combination with anthracenadions, and a well-documented efficacy in salvage regimens for relapsed aNHL. Rituximab was added, if the relapse tumor biopsy was CD20+. Aim: The aim of the present analysis was to summarize the preliminary clinical experience with the PREBEN/PEBEN regimen gathered, on a compassionate need basis, at different European sites and representing the platform for a currently ongoing Nordic phase 1/2 trial in relapsed aNHL. Methods: The adopted schedule consisted of pixantrone 50 mg/m2 i.v. day 1+8, etoposide 100 mg i.v. day 1, bendamustine 90 mg i.v. day 1 with or without the addition of rituximab 375 mg/m2 i.v. day 1 (PREBEN/PEBEN). If feasible, each cycle was given at 3-weekly intervals for a maximum of 6 cycles. All patients were assessed for chemosensitivity with PET/CT, already after cycle 1 or 2. G-CSF support was applied and administered according to local practice. Results: A total of 30 heavily pre-treated patients (19 males and 11 females, age range 49-81 yrs; mean N of previous regimens: 3, range 1-7) with aNHL were treated according to the PREBEN/PEBEN schedule. Seventeen had diffuse large B-cell (DLBCL), six transformed indolent (tIND), and seven peripheral T-cell lymphoma (PTCL). All patients had intermediate or high risk IPI prior to start of salvage therapy. Eight patients (27%) had a complete metabolic response (CMR) and seven (23%) a partial one (PMR), resulting in an overall response rate (ORR) of 50%. Among the histological subtypes, the patients with DLBCL, PTCL and tIND had an ORR of 53% (CMR 35%), 57% (CMR 14%), and 33% (CMR in one out of two responders), respectively. Most responses were achieved early (prior to course nr. 4). Response durations ranged between 2 and 23+ months. Among the 17 patients with DLBCL, nine were frail, non transplant-eligible with relapsed disease, six had primary refractory lymphoma progressing through anthracycline-containing 1st line and platinum-containing salvage therapies, and two had relapses occurring after a post-transplant remission period. While most of the relapsed patients with DLBCL responded , i.e. seven (five CMR and two PMR) of the nine (78%) frail relapsed patients and one of the two (50%) patients with post-transplant relapses, only one out six (17%) primary refractory patients exhibited some chemosensitivity. Interestingly, four out of seven PTCL patients achieved a PMR or CMR allowing them to undergo non-myeloablative allogeneic transplant with subsequent sustained response durations. The treatment schedule was feasible and most patients received it on an out-patient basis. The most common grade 3-4 toxicity was of hematological type (mainly neutropenia and thrombocytopenia), occurring in 52% of the patients. Grade 3-4 infections were observed at a frequency of 21%. No septic deaths were recorded. A previously anthracycline exposed, heavily pre-treated 60-year old female PTCL patient developed symptomatic congestive heart failure effectively reversed by angiotensin converting enzyme inhibitors with normalization of the myocardial ejection fraction. One previously ibritumomab tiuxetan exposed, heavily pretreated patient with tIND developed acute myeloid leukemia with therapy-related cytogenetic features. Conclusions: The PREBEN/PEBEN salvage regimen was feasible in a heavily pre-treated cohort of elderly patients with high-risk aNHL. In individual patients it elicited substantial and durable responses early in the course of therapy. In some younger patients, it proved useful as bridging strategy to a non-myeloablative allogeneic transplant. A phase 1/2 study in relapsed (non-refractory) aNHL was launched in June 2016 (ClinicalTrial.gov identifier: NCT02678299; EudraCT number: 2015-000758-39) and is currently accruing (N=5 pr. Aug 1st, 2016). Disclosures Clausen: Takeda: Research Funding; Novartis: Other: Travel expences; Abbvie: Other: Travel expences. Leppa:Mundipharma: Research Funding; Roche: Honoraria, Other: Travel expenses, Research Funding; Bayer: Research Funding; Janssen: Research Funding; Takeda: Honoraria, Other: Travel expenses; CTI Life Sciences: Honoraria; Amgen: Research Funding; Merck: Other: Travel expenses. Willenbacher:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; European Commision: Research Funding. d'Amore:Servier: Honoraria, Other: Advisory Boards; CTI LIfe Sciences: Honoraria, Other: Advisory Boards.

The introduction of the anti-CD20 antibody rituximab in combination with chemotherapy (R-chemo) has improved the prognosis of patients with follicular lymphoma (FL). During the last decade, the addition of a maintenance treatment with rituximab (MR) after R-chemo has been tested with the hope of further improving the outcome of these patients. Using 2 independent population-based cohorts, we investigated the effect of up-front MR on time related end points as well as the risk of histological transformation (HT). FL patients were included if they: (1) completed first-line induction treatment with R-chemo, (2) were alive after induction treatment and eligible for MR, and (3) had no evidence of HT at this time point. The training cohort consisted of 733 Danish patients of whom 364 were consolidated with MR; 369 were not. Patients receiving MR more often had advanced clinical stage (90% vs 78%), high Follicular Lymphoma International Prognostic Index (FLIPI) score (64% vs 55%), and bone marrow infiltration (49% vs 40%). Those consolidated with MR had an improved 5-year overall survival (OS; 89% vs 81%; = .001) and progression-free survival (PFS; 72% vs 60%; < .001). In the training cohort, MR was associated with a reduction of HT risk ( = .049). Analyses of an independent validation cohort of 190 Finnish patients confirmed the favorable impact of MR on 5-year OS (89% vs 81%; = .046) and PFS (70% vs 57%; = .005) but did not find a reduced risk of HT. The present population-based data suggest that the outcome of patients with FL has improved after consolidation of R-chemo with MR.

Background: With currently available therapies, relapsed/refractory aggressive non-Hodgkin lymphoma (NHL) after high-dose therapy or, in not transplant-eligible patients, after first-line chemotherapy represents an unequivocally unmet clinical need. Aim and Methods: Therefore, we aimed at evaluating a combination chemotherapy regimen based on pixantrone (Pix), a novel aza-anthracenadione recently approved by the European Medicines Agency in adult patients with multiply relapsed or refractory aggressive non-Hodgkin lymphoma (NHL). Etoposide and bendamustine were chosen as companion compounds due to available feasibility data in combination with Pix, as well as to their documented efficacy in salvage regimens in relapsed/refractory aggressive NHL and to a well-known feasibility profile when given alone or in combination. The monoclonal anti-CD20 antibody rituximab was added if tumor cells in the relapse biopsy specimen were CD20-positive. The adopted schedule consisted of Pixantrone 50 mg/m2 i.v. day 1+8, Etoposide 100 mg i.v. day 1, Bendamustine 90 mg i.v. day 1 with or without the addition of Rituximab 375 mg/m2 i.v. day 1 (PREBEN/PEBEN). If feasible, each cycle was given at 3-weekly intervals for a maximum of 6 cycles. All patients were assessed for chemosensitivity with PET/CT after cycle 1 or 2. G-CSF support was administered according to local guidelines. Results: A total of 8 evaluable patients with relapsed/refractory aggressive NHL were treated according to the PREBEN/PEBEN schedule. Abstract 5435. Table 1summarizes the clinico-pathological features of the patient cohort along with selected feasibility and efficacy parameters related to the PREBEN/PEBEN regimen (PET/CT status after 1 or 2 courses):Patient characteristicsPREBEN/PEBEN-related parametersPt #DxAgeSexCS at relapseN of prior Rx linesPrior TxN coursesTox grade 3-4Best responseDoR1DLBCL (ABC)70MIV3N6thrombocytopeniaCR*6 mo2DLBCL (ABC)49MIV3Y2-PD-3DLBCL (ABC)53MIV2N2neutropenic fevergoodPR4+ mo4DLBCL (ABC)64MIV2N2neutropenic fevergoodPR3+ mo5DLBCL (GCB)69FIV3N2-CR2+ mo6tFL62MIII3Y2neutropenic feverSD-7tCLL51FIV5Y2neutropenic feverPD-8PTCL-NOS57FIV2N6diarrhoeaCR4+ mo Baseline (pt#1) after 1 x PREBEN (pt#1) Figure 1 Figure 1. Figure 2 Figure 2. Conclusion: The PREBEN/PEBEN schedule is feasible (out-patient regimen) and in individual patients it elicits profound responses early in the course of therapy. A phase 1-2 study in relapsed/refractory DLBCL and PTCL is in preparation. Disclosures d'Amore: Amgen: Research Funding; Sanofi Aventis: Research Funding; CTI Life Sciences: Advisory board, Advisory board Other, Speakers Bureau; Mundipharma: Advisory board, Advisory board Other, Speakers Bureau; Takeda: Advisory board, Advisory board Other, Speakers Bureau; Kyowa Kirin Pharmaceuticals: Advisory board Other, Speakers Bureau; Roche: Research Funding.