ALBERT

Description: BACKGROUND: Patients (pts) with relapsed DLBCL who cannot be treated with consolidative ASCT or allogeneic transplantation exhibit a poor prognosis, with a 1-year PFS of 30-40%. Despite a high response rate to salvage therapy, these pts invariably experience early relapse and die of lymphoma. Single-drug maintenance may be a good alternative to intensified consolidation to prolong response duration in these high-risk pts. Lenalidomide is an oral immunomodulatory agent, active against DLBCL, which can be taken for years with an excellent safety profile. Accordingly, we designed a multicenter phase II trial addressing safety and efficacy of lenalidomide maintenance in pts with chemosensitive relapse of DLBCL not eligible for consolidative ASCT or experiencing relapse after ASCT (NCT00799513). Herein, we report the primary endpoint analysis. METHODS: Selection criteria were: 1) adult HIV-negative pts; 2) histologically-proven de novo or transformed DLBCL; 3) relapsed disease responsive (partial or complete response) to conventional-dose rituximab-containing salvage therapy; 4) ECOG PS ≤3; 5) time to progression (TTP) from the previous line ≥3 months. After confirmation of objective response to salvage therapy, pts were registered and treated with lenalidomide 25 mg/day once daily for 21 days out of 28, for two years or until lymphoma failure or unacceptable toxicity. Primary endpoint was the 1-yr PFS. Simon's two-stage optimal design was used. The null hypothesis that the true 1-yr PFS is 30% was tested against a one-sided alternative. The trial design yields a type I error rate of 5% and power of 80% when the true 1-year PFS is 50%. To demonstrate this PFS improvement, 47 pts were needed. The null hypothesis would be rejected if 19 or more pts progression-free at one year were observed. RESULTS: 41 pts were enrolled (median age 72, range 34-86; M:F ratio: 1.5). Thirty pts had a de novo DLBCL, 11 had a transformed DLBCL; 29 pts were enrolled after the first relapse, 12 after the 2nd - 4th relapse. All pts were previously treated with anthracycline- and rituximab-based combination, plus ASCT in 6 pts. The median TTP after the previous line was 17 months (range 3-121). Most pts had unfavourable features: IPI ≥2 in 34 (83%) pts, advanced disease in 33 (80%), extranodal disease in 29 (71%), high LDH in 18 (44%). Twelve pts had HCV and/or HBV infection. Salvage combination included high-dose-cytarabine in 23 pts, high-dose-ifosfamide in 6, anthracycline in 6 and bendamustine in 6. Response to salvage therapy was complete in 25 pts and partial in 16. Twenty-three pts received the planned maintenance; lenalidomide was interrupted due to lymphoma relapse in 8 pts, toxicity in 5 (diarrhoea in 2, rash, prolonged neutropenia, intestinal infarction), and patient's refusal in 5 (diarrhoea in 4, rash). Dose reduction to 10 or 15 mg/d, mostly due to rash or neutropenia, was indicated in 17 pts. Toxicity was mild; there were 6 SAEs (febrile neutropenia in 4, diarrhoea, intestinal infarction) in 5 pts. Grade 4 haematological toxicity consisted of neutropenia in 17 pts and thrombocytopenia in 2. Grade 3-4 non-haematological toxicity consisted of diarrhoea in 3 pts and rash in 5. HBV/HCV seropositivity was not associated with higher toxicity. Six of the 16 pts in partial response after salvage therapy achieved a complete remission during lenalidomide maintenance. At a median follow-up of 16 months, 29 pts remained relapse free, with a 1-year PFS of 75±8%. Importantly, 21 pts were progression-free at one year, with the early achievement of the primary endpoint. Thirty-two pts are alive (NED in 25), 8 pts died of lymphoma and one of intestinal infarction, with a 1-yr OS of 84±7%. Age ≤70 years, normal LDH level, and complete response at registration were independently associated with better PFS and OS, whereas gender, DLBCL category, HBV/HCV infection, and TTP after previous line (〈 vs. ≥12 months) were not. Assessment of prognostic effect of ontogenic stratification by NanoString is ongoing. CONCLUSIONS: With the early achievement of the primary endpoint, this is the first prospective trial showing a positive effect of maintenance in pts with relapsed DLBCL. Lenalidomide maintenance is feasible and well tolerated in this elderly population, but diarrhoea and rash remain frequent dose-limiting side effects. The evident improvement in survival figures warrants further investigation of immunomodulators maintenance in these high-risk pts. Disclosures Ferreri: celgene: Consultancy, Research Funding. Rusconi:Roche: Honoraria.

Description: Background: Patients (pts) with rDLBCL not eligible for ASCT or experiencing relapse after ASCT have a low likelihood of cure. Single-drug maintenance after salvage therapy may be an attractive strategy to prolong survival in these pts. Lenalidomide (LEN) is a suitable candidate for long-lasting maintenance as it is an oral drug, active against DLBCL, that can be taken for years with an acceptable toxicity profile. Accordingly, we designed a multicentre phase II trial addressing LEN maintenance in pts with chemosensitive relapse of DLBCL not eligible for ASCT or experiencing relapse after ASCT (clinicaltrials.gov NCT00799513). Methods: HIV-neg pts (age ≥18 ys) with histologically-proven de novo or transformed DLBCL and relapsed disease responsive to conventional rituximab-containing salvage therapy were registered and treated with LEN 25 mg/day for 21 days out of 28, until lymphoma progression or unacceptable toxicity. Primary endpoint was 1-year progression-free survival (PFS). Simon's two-stage optimal design was used. To demonstrate a 1-yr PFS improvement from 30% (P0) to 50% (P1), 47 pts (one-sided; α 5%; β 80%) were needed. Maintenance would be considered effective if ≥19 pts were progression-free survivors at 1 yr. Cell of origin was assessed by NanoString Technology and Hans algorithm, and cereblon expression was assessed by immunohistochemistry. Results: 46 of 48 enrolled pts were assessable (median age 72 ys; range 34-86); 36 pts had de novo DLBCL, 10 had transformed DLBCL. All pts were previously treated with anthracycline- and rituximab-based combination, plus ASCT in 6 pts; the median TTP after the prior therapy was 16 months (range 3-121). Thirty-three pts were enrolled at 1st relapse, 13 at 2nd relapse; salvage therapy contained high doses of cytarabine or ifosfamide in two-thirds of cases, and response was complete in 26 pts and partial in 20. Most pts had unfavourable features: IPI ≥2 in 38 (83%) pts, advanced stage in 35 (76%), extranodal disease in 29 (63%), high LDH level in 21 (46%); 28 (61%) pts were older than 70 ys. At a median follow-up of 25 (range 6-87) months, 556 LEN courses were delivered, with an average of 12 courses/pt (range 3-41); 19 pts are still in treatment. LEN was well tolerated: with the exception of neutropenia, grade 3-4 toxicities were uncommon, occurring in ≤3% of delivered courses. Infections were rare, and well controlled with oral antibiotics (grade 1-2 in 8 courses; grade 3 in 3). LEN dose reduction was indicated in 23 pts (transient in 19), and was due to neutropenia (12), rash (7), diarrhoea (2), and neurotoxicity (2); LEN was discontinued in 6 of them. One (2%) pt died of acute toxicity (intestinal infarction) and one due to secondary myelodysplastic syndrome at 56 months of follow-up. Pts with HBV/HCV seropositivity (n=12) or prior ASCT (n=6) did not experience unexpected toxicity after 〉1 yr of treatment. At one year from trial registration, 28 pts were still progression free, which was significantly higher than the pre-determined efficacy threshold (n≥19). During the whole observation period, there were 21 events: progressive disease in 19 pts, death of toxicity in one, death while off therapy in one, with a 1-yr PFS (primary endpoint) of 70 ± 7%. The duration of response to LEN was longer than response duration after the prior treatment line in 27 (59%) pts, and was twice as long in 15 of them. The benefit of LEN maintenance was observed both in pts with de novo or transformed DLBCL. According to the Hans' algorithm, the 1-yr PFS was 64 ± 11% for GCB-DLBCL and 67 ± 11% for nonGCB-DLBCL (p= 0.67). Results using the Nanostring technique were consistent with the Hans' algorithm, with a concordance rate of 86%. There was no significant association between cereblon expression and PFS. Multivariate analysis confirmed that treatment at first relapse and a prior TTP ≥12 months were independently associated with better PFS. Overall, 33 (72%) pts are alive, with a 1- and 3-yr OS of 81 ± 6% and 71 ± 8%, respectively. Conclusions: With the limitations of a non-randomized design, this trial soundly promotes the use of LEN maintenance in pts with chemosensitive relapse of DLBCL not eligible for ASCT or experiencing relapse after ASCT. LEN was well tolerated in this elderly population, with survival benefit both in pts with de novo or transformed DLBCL, and both in pts with GCB- or nonGCB-DLBCL. These results warrant further investigation of immunomodulatory drugs as maintenance in these high-risk pts. Disclosures Spina: Teva Pharmaceuticals Industries: Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fee; Mundipharma: Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fee. Rusconi:Teva: Consultancy, Other: Congress attendance; Takeda: Consultancy; Janssen: Consultancy, Other: Congress attendance. Couto:Celgene: Employment, Equity Ownership. Ren:Celgene: Employment, Equity Ownership.

Description: Backgrounds: ABVD is considered the standard of care for Hodgkin’s Lymphoma (HL) patients; however few prospective studies have evaluated his efficacy and safety in elderly patients. Moreover anthracycline-based chemotherapy is not feasible in patients with moderate/severe concomitant heart disease. In comparison with conventional doxorubicin, non–pegylated liposomal doxorubicin (TLC-D99; Myocet ™) has shown a selective uptake and a reduced clearance by the tumor cells resulting in improved cardiac safety. Purpose: Aim of the study was to investigate efficacy and safety of an ABVD-like regimen with non-pegylated liposomal doxorubicin (TLC-D99; Myocet ™) instead of conventional doxorubicin. Patients and Methods : From March 2010 to January 2013, 41 non-frail elderly (age³ 70) and 6 younger cardiopathic patients with untreated HL were enrolled by 22 FIL centers. “Non-frail” definition was based on less than 3 grade CIRS-G co-morbidities, no grade 4 CIRS-G and no geriatric syndrome at diagnosis. Cardiac disorder was defined according to the presence of at least one of the following: left ventricular ejection fraction (LVEF) 〈 50%, left ventricular hypertrophy, uncontrolled moderate/severe arterial hypertension, history of ischemic cardiopathy, clinically significant ventricular arrhythmia, atrial fibrillation, pulmonary hypertension, moderate/severe mitral valvular disorder, moderate aortic valvular disorder. For advanced disease (IIB-IV) the treatment plan was 6 courses of MBVD ( Myocet 25 mg/m2; bleomycin 10 mg/m2; vinblastine 6 mg/m2; dacarbazine 375 mg/m2) plus radiotherapy (RT) on bulky disease or residual PET positive area; for early stages (I-IIA) the treatment plan was 3 courses of MBVD plus RT involved field (IF). Preventive use of granulocyte growth factors was recommended in elderly patients; erythropoietin treatment was considered for all patients if the haemoglobin value was 〈 11 gr/dl. The two primary objectives of the study were to evaluate the complete remission (CR) rate according to international criteria (Cheson 2007) and the rate of cardiac events (CE) defined as a reduction of LVEF ³ 15% from baseline or the occurrence of any significant cardiac disorder. Results. Patients’ median age was 75 (range 46–84); thirteen patients (28%) were in early stage and the remaining 34 (72%) in advanced stage. According to CGA-G scale one or more G2-3co-morbidities were present in 28 patients (60%). All the 13 early stages patients regularly ended the three planned courses of chemotherapy in an outpatients setting without complications; 1 of them refused subsequent RT IF. Among the advanced stage, 13 out 34 patients (38%) interrupted their treatment, mainly from course three to six, for the following reasons: 9 for severe toxicity; 1 for disease progression; 2 for poor compliance or consent retirement; 1 for lung cancer. Fifty-one % of patients experienced at least one episode of grade 3-4 haematological toxicity; severe infections were reported in 3 patients (6%); grade 4 acute cardiac toxicity in only 1 patient. A LVEF reduction ³ 15% from baseline was never documented. The final CR rate was 100% in early stage and 68% in advanced stage patients. At a median follow-up of 28 months all patients with early disease are alive and in CR. In advanced stage patients the 30 months actuarial OS rate is 62%, while the 30 months actuarial PFS rate is only 34% with a median PFS of 20 months. So far, 10 advanced patients have died: 3 of HL; 3 of acute toxicity including 1 sepsis, 1 pneumonia and 1 myocardial infarction, resulting in a 6% treatment-related mortality (TRM); moreover 2 patients died of lung cancer diagnosed within 7 months after the end of their treatment; 1 of heart failure and 1 of pneumonia, thrombocytopenia and gastrointestinal bleeding , both 1 year later the end of treatment. Acute and late CE with fatal exit from the study occurred in 2 patients (4%). Conclusions: In elderly patients with advanced disease MBVD shows an unfavourable toxic profile, not really different from ABVD, even if cardiac toxicity was spared. Prospective studies with baseline definition of comorbidity score and new less aggressive strategies are needed. Disclosures Off Label Use: Lenalidomide in MCL. Spina:Teva: Honoraria.

Description: Introduction Patients (pts) with relapsed DLBCL who can not be managed with consolidative autologous or allogeneic transplantation exhibit a poor prognosis. Despite a high response rate to induction chemo(immuno)therapy, these pts invariably experience early relapse and die of lymphoma progression. Single-drug maintenance may be a good alternative to intensified consolidation to prolong response duration in these pts. Lenalidomide is an oral immunomodulator, active against DLBCL, which can be taken for several years with an excellent safety profile. Accordingly, we designed a multicenter phase II trial addressing safety and efficacy of lenalidomide maintenance in pts with chemosensitive relapse of DLBCL who are not suitable for intensified consolidation or experienced a failure after autologous transplant (NCT00799513). Herein, we report the interim analysis on the first 17 enrolled pts. Methods Selection criteria were: 1) adult HIV-negative pts; 2) histologically-proven de novo or transformed DLBCL; 3) relapsed disease responsive (partial or complete response) to conventional salvage therapy; 4) ECOG PS ≤3; 5) time to progression from the previous line ≥3 months. Pts with CNS involvement, HBV-DNA or HCV-RNA positivity or active infections were excluded. After confirmation of objective response to salvage therapy, pts were registered and treated with lenalidomide 25 mg/day once daily for 21 days out of 28, for two years or until lymphoma failure or unacceptable toxicity. Primary endpoint was the 1-year PFS. With the null hypothesis (P0) of 1-year PFS of 30%, this study will consider a satisfactory efficacy of lenalidomide a P1 corresponding to a 1-yr PFS of 50%, 47 pts will be needed (α: 0,05; β: 80%). Results 17 pts were enrolled (median age 73, range 52-86; M:F ratio: 1.1). Eleven pts had a de novo DLBCL, 6 had a transformed DLBCL. Fifteen pts were enrolled after the first relapse, two pts after the 3rd and 4th relapse. All pts experienced a relapse after anthracycline- and rituximab-based chemotherapy, with a median time to progression after the previous line of 16 months (range 6-88). Only one patient was previously managed with autologous transplant. Most pts had unfavourable features: IPI ≥2 in 15 cases, advanced stage in 14, extranodal disease in 13, high LDH in 7. Two pts had bone marrow infiltration; one had HCV and HBc seropositivity. Salvage chemotherapy consisted of high-dose-cytarabine-based combinations in 12 pts, high-dose-ifosfamide-based regimens in 3 and anthracycline-based regimens in 2; all pts received rituximab as part of salvage therapy. Response to salvage therapy was complete in 12 pts and partial in 5. Three pts completed the planned maintenance, treatment is ongoing in 4; 3 pts interrupted maintenance due to lymphoma relapse, treatment was interrupted due to toxicity in 7 pts (diarrhoea in 3, rash in 2, prolonged neutropenia, anorexia) after 3, 10, 14, 6, 8, 12, and 1 course, respectively. Eight pts needed a transient dose reduction to 10 or 15 mg/d due to rash (n=5), neutropenia (n=2) and neuropathy. There were 4 SAEs (febrile neutropenia and diarrhoea) in 3 pts. Grade 3-4 haematological toxicity consisted of neutropenia in 7 pts and thrombocytopenia in 2. Grade 3-4 non-haematological toxicity consisted of diarrhoea in 3 pts and rash in 5. Four of the 5 pts in partial response after induction chemoimmunotherapy achieved a complete remission during maintenance. At the last delivered lenalidomide course, 14 (82%; 95%CI: 64-100%) pts were in complete remission, and 3 pts experienced progressive disease, with a median response duration of 26+ months. At a median follow-up of 23 months, 12 (71%) pts remained in complete remission, two responders experienced relapse (27 & 34 months). The 1-year (primary endpoint) PFS was 79% for the whole series. Pts who received at least six lenalidomide courses had a 2-year PFS of 90%. Dose reductions were non influential on PFS (1-year: 75% vs. 83%). All pts are alive (NED in 14). Conclusions Lenalidomide maintenance is feasible and well tolerated in pts with relapsed DLBCL. As expected, diarrhoea and rash remain frequent dose-limiting side effects in this elderly population. With obvious limitations, this interim analysis shows encouraging PFS figures, with long-lasting remission in most pts who received at least six lenalidomide courses. Accrual completion is warranted. Disclosures: No relevant conflicts of interest to declare.