ALBERT

Description: Key Points An accumulation of alterations in epigenetic modifiers and genes in the JAK/STAT pathway likely drives BI-ALCL oncogenesis. Whole exome sequencing of a large series of BI-ALCL demonstrates recurrent mutations in epigenetic regulators.

Description: We previously reported that hemoglobin (Hb) recovery was hastened after RIC ASCT as compared with ASCT after myeloablative conditioning (Transfusion, 44:501–8, 2004). In this setting pretransplant Hb level becomes the major predictive factor for early Hb recovery posttransplant and RBC transfusion (RBCT) requirements. We subsequently reported the efficacy of early rHuEpo administration after RIC ASCT to hasten Hb reconstitution (BMT, 36:901–6, 2005). Here we further confirm the efficacy of early posttransplant administration of rHuEpo after RIC reducing RBC requirements and maintaining high levels of posttransplant Hb in the 2 months following transplant.Forty patients surviving at least 60 days were analyzed. Patients characteristics were as follow: age: 50 (27–64); M/F: 28/12; with myeloid (4), lymphoid (29) or solid (7) malignancies. They received a RIC (Fludarabin (150 mg/m²; Busulfan (8mg/kg) and thymoglobulin (2.5 to 5 mg/kg)) followed with an ASCT (all PBSC) from a HLA identical sibling. Aranesp® (Amgen, France) was started on day 1. The 20 first patients received an infusion of 150 mcg/week while the 20 last patients were subsequently treated with 500 mcg/3 weeks. Aranesp® was administered intravenously when inpatient and subcutaneously when outpatient. Aranesp® administration was sustained until day 60 or when patients reached a Hb level of 140 g/L, whichever occurred first. Overall patients were treated for a median of 7 weeks post transplant. No serious adverse effect or thrombosis episode related to Aranesp® was reported in these patients. This cohort of 40 patients experienced a quicker Hb recovery and lower RBCT requirements than a historical and comparable control group of 27 patients (Day +30 Hb: 114 (94–141) vs. 100 (80–129), p

Description: Abstract 3695 Despite recent immunochemotherapy advances approximately 50% of DLBCL patients relapse. Data emerging from initial clinical trials demonstrated that Lenalidomide has a significant activity against different subtypes of relapsed/refractory aggressive B-cell lymphoma. Clinical responses are histology subtype-dependent and most prominent in mantle cell lymphoma. The results in DLBCL were less encouraging with ORR of 26%, CR of 9%, PFS of 2.7 mo. Concurrently targeting the tumor cell itself with monoclonal antibody and targeting the immune response and microenvironment with Lenalidomide may be a promising therapeutic strategy. Encouraging by our initial results of Lenalidomide-Rituximab (LR) combination in patient with refractory (R/R) DLBCL (Ivanov V. et al., 2010), Institutional Multidisciplinary Meeting proposed this combination for 17 patients with R/R DLBCL. All pts were refractory to three or more (range: 2–5) previous lines of conventional immuno-chemotherapy. All eligible pts, except 4 primary-refractory, were previously autografted. Median age for the whole group was 62,5 years, (range: 43–79), 5 pts are female. 65% of patients were younger than 65 y. Patients received combination of Rituximab 375 mg/m2 on day 1 or day 7; Lenalidomide (Revlimid), 15 mg/d for the first pt and 25 mg/d for other 16 pts, for 21/28 days. Dexamethasone 40mg, day 1–4 was given for first 7 pts. Initial decision on adding Dexamethasone was based on the extrapolation from the recommended regimen used in multiple myeloma, but it was abandoned in last 10 pts. Initially the treatment duration was established for 6 months, but it was prolonged to 7–11 months for patients in CR. Of 17 pts enrolled on study, 3 patients stopped the treatment during the first course: 1 pt because of grade 3 toxicity and 2 pts because of explosive disease progression. Both patients were switched to palliative care. In 14 pts, received more than 1 course of treatment, 7 (50 %) responded to LR combination, including 6 pts (43%) with CR and 1 (7%) patient with PR. One pt with clinical and PET-FDG scan improvement after 3 courses of LR was included into “auto-allo” tandem program and actually in CR at +12 months after PBSCT. Six pts progressed on LR treatment and were switched to palliative regimens. In intention to treat analysis the CR rate for the whole group was 35%. As regards the follow-up, all 7 pts in PR and CR are evaluable for evaluation. The patient in PR progressed after 5 courses of LR. Six patients in CR group received an average of 8 (range: 7–11) courses of LR treatment. Two patients relapsed after 5 and 26 months of CR and other 4 patients are actually in CR at +7, +17, +18 and +24 months. Adverse events were manageable and the most common toxicity included thrombocytopenia and neutropenia. In relapsed/refractory DLBCL modest initial results of Lenalidomide monotherapy emerge the use of new effective combinations. Recently the combination Lenalidomide-Rituximab (LR) was shown to be highly efficacious in phase 2 study in elderly (〉65 y.o.) patients with DLBCL (Zinzani et al., 2011). Into the group of 23 pts the ORR rate at the end of 6-months induction phase was 35%. Our data confirm results of Bologna group in the younger group of patients. Given the poor prognosis of refractory DLBCL, enrolment in already running prospective clinical trials with Lenalidomide are underway and the investigation of the combination of Lenalidomide and Rituximab is further warranted. Disclosures: No relevant conflicts of interest to declare.

Description: Background: High dose chemotherapy followed by autologous stem cell transplantation (ASCT) remain standard of care in patients with relapsed non Hodgkin’s lymphoma (NHL) and Hodgkin’s lymphoma (HL). This regimen is also proposed as consolidation therapy in patients with poor prognosis aggressive NHL and mantle cell lymphoma in first complete remission (CR). BEAM (BCNU, etoposide, cytarabine, melphalan) is the standard protocol chemotherapy used as conditioning regimen. A few previous studies with Bendamustine replacing BCNU have been reported with promising results. BendaEAM seems to show less toxicity and might improve results in relapsed Hodgkin/non-Hodgkin’s lymphoma (R-HL/NHL) patients. Method: From January 2014 to July 2014, patients with NHL and HL were enrolled in this study. Previous therapy consisted in Rituximab (R)-CHOP (cyclophosphamide, doxorubicine, vincristine, prednisone) for all NHL patients transplanted in first CR. Patients with relapsed NHL and HL received high-dose cytarabine based salvage regimen. No patient presented significative comorbidity. Functional pulmonary test and cardiac evaluation were performed for all patients. with the conditioning regimen consisted in Bendamustine on day -7 and -6 (200 mg/m²/d), cytarabine daily from day -5 to day -2 (200 mg/m²/d), etoposide daily from day -5 to day -2 (200 mg/m²/d) and melphalan on day -1 (140 mg/m²). Autologous stem cells were infused on day 0. Prophylactic use of colony-stimulating factors was not allowed except for patients with less than 2x106 in the apheresis product. Patients received antimicrobial prophylaxis with oral fungizone. Red cells and platelets transfusions were administered to maintain hemoglobin level 〉8g/dl and a platelet count (PLT) 〉10x109/l. Broad spectrum antibiotics were delivered when fever developed. Results: There were 25 patients: 10 patients with diffuse large-B cell lymphoma and high international prognostic score (IPI) score in first CR, 5 patients with relapsed NHL or HL, 4 patients with mantle cell lymphoma in first CR, 5 patients with relapsed follicular lymphoma, and 1 patient with peripheral T cell lymphoma. A median number of 4,1x106 (range: 1.5-8.1) CD34 cells/kg was infused. All patients fully engrafted after a median time of 19.5 days (range: 14-24). Median times to PLT〉20x109/l and PLT〉50x109/l were 20 days (range: 16-52) and 22 days (range: 18-52) respectively. All patients experienced grade 3-4 fever with a documented infection in 9 cases Five patients were admitted in intensive care unit for septic shock and one patient died. One patient presented a total resolutive grade 4 renal failure. Three patients (12%) developed grade 3 cardiotoxicity (atrial fibrillation). No pulmonary toxicity was observed. Median time to hospital discharge was 23 days (range: 18-77). With a median follow-up of 2 months (range: 1-6) 24 patients are alive in CR. Conclusion: BendaEAM as conditioning regimen followed by ASCT is feasible in patients with NHL and HL. Toxicity of this chemotherapy is acceptable and seems comparable to that observed with the standard BEAM regimen (data will be presented). While the follow-up remains short, results are encouraging in patients with NHL or HL, as well as in first CR or subsequent CR. Thus, the use of bendamustine in lymphoma conditioning regimen can be recommended on the basis of its high anti-lymphoma activity, but also according to the safety of the drug with a lower pulmonary toxicity. Disclosures No relevant conflicts of interest to declare.

Description: Introduction: R-miniCHOP is the standard chemotherapy for patients over 80 years (y) with DLBCL. In the LNH 03-7B trial, the 2-year overall survival was 58.9% [95% CI: 49.3-67.2%]. Grade III/IV toxicity and deaths occurred during the two first cycles mainly (Lancet Oncol. 2011 May;12(5):460-8). In order to improve overall survival (OS) rituximab (R) was replaced by Ofatumumab (OFA), a humanised anti-CD20 monoclonal antibody. In vitro data suggest that OFA induces more potent complement-mediated cytotoxicity than rituximab, and clinical data demonstrate activity of OF in rituximab-refractory lymphomas). In addition, to reduce early toxicity a pre-phase (PP) with vincristine and prednisone (P) was tested. Patients and methods: Patients older than 80 y with untreated CD20+ DLBCL, Ann Arbor stage I to IV, left ventricular ejection fraction 〉 50%, and a performance status (PS) of 0 to 4 were eligible. Patients received a PP with vincristine (1 mg TD D-7) and P (60 mg TD D-7 to D-4) before the first cycle of OF-miniCHOP. PP was followed by miniCHOP chemotherapy (cyclophosphamide: 400 mg/m² D1; doxorubicine: 25 mg/m² D1; vincristine: 1 mg total dose D1 and prednisolone 40 mg/m² by oral route from D1 to D5) plus OFA (1000 mg TD) every 21 days for 6 cycles. GCSF was optional. The primary objective was to evaluate the efficacy of PP OF-mini-CHOP as measured by the OS. Secondary endpoints were response rate (RR), progression free survival (PFS), event-free survival (EFS), disease-free survival (DFS) for complete responders and toxicities. Survival results are presented for all included patients on an intend-to-treat basis (n=120). Response to treatment was evaluated according to 1999 Cheson criteria. Results: From June 2010 to November 2011, One-hundred-twenty-patients (male, female) were included in 41 centers of the LYSA. The median age was 83 years (range 89-95). Seventy-seven percent of patients had a stage III/IV. LDH level was elevated in 58% of patients. Age-adjusted (aa) IPI was 2-3 in 57% of patients. One-hundred-twenty patients completed the PP, 107 the first three cycles and 89 received the whole regimen. For patients who started the first cycle, the mean relative Dose-Intensity during trial was 98%, 97% and 96 % for OFA, doxorubicine and cyclophosphamide respectively. Seventy-eight percent of patient received at least one injection of GCSF. The overall RR was 67.5%, including 35.8% of complete response and 20 % of unconfirmed complete response. At the time of this analysis, in September 2013, the median follow-up time was 26.6 months. The 2-year overall survival was 64.7% [95% CI: 55.3-72.7%]. The two-year PFS, EFS and DFS were 57.2% [95% CI: 47.7-65.6%], 53.1% [95% CI: 43.7-61.6%] and 66.6% [95% CI: 54.0-76.5%] respectively. Haematological toxicity was the most common side effect. Grade 3-4 neutropenia was observed in 20.8% of the patients and grade 3-4 thrombocytopenia in 1.7%. Seven patients (5.8%) experienced at least one episode of febrile neutropenia. Infusion reaction related to OFA was reported in 12.5% of patients. Prolonged hospitalization (〉 or = 10 days) was observed in 17 cases (14.1%) and mainly occurred during cycle 1 to cycle 3. Forty-five patients died during the treatment evenly distributed between lymphoma (62.2%), intercurrent and other causes (22.2%), and concurrent illness (15.6 %). No toxic death was reported. Six patients died during treatment (1 during PP, 4 during cycle 1 to cycle 3, 1 during cycle 4 to cycle 6) Thirty-nine patients died during follow-up. In univariate analysis, low aaIPI (0 /1) is the unique statistically significant prognostic factor of prolonged OS (OR 3.083, [1.458-6.517] CI95%). Instrumental Activities of Daily Living (IADL) score equal to 4 is associated with a longer PFS. By contrast, low Albuminemia level, undernutrition according to buzby index and high Charlson comorbidity index (CCI) were not predictive of survival. Conclusion: In DLCBL patients over 80 y, immunochemotherapy with PP OFA-mini-CHOP appears to be safe and effective, confirming that a substantial proportion of very old patients can be cured. The use of a PP seems to reduce the early death risk. OFA and PP seems to improve OS comparing with the previous reported data. The combination of a PP, monoclonal antibody against CD20 and miniCHOP can be the new standard regimen for DLBCL patients over 80 y. Disclosures Off Label Use: Use of ofatumumab in high grade lymphoma..

Description: Abstract 335 The cure of relapsed or refractory Hodgkin Lymphoma (HL) still remains a challenge. High dose chemotherapy followed by autologous stem cell transplantation (ASCT) is the standard of care but almost half of patients relapse after ASCT and have poor outcome. Predictive factors including an interval from end of first line therapy to relapse shorter than 12 months, an Ann-Arbor stage III or IV at relapse, and relapse in previously irradiated field are currently used to identify patients with poor outcome. Development of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) assessment improves evaluation of response both in first line and salvage treatments. The aim of our study is first to confirm the predictive value of PET status before ASCT and then to compare ASCT strategy (single versus tandem) in patients with relapsed and/or refractory HL. We here report a series of 111 consecutive patients with relapsed and/or refractory HL who achieved at least partial remission (PR) at PET evaluation after one line of salvage chemotherapy and who underwent single or tandem ASCT. PET response assessment showed 85 (77%) patients in CR (PET- group) and 26 (23%) in PR (PET+ group). Five-year overall (OS) and progression free survival (PFS) were 81% and 64% respectively. There were significant differences in 5-year PFS (79% versus 23%, p

Description: We have reported that RBCT needs inversely correlated to the conditioning intensity (Transfusion, 2004). Moreover, Hb level prior to RIC ASCT significantly influenced Hb recovery and RBCT needs (BMT, 2005). These findings invited us to test the hypothesis that post RIC allo SCT might represent an attractive setting for rHuEPO use. Here we analysed RBCT needs in the first 60 days after transplantation in 125 consecutive RIC allo geno-identical sibling PBSC ASCTs treated for lymphoid malignancies (LM) and solid tumours (ST) performed in our institution from 01/2001: age: 48 (23–68) ; M/F: 63/62 ; LM/ST: 96/39; RIC: FBA (Fludarabine (FLU)+ Busulfan (BU) + Thymoglobulin (ATG))(74), FBTLI (FLU + BU + 1 Gy TLI) (23), FLU+ 2 Gy TBI (26), FLU + Endoxan (2). 45 pts were treated with rHuEPO started on day 1 (EPO+ group). First 10 pts received epoetine-beta (Neorecormon, Roche) (10.000 IU × 3/week). The remaining 35 pts received Darbopoietine alpha (Aranesp, Amgen), (150 mkg/week: 10 pts; 500 mkg/3 weeks: 25 pts). Trt was continued until Hb level reached 12 g/dL or day +60. 80 pts did not receive EPO stimulation (EPO- group). There were no significant differences between the 2 groups in terms of patient and graft characteristics. AGVHD grade II–IV appeared before day +60 in both groups in 36% of cases. The 4 year survival probability estimates did not differ between the 2 groups (EPO+: 49.7% (32–67); EPO-: 44.7% (32–60)). Potential risk factors for RBCT needs were assessed in a univariate analysis: patient and donor age (NS), patient and donor gender (NS), donor/recipient gender compatibility (NS), ABO compatibility (NS), diagnosis (lymphoid malignancies vs solid tumours (NS)), conditioning regiments (ATG-based vs no ATG (NS) and BU-containing vs. no BU (NS)), CD34+ cell dose (

Description: Background: Administration of the monoclonal anti-CD20 antibody Rituximab has been associated with infusional toxicity, leading to strict guidelines of use, i.e., infusion times from 4 to 6 hours. Even with pretreatment acetaminophen and diphenydramine, grade 3/4 adverse events including bronchospasm and hypotension occur in ~10% of patients with the first, and in 〈 2% with subsequent infusions. Presence of circulating malignant CD20 bearing cells represents a risk factor for developing grade 3/4 reactions. The pathophysiogy of this infusional toxicity is thought to be a “cytokine release syndrome” occuring within the 2 first hours of infusion. In few cases, it can be related to an anaphylactic reaction, occurring in the first minutes of infusion. Based on these observations and because infusional toxicity may be lower by the concomitant use of steroids, we established new guidelines of rituximab administration based on the number of circulating CD20+ cells, cycle number of the infusion, and allowing a total one-hour infusion time. Methods: A 1 mg/kg dose of steroids + diphenydramine + acetaminophen were given 20 minutes before each rituximab infusion. Rituximab dose was 375 mg/m2 diluted in 500 ml bottle. In the absence of circulating CD20+ cells, patients received their first course of rituximab according to the standard recommendations (from 50 mg/h and increasing by levels of 50mg/h every 30 min) until the fifth level. Then the remaining dose was administered at 500ml/h, with a total infusion time of ~3 h. The subsequent infusions were given at 100 mg/h for 15 minutes then at 500 ml/h, i.e. in one hour. In case of circulating malignant CD20+ cells, the first rituximab administration was administrated over 2 days: 50mg/m2 in 4h on day 1, and 325mg/m2 on day 2 according to the instructions described above. The subsequent infusions were administered according the one-hour protocol. Results: 69 patients have been treated in our outpatient unit, according to this protocol, for a total of 115 courses including 21 first cycles. Patients characteristics are as follows: median age 61 (range 26–85); 50% male; histology: 27 DLCBL including (IPI ≤1: 17 patients, IPI ≥2: 10 patients), 22 follicular, 2 mantle cell, 3 marginal zone, 2 lymphoplasmocytic, 1 Castelman disease, 11 CLL and 1 idiopathic thrombopenic purpura; treatment: R-CHOP in 51 patients, R-fludarabine/cytoxan in 15, R-chlorambucil in 1 and Rituximab alone in 2. Among the 21 first courses treatment was R-CHOP in 13, R- fludarabine/cytoxan in 3 and Rituximab in 5. No grade 3/4 toxicity was noted neither during the first nor the subsequent cycles. During the first infusion 2 patients developed grade 2, and 3 developed grade 1 reactions. One CLL patient had a grade 1 reaction after the second cycle. Conclusions: Taking into account the presence of circulating malignant CD20+ cells, a 3h first and one-hour subsequent infusion protocol is safe and well tolerated, independently of diagnosis and chemotherapy regimen. This protocol allows a sparing of 2 to 4 hours treatment time, very convenient for patients and in outpatient unit management.