ALBERT

Description: Abstract 2696 Poster Board II-672 Background: High-dose methotrexate (HD-MTX)-based chemotherapy (CHT) followed by whole-brain irradiation (WBRT), the conventional approach to primary CNS lymphomas (PCNSL), is associated with relevant risk of late neurotoxicity. To avoid or reduce irradiation volumes and doses have been proposed to minimize this complication, but no studies focused on RT parameters exist and the best RT schedule remains to be defined. Methods: The impact on outcome of different RT fields and doses was assessed in a mono-institutional series of 85 HIV-negative patients (pts) with PCNSL treated with upfront CHT containing MTX 3.5 g/m2 every 3 weeks, alone or in combination, followed by RT. All pts were irradiated to the WB with photons of 6 MeV and standard fractionation, including the first two cervical vertebras and the posterior two thirds of the orbits; a tumor bed (TB) boost (2 to 4 isocentric fields) to deliver higher doses in the tumor area but limiting the WBRT dose was indicated in 46 pts. In the case of multifocal lesions, the boost volume included each single lesion. Radiation doses varied in the years, oscillating between 30 and 45 Gy to the WB and between 36 and 54 Gy to the TB. Pts were stratified according to the response to CHT for analysis of WB and TB doses. Results: Response after CHT was complete (CR) in 37 (44%) pts and partial (PR) in 17 (20%); 24 pts experienced PD and 7 died of toxicity. The median f-up was 37 months (range 13–105). Thirty-three of the 37 CRs were referred to consolidation RT: six (30%) of the 20 pts irradiated with 30 – 36 Gy to the WB and six (46%) of the 13 pts irradiated with a WB dose '40 Gy experienced relapse, with a 3-yr FFS of 64±13% and 64±14% (p= 0.31), respectively. Relapse rate was not significantly different between the 19 pts irradiated with a TB dose of 45 – 54 Gy and the 14 pts irradiated with a TB dose of 36 – 44 Gy, with a 3-yr FFS of 62±11% and 68±15% (p= 0.49), respectively. Twenty-one of the 33 pts treated with consolidation RT are alive, with a 3-yr OS of 71±9%. No survival differences were observed in subgroups of pts divided according to the WB or TB doses. Four (19%) survivors exhibited evident neurological impairment after treatment (bradipsychia, memory deterioration and dysphasia); these pts had a median age of 66 years (range 46–72) and were treated with a WBRT dose 〉40 Gy. The 17 pts in PR after CHT were referred to complementary RT; ten of them (59%) achieved a CR, while the remaining pts had a residual enhanced image at the post-radiation MRI, with a 3-yr FFS of 48±16% and 0% (p= 0.004), respectively. Median WB and TB doses in pts who achieved CR after RT were 38 Gy and 45 Gy, while median doses in pts who did not achieve a CR were 36 Gy and 38 Gy, respectively. Correspondingly, pts treated with a TB dose of 45 – 54 Gy had a significantly better FFS (3-yr: 34±11% vs. 17±10%; p= 0.05) and OS (3-yr: 44±12% vs. 17±10%; p= 0.01) with respect to pts irradiated with a lower TB dose. Five of the 17 pts treated with complementary RT are alive, with a 3-yr OS of 34±12%. In the subgroup of PR pts, the number of lesions was independently associated with survival, with a 3-yr OS of 63±17% for pts with single lesions and 11±10% for pts with multiple lesions (p= 0.02). Sixteen of the 24 pts with PD after CHT received immediate salvage RT (3 CR, 4 PR and 9 PD). All responders but one experienced relapse and died, with a 3-yr OS of 7±8%; WB and TB doses higher than 40 Gy and 45 Gy, respectively, had no impact on survival. Conclusions: In pts with PCNSL, RT parameters should be chosen on the basis of response to primary CHT. Pts in CR after CHT should be treated with WBRT with 30–36 Gy, higher doses are not advisable since they do not change outcome and could increase the risk of severe neurotoxicity. Pts in PR with single lesions should be treated with 40 Gy to the WB with a TB boost of 9–14 Gy. Therapeutic results with high-dose brain irradiation in pts with PR and multiple lesions or PD after primary CHT are disappointing; in these patients the role of additional no cross-resistant CHT before RT should be investigated. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction: Higher risk MDS is a serious disease associated with poor survival with hypomethylating agents (HMAs) the standard of care in patients ineligible for stem cell transplantation. Unfortunately, HMAs are only effective in 30-40% of patients with duration of response typically shorter than 1.5 years (Fenaux, Lancet Oncol 2009) leading to evaluation of combination therapies to improve outcomes in higher risk MDS. Inhibition of both histone deacetylation and DNA hypermethylation has been shown to induce re-expression of silenced genes in myeloid malignancies in a synergistic fashion. Studies have evaluated HMAs in combination with HDACi but the results have been disappointing due to increased toxicity and early discontinuations. Pracinostat, a potent oral Class I, II, IV HDAC inhibitor, has been studied in combination with standard dose azacitidine in a prior Phase 2 study in 102 patients with untreated IPSS intermediate-2/high risk MDS (Garcia-Manero, Cancer 2017). Pracinostat was administered at 60 mg/day on 3 alternate days/week for 3 weeks/month, with step down dose to 45 mg in case of poor tolerability. Toxicity, primarily cytopenias, nausea, vomiting and fatigue resulted in early discontinuations and insufficient treatment exposure, potentially leading to diminished efficacy and no observed benefit of the pracinostat/azacitidine combination. This follow-up study is evaluating a lower dose of pracinostat (25% reduction) in combination with standard dose azacitidine with the goal of reducing toxicity, decreasing early discontinuations, and improving outcomes. Methods: The primary objective of this Phase 2, two-stage study at 24 sites is to determine the safety/tolerability and efficacy of the pracinostat/azacitidine combination in patients with IPSS-R high-/very high-risk MDS previously untreated with HMAs. Up to 40 subjects were to enroll in Stage 1, treated with pracinostat at 45 mg, 3 days each week for 3 consecutive weeks, followed by 1 week of rest, along with azacitidine at the standard dose of 75 mg/m2 for 7 days of each 28-day cycle. Study drugs are to be administered until disease progression or intolerable toxicity, avoiding early discontinuation (1 week follow-up were decreased neutrophil count (33%), anemia (30%), febrile neutropenia (27%), and dyspnea (12%). Non-hematologic AEs of fatigue and gastrointestinal events were reduced in this initial group of patients relative to that seen in the prior study. Conclusions: The interim analysis of this study evaluating the efficacy and safety of pracinostat + azacitidine in patients with IPSS-R high-/very high-risk MDS revealed a discontinuation rate and an efficacy response rate meeting the predefined thresholds to allow for expansion of the study. These findings suggest that a reduced dose of pracinostat may allow patients to remain on treatment longer, thus increasing the likelihood of a treatment response. Based on these data, the study IDMC approved expansion of this study to enroll 60 evaluable patients. Updated data, including 6 months efficacy data on the initial cohort, will be presented. Disclosures Khaled: Alexion: Consultancy, Speakers Bureau; Daiichi: Consultancy; Juno: Other: Travel Funding. Ramies:MEI Pharma, Inc: Employment. Mappa:Helsinn Healthcare: Employment. Atallah:Jazz: Consultancy; BMS: Consultancy; Abbvie: Consultancy; Pfizer: Consultancy; Novartis: Consultancy.

Description: Abstract 2692 BACKGROUND: Worldwide experience with intensive chemotherapy plus HAART in HIV+ pts with BL is still limited. In a few available studies, this strategy was associated with complete remission (CR) rates of 70–80% and 2-year overall survival (OS) rates of 45–70%, but with a treatment-related mortality of 15–20%, mostly due to septic complications. We adapted an intensive short-term chemotherapy program used for HIV-negative childhood and adult pts with BL [Di Nicola M, et al. BJH 2004] to treat HIV+ pts with maintained efficacy and lower toxicity. Herein, we report feasibility and activity of this program addressed in a multicenter pilot experience. METHODS: Consecutive HIV+ pts with BL, age ≤65 yrs and ECOG-PS ≤3 were treated with an intensified program at three Institutions. The program included a 38-day Induction Phase (IP) of sequential doses of methylprednisolone, cyclophosphamide, vincristine, rituximab, methotrexate, VP-16, and doxorubicin, with intrathecal prophylaxis/treatment. After IP, pts in CR received consolidation phase (CP; cytarabine+cisplatin+rituximab); pts in PR received CP followed by BEAM + ASCT; pts with SD or PD received intensification phase (R-ICEx2 + high-dose cyclophosphamide + high-dose cytarabine + BEAM + ASCT). Leukaphereses were performed after CP. Pts with residual or bulky disease received consolidation radiotherapy. RESULTS: 13 pts (median age 42 yrs, range 27–63; all males; ECOG-PS 〉1 in 5) were considered. Most pts had advanced stage, increased LDH, B symptoms, bulky lesions, and extranodal disease (meningeal in 2). Eight pts received HAART before BL; median CD4+ cells at BL diagnosis was 272 (range 17–858; 4 pts had CD4+

Description: Diffuse large B cell lymphoma (DLBCL) is one of the most common types of lymphoproliferative disorder. Approximately half of all patients will be cured of their disease by primary therapy the remainder die of the disease. Clinical outcome in patients with DLBCL is poorly predictable. Gene-expression profiling in DLCBL has brought an insight into the biological heterogeneity of the disease. Two major subgroups were identified: germinal centre B (GCB) cell, activated B cells (ABC) or non-germinal centre (non-GCB). The GCB group has a significantly better survival than the ABC group. Immunohistochemistry has been evaluated as a surrogate for this molecular classification. The aim of this study was to define retrospectively the B-cell origin of 21 patients treated with R-CHOP14 and to evaluate if the intensified immuno-chemotherapy could improve their clinical outcome. We performed immunohistochemical stains on formalin-fixed paraffin-embedded tissues from diagnostic biopsies with the following antibodies: CD10, bcl-6, bcl-2, MUM1 and Mib1. Based on the algorithm published by Hans et al. we subdivided the patients in GCB origin and ABC origin. We evaluated also the prognostic value of single protein expression. Fourteen patients were male and 9 female, 9 were stage I–II and 12 stage III–IV, 12 presented symptoms at diagnosis and 13 showed bulky disease. Six patients had more than one extranodal sites involved and 13 showed abnormal LDH value, the IPI was intermediate-high risk in 7 and high risk in 3 patients. Half patients presented beta2 microglobulin and ESR elevated. According to immunohistochemistry analysis 9 patients derived from germinal centre and 12 from non-germinal centre, 14 patients presented a positive CD10, 9 a positivity for bcl6, 7 a positive bcl2 and 9 a positive MUM1. Fourteen patients (67%) obtained a complete remission (CR), 4 a partial response (PR) and 3 were non responders (NR). All patients with PR and 2 out 3 NR derived from germinal centre. Four out 14 CR patients experienced relapse, three (75%) derived from non-germinal centre. Six patients died, three derived from GCB and three from non-GCB. After a median period of observation of 500 days (range 98–1870 days) the overall survival (OS) was 71% and the failure free survival (FFS) was 49%. The statistical analysis was performed comparing the B cell origin and clinical characteristics, moreover was also evaluated the expression of bcl2 either in GCB or in non-GCB lymphomas. In univariate and multivariate analysis the overall survival was not affected by clinical characteristics nor B cell origin. In univariate analysis FFS was significantly higher in low and low-intermediate IPI risk patienta (p 0.01) and in multivariate analysis IPI and B cell origin were the only two factors that influenced the FFS. In conclusion even if few patients were evaluated we can point out that the intensification could enhance the efficacy of R-CHOP regimen improving the overall survival also in patients with ABC lymphoma. In contrast it seems that R-CHOP14 does not improve the FFS of patients with ABC origin. Further analysis with larger sample sizes of DLBCL patients are needed to verify this preliminary observations.

Description: Introduction BAY 80–6946 is a potent and reversible Class I phosphatidylinositol-3-kinase (PI3K) inhibitor with significant activity against both PI3K-δ and PI3K-α isoforms. The PI3K-α inhibitory activity may overcome a PI3K-mediated mechanism of resistance triggered by PI3K-δ inhibition. A phase I dose-escalation study (Patnaik et al, ASH 2012) established the maximum tolerated dose of BAY 80-6946 (0.8 mg/kg) and reported promising activity (6/6 PR) in follicular lymphoma. In the present study we further investigated the activity and safety of BAY 80-6946 in patients with indolent or aggressive lymphoma subtypes that have progressed after standard therapy. Methods Patients with histologically confirmed indolent or aggressive lymphoma relapsed or refractory to ≥2 prior lines of treatment were eligible. Patients received BAY 80-6946 at a dose of 0.8 mg/kg as a 1 hour infusion on days 1, 8 and 15 of a 28-day cycle. Patients continued on therapy until disease progression or unacceptable toxicity. Responses were assessed every two cycles according to the response criteria for lymphoma (Cheson et al., JCO 17:1244,1999) or the guidelines for diagnosis and treatment of chronic lymphocytic leukemia (CLL; Hallek et al., Blood111:5446-56, 2008). Results As of July 31, 2013, a total of 61 lymphoma patients (27 indolent and 34 aggressive) were enrolled and 56 started study treatment. Patients were similarly distributed among indolent and aggressive cohorts with respect to gender (52% female), median age (68 yr, range 22-90) and ethnicity (76% Caucasian) and were heavily pretreated (median number of prior therapies: 3; prior Rituximab: 84%; prior ASCT: 20%). Other characteristics included advanced stage III-IV in 85% and B symptoms in 17%. The following entities were represented: follicular (FL; n=13); CLL (n= 11); marginal zone (MZL; n=3; none staged to date); diffuse large B-cell (DLBCL; n=18); mantle cell (MCL; n=7); transformed (n=5); and peripheral T-cell (PTCL; n=4). At the time of analysis patients had received between 1 and 5 cycles of treatment. Objective responses were seen across histologic subtypes (Table 1). At the time of this interim analysis, the overall response rate (RR) and complete RR were 40% and 20% in FL, 67% and 0% in CLL, 83% and 17% in MCL, and 50% and 0% in PTCL, respectively. CR – complete response; CRu – CR unconfirmed; PR – partial response; SD – stable disease; PD – progressive disease Grade 3 adverse events (AE) were reported in 49% of patients, and grade 4 AE (all neutropenia) occurred in 15% of patients. Grade 3/4 AEs occurring in ≥5% of patients included hypertension (31%), neutropenia (16%), hyperglycemia (13%), diarrhea (5%) and fatigue (5%). Hyperglycemia of any grade occurred in 47%. Four patients required insulin therapy, but no grade 4 hyperglycemia was observed. Hypertension of any grade occurred in 46% of patients. Eight patients required antihypertensive treatment, but no grade 4 hypertension was reported. Diarrhea of any grade occurred in 25% of cases. No case of colitis was reported. There were two cases of interstitial pneumonitis, with both cases resolved following corticosteroid administration. Withdrawal of study drug due to AEs occurred in 10 patients (16%), and 4 patients required a dose reduction. Four deaths occurred; 1 due to progressive disease, 1 due to acute respiratory insufficiency, 1 due to Cryptococcal meningitis and 1 due to sepsis after start of a salvage chemotherapy regimen. Conclusions The novel PI3K inhibitor BAY 80-6946 is clinically active as a single agent and appears to have an acceptable toxicity profile in relapsed/refractory lymphoma. Preliminary efficacy results are encouraging, as promising activity has been observed in FL, CLL, MCL, and PTCL. The safety profile was consistent with prior studies. Further studies of this compound in patients with lymphoma are warranted. Disclosures: Vitolo: Roche: Speakers Bureau; Celgene: Speakers Bureau; Takeda: Speakers Bureau. Mappa:Bayer S.p.A.: Employment. Giurescu:Bayer Pharma AG: Employment. Childs:Bayer HealthCare Pharmaceuticals: Employment.

Description: Background: AML is associated with poor survival rates in patients ineligible for IC or stem cell transplant due to advanced age, comorbidities, and/or disease and patient-specific risk factors. Non-intensive therapies, including the hypomethylating agent (HMA) AZA, have historically been used in this setting; however, response rates and survival remain dismal. Pre-clinical studies in myeloid malignancies indicate that the epigenetic combination of HMAs and HDAC inhibitors induce re-expression of silenced genes in a synergistic fashion. Pracinostat, an oral pan-HDAC (class I, II, and IV isoforms) inhibitor, has shown superior pharmacokinetic and pharmacodynamic properties compared with other HDAC inhibitors. The activity of pracinostat has been shown in xenograft tumor models of AML and synergistic interactions have been observed with multiple cytotoxic and targeted anti-cancer therapeutics, including AZA. In a Phase 2 study in AML patients ≥65 years not eligible for IC, the epigenetic combination of pracinostat and AZA showed promising efficacy (Garcia Manero, Blood 2016) with a 64% overall response rate and 19.1 months median overall survival. Favorable responses were also seen in patients with high risk molecular features and adverse prognostic factors. The safety profile of pracinostat/AZA is comparable to each administered as monotherapy, with no significant added toxicity. Study Design and Methods: The Phase 3, multicenter, double-blind, randomized PRIMULA study (NCT03151408) evaluates the efficacy and safety of pracinostat administered with AZA in adult patients with newly diagnosed AML who are ineligible to receive IC based on either 1) age ≥75 years or 2) age

Description: Abstract 267 BACKGROUND: Chlamydophila psittaci (Cp) infection carries a potential pathogenic role in OAMZL and has been detected in tumor tissue of a high proportion of patients (pts), with geographic differences in its prevalence rates. The use of immunohistochemistry, immunofluorescence and electronic microscopy techniques has identified monocyte/macrophage as carriers of Cp in OAMZL, and bacteria eradication with doxycycline (DOXY) has been associated with lymphoma regression in half of pts. Notwithstanding these achievements, clinical and therapeutic knowledge on this association mainly result from retrospective studies or trials including also patients with relapsed disease after wide-ranging follow-up. Prospective studies focusing exclusively on pts with newly diagnosed OAMZL do not exist. Herein, we report the final results of the first international prospective phase II trial aimed to investigate Cp prevalence and DOXY efficacy as first-line therapy in pts with newly diagnosed OAMZL (ClinicalTrial.gov NCT01010295). AIMS: To elucidate prevalence of Chlamydiae infections, and to evaluate the efficacy of DOXY both in terms of bacterial eradication and as upfront anti-lymphoma therapy in pts with newly diagnosed OAMZL. METHODS: This trial included two different parts, named A and B. The part A included pts with newly diagnosed stage-IEA OAMZL and measurable/parametrable disease; these pts were assessed for chlamydial infection and were treated with DOXY 100 mg orally twice daily for 21 days. The part B included pts with lymphoma categories other than MZL, non neoplastic lesions of the ocular adnexae or OAMZL not eligible for part A; these pts were treated following local guidelines. Chlamydial infections were assessed on diagnostic tumor samples, conjunctival swabs and peripheral blood mononuclear cells (PBMC) from A and B pts by three different PCR protocols targeting 16rRNS and intergenic spacer 16S–23S, ompA and hsp60, respectively. Bacterial eradication was tested on conjunctival swabs and PBMC collected at basal time, at 3 and 12 months after DOXY (only part A pts). Clinical and ophthalmologic examination and MRI imaging were performed at the same timepoints, and every six months during follow-up. RESULTS: From August 2006 to November 2010, 54 pts from 6 centers were enrolled; 34 pts with OAMZL entered the part A, while 13 pts with non-parametrable OAMZL and 7 pts with other lymphoproliferative disorders entered the part B. Diagnostic material was available for molecular analysis in 44 cases; Cp was detected in biopsies of 32/37 OAMZL (86%) and in 4/7 non-MZL. All cases were negative for C. pneumoniae and C. trachomatis. Among 36 Cp+ pts, infection was detected in 100% of swabs and in 75% of PBMC; swabs or PBMCs from pts with Cp-negative OAMZL were invariably negative. All pts completed the planned DOXY treatment; no relevant toxicity was reported. Among 34 pts entering the part A, 28 were evaluable for bacteria eradication (Cp detected in swabs in 8 pts, in PBMC in one, in both samples in 19). At 3 months from DOXY, Cp was not detected in swabs and PBMC of 14 evaluable pts, with an eradication rate of 50%; at one year of follow-up, Cp was still detected in three of these apparently eradicated pts. Lymphoma regression after DOXY treatment (part A) was complete in six pts (18%; 95%CI: 5–31%), and partial in 16 (ORR= 65%, 95%CI: 49–81%); 11 had SD and one PD. At a median follow-up of 27 months (range 3–51), 13 pts experienced relapse, with a 2-year PFS of 55±9%. A trend to a higher response rate (82% vs. 53%; p=0.12) and 3-yr PFS (72% vs. 52%; p=0.14) was observed in eradicated pts. No significant association between site of presentation (conjunctiva vs. orbit) and clinical outcome was detected. There was no association between animal exposure and bacteria eradication or lymphoma response. All patients but two (stroke and myocardial infarction) are alive, with a 3-yr OS of 92%. CONCLUSIONS: Cp infection is frequent in newly diagnosed OAMZL, and could be also present in other lymphoproliferative disorders of the ocular adnexae. First-line DOXY is an active, safe and rational strategy in pts with limited-stage OAMZL, with lymphoma regression in 65% of cases. However, DOXY failed to eradicate Cp infection in half of pts, with a negative impact on outcome. Further investigations aimed to identify additional potential infective agents associated with OAMZL and more active antibiotic regimens are warranted. Disclosures: Montalban: Red Temática de Investigación Cooperativa en Cancer (RETICC): Research Funding; Asociación Española contra el Cancer: Research Funding.

Description: HES (hypereosinophilic syndrome with organ damage), CEL (chronic eosinophilic leukemia with chromosome marker and/or myeloproliferation/dysplasia) and CIH (chronic idiopathic hypereosinophilia) are diseases that pose a therapeutic challenge and are potentially Glivec-sensitive. This drug inhibits BCR-ABL type tyrosine kinase (TK) as well as Platelet-Derived-Growth-Factor Alpha and Beta (FIP1L1-PDGFRA and ETV6-PDGFRB, detectable in HES and allied conditions) and c-kit related TKs. A study was planned to assess 1) the response to escalating doses of Glivec (starting dose 100 mg/d, maximum 400 mg/d, weekly increment 100 mg/d as necessary) and 2) the diagnostic profile of Glivec-responsive cases. Eligible patients had BCR-ABL- HES, CEL, or CIH with eosinophilia 〉5x10e9/l. Diagnostic work-up included marrow morphology and cytogenetics, PDGFRA/B rearrangement study, and immunophenotype for the detection of expanded (Vbeta) T-cell clones (TCC). Glivec was kindly provided by Novartis Oncology, Italy, to be administered for 12 consecutive weeks. A complete remission (CR) was defined by an eosinophil count 0.35) was short following drug withdrawal (5 patients: 1, 1, 3, 3, 3 months). Glivec is highly active in hypereosinophilic syndromes with PDGFR rearrangements and other gene lesions that need to be properly identified. These cases respond very early even at the lower dosage. However, an early stopping of therapy can be followed by rapid progression as indicated also by the persistence of cytogenetic/molecular lesions in some cases. This dictates a continuing molecular/cytogenetic monitoring for dose titration like in chronic myelogenous leukemia.

Description: Ocular adnexal lymphomas (OAL) are malignant neoplasms which develop in the orbit, the conjunctiva and eyelid. The majority of lymphomas occurring in the ocular adnexa are represented by extranodal marginal zone B-cell lymphomas. In patients with stage IE OAL, localized radiotherapy is the therapy of choice. Complications, however, are frequent, including dryness of the eye, corneal ulcerations, cataract and retina damage. Surgical treatment is usually recommended for conjunctival and eyelids lymphomas but fails to control the growth of lymphoma. Contralateral eye or sistemic relapses are reported in about 10–25% of cases. Therefore, a systemic approach is needed. Rituximab is an anti-CD20 monoclonal antibody, and its efficacy has been demonstrated in indolent and aggressive lymphomas in combination with chemotherapy. Since December 2003 to January 2006 we treated 9 patients with OAL with a combination of Rituximab and Chlorambucil according to this schedule: four weekly infusions of Rituximab 375 mg/m2 plus Chlorambucil 0,1 mg/Kg/die for 45 days, followed by Rituximab 375 mg/m2 once a month for four months and Chlorambucil 0,1 mg/Kg/die for two weeks every month. Eight pts had a diagnosis of extranodal marginal zone B-cell lymphoma and one patient a follicular grade I lymphoma. Median age at diagnosis was 78 years (range 56–86). All pts had a stage I disease and no pts presented systemic symptoms. Disease was localized in the conjunctiva in 6 pts (4 right and 2 left), in two pts the disease was observed in the orbit and in one patient it was localized in the eyelid. IPI was evaluable in 7 pts, and all had a low risk. All pts completed the program without delays. Toxicity, both hematological and extrahematological, was mild, in spite of the high median age of the pts. At the end of treatment 8 pts obtained a complete remission (CR), and a patient obtained a partial response. After a median follow-up of 17 months all pts are alive, and 8 out of 9 (89%) are still in CR. No late toxicity of the ocular adnexa was observed. In conclusion, we hypothesize that Rituximab in combination with Chlorambucil should be take into consideration as first line treatment of primary ocular adnexa lymphomas due to its feasibility and the lacking of severe toxicity and local sequelae.

Description: The majority of patients (pts) with diffuse large-B cell lymphoma (DLBCL) are elderly and may have limited tolerance to chemotherapy due to concomitant diseases. Non-pegylated liposomal doxorubicin has an improved therapeutic index in comparison to doxorubicin, resulting in less myelosuppression, lower GI toxicity and reduced risk of cardiotoxicity at dose level equivalent to standard formulations of doxorubicin. The aim of this study was to assess the efficacy and feasibility of the combination of cyclophosphamide, vincristine, prednisone and liposomal doxorubicin with rituximab every three weeks (R-COMP21) in DLBCL elderly pts with concomitant disease or relapsed pts pre-treated with anthracyclines containing regimens. We analysed twenty-five not consecutive pts from June 2003 to December 2005 according to following negative characteristics: 5 pts over 75 years (20%), 8 pts pretreated with anthracyclines (32%), 12 pts (48%) with heart disease (5 ischemic, 2 hypokinetic and 5 hypertensive cardiomiopathy). Median age was 71 years (range 54–76). 3 pts were stage I, 6 stage II, 5 stage III and 11 stage IV. According to IPI score 8 pts were low risk, 9 low-intermediate, 7 intermediate-high and 1 high risk. The median left ventricular ejection fraction (LVEF) at diagnosis was 59% (range 42%–75%). All pts were evaluable for response to therapy: 18 (72%) obtained a complete remission (62,5% in pre-treated pts), 5 (20%) obtained a partial remission with an overall response rate of 92%. Two pts did not respond to therapy. After a total of 126 cycles we observed three toxic event (congestive heart failure, stroke and gastrointestinal bleeding). No significant hematological toxicity was recorded. Four percent of cycles were delayed. Median final LVEF was 57% (47%–65%). All pts but one had no change in LVEF, one patient developed a congestive heart failure resolved with medical therapy: he was withdrawn due to decrease of LVEF. After a median observation period of 2 years (range 2–68 months), 71% of pts are alive, five pts died two due toxicity and three due to progressive disease. We compared these outcomes with an historical control of 26 aggressive NHL pts treated from February 2001 to June 2005; these pts received no doxorubicin (10 pts) or a mitoxantrone-based scheme devised for elderly (16 pts) due to age or concomitant disease. Case matching was performed with respect to clinical stage, IPI, sex, symptoms, bulky disease, LVEF, with the exception of age (which was greater in control group: median 76 vs 71 p=.001) and heart disease which was more frequent in experimental group (48% vs 31% p=.02). Allowing for the limitations of studies using historic controls, the R-COMP regimen was associated with higher CR (72% vs 42%) and OS rates (71% vs 42%). These results did not change when only pts treated with rituximab are considered. We conclude that the general tolerability and the low incidence of cardiac events of liposomal doxorubicin warrants further studies in a subset of pts with concomitant disease limiting the use of conventional anthracyclines.