ALBERT

Description: Key Points The commonest lesions in anaplastic large cell lymphomas are losses at 17p13 and at 6q21, concomitant in up to one-quarter of the cases. PRDM1 (BLIMP1) gene (6q21) is inactivated by multiple mechanisms and acts as a tumor suppressor gene in anaplastic large B-cell lymphoma.

Description: Introduction: Secondary CNS dissemination (SCNSL) is a rare but lethal event in pts with diffuse large B-cell lymphoma (DLBCL). It can occur both at presentation, in pts with systemic disease, or at relapse, during or after primary therapy. Following the experience from primary CNS lymphoma, pts with SCNSL are currently treated with high-dose-methotrexate-based chemo and autologous transplant (ASCT). However, this strategy is associated with poor control of extra-CNS disease, and only 1/3 of pts proceed to ASCT and recover from this event. Thus, we designed a multicenter phase II trial addressing an intensified chemoimmunotherapy consolidated by ASCT in HIV-neg pts with SCNSL (NCT02329080). Methods: Inclusion criteria were: histologically confirmed DLBCL; CNS involvement at presentation (concomitant to systemic disease) or relapse (isolated or concomitant to systemic lymphoma); age 18-70 ys; ECOG-PS ≤3; no prior treatment with high-dose methotrexate. Registered pts received 3 courses of MATRIX followed by 3 courses of RICE combined with intrathecal chemo and consolidated by BCNU-thiotepa/ASCT. The primary endpoint was 1-yr PFS. The Fleming design was used; to detect a difference in 1-yr PFS from 50% (P0) to 65% (P1), 69 pts were required (one-sided, type I error 5%, power 80%), with a dropout of 10%, 76 pts were needed. If ≥41 pts were progression-free at 1 yr, the strategy would be considered effective. Results: Between 3/2015 and 8/2018, 79 pts were enrolled at 24 centers in 4 countries; 75 pts (median age 58, range 23-70; 38 males) were assessable. CNS involvement was recorded at presentation in 32 (43%) pts and at relapse in 43 (isolated site in 15, concomitant to systemic relapse in 28). CNS sites were brain parenchyma in 34 (45%) pts, brain + eyes in 10 (13%), brain + CSF in 13 (17%), brain + CSF + eyes in 6 (8%), CSF/meninges in 8 (11%), spinal cord in 2 (3%), and eyes in 2 (3%). Median time to CNS involvement was 5 months (range 1-61) in the 43 pts registered at relapse; 20 (47%) of them had refractory disease. 320 (71%) of the 450 planned chemo courses were delivered; 64 (85%) pts received intrathecal chemo. 78 SAEs were recorded in 42 pts, mostly due to FN and infections (64) or bleeding (5); 74 (95%) SAEs were followed by recovery. The 4 lethal SAEs (TRM= 5%) and the 5 transient interruptions occurred during MATRIX. Dose reductions were indicated in 33 (10%) courses. Most common g4 toxicities were thrombocytopenia in 118 (37%) courses, neutropenia in 113 (35%) and infections in 9 (3%). Stem cells collection was successful (median of 6.75M/kg; range: 2.4 - 45) in 42 (88%) of the 48 pts referred for leukapheresis. 55 (73%; 95%CI 63-83%) pts achieved a response after 2 courses of MATRIX; 19 (95%) of the 20 pts who had a CR after 2 MATRIX maintained the response after RICE; 9 (26%) of the 35 pts who had a PR after 2 MATRIX achieved a CR after RICE. Conversely, only 3 of 16 pts with PD/SD after 2 MATRIX achieved a response from RICE. 49 pts (65%; 95%CI 54-76%) achieved a response after MATRIX-RICE induction, and 36 responders received ASCT; 13 responders did not receive ASCT due to insufficient mobilization (n=4), PD due to treatment delay (5), frailty (2), neurological decline (1), and consent withdrawal (1). 45 pts (60%; 95%CI 50-70%) had responsive disease after the whole treatment. At 1 year from registration, 41 pts were progression free (efficacy threshold ≥41). At a median follow-up of 25 (12-47) months, 31 pts are progression free, with a 2-yr PFS of 42 ± 6% for the whole series and 75 ± 7% for the 36 transplanted pts (Fig. A & B). Sites of relapse/progression were CNS in 10 pts, extra-CNS organs in 9 and both in 18. Overall, 33 pts are alive, with a 2-yr OS of 42 ± 6% for the whole series and 82 ± 7% for transplanted pts. Causes of death were lymphoma (35) and toxicity (4); 3 pts died without evidence of disease due to neurological decline, PTE and sudden death. Pts with CNS disease at presentation had the best outcome (Fig. C), whereas CSF/meningeal disease (Fig. D) and age 〉60 ys were independently associated with poor outcome. Conclusions: MATRIX-RICE followed by ASCT achieved the primary endpoint in this very-poor-prognosis population, without major safety concerns. Survival figures of transplanted pts seem a little better than reported in prior trials, whereas pts with MATRIX-refractory disease had no benefit from crossing to RICE. The best survival figures were recorded in chemo-naïve pts treated at presentation and in pts without CSF/meningeal disease. Figure Disclosures Ferreri: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding. Doorduijn:Roche: Honoraria, Research Funding. Nassi:Merck: Consultancy; Takeda: Consultancy; Janssen: Consultancy. McKay:Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Davies:ADCT Therapeutics: Honoraria, Research Funding; Karyopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; MorphoSys AG: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Janssen: Honoraria, Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioInvent: Research Funding. Fox:Celgene: Consultancy; Gilead: Consultancy; AbbVie: Consultancy; Janssen: Consultancy; Sunesis: Consultancy; Takeda Pharmaceuticals: Consultancy; Atara Biotherapeutics: Consultancy; Adienne: Other: Travel Support. Osborne:Gilead: Membership on an entity's Board of Directors or advisory committees; NIL: Employment; NIL: Other: leadership; NIL: Other: Stock & other ownership interests; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; MSD: Membership on an entity's Board of Directors or advisory committees. Liberati:Incyte: Consultancy; Novartis: Other: Clinical trial support; Janssen: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Roche: Other: Clinical trial support; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Celgene: Honoraria, Other: Clinical trial support; Bristol-Myers Squibb: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zambello:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Zucca:Celltrion Helathcare: Membership on an entity's Board of Directors or advisory committees; AstraZenaca: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Merck: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Research Funding; Kite, A Gilead Company: Membership on an entity's Board of Directors or advisory committees; Abbvie: Other: Travel Grant. Cwynarski:Adienne: Consultancy; Takeda: Consultancy, Other: conference and travel support , Speakers Bureau; Roche,: Consultancy, Other: conference and travel support, Speakers Bureau; Autolus: Consultancy; KITE: Consultancy; Gilead: Consultancy, Other: conference and travel support, Speakers Bureau; Celgene: Consultancy; Atara: Consultancy; Janssen: Other: conference and travel support, Speakers Bureau.

Description: Background: The salivary gland is one of the most common sites of involvement by non-gastric extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT). This multicenter, international trial sought to characterize the clinical course, treatment and outcome of patients with salivary gland MALT lymphoma. Methods: Patients were identified from multiple international sites including the Mayo Clinic Lymphoma Database (n=89), three International Extranodal Lymphoma Study Group (IELSG) cohorts (n=138), and the University of Athens (n=21). All patients had biopsy-confirmed MALT lymphoma of the salivary gland by WHO criteria. Clinical characteristics, treatment, and outcomes were obtained from the respective patient databases. Survival probability was estimated using the Kaplan-Meier method and compared between groups with the Wilcoxon or log-rank. The impact of variables on survival was assessed by the Cox proportional hazards model. Results: Patients and clinical features: From 1983 to 2012, 247 patients with MALT lymphoma were included. Clinical characteristics are shown in Table 1. The median age at diagnosis was 59, and the male-to-female ratio was 1:3. The majority of patients (76%) presented with limited stage disease, and the parotid gland was the most common site of involvement (78%). There was a history of antecedent autoimmune disease in 41% of patients, and Sjögren’s disease was the most common (83%). Treatment: Information on initial treatment was available on 242 patients. 137/242 patients (57%) initially received local therapy with either surgery (n=81), radiation (n=26), or both (n=30). Of these, 25 received adjuvant systemic therapy. 90/242 patients (37%) were treated initially with systemic therapy, of whom 54% had localized and 46% had stage IV disease. Rituximab was used alone (n=16) or in combination with chemotherapy (n=26) in 42 of the 90. 15/242 patients (6%) were initially observed. Survival: The median OS for all patients was 18.3 years. PFS following primary therapy was 9.3 years. There was no difference in the outcomes between patients receiving local or systemic therapy in first line for all patients, or for those with stage I or II disease. On univariate analysis age

Description: BACKGROUND: Follicular lymphoma (FL) is generally characterized by a moderate metabolic activity (FDG-avidity) in nodal and extra-nodal sites and by the frequent detection of residual disease in post-treatment PET scans. Since median age at diagnosis is over 60 years, in many FL patients several conditions that affect the elderly often occur in combination with the tumor, thus complicating and limiting the use of conventional imaging for lymphoma staging and response assessment. For this reason, the choice of the imaging technique should take into account clinical needs (preservation of renal function, reduction of diagnostic radiation exposure) as well as the necessity to constrain health care costs. OBJECTIVE: The aim of the study was to investigate if there is any advantage in the use of contrast-enhanced CT (ceCT) vs. unenhanced low-dose CT (ldCT) in routine protocols for end-of-therapy PET/CT evaluation of patients with FL. METHODS: Thirty FL patients who underwent end-of-therapy PET/CT protocol with ldCT and ceCT were analyzed retrospectively. Two different observers evaluated PET/ldCT and PET/ceCT in a blinded manner. Number and sites of nodal or extra-nodal disease were compared, using PET/ceCT as gold standard in order to evaluate if the type of CT could result in changes of the DS and therapeutic strategy. RESULTS: In 26 of 30 patients (87%; 95% confidence interval, 73%-98%), PET/ldCT showed the same number and sites of lesions highlighted by PET/ceCT. The inter-observer concordance and overall concordance between imaging procedures were excellent with a very high Cohen's kappa (respectively 0.82 and 0.83). 97% of lesions (103/107) were found by PET/ldCT and in 4 of 30 patients (13%) PET/ceCT provided additional nodal lesions in the mesenteric and iliac regions (3 mesenteric nodes and 1 iliac node;

Description: Key Points A recurrent gain of a region of chromosome 11 (11q24.3) occurs in up to one-quarter of cases of diffuse large B-cell lymphoma. ETS1 and FLI1 genes are overexpressed and determine proliferation, survival, and differentiation arrest of the lymphoma cells.

Description: Background: Primary mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach is often associated with Helicobacter pylori (Hp) infection and Hp eradication therapy is widely accepted as initial treatment. The aim of this study is to report the clinical characteristics and long term outcome in a large series of patients with gastric MALT lymphoma exclusively treated with Hp eradication therapy. Methods: 105 newly diagnosed gastric MALT lymphoma patients (54 men and 51 women) with median age of 64 years (range 20–94) referred to our institutions between June 1990 and November 2006 were eligible for the study. Staging was performed according to the Lugano staging system. All patients received anti-Hp eradication therapy as initial treatment with standard regimens combining antibiotics (usually Amoxicillin, Clarithromycin and/or Metronidazole) and proton-pump inhibitors (Omeprazole in most cases). Responses, evaluated with regular endoscopic biopsies every 3–6 months were graded according to the Wotherspoon’s histological score system. Results: 100 patients had stage I and 5 patients had stage IIE1 disease. Hp was positive in 83 patients (79.5%) and was eradicated in all positive patients but 19 patients required a second line antibiotic therapy. Symptoms disappeared or markedly diminished and endoscopic features improved in almost all patients after Hp eradication. Histological regression of the gastric lymphoma was achieved in 78 of 102 evaluable patients (76%, 95% C.I.; 67%–84%) with histological complete response (Wotherspoon’s score 0–2) in 66 and partial response (score 3) in 12 patients. Of the 78 patients who achieved a lymphoma regression, the histological remission was consistently confirmed at follow-up endoscopies in 28 patients (36%), while 33 (42%) had histological score fluctuations (from 0–4), sometimes with transient histological relapses followed by spontaneous histological remissions. Ten patients had a frank lymphoma relapse (2 with high-grade transformation) and 7 died in remission for other causes. At a median follow up time of 6.3 years, the overall survival in the entire group is 92% at 5 years (95% C.I.; 84%–96%), 83% at 10 years (95% C.I.; 70%–91%) and 78% at 15 years (95% C.I.; 62%–88%). Only one patient died for lymphoma (after histological transformation). Additional tumors were observed in 22%. A history of autoimmune disease was present in 15% of the patients and did not affect the outcome. Conclusions: Hp eradication usually results in long term disease control, independently of the lymphoma pathological remission status. A watch and wait policy seems safe in patients with local histological relapse with no endoscopic evidence of gross disease.

Description: Mantle cell lymphoma (MCL) represents a subtype of B-cell lymphoma associated with a very unfavourable clinical outcome. Currently no therapy can be considered as standard, and new therapeutic approaches are needed. Forodesine is a potent inhibitor of purine nucleoside phosphorylase (PNP), whose major role is to catalyze the cleavage of inosine, deoxyinosine guanosine, and deoxyguanosine (dGuo) to their corresponding base and sugar 1-phosphate by phosphorolysis. In the presence of deoxycytidine kinase, PNP inhibition leads to an increase in the concentration of dGuo triphosphate (dGTP), followed by inhibition of DNA synthesis and cell death by apoptosis. When combined with dGuo, forodesine has been shown to have in vitro cytotoxic activity on T-cell (T-ALL, T-PLL) and on B-cell malignancies (CLL, B-ALL), and Phase I/II trials are on going in CLL and CTCL patients. Here, we report the first data on in vitro activity of forodesine in MCL. Primary MCL cells, derived from six patients, were exposed to forodesine (0, 2, 20 μM) in combination with dGuo (0, 10, 20 μM), for 48 hrs. Cells were cultured in X-VIVO 10 medium (Cambrex) with 10% FBS. Cell viability was assessed by flow cytometry with the Annexin V - propidium iodide assay. Four patient samples (67%) showed an increase in the number of Annexin V positive cells ranging from 1.9 to 5.3 times compared to untreated cells. The effect was larger for 20 μM forodesine compared with 2 μM. There was no effect of dGuo alone and only a minimal effect of increasing dGuo concentration from 10 μM to 20 μM. Cell lines did not appear to be ideal models to evaluate the efficacy of forodesine in vitro. Three established MCL cell lines (Granta-519, Rec, JeKo1) were treated with escalating doses of forodesine, but the results were not reproducible, while the same cells showed expected IC50 values between 25–30 μM when exposed to bendamustine for 72 hrs. In conclusion, the in vitro data reported here with 4/6 MCL patients primary samples sensitive to forodesine and the results from various groups on other T- and B-cell malignancies suggest that clinical trials of forodesine in MCL may be warranted.

Description: The International Extranodal Lymphoma Study Group (IELSG) is coordinating two phase II multicenter studies aimed to assess the antitumor activity and safety of bortezomib treatment in patients (pts) with relapsed or refractory extranodal marginal zone B-cell lymphoma of MALT-type. The IELSG25A study is evaluating bortezomib in pts previously treated with one prior systemic treatment, and the IELSG25B pts previously treated with more than one prior treatment. Bortezomib 1.3 mg/m2 is administered on days 1, 4, 8, and 11 of a 21-day cycle, for up to 6 cycles. Response and progression are determined by International Workshop Criteria. As of July 2007, 18 pts have been enrolled in the studies: 11 (61%) patients were male, median age was 62 years (range, 38–77). At time of enrolment, the Ann Arbor stages distribution was the following: stage I=5 pts (28%), stage II=5 pts (28%), stage IV=8 (44%). In 10 pts primary gastric localization was present, in 5 cases primary skin, in 2 cases primary subcutaneous, in 1 primary lung lymphoma. All patients had ECOG PS=0; in 2 cases (11%) elevated serum LDH was reported. More than 1 site of extranodal localization was present in 4 pts (22%). Median number of prior therapies was 2 (range, 1–3). Median follow-up was 16 months. Nine pts were assessed for response at the end of treatment plan: 3 pts had a CR (33%); 4 a PR (45%) and 2 SD (22%). Five additional pts, with ongoing therapies, have been evaluated after the first two courses of therapy: one pt achieved a CR and 2 pts a PR, in 2 cases a SD was observed. The safety profile of bortezomib is similar to that observed in multiple myeloma and other subtypes of non-Hodgkin lymphoma. The most relevant adverse events grade 3 or higher were peripheral neuropathy and fatigue. One death, non-related to treatment, was observed during the early follow up. These preliminary results suggest that bortezomib is active and safe in relapsed or refractory MALT lymphomas and encourage us to complete the studies accrual.

Description: Introduction: Diffuse large B-cell lymphoma (DLBCL) of the testis (PTL) is a rare presentation of extranodal lymphoma at poor prognosis with a 5-yr overall survival of 40-55%. Contralateral testis, CNS and extranodal sites relapses are the main cause of failures. IELSG 10 study is a prospective phase II international trial for patients with stage I or II PTL and was designed to define a standard treatment for PTL. It aims to evaluate efficacy and toxicity of a combined treatment of R-CHOP, intrathecal methotrexate and prophylactic scrotal radiotherapy (RT) with the addition, in stage II, of loco-regional RT. The trial was conducted by IELSG and Intergruppo Italiano Linfomi. Patients and methods: From June 2001 to June 2006, 50 pts with stage I-II PTL were enrolled from 26 centres. Treatment plan was: R-CHOP21 (R 375mg/m2, Ctx750 mg/m2, Doxo50 mg/m2, Vcr1.4 mg/m2 day 1 and Pdn40 mg/m2 days 1–5) for 6 courses and 2 additional ones in stage II patients with slow response; intrathecal methotrexate (IT MTX) 15mg for 4 doses during courses 1 and 2; at the end of chemotherapy 30 Gy scrotal RT to contralateral testis was planned to all pts and 30–36 Gy nodal loco-regional RT for those with stage II disease. Results: To date 45 pts who completed the treatment are evaluable. Median age was 64 (range 22–80); 36 stage I and 9 stage II disease; 3 had bilateral testicular involvement; 4 LDH〉normal and 2 B symptoms. All received R-chemotherapy as planned. Forty-two (93%) pts received adequate CNS prophylaxis (at least 4 IT MTX); 3 less than 4 IT MTX because of poor tolerance or toxicity. Scrotal RT was given to 40 pts (89%) as planned; 5 did not performe it (3 refusal, 1 progressive disease and 1 bilateral orchiectomy). Forty-four patients (98%) achieved a CR and one progressed after 4 R-CHOP courses. With a median follow-up of 28 months, 3-yr OS, 3-yr PFS and 3-yr EFS were: 88% (95% CI 69–96%), 82% (95% CI 63–92%) and 78% (95% CI 58–89%). Seven patients relapsed or progressed: 2 in nodal sites, 3 in extranodal ± nodal sites and 2 in CNS (1 isolated meningeal and 1 eningeal + nodal relapse). The actuarial risk of CNS relapse at 3 years is 2.5% (95% CI 0–7%). No contralateral testis relapses were observed. Five patients died: three because of DLBCL; one of peripheral T-cell lymphoma and one of ANLL 21 months off therapy while in CR. No toxic death occurred during treatment. Main grade 3–4 toxicities were: hematological 27% and neurological 15%. Conclusions: Although the follow-up is short, these results compare favorably with those previously reported in IELSG retrospective study in PTL (Zucca et al J Clin Oncol 2003). Contralateral testis relapses has not been observed and the incidence of CNS relapse seems to be reduced. If these results are confirmed with a longer follow-up, a combined treatment of R-CHOP, IT MTX and prophylactic scrotal RT ± nodal RT in stage II patients would improve the prognosis of these pts and should be regarded as the standard treatment in localized stage PTL. However, if further relapses are observed there will be a need for innovative strategies to address the issues of systemic and CNS relapse.