Kurzfassung: Introduction: few studies have explored the usefulness of a prognostic index specifically devised for patients with localized DLBCL. The IIL has performed a retrospective analysis of a large group of patients with limited stage DLBCL and developed a new prognostic model. Results: 1,252 patients with localized (Ann Arbor stage I-II) aggressive B-cell lymphoma (IWF: G or H, WHO:DLBCL) diagnosed from 1988 to 2002 and without CNS involvement, treated by 4 cooperative groups and 2 single institutions, are the subject of this analysis. Patient’s median age was 57 years (range, 17–91) and M/F ratio was 1.26. Clinical stage was I in 239 (19%), IE in 303 (24%), II in 356 (28%) and IIE in 354 (28%) patients, respectively. Supradiaphragmatic disease was present in 56% of patients, 13% had 〉 3 nodal sites, 53% had extranodal involvement, and 7% had 〉 1 extranodal site. Bulky disease (≥10 cm) was present in 26% of patients, ECOG-PS 〉 1 in 12% and B symptoms in 14%. Abnormal biochemical data included: elevated LDH (28%), β2-microglobulin (B2M;19%) and ESR (38%) and reduced albumin ( 〈 3.5 g/dL) in 21% of the cases. Patients were treated with anthracyclin-containing regimens ± IF-RT. After a median follow-up of 62 months for alive patients (range 1–183 months), 3 and 5-year OS rates were 73% and 71%, respectively. By univariate analysis the following 11 variables were found to be predictive of a short survival: age ≥65 yrs (P=0,0001), stage II nodal (P=0,0001), number of nodal sites (P 〈 0.0001), poor ECOG-PS (P 〈 0.0001), B symptoms (P=0.0009), bulky disease (P=0.0001), elevated ESR (P=0.0001), LDH (P 〈 0.0001), Radiotherapy (P 〈 0.001), B2M (P=0.007) and reduced serum albumin ( 〈 0.0001). By Cox multivariate analysis, age ≥65 years (p 〈 0.001), stage II nodal (P 〈 0.001), high LDH (P 〈 0.001) and bulky disease (P 〈 0.01) were indipendent risk factors (RF) for a short survival. The prognostic model was calculated with the sum of scores assigned to each variable; a score of 2 was assigned to advanced age, high LDH, and Bulky; for Stage a score of 1 was considered for stage Ie-IIe and 2 for stage II nodal. Three groups of patients with a different probability of survival (P 〈 0.000001) were identified. Patients at low (Score 0–1; 387 pts), intermediate (Score 2–3; 484 pts) or high risk (Score 4–8; 381 pts) had a 5 years OS of 87%, 77%, 51% respectively. The predictive performance of the model was internally validated through a non parametric Bootstrap method and through residues’ analysis. Conclusions: This prognostic model, developed and validated on a very large series of patients with localized DLBCL, will allow us to select appropriate therapeutic approaches on the basis of different risk categories.

Kurzfassung: Introduction: Rituximab is a monoclonal antibody commonly used in B-DLCL both in salvage regimens and in combination with first-line chemotherapy. Some studies have reported delays in neutrophil or platelet engraftment after ASCT in patients treated with high dose chemotherapy and Rituximab prior to ASCT. We investigated the effect of adding Rituximab prior to ASCT on peripheral blood stem cell (PBSC) harvest, time to engraftment and short-term toxicity post ASCT. Patients and methods: We analyze stem cell mobilization, engraftment (median time to absolute neutrophil count & gt; 500/mm3 for three consecutive days and platelets & gt; 50.000) and short-term toxicity after ASCT ( & lt; 30 days) in two groups of patients affected by B-DLCL at diagnosis enrolled into two consecutive trials with or without Rituximab in combination with chemotherapy. All patients were & lt; 61 years with B-DLCL at age-adjusted IPI Intermediate-High (IH) or High (H) risk and/or with bone marrow (BM) involvement. Group A: an intensified chemoimmunotherapy regimen R-MegaCEOP (Rituximab 375 mg/m2 day 1, CTX 1200 mg/m2 + EPI 110 mg/m2 + VCR 1.4 mg/m2 day 3 and PDN 40 mg/m2 days 3 to 7) every 14 days with G-CSF support for 4 courses; patients in complete response (CR) or partial response (PR) received two courses of intensified chemotherapy R-MAD (Mitoxantrone 8 mg/m2 + ARA-C 2000 mg/m2/12h + Dexamethasone 4 mg/m2/12h days 1 to 3 and Rituximab 375 mg/m2 day 4 and before PBSC harvest). Group B: MACOP-B 8 weeks + 2 courses of MAD (in patients in CR or PR) without Rituximab. Both groups were given ASCT with BEAM as conditioning regimen. Clinical characteristics at diagnosis were well balanced between the two groups. Results: 68 patients are evaluable: 35 pts in group A (with Rituximab) and 33 pts in group B (without Rituximab). All patients in both groups collected more than 2 x 106 CD34+ cell/kg. Median CD34+ cell/kg in group A was 13 x 106 (range 0-37) compared with 41 x 106 in group B (range 0–253) with no statistically significant difference. Median time to neutrophils engraftment after ASCT was similar in the two groups: 9 days in group A and 10 days in group B. No delay in the platelet recovery was observed in patients treated with chemoimmunotherapy: 15 days in group A vs 16 days in group B. Few severe early toxicities (WHO grade 3–4) were reported with no differences between group A vs B: severe mucositis in 11 pts vs 23 pts, gastrointestinal in 6 pts vs 4 pts. Severe infections occurred in 10 patients: group A 6 patients (2 Gram+ sepsis, 1 Gram- sepsis, 1 FUO, 2 bacterial pneumonia); group B 4 patients (2 FUO, 1 bacterial and 1 viral pneumonia). One patient in group A died of bacterial pneumonia after ASCT. Conclusions: Treatment with Rituximab may be safely included in a pre-ASCT high dose chemotherapy regimen with no delay in stem cell harvest, engraftment and without increased early toxicity after ASCT.

Kurzfassung: CD5‐negative chronic B cell lymphoproliferative disorders in leukemic phase (B‐CLPD) are heterogeneous and relatively uncommon pathologies that often lack a histopathological definition because of the absence of accessible pathological tissue. We describe the clinical features and evolution‐related variables of 156 patients with CD5/CD10‐negative B‐CLPD (median age 66 years, range 25–86). The median follow‐up was 51 months (range 6–216), and overall 3‐ and 5‐year survival was respectively 87 and 76%; 50 patients needed therapy at diagnosis, 56 during follow‐up, and 50 remained untreated until the last control. A combined clinical, histological, cytomorphological, immunophenotypical, and cytogenetic diagnostic approach allowed the complete classification of only a minority of patients as being affected by splenic marginal zone or lymphoplasmacytic lymphoma; the majority of cases remained unclassifiable. Multivariate analysis showed that the clinicohematological variables adversely related to overall survival were serum LDH levels and age, whereas high serum LDH levels, hemoglobin levels of 〈 11 g/dl, and splenomegaly related to treatment‐free time (in “wait and see” cases); only splenomegaly related to time to progression (in treated patients). In conclusion, our retrospective study describes the clinical features and variables related to evolution in a large group of patients with CD5/CD10‐negative chronic B‐cell lymphoid leukemias and underlines the fact that a probable lymphoplasmacytic or marginal zone normal cell origin can be supposed in such leukemic forms, but never surely demonstrated. Am. J. Hematol. 2008. © 2008 Wiley‐Liss, Inc.

Kurzfassung: Background. Ara-c based chemo-immunotherapy followed by autologous stem cell transplantation (ASCT) is the most effective approach in young mantle cell lymphoma (MCL) patients, though few if any patients are cured. Recent data indicate that subsequent Rituximab maintenance (RM) prolongs PFS and OS (Le Gouill NEJM 2017). Lenalidomide is an oral agent effective in MCL, considered suitable for prolonged maintenance programs, but has never been tested in this setting. The FIL MCL0208 trial (NCT02354313) is a prospective, international randomized, phase III trial, comparing Lenalidomide maintenance (LM) vs observation (OBS) after an intensive Ara-c containing chemo-immunotherapy (R-HDS) program, followed by ASCT in previously untreated MCL patients. Patients and Methods. Adult patients aged 18-65 years, with advanced stage MCL without clinically significant comorbidities were enrolled. Patients received 3 R-CHOP-21, followed by R-HDS i.e. R-high-dose Cyclophosphamide (R-HD-CTX) (4g/m2), 2 cycles of R-high-dose Ara-C (R-HDAC) (2g/m2 q12x3 d). CD34+ cells were collected after the first course of R-HDAC. The conditioning regimen for ASCT was BEAM. After ASCT, responding patients were randomized between LM (15 mg days 1-21 every 28 days) for 24 months or observation. Primary endpoint analysis was scheduled at the occurrence of the 60th PFS event in the randomized population, which occurred on June 20th, 2017 and data were analyzed for the present abstract on March 3rd 2018. Results. Three-hundred three patients were enrolled from May 2008 to August 2015 by 48 Italian and 1 Portuguese Center. Three patients were excluded after central histological review. Median age was 57 years (IQR 51-62), M/F ratio 3.6/1. Ninety-two percent of patients had stage IV, 33% bulky disease ( 〉 5 cm), 33% elevated LDH, and 75% BM infiltration. Ki67 ≥30% was observed in 32%, MIPI was low (L) in 54%, intermediate in 31% and high (H) in 15% of patients. MIPI-c was L in 49%, low-intermediate (LI) in 29%, high-intermediate (HI) in 14%, H in 9%. Nine percent had blastoid variant. Fifty-two (17%) patients interrupted treatment before randomization (8 toxic deaths, 1 death for car accident, 24 progressions and 19 toxicity/refusals). On an ITT basis, the R-HDS + ASCT program induced 78% of CR, 7% of PRs, 10% of PD, 3% of toxic deaths (TRM) and 2% NA. Median follow-up (mFU) from inclusion was 51 months. Three years PFS and OS for the enrolled population were 67% and 84%, respectively. Of 248 patients who received ASCT, 205 were randomized either to LM (n=104) or OBS (n=101) and 43 (17%) were not because of: lack of response (8), refusal/PI decision/delay (8), unresolved infections (3) and inadequate hematopoietic recovery (24). Feasibility and efficacy were assessed on an ITT basis while toxicity was analyzed on subjects receiving at least one Lenalidomide dose. In the LM arm, 53 out of 104 patients did not start or complete the planned maintenance because of death (2), AE (26), PD (7), still ongoing (2), other causes (16). In the OBS arm 32 patients did not complete the observation phase because of death (1), AE (1), PD (20), still ongoing (10), other causes (1). Overall 28% of patients received less than 25% of the planned Lenalidomide dose. Despite suboptimal exposure to study drug, with a mFU from randomization of 35 months, 22 PFS events were recorded in the LM cohort vs 38 in the OBS arm, resulting in a 3y-PFS of 80% (95% CI; 70%-87%) in the LM arm vs. 64% in the OBS arm (95% CI; 53%-73%), stratified HR 0.51; 95% CI 0.30-0.87; p=0.013 (Fig 1A). OS was superimposable in the two arms: 93% vs 86%, stratified HR 0.96, 95% CI 0.44-2.11, p= 0.91 (Fig1B). Two deaths were observed in the LM arm due to pneumonia and thrombotic thrombocytopenic purpura and one in the OBS arm due to pneumonia. Grade 3-4 hematological toxicity was seen in 63% of patients in LM vs 11% in the OBS arm with 59% vs 10% of patients experiencing granulocytopenia. Non-hematological grade 3 toxicity was comparable in the two arms except grade 3-4 infections (11% vs. 4%; Fisher's p=0.10). Second cancers occurred in 7 patients in the LM and 3 in the OBS arm (Fisher's p=0.20). Conclusions. Results from the MCL0208 trial indicate that LM has a clinically meaningful anti-lymphoma activity in MCL. However, the applicability of LM has some limitations in the context of patients undergoing intensified chemoimmunotherapy. Overall these data support the use of a maintenance regimen after ASCT in young MCL patients. Disclosures Ladetto: Roche: Honoraria; Celgene: Honoraria; Acerta: Honoraria; Jannsen: Honoraria; Abbvie: Honoraria; Sandoz: Honoraria. Di Rocco:Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Rossi:Novartis: Honoraria; Jazz: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Janssen: Membership on an entity's Board of Directors or advisory committees, Travel expenses; Roche: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Mundipharma: Honoraria; Sandoz: Honoraria; Seattle Genetics: Research Funding; Alexion: Other: Travel expenses. Chiappella:Janssen: Membership on an entity's Board of Directors or advisory committees, Other: lecture fees; Roche: Other: lecture fees; Teva: Other: lecture fees; Nanostring: Other: lecture fees; Amgen: Other: lecture fees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: lecture fees. Rusconi:Celgene: Research Funding. Gomes da Silva:Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees, Institution's payment for consultancy, Travelling support; Celgene: Other: Travelling support; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees; Roche: Other: Institution's payment for consultancy, Travelling support; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees, Research Funding. Vitolo:Takeda: Speakers Bureau; Sandoz: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Speakers Bureau. Martelli:Sandoz: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; F. Hoffman-La Roche: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Kurzfassung: Background. Peripheral T cell Lymphoma (PTCL) represent a major therapeutic challenge. In the previous Verona experience (Todeschini G et al. Cancer2005;104:555–560), the novel intensive regimen HyperCHiDAM Verona897 (high-dose IV MTX 2 g/sqm 400 sqm bolus, 1600 sqm CI day 1 with IV leucovorin rescue; hyperfractionated IV CTX 300 mg/sqm Q12h, dd 2–4; high-dose IV AraC 2g/sqm Q12h, dd 2-4; plus G-CSF) achieved salutary results in refractory/relapsed aggressive lymphomas, in particular in PTCL. Supportive measures included hydratation 3000 ml/sqm/day, antimicrobial prophylaxis comprising oral ciprofloxacin, itraconazole, trimethoprim/sulfamethoxazole. CMV antigenemia (pp65) was monitored 2 times a week. Patients. Following these results, 7 centers belonging to the Italian co-operative group GITIL (Gruppo Italiano Terapie Innovative Linfomi) treated with 2 cycles of HyperCHiDAM Verona897, 33 patients affected by PTCL (17 upfront, 16 refractory/relapsed) followed in the majority of cases by stem cell transplant. Patients: M/F 21/12, median age 49 (19–63) years; histology: PTCL-NOS 15, ALCL ALK-negative 9, EALTC 4, AIL 3, T-NK nasal 1, Angiocentric 1; stage IV 19/33 (57.5%), bone-marrow positive 10/33 (30.3%), extranodal involvement 24/33 (72.7%), high LDH 18/33 (54.5%). Seven patients needing urgent treatment were treated before HyperCHiDAM with 1 cycle of Campath-CHOP (4 patients) or CHOP + L-ASE (3 patients). Results. Upfront patients: after 2 cycles of HyperCHiDAM, CR were 82.3% (14/17), early toxic deaths 0 (1 late toxic death occurred after SCT, due to CMV pneumonia), relapses 3/14. With a median follow-up of 21 months (3–90+), 11/17 (64.7%) patients are disease-free, 10 in first CR, 1 after rescue with stem cell transplant. Three of the CCR patients received HyperCHiDAM alone. Refractory/relapsed patients: CR were 5/16 (31.2%), CCR 4/16 (25%), with a median follow-up of 24 months (5–64+). The progression-free survival was significantly superior in upfront patients (p=0.036). Overall, toxic deaths were 3/33 (9%), 1/17 (5.8%) in upfront and 2/16 (12.5%) in refractory/relapsed patients. One patient had major cerebellar toxicity. Conclusions. The intensive regimen HyperCHiDAM Verona897 is effective in inducing CR in aggressive PTCL, in particular as upfront therapy. The intensiveness of this treatment requires a careful supportive therapy. Following these results, HyperCHiDAM has been included in a national trial for treatment of PTCL, after 2 cycles of Campath-CHOP and before stem cell transplant (allogeneic or autologous depending on the availability of an HLA-matched sibling). The co-operative study is recruiting.

Kurzfassung: Abstract 2808 Poster Board II-784 Background and aims: Characterization of the IgH receptor provides useful insights to understand the pathogenesis and natural history of lymphoid tumors. For example the recognition of stereotyped clusters of immunoglobulin receptors has been a major step forward to understand the pathogenesis of chronic lymphocytic leukemia (CLL). IgH rearrangements have been less extensively investigated in MM, mostly because of lack of large databases of IgH sequences. At our Institution a large number of MM patients has undergone IgH sequencing for minimal residual disease (MRD) evaluation. This database has been merged with MM IgH sequences available in the literature, resulting in 308 MM sequences which have been employed to comprehensively investigate the characteristics of the IgH rearrangement in this tumor. Patients and methods: 131 IgH genes from MM patients were amplified and direct sequenced at our Institution (mostly for MRD detection purposes) from specific cDNA obtained at diagnosis, as already described (Voena et al, Leukemia 1997). 177 MM IgH sequences were derived from published databases (NCBI and EMBL). To further characterize the IgH repertoire, we have then compared the MM complementarity-determining region 3 (HCDR3) amino acid (AA) sequences to a panel of productive, non redundant 27413 HCDR3 AA sequences retrieved from public databases (EMBL, NCBI, IMGT/LIGM-DB: 25655 sequences) and from our unpublished laboratory database (1758 sequences), including sequences from malignant B-cell clones (3197 CLL, 1217 lymphomas) and from non malignant repertoire (2685 autoreactive, 4408 immunederegulation/immunodeficiency, 15429 normal and 477 phage display libraries). All the sequences have been analyzed using the IMGT database and tools (Lefranc et al., Nucleic Acid Res. 2005; http://imgt.cines.fr/) to identify IGHV, IGHD and IGHJ gene usage, to assess the somatic hypermutation (SHM) rate and to identify HCDR3 AA sequences. HCDR3 AA sequences were aligned together, in search of subsets of stereotyped receptors, using the ClustalX 2.0 software (http://www.clustal.org/). To define subsets of stereotyped IgH receptors, we followed the criteria proposed by Messmer et al. (J Exp Med. 2004) and Stamatopoulos et al. (Blood, 2007). Results: No significant differences were noted between our Institutional and published MM databases. Overall IGHV usage in MM appeared in keeping with the normal B cell repertoire with predominance of IGHV3 family (53.9%) followed by IGHV4 (slightly under-represented in MM, 17.2% vs 23.2%, p=0.02) and IGHV1 (12%); besides an over-representation of IGHV2 (7.8% vs 2.3%, p 〈 0.001) was noticed. A modest but significant (p 〈 0.05) over-representation of the IGHV3-9 (5.2% vs 2.6%), IGHV3-21 (4.5% vs 2%), IGHV5-51 (4.5% vs 2.2%) genes and under-representation of the IGHV3-23 (8.1% vs 12.2%) and IGHV4-34 (1% vs 6.5%, p 〈 0.001) were observed. IGHD and IGHJ followed a distribution similar to that of normal IgH repertoire. The median SHM rate was 7.5% (range 0-28%): interestingly we found one single patient with 100% identity to the germline sequence and only three patients with 〉 98% identity. The median length of the HCDR3 was 15 AA (range 7-29), again in line with normal IgH repertoire. Intra MM search for HCDR3 similarity showed no association which met minimal requirements to define stereotyped receptors. The comparison of MM sequences with non MM database showed that 98% of MM sequences are unrelated to known CLL subsets. Among the remaining, 3 MM sequences could be assigned to previously identified CLL subsets (namely n. 25, n. 37 and n. 71 according to Murray et al., Blood 2008) whereas 2 MM formed 2 novel provisional subsets with CLL. When HCDR3 MM were compared to the database of non MM/CLL HCDR3, similarities were found with clones from normal B cells, while similarities with autoreactive clones and other B cell malignancies were sporadic. Conclusions: The analysis of the largest database of MM IgH sequences so far reported indicate the following: 1) Family usage in the MM IgH repertoire follows a nearly physiological distribution apart for modest skewing of a number of IGHV genes; 2) MM specific HCDR3 clusters do not occur to a frequency detectable with currently available databases; 3) The vast majority of MM sequences are not related to known CLL clusters; 4) MM IgH sequences share more similarities with normal IgH sequences compared to those derived from pathological B lymphoid cells. Thus to state of current knowledge there is little evidence in favor of an antigen driven pathogenesis for this neoplasm. Disclosures: No relevant conflicts of interest to declare.

Kurzfassung: Abstract 701 Introduction: Hairy cell leukemia (HCL) is generally responsive to intravenous Cladribine (iv2CdA). Subcutaneous Cladribine (sc2CdA) is an alternative route with 100% bioavailability. In indolent non-Hodgkin lymphomas other than HCL, at the dose of 0.7 mg/kg/cycle, efficacy of sc2CdA is similar to iv2CdA and reduction to 0.5 mg/kg/cycle determines equivalent efficacy and lower toxicity. Aims: In a national multicentre clinical trial (protocol EudraCT code: ICGHCL 2004), we prospectively evaluated toxicity and efficacy of sc2CdA given 0.1mg/kg/die for 5 (total dose 0.5 mg/kg, arm A) or for 7 consecutive days (total dose 0.7 mg/kg, arm B) as a single course in classic HCL requiring first treatment. Method: Clinical data and diagnostic samples were collected from all patients for central revision of classical HCL diagnosis (WHO criteria) and for molecular analyses at the University of Siena, prior to study entry. Early grade 3–4 toxicity was assessed on days 7 to 30 after treatment, according to the 2003 NCI/CTCAE v3 criteria and occurrence of second tumors was assessed at every subsequent follow-up. Enpoints of sc2CdA efficacy were response to treatment, treatment free interval (TFI), relapse free survival (RFS), time to second tumor (TTST) and overall survival (OS). Responses to treatment were assessed on days 60 and 180 after treatment and defined according to the 1987 Consensus criteria. Complete Remissions (CR) and Partial Remissions (PR) were rated as beneficial responses (CR/PR), while minor Responses (mR) and No Responses (NR) were rated as treatment failures (mR/NR). TFI was measured as the time elapsed from sc2CdA initiation to second treatment because of new progression or failure to sc2CdA. RFS was measured in patients with a CR/PR from treatment inititation to relapse. OS was measured from sc2CdA initiation to death for any cause. Result: of 156 patients screened centrally, 148 scored as classical HCL and entered the study. Gender (male total 116/148, 78,4%; arm A: 62/77, 80,5% vs arm B: 54/71, 76,1%), age (total: median age 52 years, range 30–83; arm A: median 56, range 30–83; arm B: median 51, range 33–82), clinical and laboratory parameters prior to treatment (including spleen, hemoglobin, platelet, leucocyte and hairy cell counts) were equally balanced in the two arms. Dose reduction was required in no patients from arm A and in 2 patients from arm B due to concurrent infection. Overall hematological toxicity was no different among the two treatment arms. Requirement of platelet transfusions (total 7/148, 4,7%; arm A: 2/77, 2,6% vs arm B: 5/71, 7%), red blood cell transfusion (total 32/148; 21,6%, arm A: 15/77, 19,5% vs arm B: 17/71, 23,9%), or G-CSF (total 102/148; 68,9%, arm A: 55/77, 71,4% vs arm B: 47/71, 66,2%) was no different among the two arms. However, a significantly higher non hematological toxicity (total 28/148; 18,9%, arm A: 9/77, 11,7% vs arm B: 19/71, 26,8%) was observed in arm B (p=.019). Non haematological toxicity was mainly represented by infections or FUO (total 25/148; 16,9%) that were significantly more frequent in arm B (arm A: 8/77, 10,4% vs arm B: 17/71, 23,9%, p=.028). Higher prevalence of toxicity resulted in a higher hospitalization rate in arm B than in arm A (total 29/148; 19,6%, arm A: 9/77, 11,7% vs arm B: 20/71, 28,2%, p=.012) and one early death was experienced because of lung aspergillosis in arm B. Onehundred-forty patients (94,6%) had a beneficial response (101 CR, 68,2%; 39 PR, 26,4%) and 8 (5,4%) failed treatment (5 mR, 3,4%; 3 NR, 2%). Responses were equivalent in the two arms, with 72/77 (93,5%) beneficial responses (49/77 CR, 63,6%; 23/77 PR, 29,9%; 4/77 mR, 5,2% and 1/77 NR, 1,3%) in arm A versus 68/71 (95,8%) beneficial responses in arm B (52/71 CR, 73,2%; 16/71 PR, 22,5%; 1/71 mR, 1,4%; 2/71 NR, 2,8%). After a median follow-up of 36 months (range 12–66), 5 year TFI, RFS, TTST and OS were 67%, 71% 87% and 94%, respectively. Causes of late death were 2 cardiac events and 3 second tumors. No differences of TFI, RFS, TTST and OS were observed in the 2 arms of treatment. Conclusion: The present data indicate that overall activity of sc2CdA is similar to iv2CdA (Cheson, 1998). Furthermore, this study indicates that sc2CdA given at 25% reduced doses (0.5 mg/kg) has equivalent activity and significantly lower toxicity than sc2CdA at standard doses (0.7 mg/kg). The reduced infection rates and hospitalization rates of sc2CdA have important pharmaco-economic implications. Disclosures: No relevant conflicts of interest to declare.

Kurzfassung: INTRODUCTION We retrospectively analyzed the impact on post-relapse survival of selected prognostic factors and salvage therapy (finalized to perform an allo-SCT) in 145 patients (pts) with non-APL AML who had been initially treated with standard induction and risk-adapted consolidation. The aim was to identify factors associated with a better outcome at first relapse. METHODS All pts were at first recurrence following consolidation of CR1 with (i) high-dose Ara-C (HiDAC) multicycle therapy supported by blood stem cells (standard risk, as defined by mixed clinico-cytogenetic criteria) or (ii) allo-SCT in case of high-risk prognostic profile. Median pt age was 55 y (range 21–68). CR1 duration was ≤ 6 months in 49 pts (34%), ranging from 0.6 to 6 mo (median 3.7). 25/68 pts (37%) had an unfavourable cytogenetics (CG), and 8.2 % had MDS-related AML. 96 pts (66%) had received HiDAC and 21 (15%) an allo-SCT according to study design. RESULTS 105 pts (72%) received salvage chemotherapy, 10 pts (7%) underwent directly allo-SCT, while the remaining 30 (21%) received palliation and all of them died. Salvage therapy consisted again of HiDAC alone or in combination with fludarabine or anthracyclines. After reinduction, 52/105 pts (49.5%) achieved CR2 and 15 (14%) died of complications. Altogether, 42 pts (29%, group 1) received an allo-SCT following relapse, 27 (64%) in CR2, 5 beyond CR2 and 10 soon after relapse. Of 20 more pts (14%, group 2) in CR2 but without HLA identical donor, 13 could be given further intensive consolidation therapy. Both groups were comparable regarding adverse prognostic features such as age 〉 55 y, WBC count 〉 50,000/μL, unfavourable CG, presence of FLT-3 ITD, prior allo-SCT and 1st CR lasting ≤ 6 mo. At the end of treatment, 37/42 pts (88%) receiving SCT and all 20 pts (100%) given only chemotherapy were in CR2. Logistic regression analysis showed that intensive treatment without HiDAC at induction (p=0.04) as well as CR1 lasting 〈 6 mo (p=0.01) negatively affected CR2 rate. Median duration of CR2 was 7.5 mo (range 1–49) in group 1 compared to 4 mo (range 1–15) in group 2. Day 100 non-relapse mortality in the 2 groups was 7% and 10%. After a median follow-up of 9.4 mo in group 1 (range 3–49) and 10 mo in group 2 (range 2–65), 2-y OS was 24% and 15.5%, respectively. Notably, 2-y OS in allo-SCT group ranged from 42% in pts ≤ 45 years to 14% in older ones. Moreover, survival was affected by risk category. In fact 2-y OS of 14/37 (38%) standard risk pts undergoing allo-SCT at salvage was 41% vs 17% in 28/108 (26%) comparable high risk pts. Cox regression analysis revealed achievement of CR2 being the only independent prognostic factor related to overall survival (p=0.0001). CONCLUSIONS AML patients receiving intensive chemotherapy including HiDAC at 1st relapse reached a high CR2 rate, regardless of type of prior risk-adapted consolidation. Further intensification with allo-SCT may offer substantial salvage rates to younger standard risk patients, thus adding value to the underlying concept of a risk-oriented first-line therapy.

Kurzfassung: Background. Mantle Cell Lymphoma (MCL)represents an aggressive lymphoma for which an effective treatment has still to be determined. The FIL-MCL0208 phase III trial (EudraCTNumber: 2009-012807-25) is exploring R-CHOP followed byi) high-dose cytarabine, autologous stem cell transplantation, and ii) randomization between lenalidomide maintenance vs observation (Cortelazzo et al, EHA 2015). We performed genome-wide DNA profiling to identify unbalanced copy number variations (CNVs) with a clinical significance in patients enrolled in the FIL-MCL0208 phase III trial. Patients and Methods. The study included untreated, advanced stage MCL patients ( 〈 65 years) enrolled into the MCL0208 trial. Clinical results of the first interim analysis (without random unblinding) have been already reported and are the basis of the present analysis: median follow-up of alive patients was 26 months, and at 2-years, 79% of patients were progression free and 91% alive (Cortelazzo et al EHA 2015). DNA profiling with the Illumina HumanOmni2.5 arrays was performed on 174 DNA samples derived from baseline bone marrow CD19+ purified tumor cells. Genomic profiles were segmented with the Fast First-derivative Segmentation Algorithm (Rinaldi et al, BJH 2013; Kwee et al, bioRxiv 2016). Recurrent CNVs were defined applying both the minimal common regions and the GISTIC algorithms (Lenz et al, PNAS 2008; Mermel et al, Genome Biol 2011). CNVs were integrated with somatic mutational data obtained for 8 genes recurrently affected in MCL (ATM, BIRC3, CCND1, KMT2D, TP53, TRAF2, WHSC1, NOTCH1) (Rossi et al, ASH 2015). Progression free survival (PFS) was the primary endpoint of the analysis. Results. 161 patients were currently evaluable for CNVs and clinical outcome. Patients had an intermediate/high-risk MIPI and a Ki67 ³ 30% in 43% and 42% of the cases, respectively. Twenty-five recurrent unbalanced CNVs were defined (Table 1). By multiple test corrected univariate analysis, seven CNVs had a negative impact on PFS: +3, 7p gain, 9p loss (CDKN2A), 17p loss (TP53), 8p loss, and 2 losses at 22q (Table 1). MIPI (intermediate/high vs low risk), Ki67+ and the TP53/KMT2D model (Rossi et al, ASH 2015) were also statistically significant. Combining CNVs and mutations, TP53 was inactivated in 27/147 cases (18%): mutated/deleted in 7/147 (5%), deleted but not mutated in 14/147 (10%), and mutated but not deleted in 6/147 (4%). The negative prognostic impact was equal for all the 3 inactivation modalities, which were then considered as a single group for further analyses. ATM was inactive in 69/147 (47%): mutated/deleted in 24/147 (16.3%), deleted in 12/147 (8%), and mutated in 33/147 (22.4%). KMT2D (MLL2) was inactive in 18/147 (12%): mutated/deleted in 1/147 ( 〈 1%), deleted in 1/147 ( 〈 1%), and mutated in 16/147 (11%). The lesions with a significant impact at univariate were included in a multivariate analysis alongside MIPI, KMT2D inactivation and Ki67+ as continuous variable. Only TP53 inactivation by deletion and/or mutation, 7p22.2-p12.1 gain and KMT2D inactivation maintained their independent prognostic significance. Conclusions. Genome wide DNA profiling in the FIL-MCL0208 phase III trial identified lesions, namely TP53 and KMT2D inactivation and gains at 7p, which maintain a poor outcome significance in young MCL patients even following high-dose cytarabine and autologous stem cell transplantation. Disclosures Rossi: Gilead: Honoraria, Research Funding; Abbvie: Honoraria; Janseen: Honoraria. Stelitano:Azienda Ospedaliera: Employment. Gaidano:Janssen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Morphosys: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria.