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Background Chronic Myeloid Leukemia (CML) is a clonal myeloproliferative disorder which molecular base is represented by the bcr-abl fusion gene, encoding for the constitutionally activated BCR-ABL tirosine-kinase. Three Tirosin-Kinase Inhibitors (TKI) are approved for first line treatment: Imatinib (IM) and the second generation (2G) TKI Nilotinib (NIL) and Dasatinib. 2G TKI are known to provide faster and deeper molecular responses (MR) compared to Imatinib, but serious toxicities may hamper long term treatment with these molecules. Furthermore, 2G TKI were usually employed as second line after IM failure, while the inverse sequence from second to first generation TKI (like an induction-maintenance model) has not been explored yet. We used this schedule in a small group of patients in the PhilosoPhi34 study (EudraCT: 2012-005062-34), a clinical trial designed by the REL (Rete Ematologica Lombarda) cooperative group. This study was composed by three consecutive phases: a Recruitment Phase, a Core Phase (CP) in which patients received NIL 300 mg BID for 12 month (mos), and an Observational Phase (OP), restricted for patients who obtained at least complete cytogenetic response at the end of the CP. During OP, treatment choice was up to the physician and any TKI approved for first line treatment could be used, including IM. In 2017 we presented preliminary data showing that a 12-mos-NIL treatment followed by IM appears as a safe and effective choice for first line therapy in chronic phase CML. Fluctuations in BCR/ABL ratio were similar between IM and NIL treated pts, and the probability of loss of MR4 or MR3 was the same in the two groups; furthermore, despite fluctuations, MR was maintained or improved over time in IM subgroup. Our purpose is to verify these data after 24 mos follow up (FU) at the end of OP. Methods We analyze PhilosoPhi34 database; MR is reported at 3, 6 and 12 mos during the CP and every 6 mos during the OP. The last pt completed the 24 mos of OP in June 2018. Database is still open, evaluations ongoing, and some data can be missing yet: our preliminary observations concern pts with available data of 24 mos OP. Results Seventy-nine pts started the OP. Fourteen pts switched to IM during the OP (Table 1) due to high cardiovascular risk or grade 1-2 chronic AEs . Only 11 pts started IM since the beginning of OP, and we consider these pts in our analysis. Sokal score was high in 2 pts (18%), intermediate in 5 (45.5%), low in 4 (36.5%). At the beginning of OP, 6 pts had a MR ≥ 4 (54.5%), 5 had MR3 (45.5%). At 12 mos of the OP, 7 had MR ≥ 4, 3 had MR3 and 1 had lost MR3 with PCR 0.192%IS (1/5, 20%). At 24 mos of the OP, 9 had MR ≥ 4 (81,8%), and 2 had MR3. Notably, none of pts lost MMR; 2/3 pts(66%) improved response from MR 3 to MR 4 and the pt who transiently lost MMR at 12 mos, recovered it at 24. Sixty-four pts maintained 2G TKI: 62 NIL, 2 other TKI (not considered for analysis). Of them, 4 were lost during this phase: 2 within the first year of OP, other 2 within 12 and 24 mos of OP. In the NIL group, Sokal score was high in 10 pts (16.6%), intermediate in 19 (31.6%) and low in 31 (51.6%). At the beginning of OP, 32 pts had MR ≥ 4 (51.6%), 21 had MR3 (33.8%) and 9 less than MR 3 (14.5%). Responses were improved over time: at 12 mos, 36 pts had MR ≥ 4 (60%), 20 had MR3 (33%) and 4 less than MR3 (6%). At 24 mos 46 pts had MR ≥ 4 (78%), 8 MR3 (13.5%) and 4 less than MR3 (8,5%), Among them, 1 pt experienced disease progression due to a mutation. In particular, during the second year of OP, 11 pts improved response from MR3 to MR ≥ 4(11/20, 55%). Discussion Our data show progressive MR improvement in both IM and NIL group. In particular, risk of loss of MMR is not increased in IM group. More data, more balanced groups and a longer FU are necessary to further confirmations, but after three years of FU, we consider this combination of NIL-followed-by-IM a possible strategy for first line treatment in chronic phase CML, in particular for pts with cardiovascular risk factors. Disclosures Rossi: Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria; BMS: Honoraria; Sandoz: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

Haploidentical hematopoietic stem cell transplantation provides an option for patients with advanced hematologic malignancies lacking a compatible donor. In this prospective phase 1/2 trial, we evaluated the role of reduced-intensity conditioning (RIC) followed by early add-backs of CD8-depleted donor lymphocyte infusions (DLIs). The RIC regimen consisted of thiotepa, fludarabine, cyclophosphamide, and 2 Gy total body irradiation. Twenty-eight patients with advanced lymphoproliferative diseases (n = 24) or acute myeloid leukemia (n = 4) were enrolled. Ex vivo and in vivo T-cell depletion was carried out by CD34+ cell selection and alemtuzumab treatment. The 2-year cumulative incidence of nonrelapse mortality was 26% and the 2-year overall survival (OS) was 44%, with a better outcome for patients with chemosensitive disease (OS, 75%). Overall, 54 CD8-depleted DLIs were administered to 23 patients (82%) at 3 different dose levels without loss of engraftment or acute toxicities. Overall, 6 of 23 patients (26%) developed grade II-IV graft-versus-host disease, mainly at dose level 2. In conclusion, our RIC regimen allowed a stable engraftment with a rather low nonrelapse mortality in poor-risk patients; OS is encouraging with some long-term remissions in lymphoid malignancies. CD8-depleted DLIs are feasible and promote the immune reconstitution.

Background: the Registro Italiano Trombocitemie (RIT) was activated mainly to evaluate the diagnosis and therapy appropriateness in the thrombocythemic patients with Ph-negative myeloproliferative neoplasm (MPN) observed in the adhering centers. Objective: to evaluate how the diagnostic and therapeutic approach changed in the RIT patients diagnosed with thrombocythemic MPN in the last two decades. Methods: the RIT centers registered by a web-based system during the years 2005-2014 their thrombocythemic MPN patients, and semesterly updated their follow-up data. For patients diagnosed before 2005, the data on diagnosis and prior follow-up were retrospectively collected. The diagnostic process and the initial treatment (started into the first year after diagnosis) were comparatively analyzed in the patients diagnosed before and after 2005. Results: the RIT centers registered 2629 patients. 2388 of them, object of this analysis, were diagnosed between1995 and 2014: 1098 (46%) in the decade 1995-2004 (Group I), and 1290 (54%) in the decade 2005-2014 (Group II). The diagnostic process in the patients of Group II and Group I included bone marrow biopsy (BMB, performed into 1 year and before any cytoreduction): 85% vs 80%, p The patients of Group II, as compared with those of Group I, showed a similar gender distribution (M/F ratio 0.61 vs 0.65, p 0.452), and had at diagnosis: a higher age (median 60 vs 57 years, p 60 years in 50% vs 45% of cases, p Moreover, they had: a lower platelet (PLT) count (median 737 vs 775 x 109/L, p 10 x 109/L in 28% vs 26% cases); a similar median levels of hematocrit (HCT %, in females 41.4 vs 41.0; in males 44.7 vs 44.6) and hemoglobin (Hb g/dL, in females 13.8 vs 13.6; in males 15.0 vs 14.9). The BMB, revised according to the WHO 2008 criteria, showed a not different distribution (p 0.21) of ET (64% vs 61%), ep-PMF (16% vs 17%), PMF (3% vs 2%), PV (4% vs 4%), and U-MPN (13% vs 16%. The JAK2 V617F mutation in patients of Group II (at diagnosis) and of Group I (after diagnosis) was found in 62% and in 58% of tested cases (p 0.054), respectively. The patients at high standard thrombotic risk were 58% vs 52%, p 0.004. In the patients of Group II and Group I the distribution of the treatment started into the first year was significantly different (p The treatment CYT ± AntiPLT was started in the patients at high standard thrombotic risk with a rate of 81% vs 80%, respectively, and in the patients at low standard thrombotic risk in 37% vs 43% of cases, respectively. The initial treatment CYT±AntiPLT was related, in multivariate analysis, both in patients of Group II and Group I, with older age (>60 and 40-60 vs 1000 and 700-1000 vs Conclusion: in the studied thrombocythemic MPN patients the real-life diagnostic approach was improved after 2005 not only due to the routine use of JAK2 tests, but also due to the higher rate of BMB done (85% vs 80%). The appropriateness of the cytoreductive treatment (CYT±AntiPLT started into one year from diagnosis) remained high in patients at high standard thrombotic risk (over 80% of cases were treated). Concomitantly, the inappropriate use of the cytoreductive drugs in patients at low standard thrombotic risk appreciably decreased (from 43% to 37% of cases). Moreover, it has to be remarked that the therapeutic approach was significantly influenced not only by older age and prior thrombosis, but also by thrombocytosis (PLT count >700 x 109/L), disease-related symptoms, and inconstantly by leukocytosis and CVRFs. Table Table. Disclosures Gugliotta: SHIRE Co.: Honoraria. Gugliotta:Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria.

Background: Second-line salvage chemotherapy(CT) followed by high-dose (HD) CT and autologous stem cells reinfusion (ASCT) is standard treatment forR/R HL patients, although long-term cure can be achieved in only half of them, depending on risk factors. Chemosensitivity to salvage CT before ASCT, mainly represented by a negative PET scan, is highly predictive of a favorable outcome. The availability of new markers of prognosis, like the measurement of the serum chemokineTARC, could help identifying those patients who may require further treatment, i.e. new drugs like Brentuximab Vedotin or Nivolumab or Pembrolizumab, before ASCT, in order to achieve a durable remission.Therefore we planned to prospectively evaluate the prognostic role of serum TARC levels collected at different time points in cHL R/R patients. Methods: Serum TARC levels were measured by commercially available ELISA test kits (R & D Systems, Minneapolis, USA) in 41 patients treated with IGEV (ifosfamide, gemcitabine, vinorelbine, prednisone) salvage CT, followed by myeloablative B(F)EAM (carmustine, (fotemustine), etoposide, cytosine arabinoside, melphalan) + ASCT at Istituto Nazionale Tumori of Milan, Italy, from January 2007 to December 2013. The 99th centile of TARC distribution in a group of 156 independent healthy subjects corresponding to 800 pg/mL, was considered as cut-off value discriminating between normal and abnormal TARC values. TARC evaluation was performed before starting salvage CT(T0), after the first IGEV cycle (T1) and before ASCT (T-preASCT). The Wilcoxon Mann Whitney test was used to analyze TARC as a function of patient and disease characteristics and PET results. Kaplan-Meyer curves and log-rank test were used to assess differences in PFS according to TARC levels. Cox model was used for multivariate analysis. Results: Main patient characteristics at relapse/progression were as follows: males/females: 19/22, median age: 31 years (range,19-69), B symptoms: 34%, bulky disease: 27%, stage III/IV: 39%, extra nodal involvement: 34%, refractory vs relapsed < 12 months vs relapsed ≥ 12 months: 49% vs 34% vs 17%. Median (IQ range) T0, T1 and T-preASCT were: 1856 (8801-9983) pg/mL, 1148 (544-2532) pg/mL and 829 (454-1725) pg/mL, respectively. Patients with bulky disease had higher median T0 than their counterpart (3241 vs 1462 pg/mL; p=.016). Median T-preASCT was significantly higher in patients with refractory disease compared to relapse < or ≥ 12 months (1100 vs 595, vs 548 pg/mL, p=.027). A positive PET was recorded in 57.5% of patients after 2 IGEV cycles and in 32% before ASCT. Forty-one percent of patients needed ≥ 2 salvage CT before ASCT and 63% had ≥ 2 risk factors. At each time point, median TARC values were significantly higher in PET-2 positive patients compared to their counterpart (T0: 3238 vs 1310; T1: 1866 vs 624; T-preASCT: 908 vs 544; pg/mL). Median (IQ range)T-preASCT levels were significantly higher in patients with a positive PET before ASCT:1091 (596-10578) pg/mL compared to those with a negative one: 651 (447-964) pg/mL. After a median follow-up of 65 months, 5-year PFS and OS (95% CI) were 70 (57-88)% and 84 (72-98)%, respectively. In univariate analysis T-preASCT > 2000 pg/mL, PET-2, PET-preASCT, ≥ 2 risk factors and ≥ 2 salvage CT lines significantly affected PFS. In multivariate analysis only T-preASCT > 2000 pg/mL was significantly associated with a poor PFS (HR 6.65, CI95% 1.12-39.35, p=0.036) as shown in Figure 1. Conclusions: Results of this single institution prospective study suggest that a cheap and easy to perform test, like serum TARC levels measurement before ASCT, may help to ameliorate the identification of those patients at risk of failing ASCT, for whom anticipated use of new active drugs, like anti-CD30 immunoconjugates and/or anti-PD1 blockers, should be explored, in order to improve the cure rate of ASCT. Figure 1 PFS according to TARC levels Figure 1. PFS according to TARC levels Disclosures No relevant conflicts of interest to declare.

Background CML is a clonal disorder characterized by the presence of the Philadelphia (Ph) chromosome which encodes for the bcr-abl tyrosine-kinase (TK). Target therapy with the TK inhibitors (TKIs)) has greatly improved its outcome. Treatment with second generation TKIs - e.g. nilotinib (NIL) - results in deeper and faster responses and prevents disease progression. Sustained responses may enable TKI discontinuation. However, even in the event of qPCR negativity, a fraction of patients (pts) experience disease recurrence possibly due to persistence of quiescent leukemic stem cells (LSCs). Degree and mechanisms of LSCs clearance during TKI treatment are not established yet and conflicting results are reported in the literature. Work from the group of Bocchia (Bocchia 2008; Defina 2012) showed reduction of LSCs during long term imatinib (IM) therapy; moreover, in CCyR pts residual LSCs are more rarely detected after NIL compared to IM therapy and, in a small fraction of pts this occurs after very short-term NIL therapy. This data conflicts with in vitro evidence that NIL is not superior to IM in inducing growth suppression in CML LSCs (Konig, 2008). To verify the in vivo activity and time-course of first-line NIL therapy on bone marrow (BM) Ph+ stem cells (CD34+/lin-) clearance, on behalf of the Rete Ematologica Lombarda (REL) the PhilosoPhi34 study (EudraCT: 2012-005062-34) was designed. Primary efficacy endpoint was to measure the rate of BM residual CD34+/lin-Ph+ cells in CCyR pts at 6 months of treatment. Methods BM cells were collected and stored at diagnosis and at 3,6 and 12 mos of treatment. CD34+/lin- cells were purified using a Diamond CD34 Isolation Kit Miltenyi (97% of purity). FISH analysis of selected unstimulated CD34+/lin- cells was performed according to standard procedures; considering the low sensitivity of the test, in order to define the test as negative at least 200 nuclei were examined. The A'Hern single stage design was chosen for the present study; considering the CCyR results obtained in the ENESTnd study and the anticipated number of un-evaluable tests, a minimun of 87 pts were required. Results Enrolment of the 87 pts was completed by June 2015. Table 1 summarises pts' characteristics and response to treatment. FISH results are as follows: at 3 mos, 8/65 (12,3%; CI 95%: 2,3%-15,7%) evaluable FISH tested positive (10 negative tests not evaluable); at 6 mos 5/71 (7%; CI 95% :2,3-15,7%) evaluable FISH tested positive (7 negative tests not evaluable); at 12 mos, 0/68 (0%; CI95%:0,0-5,2%) evaluable FISH tested positive (9 negative tests not evaluable). At any time point, Sokal score did not predict for FISH results. However, as outlined in Table 2, H-Sokal score pts are less prevalent among pts who achieve a CCyR, a requirement for FISH analysis. Of the 4 pts who failed the treatments' objectives by 12 mos, 1 was in CCyR with detectable residual CD34+/lin-Ph+ cells at 3 mos; 2 were not in CCyR and with residual CD34+/lin-Ph+ cells at 3mos; 1 was in CCyR and with CD34+/lin-Ph- cells at 3 and 6 mos but with increasing qPCR. Only 1 pt with CD34+/lin-Ph- cells at all time points and with optimal molecular response harboured a NIL-resistant mutation at 26 mos of treatment. None of the 22 pts (including 4 H-Sokal score pts = equal proportion of study cohort) in Molecular Response (MR) 3.0 at 3 mos had a positive FISH at 3 and 6 mos or failed treatment at follow-up. Conclusion. Our final results on the whole cohort of pts confirm our preliminary data on the efficacy of NIL 300 g BID in early clearance of BM LSCs (CD34+/lin-Ph+) in newly diagnosed CP-CML patients tested at 3, 6 and 12 mos of treatment. Moreover, according to our data, fast disease debulking seems crucial for obtaining BM LSCs clearance and it can be speculated that the same mechanism responsible for this early MR 3.0 achievement is also capable of preventing H-Sokal risk pts from failing treatment. Disclosures Orlandi: Ariad: Honoraria; BMS: Honoraria; Novartis: Honoraria.

Mantle cell lymphoma (MCL) is a rare and aggressive subtype of non-Hodgkin Lymphoma. Although a typical presentation as an indolent lymphoma, without systemic symptoms and with a good performance status, the mantle cell lymphoma is an aggressive one, hardly curable with standard chemo-immunotherapy. Although current approaches to mantle cell lymphoma, including newer agents (such as bortezomib, lenalidomide, temsirolimus and ibrutinib) and autologous stem cell transplantation, have greatly improved the outcomes of affected patients, this disease is still characterized by high relapse rates, with most patients eventually dying of lymphoma progression. Before official approval by EMA, patients with relapsed/refractory mantle cell lymphoma with unsatisfied critical medical urgency were granted ibrutinib early access through a Named Patient Program in Italy (NPP, DM 8 May 2003). This observational, non-interventional, retrospective, multicenter study focuses on collecting information about the effectiveness and safety of ibrutinib as single-agent in patients who received at least one dose of ibrutinib under the NPP in the period between 29/Jul/2014 and 25/Jan/2015 in Italy. Data from patients treated with ibrutinib outside a controlled clinical trial within a NPP could give additional information about the clinical use, treatment duration, efficacy and toxicity of ibrutinib given to relapsed or refractory MCL patients in a real life context. Fifty-three heavily pretreated patients were enrolled. They had received a median of previous therapies of 3, comprising lenalidomide, bortezomib, temsirolimus and autologous stem transplant. Ninety-one percent had measurable disease and 83.0% had and ECOG performance status ≤2. At the end of therapy there were 11 complete responses (20.8%), 7 partial responses, 5 stable diseases and 30 progressions with an overall response rate of 33.9%. Twenty-six patients received ≥3 concomitant medications during ibrutinib therapy. At 20 months overall survival (OS) was 26.8% (median reached at 9 months) and disease free survival (DFS) 75% at 15 months: 10/11 patients are in continuous complete response with a median of 10.5 months. Hematological toxicities were manageable, 6 thrombocytopenia occurred, of which only 2 grade 4 (due to disease bone marrow infiltration) and the other 4 related to ibrutinib. Main extra-hematological toxicities were diarrhea (9.4%) and lung infections (7.5%) which all lead to early drug discontinuation. The observed occurrence of diarrhea by severity was 0 for CTCAE Grade 1, 4 for Grade 2, 2 for Grade 3 and 0 for Grade 4. Lung infection had a lower occurrence: 0, 2, 2 and 0 split by CTCAE Grade 1, 2, 3 and 4 respectively. There is a boundary zone in the passage from phase III to phase IV trials, i.e. from experimental to marketing and free use phases: in this zone we can find NPP and compassionate and off-label use. Despite the known potential bias of all the observational retrospective studies, reports on the real life experience make an important contribution to medical knowledge prior to widespread utilization: ibrutinib therapy is effective and tolerable also in a clinical setting mimicking the real world. Our results, in fact, are superimposable to those obtained in clinical trials: for safety, thrombocytopenia, diarrhea and lung infections are the relevant adverse events to be clinically focused on; for effectiveness, ibrutinib is confirmed to be a valid option for refractory/relapsed MCL. Disclosures Cascavilla: Janssen-Cilag: Honoraria. Zinzani:Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celegene: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees.

Background Allogeneic SCT remains the only curative option in myelodysplastic syndromes (MDS). We prospectively evaluated in a multicenter phase 2 GITMO (Italian Bone Marrow Transplantation Group) trial, the feasibility of allogeneic stem cell transplantation (ASCT, primary protocol end-point) after induction treatment with azacitidine (Vidaza, Celgene). According to the protocol, patients had to perform at least 4 and up to 12 cycles of azacitidine as induction treatment before ASCT. Patients not eligible for ASCT could continue treatment until disease progression. Methods Between November 2010 and September 2014, 102 patients were enrolled by 20 Italian hematology centers. Nine patients never started treatment due to progressive disease (PD, n=2), refusal (n=3), or unknown causes (n=4). Of remaining 93 patients, 70 had with IPSS Int-2/High-risk MDS, 15 WHO-defined acute myeloid leukemia (AML) and 8 chronic myelomonocytic leukemia (CMML). There were 32 females and 61 males with median age 59 yrs (range 21-66.5 yrs). At treatment start, ECOG performance status was: 0 in 66 patients, 1 in 17 and 2 in 10 patients, while MDS HCT-index was: low (0) in 43 patients, intermediate (1-2) in 31 and high (>2) in 18 patients. All 93 patients started azacitidine s.c. at the standard dose of 75 mg/sqm/day, 7 days/month, at a median of 0.8 months (range 0-105 months) from initial MDS diagnosis. Results At response assessment after a median of 4.5 cycles (range 1-11), 25% of patients (n=19) achieved complete remission (CR), 3% marrow-CR (n=2), 14% partial remission (PR, n=11), 9% hematologic improvement (HI, n=7), 35% had stable disease (SD, n=27) and 14% PD (n=11). ASCT was performed in 48 patients (52%), after a median of 4.5 azacitidine cycles (range: 1-11). Data on ASCT are presently available for 45 patients, transplanted with bone marrow (n=10 pts) or peripheral blood stem cells (n=35 pts) from an HLA-identical donor (sibling in 11, and MUD in 34 cases). Forty-five patients did not receive ASCT due to: disease relapse or progression (n=16, 35%), adverse events (n=12, 27%), refusal (n=5, 11%), or other causes (n=12, 27%). At a median follow-up of 18.5 months (range 0.2-31.5), 43 patients are alive (25 received ASCT), and 50 patients died. Causes of death are reported in Table 1. Median overall survival (OS) for the whole patient cohort was 13.4 months (95% CI: 10.9-18.6, Figure 1). Disease status after azacitidine was predictive of significantly improved survival for patients in CR/PR/HI, compared to SD or PD (n=77 patients who completed at least 4 cycles, Figure 2). ASCT considered as time-dependent covariate was associated to a significantly longer survival (p=0.008, HR 0.4, 95% CI: 0.2-0.8). Stratification of MDS according to IPSS and karyotype was not associated to survival. Conclusions Our study shows that allogeneic transplantation following azacitidine is feasible in HR-MDS/CMML and AML, with about 50% of patients being able to undergo HSCT. These data favourably compare with previous studies in MDS on ASCT preceded by conventional chemotherapy. Disease status at the time of HSCT confirms its significant prognostic role for survival, also in the context of hypomethylating treatment, where stabilization of disease also represents a therapeutic target. Disease relapse or progression remain the major causes of death indicating the need for other strategies aimed at improving disease control in MDS. Figure 1. Overall survival (n=93 pts) Figure 1. Overall survival (n=93 pts) Figure 2. Survival according to disease status at response assessment after a median of 4.5 azacitidine cycles (n=77 evaluable pts) Figure 2. Survival according to disease status at response assessment after a median of 4.5 azacitidine cycles (n=77 evaluable pts) Disclosures Voso: Celgene: Honoraria, Research Funding. Off Label Use: Azacitidine used as induction treatment before allogeneic stem cell transplantation in MDS. Finelli:Janssen: Other: Speaker; Novartis: Other: Speaker; Celgene: Other: Speaker, Research Funding.

Introduction. Relapsed and primary refractory peripheral T-cell lymphomas (PTCL) show a dismal outcome, with a 5-year overall survival of only 30%. There is no standard salvage chemotherapy for these patients. Gemcitabine was proved to be an effective monotherapy, yelding 60-70% overall response rates in patients with advanced heavily pre-treated disease. Romidepsin, a histone deacetylase inhibitor recently approved by Food and Drug Administration, has demonstrate an overall response rate (ORR) of 30% and a complete response (CR) rate of 16%. We have recently designed a multicentric trial to investigate the role of the combination of gemcitabine plus romidepsin (GEMRO regimen) in relapsed or refractory PTCL, looking for a potential synergistic effect of the two drugs. Methods. Twenty relapsed/refractory PTCL patients were included in a multicentric, prospective phase II trial which contemplated an induction with romidepsin 12 mg/m2 intravenously (i.v.) on days 1, 8, 15, and gemcitabine, 800 mg/m2 i.v. on day 1 and 15, for 6 cycles, each cycle to be repeated every 28 days. After the induction phase, patient who obtained at least a partial remission (PR) proceeded onto romidepsin maintenance at the dose of 14 mg/m2 i.v. until disease progression. The primary endpoint was to evaluate the efficacy of GEMRO regimen after the induction phase, as assessed by complete response (CR) rate; safety assessment was regarded as a secondary objective. The trial was registered under EudraCT (2012-001404-38). Results. Twenty patients have been recruited for this study. At present time, all patients underwent the induction phase and are evaluable for response and toxicity. The median age of patients was 55 years (range, 24-77). According to histology, 10 patients had PTCL not otherwise specified, 9 had an angioimmunoblastic T-cell lymphoma, 1 had a kinase negative anaplastic large cell lymphoma. The median number of prior therapies was 2 (range, 1-4); 7/20 (35%) patients had failed a prior stem cell transplant. Nineteen out of 20 (95%) patients presented with advanced stage. At the end of induction phase, the ORR was 31% including 2 CRs and 3 PRs. One of the 2 CR patients discontinued the treatment after 4 cycles due to cardiac toxicity, however maintaining a continuous CR with a follow up of 2 years. The other CR patient is still on treatment in maintenance phase. Grade ≥3 adverse events were represented by thrombocytopenia (60%), neutropenia (50%), and anemia (20%). Conclusions. To date, data failed to show a superiority of the GEMRO combination regimen over single agent romidepsin as salvage therapy for refractory or relapsed PTCL patients. More mature data and an adequate follow-up will be required to better understand the role of this combination regimen. Disclosures Zinzani: Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; J&J: 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, Speakers Bureau.

The present study retrospectively analyzed a cohort of consecutive relapsed/refractory Hodgkin lymphoma (RR-HL) patients receiving allogeneic stem cell transplantation (alloSCT) in a single center with a thiotepa-based conditioning to understand whether the timing of relapse after autologous stem cell transplant (ASCT) or the primary refractory disease would change the survival. Of 247 patients with HL referred to our division from 2001 to 2014, 109 had RR-HL (64 primary refractory). After receiving salvage treatment, 62 patients (57%) underwent alloSCT with a thiotepa-based conditioning; 4 patients (4%) received fludarabine-melphalan conditioning in a phase II study, 43 patients (39%) did not receive alloSCT for progressive disease (31), advanced age (>65 years, 3 patients) or for achieving a complete response after a third-line chemotherapy consolidated by ASCT (9). This study analyzes the outcomes of the 62 consecutive patients allografted with thiotepa-based conditioning, which consisted of thiotepa, fludarabine, and cyclophosphamide (TFC) for patients with an HLA identical sibling donor, TFC plus anti-thymocyte globulin for matched unrelated (MUD) donors, TFC plus alemtuzumab and 2-Gray (Gy) total body irradiation (TBI) for T-deplete haploidentical alloSCT, or TFC plus 2-Gy TBI and post-transplant cyclophosphamide for T-replete haploidentical alloSCT. Multivariate analysis of alloSCT outcomes included as covariates the pre-transplant disease status (CR vs PR vs resistant), donor (HLA identical, MUD, or T-deplete or T-replete haploidentical), primary refractory disease (yes vs no) and timing of relapse after ASCT (12 mos vs no ASCT). Patients had a median of 33 years at alloSCT, 76% of them had a primary refractory disease at diagnosis. 74% of patients relapsed 12 months after ASCT, 11% underwent alloSCT without previous ASCT. At alloSCT, 25% had resistant disease whereas 75% were in partial (31%) or complete response (44%) after the last salvage treatment. Donors were HLA identical siblings (42%), MUD (29%), or haploidentical (21% T-deplete, 8% T-replete). Median follow-up was 5.4 years. Three- and 5-years OS was 61 and 59%, PFS and relapse incidence were 46% and 38% at both 3 and 5 years. Non-relapse mortality (NRM) was 10% at 100 days, 17% at 1 year and for the entire follow-up. In multivariate analysis, the timing of relapse after ASCT and primary refractory disease did not impact the transplant outcomes. OS was reduced by resistant disease at alloSCT (HR=4.01, CI95% 1.34-11.97, p=0.012) and by T-depleted haploidentical transplant (HR=3.81, CI 95% 1.36-10.66, p=0.010). PFS and relapse incidence were impacted only by resistant disease (HR=5.54, CI 95% 2.13-14.37, p In conclusion, the pre-transplant disease status and not the timing of relapse after ASCT or primary refractory disease, impacts OS, PFS and relapse of RR-HL patients allografted with thiotepa-based conditioning. An optimal response before alloSCT is critical to maximize the long-term benefit of alloSCT. In the era of novel agents this can be a realistic goal for the majority of patients. Disclosures Viviani: Takeda Italia SpA: Consultancy; Teva Italia SpA: Consultancy; Italfarmaco SpA: Consultancy; Takeda International: Consultancy.

Introduction: Despite novel therapies are under investigation in peripheral T-cell lymphomas (PTCL), the majority of the patients (pts) still have a dismal outcome. AlloSCT seems an effective approach in the salvage setting, but very small series of pts have been transplanted at diagnosis. Methods: We report the long-term outcome (median follow-up of 60 months) of 72 pts affected by PTCL who underwent AlloSCT at diagnosis (Allo1) (n=23) or for chemosensitive relapse (Allo2) (n=49) that have been enrolled in two transplantation protocols. Pathological classification included: 20 PTCL-not otherwise specified (PTCL-NOS), 2 anaplastic large cell lymphoma (ALCL) and 1 rare subtype in Allo1 group; 18 PTCL-NOS, 11 ALCL, 8 AILD and12 rare subtypes in Allo2 group. Donor sources were HLA-matched siblings [n=39: n=13 Allo1 and n=26 Allo2 (p=0.80)], matched or mismatched unrelated donors [n=25: n=10 Allo1 and n=15 Allo2 (p=0.30], and haploidentical family donors [n=8, only in the Allo2 group]. All pts underwent transplant with chemosensitive disease: 45 in complete remission (CR) (63%) [n=20 Allo1, n=25 Allo2 (p=0.003)]; 27 in partial remission (PR) (37%) [n=3 Allo1, n=24 Allo2 (p=0.003)]. In the Allo2 group, 37 pts (75%) were allografted in first relapse and 12 in second relapse. Results: In the Allo1 group, at a median follow-up of 59 months, of the 23 pts 15 (65%) are alive in CR, 4 (17%) died for progressive disease (PD), 3 for non-relapse mortality (NRM, 13%) and 1 for myocardial infarction. In the Allo2 group, at a median follow-up of 64 months, of the 49 pts 31 (63%) are alive (29 in CR), 11 (22%) died for PD and 6 (12%) for NRM while 1 for a second cancer. Five years crude cumulative incidence of relapse was 18% and 38% in Allo1 and Allo2 group (p=0.11), respectively. Five-year relapse-free survival (RFS), progressive-free-survival (PFS), and overall-survival (OS) were as follows: 80%, 60% and 62%, respectively, in Allo1 group; 61%, 47%and 59%, respectively, in Allo2 group without any statistical difference. However, we observed a significant difference in PFS between pts allografted at diagnosis and those in second-relapse (5-year PFS 61% versus 16%, p=0.0044) but not between the allografted at diagnosis and first-relapse (5-year PFS 61% versus 57%, p=0.92). When analyzed pts affected by PTCL-NOS, a better PFS trend was confirmed in pts receiving allograft at diagnosis or in first relapse as compared to second relapse [5-year PFS: 65% versus 55% versus 25%, respectively, (p=0.2)]. Pts who went to alloSCT in first CR did not have a significant advantage [5-year PFS and OS: 59% versus 43% (p=0.44); 60% versus 58% (p=0.82) in Allo1 and Allo2 group, respectively]. Conclusions: Despite the limitations due to the sample size, this is the first analysis in this setting. AlloSCT should be not indicated as a consolidation of first complete or partial remission approach/treatment outside a clinical trial. In fact, AlloSCT is very effective in patients with chemosensitive first relapse. Disclosures No relevant conflicts of interest to declare.

Introduction Allogeneic stem cell transplantation (alloSCT) is an effective salvage therapy for relapsed B-cell lymphomas. Different studies have shown that Rituximab (R) is implicated in the pathophysiology of acute and chronic GVHD. Methods: We analyzed 153 adult patients who received alloSCT for relapsed/refractory B-cell lymphomas. All patients received the same preparative conditioning consisting of thiotepa/cyclophosphamide/fludarabine, and GVHD prophylaxis consisting in cyclosporine and short course methotrexate. ATG (7 mg/kg) was added to patients allografted from class I antigen mismatched sibling or unrelated donors. Eighty-two patients (group A) received high-dose Rituximab (R 500 mg/ms on day -6) and were enrolled in a prospective multicenter study, whereas 71 consecutive patients (group B, control group) were part of a previous study without R. The two groups were not significantly different in terms of diagnosis (p=0.10), donor types (p=0.74), rate of complete remission at transplant (p=0.51). Results: The cumulative incidence (CI) of non-relapse mortality (NRM) at 2-years was 16% in group A and 18% in group B (p=0.84). Main cause of death were infections without GVHD in group A (7/13) and extensive GVHD in group B (6/14). Deaths associated to acute or chronic GVHD were significantly lower in group A (5 of 13) as compared to group B (13 of 14) (p=0.004). The CI of grade II-IV and III-IV acute GVHD was 23% versus 35% (p=0.11) and 7% versus 14% (p=0.11) in group A versus B, respectively. The CI of chronic GVHD was 48% versus 47% (p=0.73) in group A versus group B, respectively. The CI of acute GVHD and chronic GVHD in unrelated recipients was 20% versus 31% (p=0.41) and 32% versus 40% (p=0.83) in patients who received R in the conditioning comparing to group B. A delayed immune reconstitution of B-cells was still evident at 2 years after alloSCT in group A versus B [median value CD19+: 126/µL versus 300/µL with a significant higher percent of IgD+CD27- in group A and reduced immunoglobulin production: 502 versus 778 mg/dL of IgG (p=0.04)]. Progression free survival (PFS) and overall survival (OS) at 3-years were similar in group A and group B [PFS: 54% versus 58% (p=0.50); OS: 64% versus 67% (p=0.51)]. PFS at 3-years in indolent and aggressive lymphomas was 66% versus 75% and 42% versus 43% with and without R; OS at 3-years in indolent and aggressive lymphomas was 74% versus 78% and 55% versus 57% with and without R. In multivariate analysis, acute GVHD, extensive chronic GVHD and aggressive hystotype were associated to a lower OS [HR=3.6, p=0.0003; HR=2.3,p=0.03;HR=2.1,p=0.01] and only acute GVHD and aggressive hystotype to lower PFS [HR=2.7, p=0.002; HR=2.3, p=0.001]. Rituximab in the conditioning regimen, year of transplant and donor type did not influence the outcome. Conclusions: Rituximab administration in the setting of alloSCT is associated with reduced GVHD-related deaths and increased infection-related deaths, likely due to delayed B-cell immune-reconstitution. Disclosures: No relevant conflicts of interest to declare.

Abstract 1960 Introduction. Lenalidomide (Len) is a highly effective drug against multiple myeloma (MM). It acts through several mechanisms, such as a direct cytotoxic effect, anti-angiogenesis, microenvironment modifications, and immunomodulation. The latter property is particularly interesting in the setting of allogeneic stem cell transplantation (AlloSCT), since Len may interact favourably with the graft-versus-myeloma (GVM) effect. On the other side, the possibility of an over activation of the donor immune system raises some concerns about the safety of this treatment. In order to verify if Len is more effective when given after AlloSCT, we conducted among 7 Italian transplant centers a case-matched analysis comparing Len after autologous SCT (AutoSCT) vs. Len after AlloSCT. The hypothesis is that Len is more active when administered after AlloSCT. A secondary end-point of the study was the safety profile. Methods and results. In this retrospective study, the main matching criterion was represented by the number of treatment lines received before Len. In an attempt to uniform the treatment regimens, an intra-center matching was carried out. We collected data from 40 patients in each group. Baseline characteristics between Auto and Allo patients (pts) were similar, except for age at diagnosis (55 years, range 39–70, in Auto pts; 47 years, range 29 – 62, in Allo pts). The median number of previous lines of treatment was 3 (range 1–6) for both groups. Thirty-one (77%) Auto and 36 (90%) Allo pts received bortezomib. Similarly, 35 (87%) Auto and 21 (52%) Allo pts were previously treated with thalidomide. Twenty-one out of 40 (52%) Allo pts received SCT as a second or subsequent line of therapy. Before Len treatment, 14 (35%) Allo pts had acute graft-versus-host disease (aGVHD) (G1, 3 pts; G2, 8 pts; G3, 2 pts; G4, 1 pts), and 15 (37%) pts had chronic GVHD (cGVHD) (limited, 6 pts; extensive 9 pts). Median time between diagnosis and Len start was 65 months (range 14–162) in Auto, and 72 months(range 19–246) in Allo pts. Median time from transplant to Len start was 50 months (range 7–159) in Auto, and 21 months (range 6–134) in Allo pts. In all cases Len dosage was 25 mg, and it was combined with high or intermediate dose dexamethasone. Best responses for Auto and Allo patients were as follows: 5 vs. 3 CR, 6 vs. 8 VGPR, 12 vs. 13 PR, 9 vs. 8 SD, 8 vs. 8 PD. Time from Len start to the best response was 4 months for both groups. With a median follow-up from Len start of 22 months (range 2–60+), 3-years progression-free survival (PFS) was 13% in the Auto, and 43% in the Allo group (p=0.03). Median PFS was 9 months in Auto, and 16 months in Allo pts. Median OS was 22 months in the Auto group, and was not reached in the Allo group (p=0.05). Hematological toxicities were similar among the 2 groups. Neutropenia was observed in 16 (40%) patients in both the Auto and Allo group, thrombocytopenia in 10 (25%) Auto and 8 (20%) Allo pts, and anemia in 5 (12%) Auto and 2 (5%) Allo pts. Non-hematological toxicities were mild in both groups. In the Allo group one patients developed aGVHD after donor lymphocyte infusion, and 3 pts had a worsening of a pre-existing extensive cGVHD. Conclusions. The comparison between Auto and Allo pts has shown a benefit in terms of PFS and OS in the Allo group. This observation supports the hypothesis that Len may be synergic with the GVM effect. Interestingly, despite the same response rate between the 2 groups, clinical responses in Allo pts were more durable, reinforcing the hypothesis of the immunological control. On the other side, since Len has a potent immunomodulatory effect, this can raise concerns about its use after AlloSCT. The Dutch HOVON 76 trial has shown that the early administration of Len 10 mg after AlloSCT induces aGVHD in a substantial proportion of patients, causing unacceptable toxicity and the premature discontinuation of the study. However, in our retrospective study the median time between AlloSCT and Len administration was 21 months, and we did not observed any increase of GVHD. This suggests that the mechanisms of immune tolerance can mitigate the activation induced by Len, allowing a safe administration. Moreover, since in all cases dexamethasone was given with Len, its immunosuppressive effects may have harnessed the Len-induced immune activation, contributing to the treatment tolerability. In conclusion our case-matched study suggests that Len is more active when given after AlloSCT, still retaining a favorable toxicity profile. Disclosures: No relevant conflicts of interest to declare.

Abstract 1996 Introduction. Lenalidomide (Len) is a highly effective drug against multiple myeloma (MM). It acts through several mechanisms, such as a direct cytotoxic effect, anti-angiogenesis, microenvironment modifications, and immunomodulation. The latter property is particularly interesting in the allogeneic hematopoietic stem cell transplantation (Allo-HSCT) setting, since Len may interact favourably with the graft-versus-myeloma (GVM) effect. Preliminary results from retrospective studies on heterogeneous patient populations have suggested that Len is more effective when given after Allo-HSCT. In order to verify this observation, we have conducted a case-matched analysis comparing Len after autologous stem cell transplantation (Auto-HSCT) vs. Len after Allo-HSCT. The hypothesis is that Len may be more potent when administered after Allo-HSCT. Methods and results. In this retrospective study the matching criteria was represented by the number of treatment lines received before Len. In an attempt to uniform the treatment regimens, an intra-centre matching was recommended. To April 2011 we collected data from 39 patients in each group. Baseline characteristics between Auto and Allo patients were similar, except for age at diagnosis (53 years, range 39–70, in Auto patients; 47 years, range 29 – 61, in Allo patients). The median number of previous lines of treatment was 3 (range 1–6 ) for both groups. Twenty-one out 39 (54%) Allo patients received Allo-HSCT as second or subsequent line of therapy. Thirty-two (82%) Auto and 35 (90%) Allo patients received bortezomib in previous lines. Similarly, 34 (87%) Auto and 12 (54%) Allo patients were previously treated with thalidomide. Len was always combined with dexamethasone. Median time between Auto-HSCT and Len start was 38 months (range 7–159), and for Allo-HSCT 29 months (range 4–215). Best responses were for Auto and Allo patients as follows: 5 vs. 4 CR, 6 vs. 8 VGPR, 11 vs. 12 PR, 6 vs. 8 SD, 11 vs. 7 PD. Time from Len start to the best response was 4 months for both groups. With a median follow-up of 11.5 months (range 1–39), 1 year and 2 year progression-free survival were 41% and 6% for Auto patients, and 52% and 44% for Allo patients (p=0.03), respectively. Two years overall survival was 48% for Auto and 75% for Allo patients (p=0.03). Similar results were observed regardless of previous thalidomide treatment. No unexpected toxicities were reported. Two (10%) patients had worsening of a pre-existent extensive chronic GVHD. Discussion and Conclusion. The comparison between Auto and Allo patients has shown a benefit in terms of PFS and OS in favor of Len administered after AlloHSCT. This observation supports the hypothesis that Len is synergistic with the GVM effect. Since Len has a potent immunomodulatory effect, this can raise concerns about its use after AlloHSCT. A Dutch prospective study showed that the early administration of Len 10 mg daily after non-myeloablative Allo-HSCT induces late onset acute GVHD in a substantial proportion of patients, causing the premature discontinuation of the study. On the contrary, our retrospective study has shown that a later administration is feasible and safe, without an excess of GVHD, suggesting that a more mature immune system can better tolerate Len. Moreover, since in all cases dexamethasone was given in combination with Len, its immunosuppressive effect may have harnessed the Len-induced immune activation. In conclusion our study suggests that Len is particularly active after AlloHSCT, still retaining a favorable toxicity profile. Disclosures: No relevant conflicts of interest to declare.

Abstract 828 Introduction: Patients with multiple myeloma (MM) relapsing or progressing after allogeneic stem cell transplantation (alloSCT) have limited therapeutic options. Donor lymphocyte infusions (DLI) are used to exploit the graft-versus-myeloma effect, and pilot studies have shown that cytoreduction before DLIs could increase their efficacy. These patients are often chemo-refractory or frail, so the new drugs are an attractive option in this setting. Based on experimental and pilot studies showing the high efficacy of bortezomib in alloSCT relapse of MM, we designed a prospective multicenter study to treat these patients with 3 cycles of bortezomib-dexamethasone (VD) followed by escalating doses of DLIs (VD-DLI). The primary objective was the efficacy in terms of response as defined by IMWG criteria. Secondary objectives were to assess the incidence of GVHD, the incidence of graft failure, the progression free survival (PFS), the overall survival (OS), and the safety. Methods: Patients with relapsing or progressive MM after alloSCT were enrolled. Treatment consisted of three 21-day cycles with bortezomib 1.3mg/sqm/day iv at days 1, 4, 8, 11, and oral dexamethasone 20mg/day at days 1–2, 4–5, 8–9, 11–12, followed by 4 DLIs at escalating cell doses administered every 6 weeks. The DLIs started from 5×10^6 CD3+/kg cell dose for HLA-identical sibling donors, or 5×10^5 CD3+/kg for mismatched siblings, matched unrelated (MUD), or haploidentical donors. For every patient, the cell dose was escalated by 0.5 Log at each DLI until a maximum of 1×10^8 CD3+/kg and 1×10^7 CD3+/kg dose at the fourth DLI for HLA identical and alternative donors, respectively. DLIs were stopped anytime in case of acute GVHD, or if patients achieved >=CR after at least 2 DLIs. A safety interim analysis was run after the enrollment of the first 10 patients. Here we presented the final analysis of the study. Results: Nineteen patients were enrolled at 4 Italian transplant centers between 2007 and 2010. Sixteen patients had ISS stage I MM, two had ISS stage II, and one had ISS stage III MM. FISH data were not available. Median patients' age was 58 years (range, 34–68 years), 8 patients were female. Patients had been treated with a median of 2 lines of therapy (range, 2–5 lines): all the patients had received at least one autologous transplant, 10 had received thalidomide, 4 patients had received bortezomib and none of them was bortezomib-refractory. Two patients had grade (G) 1 peripheral neuropathy (PN) owing to previous treatments. Fifteen alloSCT donors were HLA identical siblings, 3 were MUD and one was haploidentical. One patient received one VD, one 2 VD, and 17 patients all the 3 planned VD. Two patients received one DLI, 1 patient 2 DLIs, 6 patients 3 DLIs, and 8 patients 4 DLIs. The median follow-up of the 15 (79%) surviving patients is 22 months (range, 12.5–55 months). Overall response rate (ORR) to VD was 63%: 3 patients achieved PR, 7 patients VGPR, 1 patient CR and 1 sCR; patients with SD were 5. The 17 patients receiving VD and DLIs had a 71% ORR, with 1 patient achieving PR, 7 patients achieving VGPR, 2 patients CR and 2 sCR; disease was stable in 4 patients. Twelve patients (63%) eventually progressed at a median time of 8.7 months (range, 1–22 months). Progression-free survival was 47% at one year and 33% at both 2 and 3 years of follow-up (median PFS, 12 months). Overall survival was 90% at 1 year and 79% at both 2 and 3 years of follow-up (median not reached). The incidence of aGVHD was 18% (3 patients: 2 had grade 1 and one grade 2). Five patients (29%) had limited cGVHD, none had extensive cGVHD. None of the patients experienced graft failure. During VD, 2 patients experienced G2 hematologic toxicity (thrombocytopenia). PN occurred in 5 patients (26%): 4 patients had G2 PN, and one patient had G3 PN. Other extra-hematologic toxicities more than G2 occurred only in one patient (G3 infection event). During DLI there were no >G2 hematologic or extra-hematologic toxicities. There were no treatment-related mortalities. Conclusion: This prospective study shows that VD-DLIs is feasible, well tolerated, and it can offer a high remission rate to patients with MM relapsed or refractory after alloSCT. Interestingly, the PFS and OS curves show a plateau, suggesting the achievement of a response more prolonged respect to the series previously published, relative to the non allotransplant setting. [protocol EudraCT number: 2006-004815-24]. Supported by Janssen-Cilag. Disclosures: Off Label Use: Bortezomib and Thalidomide as post autotransplantation consolidation therapy in myeloma.

Abstract 4577 Patients with therapy-related acute myeloid leukemia (tAML) and myelodysplastic syndromes (tMDS) have a bad prognosis. Allogeneic stem cell transplantation (alloSCT) is potentially curative, but the majority of these patients die because of the high incidence of relapse (RI) and non relapse mortality (NRM). Since it is critical to understand which patients should receive alloSCT, we designed this retrospective study to assess which patients’ characteristics may predict the alloSCT outcome in tAML/tMDS. All the patients affected by tAML or tMDS and allografted in 4 Italian hematology units between 1998 and 2009 were included. Total patients were 28: 24 (86%) had tAML, 4 (14%) had tMDS. Patients had a median age of 49 years (range 21–65) at transplant; 15 patients were female (54%). Previous neoplasia was lymphoma in 23 patients (82%, 15 Hodgkin and 8 non-Hodgkin), or non-hematologic cancer (5, 18%) like breast carcinoma (2), seminoma (1), testicular embryonal carcinoma (1), and osteosarcoma (1). Previous cancer had been treated with chemotherapy (CT, 7 patients, 25%), radiotherapy (RT, 4 patients, 14%), or both (17, 61%). Fourteen patients (50%) had received >=2 therapy lines, 6 (21%) had received autologous stem cell transplant. tAML/tMDS occurred after a median time of 86 months (range 13–253) after the previous cancer treatment. Cytogenetic analysis was performed in 24 patients (86%): 8 patients (33%) had intermediate risk and 16 (57%) high risk cytogenetics according to Medical Research Council AML10 Trial definitions. Twenty-three patients (82%) received induction CT for tAML/tMDS, 19 (68%) received consolidation; 5 patients (18%) received upfront alloSCT. Induction consisted of idarubicin+cytarabine+/−etoposide (12 patients, 43%) or fludarabine+cytarabine+/−idarubicin (11 patients, 39%); 15 patients (54%) had an infection after induction. Median time from tAML/tMDS diagnosis to alloSCT was 5.7 months (range 0–25). At transplant, 10 patients (36%) had a Karnofsky Performance Status (KPS)1. Donor was identical sibling for 9 patients (32%), and alternative for 19 patients (68%): mismatched related (1, 3%), matched unrelated (15, 54%) or haploidentical (3, 11%). Disease status of patients at transplant was as following: 12 patients (43%) were in CR (11 in CR1), 4 (14%) in PR and 7 (25%) in PD; 5 patients (18%) received alloSCT at diagnosis. Patients underwent reduced intensity (11 RIC, 39%) or myeloablative (17, 61%) alloSCT. Myeloablative conditioning was mainly busulfan-based (15 patients, 54%); the majority of RIC patients received thiotepa+cyclophosphamide-based conditioning (9, 32%). Twelve patients (43%) are alive at last follow-up, 7 patients (25%) died of disease, 9 (32%) died of NRM. The main reason of death by NRM was infection (8 patients, 29%). Median follow-up of surviving patients was 528 days (55-1704). One- and 2-years overall survival (OS) was 50% and 36%, progression free survival (PFS) was 42% and 38%. RI was 28% at both 1 and 2 years, NRM was 18% at 100 days, 30% at 1 year and 35% at 2 years. Nine (32%) patients had acute GVHD of grade >=2, 8 patients had chronic GVHD (cGVHD, 29%), 3 patients (11%) had extensive cGVHD. OS and PFS were reduced in patients with high-risk cytogenetics (p=0.03 and p=0.01, respectively) and KPS2 CT lines had a worse NRM (p=0.005) and a reduced OS (p=0.05); treatment type (CT vs RT vs CT+RT) did not have a significant impact on OS, PFS nor NRM. NRM was higher in patients who had infections after induction (p=0.009), or received consolidation (p=0.03). AlloSCT after >180 days from tAML/tMDS diagnosis increased NRM (p=0.05). Conditioning (RIC vs myeloablative), donor type (identical sibling vs alternative) and type of previous neoplasia (hematologic vs non-hematologic) did not affect survival (OS and PFS), NRM and RI. In conclusion, alloSCT is effective in a minority of patients with tAML/tMDS. Survival is reduced by high risk cytogenetics and poor KPS. Number of previous treatments, infections after induction, and consolidation CT increase NRM. Thus, patients’ selection for alloSCT in tAML/tMDS setting should be based on cytogenetics, KPS, and treatment history. Prospective trials are awaited in order to confirm these results. Disclosures: Corradini: Novartis Pharmaceuticals, Inc: Consultancy; Genezyme: Consultancy; Roche: Speakers Bureau; Celegene: Speakers Bureau.

Abstract 875 Conventional therapies and autologous stem cell transplantation lead to disappointing results in relapsed PTCL, therefore allo-SCT has been investigated in the last years. There are evidence supporting the existence of a “graft-versus-PTCL” effect, but the majority of the studies have a limited number of patients with a short follow-up. We conducted a retrospective analysis on 53 patients (pts) affected by relapsed/refractory PTCL who received a RIC regimen followed by allo-SCT. The main histopathological subtypes were PTCL-not otherwise specified (PTCL-NOS, n=24), anaplastic large-cell lymphoma (ALCL, n=11), and angioimmunoblastic (AILD, n=6). The remaining cases were rare subtypes (n=12). Median age was 47 years (range, 15-64 years). Patients were allografted from matched related siblings (n=34, 64%) or alternative donors (n=19, 36%). The majority of pts had chemosensitive disease (n=39, 74%), received allo-SCT more than 12 months from diagnosis (n=38, 72%) and were treated with only 1 or 2 lines of therapy before transplantation (n= 37, 70%). At last follow-up (median 49 months, range 6-118), 29 pts are alive (55%, 26 in CR) and 24 died [n=20 for disease progression, n=4 for non-relapse mortality (NRM)]. The majority of relapsing patients (20 of 25, 80%) died at median time of 7 months after allo-SCT. The crude cumulative incidence (CCI) of relapse was 32% and 50% at 6 months and at 4-year after allo-SCT. The CCI of relapse was influenced by status of disease [chemosensitive versus chemorefractory: 41% versus 77% at 4 years (p 2: 40% versus 70% at 4 years (p Disclosures: No relevant conflicts of interest to declare.

Abstract 4946 Multiple myeloma (MM) treatment greatly improved in the last decade due to the introduction of new drugs such as thalidomide, bortezomib and lenalidomide. Lenalidomide is the more recent, and is active in relapsed MM patients, but the data on long term responses are still lacking. For such a reason, we conducted a retrospective multicenter study to evaluate the existence of long term responders to lenalidomide. Eleven Italian hematology centers participated to the study. Consecutive patients relapsing after >=2 lines of therapy receiving a treatment with lenalidomide were considered eligible. Patients treated with >=2 cycles of lenalidomide were considered evaluable for response defined as per International Uniform Response Criteria. Long term response was defined as a response equal or better than PR lasting >=12 months. Overall (OS) and progression free survival (PFS) were analyzed with Kaplan-Meier method and log-rank test. Cumulative incidence (CI) of relapse was analyzed with CI method with competing risks. Group characteristics were compared by Mann-Whitney test. A multivariate logistic regression analysis was applied to assess which patient characteristics might predict a long term response to lenalidomide. Ninety-five patients were enrolled, 81 had a complete data set and were evaluable. Median age was 65 years (range 42-89), 33 (41%) patients had >=70 years, 48 (59%) had IgG, 22 (27%) IgA, 10 (12%) light chain and 1 IgD MM (1%). All patients relapsed after >=2 lines of chemotherapy, 29 (36%) received >3 lines; 53 (65%) had failed an autologous (autoSCT) and 11 (14%) an allogeneic transplant (alloSCT). All patients were treated with lenalidomide daily for 21 days every 28 per course. Seventy-three patients (90%) were treated with a dose of 25 mg/die, 8 received 15 or 10 mg/die due to hematologic toxicity. Median administered courses were 6 (range 3-29); 28 patients (35%) received >=12 months of treatment. Overall response rate was 85.5%. Two (2.5%) patients obtained sCR, 8 (10%) CR, 11 (14%) VGPR, 48 (59%) PR, 7 (9%) SD, and 5 (6%) PD. One- and 2-years OS (median not reached) was 83 and 64%, 1- and 2-years PFS (median 514 days) was 62% and 45%. One- and 2-year CI of relapse was 34% and 54%. Age, isotype, stage, previous lines of therapy, autoSCT, alloSCT and lenalidomide dose did not impact OS and PFS. Twenty-eight (35%) patients obtained PR or a better response lasting >=12 months. One patient (3.5%) died and 7 (25%) relapsed after long term response. The 2-year OS and PFS was 93% and 64%; median OS and PFS were not reached by long term responders. Pre-treatment characteristics and lenalidomide dose did not significantly affect their survival outcomes. The group of 53 patients relapsed before 12 months had 2-years OS (median not reached) and PFS (median 320 days) of 56% and 23%, respectively. Twenty-three patients (43%) progressed and/or died. Older age (>=70 years) influenced PFS (p=0.04) and there was a trend also for OS (p=0.07); the other patient characteristics had no impact on survival. Response to lenalidomide, even if short lasting, improved OS (p Disclosures Patriarca: Celgene: Speakers Bureau; Janssen-Cilag: Speakers Bureau. Guglielmelli:Celgene: Honoraria. Corradini:Celgene: Honoraria; Roche: Honoraria; Novartis: Honoraria, Speakers Bureau.

Abstract 4320 Background Salvage treatments containing thalidomide, lenalidomide or bortezomib can induce a response rate in 30 to 60% of multiple myeloma (MM) patients (pts) relapsing after single or tandem autologous transplantation (auto-SCT) with a median response duration between 6 and 12 months. However, long-term disease control or cure cannot be commonly achieved. Allogeneic stem cell transplantation (allo-SCT) employing reduced intensity conditioning (RIC) has been increasingly performed in MM, but its efficacy in this clinical setting is still a matter of debate. Aims We investigated the role of RIC allo-SCT in MM pts who relapsed after auto-SCT and were then treated with a salvage therapy based on novel agents. In order to limit any selection bias, our study was structured similarly to an intention to treat analysis and included only those pts undergoing a HLA-typing immediately after the failure of auto-SCT. The cohort of pts having a donor (donor-group) was compared with the one not having a suitable donor (no-donor group). Patients and methods One hundred thirty–six consecutive pts were retrospectively evaluated in a multicenter study. Fifty-seven found a donor and 50 (88%) underwent an allo-SCT: 16 identical sibling (32%), 34 MUD (68%). Conditioning regimens were fludarabine, melphalan±thiotepa in 21 patients (42%), fludarabine + 2 Gy TBI in 15 cases (30%), fludarabine and cyclophosphamide in 8 patients (16%) and fludarabine and treosulfan in the remaining 6 cases (12%). Seven pts having a donor did not receive allo-SCT for progressive disease or severe comorbidities. Median age of donor-group was significantly younger than no-donor group (53 versus 60 years, p=0,000045). No differences were detected between the donor and no-donor group with regard of median time between auto-SCT and relapse (17 months in both groups), treatment of first relapse (thalidomide-based 55% vs 31%, bortezomib-based 35% vs 46%, lenalidomide 10% vs 23%), median duration of salvage treatment (4,5 months versus 4 months) and percentage of responsive patients after treatment of first relapse (CR + VGPR 37% versus 30%, PR 46% vs 34%, SD 12% vs 18%, PD 5% vs 18%). Results The median follow-up for all patients was 15 months (1-97) after relapse. The median time to progression (TTP) and overall survival (OS) for all patients were 16 and 25 months, respectively. Two-year TTP was 55% in the donor-group and 18% in the no-donor group (p Conclusions We conclude that the association of a salvage treatment containing novel agents consolidated by RIC allo-SCT seems a feasible strategy with a rather low mortality and an encouraging TTP and OS in patients relapsing after auto-SCT. Both availability of a donor as well as late (>12 months) relapse from auto-SCT positively impacted on OS. Disclosures: Einsele: celgene: Research Funding; orthobiotech: Research Funding.

Abstract 3310 Poster Board III-198 Lymphoma patients relapsing after allogeneic stem cell transplantation (alloSCT) have a dismal prognosis. Relapsed disease is often chemorefractory and few therapeutic options are available. Few reports have assessed the efficacy of donor lymphocyte infusions (DLI) for relapse treatment. We conducted a retrospective study to assess whether DLI may improve survival outcomes of relapsed patients as compared to salvage chemotherapy, and to explore the potential benefit of Rituximab as salvage treatment. We collected data of 146 consecutive patients with Hodgkin's (HL) and non-Hodgkin's (NHL) lymphoma allografted with reduced intensity conditioning in 2 Italian hematologic centres between 1999 and 2007. Patients relapsed after alloSCT were the target population of our study, and their treatment and survival outcomes were analyzed. Progression free (PFS) and overall survival (OS) were defined as the time from first to second relapse or death and the time from first relapse to death, and were analyzed by Kaplan-Meier method and log-rank test. Relapse incidence (RI) was defined as the time from first to second relapse considering non-relapse mortality as competing event, and it was analyzed by Cumulative Incidence method and Gray's test. Multivariate analysis was done with Cox method. Fifty-seven (39%) of all 146 patients relapsed at a median of 545 days, 48 of them (84%) were treated for relapse, 9 (16%) were not treated due to early death for progression (6) or infection (2) or response to cyclosporine withdrawal (1). Treated patients had a median age of 50 years (range 19-65), 18 (38%) were female, 12 (25%) had HL, 13 (27%) indolent and 23 (48%) aggressive NHL. Previous lines of chemotherapy were 3 (range 2-7). Twenty-four (50%) patients had undergone an autologous transplant (autoSCT). All patients were allografted from siblings (32, 67%) or from matched unrelated donors (16, 33%). Twenty-four (50%) had >1 comorbidity Sorror score at transplant. Twenty-four (50%) patients received DLI alone or with chemotherapy for relapse treatment, 24 (50%) received chemotherapy alone. Median DLI administered were 2 (range 1-5) with a median of 1×10 7CD3+ per DLI. Ten patients (21%) could not receive DLI because of GVHD (5), progressive disease (3), infection (1), donor's loss of eligibility (1). Seventeen patients (35%) were treated with Rituximab alone or combined with chemotherapy, 10 (21%) received both DLI and Rituximab. One- and 2- years OS (median 720 days) and PFS (median 269 days) were 61% and 50%, 39% and 30%, respectively. One- and 2-years RI were 45% and 65%. Age, sex, pre-transplant disease status, therapy lines, comorbidities, donor type, autoSCT did not influence OS nor PFS or RI. Patients with aggressive NHL had a worse PFS (p=0.01), a higher RI (p=0.01) and a trend to reduced OS (p=0.05). Patients treated with DLI had a better PFS than patients treated with salvage chemotherapy alone (1-year PFS 54% with DLI vs 24% without, p=0.005), a significantly reduced RI (1-year RI 38% with DLI vs 67% without, p=0.007), and a trend towards a better OS (1-year OS 79% with DLI vs 38% without, p=0.06). Rituximab treatment improved OS (1-year OS 82% with Rituximab, 50% without, p=0.009) but did not significantly impact PFS or RI. As compared to chemotherapy alone, patients treated with both DLI and Rituximab had better PFS (1-year PFS 60% vs 37%, p=0.04) and OS (1-year OS 90% vs 50%, p=0.006) and a trend to reduced RI (1-year 30% vs 58%, p=0.05). The multivariate analysis considered as covariates disease (HL vs indolent NHL vs aggressive NHL), age (1), treatment with DLI (DLI vs no DLI) and Rituximab (Rituximab vs no Rituximab). In multivariate analysis DLI significantly improved PFS (HR=0.3, CI95%=0.18-0.85, p=0.02) and Rituximab improved OS (HR=0.2, CI95%=0.07-0.66, p=0.006). Treatment with DLI and Rituximab improved both PFS (HR=0.3, CI95%=0.1-0.8, p=0.02) and OS (HR=0.1, CI95%=0.02-0.5, p=0.005). Other covariates did not impact OS or PFS. In conclusion, patients with lymphoma who relapse after alloSCT may be treated with DLI, which may improve survival and reduce relapse incidence as compared to salvage chemotherapy. Relapse treatment with Rituximab may offer an OS benefit. Combined treatment with DLI and Rituximab may improve both PFS and OS of these patients, and may be the optimal salvage strategy. Prospective data are needed in order to confirm these results. Disclosures Patriarca: Janssen-Cilag: Speakers Bureau; Celgene: Speakers Bureau. Corradini:Celgene: Honoraria; Roche: Honoraria; Novartis: Honoraria, Speakers Bureau.

Abstract 4494 1.Background Mismatches of minor Histocompatibility antigens (mHAg) have been considered as an important immunogenetic factor influencing outcomes and immune responses following allogeneic stem-cell transplantation (alloSCT) despite fully matched HLA of donor and recipient. 2. Aim Aim of this study was to assess whether mHAg incompatibilities may affect overall survival (OS), progression free survival (PFS) and GVHD incidence (acute and chronic, aGVHD and cGVHD) in patients receiving alloSCT for lymphoid malignancies. 3. Methods Sixty-four consecutive patients with B-cell lymphomas who underwent alloSCT were studied. Ten patients had chronic lymphocytic leukemia (CLL, 15.8%), 3 had follicular lymphoma (FCL, 4.7%), 1 had diffuse large B cell lymphoma (DLBCL, 1,5%), 17 had Hodgkin's lymphoma (26.5%) and 33 had multiple myeloma (51.5%). All underwent peripheral blood stem-cells allograft with non-myeloablative (13 patients, 20%) or reduced intensity (51 pts, 80%) Fludarabine-based conditioning; GVHD prophylaxis included methotrexate and oral cyclosporine +/- micomofetil fenolate in case of matched unrelated donors. Median age was 51 years (range 18-66); 35 patients were male (55%), median number of previous chemotherapies was 3 (0-7), 49 patients had a previous autologous transplant (76%). Twenty-five patients were in complete remission (CR, 39%), 30 and 9 were in partial response and progression (PR 47% and PD 14%). Karnofsky performance status (PS) was >80% in 50 patients (78%). Forty-four patients allografted from HLA-matched siblings (69%), 20 from matched unrelated donor (31%): all were matched at allelic level for HLA-A, -B, -Cw, -DRB1 and -DQB1 loci. Allelic mHAs typing was performed by PCR with sequence-specific primers for 14 autosomic mHAg and H-Y. Host versus Graft or Graft versus Host direction of immune responses in donor/recipient pairs was analyzed with use of the minor Histocompatibility Database of Leiden University Medical Center. OS and PFS were analyzed with Kaplan-Meier method and log-rank test. aGVHD and cGVHD were analyzed with a multivariate logistic regression including as covariates age, sex, previous lines of chemotherapy, disease, pre-transplant status, PS and mHAs mismatches; grade >=2 aGVHD and extensive cGVHD were considered events. 4. Results Median follow-up was 34 months (2-83). One-year OS was 85%, 2- and 3-years OS were 82% and 77%. One-year PFS was 61%, 2- and 3-years PFS were 49% and 41%. The univariate analysis which considered transplant characteristics showed that OS and PFS were significantly affected by disease status at transplant (p80, p 5. Conclusions This study showed that in the non-myeloablative and RIC setting, mHAg mismatches may have a significant role in determining aGVHD. Assessing mHAg mismatches may be a useful tool to choose patient-specific GVHD prophylaxis in conditioning regimens and in post transplant follow-up. Larger prospective data are needed in order to confirm these results. Disclosures: No relevant conflicts of interest to declare.

Purpose: Haploidentical hematopoietic stem cell transplantation (haplo-SCT) provides an option for cancer patients lacking a compatible donor. However, the delayed immune reconstitution increases incidence of opportunistic infections and disease relapse. We conducted a phase I-II prospective trial to evaluate the effect of escalating doses of CD8-depleted (Miltenyi Device) donor lymphocyte infusions (DLIs) following RIC haplo-SCT. Here, we present the data on the immune reconstitution. Patients and Methods: Twenty-eight patients (pts) with advanced lymphoproliferative diseases (n=24) or acute myeloid leukaemia (n=4) were enrolled in this study. Fifteen (54%) of 28 pts had refractory disease. All pts received a thiotepa-fludarabine based RIC regimen, with an ex vivo and in vivo T-cell depletion performed by CD34+ cell selection and alemtuzumab infusion. Fifty-four CD8-depleted DLIs were administered to 23 pts [dose level 1 (n=4): 1×104/kg on days + 45, +75, +105; dose level 2 (n=11): 5×104/kg on days + 45, +75, +105; dose level 3 (n=8): 1×104/kg on day+ 45, 5x104/kg on days +75 and +105]. Results: At a median follow-up of 29 months, 12 pts are alive (n=3 Hodgkin Lymphoma, n=6 Non-Hodgkin Lymphoma, n=1 Multiple Myeloma, n=2 Acute Myeloid Leukemia) and 16 died from any cause [n=6 for non-relapse mortality (NRM), n=10 for disease progression] with a 2-year estimates of overall survival of 39%. The 2-year cumulative incidence of NRM and relapse were 26% and 51%, respectively. Six pts (26%) developed grade II-IV acute graft-versus-host disease (GVHD) (dose level 1: no GVHD; dose level 2: 5 cases; dose level 3: 1 case). Following CD8-depleted DLIs, the major findings were:(i) a significant expansion of memory CD4+ cells and CD19+ cells (median value 107/μL and 135/μL, respectively) at 120 days after haplo-SCT; (ii) de-novo T-cell responses to cytomegalovirus (CMV) peptides performed by activation-induced CD137 expression: the median frequency of CMV-specific CD8+/CD137+ and CD4+/CD137+ cells were 2% and 0.4% at 200 days after haplo-SCT, respectively, as evaluated in a subset of pts at risk for CMV reactivation (R CMVpos/D CMVpos/neg); this frequency was associated to a clearance of CMV antigen; (iii) recovery of thymopoiesis: 10 of 20 (50%) pts showed measurable TREC at 1 year after haplo-SCT; (iv) the increase of CD19+ cells was associated to reconstitution of B lymphocyte repertoire as analysed by Immunoglobulin heavy chain (IgH) CDR3 spectratyping: median number peaks in normal donors and pts, at day 360 after haplo-SCT, were 17 (range, 14–21) versus 12 (range, 7–14), respectively. Conclusions: Our study showed that CD8-depleted DLIs are a feasible procedure with low acute GVHD when using dose level 3. Long-term disease remissions can be observed in advanced lymphoid malignancies. Escalated doses of CD8-depleted DLIs exert complex effects on immune reconstitution: (i) provide help to expansion of CD8 T-cell clones, as suggested by the occurrence of the anti-CMV reactivity; (ii) support B-cell recovery, as demonstrated by a partial recovery of CDR3 polyclonality.

The hematopoietic cell transplantation-specific comorbidity index (HCT-CI) has been developed to identify patients at high risk of toxic mortality after an allogeneic stem cell transplant (alloSCT). Reduced intensity (RIC) and non-myeloablative regimens have decreased the non-relapse mortality (NRM) in heavily pre-treated and elderly patients. We performed a retrospective multicenter study to assess whether comorbidities, according to the HCT-CI, might influence the outcome of lymphoma and multiple myeloma patients undergoing RIC or non-myeloablative alloSCT. Two-hundred and three patients affected by non Hodgkin’s lymphoma (n=108), multiple myeloma (n=69) and Hodgkin’s lymphoma (n= 26) received an alloSCT from HLA matched sibling (n= 121) or unrelated (n=82) donors. Median age at transplant was 53 years (range, 17–69). The median number of previous chemotherapy was 3 (range, 0–7) and 68% of the patients received at least one autologous stem cell transplant (autoSCT). Twenty-five percent of the patients were transplanted in complete remission (CR), 50% in partial response (PR) and 25% in progressive disease (PD). RIC fludarabine-based regimens were used in 154 patients, whereas 49 patients received a non-myeloblative conditioning based on 2 Gy total-body irradiation+/− fludarabine. Variables included in multivariate analysis were age (80% vs ≤80%), disease type (lymphoma vs myeloma), disease status before transplant (CR vs no-CR), the number of previous lines of therapy (≤2 vs >2), a previous autoSCT (0 vs ≥1), the donor type (sibling vs matched unrelated) and the conditioning regimen (non-myeloablative vs RIC). Patients with a HCT-CI of 0, 1–2 and ≥3 were 32%, 31% and 37%, respectively. The cumulative incidence of NRM was 5%, 16%, 20% at 1 year and 6%, 24% and 27% at 2 years, for patients with HCT-CI of 0, 1–2 and ≥3, respectively (p=0.04). The multivariate analysis for NRM showed that a high HCI-CI score (HR=1.60, p=0.03), as well as a low Karnofsky PS (HR=2.12, p=0.04) were correlated with a significantly worst outcome. Similarly, HCT-CI and the Karnofsky PS were able to predict overall survival (OS, HR=1.62, p80% (p80% (p=0.09 and p=0.07, respectively). When patients were analysed separately based on the conditioning regimen, OS was different for HCT-CI of 0, 1–2 and ≥3 either with RIC (p=0.001) or non-myeloablative regimens (p=0.02). Patients with HCT-CI 0, 1–2, and ≥3 had a similar NRM (p=0.19 for HCT-CI 0, p=0.87 for HCT-CI 1–2, p=0.33 for HCT-CI ≥3) and OS (p=0.94 for HCT-CI 0, p=0.76 for HCT-CI 1–2, p=0.18 for HCT-CI ≥3) when transplanted with non-myeloablative or reduced intensity conditioning. HCT-CI was inversely associated with Karnofsky PS (p

Several studies have shown that therapy-related MDS (tMDS) and AML (tAML) have a poor outcome with very few long-term survivors. Curative treatment strategies are not yet standardized and the role of hematopoietic stem cell transplantation (SCT) is still not fully elucidated in standard care treatment. We performed a retrospective outcome research with the aim of looking at the survival curves of tMDS and tAML patients treated at 7 different Institutions. According to the presence of comorbidities or a matched donor, 71 patients (pts) received the best treatment option based on attending physician opinion: 24 pts (group A) with tAML (n=13, FAB M0, M1, M2, M4) and tMDS (n=7 RAEB-2. n=4 RAEB-1) received allogeneic transplantation, 28 pts (group B) with tAML (n=20, FAB M0, M1, M2, M4, M5) and tMDS (n=3 RAEB-2, n=4 RAEB-1, n=1 RA) received chemotherapy and 19 pts (group C) received supportive care only (n=1 tAML, n=18 low-risk MDS or RAEB-1 (n=5)). Median age was 55 years (range 23–67) in group A, 61 years (range 27–73) in group B and 55 years (range 22–70) in group C. Conventional karyotype analysis was available in 12 pts of group A (n=7 complex, n=1 normal, n=2 isolated del(7q) or monosomy 7, n=1 isolated del(5q), n=1 trisomy 21) and in 15 pts of group B (n=3 complex, n=8 normal, n=1 isolated del(Y), n=1 isolated del(11), n=1 isolated trisomy 11, n=1 isolated trisomy 8). In the group A, all pts, because of age and/or comorbidities, received a fludarabine-based reduced-intensity conditioning followed by allogeneic peripheral blood SCT. Disease status at transplant was categorized as low risk (n=9 CR1 or CR2), high risk (n=3 PR, n=6 PD, n=2 refractory) and 4 pts were treated up-front. The median time from diagnosis to allografting was 6 months (range: 1–80 months). Pts received allogeneic stem cells from HLA-matched siblings (n=16), or HLA-matched unrelated donors (n=6), or haploidentical related donors (n=2). All pts engrafted. Acute GVHD grade II–IV occurred in 6 pts (n=1 post-DLIs), chronic GVHD developed in 6 pts (n=1 post-DLIs). OS at 5 years was 5.5%, the 4-year EFS was 0%, TRM at 100 days and at 1 year were 28%. No statistical differences were observed in TRM, EFS, and OS according to disease status at transplant and diagnosis of tMDS or tAML. DFS for pts in CR at transplant was 23% at 1 year. In the group B, pts received chemotherapy and 11 of them an autologous stem cell transplantation. OS at 5 years was 16%, EFS at 5 years was 10%, DFS at 1 year was 31%. TRM at 5 years was 30%. In the group C, OS was 28% at 5 years. Our data show that, in daily clinical practice, the outcome of patients receiving chemotherapy followed by allogeneic SCT is not improved compared to the patients not having a suitable donor. At the present time, considering the very low chance of cure, in therapy-related disorders the main goal for clinicians should be prevention.

Osteonecrosis of the jaw (ONJ) is a frequent complication in bisphosphonate-treated multiple myeloma (MM) patients. The pathogenesis is unclear, and major risk factors are duration of bisphosphonate treatment and dental procedures. The histology of osteonecrotic bone shows osteomyelitis and inflammatory infiltrates, and, in most cases, presence of Actynomycetes. Since dental procedures are a major risk factor for ONJ development and oral microflora can be involved in the pathogenesis of the disease, we conducted a retrospective observational trial comparing ONJ occurrence and related risk factors in two groups of MM patients, who received zoledronic acid treatment at two Italian hematological centres. In one centre all patients systematically received as antibiotic prophylaxis amoxicillin-clavulanate 1 gm bid or levofloxacin 500 mg once a day starting from one day before to 3 days after any dental procedure (group A, 52 patients), while in the other centre patients did not receive any prophylaxis (group B, 61 patients). Dental procedures were categorized according to their invasivity and their supposed probability to cause ONJ. Extractions, implants, and professional cleanings were considered at high risk, while fillings were considered low risk procedures. Thirty-three group A patients (63%) and 32 group B patients (52%) received high risk procedures; 4 group A patients (8%) and 5 group B patients (8%) received low risk procedures, while 15 (29%) and 24 (39%) patients, respectively, had a denture. The duration of zoledronic acid exposure differed significantly between the two groups, with a median of 26 months for A patients and 12 months for B patients (p