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The safety and activity of immune checkpoint inhibitors have been characterized in interventional and observational studies. However, only small studies have specifically investigated these agents in patients who are excluded or underrepresented in clinical trials, frequently referred to as “special populations” or “underrepresented populations.” These include older adults, those with dysregulated immune activation, patients with a compromised immune function, and those carrying major viral infections, lymphoproliferative diseases, and major organ dysfunctions. Therefore, there remains substantial uncertainty regarding the use of immune checkpoint inhibitors in these specific settings. The Network of Italian Supportive Care in Oncology has carried out a multidisciplinary project, with the contribution of oncologists and other specialists, to retrieve the existing evidence on the use of immunotherapy in patients with solid and hematological cancers with the final aim to provide an expert guidance. The results of this effort are presented in this article, which is focused on patients with major viral infections or those with immune dysregulation/autoimmune diseases, and could be useful to guide decisions in clinical practice and to design prospective clinical trials focusing on the use of immunotherapy in these populations. Implications for Practice Substantial uncertainty remains regarding the use of immune checkpoint inhibitors in “underrepresented” patients, such as older adults, those with dysregulated immune activation, and patients with a compromised immune function, major viral infections, lymphoproliferative diseases or major organ dysfunctions. The Network of Italian Supportive Care in Oncology has carried out a multidisciplinary project to retrieve the existing evidence on the use of immunotherapy in underrepresented patients with cancer in order provide an expert guidance. The results of this effort, with a focus on patients with major viral infections or those with immune dysregulation/autoimmune diseases, are presented in this article and could be useful to guide decisions both in clinical practice and to design clinical trials.

HER2 alterations are potential candidates for targeted treatments in metastatic urothelial/bladder cancer (mUC). ERBB2 gene amplification and mutations are found in around 6% and 4% of mUC, respectively.This is a systematic review of clinical trials evaluating HER2-targeting (amplification and mutations) in mUC. We assigned each study to one of the following strategies: HER2-targeting with single agents, anti-HER2 agents in combination with cytotoxic chemotherapy, dual HER2 blockade, HER2-targeted antibody-drug conjugates (ADCs), and other novel therapeutic approaches.36 clinical trials (17 with results and 19 ongoing) were included. As for ERBB2 amplification, anti-HER2 single agents (5 studies) and combinations with chemotherapy (4 studies) failed to provide any benefit, whereas dual HER2 blockade through monoclonal antibodies proved active in one trial in pretreated patients. Two studies assessed single-agent targeting for ERBB2 mutations with negative results. Most promising data come from 2 studies with ADCs in ERBB2 amplified tumors (disitamab-vedotin and trastuzumab-duocarmazine), while 2 other studies with TDM-1 and ADCT-502 was discontinued due to toxicity. In this category, trastuzumab-deruxtecan and other ADCs are still under investigation for either ERBB2-amplified or mutated mUC. Novel approaches include ADCs with immunotherapy (1 study with results), CAR-T cells, and HER2-sensitising vaccines.ERBB2 amplification could become a novel target in mUC, although the magnitude of clinical benefit remains to be clarified. To this regard, novel ADCs are the most promising strategy. ERBB2 mutations are still at very early stage of clinical study.

In situ resource utilization (ISRU) increasingly features as an element of human long-term exploration and settlement missions to the lunar surface. In this study, all requirements to test a novel, biological approach for ISRU are validated, and an end-to-end mission architecture is proposed. The general mission consists of a lander with a fully autonomous bioreactor able to process lunar regolith and extract elemental iron. The elemental iron could either be stored or directly utilized to generate iron wires or construction material. To maximize the success rate of this mission, potential landing sites for future missions are studied, and technical details (thermal radiation, shielding, power-supply) are analyzed. The final section will assess the potential mission architecture (orbit, rocket, lander, timeframe). This design might not only be one step further towards an international “Moon Village”, but may also enable similar missions to ultimately colonize Mars and further explore our solar system.

Chronic Myeloid Leukemia is a clonal disorder characterized by the presence of the Ph-chromosome and the BCR-ABL tyrosine-kinase (TK). Target-therapy with Imatinib has greatly improved its outcome. Deeper and faster responses are reported with the second-generation TKI Nilotinib. Sustained responses may enable TKI discontinuation. However, even in a complete molecular response, some patients experience disease recurrence possibly due to persistence of quiescent leukemic CD34+/lin−Ph+ stem cells (LSCs). Degree and mechanisms of LSCs clearance during TKI treatment are not clearly established. The PhilosoPhi34 study was designed to verify the in-vivo activity and timecourse of first-line Nilotinib therapy on BM CD34+/lin−Ph+ cells clearance. Eighty-seven CP-CML patients were enrolled. BM cells were collected and tested for Ph+ residual cells, at diagnosis, 3, 6 and 12 months of treatment. FISH analysis of unstimulated CD34+/lin− cells in CCyR patients were positive in 8/65 (12.3%), 5/71 (7%), 0/69 (0%) evaluable tests, respectively. Per-Protocol analysis response rates were as follows: CCyR 95% at 12 months, MR4.5 31% and 46% at 12 and 36 months, respectively. An exploratory Gene Expression Profiling (GEP) study of CD34+/lin− cells was performed on 30 patients at diagnosis and after, on 79 patients at diagnosis vs 12 months of nilotinib treatment vs 10 healthy subjects. Data demonstrated some genes significantly different expressed: NFKBIA, many cell cycle genes, ABC transporters, JAK-STAT signaling pathway (JAK2). In addition, a correlation between different expression of some genes (JAK2, OLFM4, ICAM1, NFKBIA) among patients at diagnosis and their achievement of an early and deeper MR was observed.

Simple Summary The BRAFV600E mutation accounts for 8–10% of metastatic colorectal cancer (mCRC) patients and it is an established prognostic factor. Median overall survival of this subset of patients is indeed so poor that it is similar to first line PFS of patients without this molecular alteration. An exception is represented by patients displaying concomitant MSI-H status who can benefit from immunotherapy with checkpoint inhibitors (CPIs). Recently, a targeted therapy with the combination of encorafenib and cetuximab provided for the first time a survival gain and thus translation in the clinic, even though acquired resistance limits the possibility of more than an incremental benefit. Many studies exploiting other different strategies are ongoing. In this review we present current therapies specifically headed to BRAFV600E mutant mCRC and systematically review ongoing clinical trials identifying different approaches under investigations: targeting MAPK pathway (monotherapy or combinations), targeting MAPK pathway combined with cytotoxic agents, intensive cytotoxic regimen combinations, targeted agents combined with CPIs, oxidative stress induction, and cytotoxic agents combined with antiangiogenic drugs and CPIs. Abstract The BRAFV600E mutation is found in 8–10% of metastatic colorectal cancer (mCRC) patients and it is recognized as a poor prognostic factor with a median overall survival inferior to 20 months. At present, besides immune checkpoint inhibitors (CPIs) for those tumors with concomitant MSI-H status, recommended treatment options include cytotoxic chemotherapy + anti-VEGF in the first line setting, and a combination of EGFR and a BRAF inhibitor (cetuximab plus encorafenib) in second line. However, even with the latter targeted approach, acquired resistance limits the possibility of more than an incremental benefit and survival is still dismal. In this review, we discuss current treatment options for this subset of patients and perform a systematic review of ongoing clinical trials. Overall, we identified six emerging strategies: targeting MAPK pathway (monotherapy or combinations), targeting MAPK pathway combined with cytotoxic agents, intensive cytotoxic regimen combinations, targeted agents combined with CPIs, oxidative stress induction, and cytotoxic agents combined with antiangiogenic drugs and CPIs. In the future, the integration of new therapeutic strategies targeting key players in the BRAFV600E oncogenic pathways with current treatment approach based on cytotoxic chemotherapy and surgery is likely to redefine the treatment landscape of these CRC patients.

Background: Carcinomas of unknown primary (CUP) account for 3-5% of all malignancy and, despite a reduction in incidence, the overall survival has not improved over the last decade. Chemotherapy regimens have not provided encouraging results. New diagnostic technologies, such as next generation sequencing (NGS), could represent a chance to identify potentially targetable genomic alterations in order to personalize treatment of CUP and provide insights into tumor biology. Methods: A systematic review of studies of patients with CUP, whose tumor specimen was evaluated through a NGS panel, has been performed on June 10th, 2019 according to PRISMA criteria from PubMed, ASCO meeting library and Clinicaltrial.gov. We have identified potentially targetable alterations for which approved/off-label/in clinical trials drugs are available. Moreover, we have included case reports about CUP patients treated with targeted therapies driven by NGS results in order to explore the clinical role of NGS in this setting. Results: We have evaluated 15 publications of which eleven studies (9 full-text articles and 2 abstracts) have analyzed the genomic profiling of CUPs through NGS technology, with different platforms and with different patients cohorts, ranging from 16 to 1,806 patients. Among all these studies, 85% of patients demonstrated at least one molecular alteration, the most frequent involving TP53 (41.88%), KRAS (18.81%), CDKN2A (8.8%), and PIK3CA (9.3%). A mean of 47.3% of patients harbored a potentially targetable alteration for which approved/off-label/in clinical trials drugs were available. Furthermore, we have identified 4 case reports in order to evaluate the clinical relevance of a specific targeted therapy identified through NGS. Conclusions: NGS may represent a tool to improve diagnosis and treatment of CUP by identifying therapeutically actionable alterations and providing insights into tumor biology.

439 Background: Avelumab (ave) was approved as maintenance therapy after platinum-based first line (1L) therapy for patients (pts) with aUC based on ph. 3 Javelin Bladder 100 study (NCT02603432), showing significant overall survival (OS) improvement. Here we tested the activity of ave as 1L of therapy in cis-unfit pts with aUC and PD-L1+ve expression. Methods: ARIES is a single-arm, multi-site, open-label phase II trial. Enrolled pts had aUC, were cis-unfit (at least one of: ECOG-PS = 2, CrCl < 60 mL/min, grade ≥2 peripheral neuropathy/hearing loss, progression within 6-mos before the end of neo/adj chemo), had not previously received chemo for aUC and PD-L1≥5% (SP263) centrally assessed. Pts received ave 10 mg/Kg IV Q2W until progression, unacceptable toxicity and withdrawal, whichever occurred first. The primary endpoint was the 1-year OS. Key secondary endpoints were median-OS, -PFS, ORR and safety. Results: A total of 198 eligible cis-unfit pts have been tested for PD-L1 and 71 (35.6%) have been found positive. Among enrolled patients (N = 71), median age was 75 y, 35 (49.3%) had visceral disease, and 22 (31.0%) had ECOG-PS = 2; 50 (70.4%) had CrCl < 60 mL/min and 9 (12.7%) progressed within 6-mos from the end of neo/adj chemo. At the cut-off data (Oct 7, 2021), median follow up was 9.0 mo and 13 patients are still on treatment. The median OS was 10.0 mos (95% CI, 5.7-14.3), and 40.8% of patients were alive at 1-year. The ORR for all patients was 22.5%; complete response, 1.4% (n = 1); partial response, 21.1% (n = 15). Clinical benefit was 43.6% (n = 31). Median PFS was 2.0 mos (95% CI, 1.4-2.6). Among the 56 pts who received at least 3 cycles (29 days) of therapy the median OS was 16.0 vs 1.0 mos. Five (7.0%) grade 3 ave-related adverse events, and no treatment-related death were reported. Conclusions: Ave is active and safe in pts with cis-unfit, PD-L1+ve aUC and poor baseline characteristics. Clinical trial information: NCT03891238.

BACKGROUND: Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder with heterogeneous biological and clinical features. The biomolecular mechanisms of CML response to tyrosine-kinase inhibitors are not fully defined. OBJECTIVE: We undertook a gene expression profiling (GEP) study of selected bone marrow (BM) CD34+/lin-cells of chronic-phase CML patients at diagnosis and after 12 months of TKI nilotinib to investigate molecular signatures characterizing both conditions. METHODS:We selected and counted BM CD34+/lin- cells of 30 CML patients at diagnosis and during 3, 6 and 12 months of first-line nilotinib treatment. GEP was performed between CD34+/lin- cells of patients at diagnosis and the same patients after 12 months of nilotinib. RESULTS: The number of BM CD34+/lin- cells dramatically decreased after 3, 6 and 12 months of nilotinib. GEP detected 264 statistically significant differentially expressed genes at diagnosis vs. 12 months of nilotinib. Functional enrichment analysis revealed groups of genes belonging to 14 pathways differentially active during nilotinib treatment. CONCLUSIONS: In conclusion, lipid, glucose and sphingolipid metabolism, insulin resistance, complement and coagulation, platelet activation, cytoscheleton, cell adhesion, transport, B cell differentiation, RAS-signaling pathway, proliferation, growth factors, and apoptosis were significantly deregulated between CML patients at diagnosis and after 12 months of nilotinib.

Many efforts have been made to predict prognosis of newly diagnosed Hodgkin Lymphoma (HL) patients. Objective of this study was to investigate the association between early reduction of Thymus and Activation-Regulated Chemokine after the first ABVD cycle (TARC-1) and prognosis of HL patients.Serum samples of 116 HL patients were collected at baseline, after every ABVD cycle and during follow-up. The 99th centile of TARC distribution in a group of 156 independent healthy subjects (800pg/ml) was considered as cut-off for discriminating between abnormal and normal TARC values.101 patients out of 116 had baseline TARC above 800pg/ml (median value 27515pg/ml (IQR, 11001-68139)) and were the object of this analysis. TARC-1 significantly decreased to a median value of 556pg/ml (IQR, 378-977pg/ml). TARC-1 values below 800pg/ml were associated with success of therapy (p=0.0003) and PET-2 negativity (p=0.001). TARC-1≤800pg/ml identified a population with a significantly higher 5-years PFS in the whole cohort (90.1% vs 55.6%; p0.0001) and in both subgroups of advanced (p=0.003) and early stage patients (p=0.021). At multivariable analysis, TARC-1 was significant independent predictor of PFS (p=0.0035).Early reduction of TARC serum levels can predict success of treatment, being associated with achievement of interim PET-2 negative and favorable long-term outcome in HL patients receiving ABVD as front-line therapy.

Chronic myeloid leukemia (CML) is characterized by the constitutive tyrosine kinase activity of the oncoprotein BCR-ABL1 in myeloid progenitor cells that activates multiple signal transduction pathways leading to the leukemic phenotype. The tyrosine-kinase inhibitor (TKI) nilotinib inhibits the tyrosine kinase activity of BCR-ABL1 in CML patients. Despite the success of nilotinib treatment in patients with chronic-phase (CP) CML, a population of Philadelphia-positive (Ph+) quiescent stem cells escapes the drug activity and can lead to drug resistance. The molecular mechanism by which these quiescent cells remain insensitive is poorly understood. The aim of this study was to compare the gene expression profiling (GEP) of bone marrow (BM) CD34+/lin- cells from CP-CML patients at diagnosis and after 12 months of nilotinib treatment by microarray, in order to identify gene expression changes and the dysregulation of pathways due to nilotinib action. We selected BM CD34+/lin- cells from 78 CP-CML patients at diagnosis and after 12 months of first-line nilotinib therapy and microarray analysis was performed. GEP bioinformatic analyses identified 2,959 differently expressed probes and functional clustering determined some significantly enriched pathways between diagnosis and 12 months of nilotinib treatment. Among these pathways, we observed the under expression of 26 genes encoding proteins belonging to the cell cycle after 12 months of nilotinib treatment which led to the up-regulation of chromosome replication, cell proliferation, DNA replication, and DNA damage checkpoint at diagnosis. We demonstrated the under expression of the ATP-binding cassette (ABC) transporters ABCC4, ABCC5, and ABCD3 encoding proteins which pumped drugs out of the cells after 12 months of nilotinib. Moreover, GEP data demonstrated the deregulation of genes involved in the JAK-STAT signaling pathway. The down-regulation of JAK2, IL7, STAM, PIK3CA, PTPN11, RAF1, and SOS1 key genes after 12 months of nilotinib could demonstrate the up-regulation of cell cycle, proliferation and differentiation via MAPK and PI3K-AKT signaling pathways at diagnosis.

5052 Background: Enzalutamide is a second-generation androgen receptor inhibitor that showed to prolong survival in different setting of prostate cancer. Visceral metastases, occurring in 10–30% of mCRPC pts, have been associated with poor outcomes. Given the poor prognosis, trial investigating hormone therapies often excluded men with visceral disease, especially in the pre-docetaxel setting. To date, there are no prospective studies designed ad hoc to test hormone therapies in this subgroup of pts. Methods: In this open label phase II multicentre study mCRPC pts with visceral metastases were treated with enzalutamide 160 mg orally once daily as first or second line after docetaxel until progressive disease or unacceptable toxicity. Pts were eligible if they had documented measurable metastatic visceral disease (according to RECIST 1.1 criteria), including lesions in lung or liver or extraregional lymphnodes. Pts must have PSA progression or radiographic progression (according to PCWG2). Primary endpoint was to determine the clinical benefit, as measured by 3-months (mo) disease control rate (DCR) defined as the proportion of pts with best overall response of confirmed complete (CR) or partial responses (PR) or stable disease as per RECIST 1.1 at mo 3. Secondary endpoints were safety, quality of life (assessed by EQ-5D-5L e FACT-P questionnaire), pain assessment (by BPI-SF questionnaire). Exploratory objectives were to assess the association between ARv7 splicing variants (in CTCs samples) and treatment response/resistance. For CTC and ARv7 detection, we used the Adna test Prostate Cancer Panel. Results: From March 2017 through January 2021, 68 pts were enrolled at 6 Italian centres. One pt never started treatment because of withdrawal of consent. Median age was 70 years (IQR 65- 78). All pts presented with visceral disease at baseline: 27, 6, 55 pts presented with lung, liver and lymphnodes lesions, respectively. 26 pts presented with only one metastatic site, 22 pts with two, while the remaining part with multiple sites. 15 pts received a previous treatment with docetaxel in the mCRPC phase. The median follow-up was 10 mo. The median time on treatment was 8 mo. At mo 3, 24 pts presented a stable disease, 1 pt achieved a confirmed CR and 20 pts a PR for a 3 mo-DCR of 67% (45/67). Discontinuations due to adverse-events, disease-related death, or disease progression occurred in 6%, 7%, and 40% of pts, respectively. So far, only 26 patients were evaluated for baseline CTC and ARv7. Interestingly, 75% of patients experiencing a progression at month 3 were classified as ARv7 positive at baseline. Conclusions: The study met its primary endpoint showing enzalutamide is an active treatment option for men with mCRPC and visceral disease in both pre or post-docetaxel setting. CTCs status combined with ARv7 detection could be useful to personalize treatments. Clinical trial information: NCT03103724.

In the PhilosoPhi34 study (EudraCT: 2012-005062-34) on 87 CP-CML patients, we analyzed the gene expression profiling (GEP) of bone marrow (BM) CD34+/lin- cells of 79 patients with chronic-phase chronic myeloid leukemia (CP-CML) patients at diagnosis and after 12 months of nilotinib treatment (Pungolino et al. AM J Hematol. 2018). FISH analyses identified CD34+/lin- Ph+ cells in all 79 CML-CP patients at diagnosis. 78/79 patients achieved at least a complete cytogenetic response after 12 months of nilotinib whereas 1/79 patients relapsed at 12 months. No Ph+ nuclei were detected in 78/79 patients at 12 months. We have demonstrated that genes involved in the JAK-STAT signaling pathway, the cell cycle, and the ATP-binding cassette (ABC) transporters were significantly over expressed in patients at diagnosis compared to 12 months of nilotinib treatment (Trojani et al, PLoS One. 2019). In this preliminary study, we isolated BM CD34+/lin- cells from 9 healthy donors (CTRLs). We investigated the gene expression profiling of 79 CP-CML patients at diagnosis vs. the same patients after 12 months of nilotinib treatment (12 months) vs. 9 CTRLs using Affymetrix HTA 2.0. Data was preprocessed and normalized using RMA and ComBat. Selection of differentially expressed genes (DEg) was performed at diagnosis vs. 12 months of nilotinib vs. CTRLs, using Statistical Analysis for Microarrays (SAM) on 3 groups and a Benjamini Hochberg false discovey rate threshold of 5%, followed, for significance comparisons, by a pair-wise SAM test. We focused on 34 genes of the cell cycle and mitosis, 6 genes belonging to the JAK-STAT signaling pathway, and the ABC transporter gene ABCD3 which were significantly under expressed at diagnosis vs. 12 months of nilotinib vs. CRTLs (Tab.1). In the cell cycle, we found that ORC2, ORC4, ORC5, MCM6, and HDAC2 (G1 phase) were progressively significantly down regulated at diagnosis vs. 12 months vs. CTRLs. We noticed HDAC2 which showed the high fold changes of 2.89 and 4.29 in the comparison between 12 months vs. CTRLs and between diagnosis vs. CTRLs, respectively. This gene plays a crucial role in CML, as HDAC inhibitors treatment represent an effective strategy to target leukemic stem cells in CP-CML patients receiving tyrosine kinase inhibitors. CCNA2, CDK7, CDC6, DBF4 (S phase), WEE1, PRKDC, ATM, MDM2, CCNB1 (G2 phase), and TTK, MAD2L1, BUB1, BUB3, ANAPC4, CDC27, SMC3, YWHAE, and YWHAZ (M phase) were progressively down regulated at diagnosis vs. 12 months vs. CTRLs. Among them, SMC3, YWHAE and YWHAZ showed the following high fold changes in the comparison between 12 months vs. CTRLs and between diagnosis vs. CTRLs: 2.31 and 3.15, 2.59 and 3.94, 2.75 and 4.15, respectively. Notably, the proto-oncogene MDM2 which promotes the development of tumors by targeting p53, was progressively up regulated in CTRLs vs. 12 months vs. diagnosis. In the mitosis, we detected that 10 genes playing a crucial role in mitotic chromosome organization, were progressively under expressed at diagnosis vs. 12 months vs. CTRLs (Tab.1). Notably, CLAPS2, ZW10 and ANLN (hematopoietic cell differentiation) regulate the exit from mitosis. NDC80, SMC4, ZNF207, and NEK2 take part in the mitotic sister chromatid segregation whereas CENPE and SMC2 are mitotic cell cycle check points. In the JAK-STAT signaling pathway, SOS1, PIK3CA, IL7, JAK2, STAM, and PTPN11 were progressively up regulated in CTRLs vs. 12 months vs. diagnosis (Tab.1). ABCD3, encoding a protein which pumped drugs out of the cells, was progressively under expressed at diagnosis vs. 12 months vs. CRTLs as shown in Tab.1. In conclusion, we found progressive gene expression changes in BM CD34+/lin- cells of 79 CP-CML patients at diagnosis vs. 12 months of nilotinib vs. the normal cell counterparts of 9 CTRLs in the cell cycle, JAK-STAT, and the ABC transporter ABCD3. FISH analyses demonstrated that the BM CD34+/lin- cells of 78/79 patients after 12 months of nilotinib were Ph-negative. Despite, our GEP results suggested that BM CD34+/lin- cells after 12 months of nilotinib treatment and the normal cell counterparts differed mostly in the expression of genes regulating the cell cycle and the JAK-STAT signaling pathway. Disclosures Rossi: Daiichi-Sankyo: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Mundipharma: Honoraria; BMS: Honoraria; Sandoz: Honoraria. Elena:Novartis: Consultancy; Pfizer: Consultancy. Iurlo:Pfizer: Other: Speaker Honoraria; Incyte: Other: Speaker Honoraria; Novartis: Other: Speaker Honoraria.

Myeloproliferative neoplasms (MPNs) are clonal disorders that include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Patients with MPNs have a higher risk than the general population of developing a lymphoid neoplasm.1 It is still unclear whether this holds true for nonhematological second primary malignancies (SPMs).2-4 However, among 20 250 MPN patients included in the Surveillance, Epidemiology, and End Results (SEER) Program database, the 10-year cumulative incidence of SPMs was 12.7%, significantly higher than that expected in the general US population.5 Ruxolitinib (RUX) is an oral JAK inhibitor (JAKi) approved for International Prognostic Scoring System (IPSS)/Dynamic IPSS (DIPSS) intermediate- and high-risk myelofibrosis (MF)6,7 and for inadequately controlled PV. More than 2600 RUX-treated MF patients have been prospectively observed for at least 2 years within the 2 pivotal COMFORT trials8,9 and the expanded-access JUMP trial.10,11 Safety data from these trials underline a possibly increased incidence of nonmelanoma skin cancers (NMSCs), but no significant increase of lymphoproliferative neoplasms, similarly to what occurs in PV.12,13 Recently, Porpaczy et al alerted, however, on the possible 16-fold increased risk of developing aggressive lymphomas in MPN patients treated with JAKis, especially in the presence of a preexisting B-cell clone.14 The publication included a total of 1555 MPN patients, 126 of whom were treated with a JAKi (ruxolitinib, gandotinib, fedratinib, momelotinib), obtained assembling 2 broad academic data sets. In the well-described Viennese cohort, 3 of 31 MF patients treated with JAKi developed lymphomas. Median time from JAKi initiation to lymphoma diagnosis was 25 months. Subsequent analyses of other large academic data sets did, however, not confirm an increased risk of aggressive lymphoma development under JAKis in MPNs15,16 and in post-PV and post-ET MF (secondary MF [SMF]).17 These contradictory results were derived either from clinical trials with strict eligibility criteria, possibly at the expense of uncertainty about the generalizability of results, or from highly selected data sets of patients evaluated at referral centers, thus highlighting the need for real-world data (RWD). We consequently set out to assess the occurrence of SPMs, including lymphoproliferative neoplasms, in RUX-treated MF patients on the basis of RWD provided by the health authority of the Lombardy Region, integrated with institutional data.

In the frame of a circular economy, the maximization of secondary raw-material recovery is necessary to increase the economic and environmental sustainability of landfill mining and reclamation activities. In this paper, the polyethylene-rich plastic fraction recovered from the reclamation of an abandoned industrial landfill (landfill-recovered plastic, LRP) has been characterized through spectroscopic, thermal, morphological, and mechanical analyses. Then, an economically viable valorization and recycling strategy was set up. The effectiveness of this strategy in the enhancement of LRP properties has been demonstrated through morphological and mechanical characterizations.

This monocentric retrospective study included 70 consecutive relapsed/refractory Hodgkin lymphoma (RR-HL) patients receiving reduced-intensity allogeneic stem cell transplantation (alloSCT). We evaluated overall and progression-free survival (OS, PFS), graft-versus host disease/relapse-free survival (GFRS), and chronic GVHD-free OS (cGVHD-free OS) defined as OS without moderate-to-severe cGVHD. Patients had a median age of 33 years (range, 18-60 years), 23% had refractory disease (SD/PD). Donors were HLA identical (39%), unrelated (30%), or haploidentical (31%). Median follow-up was 6.2 years. Five-year OS was 59% and PFS was 49%. NRM was 16% at 1 year. 44% of patients had cGVHD, and 14% moderate-to-severe cGVHD at last follow-up. GFRS and cGVHD-free OS were 26 and 48% at 5 years. In multivariate analysis, resistant disease at alloSCT impacted survival and GFRS. In conclusion, disease response before alloSCT impacts survival and GFRS. GVHD outcomes may help comparing the long-term effects of the new salvage treatments that bridge patients to alloSCT.

Although sometimes presenting as an indolent lymphoma, mantle cell lymphoma (MCL) is an aggressive disease, hardly curable with standard chemo-immunotherapy. Current approaches have greatly improved patients' outcomes, nevertheless the disease is still characterized by high relapse rates. Before approval by EMA, Italian patients with relapsed/refractory MCL were granted ibrutinib early access through a Named Patient Program (NPP). An observational, retrospective, multicenter study was conducted. Seventy-seven heavily pretreated patients were enrolled. At the end of therapy there were 14 complete responses and 14 partial responses, leading to an overall response rate of 36.4%. At 40 months overall survival was 37.8% and progression free survival was 30%; disease free survival was 78.6% at 4 years: 11/14 patients are in continuous complete response with a median of 36 months of follow up. Hematological toxicities were manageable, and main extra-hematological toxicities were diarrhea (9.4%) and lung infections (9.0%). Overall, 4 (5.2%) atrial fibrillations and 3 (3.9%) hemorrhagic syndromes occurred. In conclusions, thrombocytopenia, diarrhea and lung infections are the relevant adverse events to be clinically focused on; regarding effectiveness, ibrutinib is confirmed to be a valid option for refractory/relapsed MCL also in a clinical setting mimicking the real world.

We report the long-term clinical outcomes of a retrospective multicenter study that enrolled 169 patients with multiple myeloma (MM) in first relapse after failing autologous stem cell transplantation (SCT). After HLA typing at relapse, 79 patients with a suitable donor, 72 (91%) of whom eventually underwent salvage allogeneic SCT (allo-SCT), were compared with 90 patients without a donor who were treated with multiple lines of salvage treatment with bortezomib and/or immunomodulatory agents. At a median follow-up of 30 months (range, 2-180 months) for all patients and 110 months (range, 38-180 months) for surviving patients, 7-year progression-free survival (PFS) was 18% in the donor group and 0% in the no-donor group (hazard ratio [HR], 2.495; 95% confidence interval [CI], 1.770-3.517; P .0001). Seven-year overall survival (OS) was 31% in the donor group and 9% in the no-donor group (HR, 1.835; 95% CI, 1.306-2.577; P .0001). By multivariate analysis, chemosensitivity to salvage treatments and presence of a suitable donor were significantly associated with better PFS and OS. The long-term follow-up of this study confirms the significant PFS benefit and provides new evidence of an OS advantage for patients with MM who have a suitable donor and undergo allo-SCT. Allo-SCT should be considered as a treatment option in young relapsed patients with high-risk disease features after first-line treatment.

Immunomodulatory drugs (IMiDs) may favor autoimmune disease (AD) occurrence. We conducted a retrospective study to evaluate AD occurrence among IMiD-treated patients with myeloma. Patients were grouped into three classes depending on the type of IMiD engaged. The first group included patients treated with thalidomide (Thal) (n = 474), the second group with lenalidomide (Len) (n = 140) and patients in the third group were first treated with Thal followed by Len (Thal-Len) (n = 94). Absolute risk of AD was 0.4% for patients treated with Thal, 4.3% for Len and 1.1% for Thal-Len. ADs manifested prevalently as autoimmune cytopenias (55%), although we observed one vasculitis, one optic neuritis, one Graves' disease and one polymyositis. ADs occurred preferentially in the first months of IMiD treatment. A previous autologous transplant was shown to be a significant risk factor. All ADs were managed with IMiD discontinuation and steroids, resolving in a few weeks, except for Graves' disease and polymyositis.

Cytomegalovirus (CMV) replication after allogeneic hematopoietic stem cell transplantation (HSCT) was historically associated with increased nonrelapse mortality (NRM). More recently, different groups have reported an association between CMV replication and reduced risk of acute myeloid leukemia (AML) relapse. Given the conflicting results, we evaluated the impact of CMV replication and other covariates on the outcome of a retrospective cohort of 265 adults with B cell lymphoma receiving allogeneic HSCT from HLA-identical siblings or alternative donors. In time-dependent multivariate analysis, CMV replication, evaluated by pp65 antigenemia, had no independent effect on the risk of relapse (hazard ratio [HR], 1.0; 95% confidence interval [CI], .6 to 1.6; P = .9), although it was associated with a reduced overall survival (HR, 2.0; 95% CI, 1.3 to 3.2; P = .001) and an increased NRM (HR, 2.5; 95% CI, 1.1 to 5.3; P = .01). Consistently, donor and/or recipient CMV seropositivity were not associated with a different outcome relative to CMV double-negative serostatus. In multivariate models, a diagnosis of follicular lymphoma (P

Plerixafor "on demand" after chemotherapy plus granulocyte-colony-stimulating factor (G-CSF) is efficient in peripheral stem cell mobilization, but the timing of administration and criteria for patient selection are under investigation. To devise an algorithm for the "on demand" use of plerixafor at the first mobilization attempt, we analyzed the kinetics of hematopoietic recovery and peripheral blood CD34+ cells in 107 patients treated with high-dose cyclophosphamide plus G-CSF. Fifty-one patients with myeloma were treated with cyclophosphamide 3-4 g/m(2) on day 0 followed by G-CSF 10 μg/kg from day + 6, and 56 patients with lymphoma received cyclophosphamide 6-7 g/m(2) followed by G-CSF 5 μg/kg from day + 1. Peripheral blood CD34+ cell monitoring was started on day + 8 in patients with myeloma and day + 10 in patients with lymphoma. The outcome of interest was a collection of ≤ 2 × 10(6) CD34+/kg. By a multivariate logistic regression model, CD34+ cell count10/μL at leukocyte recovery (1000/μL) or leukocyte count1000/μL after day + 12 in myeloma and day + 14 in lymphoma predicted the failure of mobilization by 2.7 and 2.8 times (p = 0.001 and p = 0.02) with a sensitivity of 89% and specificity of 88%, respectively. Plerixafor "on demand" may be considered in patients with myeloma and lymphoma with delayed hematopoietic recovery and10/μL CD34+ cells, as a first-line mobilization strategy.

Multiple myeloma relapsing after allogeneic stem cell transplantation (alloSCT) has a poor outcome. To assess the safety and efficacy of bortezomib and dexamethasone (VD) combination followed by donor lymphocyte infusions (DLIs) in myeloma patients relapsing or progressing after alloSCT, a prospective phase II study was designed. The treatment plan consisted of three VD courses followed by escalated doses of DLIs in case of response or at least stable disease. Nineteen patients were enrolled with a median age of 57 years (range, 33 to 67); 14 patients were allografted from human leukocyte antigen–identical siblings and 5 from alternative donors. Sixteen of 19 patients received the planned treatment, but 3 patients did not: 2 patients because of disease progression and 1 refused. After the VD phase the response rate was 62%, with 1 complete remission, 6 very good partial remissions, 5 partial remissions, 2 patients with stable disease, and 5 with progressive disease. After the DLI phase, the response rate was 68%, but a significant upgrade of response was observed: 3 stringent complete remissions, 2 complete remissions, 5 very good partial remissions, 1 partial remission, 4 with stable disease, and 1 with progressive disease. With a median follow-up of 40 months (range, 29 to 68), the 3-year progression-free survival and overall survival rates were 31% and 73%, respectively. Neither unexpected organ toxicities, in particular severe neuropathy, nor severe acute graft-versus-host disease flares were observed. VD-DLIs is a safe treatment for multiple myeloma patients relapsing or progressing after alloSCT and may be effective.

Allogeneic stem cell transplantation (allo-SCT) using reduced-intensity conditioning (RIC) is a feasible procedure in selected patients with relapsed multiple myeloma (MM), but its efficacy remains a matter of debate. The mortality and morbidity related to the procedure and the rather high relapse risk make the use of allo-SCT controversial. In addition, the availability of novel antimyeloma treatments, such as bortezomib and immunomodulatory agents, have made allo-SCT less appealing to clinicians. We investigated the role of RIC allo-SCT in patients with MM who relapsed after autologous stem cell transplantation and were then treated with a salvage therapy based on novel agents. This study was structured similarly to an intention-to-treat analysis and included only those patients who underwent HLA typing immediately after the relapse. Patients with a donor (donor group) and those without a suitable donor (no-donor group) were compared. A total of 169 consecutive patients were evaluated retrospectively in a multicenter study. Of these, 75 patients found a donor and 68 (91%) underwent RIC allo-SCT, including 24 from an HLA-identical sibling (35%) and 44 from an unrelated donor (65%). Seven patients with a donor did not undergo allo-SCT for progressive disease or concomitant severe comorbidities. The 2-year cumulative incidence of nonrelapse mortality was 22% in the donor group and 1% in the no-donor group (P < .0001). The 2-year progression-free survival (PFS) was 42% in the donor group and 18% in the no-donor group (P < .0001). The 2-year overall survival (OS) was 54% in the donor group and 53% in the no-donor group (P = .329). In multivariate analysis, lack of a donor was a significant unfavorable factor for PFS, but not for OS. Lack of chemosensitivity after salvage treatment and high-risk karyotype at diagnosis significantly shortened OS. In patients who underwent allo-SCT, the development of chronic graft-versus-host disease had a significant protective effect on OS. This study provides evidence for a significant PFS benefit of salvage treatment with novel drugs followed by RIC allo-SCT in patients with relapsed MM who have a suitable donor.

Patients with therapy-related acute myeloid leukemia (t-AML) and myelodysplastic syndromes (t-MDS) have poor survival and high non-relapse mortality (NRM) after allogeneic stem cell transplantation. This retrospective study assessed the transplant outcomes of 29 consecutive patients with t-AML (83%) or t-MDS (17%) treated with allogeneic transplantation. The median age of patients was 51 years. Donors were mostly matched unrelated (52%), and 59% of patients received myeloablative conditioning. Two-year overall survival, event-free survival and relapse incidence were 37%, 34% and 33%; NRM was 17% at 100 days, and 32% at 2 years. Event-free survival was reduced in patients with high-risk cytogenetics (p = 0.02), Karnofsky performance status ≤ 80% (p = 0.001) and disease after induction ± consolidation (p = 0.006). NRM was higher in patients receiving > 2 therapy lines for previous cancer (p = 0.01) and in those allografted > 6 months from diagnosis (p = 0.03). In conclusion, allogeneic transplantation should be proposed timely to these patients after an accurate analysis of patient history.

Evidence of long-term response to lenalidomide in heavily pretreated patients with multiple myeloma is lacking. This study sought to assess whether long-term responders exist, long-term responders' characteristics, and predictive factors of a long-term response. One hundred and four patients with multiple myeloma treated with lenalidomide and dexamethasone after ≥2 therapy lines (median, 3) were analyzed. Long-term response was defined as at least a partial response (≥PR) lasting ≥12 months. The overall response rate was 73%, and 80.3% of the responses were achieved within 5 months. The median response was 14.3 months. Patients evaluable for long-term response numbered 87, and a total of 47% were long-term responders. Compared to non-long-term responders, long-term responders had better overall survival, less light-chain multiple myeloma, and higher incidence of t(11;14). Previous allogeneic transplant (alloSCT) and the response quality predicted a long-term response. In conclusion, patients treated with lenalidomide can become long-term responders; alloSCT and response quality predict long-term response.

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.

e21623Background: Fatigue is one of the most distressing symptoms of cancer pts. Incidence, characteristics, impact on quality of life and treatment of cancer-related fatigue in Italian oncological...

Plerixafor ‘on demand’: results of a strategy based on peripheral blood CD34+ cells in lymphoma patients at first or subsequent mobilization with chemotherapy+G-CSF

The study analyzed 30 chronic phase CML patients at diagnosis and at 3, 6 and 12 months of first-line nilotinib treatment. As optimal molecular response was achieved at 3, 6 and 12 months after nilotinib in all the 30 patients (figure 1), we established cut off values of molecular response (MR) to define groups of CML patients (n =30), and to investigate differences of gene expression profiles between patients at diagnosis based on the MR achieved after 3, 6 and 12 months of nilotinib, respectively. We used the following cut off values: 1% IS at 3 months of nilotinib, 0.1% IS at 6 months of nilotinib, and 0.01% IS at 12 months of nilotinib. Patients were divided into 2 groups based on MR values of each patient at 3 months of nilotinib: group A (n =24) with MR ≤1.0% IS and group B (n =6) with MR >1% IS. Based on the values of MR at 6 months of nilotinib, patients were divided into 2 groups: group C (n =22) with MR ≤0.1% IS and group D (n =8) with MR >0.1% IS. At 12 months of nilotinib, patients were divided into the following groups: group E (n =18) with MR ≤0.01% IS and group F (n =12) with MR >0.01% IS. Gene expression profiling (GEP) on the selected bone marrow (BM) CD34+/lin- cells of 30 CML patients at diagnosis was performed using Affymetrix GeneChip HTA 2.0. GEP data was preprocesses using RMA. SAMR and GSEA were used to detect differentially expressed genes and pathways (i.e. MSigDB Canonical pathways and GOBP gene sets) associated with the different groups, respectively. In both cases, correction for multiple testing was performed using the false discovery rate procedure with a threshold 0.05 for SAMR and 0.25 for GSEA as suggested by the software developers. GSEA detected significant differences in the transcriptional signature between group A and group B associated with the MR at 3 months as well as between group C and group D in respect to the MR at 6 months of nilotinib, whereas no genes were identified as significantly differentially expressed. Based on the MR at 3 months, we identified Reactome pathways "P130 cascade" and "GRB2 SOS linkage to MAPK signaling for integrins" significantly upregulated in group A compared to group B. FGA, FGB, FGG, APBB1IP, ITGA2B and CRK genes contributed to call the pathways upregulated. In vitro studies (Ding J et al. PloS One, 2013) demonstrated that nilotinib induced dephosphorilation of the BCR-ABL1 target CRK oncogene which acts in the CML hematopoietic stem cells like an adaptor in diverse signaling pathways and cellular processes playing an apoptotic role in CML. Our GEP results highlighted that the Reactome pathway involved in MAPK signaling (CRK gene) wasover expressed in CML patients with a better MR ≤1% IS at 3 months of nilotinib. Pathway "aminoacid and amine transport across the plasma membrane" was also significantly over expressed, whereas "lipid metabolism" was significantly down regulated (genes AKR1C1 and ANGPTL3) in group A compared to group B, respectively. Based on the MR at 6 months, GEP results showed that "positive regulation of cytokine secretion" and "interleukin 1 secretion" were significantly upregulated in group C compared to group D, involving PYCARD8, NLRP2, NLRC4, NLRP3 and CARD8 genes. Of note, PYCARD and CARD8 represent key mediators, which promote caspase-mediated apoptosis processes involving the recruitment of certain recognition receptors, such as NLRP2, NLRP3 and NLRC4. In addition, CARD8 and PYCARD promote apoptosis inhibiting NFKB activation. In conclusion, the study showed that MAPK signaling for integrins and amine transport across the plasma membrane were significantly over expressed in CML patients with a MR ≤1.0% IS while lipid metabolism was significantly over expressed in CML patients with a MR >1% IS after 3 months of nilotinib. After 6 months of nilotinib, positive regulation of cytokine secretion and interleukin 1 secretion were significantly over expressed in CML patients with a MR ≤0.1 IS compared to patients with a MR >0.1% IS. We identified distinct sets of genes involved in apoptotic processes differentially expressed in 30 CML patients based on the MR at 3 months as well as 6 months of first-line nilotinib treatment. Studies in a larger cohort of CML patients are ongoing to define the expression, role and functions of the genes regulating apoptosis CRK, PYCARD and CARD8 as candidate prognostic factors for molecular response to first-line nilotinib treatment. Disclosures No relevant conflicts of interest to declare.

Background. Chronic Myeloid Leukaemia (CML) can be effectively treated with the first generation Tyrosine Kinase Inhibitor (TKI) Imatinib, and more effectively with the second generation TKI, like Nilotinib. However, despite the deeper and faster responses induced by nilotinib in a large proportion of patients, the possible eradication of the pathological stem cells is not yet clearly elucidated. In fact, in vitro data suggest that quiescent stem cells are not sensitive to Bcr/Abl inhibition (Corbin AS, et al 2011; Hamilton A, et al 2012). A preliminary in-vivo study (Defina M, et al 2012) shows that in patients in CCyR even after short-term of nilotinib therapy, residual leukemic progenitors are rarely detected. Methods. On behalf of Rete Ematologica Lombarda (REL), Italy, we designed a single arm prospectic study, PhilosoPhi34 (EudraCT: 2012-005062-34), with the aim to investigate the efficacy of nilotinib 300 mg BID in obtaining the disappearance of Bone Marrow (BM) leukemic stem cells (CD34+/lin-Ph+) in newly diagnosed CP-CML. Primary objective of the study: to enumerate the BM CD34+/lin-Ph+ cells at the end of 6 months of treatment. Secondary objectives: to enumerate the BM CD34+/lin-Ph+ cells at 3 and 12 months; to assess the percentage of patients showing MR ≤10% IS at 3 months and MR ≤1% IS at 6 months and the MMR IS and MR4.5 IS by 3, 6 and 12 months of treatment. BM blood samples (range of 5-20 ml) were collected at diagnosis and after 3, 6 and 12 months of nilotinib treatment. BM mononuclear cells were purified by density gradient centrifugation and then CD34+/lin- cells were isolated using Diamond CD34 Isolation Kit (Miltenyi Biotec). The purity of CD34+/lin- cells was about 97% as determined by flow cytometry. BM CD34+/lin- cells were counted and a range of 100,000-800,000 has been noted at diagnosis. After the treatment we observed that the number of CD34+/lin- cells dramatically decreased after 3 (1,000-600,000), 6 (1,000-260,000) and 12 months (100-130,000). In particular, CD34+/lin- cells were even less than 1000 at 12 month of treatment. In order to verify the disappearance of leukemic stem cells, isolated CD34+/lin- cells were tested by standard FISH (i.e. to categorize a sample as negative at least 200 nucleus were examined). From April 2013 and June 2015 we enrolled 87 pts, as for protocol. We report here the preliminary results. Results. Of 56 patients in CCyR after 6 months of treatment, FISH performed on BM CD34+/lin- cells nuclei was evaluable in 51 cases (5 negative cases were excluded because of less than 200 nucleus were analysed). In 4 out of 51 patients (7.8%), Ph+ nuclei were detected. The Sokal score of these 4 patients was 1 low, 2 intermediate and 1 high risk with a ratio (positive nuclei/total nuclei) of 295/300, 1/200, 2/92, 3/300, respectively. Among 58 patients tested at 3 months and 44 tested at 12 months of treatment, the number of evaluable patients was 48 and 37, respectively; 8/48 (16.6%) and 0/37 (0%) patients showed Ph+ nuclei. Only 2 out of 8 positive patients had a high Sokal score. Regarding efficacy of treatment, Table 1 summarizes the MRs IS observed after 3, 6 and 12 months of treatment in 71, 57 and 41 patients, respectively. Conclusion. Data of this prospective study confirms that nilotinib 300 mg BID, rapidly and progressively induces the clearance of BM CD34+/lin-Ph+ cells in CP-CML patients. In particular, on CD34+/lin- cells, after 6 months of treatment, only 7.8% of patients showed positive nuclei. On 37 patients after 12 months of treatment, no positive nuclei were detected. So far, the kinetic of reduction of such cells seems not influenced by Sokal score. According to international studies, PhilosoPhi34 shows a very high efficacy of Nilotinib to induce MRs in CP-CML patients, at the standard time points. Table 1. Molecular Response (MR) in CP-CML patients treated with Nilotinib 300mg BID from diagnosis. MR IS 3 months 6 months 12 months ≤10% 67/71 94% 57/57 100% 40/41 97.50% ≤1% 57/71 80% 55/57 96.50% 40/41 97.50% ≤0.1% 17/71 24% 41/57 72% 35/41 85% ≤0.01% 3/71 4% 19/57 33% 20/41 48.70% MR4.5(UD) 2/71 2.80% 10 (6)/57 17.5% (10.5%) 15 (9)/41 36.5% (22%) UD: undetectable We acknowledge all REL Colleagues for their collaboration and Novartis SpA for the partial financial support to the study. Disclosures No relevant conflicts of interest to declare.

e282 survival (OS) and progression-free survival (PFS) were 69% (95% CI:6-55%) and 35% (95% CI:6-22%), respectively (Figure 1). On multivariate analysis, chemorefractory disease at alloHCT was associated with an inferior PFS (Hazard risk [HR] 5.75 [95% CI:2.32-14.23]), inferior OS (HR 5.19 [95% CI:2.05-13.14]), higher toxicity related mortality (TRM, HR 6.60 [95% CI: 1.1139.02]) and higher RI/POD (HR 4.04 [95% CI: 1.07-15.21]). Being younger than 55 years emerged as a protective factor for both PFS (HR0.29 [95%CI:0.14-0.60]) and OS (HR 0.29[0.01-0.10]). Chronic GVHD conveyed a higher TRM (HR 1.15 [95%CI:1.021.30]) but not a reduced RI/POD. Conclusion: Our retrospective data show that RIC alloHCT is a safe and effective therapeutic option in MM patients, allowing long survival outcomes even in heavily pretreated patients. Figure 1 OS (A) and PFS (B) of the whole study population 15th International Myeloma Workshop, September 23-26, 2015 PO-349 Durable Remission and Survival in Relapsed/Refractory Multiple Myeloma After Allogeneic Hematopoietic Stem Cell Transplantation A.M. Cornelison, R.M. Saliba, S. Ahmed, Y. Nieto, Q. Bashir, N. Shah, S. Parmar, K. Patel, C. Hosing, U. Popat, E. Shpall, R. Champlin, M.H. Qazilbash Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas Background: The role of allogeneic hematopoietic stem cell transplantation (allo-HCT) in the setting of refractory multiple myeloma (MM) is still controversial. Although potentially curative in a subset of pts, 10-15% treatment related mortality (TRM) and chronic graft vs. host disease (cGVHD) preclude its universal use. In this study, we evaluated the role of allo-HCT for pts with relapsed MM. Methods: We identified 110 consecutive pts with relapsed MM who underwent allo-HCT at our institution between 2000 and 2014. The primary objective was to assess progression-free (PFS) and overall survival (OS). Results: Median age at allo-HCT was 54 (range, 32-71) years and median time from diagnosis to alloHCT was 35.7 (range, 8.6 to 228.8) months. Fifty-two (47%) and 49 (45%) pts had standard-risk (SR) and high-risk (HR) cytogenetics (CG) at the time of allo-HCT, respectively. Pts received a median of 5 (range, 1-9) prior chemotherapy regimens and 99 pts (90%) had at least 1 (range, 0-3) prior auto-HCTs. One hundred one(92%) pts received either a proteasome inhibitor (PI) or an immunomodulatory drug (IMiD) prior to allo-HCT, with 65 (59%) receiving both. Sixty eight (62%) received allo-HCT from a matched related, 34 (31%) from a matched unrelated, 5 (4%) from a cord blood, and 3 (3%) from a mismatched donor. Preparative regimen was fludarabine/melphalan-based in 88 (80%) and fludarabine/busulfan-based in 16 (15%) patients. Median time to neutrophil and platelet engraftment was 12 (range, 8-30) and 13 (range, 0-81) days, respectively. Ten pts died of non-relapse causes within 100 days (100-day TRM: 9%) and 20 (18%) within 1 year. Grade 1-4 acute GVHD was seen in 50 (45%) and cGVHD in 35 (32%) pts, respectively. Eighteen (16%) achieved a CR, 26 (23%) a VGPR and 38 (34%) achieved a PR, with an overall response rate of 73%. With a median follow up of 11.4 months (range 0.3 to 164) in all pts, and 32.7 months (range 3.6 to 164.3) in surviving pts, 1and 2-year PFS were 24% and 16%, respectively. Similarly, 1and 2-year OS were 52% and 32%, respectively. HR CG at allo-HCT and a response

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.

Objectives The efficacy of a novel vaccine against influenza virus A (H1N1) in patients with hematologic malignancies is largely unknown. Methods We prospectively evaluated the humoral and cellular immune responses after one injection of monovalent adjuvanted 2009 H1N1 vaccine in 47 adults with hematologic malignancies and 77 controls by hemagglutination-inhibition assay and flow-cytometry analysis on day 0, 28, 50, and 90. Results On day 28 postvaccination, patients had lower seroprotection (95.2% vs. 75.2%, P

Rescue chemotherapy or autologous stem cell transplantation (autoSCT) gives disappointing results in relapsed peripheral T-cell lymphomas (PTCLs). We have retrospectively evaluated the long-term outcome of 52 patients receiving allogeneic SCT for relapsed disease. Histologies were PTCL-not-otherwise specified (n = 23), anaplastic large-cell lymphoma (n = 11), angio-immunoblastic T-cell lymphomas (n = 9) and rare subtypes (n = 9). Patients were allografted from related siblings (n = 33, 64%) or alternative donors (n = 13 (25%) from unrelated and 6 (11%) from haploidentical family donors), following reduced-intensity conditioning (RIC) regimens including thiotepa, fludarabine and cyclophosphamide. Most of the patients had chemosensitive disease (n = 39, 75%) and 27 (52%) failed a previous autoSCT. At a median follow-up of 67 months, 27 of 52 patients were found to be alive (52%) and 25 (48%) were dead (n = 19 disease progression, n = 6 non-relapse mortality (NRM)). The cumulative incidence (CI) of NRM was 12% at 5 years. Extensive chronic graft-versus-host disease increased the risk of NRM (33% versus 8%, P = 0.04). The CI of relapse was 49% at 5 years, influenced by disease status at the time of allografting (P = 0.0009) and treatment lines (P = 0.007). Five-year overall survival and progression-free survival (PFS) were 50% (95% CI, 36 -63%) and 40% (95% CI, 27 - 53%), respectively. The current PFS was 44% (95% CI, 30-57%). In all, 8 out of 12 patients (66%) who received donor-lymphocytes infusions for disease progression had a response. At multivariable analysis, refractory disease and age over 45 years were independent adverse prognostic factors. RIC allogeneic SCT is an effective salvage treatment with a better outcome for younger patients with chemosensitive disease. Leukemia (2012) 26, 520-526; doi:10.1038/leu.2011.240; published online 9 September 2011

Abstract 3534 Background: Allogeneic stem cell transplantation (allo-SCT) employing reduced intensity conditioning (RIC) is a feasible procedure in selected patients with relapsed multiple myeloma (MM), but its efficacy is still a matter of debate. The mortality and the morbidity related to the procedure and the rather high relapse risk have made the use of allo-SCT controversial. In addition, the availability of novel anti myeloma treatments, such as bortezomib and lenalidomide, have made the use of allo-SCT less appealing for clinicians. Aims: We investigated the role of RIC allo-SCT in MM pts who relapsed after autologous stem cell transplantation (auto-SCT) and were then treated with a salvage therapy based on novel agents. 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 sixty-nine consecutive pts were retrospectively evaluated in a multicenter study between 2002 and 2008. Seventy-five found a donor and 68 (90%) underwent an allo-SCT: 24 identical sibling (35%), 44 MUD (75%). Conditioning regimens were fludarabine, melphalan±thiotepa in 28 patients (41%), fludarabine + 2 Gy TBI in 24 cases (35%), fludarabine and cyclophosphamide in 8 patients (12%) and fludarabine and treosulfan in the remaining 8 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 59 years, p Results: The median follow-up after the beginning of first salvage treatment was 19 months (1-97) for all patients and 29 months for living patients. Two-year cumulative incidence of non relapse mortality (NRM) was 22% in the donor group and 1% in the no-donor group (p Conclusions: This study comparing salvage treatment with novel agents consolidated by RIC allo-SCT versus salvage treatment alone after a failed auto-SCT provides evidence for a significant PFS benefit in MM patients having a donor. However, we could not detect a OS advantage. The protective effect of chronic GVHD in transplanted patients indicated a possible role of graft-versus-myeloma effect. These results suggest that allo-SCT is still a reasonable option in young patients with relapsed myeloma having a donor, but new transplant strategies that will reduce NRM and novel agents as consolidation/maintenance after allo-SCT have to be investigated. Disclosures: No relevant conflicts of interest to declare.

The hematopoietic cell transplantation specific comorbidity index (HCT-CI) has been developed to identify patients at high risk of mortality after an allograft. Reduced-intensity/non-myeloablative regimens have decreased the non-relapse mortality (NRM) in elderly and/or heavily pretreated patients. We performed a retrospective study to assess whether HCT-CI may predict clinical outcomes in a cohort of 203 patients with non-Hodgkin's (NHL; n=108), Hodgkin's lymphomas (HL; n=26), and multiple myeloma (MM; n=69), who were transplanted from a human leucocyte antigen (HLA)-matched sibling (n=121) or an unrelated donor (n=82) after a reduced-intensity regimen (n=154) or a low-dose total body irradiation-based non-myeloblative regimen (n=49). Cumulative incidence of NRM was 5, 16 and 20% at 1 year and 6, 24 and 27% at 2 years, for patients with an HCT-CI of 0, 1-2 and > or =3, respectively. By multivariate analysis, HCT-CI significantly predicted NRM (hazard ratio (HR)=1.6, P=0.03), overall survival (OS; HR=1.62, P

Background The graft-versus-leukemia effect is able to induce clinical responses in patients with chronic lymphocytic leukemia treated with a reduced intensity conditioning regimen, followed by allogeneic stem cell transplantation. We investigated whether molecular remissions could be attained after reduced intensity conditioning and allogeneic stem cell transplantation in patients with relapsed chronic lymphocytic leukemia and whether the assessment of minimal residual disease might be used to predict the clinical outcome. Design and Methods Minimal residual disease was monitored by polymerase chain reaction using the immunoglobulin heavy-chain gene rearrangement as a molecular marker in 29 relapsed patients who achieved complete remission following reduced intensity conditioning and allogeneic stem cell transplantation. A nested-polymerase chain reaction with patient-specific primers derived from complementarity determining regions (CDR2 and CDR3) was carried out in all the patients. Real-time polymerase chain reaction was performed in patients whose nested reaction gave positive or mixed results. Results Three patterns of minimal residual disease were observed: negative (31%), mixed (24%), and always positive (45%). The cumulative incidence of relapse according to the minimal residual disease status at 6 and 12 months after transplantation was significantly different between polymerase chain reaction-negative and -positive patients ( p =0.031 and p =0.04, respectively). Two-year disease-free survival was 93% and 46% for polymerase chain reaction-negative and -positive patients at 6 months after transplantation, respectively ( p =0.012). Similarly, 2-year disease-free survival was 100% and 57% for polymerase chain reaction-negative and -positive patients at 12 months, respectively ( p =0.037). No clinical or biological factors were predictive of the achievement of polymerase chain reaction negativity after allogeneic stem cell transplantation. Graft-versus-host disease was more frequent in patients who did not relapse ( p =0.04). Quantitative monitoring of minimal residual disease was able to identify polymerase chain reaction-positive patients with a higher risk of relapse. Conclusions These findings demonstrate that relapsed patients can achieve molecular remission after reduced intensity conditioning and allogeneic stem cell transplantation and suggest a minimal residual disease-driven intervention that might be useful to prevent overt hematologic relapse.

Osteonecrosis of the jaw (ONJ) can be a severe complication of patients with multiple myeloma (MM) treated with bisphosphonates. Dental procedures are a major risk factor for ONJ occurrence. We retrospectively analysed the data of 178 patients with MM to evaluate if antibiotic prophylaxis before dental procedures may prevent ONJ. A correlation between dental procedures, antibiotic prophylaxis, incidence of ONJ and relevant clinical features was performed. Overall nine out of 178 patients developed ONJ (5 year crude cumulative incidence: 7.7%). Only one case of ONJ was not correlated with dental procedures. Seventy-five patients received at least one dental procedure and 43 received antibiotic prophylaxis. Eight cases of ONJ were observed, all in the group of patients without antibiotic prophylaxis. The only variable significantly associated with ONJ was antibiotic prophylaxis (p = 0.012), which had a protective effect. Thus, we speculated that antibiotic prophylaxis may prevent ONJ occurrence after dental procedures.

We conducted a retrospective analysis on adult patients with advanced soft tissue sarcoma (STS) other than rhabdomyosarcoma who received allogeneic stem cell transplantation and were registered at the EBMT database. The aim of of the study was to assess whether an immune-mediated graft-versus-tumor (GVT) effect could be generated in this disease. Among 26 patients included in the registry, 14 were eligible for this analysis as they had received reduced intensity stem cell transplantation for chemorefractory disease. Two patients died of transplant-related complications and eight of progressive disease; four are alive and experienced long-lasting disease stabilisation following transplant. Our study may suggest that an immune-mediated effect cannot be excluded in some STS.

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.