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Objectives: Treatment of older patients with acute myeloid leukemia (AML) is still controversial. To facilitate treatment decisions, the “fitness criteria” proposed by Ferrara et al. (Leukemia, 2013), including age > 75 years, performance status and comorbidities, were verified retrospectively in 699 patients with AML (419 de-novo, 280 secondary AML), diagnosed at 8 Hematological Centers (REL). Methods: Patients were categorized in FIT to intensive chemotherapy (i-T) (292, 42.5%), UNFIT to i-T (289, 42.1%), or unfit even to non-intensive therapy (non i-T) (FRAIL) (105, 15.3%). Biological characteristics and treatment actually received by patients [i-T, 274 patients (39.2%); non i-T, 134 (19.2%), best-supportive care (BSC), 291 (41.6%)] were recorded. Results: “Fitness criteria” were easily applicable in 98.1% of patients. Overall concordance between “fitness criteria” and treatment actually received by patients was high (79.4%), 76% in FIT, 82.7% in UNFIT and 80% in FRAIL patients. Fitness independently predicted survival (median survival: 10.9, 4.2 and 1.8 months in FIT, UNFIT and FRAIL patients, respectively; p = 0.000), as confirmed also by multivariate analysis. In FRAIL patients, survival with any treatment was no better than with BSC, in UNFIT non i-T was as effective as i-T and better than BSC, and in FIT patients i-T was better than non i-T or BSC. In addition, a non-adverse risk AML, an ECOG PS

Consolidation treatment in acute myeloid leukemia (AML) patients achieving complete remission (CR) is warranted. High-dose cytarabine (HDAC) is considered first choice in favorable risk and an option in intermediate-risk AML. However, its optimal dose and schedule, as well as the benefit of additional chemotherapy agents remain controversial. Herein, we report on the long-term outcome of consecutive unselected AML patients treated with repeated courses of HDAC, with the addition of idarubicin, followed by autologous peripheral blood stem cell (PBSC) support, in order to limit toxicity, according to Northern Italy Leukemia Group (NILG) AML-01/00 study (EUDRACT number 00400673). Among 338 patients consecutively diagnosed from 2001 to 2017 at our center, 148 with high-risk AML (adverse cytogenetic, isolated FLT3-internal tandem duplication mutation, refractory to first induction) were addressed to allogeneic stem cell transplant. All other cases, 186 patients (55%), median age 53 (range 19-75), were considered standard-risk and received the NILG AML-01/00 program. After achieving CR, patients were mobilized with cytarabine 8 g/sqm to collect autologous CD34+-PBSC and received three consolidation cycles with HDAC (20 g/sqm) plus idarubicin (20 mg/sqm) per cycle, followed by reinfusion of limited doses of CD34+ PBSC (1-2x106/kg). The program was completed by 160 (86%) patients. Toxicity was acceptable. Neutrophils recovered a median of 10 days. Treatment-related mortality was 3/160 (1.8%). After a median follow-up of 66.4 months, overall survival (OS) and relapse-free survival (RFS) at 5-years were 61.4% and 52.4%, respectively. Twenty-eight selected patients aged >65 had similar outcomes. According to European leukemia net-2010 classification, the OS and RFS at 5-years were 76.4% and 65% in favorable risk, without differences between molecular subgroups, 52.3% and 47.2% in Intermediate-I, 45.2% and 36.5% in Intermediate-II risk patients, respectively. In conclusion, consolidation including repeated courses of high dose cytarabine and idarubicin, with limited PBSC support, proved feasible and very effective in nonhigh risk patients. The incorporation of novel agents in its backbone may be tested to further improve patient's prognosis.

Hodgkin lymphoma (HL) has a bimodal age distribution curve, with a second peak in people aged more than 60 years. Interim PET/CT (iPET/CT) is highly predictive for PFS and OS in young HL, but it has not been sufficiently studied in the elderly. In this retrospective dual-center study, 82 patients with HL and aged 65 or more who performed iPET/CT were included. At iPET/CT, 60 patients had a complete metabolic response, 18 partial responses, and 4 progressions of disease. Baseline PET/CT metabolic features were not significantly correlated with the metabolic response at interim. In patients with interim complete metabolic response, PFS and OS were significantly longer than in patients without complete response(

Elderly Hodgkin lymphoma (HL) is an aggressive lymphoma subgroup with high 18F-FDG avidity at 18F-FDG-PET/CT but no shared criteria for PET/CT in treatment evaluation and prediction of outcome are available. The aim of our bicentric study was to investigate whether the metabolic baseline PET/CT parameters can predict treatment response and prognosis in elderly HL. We retrospectively included 123 patients who underwent baseline 18F-FDG-PET/CT and end of treatment PET/CT scans. The PET images were analyzed visually and semi-quantitatively by measuring the lesion to liver SUVmax ratio (L-L SUV R), lesion to blood-pool SUVmax ratio (L-BP SUV R), metabolic tumor volume (MTV), and total lesion glycolysis (TLG). Survival curves were plotted according to the Kaplan-Meier method. At a median follow-up of 40 months, the median PFS and OS were 29 and 37 months. L-BP SUV R, L-L SUV R, MTV, and TLG were significantly higher in patients with no complete response compared with complete response group at end of treatment. Moreover, these parameters were demonstrated to be independent prognostic factors for PFS together with tumor stage, while only L-L SUV R and L-BP SUV R for OS. End of treatment PET/CT results using Deauville criteria were significantly correlated with outcome survival. End of treatment PET/CT results (using Deauville criteria) and semiquantitative baseline PET/CT parameters were significantly correlated with response to treatment and long-term outcome.

The ability of patients with hematologic malignancies (HM) to develop an effective humoral immune response after COVID-19 is unknown. A prospective study was performed to monitor the immune response to SARS-CoV-2 of patients with follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), chronic lymphoproliferative disorders (CLD), multiple myeloma (MM), or myelodysplastic/myeloproliferative syndromes (MDS/MPN). Antibody (Ab) levels to the SARS-CoV-2 nucleocapsid (N) and spike (S) protein were measured at +1, +3, +6 months after nasal swabs became PCR-negative. Forty-five patients (9 FL, 8 DLBCL, 8 CLD, 10 MM, 10 MDS/MPS) and 18 controls were studied. Mean anti-N and anti-S-Ab levels were similar between HM patients and controls, and shared the same behavior, with anti-N Ab levels declining at +6 months and anti-S-Ab remaining stable. Seroconversion rates were lower in HM patients than in controls. In lymphoma patients mean Ab levels and seroconversion rates were lower than in other HM patients, primarily because all nine patients who had received rituximab within 6 months before COVID-19 failed to produce anti-N and anti-S-Ab. Only one patient requiring hematological treatment after COVID-19 lost seropositivity after 6 months. No reinfections were observed. These results may inform vaccination policies and clinical management of HM patients.

Introduction: Patients (pts) with aggressive B-cell lymphoma and MYC rearrangement exhibits poor outcome after R-CHOP treatment. In the last decade, these pts were treated with a new dose-dense, short-term therapy termed “CARMEN”, at several Italian Centers. Excellent efficacy and safety profile have been reported in HIV/AIDS pts with high-risk Burkitt lymphoma (BL) [Ferreri et al. BJH 2021], but its efficacy in pts with high-grade B-cell lymphoma with MYC rearrangement (HGBCL) remains to be defined. Herein, we report a retrospective series of consecutive pts with BL or HGBCL treated with CARMEN regimen. Methods: Either HIV-negative and HIV-positive pts aged 18-80 years with BL or HGBCL and MYC rearrangement positive by FISH were treated with CARMEN regimen, which includes a single 36-day induction course of sequential doses of cyclophosphamide, vincristine, rituximab, methotrexate, VP16, and doxorubicin plus intrathecal chemotherapy, followed by consolidation with HD-cytarabine ± cisplatin. Pts who did not achieve complete remission (CR) after induction received BEAM/ASCT after consolidation. Results: 63 pts (22 HGBCL;41 BL) received the CARMEN regimen (Table). Treatment was well tolerated: 56 (89%) pts completed the induction, and 55 (87%) completed the consolidation. G4 hematological toxicity during induction was neutropenia in 48 (76%) pts, thrombocytopenia in 24 (38%) and anemia in 7 (11%), which were recorded after consolidation in 34 (62%), 38 (69%) and 1 (2%) pt, respectively. G4 non hematological toxicity was uncommon: mucositis in 4 (6%) pts and tumor lysis syndrome in 1 (2%) during induction, and heart failure and bleeding in 1 (2%) pt each after consolidation. G4 infections were recorded in 4 (6%) pts during induction and in 2 (3%) after consolidation. Induction and consolidation doses were reduced in 6 (9%) and 4 (7%) pts, respectively. Seven HGBCL and 9 BL pts received ASCT, with expected tolerability. 4 HGBCL and 2 BL pts died of toxicity (sepsis in 4;respiratory failure;COVID-19), with a TRM of 9%. After induction, 18 (82%) HGBCL and 37 (90%) BL pts achieved a response, which was CR in 10 (45%) and 26 (63%) pts, respectively. After the whole treatment, 15 (68%) HGBCL pts and 32 (78%) BL pts achieved a CR, and, at a median follow-up of 54 (2-131) months, 15 (100%) HGBCL and 29 (91%) BL pts remain relapse-free, with a 5-yr PFS of 67% and 70%, respectively. 15 HGBCL and 32 BL pts are alive, with a 5-yr OS of 66% and 77%, respectively. HIV seropositivity did not modify outcome. Age and LDH level were independently associated with OS. Conclusions: With the limitations of a retrospective series, this study shows that CARMEN is a safe and active treatment both in HIVnegative and-positive pts with HGBCL and MYC rearrangement and BL. Survival figures in HGBCL pts compare favorably with results reported with R-CHOP or analogous, and are similar to those achieved in BL pts.

MYC translocations, a hallmark of Burkitt lymphoma, occur in 5-15% of diffuse large B-cell lymphoma, and have a negative prognostic impact. Numerical aberrations of MYC have also been detected in these patients, but their incidence and prognostic role are still controversial. We analyzed the clinical impact of MYC increased copy number on 385 patients with diffuse large B-cell lymphoma screened at diagnosis for MYC, BCL2, and BCL6 rearrangements. We enumerated the number of MYC copies, defining as amplified those cases with an uncountable number of extra-copies. The prevalence of MYC translocation, increased copy number and amplification was 8.8%, 15%, and 1%, respectively. Patients with 3 or 4 gene copies, accounting for more than 60% of patients with MYC copy number changes, had a more favorable outcome compared to patients with >4 copies or translocation of MYC, and were not influenced by the type of treatment received as first-line. Stratification according to the number of MYC extra-copies showed a negative correlation between an increasing number of copies and survival. Patients with >7 copies or the amplification of MYC had the poorest prognosis. Patients with >4 copies of MYC showed a similar, trending towards worse prognosis compared to patients with MYC translocation. The survival of patients with >4 copies, translocation or amplification of MYC seemed to be superior if intensive treatments were used. Our study underlines the importance of fluorescence in situ hybridization testing at diagnosis of diffuse large B-cell lymphoma to detect the rather frequent and clinically significant numerical aberrations of MYC.

Background Stopping tyrosine kinase inhibitor (TKI) treatment has become a realistic and safe objective for patients who have chronic myeloid leukemia (CML). Both a sustained deep molecular response (sDMR) and the lack of a molecular recurrence after TKI discontinuation are required to reach a durable treatment-free remission (TFR). Methods The potential predictive role of BCR-ABL transcripts in attaining an sDMR and a TFR was analyzed in a strictly consecutive, unselected series of 194 patients who were diagnosed and treated with TKIs at the authors' center. Results Of 173 fully evaluable patients, 67 (38.7%) had the e13a2 transcript, and 106 (61.3%) had the e14a2 transcript. Complete cytogenetic and major molecular remissions were not affected, whereas the achievement of both a DMR (P = .008) and an sDMR (P = .004) was favored significantly in patients who had the e14a2 transcript. After a median of 68 months, the sDMR rate was 39.6% in those with the e14a2 transcript and 19.4% in those with the e13a2 transcript. In addition to transcript type, both the early achievement of a molecular response and starting treatment with a second-generation TKI positively affected the attainment of an sDMR in multivariate analysis. The use of a second-generation TKI as frontline treatment increased the sDMR rate in both transcript types. However, in patients who had the e13a2 transcript, the probability of attaining an sDMR was 37% after 60 months and did not increase further despite continuing therapy. Among 51 of 60 patients who attained an sDMR after discontinuing TKIs, 24 experienced a molecular relapse, but all regained molecular remission after resuming TKI treatment. Again, transcript type influenced TFR maintenance (P = .005), because only 2 patients (3%) with the e13a2 transcript enjoyed a durable TFR compared with 25 (23.5%) of those with the e14a2 transcript. Conclusions The e13a2 transcript hinders the achievement of deep responses and the possibility of stopping TKI treatment in patients with CML.

Background: Patients with cancer are considered highly vulnerable to the recent coronavirus disease 2019 (COVID-19) pandemic. However, there are still few data on COVID-19 occurring in hematologic patients. Methods: One hundred two patients with COVID-19 symptoms and a nasopharyngeal swab positive for severe acute respiratory syndrome coronavirus 2 seen at 2 hematologic departments located in Lombardy, Italy, during March 2020 were studied. Risk factors for acquiring COVID-19 were analyzed by comparisons of patients with COVID-19 and the standard hematologic population managed at the same institutions in 2019. Thirty-day survival was compared with the survival of matched uninfected control patients with similar hematologic disorders and nonhematologic patients affected by COVID-19. Results: Male sex was significantly more prevalent in patients with COVID-19. The infection occurred across all different types of hematologic disease; however, the risk of acquiring a COVID-19 infection was lower for patients with chronic myeloproliferative neoplasms, including chronic myeloid leukemia, and higher for patients with immune-mediated anemia on immunosuppressive-related treatments. The 30-day mortality rate was 39.2%, which was higher than the rates for nonhematologic patients with COVID-19 (23.5%; P =.02) and uninfected hematologic controls (3%; P

Summary Background Fit patients with mantle cell lymphoma aged 18–65 years are usually given cytarabine and rituximab-based induction regimens followed by autologous haematopoetic stem-cell transplantation (HSCT). We investigated whether post-autologous HSCT maintenance with lenalidomide improves progression-free survival in this population. Methods This open-label, randomised, multicentre, phase 3 trial was done at 49 haematology and oncology units in Italy and Portugal. Eligible patients had Ann Arbor stage III or IV treatment-naive mantle cell lymphoma (or stage II plus bulky disease [≥5 cm] or B symptoms), and had evidence of cyclin D1 overexpression or the translocation t(11;14)(q13;q32). Patients were aged 18–59 years with Eastern Cooperative Oncology Group (ECOG) performance status 0–3, or aged 60–65 years with ECOG 0–2. After an optional prephase with vincristine and steroids (intravenous vincristine 1·4 mg/m2 on day 1, oral prednisone 100 mg [total dose] on days 1–5), patients were given three courses of R-CHOP (21-day cycle, intravenous rituximab 375 mg/m2 on day 1; intravenous doxorubicin 50 mg/m2, vincristine 1·4 mg/m2, and cyclophosphamide 750 mg/m2 on day 2; oral prednisone 100 mg/m2 on day 2–6). Patients then received one cycle of high-dose CTX (intravenous cyclophosphamide 4 g/m2 on day 1, intravenous rituximab 375 mg/m2 on day 4). After restaging, patients received two cycles of R-HD-cytarabine (high-dose intravenous cytarabine 2 g/m2 every 12 h on days 1–3, intravenous rituximab 375 mg/m2 on days 4 and 10). Patients with complete remission or partial remission proceeded to autologous HSCT and responding patients (complete remission or partial remission) with haematological recovery were randomly assigned (1:1) to receive 24 courses of oral lenalidomide maintenance (15 mg per day for patients with platelets >100 × 109 cells per L or 10 mg per day for platelets 60–100 × 109 cells per L, days 1–21 every 28 days) for 24 months, or observation. The primary endpoint was progression-free survival, measured in the randomised population. This study is registered with EudraCT (2009–012807–25) and ClinicalTrials.gov ( NCT02354313 ). Findings Between May 4, 2010, and Aug 24, 2015, 303 patients were screened for inclusion and 300 patients were enrolled (median age 57 years, IQR 51–62; 235 [78%] male). 95 patients were excluded before randomisation, mostly due to disease progression, adverse events, and inadequate recovery. 104 patients were randomly assigned to the lenalidomide maintenance group and 101 patients to the observation group. 11 (11%) of 104 patients assigned to lenalidomide did not start treatment (3 withdrew, 6 adverse events or protocol breach, 2 lost to follow-up). At a median follow-up of 38 months after randomisation (IQR 24–50), 3-year progression-free survival was 80% (95% CI 70–87) in the lenalidomide group versus 64% (53–73) in the observation group (log-rank test p=0·012; hazard ratio 0·51, 95% CI 0·30–0·87). 41 (39%) of 104 patients discontinued lenalidomide for reasons including death or progression. Treatment-related deaths were recorded in two (2%) of 93 patients in the lenalidomide group (1 pneumonia, 1 thrombotic thrombocytopenic purpura), and one (1%) of 101 in the observation group (pneumonia). 59 (63%) of 93 patients in the lenalidomide group had grade 3–4 haematological adverse events versus 12 (12%) of 101 patients in the observation group (p Interpretation Despite non-negligibile toxicity, lenalidomide after autologous HSCT improved progression-free survival in patients with mantle cell lymphoma, highlighting the role of maintenance in mantle cell lymphoma. Funding Fondazione Italiana Linfomi and Celgene.

The International Prognostic Score (IPS) is the most commonly used risk stratification tool for patients with advanced Hodgkin lymphoma (HL). It incorporates seven clinical parameters independently associated with a poorer outcome: male sex, age, stage IV, hemoglobin level, white blood cell and lymphocyte counts, and albumin level. Since the development of the IPS, there have been significant advances in therapy and supportive care. Recent studies suggest that the IPS is less discriminating due to improved outcomes with ABVD therapy. The aim of the present study was to asses if classic prognostic factors maintain their prognostic meaning at the time of response-adapted treatment based on interim PET scans. We evaluated the prognostic significance of IPS in the 520 advanced stage HL patients enrolled in the PET-guided, HD0801 trial in which PET2-positive patients underwent a more intense treatment with an early stem-cell transplantation after 2 cycles of ABVD. We observed that in these patients, the IPS completely loses its prognostic value together with all the single parameters that contribute to the IPS. Furthermore, neutrophils, monocytes, lymphocytes, and the ratio among them also no longer had any predictive value. We believe that the substantial improvement in survival outcomes in PET2-positive patients treated with early autologous transplantation could explain the complete disappearance of the residual prognostic significance of the IPS.

FDG-positron emission tomography (PET) performed early during therapy in advanced Hodgkin lymphoma patients has been confirmed as being important for progression-free survival. A group of patients with a negative interim-PET (i-PET) showed a positive end induction PET (e-PET). The aim of this study was to evaluate the clinical characteristics of patients with a positive e-PET as a secondary end point of the HD0801 study. A total of 519 patients with advanced-stage de novo Hodgkin lymphoma received initial treatment and underwent an i-PET. Patients with negative results continued the standard treatment. i-PET negative patients were then evaluated for response with an e-PET and those patients found to have a positive one were also then given a salvage therapy. Among 409 i-PET negative, 16 interrupted the therapy, 393 patients were evaluated with an e-PET, and 39 were positive. Sixteen out of 39 underwent a diagnostic biopsy and 15 were confirmed as HD. Seventeen out of 39 e-PET were reviewed according to the Deauville Score and, in sixteen, it was confirmed positive (10 DS 5, 6 DS 4). With the exception of high LDH value at diagnosis (p = 0.01; HR 95% CI 1.18-4.89), no clinical characteristics were significantly different in comparison with e-PET negative patients. Positive e-PET after a negative i-PET has a worse outcome when compared with i-PET positive patients salvaged with therapy intensification. It was not possible to identify clinical characteristics associated with a positive e-PET.

Burkitt's lymphoma is a lymphoma with unclear metabolic behavior at 18F-FDG-PET/CT and no validated criteria in treatment evaluation and prediction of outcome exist. Sixty-five patients were retrospectively included: all underwent baseline 18F-FDG-PET/CT, 56 interim PET/CT (iPET/CT) and 54 end of treatment PET/CT (eotPET/CT) after chemotherapy. Interim and eotPET/CT results were visually interpreted according to the criteria of the IHP and Deauville-five-point-scale. Results were correlated with PFS and OS to assess and to compare the predictive value of iPET and eotPET according to each criterion. All baseline PET/CT showed increased 18F-FDG uptake in nodal and extranodal lesions. The median PFS and OS were 44.6 and 48.2 months with 3-year and 5-year PFS of 76% and 62% and 3-year and 5-year OS of 71% and 57%, respectively. EotPET/CT results using DC and IHP significantly correlate with OS and PFS; while iPET/CT did not correlated with OS and PFS.

Introduction: In the general HIV negative population, patients (pts) with diffuse large B cell lymphoma (DLBCL) or high grade B cell lymphoma (HGBCL) carrying MYC rearrangements and BCL2 and/or BCL-6 translocations [double hit (DHL) or triple hit lymphomas (THL)] have shown a dismal prognosis when treated with standard R-CHOP and are frequently candidates to intensive therapeutic regimens, without having a standard of care. Moreover, several authors have demonstrated a negative prognostic impact of isolated MYC rearrangements [single hit lymphomas (SHL)] and the best therapeutic approach for SHL are even less clear. In HIV-associated "non Burkitt" large B cell lymphomas (Ly), scanty data are available on the prevalence and the clinical and prognostic impact of MYC rearrangements, with or without BCL2 and BCL6 concomitant translocations. Due to the peculiar biology and pathogenesis of HIV-associated Ly, data from HIV negative population cannot be simply translated to the HIV positive pts. Aim: To evaluate the impact of MYC rearrangements or translocations (isolated or with BCL2 and/or BCL6 translocations) on clinical features and outcome of HIV-associated large B cell Ly. Methods: Retrospective analysis of clinical characteristics, treatment received and outcome of all HIV-associated large B cell Ly [including DLBCL, B cell Ly unclassifiable, with features intermediate between DLBCL and Burkitt (BCLU), and HGBL] with MYC rearrangements or translocations, evaluated by FISH analysis, in 11 European centers, and comparison with pts who do not have the MYC alterations. Results: One hundred-sixty-one pts were enrolled, 49 (30%) had MYC translocation or other MYC rearrangements (MYC+ pts), and 112 (70%) were negative for MYC mutation (7 pts had MYC increased copy number) (MYC- pts). Table 1 shows the clinical characteristics of the two groups, and the treatment received. MYC+ pts had higher involvement of central nervous system at presentation (17% vs 3%, p 0,023), higher Ki67% (median 91% vs 85%, p 0,005), histology other than DLBCL (32% vs 9%, p 0,0001), concomitant translocation of BCL2 (14% vs 3%, p 0,022), germinal center B phenotype (according to Hans algorithm) (85% vs 49%, p 0,0001). No differences in CD4 count or HIV viral load at Ly diagnosis were found, while a previous diagnosis of AIDS was more frequent in the MYC- group (27% vs 10%, p 0,023). MYC+ pts received more frequently intensive treatment (iCT) (41% vs 12%, p 0,0001) and less frequently the standard CHOP regimen (41% vs 74%, p 0,001). Ten pts (9%) had a DHL/THL and had similar clinical characteristics compared to SHL. With a median follow-up of 62 months, there were no significant differences in overall survival (OS) and progression-free survival (PFS) between MYC+ and MYC- pts (5 years-OS and PFS were respectively 55% and 47% in MYC+ and 59% and 53% in MYC- pts). In univariate analysis for the whole population, IPI≥3, ECOG≥ 2 and increased LDH were related to a worse OS and PFS while BCL2 translocation correlated with shorter PFS alone. In multivariate analysis ECOG and IPI mainteined their negative prognostic impact on OS and PFS. In the MYC+ group, 41% pts received R-CHOP or CHOP-like treatment (group 1), 16% infusional therapy (group 2), 41% iCT (group 3), 2% palliative therapy (PT) (group 4); 5-years OS and PFS were 47% and 32% for group 1, 47% and 37% for group 2, 67% and 68% for group 3 and both 0% for group 4. Median OS and PFS were respectively 18 and 2 months for group 1, 29 and 7 months for group 2, both not reached for group 3, both 2 months for group 4. A significant difference between group 3 and group 1 both in therm of OS (p 0,054) and PFS (p 0,005) was observed (Figure 1). Pts with DHL/THL received R-CHOP (40%), infusional schedule (30%), iCT (20%) and PT (10%). No significant difference in term of PFS and OS were observed for each treatment group with DHL/THL respect to those with SHL. In DHL/THL, 5 years OS and PFS were 50% and 30%, respectively; in SHL 56% and 51%, respectively. Of note, no pts treated with iCT died from toxicity in the MYC+ group. Conclusion: In this retrospective analysis, MYC+ pts had not different clinical characteristics compared to MYC- pts other than higher proliferative index and and more CNS involvement at diagnosis. MYC+ pts were frequently treated with iCT, this aggressive approach seemed feasible and could allow to obtain better outcome compared to standard R-CHOP treatment but further prospective studies are needed. Figure 1 Figure 1. Disclosures Bastos-Oreiro: F. Hoffmann-La Roche: Honoraria, Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Kite: Speakers Bureau; Gilead: Honoraria; BMS-Celgene: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Arcaini: Celgene, Roche, Janssen-Cilag, Gilead: Other: Travel expenses; Bayer, Celgene, Gilead Sciences, Roche, Sandoz, Janssen-Cilag, VERASTEM: Consultancy; Gilead Sciences: Research Funding; Celgene: Speakers Bureau. Rossi: Novartis: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria; Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: 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; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Tucci: janssen: Membership on an entity's Board of Directors or advisory committees; Gentili: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees.

Introduction: We recently demonstrated in a large multicentre study that sGA can identify fit older patients with aggressive lymphoma able to tolerate first-line intensive treatment with curative intent and to obtain similar results than younger people (Merli at al JCO 2021). Regardless of age, about 40% of patients with aggressive lymphoma are either refractory or will eventually relapse after treatment with curative intent. Salvage platinum-based regimens followed by ASCT in responsive disease is a standard of care to obtain longer second remission. However, in many case series, patients over 65 years are excluded from the transplant approach because of potential severe toxicities of high-dose therapy in older patients. This study was designed to evaluate the feasibility and activity of high-dose treatment followed by ASCT in older FIT patients with R/R aggressive lymphoma selected with a sGA. Methods: Patients with R/R aggressive lymphoma after one line of treatment, aged between 65 and 75, and FIT to sGA were eligible for the study. Salvage treatment could be chosen between R-DHAP, R-ICE or other platinum or gemcitabine-containing regimens and stem cells were mobilized after 1 or 2 cycles. Patients achieving at least partial response after 3 courses and who remained FIT to sGA evaluation were eligible for ASCT and were conditioned with either BEAM or FEAM. Results: From May 2014 to August 2019, seventy-five patients from 16 FIL centres were enrolled and 70 were eligible for the study. Sixty-six of them had a diffuse large B-cell lymphoma, one had follicular 3b, 2 mantle cell and 1 Burkitt histology. Salvage treatment was R-DHAP in 48 patients, R-ICE in seven and gemcitabine or oxalyplatinum containing regimens in the remaining ones. Overall response rate after three courses was 44% (21 complete and 10 partial remission). Among the 39 unresponsive patients, 29 had progressive and 4 stable disease, 2 patients died of septic shock and heart failure during salvage and 4 patients withdrew their consent to ASCT. Four patients relapsed soon after response achievement before undergoing the transplant. ASCT was performed in 27 patients with a median of 5.6 x 10 6 CD34/Kg reinfused. No differences emerged in demographic and clinical characteristics between patients reaching the ASCT timepoint or not (Tab 1a). By intention to treat analysis, 2-y overall survival (OS) and PFS of the entire intention-to-treat population were 65% (95%CI: 50-76%) and 34% (95%CI: 22-46%) respectively, without differences according to age (Tab 1b). After a median of 27 months, 2-y OS was 79% (95CI: 51-86%) and EFS 56% (95CI: 32-75%). Twenty-four patients obtained a complete remission (CR) and 20 of them are in continuous CR after more than 12 months. Three patients progressed 1-8 months after ASCT and died. Most common non-hematologic grade 3-4 adverse events were gastrointestinal (10%) and infectious (8%). Conclusion: This study shows that sGA can identify older patients with R/R aggressive lymphoma who are able to tolerate and can benefit from high-dose therapy and ASCT. The poor response to second-line immunochemotherapy remains the major drawback of this approach since less than 50% of patients could actually receive ASCT. Nevertheless the 2-y survival of 65% in the intention to treat population is remarkable and sets the stage for the evaluation of new approaches such as CAR-T or bispecific antibodies also in older patients. A next step should be to explore the usefulness of sGA in the selection of candidates to these innovative treatments. Figure 1 Figure 1. Disclosures Tucci: Takeda: Membership on an entity's Board of Directors or advisory committees; Gentili: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees. Musuraca: janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Cavallo: ROCHE: Membership on an entity's Board of Directors or advisory committees; Servier: Speakers Bureau; Gilead: Speakers Bureau. Zilioli: Roche, Italfarmaco: Consultancy, Honoraria; MSD, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations; Gentili, Takeda, Gilead, Servier: Consultancy, Speakers Bureau; Takeda: Other: travel expenses, accommodation. Merli: EUSA Pharma: Other: Travel, Accomodations, Expenses; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; MSD: Membership on an entity's Board of Directors or advisory committees; Gilead Science: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Celgene: Other: Travel, Accomodations, Expenses. Marcheselli: sandoz: Membership on an entity's Board of Directors or advisory committees. Rossi: Abbvie: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: 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; Sanofi: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees.

Introduction: Acute Myeloid Leukemia (AML) is a heterogeneous disorder characterized by a wide range of cytogenetic and molecular aberrations, that affect prognosis and guide treatment decisions. However there is a still large group of patients (pts) considered at intermediate risk whose outcome needs to be better defined. Next-generation sequencing (NGS) can simultaneously detect various mutations, leading to better define its prognostic profile. The role of some mutations, including isocitrate dehydrogenase (IDH) mutations (IDHm), is still controversial. Aim: We evaluated by NGS monitoring at different time points the prognostic role of IDH1/2m in AML pts with normal karyotype, both in the subgroup with mutations of NPM1 (NPM1m) or FLT3 (FLT3m) and in the subgroup without detectable mutations (wt-AML). Methods: Using Sophia Myeloid Solution kit (SOPHiA Genetics), we performed targeted NGS, covering 30 gene regions, in 104 bone marrow samples collected at diagnosis (53), after first consolidation (30) and at relapse (21), in 53 pts (M/F: 24/29; median age: 56 y, range 22-74), treated according to NILG-AML00 protocol (NCT00400673). Standard PCR to detect NPM1m and FLT3m was performed and we identified 20 NPM1m, 3 NPM1+FLT3-ITDm, 4 FLT3-ITDm and 26 wt-AML. Results: At diagnosis, among 219 pathogenic mutations detected, IDHm represented 10.5% of them (median VAF: 39.1%; range 6.2-49.6%). IDHm was observed in 23/53 pts (43.4%) (IDH1m in 11 and IDH2m in 12). In these pts , more frequently commutated genes were DNMT3A (28%), NPM1 (13%), FLT3-ITD/TKD (14%), ASXL1 (6%), SRSF2 and NRAS (9% each). Complete remission (CR) was achieved in 49/53 (92.5%) pts without difference in response rate according to IDH status (86% in IDHm vs 94% in IDH wild-type, wt). Relapse occurred in 28/49 (57%) pts after a median of 11 months (mo), range 2-61. The frequency of relapse was not significantly different across all types of mutations identified, except for IDH2m which was associated with a higher risk of relapse (10/11 in IDH2m vs 18/38 in IDH2wt; p: 0.014), without differences between R172K and R140Q. On the contrary, IDH1m, present in 18% of relapsed pts, did not impact on relapse (5/10 vs 23/39, p: 0.7). Particularly, in the wt-AML group, the IDH2m was prevalent in pts developing relapse (6/11, 54.5%) and all pts with IDH2m relapsed, with median of 13 mo, range 6-24 (6/6 in IDH2m vs 5/17 in IDH2wt, p:0.0046). Among the co-occurrence mutations, the IDH2/DNMT3A was associated with higher relapse risk (9/9 vs 19/40; p: 0.0063). DNMT3A associated with other mutations did not impact on relapse risk. At a median follow-up of 23 mo, median relapse free survival (RFS) and overall survival (OS) of whole population were 24 and 53 mo, respectively. The IDH2m impacted on OS: 23.5 mo in IDH2m vs 72 in IDH2wt pts (p:0.0093) (Fig 1a), but not in RFS (13 vs 29 mo in IDH2m and IDH2wt, respectively (p:0.1). Considering the subgroups of wt-AML, the RFS (Fig. 1b) and OS were 13 and 23.5 mo in IDH2m vs undefined in IDH2-wt (p:0.0014 and p:0.1), respectively. In pts with NPM1 or FLT3m, RFS and OS were 9 and 53 mo in IDH2m vs 29 and 73 mo in IDH2-wt (p:0.2 and p:0.15), respectively. We did not find the other genomic pattern predicting relapse in this group. After consolidation, NGS monitoring was performed in 30 pts in CR. Of the 13 IDH AML pts evaluated, no mutations was observed in 4 (28.5%); the persistence of IDHm was not associated with a significantly higher relapse (p:0.5). Among other mutations present at diagnosis, NGS clearance after consolidation occurred in pts with NRAS, KRAS, PTPN11 and FLT3-ITD/TKD. Conversely, it was limited for the following mutations: TET2 (8/11), DNMT3A (7/13), SRSF2 (6/6), IDH2 (4/5), ASXL1 (2/2), IDH1 (2/4) and NPM1 (1/12). Overall, the persistence of any type of gene mutations after consolidation was predictive of relapse (2/9 vs 6/7, p:0.04), only in wt-AML subgroup. At relapse, of the 11 IDHm pts analyzed, 7/7 IDH2m and 3/4 IDH1m showed the reappearance of mutations. Conclusion: In this retrospective monocentric study, the presence at diagnosis of IDH2m correlated with relapse risk and with survival, suggesting that additional treatment with targeted agents and or consolidation with allogeneic transplant should be considered. In addition, in AML without NPM1m or FLT3m, the persistence of genes mutation detected by NGS monitoring after consolidation had a significant prognostic value to predict subsequent relapse. Figure 1 Figure 1. Disclosures Borlenghi: Amgen, Janssen: Consultancy. Rossi: Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: 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; Daiichi Sankyo: Consultancy, Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Tucci: Gentili: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees.

Introduction. Covid-19 patients (pts) with hematologic malignancies have a severe prognosis with mortality rates around 40%, particularly when on active treatment (Cattaneo et al, Cancer, in press). However, the long-term prognosis and persistence of specific immune responses among those who survive acute infection are unclear. Aim: Pts with hematological diseases were followed longitudinally after the acute phase of COVID-19 according to protocol NP4156 approved by the local EC. Clinical outcome and specific antibody responses to SARS-CoV-2 were monitored during convalescence, and correlated to the diagnosis and treatment of the underlying hematological disease. Pts and Methods. Pts affected by multiple myeloma (MM), follicular (FL) and diffuse large B-cell (DLC) lymphoma (NHL), chronic lymphoproliferative disorders (CLD), myelodysplastic/chronic myeloproliferative syndromes (MDS/MPN) and surviving the acute phase of virologic-proven COVID-19 were eligible. Immune response parameters were evaluated at +1, +3, +6, +9 and +12 months after nasal swab negativization. Antibodies (Ab) to different conformations of COVID-19 virus proteins, nucleocapsid (N) and spike (S), were measured using a highly sensitive luciferase-immunoprecipitation system (LIPS) assay. Results. Of 51 eligible pts, 41 were tested for SARS-CoV-2 Ab at first timepoint (+1m) (6 pts too early, 2 refusal, 2 lost to follow-up). For 9 of them, Ab levels at +3m were also available. Ab levels of 14 controls without hematologic disorders (Ctrls) also surviving COVID-19 were evaluable at +1m and in 9 of them at +3 months as well. Diagnoses included FL (9) and DLC (6) NHL, CLD (7), MM (10), MDS/MPS (9). The status of hematological disease at the time of COVID-19 diagnosis was as follows: diagnosis (n=4; 10%), complete or partial remission (n=16; 39%), relapse/refractory (n=6; 15%; stable (n=15; 36%). Twenty-one pts (51%) were on active treatment, including 6 on chemoimmunotherapy; 7 pts had received chemoimmunotherapy previously. Median time from SARS-CoV-2 detection to swab negativity was 30d (range 8-63), and was not influenced by sex, age, hematologic diagnosis, disease status, nor treatment received. Two pts, both affected by DLC secondary to FL, remained swab-positive at day 119+ and 123+. At +1m, both N- and S- seropositivity rate was slightly lower in pts [N+ in 30/41 (73%); S+ in 27/41 (66%)] vs 13/14 for both N+ and S+ in Ctrls (93%) (P=0.16 and 0.08, respectively). Discrepancies between N and S seropositivity were observed in 7 (17%) pts, all with lymphoid disorders. Ab levels were similar in hematologic pts and in Ctrls (N+ 894,707 vs 870,541 LU and S+ 907,591 LU vs 724,120 LU, respectively, P=NS) (Fig.1a). Both seroconversion rates and Ab levels were not influenced by age, sex, status of hematologic disease, ongoing treatment, time to swab negativity, severity of pneumonia and steroid treatment during acute COVID-19. However, a diagnosis of NHL negatively impacted on seroconversion for both N and S. In 15 pts with NHL compared to 26 pts with other hematologic cancers, the N-seropositivity rate was 47% vs 92%, and the S-seropositivity rate was 40% vs 85%y (P=0.002 and 0.0053, respectively). N and S Ab levels were also lower than in other hematologic diseases (515,281 LU vs 1105409 LU, P=.002 and 474,309 LU vs 1,148,303 LU, P=.005 respectively) (Fig.1b). Rituximab (RTX) had been used in 13 of 15 NHL (87%), and treatment was ongoing in 6/13. While N-seroconversion and Ab levels were not influenced, no pts on ongoing RTX had S-seroconversion vs 5/7 pts with past RTX use (P=0.021) and mean antibody levels were 17622 LU vs 668548 LU, respectively (P=0.008). At +3m, no significant variations of both anti-N and anti-S antibody levels had occurred compared to timepoint +1m. Seroconversion status was maintained by 9/9 Ctrls and by 8/8 pts; the only pt with Ab levels below the cut-off at +1m did not show seroconversion at+3m. Conclusions: Overall, hematologic pts surviving COVID-19 have N- and S- antibodies levels and seroconversion rates similar to controls without hematologic disorders, although time to swab negativity seems more similar to critically ill pts than in the general population. A diagnosis of NHL negatively impacts on seroconversion and Ab levels, and ongoing RTX seems to have a negative role specifically on anti-S Ab production. Ab response persists at 3 months; the study is ongoing and further data will be available at time of meeting. Disclosures Tucci: Amgen: Consultancy. Rossi:Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Amgen: Honoraria; Novartis: Other: Advisory board; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria. Imberti:Biogen: Honoraria; Genzyme-Sanofi: Honoraria; Meck-Serono: Honoraria; Novartis: Honoraria; Biogen: Other: Advisory board; FISM (Fondazione Italiana Sclerosi Multipla): Research Funding; Regione Lombardia: Research Funding. Notarangelo:NIAID, NIH: Research Funding. Cohen:NIAID, NIH: Research Funding.

Polycythemia Vera (PV) is a chronic myeloproliferative neoplasm characterized by erythrocytosis, constitutively active mutations in JAK2 and an increased susceptibility to thrombotic events (TEs). There is still controversy about the role of increased hematocrit and of other variables including elevated white blood cell count as risk factors for the occurrence of TEs. A better definition of the relative prognostic importance of hematologic parameters would help us to better tailor the therapeutic approach to PV patients (pts), which is currently mainly based on the use of acetilsalycilic acid (ASA), venesection and hydroxyurea . The aim of our study was to analyze if any clinical or laboratory variables were significantly associated to the occurrence of TEs both at PV diagnosis and during the course of the disease in a large series of PV pts uniformly followed at a single Center over a period of 29.5 years from January 1986 to June 2019. Clinical and laboratory data were obtained from the time of diagnosis until death, progression to acute leukemia or last follow-up. Hematocrit (Hct), hemoglobin (Hb), white blood cell (WBC) and platelet (PLT) levels were recorded for each patient at least every 6 months. Among a total of 331 pts, the median age was 65 years (range 30-92 years), and 56% were male. "High risk" features (age ≥ 60 years and/or history of prior thrombosis) were present in 221 pts (66.7%). The incidence of cardiovascular risk factors was: hypertension 64%, diabetes 15%, hyperlipidemia 28%, history of active or remote smoking 41%. Patients on ASA were 279 (84%), 19 (6%) were on oral anticoagulation, while 27 (8%) were on ASA+oral anticoagulant. At PV diagnosis 54 pts (16%) presented with thrombosis, arterial in 32 (59%) and venous in 22 (41%). A previous TE was recorded in 57 pts (17%): in 43 (75%) arterial, in 12 (22%) venous and in 2 (3%) mixed (arterial+venous). Previous thrombosis was the only variable significantly associated with the presence of a TE at PV diagnosis (P=0.02). After PV diagnosis, with a median follow-up of 81 months (range 1-374 months), 63 pts (19%) experienced a TE and 11 of them a further episode, for a total of 74 TEs. The incidence rate (pts/year) of TEs was 2.7%. Forty-two events were arterial (57%), 31 were venous (42%) and 1 (1%) was mixed. It was the first TE for 37 pts. Cerebrovascular accidents and deep-venous thrombosis were the most frequent arterial and venous TEs both at PV diagnosis and throughout the disease course, with a relative incidence of 50% and 32% respectively. The table compares the characteristics of patients who did or did not develop a TE after PV diagnosis. At univariate analysis, PV high risk status, a previous TE and hyperlipidemia at PV diagnosis were significantly associated with a subsequent TE. Among hematologic variables an elevated WBC count at the time of thrombosis, but not Hct or PLT levels, was highly significantly associated with the development of a TE. At multivariate analysis, WBC count ≥10.4 x 10^9/L and hyperlipidemia maintained their independent prognostic value, while high risk status and a previous TE lost their prognostic significance. Both at univariate and multivariate analysis, hyperlipidemia at diagnosis (P=0.009 and P=0.002) and high WBC count at thrombosis (P=0.001 and P= In conclusion, our analysis confirms that elevated WBC count at the moment of the event more than increased hematocrit is associated to the development of thrombosis in PV pts. We also found that hyperlipidemia was an independent risk factor for arterial thrombosis, calling for an accurate management of increased lipid levels. Whether a reduction of the WBC count during the course of PV may reduce the frequency of TE remains to be demonstrated by prospective studies. Table Disclosures D'Adda: Novartis: Other: Advisory board; Incyte: Other: Advisory board; Pfizer: Other: Advisory board. Rossi:Daiichi Sankyo: Consultancy, Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Advisory board; Alexion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.

Introduction: We have previously reported short-term efficacy of six courses of R-DA-EPOCH in patients with aggressive B cell lymphomas carrying concomitant MYC and BCL-2 and/or BCL-6 rearrangement (DHL/THL) or gene increase copy number (ICN) (Tucci et al. Blood S1: 4154, 2017). Further experience with the same program has been described in the meantime in patients with aggressive lymphoma and c-MYC rearrangement, either as single hit or DHL/THL (Dunleavy et al. Lancet Haematol, 2018). We report here long-term results in a larger unselected series of DHL/THL with the aim to confirm our preliminary results and to define the role of consolidation with autologous stem cell transplantation (ASCT) after R-DA-EPOCH remission induction. Methods: The study includes patients consecutively seen in four Italian centres. From January 2014, fit patients aged less than 80 years, with diffuse large B cell lymphoma (DLBCL), lymphoma with intermediate features between DLBCL and Burkitt (BCLU) or high grade lymphoma (HGBCL) histology, diagnosed as DHL or THL by fluorescent in situ hybridization (FISH), were treated with R-DA-EPOCH and central nervous system prophylaxis. Patients with MYC -ICN (three or more extra signals in more than 30% of nuclei, Schieppati et al. Haematologica, 2019) plus BCL-2 and/or BCL-6 gene rearrangement or ICN were also included. Pre-treatment with one cycle of R-CHOP was allowed in patients in need of urgent treatment, pending the results of FISH analysis. Consolidation with ASCT was planned in three of the four centres for stage II-IV patients aged less than 71 who reached at least a partial remission (PR) after six R-DA-EPOCH courses. Immunohistochemistry (IHC) was used to define cell of origin (COO) according to Hans' algorithm, double expressor cases (MYC and BCL-2 protein >40% and 50% respectively) and Ki67 expression. Results: Sixty-three patients were treated (51 DLBCL, 5 BCLU, 7 HGBCL, including 16 with histologic transformation from an indolent lymphoma). Their median age was 63 years (range 23-79) and 43 (68%) were males. Fifty-four (86%) had Ann-Arbor stage III/IV, 18 (28%) B symptoms and 41 (65%) high-intermediate/high risk score according to International Prognostic Index (IPI), with extranodal disease in 79% of patients, mainly in bone and gastrointestinal tract. According to FISH analysis, 34 cases were DHL, 10 THL and 19 c-MYC-ICN. According to IHC, 81% were of germinal center origin, 73% were double expressors and median Ki-67 was 91% (range 35-100%). Patients received a median of six courses of R-DA-EPOCH (range 1-6). Twelve patients were pre-treated with one R-CHOP course and 24 patients (17 in complete remission, 6 in PR and 1 with disease progression) received transplant consolidation (allogeneic SCT in one PR patient), according to the policy of the centre and eligibility criteria. In the entire cohort, the overall response rate was 81%, including 68% complete responses (CR) and 3y-PFS and OS were 67% and 69% respectively. Two patients died of infectious complications during chemotherapy. Of the 10 chemo-refractory patients, all have died of lymphoma. Median length of follow-up was 32 months. At univariate analysis, IPI > 3 and THL were significantly associated with a worse outcome while cMYC-ICN and ASCT with a better OS. At multivariate analysis, only ASCT remained significantly associated with better survival (HR 0.146, IC 95% 0.032-0.667, p 0.013). Focusing on patients who achieved CR with R-DA-EPOCH, all 17 patients who underwent transplantation (100%) are alive (after a median of 27 months from transplant), versus 19 out of 24 patients (79%) who did not. Only one patient relapsed after ASCT and is alive after receiving CAR-T cells. 3y-OS and PFS of patients in CR after induction therapy who received or not ASCT consolidation were 100% vs 76% and 94% vs 72% respectively (Fig.1). Clinical characteristics of the two subgroups were similar except for median age that was lower in the former one (59 vs 69 years). Conclusions: These results confirm the favourable outcome of patients with MYC and BCL-2 and/or BCL-6 rearrangements or gene ICN with R-DA-EPOCH therapy. The role of consolidative ASCT and its usefulness seems encouraging, but remains to be proven by prospective randomized studies. The poor outcome of chemo-refractory patients represents an unmet need and greater expansion of CAR-T cell programs could improve these results in the near future. Disclosures Tucci: Amgen: Consultancy. Carlo-Stella:Boehringer Ingelheim and Sanofi: Consultancy; Servier, Novartis, Genenta Science srl, ADC Therapeutics, F. Hoffmann-La Roche, Karyopharm, Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb, Merck Sharp & Dohme, Janssen Oncology, AstraZeneca: Honoraria; ADC Therapeutics and Rhizen Pharmaceuticals: Research Funding. Corradini:Takeda: Consultancy, Honoraria, Other; BMS: Other; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; KiowaKirin: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel and accommodations paid by for; F. Hoffman-La Roche Ltd: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Amgen: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Daiichi Sankyo: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Incyte: Consultancy; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations paid by for. Rossi:Janssen: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Advisory board; Abbvie: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Jazz: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria.

Burkitt’s lymphoma (BL) is an aggressive lymphoma subtype with high 18F-FDG avidity at 18F-FDG-PET/CT, but no validated criteria for PET/CT in treatment evaluation or prediction of outcome in BL are available. The aim of our study was to investigate whether the metabolic baseline PET/CT parameters can predict treatment response and prognosis in BL. We retrospectively enrolled 65 patients who underwent baseline 18F-FDG-PET/CT, interim and end of treatment PET/CT. The PET images were analyzed visually and semi-quantitatively by measuring the maximum standardized uptake value body weight (SUVbw), the maximum standardized uptake value lean body mass (SUVlbm), the maximum standardized uptake value body surface area (SUVbsa), lesion to liver SUVmax ratio (L-L SUV R), lesion to blood-pool SUVmax ratio (L-BP SUV R), total metabolic tumor volume (tMTV) and total lesion glycolysis (TLG). Survival curves were plotted according to the Kaplan–Meier method. At a median follow-up of 40 months, the median PFS and OS were 34 and 39 months. MTV and TLG were significantly higher in patients with partial response compared to complete response group at end of treatment, while no significant differences were found at interim. Other metabolic PET/CT parameters were not related to treatment response. MTV and TLG were demonstrated to be independent prognostic factors for both PFS and OS; instead SUVbw, SUVlbm, SUVbsa, L-L SUV R and L-BP SUV R were not related to outcome survival. Metabolic tumour features (MTV and TLG) were significantly correlated with response to treatment and long-term outcome.

Although the ELN MRD Working Party (Schuurhuis, 2018) recommends that Acute Myeloid Leukemia (AML) patients (pts) with mutated NPM1 (NPM1+) should have molecular assessment of measurable/minimal residual disease (MRD), the most clinically significant timepoints (TPs), the thresholds, the best source of samples, bone marrow (BM) or peripheral blood (PB) and especially the management of molecular relapse, remain controversial. We evaluated the prognostic significance of NPM1 molecular monitoring, its impact on disease recurrence and the outcome of salvage treatment. From Jul 2010 to dec 2018, 83 consecutive NPM1+ AML pts (M/F: 44/39; median age 59 y, 27-74) eligible for intensive chemotherapy (i-T) were treated, according to the NILG-AML00 protocol (ClinicalTrial.gov: NCT00400673): ICE (idarubicine-ARAC-etoposide) as induction, followed by IC consolidation and 3 further consolidation cycles of high-dose ARAC. Allogeneic stem cell transplant (HSCT) was considered at relapse. Quantitative RT-PCR was performed to detect NPM1 mutation (Gorello, 2006) on BM and PB samples at diagnosis (TP0) and at given TPs: at complete remission (CR) (TP1), post-IC (TP2), post-1st ARAC consolidation (TP3) and at the end of treatment (TP4). Serial MRD monitoring during follow-up was made on PB every 3 months (mo) for 5 years (y) or until relapse. Molecular relapse (mR) was defined as the NPM1 level increase at least 1 log in 2 consecutive samples, in absence of hematological relapse (hR). At baseline, karyotype (K) was abnormal in 8 pts (9.6%); 25 (30%) were FLT3-ITD mutated with a median Allelic Ratio (AR) of 0.35 (range: 0.2 to 2.18) (Pratcorona, 2013). During treatment, 608 samples were studied (383 BM and 225 PB), for a median of 8 per patient (range: 3 to 10). At TP1, a higher level of NPM1 unfavorably impacted on relapse (p 0.02) and a cut-off >200 *10^4/ABL was significantly associated with a higher relapse risk (RR) (68.7%) and lower RFS (p 0.006). Moreover, MRD positivity (value >0*10^4 NPM1/ABL) at TP2 on PB was associated to a higher RR (38.8%; p 0. 041) and a level >0.5*10^4/ABL allowed to predict relapse in 75% of pts, also impacting on RFS (p 0.0001) (Figure 1).Molecular NPM1 relapse/progression occurred in 10 pts early during treatment, after a median of 3.5 mo (1.4-6) from diagnosis and in 8 of them simultaneously with hR. In 16 pts mR occurred after a median CR duration of 18.5 mo (10.5-61.5) (late relapse). Hence a mR was more frequent in late than in early relapse (87.5% vs 20%; p 0.001). Median survival was 8.3 mo in early relapsing pts and was not reached in late relapsing pts (p. 0.0002). Age, NPM1 level at TP0, FLT3-ITD mutation, ITD-AR or abnormal K did not impact on type of relapse (mR or hR), but FLT3-ITD was more frequent in early than late relapse (60% vs 18.7%; p 0.04). After a median follow-up of 42 mo (4-108), 5-y relapse-free survival (RFS) and overall survival were 64.2% (+/-6.5% SE) and 71.1% (+/-6.1% SE), respectively. Overall, considering both mR and hR, 26 pts (31.3%) relapsed after a median of 13.5 mo after CR; 24/26 pts received a salvage treatment and 14 (53.8%) (median age 49y, 27-64) could proceed to HSCT after a median of 2.9 mo (5 too old, 7 early progression). Salvage treatment before HSCT was i-T in 7/14 and non-i-T in 7/14 pts (2 ATRA and 5 D-actinomycin, Falini 2015) for a median of 3 cycles (range 2-4). Disease status at HSCT was: mCR in 3 pts, CR with detectable MRD (median NPM1: 125*10^4/ABL, range 17.8-3849) in 9, refractory in 2 pts. Nine/14 HSCT pts (64.2%) are alive and in remission at a median of 29.6 mo (13-49) from HSCT, 2 pts died of sepsis in c-GVDH at 6.2 and 37.5 mo after HSCT, 1 died of VOD and 2 of disease progression. At 3 months after HSCT all MRD positive pts were NPM1 negative. mR occurred in 3 pts at 8, 12 and 15 mo after HSCT and was successfully treated with early pre-emptive donor lymphocyte infusions. With the limits of small numbers, age, type (mR or hR) or timing of relapse (early or late), disease status at HSCT, donor source and conditioning intensity didn't influence survival. Our study shows that PCR monitoring during treatment can identify pts at higher RR according to the transcript levels in BM and PB samples. In NPM1+ AML, molecular monitoring in PB during follow-up is of crucial importance in detecting late molecular relapse allowing to use less toxic molecular-oriented treatments as a bridge to HSCT. Further studies on larger cohorts hopefully will help to confirm its usefulness to guide the treatment approach. Disclosures Rossi: Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Mundipharma: Honoraria; BMS: Honoraria; Sandoz: Honoraria; 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; Daiichi-Sankyo: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: D-actinomicin

Mantle cell lymphoma (MCL) is an aggressive lymphoma sub-type with poor prognosis and high 18F-FDG avidity at PET/CT; nowadays, no validated criteria for PET/CT in treatment response evaluation and prediction of outcome are present. The aim of study was to investigate whether the metabolic PET/CT features may predict treatment evaluation and prognosis in MCL. We retrospectively enrolled 87 patients who underwent baseline 18F-FDG PET/CT and 85 end-of-treatment (eot) PET/CT. The baseline PET images were analyzed visually and semi-quantitatively by measuring the maximum standardized uptake value body weight (SUVbw), lean body mass (SUVlbm), body surface area (SUVbsa), lesion-to-liver SUVmax ratio (L-L SUV R), lesion-to-blood pool SUVmax ratio (L-BP SUV R), metabolic tumor volume (MTV) and total lesion glycolysis (TLG). EotPET/CT was visually interpreted according to the criteria of the Deauville 5-point scale (DC). Survival curves were plotted according to the Kaplan–Meier method. At a median follow-up of 40 months, relapse/progression occurred in 47 and death in 23 patients. Median PFS and OS were 30 and 41 months. Baseline MTV and TLG were significantly higher in patients with progressive metabolic response compared to complete/partial response group. EotPET/CT results using DC significantly correlated with PFS, not with OS. MTV and TLG were demonstrated to be independent prognostic factors for PFS; instead the other metabolic parameters were not related to outcome survival. Considering OS, no variable was significantly associated. EotPET/CT results (using DC), MTV and TLG were significantly correlated with response to treatment and PFS.

Risk stratification in acute myeloid leukemia (AML) patients using prognostic parameters at diagnosis is effective, but may be significantly improved by the use of on treatment parameters which better define the actual sensitivity to therapy in the single patient. Minimal residual disease (MRD) monitoring has been demonstrated crucial for the identification of AML patients at high risk of relapse, but the best method and timing of MRD detection are still discussed. Thus, we retrospectively analyzed 104 newly diagnosed AML patients, consecutively treated and monitored by quantitative polymerase chain reactions (Q-PCR) on WT1 and by multiparametric flow cytometry (MFC) on leukemia-associated immunophenotypes (LAIPs) at baseline, after induction, after 1st consolidation and after 1st intensification. By multivariate analysis, the factors independently associated with adverse relapse-free survival (RFS) were: bone marrow (BM)-WT1 ≥ 121/10(4) ABL copies (P = 0.02) and LAIP ≥ 0.2% (P = 0.0001) (after 1st consolidation) (RFS at the median follow up of 12.5 months: 51% vs. 82% [P

We report a case of an 81-year-old man, hospitalized for sepsis unresponsive to targeted antibiotic therapy, who underwent abdominal aortic aneurysmectomy with stent placement before 12 years. Point-of-care ultrasound examination showed the presence of a voluminous and inhomogeneous lesion adjacent to the anterior wall of aortic bifurcation with pulsatile flow from the aorta into the lesion, highlighted by Color-Doppler, and peripheral (closely with intestinal loops) floating hyperechoic spots marked by posterior comet tail artifact, suggestive for the presence of air bubbles. The presence of an aortoenteric fistula not excluding in differential diagnosis and the possibility of an abscess of aneurysmatic sac with colonization of gas-producing bacteria were suspected; an abdominal contrast-enhanced computed tomography was requested and it confirmed the suspicion of an aortoenteric fistula. The patient underwent emergency surgical intervention with good technical success (evidence of aorto-appendicular fistula), but he died the day after of cardiac arrest.Descriviamo il caso di un uomo di 81 anni, ricoverato per sepsi non responsiva ad antibioticoterapia mirata, sottoposto 12 anni prima ad aneurismectomia dell'aorta addominale con innesto protesico. L'esame ecografico eseguito al letto mostrava la presenza di una voluminosa formazione disomogenea a livello della parete anteriore della biforcazione aortica, con evidenza, al Color-Doppler, di flusso pulsatile dall'aorta all'interno della lesione, e presenza di spot iperecogeni mobili con artefatto a coda di cometa nella parte più periferica (a stretto contato con le anse intestinali), come per presenza di componente gassosa. Si formulava quindi il sospetto di una fistola aortoenterica, non potendosi escludere, in diagnosi differenziale, una raccolta ascessuale della sacca aneurismatica con colonizzazione di batteri produttori di gas. Veniva richiesta una TC addome urgente con mezzo di contrasto che confermava il sospetto di fistola aorto-enterica; il paziente, veniva sottoposto in urgenza ad intervento chirurgico tecnicamente efficace (riscontro di fistola aorto-appendicolare), ma decedeva nella fase post-operatoria per arresto cardiaco conseguente a infarto miocardico acuto.

Optimal treatment for transformed follicular lymphoma (tFL) is not fully defined. Clinical characteristics and treatments that impact on post-transformation outcome of 176 biopsy-proven tFL were analysed. Transformation occurred at initial diagnosis in 52% (Group 1) and after a FL diagnosis in 48% (Group 2). Five-year overall survival was 84% for Group 1 and 51% for Group 2 (P < 0·001). In Group 1, 5-year progression-free survival was superior after rituximab maintenance compared to observation only (94% vs. 53%, P = 0·024). In Group 2, an inverse trend was found between survival and both a higher number of pre-transformation treatment lines and a short time-to-transformation.

Invasive fungal diseases (IFDs) remain a major clinical issue in patients with hematological malignancies (HMs). To confirm the efficacy and safety of the new azole isavuconazole (ISV) in a clinical care setting, we planned a multicenter retrospective study; we collected data on all possible/probable/proven IFDs in patients with HMs treated with ISV in 17 centers. Between July 2016 and November 2018, 128 patients were enrolled, and 122 were fully evaluable. ISV was employed as the 1st line therapy in 43 (35%) patients and as a subsequent therapy in 79 (65%) patients. The response rate was 82/122 patients (67.2%); it was similar when using ISV as a 1st or 2nd line treatment (60.5% vs 70.9%, respectively; p = 0.24). In multivariate analysis, both female sex (OR: 2.992; CI: 1.22–7.34) and induction phase of treatment (OR: 3.953; CI: 1.085–14.403) were predictive of a favorable response. At a median follow-up of 5 months, 43 (35.2%) patients were dead; the 1-year overall survival (OS) was 49.9%. In multivariate analysis, the response to ISV (OR: 0.103; CI: 0.041–0.262) and IFD refractoriness to previous antifungals (OR: 3.413; CI: 1.318–8.838) were statistically significant for OS. Adverse events (AEs) were reported in 15/122 patients (12.3%); grade 3–4 AEs were reported in 5 (4%) and led to ISV discontinuation. Our study confirms the safety and tolerability of ISV, also in diseases other than acute leukemia. Phase of hematological disease, gender and refractoriness to previous antifungals are the main predictive factors for the aforementioned response and outcome.

BACKGROUND Tyrosine Kinase Inhibitor (TKIs) discontinuation has become, nowadays, under proper conditions, a feasible option for chronic myeloid leukemia (CML) also in "real life" setting. Different papers investigated which factors (age, sex, type of TKI, previous r-interferonα -r-INFα- therapy, line of therapy at stop, type of transcript, duration of TKI therapy and of sustained deep molecular response -sDMR-, Sokal risk score) could predict a successful TKIs discontinuation either within protocols or outside of clinical trials, and the results are not unique. AIM We retrospectively evaluated our CML pts who stopped TKI after sDMR in order to assess the variables that could influence the probability of a durable TFR. METHODS BCR-ABL transcripts were determined by RQ-PCR performed according to EAC protocol (Gabert et al, 2003) and to the standards of the Italian National Network Labnet. Criteria for TKI discontinuation was sustained DMR (MR4 or better) for at least 2 years. After TKI withdrawal, RQ-PCR for BCR-ABL was performed every month during the first year and every 2 months thereafter. TKI treatment was reintroduced if DMR loss occurred.TFR was assessed using the Kaplan-Meier method; potential prognostic factors were considered for multivariable analyses at a level less than .20. RESULTS Between October 2010 and January 2019, 68 patients discontinued TKIs, 18 of them after less than 5 years of treatment because of pregnancy desire (3), intolerance (6), patient's desire/non compliance (5), enrollment in study protocols (4). At discontinuation median age was 63 years (30-85), median time from TKI start 85 months (30-190), median duration of sustained DMR 48 months (24-153). Sokal distribution was 48%, 31% and 18% for low, intermediate and high risk respectively (2 patient was not evaluable). E14a2 transcript type was present in 52 pts and e13a2 in 16 pts. Thirty-eight patients stopped imatinib, 25 nilotinib (19 in 1st line, 6 in 2nd line), 5 dasatinib. Before imatinib 15 patients received r-IFNα, for a median time of 60 months (3-256). Median follow up after TKI stop was 39 months (5-105, >24 in 61, 60 months (p = 0.025) and previous r-IFNα therapy (p=0.021) were significantly linked to better outcome after TKI discontinuation; sDMR > 72 months is very close to be a significant variable (p=0.055). At multivariate analysis only the type of BCR-ABL transcript (p=0.027) and previous r-IFNα ( p=0.016) remained independent significant prognostic factors -figure A and figure B-. CONCLUSION e14a2 transcript type was confirmed as a robust favorable prognostic factor for TFR maintenance. In our experience, 2GTKIs didn't impact favorably TFR duration after TKIs discontinuation, conversely r-IFNα treatment before TKI improved the probability of maintaining DMR after TKI withdrawal, particularly in e13a2 patients. In fact r-IFNα before imatinib reversed the negative prognostic impact on TFR maintenance of the e13a2 transcript type. Disclosures D'Adda: Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Rossi: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; 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; Mundipharma: Honoraria; BMS: Honoraria; Sandoz: Honoraria; 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; Daiichi-Sankyo: Consultancy.

Monitoring of BCR-ABL1 levels by quantitative PCR (qPCR) is essential for the management of CML patients treated with TKIs. Because of intrinsic limits, qPCR does not appear to be an optimal assay to select the best candidates to TKIs discontinuation. Up to 40% of CML patients treated with TKIs can achieve a Deep Molecular Response (DMR), but only 50% maintain a stable Treatment Free Remission (TFR) after therapy discontinuation. Digital PCR (dPCR), giving an absolute quantification of BCR-ABL1, is expected to be more sensitive and accurate than qPCR in the assessment of molecular MRD. dPCR performed on a QuantStudio 3D Digital PCR System (Life Technologies) by using a TaqMan-MGB probes targeting the BCR-ABL1 transcript was used to comparatively analyse 102 CML patients with Major (MR3.0 = 31 cases) or Deep (MR4.0= 33 cases; MR4.5 = 24 cases and MR5.0 = 14 cases) molecular response. Preliminary results showed that: a) ≥77% of deep responders (MR4.0, MR4.5 and MR5.0) fell under the value of 0.468 BCR-ABL1 copies/▢l indicated by the ROC analysis as the value below which the patients with lower levels of MRD might be dissected (spec.=71%, sens.=77%; AUC=0,79); b) BCR-ABL1 transcript levels were detectable by dPCR also in cases resulted undetectable by qPCR. In this study, we analysed the BCR-ABL1 transcript levels by dPCR in 207 samples related to 102 CML patients. Fourteen (14%) out of 102 CML patients discontinued the TKIs therapy. Among them, 3 patients (21%) lost DMR and all of them showed dPCR values > 0.468 BCR-ABL1 copies/▢l (previously described as cut-off for a deep MRD), while 11 (79%) maintained a stable DMR and 9 of them (82%) fell under the value of 0.468 BCR-ABL1 copies/▢l. These latter patients stratified in different DMR classes by qPCR and all had undetectable level of BCR-ABL1 by qPCR. In 149 out of 207, qPCR revealed DMR. They were: MR4.0= 59 samples; MR4.5= 61 cases; MR5.0 = 29 cases. One hundred twenty-five (84%) fell under the value of 0.468 BCR-ABL1 copies/▢l. A linear regression analysis in these samples did not show any correlation between BCR-ABL1 copies/▢l detected by qPCR with the ones detected by dPCR (R2 < 0.01). On the basis of our preliminary results, TFR seems to be correlated to the maintenance of dPCR values < 0.468 BCR-ABL1 copies/▢l. The concordance between qPCR and dPCR quantification in patients with DMR and with BCR-ABL1 copies/▢l value < 0.468 was poor. Patients with dPCR values < 0.468 BCR-ABL1 copies/▢l may have 75% of probability to maintain TFR status. These results suggest that dPCR may be more sensitive to detect the MRD and could be more useful for DMR monitoring and for dissecting the best candidate to discontinuation of therapy with TKIs. Disclosures Tiribelli: Ariad Pharmaceuticals: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Castagnetti:Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; ARIAD Pharmaceuticals: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Soverini:Novartis: Consultancy; Ariad: Consultancy; Bristol-Myers Squibb: Consultancy. Rosti:Pfizer: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Incyte: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Martinelli:Roche: Consultancy; ARIAD: Consultancy; Pfizer: Consultancy, Speakers Bureau; Genentech: Consultancy; Amgen: Consultancy; MSD: Consultancy; Roche: Consultancy; ARIAD: Consultancy; Pfizer: Consultancy, Speakers Bureau; BMS: Speakers Bureau; Genentech: Consultancy; Amgen: Consultancy; Novartis: Speakers Bureau; MSD: Consultancy.

Aim Assessment of hematologic improvement, survival and peri-operative morbidity after first-line splenectomy for splenic marginal zone lymphoma (SMZL). Methods Forty-three patients undergoing open splenectomy were prospectively analyzed. Perioperative clinical course, overall and progression-free survival (OS-PFS) were evaluated. Risk factors analyzed were gender, age, ASA-grade, ECOG performance status, presence of B-symptoms, body mass index, steroidal treatment, serum albumin concentration, IIL-score, operative time, spleen size and weight. Results The median follow-up was 31 months (IQR 15–76; range 24–154). Anemia and thrombocytopenia resolved in 80% of patients at 6 months; in 60% at 2 years. The 5-year and 10-year PFS were 35% and 13% respectively, with a median of 35 months (shorter in patients with ECOG performance status ≥2 and B-symptoms). Nineteen cases (44.2%) had a progression of disease within 2 years. Of these, 14 (32.6%) received adjuvant chemotherapy (mainly R-FC or R-CVP). Progression was attributed to high-grade B lymphoma in 7 (16.3%) patients. The median time between diagnosis and progression to aggressive lymphoma was 25.5 months (range 18.8–81.8). The median time to next treatment was 83.5 months (95% CI 49–118). The 5-year and 10-year OS were 75% and 53% respectively. Mortality was due to disease progression and histological transformation in high-grade B lymphoma in 50% of cases, myelodisplastic syndrome in 15%, recurrence of hemolytic anemia in 15%, Hodgkin lymphoma in 7% and to infections (mainly pulmonary) in the remaining 13% of cases. Post-operative morbidity was 2.3% (1 patient with grade-3 complication). Overall grade ≥2 complication rate was 32.5% (mainly hemorrhagic and pulmonary complications). Spleen weight was the only independent risk factor for morbidity. Mortality was nil. Conclusion Splenectomy is safe and effective as regards cytopenia resolution and OS, although disease progression is frequently observed at follow-up. Such results are strictly linked to accurate pre- and post-operative clinical management and optimal anesthesiologic approach.

INTRODUCTION: Although diffuse large B cell lymphoma (DLBCL) is considered a curable disease in the immunochemotherapy (ICT) era, about 40% of patients relapse or are refractory to first line treatment, representing an unmet clinical need. The role of upfront autotransplantation (ASCT) in high-risk cases is still debated, while its role in relapsed/refractory (R/R) disease is established in all guidelines. However less than 50% are actually cured with salvage ASCT (Gisselbrecht C et al, J Clin Oncol. 2010) and outcome of patients who relapse after ASCT is very poor (Crump M. et al, Blood 2017; Van Den Neste E et al, BMT 2017). Prognosis of aggressive lymphomas with characteristics intermediate with Burkitt's lymphoma (BCLU), recently reclassified (WHO 2016) as high grade lymphoma, unspecified with or without c-myc translocation, is less favourable. Regimens containing HD-MTX/ARA-C were generally used to treat these lymphoma subtypes as well as lymphoma with central nervous system (CNS) localization. Aim of this study was to evaluate the prevalence and outcome of R/R lymphoma after upfront or salvage ASCT or after HD-MTX/ARA-C regimens in the clinical care setting and to identify potential salvage approaches. PATIENTS and METHODS: We retrospectively analysed all consecutive HIV-negative patients seen at our Institute from January 2008 to December 2016 with de novo or transformed DLBCL, Primary mediastinal B-cell lymphoma or high-grade lymphoma/BCLU. First-line treatment used was R-CHOP/CHOP-like regimens. Consolidation with ASCT was performed in all high/intermediate-high IPI risk patients less than 65 years old, while salvage ASCT was performed after salvage ICT for R/R disease; HD-MTX/ARA-C regimens were used in DLBCL patients with CNS involvement or in BCLU cases. Relapsed or refractory patients after upfront or salvage ASCT or after HD-MTX/ARA-C were selected and their demographic and histological features as well as their outcome was analysed in term of duration of Response (DOR) from ASCT or MTX/ARA-C regimen to relapse and Overall Survival (OS) from relapse to the last follow-up or death. We recorded salvage treatments carried out according to age, performance status, available clinical protocols or international guidelines (more than one line in some patients). RESULTS: Among 571 patients consecutively seen during the time period, 156 (27.3%) proved refractory or relapsed after first-line treatment. ASCT was performed in 86 patients as consolidation (group A) and in 33 as salvage (group B). First line HD-MTX/ARA-C regimens were used in 16 patients (group C). Relapse occurred in 9/86 group A (10%), 20/33 group B (61%) and 8/16 group C (50%) patients respectively, representing 6.5% of the whole patients initially diagnosed. First relapse occurred after a median DOR of 4, 7, and 3.5 months in group A, B and C respectively. The main demographic and histological characteristics of relapsed patients are summarized in the Table 1, which also shows treatments used after relapse. Response rates in patients treated with curative intent were 29% (6/21). Mortality rates were high in all groups (78%, 90% and 100% respectively), with an OS significantly better in group A comparing to group B and C patients (p 0.0243) (Fig.1a) and in patients treated with curative intent compared to patients that received palliation (p CONCLUSIONS: This analysis shows the very poor prognosis of patients with aggressive lymphoma relapsing after high dose therapy (ASCT or MTX/ARA-C). The recurrence of disease in these patients is early and salvage therapies are ineffective in most of the cases, although trying to treat these patients with curative intent shows a survival advantage over palliation. Patients treated with multiple lines of chemotherapy (group B) or with upfront HD-MTX/ARA-C (group C) have the worse prognosis. These data justify intensive follow-up programs during the first year after the end of therapy, and underline the need to develop new therapeutic strategies for this setting of patients, which could represent an ideal indication for CAR-T cell treatments. Disclosures Rossi: GILEAD: Other: ADVISORY BOARD; SANOFI: Other: ADVISORY BOARD; NOVARTIS: Honoraria; ABBVIE: Other: ADVISORY BOARD; CELGENE: Other: ADVISORY BOARD; AMGEN: Other: ADVISORY BOARD; JAZZ: Other: ADVISORY BOARD; JANNSEN: Other; MUNDIPHARMA: Honoraria; BMS: Honoraria; PFIZER: Other: ADVISORY BOARD; TEVA: Other: ADVISORY BOARD; ROCHE: Other: Advisory Board; SANDOZ: Honoraria.

Introduction: Autologous stem cell transplantation (ASCT) is considered safe and effective in patients with HIV-associated lymphoma (HIV-Ly). The reported studies usually analyze togheter different histological subtypes, including classical Hodgkin lymphoma (HL) and a variety of aggressive non Hodgkin lymphoma (NHL), and different indications for ASCT, and report composite outcomes. Aim: We report our single center experience on a large single institution series of patients (pts) with HIV-Ly undergoing ASCT and analyse efficacy according to histology subtypes, indications for ASCT, previous therapy and lymphoma status at transplant, to understand the settings where this treatment approach is most effective and useful. Methods: Retrospective analysis of clinical characteristics and outcome of all consecutive pts with HIV-Ly transplanted at our Institution from March 2001 to February 2018. Results: 62 pts with HIV-Ly underwent ASCT during the study period. Ninety-four % were male; median age was 46 years (range, 29-62). Lymphoma histology was HL in 11 (18%), diffuse large B-cell lymphoma in 22 (35%), Burkitt or Burkitt-like in 13 (21%) , plasmablastic in 10 (16%), T-cell aggressive NHL (3 anaplastic large cell lymphoma, ALK negative, and 1 extranodal NK/T-cell lymphoma, nasal type) in 4 (6%), and indolent B-cell lymphoma (1 follicular lymphoma, and 1 extranodal marginal zone lymphoma) in 2 (3%) pts, respectively. Median CD4+ cells count at ASCT was 208/mL (range, 55-720); 8 pts (13%) had detectable HIV viral load. Eighteen pts (29%) had concomitant hepatitis C and 2 (3%) hepatitis B infection. Indications for ASCT were primary refractory disease (26%), first or subsequent relapse (37%), and consolidation after first line therapy for partial remission (PR) or high risk complete remission (CR) (37%). At the time of ASCT, 10 pts (16%) were in first CR, 45 (73%) had chemosensitive disease (i.e. first PR, chemosensitive relapse/refractory disease), and 7 (11%) had disease refractory to the last chemotherapy (CT) received. Twenty-three patients (37%) had received only 1 line of CT before ASCT, 29 (47%) 2 lines, and 10 (16%) 3 or more lines. Conditioning regimen was BEAM in 47 patients (76%), FEAM in 13 (21%), and 1 each Mitoxantrone-Melphalan and BiCNU-Thiotepa. All pts were receiving cART throughout ASCT except 3 who suspended cART for at least 1 week, due to toxicity and/or oral mucositis. Neutrophil engraftment (neutrophils > 500/mcl) occurred in all pts at a median of 10 days (range, 8-12), and platelet engraftment (platelet count > 20.000/mcl) occurred in all pts at a median of 13 days (range, 9-46), except in one with refractory disease who died of sepsis early after ASCT (treatment-related mortality 1.6%). Twenty-three pts (70%) experienced grade 3-4 toxicity, including oral mucositis (17 patients), gastrointestinal toxicity (8), hepatic toxicity (1), and seizures (1). Twenty-five pts (41%) had an episode of fever of unknown origin. Before engraftment, 22 documented bacterial infections, 1 fungal infection, 2 herpes zoster infections and 5 CMV reactivations were recorded. After a median follow-up of 59 months (range, 1-177) from ASCT, the 5 years-progression free survival (5y-PFS) and OS (5y-OS) were 66.6% and 69.7% respectively, with no significant differences according to different histologies (figure 1). The outcome was satisfactory regardless of the indication for transplant (primary refractory disease, 5y-PFS 50% and 5y-OS 49% , relapse, 5y-PFS 62.6% and 5y-OS 70.7%, and first line consolidation, 5y-PFS 80.3% and 5y-OS 80.1%, P=NS), and number of CT lines before ASCT (1 line, 5y-PFS 80.3% and 5y-OS 80.1%, 2 lines, 5y-PFS 61.3% and 5y- 63.4%, and 3 or more lines, 5y-PFS 53.3% and 5y-OS 66.7%, P=NS). According to the status of lymphoma at the time of ASCT, pts in first CR had a 5y-PFS of 77.8% and 5y-OS of 77.8% and pts with chemosensitive disease 73.7% and 80.3%, while all chemorefractory pts died within 5 months from ASCT, with median PFS and OS of 2 and 3 months respectively (P< 0.001) (figure 2). Conclusion: This is the largest single institution series of HIV-Ly receiving ASCT. We confirm the feasibility and long-term efficacy of this treatment approach in different histological subtypes. ASCT was beneficial also in primary refractory disease and heavily pre-treated pts, provided that lymphoma proved chemosensitive to the last CT received before ASCT. Disclosures Rossi: ABBVIE: Other: ADVISORY BOARD; PFIZER: Other: ADVISORY BOARD; SANDOZ: Honoraria; GILEAD: Other: ADVISORY BOARD; AMGEN: Other: ADVISORY BOARD; SANOFI: Other: ADVISORY BOARD; JANNSEN: Other; JAZZ: Other: ADVISORY BOARD; TEVA: Other: ADVISORY BOARD; CELGENE: Other: ADVISORY BOARD; ROCHE: Other: Advisory Board; NOVARTIS: Honoraria; MUNDIPHARMA: Honoraria; BMS: Honoraria.

Introduction. The outcome of invasive fungal infections (IFI), particularly aspergillosis in acute leukemia (AL) patients (pts), has improved over the last years, but IFI still remain a major clinical issue in hematological pts, both for its severity and for the toxicity and potential drug interactions of antifungal treatments. Isavuconazole (ISV) is a new antifungal agent, with a modest drug-drug interaction profile, reduced drug-related adverse events and efficacy similar to voriconazole as demonstrated in a non-inferiority trial of IFI treatment (Maertens, Lancet 2016). To confirm the efficacy and safety of ISV in a clinical care setting, we planned a multicenter retrospective epidemiological study on behalf of SEIFEM (Sorveglianza Epidemiologica delle Infezioni nelle Emopatie) Group, collecting all cases of IFI treated with ISV in hematological pts. Patients and Methods. Since July 2016, we collected all cases of IFI occurring in adult and pediatric hematological pts who were treated with ISV in 13 Centers. IFI was diagnosed according to EORTC/MSG criteria and categorized as possible (poss) or probable/proven (p/p). The effects on outcome of age, gender, type and status of hematological disease at IFI (diagnosis [Dx], complete and partial remission [CR/PR], relapse/refractory [Rel/Refr]), type of IFI, allogeneic stem cell transplantation (alloSCT), neutropenia and timing of ISV treatment were evaluated. Results. IFI was diagnosed in 69 pts (M/F ratio: 47/22, median age 54.5y, range 5-80), affected by AL in 49 (71%) (myeloid 35, 51%; lymphoblastic 14, 28%), lymphoma in 15 (22%), myeloma in 2 (3%), severe aplastic anemia in 2 (3%) and myelodysplastic syndromes in 1 (1%) pts, respectively. AlloSCT pts were 20 (29%). IFI were categorized as p/p in 36 (52%) and as poss in 33 (48%) cases. Aspergillus spp was responsible for 31/36 (86%) p/p IFI; in the remaining 5 cases, 1 Rhizomucor pusillus was isolated and in 4, despite histology proven for IFI, no specific agent could be identified. Lung was the more frequent site of IFI (58/69, 84%), followed by paranasal sinuses (5, 7%), liver (3, 5%), brain (2, 3%), and bone (1, 1%). ISV was employed as first-line therapy in 19 (28%) and as subsequent line of treatment in 50 pts (72%; 41 as second and 9 as subsequent, respectively), following voriconazole in 15 cases, L-AmB in 22, caspofungin in 1 and combination therapy in 12. The median duration of previous treatments was 17.5 days (range 5-1110). Reasons for ISV use were failure of previous treatments in 16 (32%) and intolerance in 17 (34%) of 50 cases, respectively. In 16 cases (32%) ISV was chosen because of the need to switch antifungal treatment to an oral agent for outpatients and in 3 (4%) for a favorable drug-drug interaction profile. Median duration of ISV treatment was 60 days (3-210). After a median follow-up of 4.2 mo, 24/69 (35%) pts died; IFI-attributable mortality was 10/69 (15%). The estimated 1-year overall survival (OS) from IFI event of the entire cohort was 56% (CI 0.22-0.45); it was similar when considering poss vs p/p IFI (62% vs 51%, p=0.39), AL vs no AL (51% vs 69%, p=0.395) and first vs subsequent line use of ISV (66% vs 59%, p=0.6). OS was significantly lower for pts with failure to previous treatments (1y OS: refractory IFI 26% vs not refractory IFI 66%, p=0.001) (Fig. 1a) and for pts with rec/ref hematological disease (1y OS: rec/ref 29% vs CR/PR 86%, p=0.0027, or vs Dx 53%, p=0.06; no differences between Dx and CR/PR, p=0.27) (Fig. 1b). Clinical and radiological overall response rate (ORR) was 44 of 64 evaluable pts (69%). In multivariate analysis, only underlying disease status was a predictive factor for response to ISV (rec/ref HR 0.202, CI 0.062-0.658). Adverse events (AE) were reported in 10/69 pts (15%) (hepatic in 5, cutaneous in 3, gastroenteric in 3 and hypokaliemia in 1); grade 3-4 AE were reported in 5 cases and led to permanent ISV discontinuation. Conclusions. ISV is widely used in hematological pts with IFI also in diseases other than acute myeloid leukemia and it is overall well tolerated. ORR to ISV is at least comparable with other antifungal agents. A rec/ref underlying hematological disease impacts both on OS and response to ISV, while having an IFI refractory to other antifungal agents including azoles does not seem to compromise the response to ISV, although this promising result should be confirmed in prospective studies and larger groups of patients. Disclosures Busca: Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merk: Honoraria, Speakers Bureau; Pfizer Pharmaceuticals: Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Honoraria; Novartis: Speakers Bureau. Fanci:Gilead: Honoraria; Pfizer Pharmaceuticals: Honoraria; Merck: Consultancy, Honoraria, Speakers Bureau. Candoni:Pfizer: Honoraria, Speakers Bureau; Merck SD: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau. Fracchiolla:Amgen: Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Speakers Bureau; Pfizer Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tumbarello:MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Angelini: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nordic Pharma: Membership on an entity's Board of Directors or advisory committees; Astellas: Speakers Bureau; Pfizer: Speakers Bureau. Aversa:Merck: Honoraria; Basilea: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rossi:Amgen: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria; Novartis: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: 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; Roche: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Sandoz: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Pagano:Basilea: Speakers Bureau; Merck: Speakers Bureau; Janssen: Speakers Bureau; Pfizer: Speakers Bureau; Gilead: Speakers Bureau.

We evaluate the long-term results of a prospective clinical study enrolling more than 100 adult patients with Burkitt lymphoma/leukemia. Depending on extent of disease, treatment consisted of six to eight rituximab infusions and four to six courses of intensive chemotherapy (attenuated in patients aged >55 years) with high-dose methotrexate, fractionated ifosfamide/cyclophosphamide, other drugs in rotation, and intrathecal chemoprophylaxis. One-hundred five patients were treated (median age 47 years, range 17-78 years); 48% had Burkitt leukemia, 25% were older than 60 years, 37% had an Eastern Cooperative Oncology Group performance score >1, and 14% were positive for human immunodeficiency virus. The complete response rate and 3-year overall and disease-free survival rates were 79%, 67% and 75%, respectively, ranging from 100% to 45% for survival (P=0.000) and from 100% to 60% for disease-free survival (P=0.01) in patients with low, intermediate and high adapted International Prognostic Index scores. In multivariate analysis, only age (≤ versus >60 years) and performance status (0-1 versus >1) retained prognostic significance, identifying three risk groups with overall and disease-free survival probabilities of 88% and 87.5%, 57% and 70.5%, 20% and 28.5% (P=0.0000 and P=0.0001), respectively. The relapse rate was only 7% in patients treated with an intercycle interval ≤ 25 days. This regimen achieved 100% curability in patients with low adapted International Prognostic Index scores (21% of total), and very close to 90% in patients aged ≤ 60 years with performance score 0-1 (48% of total). Rapid diagnosis of Burkitt lymphoma/leukemia with prompt referral of patients to prevent clinical deterioration, and careful supervision of treatment without chemotherapy delay can achieve outstanding therapeutic results. ClinicalTrials.gov ID, NCT01290120.

Pseudomonas aeruginosa is a well-known cause of severe and potentially life-threatening infections among hematological patients. A prospective epidemiological surveillance program ongoing at our Hematology Unit revealed an increase over time of P. aeruginosa bloodstream infections (BSI). Their impact on outcome and antibiotic susceptibility was analyzed. BSI which consecutively occurred at our institution during a 70-month period were evaluated and correlated with type of pathogen, status of underlying disease, neutropenia, previous antibiotic therapy, resistance to antibiotics, and outcome. During the observation period, 441 BSI were recorded. Frequency of Gram-negative BSI was higher than that of other pathogens (57.3%). Overall, 66 P. aeruginosa BSI were recorded; 22 out of 66 were multiresistant (MR P. aeruginosa). Thirty-day mortality for all BSI was 11.3%; it was 27.3% for P. aeruginosa BSI and 36.4% for MR P. aeruginosa. At multivariate analysis, only active hematological disease and P. aeruginosa BSI were associated to an increased risk of death. For MR P. aeruginosa, BSI mortality was 83.3% vs. 18.8% when empiric therapy included or not an antibiotic with in vitro activity against P. aeruginosa (p = 0.011). Together with active disease, the emergence of P. aeruginosa BSI, particularly if multiresistant, was responsible for an increased risk of death among hematological patients at our institution. In this scenario, reconsidering the type of combination antibiotic therapy to be used as empiric treatment of neutropenic fever was worthwhile.

Introduction: Many studies evaluated the association of V617F Jak-2 with the risk of thrombosis in patients with essential thrombocythaemia, but the results of these studies were inconsistent. Few studies evaluated the association of V617F Jak-2 mutation with the risk of thrombosis in patients with idiopathic myelofibrosis. Therefore, we performed a systematic review of the studies that assessed the risk of thrombosis associated with V617F Jak-2 in patients with ET or IM. Materials and Methods: We searched MEDLINE and EMBASE databases and reference lists of retrieved articles. Odds ratios (ORs) and 95% confidence intervals (CI) were calculated for each trial and pooled. Results: We included 21 studies involving patients with essential thrombocythaemia and 6 studies patients with idiopathic myelofibrosis. In essential thrombocythaemia patients, V617F Jak-2 was associated with a significant increased risk of thrombosis (OR 1.92, 95% CI 1.45-2.53), both of venous (OR 2.49, 95% CI 1.71-3.61) and arterial (OR 1.77, 95% CI 1.29-2.43) vessels. In idiopathic myelofibrosis patients, the risk of thrombosis associated with V617F Jak-2 tended to be increased (OR 1.76, 95% CI 0.91-3.41). Conclusions: Our systematic review suggests that V617F Jak-2 increases the risk of thrombosis in essential thrombocythaemia patients by about two fold while its role in idiopathic myelofibrosis patients is uncertain. (C) 2009 Elsevier Ltd. All rights reserved

"Real life" data are needed to complement published trials on the efficacy of lenalidomide in patients with myelodysplastic syndrome (MDS) and del(5q) and on the risk of inducing acute myeloid leukemia (AML) progression. Here, we present results of lenalidomide treatment in a consecutive, population-based series of 21 red blood cell (RBC) transfusion-dependent elderly patients with multiple comorbidities. Of 18 evaluable patients (median follow-up: 22 months), 17 achieved an erythroid hematologic response (HI-E) and 16 an RBC transfusion independence. Cytogenetic response (CyR) rate was 80%, median overall survival was 48 months (range 3-164), and 5-year leukemia-free survival was 84%. Three patients progressed to AML; one, with baseline TP53 mutation, achieved HI-E, partial CyR, and did not progress to AML. Eighteen patients experienced hematological adverse events. Overall, lenalidomide was very effective and well tolerated even in unselected elderly patients with multiple comorbidities and did not appear to increase the risk of AML.

Background Graft versus host disease (GVHD) is a common complication of allogeneic stem cell transplantation (allo-SCT), and represents its major cause of morbidity and mortality. Some “classical” patient-, donor- and transplant characteristics, such as age, gender disparity, donor type, HLA-match, and source of stem cells, have been reported as predictors for acute and chronic GVHD. However, no studies analysed these “classical” variables together with parameters of metabolic and endocrine functions, which may potentially influence the immune system. Thus, patient-and transplant variables together with index of liver and thyroid function, and some parameters of protein and lipid metabolism were retrospectively evaluated at different time points after transplantation, in order to identify possible predictors of acute and chronic GVHD and to calculate a risk score. Methods Clinical and transplant characteristics, number and type of infections before and after SCT were analysed in 161 patients. The following variables were also analysed pre-SCT, at day +7,+14,+21,+28, at + 3 and +6 months: LDH, parameters of liver function; parameters of protein and lipid metabolism (serum albumin, urea, total protein, cholesterol, triglycerides); thyroid function tests; autoimmune parameters (anti-nuclear, anti-DNA, anti-cardiolipin antibodies); body mass index. A 2-step multivariate analysis was performed using principal component analysis (PCA) and Cox regression analysis, in order to solve the problem of the high number of variables (metabolic, patients- and transplant related) in comparison with the relatively limited and heterogeneous pool of patients. Based on the regression coefficient of Cox analysis for each significant predictor, a scoring system for acute and chronic GVHD was calculated. Results In multivariate analysis, diagnosis of Myelodisplastic Syndrome or Chronic Myeloid Leukemia (HR 4,9; p=0.0004), conditioning regimen including Total Body Irradiation (HR 3,3; p=0.0003), and pre transplantation urea > 34 mg/dl with +21 day urea > 54 mg/dl (HR 2,6; p=0.0008) were evidenced as predictors for acute GVHD. Score values for each factor are 2, 1, and 1, respectively. Hence, the score, obtained by the sum of the three score values, ranged from 0 to 4. The probability of acute GVHD ranged from 8% (score 0) to 98% (score 4). Female donor (HR 5,1; p=0.0008), pre-SCT TSH values ≥ 2 mU/L with +28 day urea ≥ 39 mg/dl (HR 3,3; p=0.02), +6 month total protein < 5,5 g/dl with gamma-GT ≥ 347 U/L (HR 7,8, p=0.0001) resulted predictors for moderate/severe chronic GVHD, with score values of 1, 1, and 2 respectively. Risk of chronic GVHD at +6,5 month ranged from 3% (score 0) to 97% (score 4). Discussion Our study evidenced that factors other than “classical” ones may be associated to GVHD. Our scoring system includes routine-parameters (urea, total protein, gamma-GT,TSH), which are easily available in clinical practice. Urea levels depend on the balance between protein intake, endogenous catabolism and urinary excretion. The inflammatory microenvironment of GVHD promotes muscle catabolism, hence, urea levels do increase. Increased urea levels could be an indirect index of increased uremic toxins as well, which may stimulate the production of pro-inflammatory cytokines and the activation of leukocytes. On the other hand, increased urea levels and uremic toxins could derive from a dysregulated metabolism of the gut microbiome, which may influence immune system. Our findings, which require a prospective validation, suggest the usefulness a deeper study of the complex network between metabolic/endocrine functions and immune system, in order to develop a holistic approach of the transplant management. Disclosures No relevant conflicts of interest to declare.

Background: Although a complete remission (CR) can be achieved in 70-80% of newly diagnosed acute myeloid leukemia (AML) patients, relapses occur in up to the 50% of cases. Thus, minimal residual disease (MRD) monitoring is a major issue for early detection of patients at high-risk of treatment failure and relapse. Aim: to dynamically evaluate WT1 pan-leukemic molecular marker of MRD in patients with AML. Matherial and methods: 107 newly diagnosed AML patients consecutively treated between 2010 and 2013 were monitored with quantitative WT-1 from bone marrow (BM) and peripheral blood (PB) at baseline, after induction, after the first consolidation course, before allogeneic stem cell transplantation (allo-SCT), at the 3rd and the 6th month after transplantation Results: At diagnosis, 104/107 (97%) had increased PB and BM WT1 levels assessed according to the ELN assay. Eighty-eight out of 107 patients (82%) achieved a complete remission (CR) after induction, 30/88 (34%) relapsed during follow up and 24/107 (22%) were addressed to allogeneic stem cell transplantation (allo-SCT). By univariate analysis, PB-WT > 50x10^4/ABL and BM-WT1 > 250x10^4/ABL after induction (PB: p=0.02; BM: p=0.04), after consolidation (PB: p=0.003), at the end of treatment (PB and BM: p=0.001), at 3rd month of follow up (PB and BM: p=0.005) and at 6th month of follow up (PB: p=0.005) were associated with a reduced overall survival (OS). By multivariate analysis, a BM-WT1 > 250 x 10^4/ABL at the end of treatment was significantly associated with a reduced OS. In order to adapt the cut-off of WT1 in our series of patients, we considered WT1 levels as continuous variables and categorized them at approximately the 25th, 50th, and 75th percentile. A cut-off of PB-WT1 > 25x10^4/ABL and BM-WT1 > 125x10^4/ABL at the end of the treatment program was identified as correlated with reduced leukemia-free survival (LFS) and OS (p=0.001). Similarly, and restricting the analysis on the 24 patients allo-transplanted in CR, 8/11 (73%) with pre-transplant PB-WT1 ≥ 5 and 4/13 (31%) with PB-WT1 < 5 relapsed, respectively (p=0.04). The incidence of relapse was higher in AML patients with PB-WT1 ≥ 5 measured at 3rd (56% vs 38%; p=0.43) and 6th month (71% vs 20%; p=0.03) after allo-SCT. Interestingly, 5/5 (100%) patients with pre-transplant PB-WT1 ≥ 5 who never reduced this level at 3rd or 6th month after allo-SCT experienced a disease recurrence. Conclusions: our data, although retrospectively collected, show that WT1 monitoring may be useful to predict the relapse in AML patients. Acknowledgments: This work was supported in part by Banca di Credito Cooperativo di Pompiano e Franciacorta and Lions Club Bassa Bresciana Association. Disclosures Russo: Celgene: Research Funding; Gilead: Research Funding; Novartis: Consultancy.

To evaluate if WT1 expression may predict relapse after allo-SCT, we analyzed WT1 levels on peripheral blood (PB) and bone marrow (BM) before and after allo-SCT in 24 AML patients with WT1 overexpression at diagnosis. Five copies of WT1/ABL × 104from PB were identified as the threshold value that correlated with relapse after allo-SCT. The same correlation was not identified when WT1 expression was assessed from bone marrow (BM). Eight out of 11 (73%) patients with a pre-allo-SCT PB-WT1 ≥ 5 and 4/13 (31%) patients with a pre-allo-SCT PB-WT1 < 5 relapsed, respectively (P= 0.04). The incidence of relapse was higher in patients with PB-WT1 ≥ 5 measured after allo-SCT, at the 3rd (56% versus 38%;P= 0.43) and at the 6th month (71% versus 20%;P= 0.03). Patients with pretransplant PB-WT1 < 5 had significantly better 2-year OS and LFS than patients with a PB-WT1 ≥ 5 (81% versus 0% and 63% versus 20%) (P= 0.02). Our data suggest the usefulness of WT1 monitoring from PB to predict the relapse in allotransplanted AML patients and to modulate the intensity of conditioning and/or the posttransplant immunosuppression in an attempt to reduce the posttransplant relapse risk.

Introduction: Postremission treatment in adult acute myeloid leukemia (AML) is mandatory to improve long-term remission duration. Allogeneic stem-cell transplantation (allo-SCT) is considered gold standard in younger patients (pts) with higher risk of relapse, whereas in pts categorized as standard-risk (SR) AML the optimal treatment remains an open issue. High-dose cytarabine (HD-ARAC) is considered the backbone of postremission treatment in SR AML. The optimal dose and schedule, and the clinical benefit of additional chemotherapeutic agents remain controversial (Schaich, 2011- Lowenberg, 2011- Lowenberg, 2013) as well as the relative efficacy of HD-ARAC in the different cytogenetic and molecular subgroups of SR AML. We analyzed the very long term outcome of consecutive unselected AML pts treated according to AML 00 NILG protocol (Bassan, Blood, 2003: 102; 11) with three repetitive HD-ARAC-based cycles, associated with idarubicin, followed by limited peripheral blood stem cell (PBSC) support, in order to reduce toxicities. Methods: We evaluated 263 consecutive AML pts, diagnosed at our Institution, from January 2001 to March 2016 (median age 52 years - range 15-65). The treatment plan included induction with ICE (Idarubicin-Cytarabine-Etoposide) followed by IC consolidation or HD-ARAC/HD-idarubicin (SPLIT therapy) in refractory cases. ARAC 1g/mq bd for 4 days (A8) was given to CR pts, to collect 3-6x10^6 CD34/kg in 3 aliquots. Patients with ELN favorable or intermediate risk AML, considered SR AML, received 3 cycles of HD-ARAC (2g/mq bd for 5 days) plus idarubicin (8mg/mq for 2 days) with PBSC reinfusion (1-2x10^6 CD34/Kg) (A20). The pts with insufficient CD34 cells yield, received 2 courses HD-ARAC (1g/mq bd for 5 days) plus idarubicin (10mg/mq day 1) (A10). The cumulative dose of ARAC and idarubicin given according to A20 protocol were 69,4 g/mq and 162 mg/mq, respectively. Results: Among 263 pts, 142 (54%) pts were considered SR and 116 (44.1%) HR. Only 5 pts were lacking molecular or cytogenetic information (1.9%) to allow ELN risk classification. Accordingly, 65 pts (25.2%) were favorable [35.4% core binding factor (CBF) positive, 9.2% CEPBA mutated and 55.4% NPM mutated], 87 (33.7%) Intermediate-I, 45 (17.4%) Intermediate II and 61 (23.7%) adverse risk. CR rate after ICE treatment was 77.6% (204/263), 95.8% in SR and 56% in HR pts and after ICE+SPLIT it was 88.2% (232/263); early or aplastic death was 6%. A8 course was administered in 218 pts, of whom 179 were successfully mobilized (82.1%). Among 136 SR pts, 127 were received HD-ARAC (A20 or A10), 4 allo-SCT for early relapse, 3 pts did not proceed to A20 because of prolonged cytopenia and 2 are ongoing. Hematological toxicity was acceptable. ANC recovered at a median of 10 days after CD34+ cells reinfusion. Two death in CR occurred within 100 days after A20 therapy (1.6%). After a median follow-up of 53.3 months (range 1-172), the median survival of SR AML patients was 118.9 months, the DFS and OS at 5 y were 51+/-4.8% and 56.5+/-4.7%, and at 10 y 43.3+/-5.9% and 49.6+/-5.7%, respectively. According to ELN risk, the OS at 5 y and 10 y was 78.3+/-6% and 68+/-8.7% in favorable (median OS not reached), 52.3+/-8% and 46+/-9.4% in Intermediate-I (median OS 118.8 months), and 42+10% and 33.6+/-10.9% in Intermediate-II (median OS 33.1 months) (p0.0034) (Figure1). According to molecular characteristics, the OS at 5-y was 100% in CEBPA-mutated, 77+/-9% (+/-SE) in CBF-mutated and 71+/-11% in NPM-mutated subgroups, respectively (Figure 2). In NPM-mutated pts it was 56+/-14% if FLT3 was mutated and 75+/-10% if not. At 8-y OS was not evaluable in CEBPA-mutated, it remained 77+/-9% in CBF mutated but dropped to 47+/-15% in NPM-mutated pts due to late relapses (28%), which occurred in pts without FLT3. The median time to relapse in NPM pts was 17 m, the latest relapse occurred after 97 months. Conclusion: A postremission program with repeated courses of HD-ARAC associated to idarubicin and limited autologous CD34+ cells support was feasible, well tolerated and very effective, also long-term, in pts with ELN favourable or intermediate risk AML. The late relapse tendency of NPM-mutated AML is puzzling and should be considered by innovative programs aimed at improving these results. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Introduction: XPO1 (CRM1, Exportin 1) is the sole transporter of many tumor suppressor proteins (including MYC, BCL2, BCL6, BTK, IkB) and is elevated in non-Hodgkin Lymphoma. Selinexor (Sel, KPT-330) is an oral covalent inhibitor of XPO1, the first clinical molecule of the Selective Inhibitors of Nuclear Export drug class. The phase I clinical trial of Sel in hematologic malignancies showed promising early single-agent efficacy with modest toxicity in relapsed Diffuse Large B-cell Lymphoma (DLBCL, Gutierrez et al, ASCO 2014). DLBCL, the most common lymphoid malignancy, is currently cured in only 10% of relapsed patients, and consists of 2 subtypes based on putative cell of origin (COO): activated B-cell (ABC) and germinal center B-cell (GCB). We performed preclinical studies of Sel, modeling its single-agent efficacy in frontline and relapsed DLBCL and its potential synergy with other clinically relevant therapeutics. Long-term follow-up data on patients(pts) treated with Radiolabeled antibody 90-yttrium-Ibritumomab Tiuxetan (RIT) are necessary to define the role of RIT-therapy (RIT-t) in current clinical practice. There are few reports about the use of RIT outside clinical trials. Outcome and toxicity of radioimmunotherapy remain a matter of concern. Incidence of MDS/AML reported after RIT-t as consolidation in front line varies from 3 to 4.3% (Czuczman et al, JCO 2007; Morschhauser et al, JCO 2012). A recent study with RIT and autologous stem cell transplantation (ASCT) as front line therapy in mantle cell lymphoma reported 20% incidence of secondary malignancies, (Arranz et al, Haemat 2013). So the aim of this study was to analyze the outcome of pts treated with RIT-t in clinical practice and to assess the incidence of secondary neoplasia particularly MDS/AML. We included in this retrospective analysis all pts with Diffuse B Large Cell Lymphoma (DBLCL), Follicular Lymphoma (FL) and Marginal Zone lymphoma (MZL), treated with RIT-t over the last decade at our Institution. We adopted the standard RIT therapeutic regimen: infusion of 250 mg/m2 rituximab on day 1, a second 250 mg/m2 dose on day 7, followed by dose of RIT (0.4 mCi/kg), administered 4 h following rituximab infusion. Response assessment was made as recommended by International Workshop criteria. Survival analysis was performed with Kaplan-Meier method and univariate analysis with Log-Rank test with a significance at 0.05. Between March 2006 and January 2014 61 pts underwent RIT-t, of these 57 had complete data and were considered for analysis. There were 16 DBLCL, 29 Follicular Lymphoma and 12 MZL. Twentythree were male, 34 female. Median age at diagnosis was 62 years(yrs) (range 36; 79), 66yrs (range 39;79) at RIT-t. Thirteen pts (all DBLCL) received RIT-t as front line consolidation. Forty-four pts (3 DBLCL, 12 MZL, 29 FL) underwent RIT-t after ≥1 therapy line: one prior line was received by 15pts, 2 by 19, 3 by 8 and 4 by 2. Before RIT-t 24pts were in relapse (2DBLCL, 2MZL, 20FL), 9 were refractory (2 MZL, 7 FL), 7 in partial response (1 DBLCL, 5 MZL, 1FL) while 4 were in complete remission (2 MZL, 2FL). Disclosures No relevant conflicts of interest to declare.

Background: According to the WHO classification, secondary acute myeloid leukemia (s-AML) includes cases occurring in patients (pts) receiving prior antineoplastic treatments as well as cases developing in pts with a history of previous hematology disorders, such as a myelodysplastic syndrome (MDS) or a chronic myeloproliferative disease (MPD). Outcomes for this large group of pts, which has a high median age and a high frequency of unfavourable cytogenetics, has been traditionally considered very poor, compared to AML developing “de novo”, and treatment with intensive chemotherapy (iCT) is not standardized in elderly pts. Indeed pts with s-AML have been excluded from molecular and cytogenetic prognostic stratification defined by the ELN criteria. Aim: Since patients with s-AML actually represent an heterogeneous subgroup of pts a multicenter retrospective study was performed to analyse their outcome in relationship to age, fitness and ELN risk stratification, in order to potentially identify subgroups at different prognosis. Patients and Methods: We evaluated 127 pts, representing 35% of a population-based series of elderly AML, aged > 65 years (y), diagnosed at five Hematology Centers of the Hematological Network of Lombardy in Northern Italy from January 2008 to May 2014. Thirteen pts (10%) had t-AML and 114 (90%) had AML secondary to previous hematological disorders (89 MDS and 25 MPD). Median age was 74 y (range 65-94 y). Performance status (PS) was evaluable in 122 pts (96%) and PS ECOG was >3 in 32 pts (26%). According to “fitness criteria”, (Ferrara et al, Leukemia, 2013), 126 pts (99%) were evaluable: 54 pts (42.5%) were fit to i-CT (FIT), 55 (43.3%) unfit to i-CT (UNFIT), 17 (13.4%) unfit to ni-CT (FRAIL). Intensive CT was given to 34 (27%), ni-CT (low-dose arac, azacytidine or experimental non-myelotoxic drugs) to 26 (20%) and best supportive care (BSC) to 67 pts (53%). Overall concordance between the fitness and the treatment actually received was 78%.The ELN prognostic criteria were applicable in 69 pts (54%), because of lack of complete molecular and cytogenetic data in the others. Six pts (8.5%, all NPM1+) were at low, 14 (20%) at intermediate-1, 11 (16%) at intermediate-2 and 38 (55%) at high risk. Results: The median OS according to fitness was 9,6, 4 and 3 months (ms), in FIT, UNFIT and FRAIL pts, respectively (p=0.0021) (Figure 1). Both the treatment received (i-CT or ni-CT vs BSC) and the risk ELN classification were related to OS (p< 0.0001 and p=0.0089, respectively). In FIT pts the median OS was 8 ms in pts treated with i-CT, 11 ms with ni-CT, and 3 ms with BSC (p The achievement of CR was related to outcome (median OS 12.7 ms vs 5 ms) (p= 0.0035). AML with antecedent hematological disorder (53.8%) or with t-AML (50%) had similar CR rate (53,8% vs 50%) as well as OS (median OS 11 ms vs 7 ms) (p =0.5). According to ELN risk, OS was better in LR/Int-1/int2 vs HR (median OS 11,4 vs 5 ms, p=0.0035) (Figure 2). Moreover, also the achievement of CR was related to ELN risk: 100% in LR, 57% in Int1/Int2, 14% in HR (p= 0.012), and percentages differed from de novo AML only in HR pts. Prognosis of the subgroup of 34 ELN low/Int1 risk pts treated with i-CT was fair with CR rate of 53%, and 2 y OS 40% compared to 10% in similarly treated Int2/HR pts (p=0.07). Conclusion: Elderly pts with s-AML are an heterogeneous subgroup both according to fitness and to ELN risk stratification and these parameters are significantly related to clinical outcome. Overall prognosis of elderly patients with s-AML is not exceedingly worse than in elderly with de novo AML. Outcome was better using i-CT or ni-CT compared to BSC, with no differences between the two treatment modalities. ELN risk stratification merits to be applied also to patients with s-AML and its integration with fitness criteria can identify a subgroup of patients which may benefit from intensive CT. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.