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PURPOSE We compared 2 years of rituximab maintenance (RM) with a response-adapted postinduction approach in patients with follicular lymphoma who responded to induction immunochemotherapy. METHODS We randomly assigned treatment-naïve, advanced-stage, high-tumor burden follicular lymphoma patients to receive standard RM or a response-adapted postinduction approach on the basis of metabolic response and molecular assessment of minimal residual disease (MRD). The experimental arm used three types of postinduction therapies: for complete metabolic response (CMR) and MRD-negative patients, observation; for CMR and MRD-positive (end of induction or follow-up) patients, four doses of rituximab (one per week, maximum three courses) until MRD-negative; and for non-CMR patients, one dose of ibritumomab tiuxetan followed by standard RM. The study was designed as noninferiority trial with progression-free survival (PFS) as the primary end point. RESULTS Overall, 807 patients were randomly assigned. After a median follow-up of 53 months (range, 1-92 months), patients in the standard arm had a significantly better PFS than those in the experimental arm (3-year PFS 86% v 72%; P < .001). The better PFS of the standard versus experimental arm was confirmed in all the study subgroups except non-CMR patients (n = 65; P = .274). The 3-year overall survival was 98% (95% CI, 96 to 99) and 97% (95% CI, 95 to 99) in the reference and experimental arms, respectively ( P = .238). CONCLUSION A metabolic and molecular response-adapted therapy as assessed in the FOLL12 study was associated with significantly inferior PFS compared with 2-year RM. The better efficacy of standard RM was confirmed in the subgroup analysis and particularly for patients achieving both CMR and MRD-negative.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease, including one-third of cases overexpressing MYC and BCL2 proteins (double expressor lymphoma, DEL) and 5-10% of patients with chromosomal rearrangements of MYC, BCL2 and/or BCL-6 (double/triple-hit lymphomas, DH/TH). TP53 mutations are detected in 20- 25% of DEL. We report the efficacy of dose-adjusted EPOCH and rituximab (DA-EPOCH-R) in a series of 122 consecutive patients, including DEL (n=81, 66%), DEL-MYC (n=9, 7%), DEL-BCL2 (n=13, 11%), or high-grade lymphomas (DH/TH) (n=19, 16%). Central nervous system (CNS) prophylaxis included intravenous methotrexate (n=66), intrathecal chemotherapy (IT) (n=40) or no prophylaxis (n=16). Sixty-seven patients (55%) had highintermediate or high International Prognostic Index (IPI) and 30 (25%) had high CNS-IPI. The 2-year progression-free survival (PFS) and overall survival (OS) for the entire study population were 74% and 84%, respectively. There was a trend for inferior OS for DH/TH (2-year OS: 66%, P=0.058) as compared to all the others. The outcome was significantly better for the IPI 0-2 versus IPI 3-5 (OS: 98% vs. 72%, P=0.002). DA-EPOCH-R did not overcome the negative prognostic value of TP53 mutations: 2-year OS of 62% versus 88% (P=0.036) were observed for mutated as compared to wild-type cases, respectively. Systemic CNS prophylaxis conferred a better 2-year OS (94%) as compared to IT or no prophylaxis (76% and 65%, respectively; P=0.008). DA-EPOCH-R treatment resulted in a favorable outcome in patients with DEL and DEL with single rearrangement, whereas those with multiple genetic alterations such as DEL-DH/TH and TP53 mutated cases still have an inferior outcome.

Background Diffusion‐weighted whole‐body MRI (DW‐MRI) is increasingly used in the management of multiple myeloma (MM) patients, but data regarding the prognostic role of DW‐MRI imaging response after treatment are lacking. The Myeloma Response Assessment and Diagnosis System (MY‐RADS) imaging recommendations recently proposed the criteria for response assessment category (RAC) with a 5‐point scale in order to standardize response assessment after therapy, but this score still needs to be validated. Methods We investigated the prognostic role of RAC criteria in 64 newly diagnosed MM patients after autologous stem cell transplantation (ASCT), and we combined the results of MY‐RADS with those of minimal residual disease (MRD) assessment by multiparametric flow cytometry (MFC). Results Superior post‐ASCT PFS and OS were observed in patients with complete imaging response (RAC1), with respect to patients with imaging residual disease (RAC≥2): median PFS not reached (NR) versus 26.5 months, p = 0.0047, HR 0.28 (95% CI: 0.12–0.68); 3‐year post‐ASCT OS 92% versus 69% for RAC1 versus RAC ≥2, respectively, p = 0.047, HR 0.24 (95% CI: 0.06–0.99). Combining MRD and imaging improved prediction of outcome, with double‐negative and double‐positive features defining groups with excellent and dismal PFS, respectively (PFS NR vs. 10.6 months); p = 0.001, HR 0.07 (95%CI: 0.01–0.36). Conclusion The present study supports the applicability of MY‐RADS recommendations after ASCT; RAC criteria were able to independently stratify patients and to better predict their prognosis and the combined use of DW‐MRI with MFC allowed a more precise evaluation of MRD., The present study supports both the applicability and the clinical usefulness of the proposed Myeloma Response Assessment and Diagnosis System (MY‐RADS) recommendations applied to DW‐MRI imaging obtained after first‐line treatment of MM including ASCT. MY‐RADS RAC criteria were able to independently stratify patients and to better predict their outcome and their prognosis. DW‐MRI proved to be a powerful tool for the assessment of residual bone disease by functional imaging: it complemented bone marrow flow cytometry and may, therefore, represent a step forward in the clinical management of the increasing number of MM patients achieving CR with the novel treatment approaches.

Introduction ABP 798 is being developed as a biosimilar to rituximab reference product (RP), a CD20-directed cytolytic antibody that is approved in the US and EU for the treatment of non-Hodgkin lymphoma (NHL). Methods This randomized, double-blind, comparative clinical study (JASMINE) evaluated the efficacy and safety of ABP 798 compared with rituximab RP. Adult, anti-CD20 treatment naïve patients diagnosed with grade 1, 2, or 3a follicular B-cell NHL expressing CD20 were randomized 1:1 to receive a 375 mg/m2 infusion of either ABP 798 or rituximab RP once weekly for 4 weeks and at weeks 12 and 20. Tumor assessments were performed at baseline and weeks 12 and 28. Primary endpoint was the risk difference (RD) of overall response rate (ORR) of complete response, unconfirmed complete response, or partial response by week 28 based on data from central, independent, and blinded assessments of disease. Results Of the 256 randomized patients, 254 were treated with ABP 798 (n = 128; 100%) or rituximab RP (n = 126; 98.4%); 96 (78.0%) patients in the ABP 798 group and 87 (70.2%) in the rituximab RP group had a best ORR by week 28. The point estimate of RD in ORR between ABP 798 and rituximab RP from the adjusted generalized linear model for stratification factors was 7.7%. Clinical equivalence was based on sequential testing of the one-sided 95% lower confidence limits and one-sided 95% upper confidence limits of RD in ORR (− 1.4% and 16.8%, respectively) which was within the prespecified non-inferiority margin (− 15%) and non-superiority margin (35.5%), respectively. Results of sensitivity analyses were consistent with the primary efficacy analysis. ABP 798 was also comparable to rituximab RP across additional secondary endpoints, further supporting the conclusion of similarity, and including: RD of ORR at week 12; trough serum concentrations; percent of patients with complete depletion of CD19+ cell count at day 8; safety; and immunogenicity. Conclusions These results support a conclusion of similar clinical efficacy between ABP 798 and rituximab RP in patients with follicular lymphoma. NCT Number NCT02747043; first posted April 21, 2016. EudraCT Number 2013-005,542-11; submitted 14 October, 2014.

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.

Unlike for diffuse large-cell lymphoma, both the management of elderly patients with follicular lymphoma and the role of comprehensive geriatric evaluation to optimize treatment choices have been rarely addressed. This review analyses available evidence on follicular lymphoma occurring in aged persons.Most retrospective studies and expert recommendations agree that the diagnostic approach and the treatment algorithm in elderly follicular lymphoma should not differ from younger patients up to the age of 80. However, slowly progressing follicular lymphoma low-tumor burden should start treatment even though asymptomatic. Prospective identification of those unfit patients is needed where a treatment deintensification may not be detrimental. Octogenarians have more aggressive disease and do not benefit from chemoimmunotherapy more than from single-agent rituximab. An activity of daily living loss significantly impact on their outcome and specific prognostic scores may help in the better manage these oldest patients.Given the lack of prospective studies there is an urgent need to investigate if geriatric assessment including comorbidities, geriatric parameters, patient's reported outcomes and quality of life issues, may help selecting those frail elderly follicular lymphoma patients less suitable for full-dose treatments. In addition, the potential usefulness of the new noncytotoxic agents of proven efficacy in follicular lymphoma warrants specific investigations in older patients.

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.

Introduction The diagnostic accuracy of fluorine-18–fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in staging mantle-cell lymphoma has not yet investigated. The aim of this 2-center retrospective study was to investigate the utility of 18F-FDG PET/CT in assessing nodal, splenic, bone marrow (BM), and gastrointestinal (GI) disease compared to CT, BM, and GI endoscopy; and to assess its clinical impact. Patients and Methods One hundred twenty-two patients with histologically proven mantle-cell lymphoma were included. PET/CT BM findings were considered positive if isolated/multiple focal uptake in the BM not explained by benign findings and/or diffuse BM uptake higher than liver with/without focal uptakes were present. PET/CT findings were considered positive for GI involvement in the presence of isolated/multiple focal uptake in the GI organ. Results All patients had positive PET/CT showing the presence of at least one hypermetabolic lesion, with the exception of one case. PET/CT results, compared to CT, detected more nodal and/or splenic lesions in 26 patients. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of PET/CT for BM were 52%, 98%, 97%, 65%, and 74%; for GI 64%, 91%, 69%, 90%, and 85%; and for GI excluding diabetic patients, 78%, 92%, 72%, 94%, and 89%. PET/CT permitted upstaging of 21 cases and downstaging of 2. Conclusion 18F-FDG PET/CT showed excellent detection rate in nodal and splenic disease—a rate better than CT. For BM and GI evaluation, in order to reach good accuracy, the selection of patients and the use of specific criteria for evaluation of these organs seems to be crucial. Moreover, PET/CT altered the management and therapeutic approach in about 20% of patients.

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 sustained MRD negativity is emerging as a surrogate biomarker of patients (pts)’ outcome in clinical trials. We implemented this tool in our clinical practice and we analyzed outcome according to sustained MRD negativity in MM pts treated with autologous stem cell transplantation (ASCT) at our Institution. Methods We retrospectively analyzed the outcome of 77 newly diagnosed MM pts (median age 61 years) diagnosed between January 2015 to December 2019 in ≥ VGPR after ASCT. Bone marrow samples were collected for MRD by 8-color FCM (Sn 10-5) at day +100 after ASCT, before maintenance. Sustained 1 year MRD negativity was also evaluated and the prognostic impact of MRD status on PFS and OS was analyzed. Results out of 77 pts, 28 (36%) were ISS stage 3 and 18 (23%) showed high risk cytogenetics. Patients were treated with the following induction regimens: VTD 51, VRD 5, Dara-VRD 5, KRD 14, KCD 2. Single ASCT with MEL200 conditioning was performed in 49 pts (64%), whereas 28 pts (36%) received double ASCT. Subsequent maintenance was performed with lenalidomide (70), daratumumab-lenalidomide (5), carfilzomib-lenalidomide (2). Response rates were VGPR 26%, CR 61% and sCR 13%. MRD before maintenance was positive in 20 pts (26%) and negative in 57 (74%). Sustained MRD negativity lasting ≥ 1 year was documented in 49 pts (64%), whereas early loss of MRD negative status was observed in 8 (10%) of cases. After a median follow up of 40.2 months, PFS was significantly longer in pts with sustained MRD negativity (≥1 year) compared to MRD positive patients before maintenance: median NR vs 41.4 months, p 0.0002, HR 0.17 (0.044-0.65). The worst PFS (24.7 months) was observed in pts with early loss of MRD negativity ( Conclusion we confirm the predictive value of MRD assessment after ASCT and therefore the importance of achieving sustained MRD negativity regardless of different treatment strategies. Moreover, the detection of early loss of MRD negativity can help the physician to identify pts with particularly poor prognosis

Lenalidomide-RCHOP (R2-CHOP21) has been shown to be safe and effective in patients with untreated diffuse large B-cell lymphoma (DLBCL). The aim of this analysis is to report long-term outcome and toxicities in newly diagnosed DLBCL patients who received R2-CHOP21 in two independent phase 2 trials, conducted by Mayo Clinic (MC) and Fondazione Italiana Linfomi (FIL). All patients received R-CHOP21 plus lenalidomide. Long-term progression-free survival (PFS), time to progression (TTP), overall survival (OS) and late toxicities and second tumors were analyzed. Hundred and twelve patients (63 MC, 49 FIL) were included. Median age was 69 years, 88% were stage III–IV. At a median follow-up of 5.1 years, 5y-PFS was 63.5%, 5y-TTP 70.1% and 5y-OS 75.4%; according to cell of origin (COO): 5y-PFS 52.8% vs 64.5%, 5y-TTP 61.6% vs 69.6% and 5y-OS 68.6% vs 74.1% in germinal center (GCB) vs non-GCB respectively. Four patients experienced grade 4–5 late toxicities. Grade ≤ 3 toxicities were infections (N = 4), thrombosis (N = 1) and neuropathy (N = 3). Seven seconds tumors were observed. Long-term follow-up demonstrates that R2-CHOP21 efficacy was maintained with high rates of PFS, TTP, and OS. Lenalidomide appears to mitigate the negative prognosis of non-GCB phenotype. Incidence of therapy-related secondary malignancies and late toxicities were low.

PURPOSE To prospectively validate the use of a simplified geriatric assessment (sGA) at diagnosis and to integrate it into a prognostic score for older patients with diffuse large B-cell lymphoma (DLBCL). METHODS We conducted the prospective Elderly Project study on patients with DLBCL older than 64 years who underwent our Fondazione Italiana Linfomi original geriatric assessment (oGA) (age, Cumulative Illness Rating Scale for Geriatrics, activities of daily living, and instrumental activities of daily living) before treatment. Treatment choice was left to the physician's discretion. The primary end point was overall survival (OS) (ClinicalTrials.gov identifier: NCT02364050 ). RESULTS We analyzed 1,163 patients (median age 76 years), with a 3-year OS of 65% (95% CI, 62 to 68). Because at multivariate analysis on oGA, age > 80 years retained an independent correlation with OS, we also developed a new, simplified version of the GA (sGA) that classifies patients as fit (55%), unfit (28%), and frail (18%) with significantly different 3-year OS of 75%, 58%, and 43%, respectively. The sGA groups, International Prognostic Index, and hemoglobin levels were independent predictors of OS and were used to build the Elderly Prognostic Index (EPI). Three risk groups were identified: low (23%), intermediate (48%), and high (29%), with an estimated 3-year OS of 87% (95% CI, 81 to 91), 69% (95% CI, 63 to 73), and 42% (95% CI, 36 to 49), respectively. The EPI was validated using an independent external series of 328 cases. CONCLUSION The Elderly Project validates sGA as an objective tool to assess fitness status and defines the new EPI to predict OS of older patients with DLBCL.

Treatment for follicular lymphoma (FL) in the elderly is not well standardized. A phase II, multicentre, single arm trial was conducted in this setting with a brief chemoimmunotherapy regimen. Treatment consisted in four monthly courses of rituximab, bendamustine and mitoxantrone (R-BM) followed by 4 weekly rituximab as consolidation; rituximab maintenance was not applied because the drug was not licensed at the time of enrolment. The primary endpoint was the complete remission rate (CR). Seventy-six treatment-naive FL patients (aged 65-80 and a "FIT" score, according to the Comprehensive Geriatric Assessment) were enrolled. CR was documented in 59/76 patients (78%), partial remission in 12 (16%) and stable/progressive disease in five (6%) with an overall response rate in 71/76 (94%). Median follow-up was 44 months with 3-year progression-free-survival (PFS) and overall-survival of 67% and 92% respectively. Nine deaths occurred, three of progressive disease. The regimen was well tolerated and the most frequent severe toxicity was neutropenia (18% of the cycles). Bcl-2/IGH rearrangement was found in 40/75 (53%) of evaluated patients. R-BM was highly effective in clearing polymerase chain reaction-detectable disease: 29/31 (96%) evaluated patients converted to bcl-2/IGH negativity at the end of treatment. A brief R-BM regimen plus rituximab consolidation is effective and safe in "FIT" elderly, treatment-naive, FL patients, inducing high CR and molecular remission rates with prolonged PFS.

Sarcopenia is considered to be a poor prognostic factor for several oncological diseases; however, some promising results for lymphoma are now available. The definition of sarcopenia is mainly based upon muscle strength, quantity or quality and physical performance, but some imaging tools (such as CT) have been introduced to estimate quantitatively the muscle areas as an indirect expression of sarcopenia. Our aim was to perform a systematic review on the prognostic role of “radiological” sarcopenia in lymphoma. A comprehensive online search of PubMed/MEDLINE, Embase and Cochrane library databases was conducted up to June 2021 to find relevant articles on the prognostic role of sarcopenia in lymphoma measured by CT. In total, 25 articles with a total of 4454 patients were included. Diffuse large B-cell lymphoma was the most common lymphoma variant studied, followed by Hodgkin lymphoma. Skeletal muscle area (SMA) was defined as the parameter to distinguish between sarcopenic and non-sarcopenic lymphoma on CT scans and was usually measured at the level of the third lumbar vertebra. In the literature, different thresholds are used to define sarcopenia, related to the features of patients included in the studies. Despite this heterogeneity, in most cases, sarcopenia was demonstrated to be significantly correlated with OS and PFS. Sarcopenia measurement with CT (high dose or low dose) is a safe, accurate and precise method.

Background Elderly classical Hodgkin lymphoma (cHL) (ecHL) is a rare disease with dismal prognosis and no standard treatment. Fitness-based approaches may help design appropriate treatments. Sarcopenia has been associated with an increased risk of treatment-related toxicities and worse survival in various solid tumours, but its impact in ecHL is unknown. The aim of this retrospective multicentre study was to investigate the prognostic role of sarcopenia in ecHL. Methods We included newly diagnosed >64 years old cHL patients who performed a baseline comprehensive geriatric assessment and high-dose computed tomography (CT) or 18fluorine-fluorodeoxyglucose positron emission tomography/CT before any treatment. Sarcopenia was measured as skeletal muscle index (SMI, cm2 /m2 ) by the analysis of high-dose CT or low-dose positron emission tomography/CT images at the L3 level. The specific cut-offs for the SMI were determined by receiver operator curve analysis and compared with those proposed in literature and studied in diffuse large B-cell lymphoma. Survival functions [progression-free survival [PFS] and overall survival (OS)] were calculated for the whole population and for different subgroups defined as per different sarcopenia cut-off levels. Results We included 154 patients (median age 71 years old, 76 female). The median L3-SMI was 42 cm2 /m2 . The specific cut-off derived in our male population was 45 cm2 /m2 ; using this cut-off, 27 male patients (35%) were defined as sarcopenic. After a median follow-up of 5.9 years, the overall 5-year PFS and OS rates were 53% and 65%, respectively, and were significantly shorter in sarcopenic male patients compared with non-sarcopenic (PFS 31% vs. 61%, P = 0.008; OS 51% vs. 74%, P = 0.042). Applying diffuse large B-cell lymphoma-derived sarcopenic thresholds, there were no significant differences between sarcopenic and non-sarcopenic patients for both PFS and OS, with a sole exception of a significant reduced PFS in sarcopenic male patients using Namakura cut-off. The comprehensive geriatric assessment-determined frail functional status was an independent adverse prognostic factor for both female and male patients. Conclusions Baseline evaluation of sarcopenia through radiological examinations performed for ecHL staging may help define a proportion of male patients with unfavourable outcome with current treatment strategies. Also the functional status evaluation could allow to identify a frail subgroup of patients with worse outcome.

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

Objectives: Solitary plasmacytoma (SP) is characterized by a single mass of clonal plasma cells. Definitive RT can result in long-term local control of the SP. Due to the small number of patients and narrow range of doses, phase III randomized trials are lacking. The aim of this study is to further support the potential use of RT for the treatment of SP. Methods: Clinical data of all patients treated for SP at our Institution between 1992 and 2018 were reviewed. A total of 42 consecutive patients were analyzed. Results: The median follow-up was 84.8months. Radiation dose did not differ significantly as a function of sex, type of SP (solitary bone plasmacytoma or as extramedullary plasmacytoma), tumor size; conversely differs significantly as a function of age (p = 0.04). The 5y-OS and 10y-OS were, respectively, 96 and 91%. Local recurrences developed in 21.4% of patients (9/42). 16 patients progressed to MM (38.1%). The 5y-progression to MM free survival (PMFS) and the 10y-PMFS were, respectively, 68.6 and 61.9%. Conclusions: Our data confirm that good results are achievable with RT to treat SP, but they don’t allow defining a dose–effect correlation; therefore, it remains uncertain which is the most effective dose and whether lower doses can guarantee adequate disease control.

Autologous stem cell transplantation (ASCT) is feasible and effective in selected older patients with Multiple Myeloma, but specific criteria for evaluating ASCT eligibility in elderly patients are lacking. We evaluated 131 patients aged 65-75 considered for ASCT at our center: The Charlson Comorbidity Index (CCI), Hematopoietic cell transplantation comorbidity index (HCT-CI) and IMWG frailty score were obtained at diagnosis, but the intensity of treatment was left to physician's choice. The scores and age's impact on outcome was analyzed: 85 patients were judged transplant eligible, whereas 46 patients received a less intensive treatment (median follow up 27 months). No patients classified as frail had been considered eligible to ASCT with a worse outcome compared to fit and unfit patients (median PFS (progression free survival): 7.9 vs 32.9 and 29.6 months; P < .001). PFS was superior in the ASCT group (35.6 vs 19.9 months, P .013). In the ASCT group, PFS was better in patients aged 65-69 years than in patients ≥70 (51.5 vs 27.7 months, P.004). Indeed, in unfit patients aged ≥70 the PFS of the ASCT group was comparable to NO ASCT group (18 vs 27 months, P = .33) whereas in unfit patients aged 65-69 PFS was superior in the ASCT group: 43.3 vs 18.4 months, P .01. ISS III and impaired functional status independently affected PFS in a multivariate analysis (P .011 and P .006). While CCI and HCT-CI did not predict different outcome in ASCT patients, the IMWG frailty score would be of help in identifying unfit patients aged 70-75, whose outcome with ASCT selected by clinical judgment was no better than with less intensive treatments.

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.

Purpose: To analyze clinical outcome, local response, survival and toxicity in patients with primary cutaneous lymphoma (PCL) treated with radiotherapy. Methods: From 1995 to 2014, 112 patients were treated. B-cell lymphomas (CBCLs; n = 86) and T-cell lymphomas (CTCLs; n = 23) were analyzed separately. Clinical and therapeutic characteristics (age, sex, histology, primary treatment and radiotherapy modality) were related to response to treatment, survival and toxicity. Results: CBCLs were divided into 4 subgroups: marginal-zone lymphoma (n = 20), follicle center lymphoma (n = 32), diffuse large-cell lymphoma (DLBCL; n = 22) and DLBCL-leg type (n = 12). No significant correlation was found between doses and systemic treatments, extent of biopsy and number of lesions. DLBCL-leg type patients were older (p = 0.05), had disseminated disease (p = 0.034), and more frequently had local (p = 0.01) or systemic recurrence (p = 0.05). CTCLs were divided into 4 subgroups: α/β CTCL (n = 3), nasal type CTCL (n = 0), γ/δ CTCL (n = 10) and mycosis fungoides (n = 10). Longer disease-free survival was observed in patients obtaining complete remission (pConclusions: Radiotherapy is feasible, safe and effective for localized PCLs. The choice of dose is related to histological subgroups and the related prognoses. Survival results are very good also in relapsing disease. In advanced cutaneous lymphoma radiotherapy alone has mainly a role in symptom palliation.

Introduction. The administration of immuno-chemotherapy (ICT) followed by rituximab maintenance (RM) is the recommended approach for the front-line therapy of high tumor burden follicular lymphoma (HTB-FL) patients. Among available ICT regimens, RB (Rituximab-bendamustine) and R-CHOP regimen, are preferred options with high, similar efficacy. Regarding RM, its use is strongly supported after R-CHOP by the results of the PRIMA randomized trial; conversely, no prospective data are available to confirm the efficacy of RM in patients initially treated with RB. The FOLL12 trial was conducted to try to demonstrate that a response adapted post induction management of patients with HTB-FL could be as effective as standard RM in terms of Progression Free Survival (PFS). The trial actually showed the better efficacy of standard RM compared to the experimental approach thus providing indirect confirmation of the efficacy of RM after ICT, 10 years after the PRIMA trial. We here analyse the impact of initial ICT in the FOLL12 study that left treatment choice between RB and R-CHOP at physician discretion and on an individual patient basis. Methods. FOLL12 is a multicenter, randomized, phase III trial that compared standard RM vs. a response adapted post induction management in treatment naïve adult patients with grade 1-3a, stage II-IV and a HTB-FL. All patients received induction immunochemotherapy with 6 cycles of either R-CHOP or R-Bendamustine both followed by two additional doses of rituximab. Choice of ICT was at the physicians' discretion. After ICT, patients in the standard arm received bimonthly rituximab for up to two years. Patients in the experimental arm were managed according to centrally reviewed metabolic and molecular response. Patients achieving complete metabolic (CMR) and molecular response were managed with observation only, those in CMR with molecular persistence received 4 weekly rituximab doses. Patients not achieving CMR were treated with radioimmunotherapy with ibritumomab tiuxetan followed by standard RM. Primary study endpoint was 3 years progression free survival (PFS). Results. A total of 786 eligible patients were enrolled and 1:1 randomized either to standard or experimental arm. By backbone therapy, 341 patients received RB and 445 received RCHOP induction immunochemotherapy. RB was more frequently prescribed in older and female patients (OR 1.6, p=0.001) whereas RCHOP was preferred in patients with bulky disease (>6cm) and grade 3a histology (OR 0.65, p=0.013). The median follow-up of the analysis was 56 months (range 1-71). In the non-randomized comparison between RB and RCHOP, no difference in terms of PFS was observed between the two regimens (HR for RB 1.07, 95%CI 0.83-1.38, p=0.597, Figure 1). Standard maintenance arm was more effective than experimental arm both in patients initially treated with RCHOP and in those treated with RB (HR RCHOP 1.61, 95% CI 1.16-2.25; HR RB 1.89, 95% CI 1.27-2.82). An unequal interaction between RB and RCHOP and post-induction therapy was observed for sex and for bone marrow involvement. Considering grade 3 to 5 adverse events (AEs), neutropenia was less frequently observed in RB (35.7%) compared to RCHOP (46.2%). Among extra-hematological AEs, higher frequency of grade 3-4 infections and of cutaneous toxicity were observed in RB treated patients (3.8% vs. 1.2% and 2.4% vs. 0.2%). Overall, 54 second malignancies (SM) have been observed including 23 hematologic malignancies and 31 solid cancers. Cumulative incidence of secondary cancer (excluding non melanoma skin cancers) at 3 and 5 years was 3.7% (95%CI 2.4-5.3%) and 8.1% (95%CI 5.8-10.9%). Conclusion. The current update of the FOLL12 trial demonstrated superiority of standard RM compared to the response adapted post induction management irrespective of prescribed regimen thus proving a first prospective non-randomized evidence of RM efficacy in patients with high tumor burden follicular lymphoma patients treated with RB. Both R-CHOP and RB were associated with a similar efficacy profile. Figure 1. Progression free survival for the standard maintenance arm (A) versus response oriented experimental arm (B) of the FOLL12 trial in patients treated with R-CHOP or R-Bendamustine (RB). Figure 1 Figure 1. Disclosures Luminari: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Janssen: Other: Travel, Accomodations, Expenses; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy; GENELAB SRL: Consultancy; Roche: Consultancy, 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. Ferrero: Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; EUSA Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Research Funding, Speakers Bureau; Morphosys: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Clinigen: Membership on an entity's Board of Directors or advisory committees; Servier: Speakers Bureau. Arcaini: Gilead Sciences: Research Funding; Bayer, Celgene, Gilead Sciences, Roche, Sandoz, Janssen-Cilag, VERASTEM: Consultancy; Celgene: Speakers Bureau; Celgene, Roche, Janssen-Cilag, Gilead: Other: Travel expenses. Pulsoni: Roche: Consultancy, Speakers Bureau; Takeda, Pfizer, Sandoz, Merk: Consultancy; Gilead, Bristol: Speakers Bureau. Musuraca: Janssen, Roche, Incyte: Honoraria; Janssen, Roche, Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen, Incyte, Roche: Consultancy.

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.

Background. Literature on the treatment of rrPCNSL is limited to a few retrospective studies and phase II trials addressing new drugs or strategies. Evidence supporting therapeutic choice in patients (pts) with rrPCNSL after modern high-dose-methotrexate (HD-MTX)-based chemotherapy (chemo) followed by consolidative whole-brain irradiation (WBRT) or autologous stem cell transplantation (ASCT) is lacking. We reviewed management and outcome of pts with rrPCNSL in the randomized trials of the IELSG, which included 294 assessable pts, treated with modern approaches, and followed for several years. Herein, we analyse efficacy of salvage options to provide recommendations for routine practice. Methods. Pts enrolled in the IELSG20 or IELSG32 trials who experienced progressive disease (PD) at any time were considered. Pts who died due to toxicity and pts with extra-CNS relapse were excluded. Pts were grouped according to the time to progression after the first-line treatment: refractory (REF; relapse/PD ≤6 months from end of treatment), early relapse (ER; 6-35 months) and late relapse (LR; ≥36 months). Effect of salvage therapy on survival after relapse (SAR) was the primary objective. SAR was estimated from date of PD/relapse to date of death or last visit. Results. 164 pts (median age 58, range: 26-70; 94 males) were considered: 119 (73%) REF, 24 (15%) ER and 21 (13%) LR. First-line chemo included HD-MTX in all pts, alone in 31, +cytarabine in 68, +cytarabine/rituximab in 36, and +cytarabine/rituximab/thiotepa (MATRIX regimen) in 29. Consolidation was part of first-line treatment in 58 (35%) pts: WBRT in 39 and carmustine-thiotepa/conditioned ASCT in 19; 106 pts did not receive consolidation due to PD during first-line chemo (n=96), pt refusal (2), poor conditions (4) or per protocol (4). Treatment of relapsed/PD was WBRT in 47 pts and chemo in 58; 59 pts received only supportive care (BSC) due to rapid neurological impairment or pt refusal. Importantly, except for performance status (ECOG PS 0-1: 49% of BSC pts, 70% of treated pts; p=0.009), pts managed with BSC showed the same characteristics (age, gender, extension of disease, first-line treatment) than pts who received salvage therapy. Salvage chemo consisted of HD-ifosfamide-based chemo (R-IE, RICE, DeVIC) in 20 pts, rechallenging with HD-MTX-based chemo (same regimen or ± other drugs) in 25, direct myeloablative chemo and ASCT in 3, single drugs in 10; 17 pts responsive to salvage chemo received consolidative ASCT (n=12) or WBRT. Pts with LR had a better outcome than REF and ER cohorts, with a 2-year SAR of 64±11%, 11±3% and 13±7% (p= 0.001), respectively. These figures were similar when only treated pts were considered, with 2-year SAR of 80±11%, 17±4% and 23±12% (p= 0.0002), respectively. All untreated pts died of lymphoma within 4 months of progression. Salvage WBRT (n= 45) and chemo (n= 31) were associated with poor outcome in REF pts (2-year SAR 18±5% vs 16±6%; p= 0.76). Salvage treatment after ER or LR consisted of chemo in 27 pts and WBRT in two; HD-MTX retreatment showed a trend to a better outcome with respect to other chemo combinations, with a 2-year SAR of 73±12% and 27±13% (p=0.25), respectively. Importantly, 12 of the 15 pts with a SAR longer than one year were treated with HD-MTX-based chemo, followed by consolidation in 5 of them. A 2-year SAR of 90±9% was observed in the 11 LR pts retreated with HD-MTX-based chemo. At a median follow-up from relapse/PD of 40 (range 3-118) months, 16 (10%) pts are alive and disease-free. Deaths were due to lymphoma in 137 (93%) pts, infections in six (4%), and thromboembolic events in two (1%); cause unknown in two pts. Multivariable analysis showed that ECOG PS 0-1, LR and HD-MTX retreatment were independently associated with better SAR and that outcome was not affected by age, gender, first-line induction and consolidation, and considered trial. Conclusions. Mortality of rrPCNSL is regrettably high (≈90%), even among selected pts enrolled in prospective trials. One-third of pts are considered unsuitable candidates for salvage treatment. WBRT provides a marginal benefit over BSC in REF pts, suggesting that other strategies, including novel agents, should be considered in routine practice. Pts experiencing LR can achieve long-lasting second remission, especially when retreatment with HD-MTX-based chemo is feasible. Efficacy of salvage therapy appears to be independent of the first-line treatment. Disclosures Ferreri: Pfizer: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Genmab: Research Funding; Amgen: Research Funding; Hutchison Medipharma: Research Funding; Beigene: Research Funding; BMS: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; PletixaPharm: Membership on an entity's Board of Directors or advisory committees; x Incyte: Membership on an entity's Board of Directors or advisory committees; Adienne: Membership on an entity's Board of Directors or advisory committees; Ospedale San Raffaele srl: Patents & Royalties. Cwynarski: Roche: Honoraria, Other: Travel / Conference Support, Speakers Bureau; Takeda: Honoraria, Other: Travel / Conference Support, Speakers Bureau; Celgene/BMS: Honoraria, Other: Travel / Conference Support; Atara: Honoraria; Gilead, KITE: Honoraria, Other: Travel / Conference Support, Speakers Bureau; Janssen: Honoraria, Other: Travel / Conference Support; Incyte: Honoraria, Speakers Bureau. Pulczynski: Roche: Research Funding. Fox: Abbvie: Honoraria, Research Funding; Astrazeneca: Honoraria; Atarabio: Honoraria; BMS/Celgene: Honoraria; Gilead: Honoraria, Research Funding; Janssen: Honoraria, Speakers Bureau; Incyte: Honoraria; Roche: Honoraria, Research Funding, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Beigene: Honoraria, Research Funding. La Rosée: AstraZeneca: Honoraria; Bristol Myers Squib: Honoraria, Speakers Bureau; Novartis: Honoraria; Janssen-Cilag: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau. Schorb: Roche: Research Funding; AbbVie: Research Funding; Riemser Pharma GmbH: Honoraria, Research Funding. 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. Roeth: Roche: Consultancy, Honoraria, Research Funding; Kira: Consultancy, Honoraria; Bioverativ, a Sanofi company: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Apellis Pharmaceuticals: Consultancy, Honoraria; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria. Linton: BeiGene: Research Funding; Celgene: Research Funding; University of Manchester: Current Employment; Genmab: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Hartley Taylor: Honoraria; Aptitude Health: Honoraria. Binder: Deutsche Krebsgellschaft, Medconcept GmbH, event Lab. GmbH: Honoraria, Other: Speaker Activity; Amgen GmbH, Janssen-Cilage GmbH, DGHO, Art tempi, Tumorzentrum Anhalt MD, Uniklinikum Hamburg, Sanofi Aventis: Honoraria, Other: Speaker Activity. Hemmaway: Abbvie: Honoraria. Pinto: Takeda: Consultancy; MSD: Honoraria; Bristol Myers Squibb-CELGENE: Honoraria; Incyte: Honoraria; Roche: Honoraria, Speakers Bureau. Zucca: Celltrion Healthcare: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Miltenyi Biomedicine: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Gilead, Kite: Membership on an entity's Board of Directors or advisory committees; Abbvie: Other: Travel Support.

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: The role of minimal residual disease (MRD) in Multiple Myeloma (MM) as a surrogate biomarker of patients' outcome, as well as the prognostic information of functional imaging response after treatment have been established in recent years. Furthermore, the predictive relevance of sustained MRD negativity assessed by marrow and imaging techniques and its association with an excellent outcome is emerging in clinical trials. Diffusion-weighted whole-body MRI (DW-MRI) is increasingly used in the management of MM patients, but data regarding the predictive role of sustained DW-MRI response after treatment are lacking. The Myeloma Response Assessment and Diagnosis System (MY-RADS) recommendations have established criteria for Response Assessment Category (RAC) (Messiou C et al, Radiology 2019) with a 5 point scale defining the probability of complete imaging response (i.e. RAC 1) or progressive disease after treatment (i.e. RAC 5). We implemented the RAC criteria in our clinical practice and DW-MRI at 1-year in MM patients treated with autologous stem cell transplantation (ASCT) followed by maintenance therapy. Patients and methods: We retrospectively analyzed the outcome of 57 newly diagnosed MM patients (median age 61 years) diagnosed at our institution from January 2015 to December 2019 receiving maintenance therapy after ASCT. Patients underwent DW-MRI evaluation according to MY-RADS criteria at day +100 after ASCT, before maintenance, and after 1 year with the aim of monitoring imaging residual disease. Bone marrow samples were collected for MRD assessment by 8-color FCM (sensitivity 10-5) at day +100 after ASCT, before maintenance, and after 1 year. We focused on sustained 1-year DW-MRI negativity evaluated according to RAC response, and its potential predictive role at that timepoint on progression free survival (PFS) and overall survival (OS). In patients with available 1-year MRD evaluations, concordance between 1-year MRD and DW-MRI results was calculated and the level of agreement was expressed by Cohen's kappa statistics. Results: Out of 57 patients, 23 (40%) were ISS stage 3 and 14 (25%) showed high risk cytogenetics. Patients were treated with the following induction regimens: VTD 42, VRD 5, Dara-VRD 6, KRD 3, KCD 1. Single ASCT with MEL200 conditioning was performed in 33 patients (58%), whereas 24 patients (42%) received double ASCT. Subsequent maintenance was performed with lenalidomide (49 patients, 86%) or daratumumab-lenalidomide (8 patients, 14%). Response rates after ASCT were PR 9%, VGPR 23%, CR 51% and sCR 17%. According to MY-RADS, a complete imaging response (RAC1) at day +100 after ASCT was observed in 34 patients (60%). Sustained 1 year complete imaging response during maintenance therapy was observed in 43 patients (75%). Some residual disease was identified at that timepoint in 14 patients (25%) [RAC 2: 6 (11%), RAC > 2: 8 (14%)]. After a median follow up of 36 months, PFS and OS were significantly longer in patients with sustained 1-year imaging negativity, compared to patients with imaging residual disease (RAC 1 vs RAC ≥2): median PFS 56 vs 24,1 months, p Conclusion: Our real-life data analysis confirms the predictive value of imaging residual disease assessment with DW-MRI after ASCT and highlights the importance of achieving sustained imaging MRD negativity during maintenance therapy regardless of different treatment strategies. Moreover, given the high rates of CR seen in patients with MM with novel effective treatment combinations, the detection of residual disease with the combined evaluation of marrow and functional imaging techniques during maintenance therapy can help the physician to identify patients with increased risk of early relapse and particularly poor prognosis. Our preliminary data regarding the high concordance observed between DW-MRI and MRD results during maintenance therapy suggest that DW-MRI could represent a reliable non-invasive technique to monitor residual disease. Disclosures Belotti: 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; Takeda: Consultancy; GSK: Membership on an entity's Board of Directors or advisory committees. Ribolla: Janssen: Membership on an entity's Board of Directors or advisory committees. Cancelli: Amgen: Membership on an entity's Board of Directors or advisory committees. Roccaro: Amgen, Celgene, Janssen, Takeda: Membership on an entity's Board of Directors or advisory committees; AstraZeneca,: Research Funding; Associazione Italiana per la Ricerca sul Cancro (AIRC): Research Funding; European Hematology Association: Research Funding; Fondazione Regionale per la Ricerca Biomedica (FRRB), Transcan-2 ERA-NET: Research Funding. Rossi: Sanofi: Honoraria; Jazz: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: 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; 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: 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 Non-pegylated liposomal doxorubicin (NPLD) is considered a good alternative to conventional doxorubicin for the treatment of older patients (pts) with aggressive lymphomas and/or at high risk for cardiological toxicity. The use of R-COMP for the treatment of older pts with DLBCL has been supported by several small retrospective studies . In this report we describe the characteristics and outcomes of pts who were prospectively enrolled in the Elderly Project (EP) and who were treated with R-COMP and compared them with pts treated with conventional R-CHOP. Methods. This analysis was conducted starting from the dataset of the EP study. The use of NPLD was allowed according to 648/96 law, treatment decision was left to physician discretion and was independent of frailty status. For the purposes of this analysis, we included all pts who were treated with full doses of R-CHOP and R-COMP. The study endpoint were progression free survival (PFS) and overall survival (OS). A propensity score analysis was conducted to account for the main confounding factors. Results Overall 691 out of 1163 pts of the EP were treated with R-CHOP (383; 55%) or R-COMP (308; 45%); median age was 71 and 76 years for R-CHOP and R-COMP, respectively (p < 0.001) (Table 1). Pts were similarly distributed among different IPI groups for R-COMP or R-CHOP. Based on simplified Geriatric Assessment (sGA) 88%, 11% and Conclusions Data from the prospective observational EP study did not show significant differences in terms of efficacy comparing R-COMP to standard R-CHOP. The higher frequency of UNFIT and FRAIL pts among those treated with NPLD suggests R-COMP is a good strategy to offer a curative treatment to these groups of pts. Figure 1 Figure 1. Disclosures 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. 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. Rigacci: Merck: Membership on an entity's Board of Directors or advisory committees; Abbvie: 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, Other: Travel, Accomodations, Expenses; Gilead Science: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Menarini: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cavallo: ROCHE: Membership on an entity's Board of Directors or advisory committees; Servier: Speakers Bureau; Gilead: Speakers Bureau. Fabbri: Servier/Pfizer: Honoraria; Takeda: Other: Travel, Accomodations, Expenses; Takeda: Honoraria. Puccini: Takeda: Membership on an entity's Board of Directors or advisory committees. Ferrero: Incyte: Membership on an entity's Board of Directors or advisory committees; Morphosys: Research Funding; Gilead: Research Funding, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; EUSA Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Speakers Bureau; Clinigen: Membership on an entity's Board of Directors or advisory committees. 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. Nassi: Takeda: Consultancy; Kyowa Kirin: Consultancy; Incyte: Consultancy; Roche: Consultancy. Musuraca: Janssen, Incyte, Roche: Consultancy; Janssen, Roche, Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen, Roche, Incyte: Honoraria. Flenghi: Janssen: Other: Travel, Accomodations, Expenses; Roche: Other: Travel, Accomodations, Expenses. Marcheselli: sandoz: Membership on an entity's Board of Directors or advisory committees. Luminari: Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Janssen: Other: Travel, Accomodations, Expenses; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy; GENELAB SRL: Consultancy.

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.

Objectives: High-dose CT (HDCT) is considered the gold-standard imaging for the measurements of skeletal muscle area (SMA), visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and intramuscular adipose tissue (IMAT) areas in the abdomen. These parameters may reflect sarcopenia, which can have a prognostic impact in several oncological diseases. The aim of this study was to compare the agreement of measurements of SMA, VAT, SAT and IMAT areas between HDCT and low-dose CT (LDCT) of 18-fludeoxyglucose positron emission tomography (18F-FDG PET)/CT in elderly patients affected by Hodgkin lymphoma (HL). Methods: We retrospectively included 90 patients affected by HL who underwent baseline 18F-FDG-PET/CT and HDCT within a mean interval of 7 days. HDCT and LDCT images were analysed by two blinded observers using segmentation software (Slice-O-Matic, Tomovision) to quantify the areas. HDCT and LDCT measurements were compared using Bland–Altman plots and Passing-Bablock regression analyses. Pearson correlation coefficient (r) was used to correlate measurements from the two imaging modalities. Results: Comparison of HDCT and LDCT data demonstrated a strong correlation for measurement of VAT(r = 0.942, p < 0.0001), SAT (r = 0.894, p < 0.0001) and SMA (r = 0.934, p < 0.0001). Instead considering IMAT, correlation was good but less significant (r = 0.742). The mean difference between the two methods was found to be very small, with a difference of 1% for SAT,+6.1% for VAT,+2.5% for SMA and −1.9% for IMAT. Conclusion: LDCT of PET/CT is a safe, accurate and precise method for the measurements of skeletal muscle area, visceral and subcutaneous adipose tissue. Their measurements are reproducible and correlate closely with HDCT. Advances in knowledge: LLDCT of PET/CT is a safe and accurate method for the measurements of SMA, VAT and SAT; their measurements are closely correlated with HDCT. LDCT can be considered an accurate alternative tool for measuring abdominal fat and muscles in the clinical practice.

Background. The Philadelphia (Ph) chromosome (chr.) is the hallmark of chronic myeloid leukemia (CML) and typically results from the reciprocal translocation t(9;22)(q34;11.2). Complex variant translocations (CVT) involving one or more additional chr. are identified in less than 5% of newly diagnosed CML. There are conflicting reports about the prognostic impact of CVT in the achievement of optimal response to tyrosine kinase inhibitor (TKI), and very few studies addressed the role of frontline treatment with imatinib or second generation (2G)-TKI in patients with CVT. Aims. To assess the response to imatinib or 2G-TKI in a large cohort of newly diagnosed CML with CVT, and to explore the impact of the different chr. translocations on outcome. Methods. This observational retrospective study was conducted in 19 hematologic centers in the framework of Campus CML, a network of Italian physicians involved in the management of CML patients. All newly diagnosed CML from 2000 to 2019 were evaluated and patients with CVT were selected for the present analysis. Karyotypes were defined according to the 2016 International System for Human Cytogenetic Nomenclature. Responses to frontline treatment were retrospectively categorized according to the 2013 ELN recommendations, as they include cytogenetic milestones. Deep molecular response (DMR, i.e. MR4or better) was defined as BCR-ABLIS ratio ≤0.01% or undetectable disease with ≥10,000 ABL copies. Patients with DMR lasting ≥2 years and at least a Q-PCR test every 6 months were defined as stable DMR responders. Failure-free survival (FFS) was calculated from the start of frontline TKI treatment to progression to advanced phase, death, or switch to other treatments for resistance. For FFS calculation, patients were censored at TKI stop for treatment-free remission (TFR) or in case of switch for intolerance only. Differences between subgroups according to the partner chr. were presented for descriptive purposes. Results. CVT were identified in 109 (3.2%) patients from a whole population of 3,361 subjects with newly diagnosed CML. Ninety-five out of 109 patients (87%) exhibited three-way translocations, with chr. 1, 4, 6, 10, 11, 12, 14, 15 and 17 representing the most common additional partners (figure). Four- and five-way translocations were identified in 13 and 1 patients, respectively. Additional chr. abnormalities (ACA) in the Ph+ cells were observed in 15/109 (13.8%) patients and were more common in older individuals (p=0.018). Overall, median age at diagnosis was 50.6 years (range 20-90). Risk distribution according to the ELTS score was 54%, 28% and 8% for L, I and H risk, respectively (10% missing). Cytogenetic result was available before the choice of frontline treatment in 45% of cases and represented a decisive factor in 28% of them (i.e. clinicians selected a 2G-TKI or high-dose imatinib, according to the available options). Frontline TKI treatment was imatinib in 80 cases (73%) and 2G-TKI (nilotinib n=22, dasatinib n=6, bosutinib n=1) in the remaining cases. The frequency of optimal response at 3, 6 and 12 months was 48%, 45% and 53%, respectively, for imatinib-treated patients, and 76%, 83% and 76%, respectively, for the 2G-TKI cohort (p The subtype of CVT had an impact on response and long-term outcome. Patients with CVT involving chr. 1, 4, 6, 11 or 12 had a higher frequency of MMR at 12 months than patients with CVT involving chr. 10, 14, 15 or 17 (75.8% vs 30.4%, respectively, p=0.001), higher frequency of stable DMR (48.7% vs 22.2%, respectively; p=0.04) and tended to have better median FFS (p=0.07), regardless of the type of frontline TKI and of the ELTS score. Conclusions. Due to its retrospective nature, this study does not allow to define which is the optimal therapy for CML harboring CVT at diagnosis. However, our data reinforce the usefulness of bone marrow karyotyping in CML. The observed differences between partner chr. may also depend on the breaking points, which are variable. Further dissection of CVT will help to identify which are associated to a poor response to TKIs. Figure Disclosures D'Adda: Incyte: Other: Advisory board; Novartis: Other: Advisory board; Pfizer: Other: Advisory board. Galimberti:Novartis: Speakers Bureau; Incyte: Honoraria. Crugnola:Celgene: Honoraria; Janssen: Honoraria; BMS: Honoraria; Novartis: Honoraria. Bocchia:Incyte: Honoraria; CELGENE: Honoraria. Krampera:Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Breccia:Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Abbvie: Consultancy; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Saglio:Novartis: Research Funding; Ariad: Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Research Funding; Incyte: Research Funding; Roche: 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.

Background: ABP 798 is a proposed biosimilar to rituximab reference product (RP). Regulatory approval of biosimilars is based on a totality of evidence (TOE) approach which includes similarity in analytical characteristics (structural and functional), in mechanism of action (MoA) -clinical pharmacology, pharmacokinetics (PK), pharmacodynamics (PD), and in comparative clinical studies. Evidence from analytical, functional, clinical PK/PD, and efficacy and safety evaluations indicate that ABP 798 is similar to rituximab RP. Similarity of efficacy and safety in patients with non-Hodgkin lymphoma (NHL) was demonstrated in a randomized, double-blind, comparative clinical study in which the primary analysis was based on data from central, independent, and blinded assessments of disease and the sensitivity analysis was based on data using investigator assessments of disease. Here we present in vitro chemo synergy, preclinical in-vivo tumor efficacy data and show how the results of the sensitivity analysis using investigator assessments of the response rate from the NHL clinical study further add to the TOE supporting similarity of ABP 798 with the RP. Methods: In vitro synergy with chemotherapeutic agents was investigated by assessing the effect of docetaxel, gemcitabine, or doxorubicin with ABP 798 and rituximab RP in SU-DHL-6 cell lines and measured using the ATP-based cell viability endpoint (ATPLite). In vivo efficacy was assessed by evaluating the anti-tumor activity of ABP 798 and rituximab RP in NHL xenograft models in NOD/SCID mice using CD20-expressing RL and Raji cell lines. A sensitivity analysis was conducted to assess the robustness of the results of the primary efficacy endpoint of the proportion of patients with the best overall response of complete response, partial response, or unconfirmed complete response (ORR) in the NHL comparative clinical study using the investigator's assessment of disease on the full analysis set. Waterfall plots of the maximum percent reduction in the sum of the products of the greatest diameters (SPD) for index nodal lesions based on both the central, independent, blinded assessment of disease and the investigator's assessment of disease were used. Results: In vitro study results demonstrated synergistic activity of the combination of docetaxel and ABP 798 or the RP (synergy score = 6.35±0.69 [with ABP 798]; 6.79±0.12 [with RP]). In contrast, combinations with gemcitabine (synergy score = 2.68±0.20 [with ABP 798] and 2.54±0.29 [with RP]) or doxorubicin (synergy score = 1.95±0.56 [with ABP 79]) and 3.23±0.53 [with RP]) were additive. In RL cell lines, ABP 798 inhibited tumor growth similarly to rituximab RP, with no statistical difference between dose groups at 3 and 30 mg/kg (p = 0.951 and p = 0.996, respectively). In Raji cells, ABP 798 and rituximab RP significantly and similarly inhibited tumor growth when compared to an IgG1 isotype control (p < 0.001 for 3 and 30 µg/kg doses). ABP 798, at both dose levels, inhibited tumor growth similarly to rituximab RP by 27-41%, with no statistical difference. In the NHL comparative clinical study, risk difference (RD) of ORR with 1-sided 95% lower and upper confidence limits from the adjusted linear model was 7.7% (-3.2%, 18.6%) using central, blinded, independent assessments of the modified full analysis set based on randomized treatment assignment. The sensitivity analysis using investigator assessments of disease of the full analysis set of all randomized subjects based on the randomized treatment assignment received was RD = 0.5% (-7.8%, 8.8%). Waterfall plots of the maximum percent reduction in the SPD for index nodal lesions further demonstrate similarity of efficacy with central or local assessments of disease. Conclusions: In vitro and in vivo preclinical studies demonstrated chemo synergy and in vivo tumor efficacy. The sensitivity analysis of ORR using local assessments in the NHL comparative clinical study was consistent with results from the primary efficacy analysis; the maximum percent reduction in index nodal lesions was similar for central and local assessments of disease. These results further support that ABP 798 is similar to the RP across a range of efficacy evaluations as well as primary and secondary mechanisms of action and add additional supporting data to the TOE. Disclosures Niederwieser: Novartis: Speakers Bureau; Cellectis: Membership on an entity's Board of Directors or advisory committees; Daiichi: Research Funding; Amgen: Speakers Bureau. Hamm:Amgen: Consultancy. Cobb:Amgen: Consultancy. Thway:Amgen: Current Employment, Current equity holder in publicly-traded company. Forsyth:Amgen: Consultancy; Janssen Pharmaceuticals Australia: Honoraria, Membership on an entity's Board of Directors or advisory committees. Tucci:Amgen: Consultancy. Delwail:Amgen: Consultancy. Hajek:Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria; PharmaMar: Consultancy, Honoraria; Oncopeptides: Consultancy. Hanes:Amgen: Current Employment, Current equity holder in publicly-traded company.

The human fibroblast growth factor/fibroblast growth factor-receptor (FGF/FGFR) axis deregulation is largely involved in supporting the pathogenesis of hematologic malignancies, including Waldenstrom's Macroglobulinemia (WM). Therefore, novel therapeutics designed to specifically target deregulated signaling pathways in WM are required. We investigated the role of FGF/FGFR system blockade in WM by using a pan-FGF trap molecule, NSC12, a small molecule identified using pharmacophore modeling of the interaction of a minimal PTX3-derived FGF-binding pentapeptide with FGF2. By interrogating the transcriptome signature of patients' BM-derived CD19-positive cells (GEO9656, GEO6691), we found a significant enrichment of FGF/FGFR-driven signaling cascades, including PI3K-AKT, MAPK and STAT3 pathways (FDR In addition, the NSC12-dependent inhibition of MYD88 resulted in silencing of the MAPK-ERK signaling cascade, thus leading to NSC12-induced Myc-silencing in WM cells. We next confirmed the efficacy of NSC12 in silencing bone marrow stromal cell (BMSC)-induced FGFR3 phosphorylation; paralleled by inhibition of of pro-survival pathways, including pAKT, the AKT-downstream pGSK3β; p-ERK; and p-STAT3. Functional sequelae of the FGF/FGFR blockade in WM cells were studied, demonstrating inhibition of WM cell growth, induction of apoptosis, enhanced ER stress and initiation of UPR. Of note, anti-WM activity of NSC12 was also documented using primary bone marrow-derived CD19+ cells isolated from patients with WM. In contrast, NSC12 did not show cytotoxicity on PBMC-derived CD19+ cells isolated from healthy donors. The anti-WM activity exerted by NSC12 was confirmed also within the context of the supportive bone marrow milieu, as shown both in vitro and in vivo. BCWM.1, MWCL1 cells were cultured with NSC12 in the presence or absence of primary WM BMSCs: adherence of WM cells to BMSCs triggered a significant increase in the proliferation, which was inhibited by NSC12in a dose-dependent manner (P Overall, our studies are reporting on the use of NSC12, as a novel potential therapeutic strategy to specifically halt the FGF/FGFR axis in WM; and demonstrate how the observed anti-WM activity exerted by NSC12 may be driven, at least in part, by inhibition of MYD88. Disclosures Motta: Roche: Honoraria; Janssen: Honoraria. Rossi:Alexion: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Advisory board; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria; Amgen: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Roccaro:Amgen: Other; AstraZeneca: Research Funding; Celgene: Other; Janssen: Other; Italian Association for Cancer Research (AIRC): Research Funding; Transcan2-ERANET: Research Funding; European Hematology Association: Research Funding.

This phase-II study assessed activity and toxicity of substituting conventional doxorubicin with nonpegylated liposomal doxorubicin in the conventional ABVD regimen for the treatment of elderly or cardiopathic patients with HL. Stage I-IIA and IIB-IV patients were treated with three courses of MBVD plus radiotherapy, or six courses of MBVD, respectively, plus radiotherapy limited to bulky or residual disease areas. The primary endpoints were CR rate and the rate of cardiac events. Forty-seven patients were enrolled. Median age was 75 years, 13 had stage I-II disease. Overall, CR was achieved by 36 patients (77%, 95% CI: 62-88), 100% and 68% in stage I-II and III-IV, respectively. With a median follow-up of 40 months (IQR: 36-45). Three-year overall survival (OS) and progression-free survival (PFS) were 70% and 43%, respectively. Cardiac events grades 3-5 were reported in two patients. In conclusion, MBVD's activity and safety profile was comparable to historical ABVD data.