Abstract: Cytokine release syndrome (CRS) represents a life‐threatening side effect after haploidentical stem cell transplantation (Haplo‐SCT) with posttransplant cyclophosphamide (PT‐Cy). Factors predictive of CRS development is still a matter of debate. We retrospectively analyzed 102 consecutive patients receiving a bone marrow (BM) (n = 42) or peripheral blood stem cells (PBSC) (n = 60) Haplo‐SCT with PT‐Cy. The two cohorts were similar in main patients’ characteristics besides disease type ( P  = .02). Cumulative incidence of grades 1, 2, and ≥3 CRS was 80%, 52%, and 15% at a median of 2, 4, and 7 days, respectively. Moderate/High‐grade fever (39°‐41°), grade 1 and grade ≥3 CRS occurred more frequently after PBSC relative to BM grafts (68% vs 33%, P  = .0005; 87% vs 71%, P  = .009; 20% vs 7%, P  = .07). Only patients experiencing grade ≥3 CRS had a worse outcome in terms of 1‐year overall survival (OS) and nonrelapse mortality (NRM): 39% vs 80% ( P  = .002) and 40% vs 8% ( P  = .005), respectively. By univariate analysis the only factors associated with the increased risk of ≥3 CRS were pretransplant disease status (8% for complete remission, 11% for partial remission, and 38% for active disease, P  = .002), HLA‐DRB1 mismatching (57% vs 14%, P  = .007), and PBSC graft ( P  = .07). By multivariable analysis, only pretransplant disease status (hazard ratio, HR: 6.84, P  = .005) and HLA‐DRB1 mismatching (HR: 17.19, P  = .003) remained independent predictors of grade ≥3 CRS. Only grade ≥3 CRS is clinically relevant for the final outcome of patients receiving Haplo‐SCT with PT‐Cy, is more frequent after a PBSC graft and is associated with pretransplant active disease and HLA‐DRB1 mismatching.

Abstract: INTRODUCTION: high-dose chemotherapy (HDC) followed by autologous hematopoietic stem cell transplantation (ASCT) is a curative option for relapsed diffuse large B-cell lymphoma (DLBCL). However, relapse within 1 year after diagnosis, previous therapy with rituximab and secondary IPI = 2 or 3 have been associated with unsatisfactory outcome even after ASCT, thus the better treatment of these patients is matter of debate and efforts are ongoing in order to improve survival. METHODS: on a total of 146 DLBCL patients receiving ASCT, we identified 78 adult patients who had responsive but still measurable disease after first-line therapy or relapsed/progressive disease with one or more adverse features as specified above. All patients were 〉 18 years old and received ASCT at our institution. Patients were grouped according to the administered treatment: 1) n= 21 patients were in response but not in complete remission (CR) after first-line and received HDC and ASCT; 2) n= 48 patients had refractory or relapsed disease and received salvage chemotherapy followed by HDC and ASCT (n=46 single ASCT, n=2 double ASCT); 3) n=9 patients received salvage therapy then tandem autologous-allogeneic SCT due to the presence of any of the above mentioned adverse features. For all patients, salvage chemotherapy was mostly VIHA or DHAP with the addition of rituximab. Most used regimens of HDC were Melphalan 200 mg/mq or BEAM. Among the nine patients undergoing tandem auto-allo, eight received Melphalan 200 mg/mq and one BEAM; allogeneic donors were either HLA-identical siblings (n=3), unrelated (n=1) or haploidentical ones (n=5). All conditioning regimens before allogeneic SCT were reduced-intensity or nonmyeloablative. RESULTS: at last follow-up, survival rate is 57% for group 1 (12 alive out of 21 patients), 27% for group 2 (13/48) and 67% for group 3 (6/9). Cause of death in this last group was disease relapse/progression for all 3 cases (2 patients were in partial remission (PR) before allo, 1 in CR). Disease status before allogeneic SCT for the 6 alive patients was CR (n=3) and PR (n=3). Their follow-up is +8, +24, +26, +40, +45 and +70 months since ASCT. Of note, survival rate was 74% for the 47 patients receiving HDC and ASCT in first CR (candidated upfront to ASCT due to high-risk IPI at diagnosis) and 62% for the 21 relapsed patients who did not present any of the above mentioned adverse features at relapse. Those two groups were taken from the same initial sample of 146 patients. CONCLUSION: for patients affected by relapsed DLBCL with one or more adverse prognostic features, administration of allogeneic SCT after ASCT as a tandem strategy provides promising results compared with patients receiving ASCT alone and deserves further investigation, especially taking into account the rapid expansion of platforms using T-cell replete haploidentical grafts. Upfront HDC followed by ASCT appears to be a valid option for those patients in PR after first-line therapy, with a 57% survival rate in our series. Disclosures No relevant conflicts of interest to declare.

Abstract: Introduction: although high-dose chemotherapy (HDC) is the golden standard for the treatment of many relapsed or refractory lymphomas, the outcome is still unsatisfactory especially in some subsets of patients with adverse prognostic features. To improve these results, we treated high-risk patients with a tandem strategy associating debulking with HDC followed by autologous stem cell transplantation (ASCT) and subsequent adoptive immunotherapy consisting in allogeneic SCT (tandem auto-allo). We report here the outcome of 111 lymphoma patients undergoing this procedure; in addition, the role of two ASCT conditioning regimens is discussed. Patients and Methods: adult patients consecutively treated at two centers (Milan, Italy and Marseille, France) were included. Criteria for receiving tandem auto-allo were: refractory disease after first-line therapy, less than CR after first salvage treatment, histology of transformed follicular, mantle-, T- and NK-cell lymphoma, relapse after prior ASCT, multiple relapses. Disease evaluation was performed by using PET scan starting from 2003. Results: 111 consecutive patients with HL or NHL were transplanted from June 2002 to September 2013. Main characteristics are shown in Table 1. Median interval between ASCT and allogeneic SCT was 85 days (range: 36-235). Sixty-two patients (56%) received BEAM (8 of them without BCNU) and 46 (41%) high-dose Melphalan (HD-Mel, 100-200 mg/m2); 3 patients received other regimens. Main characteristics were not significantly different between BEAM and HD-Mel groups with the exception of the use of more alternative donor (i.e. non HLA-identical) in the HD-Mel group: 33% vs. 13%, p=0.01. Disease status before ASCT was: CR (n=47), PR (n=38), SD (n=10), PD (n=16). Grade 3-4 mucositis occurred in 49 patients (44%) and documented infections during hospital stay in 30 (27%), without differences between BEAM and HD-Mel groups, p=0.57 and p=0.14. Disease status before allogeneic SCT was: CR (n=79), PR (n=22), SD (n=5), PD (n=5). Among the 64 patients with active disease before ASCT, the overall response rate was 87% (n=56 responders) and the rate of CR was 53% (n=34), these latter adding to the 45 (out of the 47) patients in CR before ASCT; nine patients (8%) progressed between ASCT and allogeneic SCT. Again, no differences were observed in terms of response among BEAM and HD-Mel group (p=0.28). Allogeneic SCT was performed after NMA (n=43), RIC (n=66) or MA (n=2) conditioning; donor was either HLA-identical (n=86), MUD 9/10 (n=2), haploidentical (n=20) or cord blood (n=3). After a median follow-up of 38 months after allogeneic SCT, 3-y OS of entire cohort was 68% (95% CI: 59-77), 3-y PFS was 61% (52-70), rates of acute GvHD grade 2-4 and chronic GvHD were 28% and 38% respectively. TRM rate was 18% (n=20). Last relapse event occurred at day +853. No difference between BEAM and HD-Mel group was observed for OS (73% and 64% respectively, p=0.40) or TRM (19% and 13%, p=0.44). CR before allogeneic SCT confirms to a major prognostic factors for OS (Figure 1), whereas donor type did not significantly impact on survival (p=0.68). No survival difference was observed between HL and NHL (p=0.53). Conclusions: tandem auto-allo confirms to be a feasible and effective therapeutic strategy in those lymphoma patients whose prognosis is expected to be unsatisfactory with ASCT alone. BEAM vs. HD-Mel appeared to be similar in terms of extrahematological toxicity, disease response and survival. Disease status before allogeneic SCT confirms to be a significant prognostic factor, underlying the importance of high-dose chemotherapy followed by ASCT as further tumor shrinking before allogeneic immunotherapy in this setting of high-risk patients. Table 1. Main patients’ and transplant characteristics Variable Value % N 111 100% Pt's age (median) 44 range:16-69 Gender M 66 59% F 45 41% Disease HL 44 40% DLBCL 12 11% FL 21 19% Transf FL 9 8% MCL 9 8% MZL 1 1% T lymph 13 12% Grey zone 1 1% NK lymphoma 1 1% Indication for tandem auto-allo 1ary refractory 28 25% no CR after salvage 43 39% histology 10 9% relapse after prior ASCT 6 5% multiple relapse 24 22% Prior therapy lines (median) 2 range: 0-7 Prior radiotherapy 26 23% ASCT conditioning BEAM 54 49% EAM 8 7% HD-Mel 100 1 1% HD-Mel 140 12 11% HD-Mel 200 33 30% other 3 3% Allogeneic stem cell donor HLA-id sibling 62 56% MUD 10/10 24 22% MUD 9/10 2 2% haplo 20 18% cord blood 3 3% Figure 1. OS according to disease status after ASCT. Figure 1. OS according to disease status after ASCT. Disclosures No relevant conflicts of interest to declare.

Abstract: Total marrow (lymph node) irradiation (TMI/TMLI) delivery requires more time than standard radiotherapy treatments. The patient’s extremities, through the joints, can experience large movements. The reproducibility of TMI/TMLI patients’ extremities was evaluated to find the best positioning and reduce unwanted movements. Eighty TMI/TMLI patients were selected (2013–2022). During treatment, a cone-beam computed tomography (CBCT) was performed for each isocenter to reposition the patient. CBCT-CT pairs were evaluated considering: (i) online vector shift (OVS) that matched the two series; (ii) residual vector shift (RVS) to reposition the patient’s extremities; (iii) qualitative agreement (range 1–5). Patients were subdivided into (i) arms either leaning on the frame or above the body; (ii) with or without a personal cushion for foot positioning. The Mann-Whitney test was considered (p 〈 0.05 significant). Six-hundred-twenty-nine CBCTs were analyzed. The median OVS was 4.0 mm, with only 1.6% of cases ranked 〈 3, and 24% of RVS 〉 10 mm. Arms leaning on the frame had significantly smaller RVS than above the body (median: 8.0 mm/6.0 mm, p 〈 0.05). Using a personal cushion for the feet significantly improved the RVS than without cushions (median: 8.5 mm/1.8 mm, p 〈 0.01). The role and experience of the radiotherapy team are fundamental to optimizing the TMI/TMLI patient setup.

Abstract: Background: Cytomegalovirus (CMV) reactivation still represents a common complication after allogeneic stem cell transplantation and is associated with increased non-relapse mortality (NRM) and reduced overall survival (OS). Patients receiving T cell-replete haploidentical stem cell transplantation (haplo-SCT) with high dose post-transplant cyclophosphamide (PT-Cy) are considered at higher risk of developing CMV reactivation due to their particular immuno-suppressed status. Letermovir was recently shown to significantly reduce the frequency of CMV reactivation in a phase 3 clinical trial. We decided to perform a retrospective analysis among patients treated with haplo-SCT with PT-Cy in order to identify whether every patients should receive CMV prophylaxis with letermovir or it is possible to identify a particular subgroup that may benefit more of prophylactic treatment. Methods: We retrospectively analyzed 513 consecutive patients receiving Haplo-SCT with PT-Cy at our institutions between April 2009 and December 2018. Median age was 56 years old (range 15-77), main diagnosis was represented by acute myeloid leukemia (31%), Hodgkin lymphoma (22%), non-Hodgkin lymphoma (21%) and myelodisplastic syndrome (12%). Donor/recipient CMV serostatus was as follows: neg/neg (G1) 16%, pos/pos (G2) 50%, pos/neg (G3) 12% and neg/pos (G4) 22%. Conditioning regimen was non-myeloablative/reduced intensity in 90% of the cases, graft source was represented by bone marrow for 25% of the patients. Results: With a median follow-up of 35 months, 3-year OS was 57%, 3-year NRM 24% and 3-year graft-versus-host-disease (GVHD)/relapse free survival (GRFS) 43%. 180-days cumulative incidence of grade 2-4 acute GVHD was 23% and 2-year moderate-severe chronic GVHD was 9%. Median day of CMV reactivation was 41 days (range 10-275), 100-days and 1-year cumulative incidence of CMV reactivation was 43% and 48%, respectively. Cumulative incidence of CMV reactivation was more common among seropositive recipients: G1 1% vs G2 60% vs G3 32% vs G4 67% (Table I, p 〈 0.001). Recipient CMV positive serostatus and increasing patient age (hazard ratio (HR): 1.01, p=0.033) were the only variables associated with increased risk of CMV reactivation. 3-year OS, 3-year progression-free survival (PFS) and 3-year GRFS were worse among seropositive recipients, and consistently 3-year NRM was higher for G2 and G4 (Table I). By a time-dependent analysis we investigated the impact of CMV reactivation on main outcomes. Only 180-day cumulative incidence of grade 2-4 acute GVHD, and none of the other analyzed outcomes, was more frequent after CMV reactivation (HR 2.064, p=0.001). By time-dependent multivariable analysis, positive recipient CMV serostatus, was an independent predictor of increased NRM (G2: HR 2.47 and G4 HR: 2.61, p=0.007) and worse GRFS (G2: HR 1.71, p=0.003 and G4 HR 1.32, p=0.183). Pre-transplant active disease and hematopoietic cell transplant comorbidity index (HCT-CI) ≥3 were the other independent variables affecting OS, NRM, PFS and GRFS by multivariable analysis. Based on landmark analysis at day 100, patients experiencing CMV reactivation had a higher NRM rate compared with those without reactivation (18% vs 10%, p=0.034) and a tendency for lower OS (72% vs 78%, p=0.065) and GRFS (50% vs 55%, p=0.061). Moreover, by multivariable analysis, CMV reactivation and increasing donor age were the main independent predictors of grade 2-4 acute GVHD: HR 2.21, (p=0.01) and 1.01 (p=0.016), respectively. Conclusion: Recipient positive CMV serostatus is associated with increased risk of CMV reactivation, increased rate of NRM and worse GRFS. CMV reactivation is associated with increased risk of developing grade 2-4 acute GVHD and higher NRM. We conclude that also in the platform of haplo-SCT with PT-Cy, letermovir prophylaxis should be given not to all patients, but mainly to CMV seropositive recipients, that probably may benefit the most in terms of CMV reactivation, acute GVHD incidence and NRM. Disclosures Chabannon: Gilead: Other: speaker's fees, hospitalities; Sanofi SA: Other: research support, speaker's fees, hospitalities; Novartis: Other: speaker's fees; Celgene: Other: speaker's fees; Terumo BCT: Other: speaker's fees; Miltenyi Biotech: Other: research support; Fresenius Kabi: Other: research support; EBMT: Other: Working Party Chair, Board member. Carlo-Stella:Boehringer Ingelheim: Consultancy; Rhizen Pharmaceuticals: Research Funding; Celgene: Research Funding; Genenta Science srl: Consultancy; F. Hoffmann-La Roche Ltd: Honoraria, Other: Travel, accommodations, Research Funding; ADC Therapeutics: Consultancy, Other: Travel, accommodations, Research Funding; Servier: Consultancy, Honoraria, Other: Travel, accommodations; Novartis: Consultancy, Research Funding; MSD: Honoraria; Sanofi: Consultancy, Research Funding; Amgen: Honoraria; AstraZeneca: Honoraria; Janssen Oncology: Honoraria; BMS: Honoraria; Janssen: Other: Travel, accommodations; Takeda: Other: Travel, accommodations. Santoro:Bayer: Consultancy, Speakers Bureau; MSD: Speakers Bureau; Sandoz: Speakers Bureau; Eisai: Consultancy, Speakers Bureau; BMS: Consultancy; Novartis: Speakers Bureau; Lilly: Speakers Bureau; Arqule: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Servier: Consultancy, Speakers Bureau; Celgene: Speakers Bureau; Amgen: Speakers Bureau; Abb-Vie: Speakers Bureau; Roche: Speakers Bureau; Takeda: Speakers Bureau; BMS: Speakers Bureau. Blaise:Pierre Fabre medicaments: Honoraria; Molmed: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria; Sanofi: Honoraria.

Abstract: Introduction. Investigators from Johns Hopkins University pioneered the use of post-transplantation cyclophosphamide (PT-Cy) after T cell-replete haploidentical bone marrow (BM) infusion. A significant component of this scheme is tacrolimus (FK), associated to mycophenolate mofetil (MMF), to prevent immunological complications. FK is a calcineurin inhibitor, almost 100-fold more potent than cyclosporine A (CyA) in its inhibitory activity. In this retrospective study, we analyzed 100 patients grafted with Haplo-SCT with PT-Cy, and receiving FK or CyA. Patients and Methods. From April 2009 until April 2013, we analyzed 100 consecutive patients at two institutions (Institut Paoli Calmettes Marseille, France and Humanitas Cancer Center, Rozzano, Italy). Conditioning regimen was identical consisting of Fludarabine, Cyclophosphamide, and low dose TBI. GVHD prophylaxis consisted of Cy 50 mg/kg on days +3 and +4, FK or CyA and MMF. FK (at a total dose of 1 mg) was administered as a continuous infusion and then converted to oral formulation. CyA was dosed at 3 mg/kg as a continuous infusion and was then converted to oral formulation. MMF was administered at 45 mg/kg/day until day +35. FK, CyA and MMF were started on day +5. FK and CyA were tapered by day +100-180. Stem cell source was BM or peripheral blood stem cells (PBSC). Results. Patient and transplant characteristics are shown in Table 1. The cumulative incidence of engraftment was similar between FK and CyA groups: 30-days absolute neutrophil count 〉 500 was 79% vs 91% (p 0.3), and unsupported platelet count more than 20 000 at 60 days was 77% vs 84% (p 0.7), respectively. The incidence of grade 2-4 acute GVHD was 26% vs 30% (p 0.5) and the incidence of chronic GVHD was 13% vs 8% (p 0.9), respectively. The 2-year progression free survival (PFS) and overall survival (OS) were 53% vs 64% (p 0.2) and 65% vs 65%, respectively (p 0.7). The 2-year relapse incidence (RI) was 28% vs 12% (p 0.08) and the 2-year non relapse mortality was 16% vs 14% (p 0.7), respectively. In univariate analysis, only disease status (CR vs not CR) impacted the PFS, OS, and RI. Patients were regrouped in 3 cohorts (1 patient excluded because received FK + PBSC): FK + BM (n 42), CyA + BM (n 14), and CyA + PBSC (n 43). 1-year NRM was not different (17% vs 14% vs 15%, p 0.8). Compared to FK +BM and CyA + PBSC, a trend in favor of CyA + BM was observed in terms of aGVHD (7% vs 24% vs 38%, p 0.05) and cGVHD (0 vs 13% vs 10%, p 0.9). Conclusions. Although this is a retrospective study with potential selection bias, using CyA instead of standard FK did not seem to affect any major clinical outcome, with special interest for aGVHD and cGVHD. The NRM is acceptable in line with that published. GVHD incidence was lower in the group CyA + BM compared to other 2 groups. Disease status before haplo SCT was the only prognostic factor for survival and relapse. Table 1. Patient and transplant characteristics. All pts FK CSA p N % N % 100 43 57 Male Female 58/42 22/21 51/49 36/21 63/37 0.229 Age (mean) 46 44 48 0.135 Disease status at haplo 0.466 CR 56 23 53 33 58 PR 29 14 33 15 26 SD 6 1 2 5 9 PD 9 5 12 4 7 Armand Risk 0.646 Low 9 3 7 6 11 Int 72 33 77 39 68 High/Very high 19 7 16 12 21 Previous transplant 〈 0.001 Relapse after ALLO 8 0 0 8 14 Relapse after HDC 40 21 49 19 33 Sex D/R 0.533 F/F 16 9 21 7 12 F/M 21 8 19 13 23 M/M 38 14 33 24 42 M/F 25 12 28 13 23 CMV D/R 0.009 POS/POS 70 35 81 35 61 NEG/NEG 18 2 5 16 28 POS/NEG 11 6 14 5 9 Donor 0.578 children 26 12 28 14 25 Mother 15 7 16 8 14 Father 11 6 14 5 9 Sibling 47 17 40 30 53 Cousin 1 Stem cell source 〈 0.001 BM 56 42 98 14 25 PBSC 44 1 2 43 75 HCT-CI 0.007 0 31 18 42 13 23 1-2 23 13 30 10 18 〉 3 46 12 28 34 60 CD34 (mean) 4,4 3,5 5,2 〈 0.001 Disclosures No relevant conflicts of interest to declare.