Search

Introduction: Anti-PD-1 monoclonal antibodies (mAbs) are highly active in relapsed/refractory classical Hodgkin lymphoma (cHL), but most patients (pts) will still relapse. Given this, allogeneic stem cell transplantation (alloHSCT) remains an important option for pts after PD-1 blockade, as it offers the possibility of cure. Prior reports have suggested that alloHSCT after PD-1 mAbs may be associated with severe immune-related complications including acute graft-versus-host disease (GVHD), veno-occlusive disease (VOD) and cytokine release/febrile non-infectious syndrome (CRS). Prior studies of alloHSCT after PD-1 blockade in cHL have been limited by the small number of pts and short follow-up, preventing an accurate assessment of long-term outcomes and complications, risk factors for early toxicity, and the impact of transplant strategies such as choice of GVHD prophylaxis. We therefore assembled a large retrospective international cohort of cHL pts who underwent alloHSCT after PD-(L)1 blockade to better answer these questions, including an assessment of the impact of post-transplant cyclophosphamide (PTCy) on efficacy and toxicity. Methods: Medical records and databases were reviewed at 26 European and United States transplant centers to identify pts with cHL who underwent an alloHSCT any time after receiving a PD-1 or PD-L1 mAb. Response assessment was performed by local investigators according to Lugano 2014 criteria. Overall survival (OS), progression-free survival (PFS), cumulative incidence (CumInc) of relapse (CIR), non-relapse mortality (NRM), acute (a) and chronic (c) GVHD were estimated, as was the association between baseline variables and these outcomes. Results: Between 2014 and 2019, 150 pts were identified who underwent alloHSCT after a median of 10 (range, 1-74) doses of nivolumab (n=118), pembrolizumab (n=31), or avelumab (n=1). The median age was 31 (range 17-68) and pts had received a median of 4 (range, 2-11) lines of therapy prior to PD-(L)1 blockade. 138 pts (92%) had failed BV and 111 (74%) autologous HSCT. The best overall response to PD-(L)1 mAbs was CR for 62 pts (41%), PR for 55 (37%), SD for 17 (11%), PD for 15 (10%) and unknown for 1 (1%). Median time from last dose of PD-(L)1 mAb to alloHSCT was 80 days (range, 17-756) with 70 pts (47%) receiving intervening systemic therapy. At alloHSCT, 90 pts were in CR (60%), 45 in PR (30%), 5 in SD (3%), and 10 in PD (7%). Donors were haploidentical (n=71, 47%), matched sibling (n=29, 19%), matched unrelated (n=39, 26%), mismatched unrelated (n=7, 5%), cord blood (n=2, 1%), or unknown (n=2, 1%). Stem cell source was bone marrow (n=38, 25%), peripheral blood (n=110, 73%), or cord blood (n=2, 1%). GVHD prophylaxis included PTCy in 88 pts (59%) (69/71 (97%) with haploidentical donors; 19/79 (24%) with other donors). With a median post-alloHSCT follow-up for survivors of 23.8 months (range, 1-67), the 2y OS and PFS were 79% (95CI 71-86%) and 65% (95CI 55-73%), respectively, while the 2y CumIncs of relapse and NRM were 21% (95CI 13-29%) and 14%, (95CI, 8-22%), respectively (Fig. 1A-B). 27 pts have died, 3 due to disease and 24 to NRM, including aGVHD (n=7) and VOD (n=2). Veno-occlusive disease (VOD) occurred in 5 pts (day 100 CumInc 4%) and 29 pts (19%) developed CRS (grade 1 n=16; grade 2 n=7; grade 3 n=4; grade 4 n=2). The 6-month CumIncs of grade 2-4, grade 3-4 and grade 4 aGVHD were 39%, 16% and 8%, respectively. Hyperacute GVHD (onset ≤ 14 days after alloHSCT) occurred in 4% of pts and was fatal in 2 pts. The 2y CumInc of cGVHD was 45%. Neither receipt of > 10 doses (median) of anti-PD-(L)1 mAb nor undergoing alloHSCT ≤80 days (median) after last dose of PD-(L)1 mAb were associated with PFS or OS. However, pts with a shorter time to transplant (≤80 days) appeared to have a higher risk of severe (grade 3-4) aGVHD (6m CumInc 24% vs 9%, p=0.006). Recipients of PTCy in this cohort had lower 2y CumIncs of cGVHD (34% vs 58%, p=0.01) and relapse (12% vs 31%, p=0.02), superior 2y PFS (76% vs 54%, p=0.015), and similar rates of severe aGVHD (15% vs 18%, p=0.5), 2y NRM (12% vs 16%, p=0.5), and 2y OS (82% vs 78%, p=0.6). Conclusions: With extended follow-up of a large international cohort, our results argue that alloSCT performed after PD-(L)1 mAbs is a feasible strategy associated with an excellent PFS and a very low CIR for this disease. The use of PT-Cy appears to be associated with improved outcomes and may at present represent the optimal transplant strategy in this pt population. Figure Disclosures Corradini: kite: Honoraria; Abbvie: Honoraria; Servier: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Roche: Honoraria; Novartis: Honoraria; KiowaKirin: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Daiichi Sankyo: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Ho:Jazz Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Consultancy; Omeros Corporation: Membership on an entity's Board of Directors or advisory committees. Jaglowski:Kite: Consultancy, Other: advisory board, Research Funding; Novartis: Consultancy, Other: advisory board, Research Funding; Juno: Consultancy, Other: advisory board; Unum Therapeutics Inc.: Research Funding. Herrera:Adaptive Biotechnologies: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; AstraZeneca: Research Funding; Merck: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; Pharmacyclics: Research Funding; Immune Design: Research Funding; Kite Pharma: Consultancy, Research Funding. Blaise:Jazz Pharmaceuticals: Honoraria; Sanofi: Honoraria; Pierre Fabre medicaments: Honoraria; Molmed: Consultancy, Honoraria. Hamadani:Pharmacyclics: Consultancy; Sanofi Genzyme: Research Funding, Speakers Bureau; Merck: Research Funding; Otsuka: Research Funding; Janssen: Consultancy; Medimmune: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Takeda: Research Funding; Celgene: Consultancy. Ansell:LAM Therapeutics: Research Funding; Affimed: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Affimed: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Affimed: Research Funding. Nieto:Astra-Zeneca: Research Funding; Affimed: Consultancy; Affimed: Research Funding; Novartis: Research Funding. Feldman:Celgene: Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; Pfizer: Research Funding; AbbVie: Honoraria, Other: Travel expenses, Speakers Bureau; Portola Pharma: Research Funding; Kite Pharma: Honoraria, Other: Travel expenses, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Pharmacyclics: Honoraria, Other: Travel expenses, Speakers Bureau; Kyowa Hakko Kirin: Research Funding; Eisai: Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Cell Medica: Research Funding; Roche: Research Funding; Corvus: Research Funding; Viracta: Research Funding; Trillium: Research Funding; Roche: Research Funding; Takeda: Honoraria, Speakers Bureau. McGuirk:ArticulateScience LLC: Other: Assistance with manuscript preparation; Bellicum Pharmaceuticals: Research Funding; Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gamida Cell: Research Funding; Pluristem Ltd: Research Funding; Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding; Novartis: Research Funding; Fresenius Biotech: Research Funding. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding. Stamatoulas Bastard:Celgene: Honoraria; Takeda: Consultancy. Houot:Bristol Myers Squibb: Honoraria; Merck Sharp Dohme: Honoraria. Manson:Bristol Myers Squibb: Honoraria. Orvain:Incyte: Honoraria; Novartis: Honoraria; Jazz Pharmaceuticals: Other: Travel & accommodations; Pfizer: Other: Travel & accommodations. Bouabdallah:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Frigault:Novartis: Consultancy; Kite/Gilead: Honoraria; Nkarta: Consultancy; Incyte: Consultancy; Juno/Celgene: Consultancy; Foundation Medicine: Consultancy; Xenetic: Consultancy. Chen:Takeda: Consultancy; Kiadis: Consultancy; Magenta: Consultancy; Abbvie: Consultancy; Incyte: Consultancy. Lynch:T.G. Therapeutics: Research Funding; Rhizen Pharmaceuticals S.A: Research Funding; Takeda Pharmaceuticals: Research Funding; Juno Therapeutics: Research Funding; Incyte Corporation: Research Funding; Johnson Graffe Keay Moniz & Wick LLP: Consultancy. Smith:AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck Sharp & Dohme Corp: Consultancy, Research Funding; Acerta Pharma BV: Research Funding; Portola Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Bristol-Myers Squibb (spouse): Research Funding; Denovo Biopharma: Research Funding; Genentech: Research Funding; Ignyta (spouse): Research Funding; Incyte Corporation: Research Funding; Ayala (spouse): Research Funding; Seattle Genetics: Research Funding. Byrne:Karyopharm: Research Funding. Cohen:Hutchison: Research Funding; Astra Zeneca: Research Funding; Janssen Pharmaceuticals: Consultancy; Seattle Genetics, Inc.: Consultancy, Research Funding; Bristol-Meyers Squibb Company: Research Funding; Takeda Pharmaceuticals North America, Inc.: Research Funding; Gilead/Kite: Consultancy; Genentech, Inc.: Consultancy, Research Funding; UNUM: Research Funding; ASH: Research Funding; LAM Therapeutics: Research Funding; Lymphoma Research Foundation: Research Funding. Svoboda:AstraZeneca: Consultancy; Celgene: Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Research Funding; Kyowa: Consultancy; Merck: Research Funding; BMS: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding. Santoro:Bayer: Consultancy, Speakers Bureau; MSD: Speakers Bureau; Arqule: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Servier: Consultancy, Speakers Bureau; Takeda: Speakers Bureau; BMS: Speakers Bureau; Roche: Speakers Bureau; Abb-Vie: Speakers Bureau; Amgen: Speakers Bureau; Celgene: Speakers Bureau; Novartis: Speakers Bureau; BMS: Consultancy; Lilly: Speakers Bureau; Sandoz: Speakers Bureau; Eisai: Consultancy, Speakers Bureau. Armand:Sigma Tau: Research Funding; Otsuka: Research Funding; Pfizer: Consultancy; ADC Therapeutics: Consultancy; Tensha: Research Funding; Affimed: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Adaptive: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Infinity: Consultancy; Genentech: Research Funding. Zinzani:Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Honoraria, Speakers Bureau. Carlo-Stella:Servier: Consultancy, Honoraria, Other: Travel, accommodations; Genenta Science srl: Consultancy; Boehringer Ingelheim: Consultancy; F. Hoffmann-La Roche Ltd: Honoraria, Other: Travel, accommodations, Research Funding; Novartis: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Other: Travel, accommodations, Research Funding; Sanofi: Consultancy, Research Funding; Rhizen Pharmaceuticals: Research Funding; Celgene: Research Funding; Amgen: Honoraria; AstraZeneca: Honoraria; Janssen Oncology: Honoraria; MSD: Honoraria; BMS: Honoraria; Janssen: Other: Travel, accommodations; Takeda: Other: Travel, accommodations.

In Multiple myeloma (MM) no treatment has a curative potential and even complete response to novel agents such as proteasome inhibitors (PIs) and immunomodulatory agents (IMiDs) are followed by relapse over time. Next generation sequencing (NGS) has showed how MM at diagnosis is defined by several somatic mutations, but only few drivers, even fewer "druggable" mutations, and many found at a subclonal level. At relapse, targeted studies have shown occasional mutations in drug target genes but the genomic and transcriptomic determinants of chemoresistance in MM remains elusive. We selected 42 MM patients refractory to both lenalidomide and PIs. Whole exome sequencing was performed in 40 of them, and RNAseq in 27. Clinical annotation was available for all patients. Standard analysis pipelines where applied to analyze mutations, copy number alterations (CNAs), mutational signatures, gene expression and expressed mutations. Patients received a median of 3 lines of treatment, with median overall survival of 14.6 months from sampling. We found a median of 77.5 mutations per patient, which is more than what reported at diagnosis (Bolli et al, Nature Communications 2014;5:2997). 100% of samples showed evidence of subclonality, and 37% of them exhibited a higher number of subclonal than clonal variants. Therefore, even at this advanced stage the MM genome is evolving and is composed of different subclones that may display different chemosensitivity. The mutational landscape was also different. TP53 mutations were the second most common after KRAS (20% and 17.5%, respectively). Interestingly TP53 mutations all clustered in patients receiving bortezomib as the last line of treatment. Only 2 patients showed a CRBN mutation, both subclonal. Combining mutations and CNA analysis, the TP53 pathway was the most frequently inactivated (45% of patients). Altogether, mutations or deletions of genes in the CRBN E3 ubiquitin ligase complex were found in 32.5% of patients, while proteasomal subunit genes were infrequently hit. Refractory cases were also uniquely characterized by a novel signature linked to exposure to alkylating agents, whose activity was more pronounced after high-dose melphalan suggesting a mutagenic effect of the drug on residual cells at the time of transplant. Whether this has any pathogenetic role on the disease course remains to be elucidated. RNAseq analysis did not show any influence of treatment or mutational data on the clustering of samples, which was mainly influenced by karyotypic events. The main cluster was composed by non-hyperdiploid patients with both amp(1q) and del(13): these showed CCND2 and MCL1 upregulation, the latter representing a marker of venetoclax resistance and novel target of experimental treatments. Only 26.3% of mutations were expressed, and this correlated with the clonality level of the mutation. However, most mutations in driver genes were expressed, with the notable exception of those causing nonsense mediated decay. Overall, classical high-risk features or CRBN pathway mutations were found in 65% of the cohort. However, only amp(1q) predicted survival in our cohort. The lack of prognostic value of high-risk lesions is likely explained by a higher prevalence of such features in double-refractory stages. Our data suggest that gene mutation is not a preferred mode of evolution of drug resistance in MM. Chemoresistance of the bulk tumor population is likely attained though differential, yet converging evolution of different subclones that are overall highly variable from patient to patient and within the same patient. Disclosures Kastritis: Prothena: Honoraria; Genesis: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria. Dimopoulos:Sanofi Oncology: Research Funding. Cavo:bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; novartis: Honoraria; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Corradini:Janssen: Honoraria, Other: Travel Costs; Takeda: Honoraria, Other: Travel Costs; Jazz Pharmaceutics: Honoraria; Gilead: Honoraria, Other: Travel Costs; Daiichi Sankyo: Honoraria; Celgene: Honoraria, Other: Travel Costs; Amgen: Honoraria; AbbVie: Consultancy, Honoraria, Other: Travel Costs; KiowaKirin: Honoraria; Kite: Honoraria; BMS: Other: Travel Costs; Sanofi: Honoraria; Servier: Honoraria; Roche: Honoraria; Novartis: Honoraria, Other: Travel Costs. Bolli:Celgene: Honoraria; Novartis: Honoraria; Gilead: Other: travel expenses.

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 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.

Allogeneic Hematopoietic Cell Transplantation (allo-HCT) currently represents the only potentially curative therapy for patients affected by advanced Mantle Cell Lymphoma (MCL). Haploidentical HCT (haplo-HCT) allows virtually all patients to proceed to allo-HCT. We analyzed survival outcomes of 20 MCL patients who received haplo-HCT at Humanitas Cancer Center and Institut Paoli Calmettes between 2012 and 2017. Median age of patients at transplant was 64 years (range, 35-71). Ten of them (50%) relapsed after autologous transplantation, one patient relapsed after allo-HCT (HLA identical sibling), while 9 underwent directly haplo-HCT due to the high risk of relapse (primary refractory disease). All patients except one had chemosensitive disease at transplant (75% complete response, 20% partial response, 5% progressive disease). In 10 patients, novel drugs were used as bridge to transplant to obtain response (8 patients were treated with ibrutinib, one with lenalidomide and one with bortezomib). The hematopoietic-cell-transplantation comorbidity index (HCT-CI) was 0-1 in 4 patients, 2-3 in 12 patients and 4-5 in 4 of them. In 5 patients bone marrow was used as the source of stem cells, while the other 15 received peripheral blood stem cells. Sixteen patients received a nonmyeloablative conditioning regimen while 4 patients underwent a reduced intensity conditioning regimen. In all patients, post-transplant cyclophosphamide (PT-Cy) was used as graft-versus-host-disease (GVHD) prophylaxis. Acute GVHD (aGVHD) was observed in 9 patients (grade I 2 patients, grade II 6 patients, grade III-IV 1 patient) at a median of 34 days from transplant (range, 21-80). The cumulative incidence of aGVHD grade 2-4 was 30% (95% CI, 12% to 51%) at 6 months. Three patients developed chronic GVHD (cGVHD) (1 mild, 1 moderate and 1 severe). The cumulative incidence at 2 years of moderate-severe cGVHD was 11% (95% CI, 2% to 30%). With a median follow-up of 22 months (range 5-73 months), relapse or progression were observed in 2 patients at a median of 6 months (range, 3-8 months) from haplo-HCT with a cumulative incidence of disease relapse/progression of 11% (95% CI, 2% to 29%) at 3 years. The GVHD-free/relapse-free survival (GRFS) at 1 year was 68% (95% CI, 42% to 84%). Three deaths were attributed to toxicity and occurred at a median of 123 days (range, 17-274 days) after transplant. The specific causes of death were: aGVHD, 1; infection, 1; cGVHD 1. The cumulative incidence of NRM was 16% (95% CI, 4% to 36%) at 3 years. The 3-years progression-free survival (PFS) and overall survival (OS) were 73% (95% CI, 47% to 88%) and 71% (95% CI, 43% to 77%), respectively. Comparing this cohort with a similar cohort of 20 MCL patients who underwent allo-HCT from HLA identical sibling or unrelated donors in the same centers during the same time frame, the clinical outcomes (GRFS, NRM, PFS and OS) were not statistically different, even if there was a trend for better outcomes using haploidentical donor. In conclusion, our study suggests that haplo-HCT with PT-Cy in MCL patients is feasible and is associated with a low relapse rate and NRM, even in the era of new drugs. Figure. Figure. Disclosures Carlo-Stella: Bristol-Myers Squibb: Speakers Bureau; Sanofi: Consultancy; Genenta Science: Speakers Bureau; MSD Italia: Speakers Bureau; Janssen: Speakers Bureau; ADC Therapeutics: Research Funding, Speakers Bureau; AstraZeneca: Speakers Bureau; Amgen: Speakers Bureau; Boehringher Ingelheim Italia: Consultancy; Rhizen Pharmaceuticals: Research Funding.

Introduction: Phase 1/2 trials using the programmed cell death-1 (PD-1) checkpoint inhibitors Nivolumab and Pembrolizumab in relapsed/refractory classic Hodgkin lymphoma (R/R cHL) who had failed autologous-SCT (Auto-SCT) showed high response rates and durable responses in the majority of patients. However, with extended follow-up, progression-free survival (PFS) curves from the CheckMate 205 trial failed to show a plateau, thus suggesting the need for a consolidation therapy in cHL responding to anti-PD-1. Reported here is the retrospective analysis of the outcome of 34 cHL patients who received an Allo-SCT after treatment with PD-1 inhibitors. Patients and Methods: From Nov 2014 to Apr 2017, 44 R/R cHL enrolled in the CA209-205, CA209-254 and MK3475087trials(median age, 31 years; range, 18-81) received nivolumab (n=42) or pembrolizumab (n=2) until complete remission (CR), very good partial remission (PR) defined as a tumor burden reduction >80%, or progressive disease (PD).At study entry, 30 patients (84%) had refractory disease, 39 (89%) had failed BV and 38 (86%) Auto-SCT. Tumor assessment was performed according to Cheson et al (JCO, 2014). Non-relapse mortality (NRM) was defined as death by any reason other than disease progression. Cumulative incidence of relapse, NRM, and graft-versus-host disease (GVHD) was assessed using the Kaplan-Meier method. Results: After a median duration of anti-PD-1 therapy of 10 months (range, 3-33), 18 patients (41%) experienced CR or PR whereas 26 (59%) progressed. Sixteen of 18 responding patients were allografted. Eighteen of 26 patients who progressed during anti-PD-1 therapy received additional chemotherapy and were finally allografted. Overall, 34 of 44 patients were allografted. Allografting was not performed due to age (n=1), PD (n=4), patient refusal (n=5). The median time from last nivolumab to Allo-SCT was 49 days (range, 23 - 372). At Allo-SCT, 22 patients (65%) were in CR, 11 (32%) in PR and 1 (3%) in PD. Donors were haploidentical sibling (n=23), matched sibling (n=5), or matched unrelated (n=6). Stem cell source was bone marrow (n=15) and peripheral blood (n=19).Acute graft-versus-host disease (aGVHD) was recorded in 15 patients.The cumulative incidence (CI) of grade 2-4 and grade 3-4 aGVHD at 100 days was 46% and 12%, respectively; the 2-year CI of cGVHD was 27%. Non-infectious complications including febrile syndrome, macrophage activation syndrome and cytokine release syndrome, as well as infectious complications occurring until day +100 post-allografting are detailed in a companion abstract.With a median follow-up of 18 months (range, 1.8-39.3), one patient died due to relapse and 5 to non-relapse mortality (NRM) [(acute Graft-versus-Host Disease (aGVHD) (n=1), CMV pneumonia (n=1), immune-mediated pneumonia (n=1) heart failure (n=1), post-transplant lymphoproliferative disorder (PTLD) (n=1)]. The 2-year cumulative incidence (CI) of relapse and NRM was 3.1% and 19.7%, respectively. The 2-year OS and PFS were 76% and 76%, respectively. Conclusions: With an extended follow-up, data reported herein clearly show that Allo-SCT performed after PD-1 inhibitors or the sequence PD-1 inhibitors/chemotherapy is a feasible consolidation strategy associated with an unprecedented low relapse incidence. Early transplant-related complications prompt at identification and implementation of risk-minimizing strategies. PD-1 inhibitors eventually combined with salvage chemotherapy and Allo-SCT represent a paradigm shift in the treatment of refractory cHL. Disclosures Carlo-Stella: Boehringher Ingelheim Italia: Consultancy; Sanofi: Consultancy; MSD Italia: Speakers Bureau; Amgen: Speakers Bureau; Janssen: Speakers Bureau; ADC Therapeutics: Research Funding, Speakers Bureau; AstraZeneca: Speakers Bureau; Genenta Science: Speakers Bureau; Rhizen Pharmaceuticals: Research Funding; Bristol-Myers Squibb: Speakers Bureau.

Introduction : Cell source and graft composition are known to have a prognostic role in allogeneic hematopoietic cell transplant (HCT). Currently, there are no data in the setting of haploidentical-HCT with post-transplant cyclophosphamide (PT-Cy). Patients and methods : One-hundred patients undergoing haplo-HCT with PT-Cy from Sept 2011 to Nov 2015 were included in this multicenter retrospective analysis. Bone marrow (BM) was used as graft source in 25 patients and peripheral blood stem cell (PBSC) in 75. The two groups (BM vs PBSC) were similar in terms of age, Disease Risk Index (DRI) and HCT-CI. The only differences were on disease type (lymphoid malignancies 76% vs 57%, p=0.02) and conditioning regimen (myeloablative: 100% versus 30%, p Graft cellular subsets analysis was performed by means of flow cytometry (CD34, CD3, CD4, CD8, CD56, CD19, CD38, CD31, CD25, CD45RA, CD95, CD127, CCR4, CCR6, CCR7). Overall Survival (OS) and Progression Free Survival (PFS) were performed with Kaplan-Meier analysis. Acute GVHD, chronic GVHD, Non-Relapse Mortality (NRM) and Relapse Incidence/Progression of disease (RI/POD) were obtained with competing risk analysis. Results : For the whole cohort, neutrophil and platelet engraftment cumulative incidences at day +30 were 97% (95% CI: 91-99) and 64% (95% CI: 53-73), with no differences between BM or PBSC. Grade II-IV and grade III-IV aGVHD cumulative incidences at day +100 were 36% (95% CI: 26-48) and 10% (95%CI: 5-18), respectively. Acute GVHD cumulative incidence was significantly lower for BM grafts [16% (95% CI: 5-33) vs 43% (95% CI: 31-54), p=0.02], but no differences were observed regarding grade III-IV acute GVHD [8% (CI 95%: 1-24) vs 11% (CI 95%: 5-20), p=0.73]. Chronic GVHD cumulative incidence at 18 months was 23% (95%CI: 15-32) with no difference between BM or PBSC. With a median follow up of 16.5 months (range 0.8 - 40.6), the 18-months PFS and OS were 43% (95%CI: 32-54) and 63% (95% CI: 52-73), respectively. NRM and RI/POD at 18 months were 18% (95%CI: 11-26) and 38% (95%CI: 27-49). Multivariable analysis was performed using patient (age, gender, HCT-CI, DRI) and transplant characteristics (donor gender, donor-recipient relation, graft source). A DRI>1 was the only factor associated with higher RI/POD (HR 3.45, 95% CI: 1.4-8.2, p Graft cell composition analysis was performed separately for BM and PBSC cohorts. For the BM group, univariable analysis showed that CD4 graft count ≥20x10^6/kg was associated with a prolonged PFS [60% (95%CI: 28-81) vs 0%, p Conclusions : In our retrospective analysis, we did not observe significant differences in survival outcomes based on graft source. Patients receiving BM grafts developed fewer grade II-IV aGVHD, but grade III-IV aGVHD incidence was similar between the two groups. For the BM group, a higher CD4 count was predictive of better PFS, TRM and OS, as reported with standard GVHD prophylaxis and matched donors (Waller EK, J Clin Oncol 2014. 32: 2365-2372). Interestingly, of the CD4 population, only naive T cells and RTEs were associated with an improved PFS and OS. A protective effect of CD8 cell count was observed in the PBSC group. This is similar to the non PT-Cy setting where higher CD8 cells are associated with better survival outcomes (Reshef R, J Clin Oncol 2015). These data should be validated in a prospective analysis to guide the choice of cell source in the haplo PT-Cy setting. Figure 1 Kaplan-Meier estimates of progression free survival from time of transplant associated to the CD4 graft content. Figure 1. Kaplan-Meier estimates of progression free survival from time of transplant associated to the CD4 graft content. Disclosures Corradini: Celgene: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Roche: Honoraria; Takeda: Honoraria; Sanofi: Honoraria; Servier: Honoraria; Gilead: Honoraria; Takeda: Consultancy.

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