Graft-versus-lymphoma Research Articles

Impact of GVHD on lymphoma progression: Nationwide study from Japanese Society for Transplantation and Cellular Therapy.

The graft-versus-lymphoma (GVL) effect and its association with acute and chronic GVHD (aGVHD, cGVHD) has not been comprehensively elucidated. We retrospectively analysed 2204 Japanese patients with non-Hodgkin lymphomas (NHLs; indolent B-NHLs, n = 689; aggressive B-NHLs, n = 720; mature T/NK-NHLs, n = 795) receiving a first allo-HSCT in 2003-2017. Pre-transplant lymphoma control showed complete response (CR) in 759 and non-CR in 1445. We assessed the impact of aGVHD/cGVHD on lymphoma progression and other outcomes. Although aGVHD/cGVHD showed no statistical impact on lymphoma progression in the overall cohort, their impact was clear in certain groups: Grade I-II aGVHD in CR patients (HR, 0.63; 95% CI, 0.43-0.91), especially in mature T/NK-NHL (HR, 0.46; 95% CI, 0.26-0.83) and extensive cGVHD in patients with mature aggressive B-NHLs (HR, 0.55; 95% CI, 0.31-0.97). In total, limited cGVHD was associated with superior survivals (progression-free survival: HR, 0.71; 95% CI, 0.56-0.90), whereas severe GVHDs showed negative impacts on them. Our results support the presence of GVL effects differentially associated with GVHD in different lymphoma subtypes/controls. Meanwhile, it was also suggested that we should manage GVHDs within a limited activity, considering the negative impact of severe GVHDs. As pre-transplant lymphoma control remains a strong factor influencing transplant outcomes, improving its management is an important issue to be addressed.

HUC-EVs-ATO reduce the severity of acute GVHD by resetting inflammatory macrophages toward the M2 phenotype

BackgroundBoth extracellular vesicles from mesenchymal stromal cell-derived human umbilical cords (hUC-EVs) and arsenic trioxides (ATOs) have been demonstrated to treat acute graft-versus-host disease (aGVHD) via immunomodulation. Apart from immunomodulation, hUC-EVs have a unique function of drug delivery, which has been proposed to enhance their efficacy. In this study, we first prepared ATO-loaded hUC-EVs (hUC-EVs-ATO) to investigate the therapeutic effect and potential mechanisms of hUC-EVs-ATO in a mouse model of aGVHD after allogeneic hematopoietic stem cell transplantation (HSCT).MethodsAn aGVHD model was established to observe the therapeutic effects of hUC-EVs-ATO on aGVHD. Target organs were harvested for histopathological analysis on day 14 after transplantation. The effects of hUC-EVs-ATO on alloreactive CD4+ were evaluated by flow cytometry in vivo and in vitro. Flow cytometry, RT-PCR, immunofluorescence colocalization analysis and Western blot (Wb) analysis were performed to examine macrophage polarization after hUC-EV-ATO treatment. The cytokines in serum were measured by a cytometric bead array (CBA). TEM, confocal microscopy and Wb were performed to observe the level of autophagy in macrophages. A graft-versus-lymphoma (GVL) mouse model was established to observe the role of hUC-EVs-ATO in the GVL effect.ResultsThe clinical manifestations and histological scores of aGVHD in the hUC-EVs-ATO group were significantly reduced compared with those in the ATO and hUC-EVs groups. The mice receiving hUC-EVs-ATO lived longer than the control mice. Notably, hUC-EVs-ATO interfering with alloreactive CD4+ T cells differentiation were observed in aGVHD mice but not in an in vitro culture system. Additional studies showed that depletion of macrophages blocked the therapeutic effects of hUC-EVs-ATO on aGVHD. Mechanistically, hUC-EVs-ATO induced autophagic flux by inhibiting mammalian target of rapamycin (mTOR) activity to repolarize M1 to M2 macrophages. Additionally, using a murine model of GVL effects, hUC-EVs-ATO were found not only to reduce the severity of aGVHD but also to preserve the GVL effects. Taken together, hUC-EVs-ATO may be promising candidates for aGVHD treatment.ConclusionshUC-EVs-ATO enhanced the alleviation of aGVHD severity in mice compared with ATO and hUC-EVs without weakening GVL activity. hUC-EVs-ATO promoted M1 to M2 polarization via the mTOR-autophagy pathway. hUC-EVs-ATO could be a potential therapeutic approach in aGVHD after allo-HSCT.

Inhibition of IL-1 Receptor-Associated Kinase 1 Decreases Murine Acute Graft-versus-Host Disease While Preserving the Graft-versus-Lymphoma Effect

Activation of antigen-presenting cells (APCs) is crucial in initiating inflammation and alloreaction during acute graft-versus-host disease (aGVHD), a common life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT). IL-1 receptor-associated kinase 1 (IRAK1) regulates the activation of APCs in inflammatory settings, and inhibition of IRAK1 might decrease APC activation and aGVHD. This study was conducted to explore the impact of IRAK1 inhibition on APC activation and aGVHD in mice. We administered a selective IRAK1 inhibitor, Jh-X-119-01, to recipient mice undergoing allo-HCT or co-challenged by A20 lymphoma cells. We assessed aGVHD and the graft-versus-lymphoma (GVL) effect. T cell and APC activations were analyzed as well. Jh-X-119-01 was associated with increased survival and decreased aGVHD of recipients. Jh-X-119-01 decreased the proportions of Th1 cells and Tc1 cells in the aGVHD model and in the in vitro mixed lymphocyte reaction. The IRAK1 inhibitor reduced production of TNFα and IFNγ in macrophages of recipient mice. In in vitro cultured bone marrow dendritic cells (BMDCs), Jh-X-119-01 decreased productions of inflammatory cytokines, reduced expression levels of CD80 and CD86, and decreased protein levels of antiapoptotic Bcl2 and phosphorylated NF-κB p65. RNA-seq analysis showed that Jh-X-119-01 had an impact on several pathophysiologic processes of BMDCs, including reduction of GVHD-related genes and regulation of helper T cell differentiation. Importantly, IRAK1 inhibition did not impair cytotoxic function of T cells or the allo-HCT-related GVL effect against A20 lymphoma cells. In addition, the IRAK1 inhibitor did not retard recovery of hematopoietic cells in blood or bone marrow. Our findings show that selective IRAK1 inhibition ameliorates murine aGVHD but preserves the GVL effect. Our findings may have implications for the use of an IRAK1 inhibitor in allo-HCT.

Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation in Secondary Central Nervous System Lymphoma

Introduction:Aggressive non-Hodgkin's lymphoma (aNHL) with secondary central nervous system (sCNS) involvement has a poor prognosis. Studies have reported a response to induction treatment as low as 35%, leaving less than half of patients eligible for autologous stem cell transplant (ASCT). Outcomes of patients in these clinical scenarios are dismal and treatment is ill-defined. Small case series suggest chimeric antigen receptor (CAR)-T cell therapy may play a role in the management of relapsed/refractory (R/R) B-cell lymphoma (BCL) with sCNS involvement, but follow-up is limited and response duration is uncertain. Allogeneic hematopoietic stem cell transplant (alloHCT) offers a durable remission for a subset of patients with R/R systemic aNHL primarily mediated through a graft versus lymphoma (GVL) effect, but it is unclear if GVL properties include the immune-privileged CNS. The present study aims to describe outcomes of a cohort of patients with R/R aggressive B- and T-cell NHL with sCNS involvement who underwent alloHCT at a single academic institution.Methods:This is a retrospective analysis that includes all patients with R/R aNHL with sCNS involvement who underwent alloHCT at the University of California, Los Angeles from 2005-2020. The UCLA Institutional Board Review approved this study. Relevant clinical data was extracted from medical records. Hematopoietic cell transplantation comorbidity index (HCT-CI) and time to neutrophil and platelet engraftment were measured according to Center for International Blood and Marrow Transplant Research criteria.Results:Ten patients were included (3 females, 7 males). Histologic subtypes included anaplastic BCL (1), mantle cell lymphoma (1), blastic natural killer-cell lymphoma (1), peripheral T-cell lymphoma, not otherwise specified (1), primary mediastinal BCL (1), and diffuse large B-cell lymphoma (DLBCL) (non-germinal center=3, germinal center-like=2). Two DLBCL patients had histologic transformed lymphoma (follicular lymphoma =1, chronic lymphocytic lymphoma = 1). Four patients had sCNS involvement at the time of initial diagnosis or during frontline treatment; the remaining 6 patients developed sCNS lymphoma at relapse. sCNS lymphoma was identified in the parenchymal (n=4), leptomeningeal (n=3), or both (n=3) compartments.The median age at the time of alloHCT was 49.5 (range 28-68), and 1 patient was ˃ 60. At the time of alloHCT, 1 patient had residual disease in the CNS and the remaining 9 patients were in a complete remission. Eight patients received ˃ 3 prior lines of therapy, and 3 patients failed prior ASCT. HCT-CI scores were 0 (n=1), 1 (n=2), 2 (n=3), 3 (n=1), and unknown (n = 3). Donor types included 10/10 matched related (3), 10/10 matched unrelated (4), 9/10 mismatched related (1), and double umbilical cord blood (2). Graft source was peripheral blood in 8 patients and cord blood in 2 patients. Conditioning regimens included myeloablative, reduced intensity and non-myeloablative in 6, 3 and 1 patient(s), respectively. Six patients received total body irradiation-containing conditioning. The average time to neutrophil engraftment was 18 days (range 11-29), and the average time to platelet engraftment was 26.5 days (range 18-59). One patient had primary graft failure.Of the 6 patients with day 100 disease reassessment (CR at time of alloHCT=5, PR in CNS at time of alloHCT=1), all were in CR. With a median follow-up of 341 days, 2 patients relapsed (CNS=1 and systemic = 1), and 6 patients died. Cause of death included infection (n=3), lymphoma (n=1), primary graft failure (n=1), and organizing pneumonia (n=1). Six patients developed acute graft versus host disease (GVHD) (grade 1-2, n=1; grade 3, n=5), and 4 patients developed chronic GVHD (score 1-2, n= 2; score 3, n=2). The median overall and progression-free survival for the entire cohort was 341 days (range 23-4825) and 268.5 days (range 23-4825), respectively.Conclusions:AlloHCT in patients with R/R aNHL with sCNS involvement is feasible and may provide a durable response in a subset of patients. Four patients remained alive and free of disease one year post-alloHCT and one patient converted from a PR to a CR in the CNS 100 days post-alloHCT, suggesting effective donor immune surveillance within the CNS. Transplant-related morbidity and mortality limits the widespread application of this therapeutic modality and less toxic approaches are urgently needed. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Reduced Intensity Conditioning for Allogeneic Transplantation: Modified Fludarabine Dose Plus Cyclophosphamide/Total Body Irradiation Yields Promising Outcomes

Reduced intensity conditioning (RIC) extends the curative potential of allogeneic hematopoietic cell transplantation (HCT) to patients with hematologic malignancies unsuitable for myeloablative conditioning. We prospectively studied a RIC HCT approach for patients with hematologic malignancies and sibling or unrelated donors (URD) from 2001-2016. Patients received cyclophosphamide (Cy) 50mg/kg/day IV day -6, fludarabine (Flu) 40mg/m2/d IV days -6 to -2 and TBI 200cGy on day -1 +/- anti-thymocyte globulin (ATG) on days -6 to -4 for those without prior autografting or recent multidrug chemotherapy. After identifying potential increased non-relapse mortality from excess fludarabine metabolite (F-ara-A) exposure we reduced the fludarabine dosing to 30 mg/m2/d IV days -6 to -2 in late 2009.The 292 patients (median age 58: range 19-75); median follow-up 8 years (IQR range 4-12) included 127 with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS), 40 aggressive non-Hodgkin lymphoma (NHL), 11 indolent NHL, 21 Hodgkin Lymphoma (HL), 26 multiple myeloma, 14 chronic myeloid leukemia (CML), 23 chronic lymphocytic leukemia (CLL), 17 acute lymphocytic leukemia (ALL), 13 myeloproliferative neoplasms (MPN). Five year overall survival (OS) was 73% (95% CL, 37-90%) for patients with indolent NHL, 53% (95% CL, 36-67%) for aggressive NHL, 55% (95% CL, 31-74%) for HL, 39% (95% CL, 30-48%) for AML/MDS, 32% (95% CL, 15-50%) for myeloma, 50% (95% CL, 23-72%) for CML, 45% (95% CL, 24-46%) for CLL, 15% (95% CL, 2-39%) for MPN and 34% (95% CL, 12-59%) for those with ALL. By donor source, 5 year OS was 46% (95% CL, 40-53%), 25% (95% CL, 6-50%), 38% (95% CL, 22-54%), and 11% (95% CL, 1-35%) using matched sibling donors (n=225), mismatched (MM) sibling PBSC (n=12), matched marrow unrelated donor (URD) (n=37), and matched peripheral blood URD (n=18) (p<0.01) (Figure 1). Fludarabine dosing (30 vs. 40 mg/m2/day x 5) had no significant influence on OS (45 vs. 40%, p=0.42) or 2 year NRM (25% vs. 26%, p=0.86). NRM (overall 26%; 95% CI 21-31%) was significantly worse with MM sibling or URD (either BM or PBSC) compared to matched sibling BM/PBSC. Relapse at 5 years was significantly worse in patients with myeloma (76%) and Hodgkins (53%), intermediate in AML/MDS (37%), but lowest in aggressive (25%) and particularly indolent NHL (0%).These results suggest that: 1) this Cy/Flu/TBI RIC conditioning was well tolerated by an older population; 2) indolent and aggressive NHLs responded best to RIC conditioning highlighting the importance of the graft versus lymphoma (GVL) effect; and 3) reduction in fludarabine dosing did not compromise disease control or survival but did not appear to diminish NRM. Diagnosis, donor source, and HCT-CI remain the dominant factors influencing outcomes. Targeted disease treatments or maintenance therapy to limit relapse might be the best approach to improve overall survival. [Display omitted] DisclosuresBrunstein:Novartis: Research Funding; Magenta Therapeutics: Research Funding. MacMillan:Magenta Therapeutics: Research Funding.

Long-Term Follow up of 90y-Ibritumomab Tiuxetan, Fluadarabine and TBI Based Non-Myeloablative Allogeneic Transplant Conditioning for Persistent High-Risk B-Cell Lymphoma

Purpose:Non-myeloablative allogeneic hematopoietic cell transplantation (NMA-HCT) can provide prolonged remissions in patients with advanced B-cell lymphoma (B-NHL) via the graft versus lymphoma (GVL) effect, though inferior results are seen in patients with chemoresistant, bulky, or aggressive disease. Radioimmunotherapy (RIT) can safely induce responses in B-NHL with little non-hematologic toxicity. Initial results of this approach demonstrated early safety and disease control (Blood, 2011) but with short follow up. Here we report the long-term outcomes of patients treated on this study with specific emphasis on patients achieving early remissions.Patients and Methods:Eligible patients with persistent CD20+ B-NHL or CLL, with HLA-matched related or unrelated donors, and adequate organ function, underwent NMA-HCT. Patients were not excluded based on cytopenia or marrow involvement with lymphoma. Conditioning included 0.4 mCi/kg (max 32mCi) 90Y-ibritumomab tiuxetan (day-14), fludarabine (days -7 to -5) and 2 Gy total body irradiation (day 0) followed by transplantation from HLA-matched related or unrelated donors along with post-grafting immunosuppression with cyclosporine and mycophenolate mofetil. Long-term follow up was updated through July 1, 2017.Results:We accrued 40 patients to this prospective trial. Baseline features included: median age 58 years (range 29-69), median prior regimens = 6 (range 3 to 12), chemosensitive disease = 6 (15%), CR pretransplant = 0 (0%), bulk >5 cm = 17 cm (range 5.2-18.6cm, 43%), >25% bone marrow involvement with B-NHL = 10 (25%, range of marrow involvement 40-95%), comorbidity score ≥1 = 35 (85%), median comorbiditiy score 3 (range 0-10), pretransplant IPI ≥3 = 21 (53%). Histologies included: indolent (18; CLL/SLL-10, follicular lymphoma-6, hairy cell leukemia-1, and marginal zone lymphoma-1), Diffuse large B-cell (DLBCL, 14), and mantle cell lymphoma (MCL, 8). Patients received HCT from 15 matched related or from 25 matched unrelated donors.Eleven of 40 patients are alive with a median follow up of 9 years (range 5.3-10.2). There were 14 (35%) deaths due to disease progression, and 14 (35%) deaths attributed to complications from HSCT. One patient died of a Merkel cell carcinoma. The median progression-free and overall survival of the entire group was 1.1 years and 2.9 years, respectively (Figure 1). The best outcomes were observed in patients with indolent histology with an estimated 5-year PFS and OS of 44% and 67% respectively (Figure 2). Early CR/PR was achieved by 7/8 (83%) patients with indolent lymphoma, 4/1 (36%) with DLBCL, and 2/2 (50%) with MCL. Long-term PFS was observed in 7 of 15 of patients with indolent NHL and 2 of 4 MCL with early remission. None of the patients with DLBCL were long-term disease free survivors regardless of early remission status. No late complications attributable to RIT (such as secondary myeloid malignancies) were observed in any patient.Conclusions:Long-term disease control of high-risk B-NHL not in CR who underwent NMA-HCT with 90Y-ibritumomab tiuxetan conditioning varied by histology. 90Y-ibritumomab tiuxetan based allografting induced high-early response rates and favorable long-term outcomes in patients with indolent histologies likely based on both the efficacy of RIT and GVL effect in this population. Only early MCL responders to RIT had long term PFS, and none of the DLBCL patients survived regardless of response. Improved strategies are needed for these populations. Our current study escalates the dose of 90Y-ibritumomab tiuxetan prior to NMA-HCT for DLBCL for this purpose. [Display omitted] DisclosuresFlowers:Pharmacyclics: Consultancy. Maloney:Juno Theraapeutics: Other: Advisory board, Patents & Royalties, Research Funding; Roche/Genetech: Other: Advisory board; Celgene: Other: Advisory board; Kite Pharmaceuticals: Other: Advisory board. Press:Roche: Honoraria, Research Funding; BMS: Honoraria; Bayer: Consultancy. Gopal:Seattle Genetics: Consultancy, Research Funding.

Allogeneic Hematopoietic Stem Cell Transplantation in Extranodal Natural Killer/T-cell Lymphoma

Objective:Extranodal NK/T-cell lymphoma (ENKL) is aggressive and resistant to chemotherapy and radiotherapy. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for high-risk lymphomas owing to its associated graft-versus-lymphoma (GVL) effect. However, its application to ENKL is limited. We aim to summarize the characteristics of allo-HSCT for ENKL and, more importantly, evaluate whether allo-HSCT could offer any benefits for ENKL.Materials and Methods:A systematic review and data analysis were performed to evaluate the performance of allo-HSCT in the treatment of ENKL using studies obtained from PubMed, Medline, and Embase from January 2000 to December 2019 in the English language.Results:A total of 136 cases from 17 eligible publications were included in this study. It was found that after allo-HSCT, with an average follow-up time of 34 months (range: 1-121 months), 37.5% (52) of 136 patients had acute graft-versus-host disease (GVHD) and 31.6% (43) had chronic GVHD. Furthermore, 35.3% (48) of the patients were reported to have relapsed, but 2 of those relapsed only locally and achieved complete remission (CR) again with additional irradiation, chemotherapy, and donor lymphocyte infusions for one and rapid tapering and discontinuation of cyclosporine for the other, earning more than one year of extra survival. Finally, of the 136 patients, 51.5% (70) died because of primary disease progression (42.9%), infection (20.0%), GVHD (11.4%), organ failure (7.1%), hemorrhage (4.3%), and other causes (not specified/unknown) (14.3%).Conclusion:Allo-HSCT may be a treatment option for advanced or relapsed/refractory ENKL, but its role still requires more rigorous future studies.

An Australasian Bone Marrow Transplant Registry (ABMTR) Study of the Trends and Outcomes of Allogeneic Haematopoietic Stem Cell Transplantation (HSCT) in Hodgkin Lymphoma between 2009-2019: Relapse Remains the Most Common Cause of Death Post Transplantation

An Australasian Bone Marrow Transplant Registry (ABMTR) Study of the Trends and Outcomes of Allogeneic Haematopoietic Stem Cell Transplantation (HSCT) in Hodgkin Lymphoma between 2009-2019: Relapse remains the most common cause of death post transplantation Introduction: Hodgkin Lymphoma (HL) is an eminently curable disease, with 80% of cases achieving cure with first line therapies. There are a subset of patients who relapse and require salvage therapy including autologous stem cell transplant and more recently novel agents such as brentuximab vedotin (BV) and the PD-1 inhibitors. The latter are less toxic and achieve durable responses but are not considered curative for most (LaCasce et al., 2019). In Australia BV and PD-1 inhibitors were approved in December 2013 and September 2017 respectively. Allogeneic HSCT offers a graft vs lymphoma (GVL) effect that may contribute to long term survival in some patients (Peggs et al., 2005). The introduction of reduced intensity conditioning (RIC) has seen improved outcomes with an OS of 67% (59-74%) and Progression Free Survival (PFS)of 45% (35-56%) (Rashidi et al., 2016) Patients and methods: Data was collected through the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR) for patients receiving a first allogeneic transplant for HL between 2009 and 2019. The Kaplan Meier method was used to calculate OS and PFS with log rank test for comparison. Multivariable Cox proportional hazards models were used to identify associations with OS. We divided the patients into 5 year cohorts to compare transplant outcomes over time. Results: A total of 149 patients from 16 sites in Australia and New Zealand were included. The median age at time of transplant was 31 years (range 19-61) and the majority were male (60%). Seventy-five percent of patients had undergone previous autologous HSCT with data missing for 22%. Median follow up was 75 months (range 4.7-137.1). Forty five percent of patients were in complete remission (CR), 34% in partial remission and 15% relapsed/primary refractory (RR) at the time of HSCT with information missing in 4%. The majority of donors were matched unrelated donors (47%) and sibling donors were used for 37% of patients, haploidentical in 11% and umbilical cord blood in 5%. Reduced intensity conditioning was used in 86% of patients and in vivo T cell depletion with ATG or alemtuzumab was used in 27%. Acute GVHD occurred in 53/149 (30%) of which 31% was grade III-IV. In patients who survived beyond 100 days, the incidence of chronic GVHD was 38%, of which 53% was preceded by some form of aGVHD. Non-relapse mortality (NRM) at 100 days was 8% with 5/12 of these patients dying from aGVHD. Two-year OS and PFS were 75% and 49% respectively. A period effect was not detected with no significant difference in OS (p=0.8) nor PFS (0.2) based on transplant year (figure 1a &amp; 1b). Multivariate analysis of factors associated with OS identified age at transplant of &amp;gt;40 (HR 3.24, 95% CI 1.71-6.15, p&amp;lt;0.001) and RR disease at time of transplant (HR 3.07, 95% CI 1.44-6.54, p=0.004) with a higher risk of death. The numbers of HSCT performed each year are illustrated in figure 1c, with a larger proportion of patients in CR from 2014 onward. Post-transplant relapse occurred in 38% of patients (figure 1d)with a median time to relapse of 8.5 months (range 0.2 -42). Forty-eight percent (27/56) of patients who relapsed post HSCT were in CR at the time of HSCT. Of those who relapsed, 37% died due to progressive disease with no evidence of chronic GVHD. Relapse was the most common cause of death (37%) Conclusion: Although the rates of HSCT for HL in Australia and New Zealand have not varied over the past decade despite the availability of novel agents, there is a larger proportion of patients in CR prior to transplant. Survival outcomes for HL post HSCT are comparable to those reported internationally. Despite a higher percentage of patients transplanted in CR in later years, relapse post HSCT remains the major cause of death. Further studies to examine strategies to prevent or treat relapse of HL post-allograft are needed. Disclosures Sharplin: Novartis: Other: FUnded to attend Australian Haematology Conference . Di Ciaccio:Jansen: Honoraria, Other: travel and accomodation grant. Spencer:AbbVie, Celgene, Haemalogix, Janssen, Sanofi, SecuraBio, Specialised Therapeutics Australia, Servier and Takeda: Consultancy; Amgen, Celgene, Haemalogix, Janssen, Servier and Takeda: Research Funding; AbbVie, Amgen, Celgene, Haemalogix, Janssen, Sanofi, SecuraBio, Specialised Therapeutics Australia, Servier and Takeda: Honoraria; Celgene, Janssen and Takeda: Speakers Bureau. Greenwood:Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: 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. Hamad:Abbvie: Honoraria; Novartis: Honoraria.

PD-1 antibody and ruxolitinib enhances graft-versus-lymphoma effect without increasing acute graft-versus-host disease in mice.

Boosting T cell immune response posttransplant with checkpoint inhibitors increases graft-versus-lymphoma (GVL) effects at the cost of increasing acute graft-versus-host disease (aGVHD). A combined targeted therapy is needed to decrease checkpoint inhibitors-induced aGVHD without impairing GVL. We studied whether this competition could be avoided by giving concurrent anti-PD-1 antibody and ruxolitinib in allotransplant mouse models in which recipients were challenged with A20 or EL4 lymphoma cells. Given alone the PD-1 antibody increased GVL but did not improve survival of recipients challenged with A20 cells because of increased deaths from aGVHD. Adding ruxolitinib decreased levels of effector T cells and related cytokines. Tbx21- T cells had higher PD-1 levels compared with Tbx21+ T cells. Ruxolitinib increased PD-1 levels on donor T cells by suppressing Tbx21 expression. Ruxolitinib increased apoptosis of T cells which was reversed by the PD-1 antibody. PD-1 antibody preserved expression of granzyme B and cytotoxicity of T cells which were decreased by ruxolitinib. The net result of combined therapy was increased GVL, no increase in aGVHD and increased survival. The combined therapy improved survival of recipients challenged by A20 cells which expressed high level of PD-L1, but not EL4 cells which do not express PD-L1.

Allogenic Stem Cell Transplantation for Secondary CNS Lymphoma: A Retrospective Review of 21 Patients

INTRODUCTION: Allogeneic blood or marrow transplant (alloBMT) is widely used in relapsed/refractory systemic non-Hodgkin lymphoma. The graft-versus-tumor effect has been thought to be blunted by the immune privilege of the central nervous system (CNS). Communication between the CNS and the systemic immune system suggests that CNS disease could benefit from the graft versus lymphoma (GVL) effect provided by alloBMT. METHODS: The charts of all patients who received post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis between January 2004 and October 2018 were reviewed. Survival statistics were calculated using the Kaplan-Meier method. Differences in time to death between groups were estimated using Cox proportional hazards models. RESULTS: Twenty-one patients with systemic lymphoma involving the CNS were identified. The median age was 59 years (range 24-73); 7 were over the age of 60 and 13 were male. Histology types included diffuse large B cell (71%), Burkitt (10%), T cell (10%), follicular (5%), and anaplastic large cell (5%). Prior to transplant, 12 patients were in complete remission, 9 had residual disease, and 5 had residual CNS disease by imaging. Induction therapy included CNS radiation therapy in 11 of 21 patients (52%) and high-dose methotrexate (HD-MTX) in 10 (48%). Only 1 patient was in first remission, with the remaining 20 in second or later remission. All but 1 patient received non-myeloablative conditioning using fludarabine, cyclophosphamide, and total-body irradiation; the other patient received busulfan and cyclophosphamide. Fifteen patients (71%) had haploidentical donors. Graft source was bone marrow in 18 patients and G-CSF-stimulated peripheral blood in 3. Median overall survival (OS) for the entire cohort was 1375 days (95% confidence interval [CI] 184-NR) and median progression free survival (PFS) was 1375 days (95% CI 112-NR). Three-year overall survival was 51% (95% CI 27-71%). The cumulative incidence of relapse was 29% (95% CI 9-49%) at 3 years, and non-relapse mortality was 20% (95% CI 2-38%) at 1 year. Of the 6 patients who relapsed, 2 were CNS only, 2 were systemic only, and 2 were combined CNS / systemic. There were 2 cases of grade III-IV acute GVHD and 1 case of chronic GVHD involving the mouth. Univariable analysis revealed no predictors of survival in our small data set: age &gt; 60 (hazard ratio [HR] 1.48, 95% CI 0.42-5.29, p-value 0.54), haploidentical donor (HR 4.2, 95% CI 0.53-33.66, p-value 0.17), residual disease (HR 1.3, CI 0.37-4.52, p-value 0.68), and prior CNS radiation (HR 1.5, 95% CI 0.42-5.31, p-value 0.53). DISCUSSION: Allogeneic BMT with non-myeloablative conditioning is potentially curative in patients with secondary CNS lymphoma. Post-transplant cyclophosphamide is well tolerated in this older group. Myeloablative conditioning directed at the CNS is not required for long-term survival. Given its biologic plausibility and potential as a viable treatment option in certain patient populations, the role of alloBMT in CNS lymphoma deserves further investigation. Figure Disclosures Wagner-Johnston: ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Swinnen:Pharmacyclics: Consultancy; AbbVie: Consultancy.

What Can We Expect after Performing Allogeneic Stem Cell Transplantation for Adult T Lymphoma in Patients from Romania, Europe?

Introduction: Adult T lymphoma (ATL) is a rare and aggressive disease shown to be consistently caused by the human T lymphoma virus I (HTLV-I). It generally occurs in Japan and Africa, with a low incidence in Europe. Romania is an exception to this rule, presenting an endemic representation of ATL. Aim: The aim of this study was to present our experience with allogeneic stem cell transplantation (alloSCT) for ATL. Methods: The current study was a retrospective analysis of the ATL cases that received alloSCT in the Fundeni Clinical Institute. The patients were included between January 2016 to April 2019. Results: A total of 7 patients were included in the present study, out of which 2 (28%) presented the acute form, while the rest presented the lymphomatous form. Four (57%) patients presented extranodal involvement, with 3 of those (75%), showing skin involvement. Of note, all patients presenting skin involvement also had bone marrow involvement. Thus, skin involvement was associated with a more advanced disease. Graft versus host disease (GvHD) was present in 4 (57%) patients, two of which were acute GvHD and two, chronic GvHD. Interestingly, the two patients that relapsed presented either acute or chronic GvHD, showing that the graft versus lymphoma (GVL) effect that can be observed in other lymphoma types is not observed in this cohort. Another noticeable observation is the fact that 4 out of the 6 patients tested for HTLV-I at 6 months post alloSCT presented a positive HTLV-I viral load. This event occurred, although, at 30 days, all patients presented 100% donor chimerism and the donor samples were negative for HTLV-I. This shows a possible imperfect jump of the HTLV-I from the recipient to the donor T lymphocytes or the possibility of a reinfection. Three (43%) patients presented a response less than complete remission (CR) after the first line of therapy, two of which progressed to death. The two deaths occurred at 14 and 15 months from the diagnosis, with the other follow-up periods in the cohort being higher than 26 months with the exception of one patient that had a follow-up of 6.8 moths from diagnosis. These two aforementioned patients were also the only ones to relapse thus far. Conclusion: For ATL, alloSCT represents a viable and potentially curative approach when used in chemosensitive disease. This being said, there are clear differences from other lymphomas, ATL having to be considered separately. Disclosures Tanase: Pfizer: Membership on an entity's Board of Directors or advisory committees; Bristol Myers: Consultancy. Hermine:Novartis: Research Funding; Celgene: Research Funding; AB Science: Consultancy, Equity Ownership, Honoraria, Research Funding.

Haploidentical Stem Cell Transplantation With Post-Transplantation Cyclophosphamide for Aggressive Lymphomas: How Far Have We Come and Where Are We Going?

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with post-transplant cyclophosphamide (PTCy) offers universal donor availability and can potentially cure relapsed or primary refractory Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). However, a conditioning regimen intensity that balances the graft-versus-lymphoma (GvL) effect with regimen-related toxicities (RRTs) has not yet been optimized. Limited data exist on the management of relapse, which is common post-transplant. Few prospective or randomized control trials have been conducted on lymphoma patients undergoing haplo-HSCT. Therefore, the current review aims to summarize published retrospective data in the field to help guide clinical decision making for high-risk patients. Retrospective studies in the field are characterized by variability in patient population and sample sizes, eligibility criteria, number of prior treatments (e.g., chemotherapy, radiation therapy, and autologous transplant), graft source (bone marrow or peripheral blood), as well as choice and intensity of the conditioning regimen (non-myeloablative, reduced intensity, or myeloablative). Nonetheless, common themes that emerge from the literature include: 1) Enhanced donor availability and selection with haplo-HSCT with success in heterogeneous patient populations; 2) Outcomes that are comparable if not superior to matched related (MRD) or unrelated (MUD) donor transplants; 3) The benefit of PTCy for reducing incidence of relapse and chronic graft-versus-host disease (GvHD); 4) Presence of co-morbidities leading to poorer transplant-related outcomes; and 5) The need for novel approaches to address disease relapse, particularly for patients with active disease at the time of transplant. Excellent transplant-related outcomes with haplo-HSCT with PTCy have been seen for HL and NHL based on retrospective data. Further studies are needed to determine integration with advanced cellular therapy techniques, such as chimeric antigen receptor (CAR) T-cell, antibody drug conjugates, and checkpoint inhibitors. Graft manipulation may be another avenue for future research.

Donor Lymphocyte Infusions for the Treatment of Relapsed Non-Hodgkin Lymphoma Following Allogeneic Stem Cell Transplantation: A LWP-EBMT Study

IntroductionRelapse of non-Hodgkin lymphoma (NHL) following allogeneic stem cell transplantation (alloSCT) is a common occurrence associated with a poor outcome with limited treatment options. Donor lymphocyte infusions (DLI) are commonly employed in this setting in an attempt to exploit the allogeneic graft versus lymphoma (GVL) effect to induce remissions. There is however a paucity of data describing the efficacy of DLIs in inducing remissions in NHL subtypes and the risk of subsequently developing graft versus host disease (GVHD). We report here the largest series of patients with NHL receiving DLI for relapse after alloSCT.MethodsPatients relapsing after an alloSCT for NHL and receiving DLI were identified on the EBMT database. Centres were invited to contribute additional data. 118 patients [follicular lymphoma (FL) n=28, diffuse large B cell lymphoma (DLBCL) n=28, T cell lymphoma (TCL) n=52 and mantle cell lymphoma (MCL) n=10] from 39 centres who received DLI as the only treatment for relapse were identified. Patients receiving DLI in combination with other therapy were excluded from this analysis. The median age at alloSCT was 50 (range 18-73) years. There were 81 male and 37 female patients who underwent an alloSCT with reduced intensity (RIC) (n=90) or myeloablative conditioning (MAC) (n=28) at a median of 2.4 (range 0.3-26.3) years from diagnosis. Allogeneic cells were provided from matched sibling (n=63), unrelated (n=47) or mismatched family (n=8) donors and 85 patients received either ATG/ALG or CAMPATH as part of GVHD prophylaxis. The median time from alloSCT to relapse was 3.8 months (range 18 days-67 months).ResultsPatients received a median of 1 (range 1-19) DLI at a median starting dose of 1.5 x106 CD3/kg (range 0.01-120x106 CD3/kg) at a median of 152 days (range 18-2136) post alloSCT. The median last dose of DLI was 10x106/kg (range 0.1-180x106/kg) given at a median of 353 days (range 41-2725) post alloSCT. The median time from relapse to the first DLI was 35 days (range 0-168). Acute GVHD and chronic GVHD prior to DLI was reported in 29% and 14% of patients, respectively. Of 93 evaluable patients 47 (51%) patients achieved a complete remission, 10 (11%) a partial remission, 13 (14%) stable disease and 23 (25%) had progressive disease following DLI. The median duration of response was 36 months (range 1-168). When analysed according to histology the overall response rate (ORR) (CR+PR) for FL was 84% (CR 68%), DLBCL 41% (32% CR), TCL 54% (46% CR) and MCL 86% (CR 71%). The median duration of responses for FL, DLBCL, TCL and MCL were 30 (range 2-150), 38 (4-76), 37 (range 1-168) and 50 months (13-116) respectively. With a median follow up of 77 months after the 1st DLI 36 (31%) patients remain in complete remission, 29 (25%) without any further therapy. 37 (35%) went on to receive additional antilymphoma therapy after the DLI. Of 17 patients with FL achieving a CR post DLI 12 (71%) remain in remission without further therapy at a median of 78 (9-158) months after DLI. Of 18 patients with TCL that achieved a CR with DLI, 15 (83%) remain in remission without further therapy at a median of 95 (range 42-161) months after DLI. Following the DLI 43 (36%) patients developed aGVHD (6 grade I, 13 grade II, 11 grade III, 9 grade IV, 4 grade unknown) and 33 (28%) developed cGVHD (11 limited, 20 extensive, 2 unknown). Following the first DLI the cumulative incidence of relapse was 31% (CI 22-41) at 4 years and of NRM 28% (CI 20-37). The 4-year PFS after 1st DLI was 39% (CI 30-50) and the OS, 44% (CI 35-54).ConclusionsDLI induce significant rates of disease response in patients with NHL relapsing after alloSCT providing clear proof of principle of the allogeneic GVL effect. The rates of response are most impressive in FL and MCL. The majority of patients with TCL and FL that achieve a CR post DLI remain in remission with long term follow up. Acute and chronic GVHD is a significant complication of DLI. DisclosuresRobinson:Sandoz: Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau. Chalandon:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel costs. Beelen:Medac: Consultancy, Other: Travel Support. Finke:Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding; Medac: Consultancy, Honoraria, Other: travel grants, Research Funding; Riemser: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding. Tischer:Jazz Pharmaceuticals: Other: Jazz Advisory Board. Corradini:Amgen: Honoraria, Other: Advisory Board & Lecturer; Novartis: Honoraria, Other: Advisory Board & Lecturer; Abbvie: Honoraria, Other: Advisory Board & Lecturer; Sandoz: Other: Advisory Board; Sanofi: Honoraria, Other: Advisory Board & Lecturer; Gilead: Honoraria, Other: Advisory Board & Lecturer; Takeda: Honoraria, Other: Advisory Board & Lecturer; Roche: Honoraria, Other: Advisory Board & Lecturer; Janssen: Honoraria, Other: Lecturer; Celgene: Honoraria, Other: Advisory Board & Lecturer.

Allogeneic hematopoietic stem cell transplantation in Primary Cutaneous T Cell Lymphoma.

In our retrospective study, 16 patients affected by advanced cutaneous T cell lymphoma (CTCL) underwent allogeneic hematopoietic stem cell transplantation (HSCT). Two patients (12.5%) were in complete remission (CR), nine (56.3%) in partial remission (PR), and five (31.2%) with active disease. The patients were transplanted from an HLA-identical (n = 7) from a mismatched (n = 1) or haploidentical (n = 1) sibling, from matched unrelated donor (n = 5), or from a single cord blood unit (n = 2). Conditioning regimen was standard myeloablative in 6 patients and at reduced intensity in 10. Seven patients died from non relapse mortality (NRM) and four patients relapsed or progressed, three of them achieved a second CR after donor lymphocyte infusion (DLI) or chemotherapy plus DLI. To date, with a median follow-up of 76months (range 6-130), nine patients are alive, eight in CR, and one with active disease. Overall survival (OS) and disease-free survival (DFS) at 1 and 10years are 61% (95% CI 40-91%) and 54% (95% CI 33-86%), 40% (95% CI 22-74%), and 34% (95% CI 16-68%), respectively. The time from diagnosis to transplant seems to influence negatively both OS (log-rank p < 0.04) and DFS (log-rank p < 0.05). Our results confirm on a long follow-up that CTCL appears particularly susceptible to the graft versus lymphoma (GVL) effect, so that allogeneic HSCT represents a possibility of cure for advanced CTCL. The timing of HSCT in the clinical course of disease remains an open issue.

Impact of HLA Alleles on Outcomes of Allogeneic Transplantation for B Cell Non-Hodgkin Lymphomas: A Center for International Blood and Marrow Transplant Research Analysis

Even in the modern era of targeted therapies, allogeneic hematopoietic stem cell transplantation (allo-HCT) can offer a chance of extended survival in B cell non-Hodgkin lymphoma (B-NHL) patients who relapse after or are deemed ineligible for autologous transplantation. A better understanding of the factors influencing the graft-versus-lymphoma (GVL) response would be useful in identifying B-NHL patients who may benefit from allo-HCT. Based on prior single-center reports, we hypothesized that certain HLA alleles, or haplotypes, may be associated with superior GVL compared with others after allo-HCT. To test this possibility we retrospectively evaluated whether the presence of HLA-A2, HLA-C1C1, HLA-DRB1*01:01, or HLA-DRB1*13 alleles or the presence of HLA-A1+, HLA-A2-, and HLA-B44- haplotypes is associated with outcomes in a cohort of 1314 HLA-8/8 matched sibling or unrelated donor HCT for relapsed/refractory B-NHL. We observed no significant association between any HLA allele or haplotype and overall survival or any of the secondary endpoints. In conclusion, this study represents the largest reported series of allo-HCT outcomes of B-NHL patients based on HLA type. Identification of other variables will be required to delineate the immunologic impact of donor–host interactions on outcomes of allo-HCT for B-NHL.

Allogeneic hematopoietic stem cell transplantation for mantle cell lymphoma in a heavily pretreated patient population.

7558 Background: Allogeneic hematopoietic stem cell transplantation (allo-SCT) is the only potential curative treatment option for patients with MCL due to its potent graft-versus-lymphoma (GVL) effect. Survival following allo-SCT for MCL is variable due to high rates of non-relapse mortality (NRM). Methods: We retrospectively identified all patients who were treated with an allo-SCT for MCL at Loyola University Medical Center between January 1, 1999 and January 1, 2016. Probability estimates for overall survival (OS) and non-relapse mortality (NRM) at 5 years were calculated from the date of allo-SCT to the date of patient death or last known follow-up. Significance was determined using a cox proportional hazard (CPH) model. Rates of acute graft-versus-host disease (aGVHD) and relapse were also reported. Results: Patient characteristics (n = 29) are listed in Table. Median follow-up in surviving patients is 10 years (range 5-14 years). A majority of patients (n = 23, 79%) had 3 or more lines of treatment prior to allo-SCT. The 5 year rates of OS and NRM for all patients are 42% and 53%, respectively. Univariate analysis showed a lower risk of death in patients who received TBI-based conditioning (HR: 0.19, 95 CI: 0.04 – 0.81, p = 0.03), and those who had HLA-matched related donor (MRD) transplants (HR: 0.29, 95 CI: 0.11 – 0.79, p = 0.02). Patients who received more than 3 lines of prior treatment had a higher risk of death (HR: 2.77, 95% CI: 1.05-7.34, p = 0.04). Low rates of grade III/IV aGVHD (n = 4) and relapse (n = 4) occurred in our patient population. Two patient deaths were attributable to aGVHD, and the majority of other deaths were due to treatment-related toxicities. Conclusions: In an era of numerous effective non-curative salvage therapies, the optimal timing of allo-SCT for MCL needs further clarification. Our data supports early opposed to delayed allo-SCT for select high-risk patients with MCL who have a MRD. [Table: see text]

Impact of Human Leukocyte Antigen (HLA) Alleles on Outcomes of Allogeneic Transplantation (Allo-HCT) for B-Cell Non-Hodgkin Lymphomas (B-NHL); A CIBMTR Analysis

Even in the modern era of targeted therapies, allo-HCT remains a strategy that offers a chance of extended survival in B-NHL who relapsed after, or are deemed ineligible for, autologous transplantation (auto-HCT). Moreover, it was shown that efficacy of auto-HCT in extending survival in patients with diffuse large B-cell lymphoma is limited in the post-rituximab era. The use of allo-HCT for salvage of relapsed/refractory B-NHL is likely to increase with the wide adoption of reduced intensity conditioning (RIC) since transplant-related mortality (TRM) is lower while preserving the benefit of graft vs lymphoma (GVL) effect. Further understanding of the factors likely to predict a more robust GVL response, and potentially better clinical outcomes, would be very useful in selecting patients with B-NHL who are likely to benefit from allo-HCT. Multiple prior studies have shown that the presence of certain human leukocyte antigen (HLA) alleles may be instrumental in modulating the outcomes of B-NHL after immunochemotherapy and/or allo-HCT. We hypothesized that certain HLA alleles may have superior ability to present antigens to cytotoxic T-cells or possibly modulate natural killer (NK) cell activity.We undertook a retrospective analysis of CIBMTR data to evaluate whether the presence of HLA-A2, HLA-C1C1, HLA-DRB1*01:01 or HLA-DRB1*13 alleles and HLA-A1+, HLA-A2- and HLA-B44- haplotypes were associated with outcomes of patients with relapsed/refractory B-NHL after transplantation from HLA-8/8 matched sibling (MRD) or unrelated (MUD) donors. The primary outcome was time to progression. Secondary outcomes included progression-free (PFS) and overall survival (OS), TRM, and incidence and severity of acute and chronic graft versus host disease (GVHD). Multivariate analyses were performed using Cox proportional hazards models adjusting for multiple disease and transplant related characteristics. HLA-A*02 was tested individually; HLA-DRB1*0101 and HLA-DRB1*13 were tested in 4 combinations; HLA-A1+/A2-, B44- vs. A2+ vs. neither. Because of multiple comparisons, p<0.01 is considered significant.The final analysis population was restricted to 1314 patients who received the first allo-HCT during the years of 1995-2012 for indolent (N=506), aggressive (N=514), and mantle (N=294) B-NHLs from MRD (N=708) or MUD (N=606) utilizing myeloablative; MA (N=636), RIC (N=434), non-myeloablative; NMA (N=196) or other (n=48) conditioning. The different HLA allele analysis groups were well-balanced for all disease, patient, transplant and donor characteristics. In multi-variate analysis, we have observed no significant association between any of the HLA alleles or combinations we tested with any of the primary or the secondary end-points. A power calculation suggested very large numbers would be needed to reach statistical significant based on the data analyzed so far. The marked heterogeneity of different lymphoma subtypes, conditioning regimens, donor choices, GVHD prophylaxis, supportive regimens or other center-related characteristics likely limited the ability to detect effects of differences in individual recipient HLA alleles. In conclusion, this study represents the largest reported series of allo-HCT outcomes of B-cell NHL patients based on HLA type. Further study of other variables will be required to delineate the immunologic impact of donor-host interactions on outcomes of allo-HCT for B-cell NHL. DisclosuresNo relevant conflicts of interest to declare.

Outcomes and Impact of Donor Lymphocyte Infusion after Reduced Intensity Conditioned-Alemtuzumab Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Mature Lymphoid Malignancies

Allogeneic hematopoetic stem cell transplantation (allo-HSCT) offers long-term remission for patients with lymphoid malignancies. In particular, reduced intensity conditioned (RIC) protocols with Alemtuzumab T-cell depletion lead to durable engraftment and reduced graft versus host disease (GvHD). However, such regimens may be associated with reduced graft-versus-lymphoma (GvL) effect and higher incidence of disease progression, leading to increased use of donor lymphocyte infusion (DLI). This study examined transplant outcomes and use of DLI in a large UK RIC-Alemtuzumab conditioned HSCT cohort.288 consecutive adult patients from three UK transplant centres (Birmingham, Glasgow, Oxford) undergoing first Alemtuzumab-based RIC HSCT for Hodgkin's lymphoma (57%), Non-Hodgkin's lymphoma (24%) and chronic lymphocytic leukemia (19%) between 2000 and 2012 were included. Overall survival (OS), current progression-free survival (CPFS), relapse incidence (RI), transplant-related mortality (TRM), incidence of GvHD and effects of DLI were analyzed.Median age was 49y (range 17-68) and 60% were male. Patients were heavily pre-treated with 58% having received ≥3 prior lines of treatment and 49% having failed a previous autograft. 55% received stem cells from an HLA-matched unrelated donor and 94% received a peripheral blood stem cell harvest. The most frequent conditioning regimen was Fludarabine, Melphalan and Alemtuzumab (FMC) (70%) and the median total Alemtuzumab dose was 50mg (range 30-100). Median duration of follow-up for survivors was 64 months.3y OS and CPFS were 53% and 50%, respectively. Factors negatively associated with OS in univariate (UV) analysis were previous autograft (p=0.01), no requirement for DLI (p=0.05), disease status not CR (p=0.05), previous treatment number ≥3 (p=0.007) and failure to engraft plts (p=0.001). On multivariate (MV) analysis, only previous autograft (HR 1.58 p=0.01) and failure to engraft plts (HR 2.3 p=0.0001) retained significance. Factors negatively associated with CPFS on UV analysis were no requirement for DLI (p=0.006), failure to engraft plts (p=0.0003) and previous treatment lines ≥3 (p=0.04). On MV analysis, no DLI remained a significant predictor of adverse CPFS (HR 1.8 p=0.01), as did failure to engraft plts (HR 1.77 p=0.005) and ≥3 treatment lines (HR 1.46 p=0.04).At 3y, the cumulative incidence of relapse and TRM was both 27%. The incidence of grade 2-4 acute GvHD (aGvHD) and extensive chronic GvHD (cGvHD) was 22% and 18%, respectively. UV predictors of RI were unrelated donor (p=0.0009), HLA mismatch (p=0.04), age > median (p=0.04) and lack of aGvHD (p=0.04). The presence of cGvHD may have been protective against relapse (p=0.08). No variables retained significance on MV modelling. UV predictors of TRM were failure to engraft plts (p=0.001), HLA mismatch (p=0.005), age > median (p=0.004), previous autograft (p=0.02), FMC conditioning (p=0.03), ≥3 previous lines of treatment (p=0.001) and development of aGvHD (p=0.04). On MV modelling, failure to engraft plt (p=0.001), HLA mismatch (p=0.03), age > median (p=0.003) and treatment number ≥3 (p=0.04) retained significance.62/288 patients received DLI; 37 receiving prophylactic DLI (pDLI) for mixed chimerism and 25 receiving therapeutic DLI (tDLI) for disease relapse. The median dose of DLI was 1x 10^6 CD3+ cells/kg (range 0.1 - 10 x 10^6). Median time from HSCT to first DLI was 10.5 months (range 3-30), to 2nd DLI 15 months (6-51) and to 3rd DLI 19 months (9-30). At 3y, OS after pDLI was 75% and after tDLI was 29%. 29/37 (78%) of pDLI and 14/25 (56%) of tDLI recipients achieved full or stable mixed chimerism. 3y RI after pDLI was 29% and after tDLI was 59% (p=0.02). Overall, the incidence of GvHD post-DLI was 32% (48% tDLI, 22% pDLI, p=ns). Median time to GvHD after last DLI was 46 days (range 17-249). There was no significant impact of post-DLI GvHD on RI (RI at 1y post DLI 18% in GvHD cohort vs 21% with no GvHD, p=ns), but GvHD increased TRM at 1y post DLI (17% in the GvHD cohort vs 3% with no GvHD, p=0.05).This is the largest series to date with long-term follow-up examining outcomes after Alemtuzumab-based RIC HSCT for mature lymphoid malignancy. Our data indicate that allo-HSCT is effective and is associated with good long term outcomes. Use of pDLI for was associated with excellent outcomes and supports use of DLI in patients developing mixed chimerism following allo-HSCT for lymphoid malignancies. DisclosuresNo relevant conflicts of interest to declare.

Successful allogeneic bone marrow transplantation with reduced intensity conditioning regimen for a pediatric relapsed ALK positive anaplastic large cell lymphoma.

Pediatric anaplastic large cell lymphoma (ALCL) is a chemosensitive malignancy, but about 30% of patients experience relapse. In most of these patients, a second complete remission is obtainable with salvage chemotherapy, though relapse free survival rates are as low as 30-60%. Herein, we report a 6-year-old boy with relapsed anaplastic lymphoma kinase (ALK) positive ALCL successfully treated with vinblastine monotherapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT), with a reduced intensity conditioning (RIC) regimen, from his father. One HLA locus from the father was mismatched. The boy had neither severe graft-versus-host disease nor transplantation related complications. He is currently well and has remained disease free for 10 months, to date, since transplantation. Allo-HSCT with a RIC regimen may be a promising treatment strategy for relapsed ALK positive ALCL based on obtaining graft-versus lymphoma effects as well as reducing transplantation-related mortality.

A Prospective Study of Allogeneic Hematopoietic Stem Cell Transplantation in Relapsed/ Refractory Hodgkin Lymphoma

INTRODUCTION: Patients with Hodgkin Lymphoma (HL) relapsing post autologous transplant (ASCT) are not cured with standard chemotherapy. In addition, a subset of patients with relapsed or primary-refractory HL fare poorly with ASCT. Such patients may benefit from allogeneic transplantation (allo-HCT) with its graft-versus-lymphoma (GVL) effect. METHODS: We performed a phase II study of salvage therapy (ST) followed by allo-HCT in adult patients with relapsed/refractory (rel/ref) HL (NCT00574496, Fig. 1a). Conditioning was dictated by PET status after ST, with NMA flu/cy/TBI 200 cGy for patients in CR and RIC mel/flu for those with PR/SD. Patients in the intent-to-treat (ITT) cohort were enrolled prior to ST and proceeded to allo-HCT if in CR, PR, or SD after 1 line of ST. The primary endpoint was successful allo-HCT and PFS at 1 year after allo-HCT (estimated as a proportion as all patients had at least 1 year of followup). Landmark analysis (from end of ST) with Kaplan-Meier curves and log-rank test were used to compare OS and PFS in the ITT cohort. A second cohort of patients referred with CR, PR, or SD after ST received HCT on protocol, but was not included in the ITT analysis. No differences in OS or PFS after HCT were seen between ITT and non-ITT cohorts, and patients were combined for further analysis. OS and PFS from time of HCT were estimated using all HCT patients, and PFS was compared based on baseline covariates. Cumulative incidence of GVHD, relapse/POD and nonrelapse mortality (NRM) were estimated using competing risks methodology. P-values less than 0.05 were considered significant. RESULTS: From 6/2008 to 6/2014, 25 patients were consented, 15 on the ITT analysis and 10 on the post-ST arm (Table 1). All had relapse after ASCT, primary refractory or high-risk HL relapsed within 1 year of 1st-line therapy. Allografts (n = 18) were PBSC from matched or single-allele mismatched related (n = 8) or unrelated (n = 3) donor, or double unit cord blood grafts (n = 7). Eleven were in PET CR before HCT and 7 in PR. ITT analysis (n=15) : 5 patients had POD on ST and were ineligible for allo-HCT. Of the remaining 9, 1 withdrew during conditioning. 1-year and 3-year OS were 50% (95% CI 22.5, 100) and 16.7% (95% CI 2.8, 99.7), respectively, in patients with POD after ST, and 100% at both time points if no POD after ST (Fig 1b). At median 5.6 years of follow-up, 5 patients survive. The percent of patients successfully meeting the primary endpoint was 33% (95% CI 13, 61). Allo-HCT analysis (n=18): Cumulative incidence (CI) of grade 2-4 and 3-4 aGVHD at d+100 were 23.3% (95% CI 13.1, 55.3) and 11.1% (95% CI 1.70, 30.4), respectively. CI of cGVHD at 1 year and 3 years was 11.1% (95% CI 1.7, 30.7) and 35.6% (95% CI 13.2-59.0), respectively, and of mild severity in all but 1 patient. 3-year CI of relapse/POD was 34.3% (95% CI 13.2-56.7), and NRM 23.6% (95% CI 6.8, 46.1). Estimated 3-year PFS was 42.1% (95% CI 24.1, 73.6) and OS 70.3% (95% CI 51.5, 96.1) (Fig 1c). There was no significant association between PFS and disease stage or status (CR vs. PR). There was a trend toward poorer PFS in the 5 patients without prior ASCT (3 year PFS 20.0% vs. 50.8%, p = 0.088), 3 of whom had primary refractory HL. CONCLUSION: We demonstrate that allo-HCT provides long-term survival for a substantial portion of patients with rel/ref HL. Though limited by small sample size, the ITT analysis showed more than 1/3 of patients never attained sufficient disease control for allo-HCT, and have a dismal prognosis. Of note, none had received brentuximab or a checkpoint inhibitor, and the long-term impact of these agents in those patients remains to be seen. In patients undergoing allo-HCT with chemosensitive disease, proceeding to allo-HCT in PET PR vs. CR had no significant negative impact on PFS in this limited sample. The trend toward poor outcomes in patients who had not previously undergone ASCT likely reflects poor prognosis in patients with primary refractory disease. Factors informing prognosis after allo-HCT, and interventions to attenuate risk, remain an important area for further investigation. Disclosures Perales: BeTheMatch/ National Marrow Donor Program: Membership on an entity9s Board of Directors or advisory committees; Takeda: Honoraria; Astellas: Honoraria; Merck: Honoraria; Amgen: Honoraria. Giralt: TAKEDA: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; AMGEN: Consultancy, Research Funding; SANOFI: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding. Straus: Millenium Pharmaceuticals: Research Funding. Moskowitz: GSK: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding.