High-dose Post-transplant Cyclophosphamide Research Articles

A Phase II Study of High-Dose Post-Transplant Cyclophosphamide and Bortezomib (CyBor) for the Prevention of Graft-versus-Host Disease Following Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

A Phase II Study of High-Dose Post-Transplant Cyclophosphamide and Bortezomib (CyBor) for the Prevention of Graft-versus-Host Disease Following Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Peripheral blood stem cell for haploidentical transplantation with post-transplant high dose cyclophosphamide: detailed analysis of 181 consecutive patients.

While bone marrow (BM) grafts were initially used for T-replete HLA-haploidentical related donors transplantation (Haplo-SCT) with post-transplantation cyclophosphamide (PT-Cy), the use of peripheral blood stem cell (PBSC) remains debated. We thus conducted a detailed analysis evaluating the incidence, risk factors, and prevalence of GVHD after PBSC Haplo-SCT with PT-Cy. One hundred and eighty-one patients with hematological diseases were included. Median time for neutrophil and platelet recovery was 21 and 30 days, respectively. The cumulative incidence of grade 3-4 acute GVHD and severe chronic GVHD were 8% and 4%, respectively, approaching what was observed after BM Haplo-SCT. NRM at 2 years was 21%, and 41% of the non-relapse deaths were caused by GVHD. The cumulative incidence of relapse at 2 years was 17% in the whole cohort, and 13% among AML patients (n = 54), suggesting a high GVL effect. As surrogate markers for good quality of life, we observed a 2-year GVHD-relapse-free survival probability of 50% and found that 6% and 2% of disease-free patients at 2 years were still living with GVHD and immunosuppressive treatments, respectively. Haplo-SCT with PT-Cy using PBSC grafts results in low incidence GVHD and promising disease control, making PBSCs a valuable alternative to BM graft in this setting.

CMV Viral Load after Peripheral Blood Stem Cell Transplantation (PBSCT) and Posttransplant High-Dose Cyclophosphamide (PTCy)

CMV viral load after allogeneic hematopoietic PBSCT is strongly associated with overall and non-relapse mortality. Recent studies suggest graft-versus-host-disease (GVHD) prevention with PTCy reduces GVHD risk through an immunomodulatory mechanism rather than T-cell ablation (Kanakry et al. Sci Transl Med 2013), which may preserve virus-specific adaptive immune responses. Lower rates of chronic GVHD with PTCy may also preserve thymic function and reduce cumulative corticosteroid use. We hypothesized that GVHD prophylaxis using PTCy leads to lower CMV viral load and disease compared to calcineurin-inhibitor (CNI) and methotrexate (MTX) or mycophenolate (MMF) GVHD regimens after PBSCT. We retrospectively analyzed subjects undergoing first HLA-matched unrelated or sibling donor PBSCT for hematologic malignancy between July 2007 and August 2017 at Fred Hutchinson Cancer Research Center. Inclusion criteria were CMV seropositive recipient and/or donor status and myeloablative or reduced-intensity conditioning. Subjects receiving ATG were excluded. We calculated the mean CMV viral load (obtained weekly posttransplant) for each subject divided by number of days survived through one year and compared these normalized average levels across patients using the Kruskal-Wallis test. A spline curve plotting the median viral load Log10 (CMV PCR +1) between the 3 groups was created for data visualization. Cox regression was used to compare cause-specific hazards of CMV reactivation at >0, ≥250 or ≥1000 IU/ml and CMV disease between groups, each modeled as a time-to-event outcome. 594 subjects met inclusion criteria (33 PTCy, 423 MTX, 138 MMF). Table 1 shows normalized median CMV viral load before and after day 70 in PTCy vs. MTX vs. MMF groups. The spline curve depicts median viral load across the 3 cohorts (Figure 1). The hazard ratios for CMV reactivation for MTX and MMF compared to PTCy at >0, ≥250 or ≥1000 IU/ml are shown in Table 2. CMV disease was not significantly different between PTCy vs. MTX and MMF: HR 1.13 (0.27-4.76, p = .87) and 0.93 (0.19-4.49, p = .93), respectively. While the time to first CMV reactivation at various levels and CMV disease was not statistically significantly different between the 3 groups, the kinetics of CMV viral load show initially higher, but later lower levels in subjects receiving PTCy compared to MTX or MMF regimens. This may be due to an initial period of T cell compromise associated with reduced viralimmunity in PTCy recipients, followed by rapid recovery of virus-specific T cells in the later posttransplant period. The net state of immunosuppression after PTCy may prove favorable for viral immunity and overall immune reconstitution posttransplant. Prospective randomized trials are underway.

Impact of Post-Transplant High-Dose Cyclophosphamide and Donor Sources on CMV Reactivation.

Introduction Cytomegalovirus (CMV) reactivation remains a common cause of morbidity and mortality following allogeneic hematopoietic cell transplant (HCT) despite attempts at prophylaxis. Following transplantation, surveillance of the peripheral blood CMV viral load with early aggressive treatment is commonly employed and has been an effective strategy at preventing overt infection. While a matched related donor (MRD) is often the preferred transplant type, the use of alternative donors including matched unrelated donors (MUD), mismatched unrelated donors (MMUD) and haploidentical (HI) transplants, has greatly increased over the past several years. The data regarding CMV infection among these alternative donor types is scarce. Objectives To better characterize the extent and risk factors for CMV reactivation among patients who received an allogeneic HCT for hematologic malignancies, particularly among HI transplant recipients and those who received post-transplant high-dose cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis. Methods A retrospective analysis was performed on 88 adults with hematologic malignancies who received an allogeneic HCT at our institution from 2012-2017. Only cases with CMV seropositive donors and/or recipients were included. We compared donor types/sources, conditioning regimens, GVHD prophylaxis regimens, and assessed for CMV reactivation utilizing the peripheral blood polymerase chain reaction (PCR) values that are monitored in post-transplant clinic visits. Results Nineteen (22%) patients received MRD transplants, while the remainder received alternative donor sources, including 17 (19%) HI transplants. Overall, the rate of CMV reactivation was 27% with a significant difference noted between donor sources (p= Conclusion HI HCT transplant recipients are at high risk for CMV reactivation. The use of myeloablative conditioning regimens or PTCy did not affect the rate of CMV reactivation.

Treosulfan Based Conditioning Regime for Allogenic HSCT in Resource Poor Setting

Allogenic stem cell transplantation is a curative procedure for many blood disorders including haemtological malignancies. The outcomes are very dependent on the conditioning regime used. Infections from a variety of micro-organisms and graft vs host disease(GVHD) can be the other parameters affecting outcomes. Relapse rate specially in a malignant condition influences the choice of regime as does the prevention of certain conditions like veno occlusive disease- Sinusoidal obstruction syndrome.Busalfan based regimes have been used extensively but shows a high rate of veno occlusive disease (VOD) specially when used with post transplant high dose Cyclophosphamide for GVHD prevention. Also Buslfan drug monitoring is not available in many places making this kind of transplants risky. Once VOD develops, the mortality is very high and it is better prevented. The use of drugs like Defibrotide makes the transplant very expensive also. We developed a conditioning regime using Treosulfan (di hydroxy Busulfan), followed by post transplant Cyclophosphamide and did not see a single patient suffering from VOD in the 15 patients transplanted so far. These were for a variety of malignant conditions including Myelodysplasia, Acute myeloid leukaemia, Acute Lymphoblastic leukaemia, Chronic Myeloid leukaemia, Follicular Lymphoma. The age group varied from 10-58 years(median=35) and there was almost an equal sex distribution. Among the 15 patients transplanted 7 patients were in CR(complete remission)1, 6 in CR2 and 2 in CR3. The graft was a peripheral stem cell graft taken from a mix of Haploidentical donors, Matched unrelated donor and sibling donors. 10 patients are alive so far and are in CR. 2 relapses were seen who ultimately died in agressive acute myeloid leukaemia, 2 died of a secondary infection, 1 transplant related mortality due to microangiopathy was seen. 1 grade 4 GVHD was noted which was treated with steroids. In conclusion, Treosulfan gives an advantage over Busulfan in our results and with the advent of generic Treosulfan the cost of the transplant procedures have gone down also. The avoidance of medicines like Defibrotide and no requirement of drug monitoring make these procedures simple and cheaper and is much suited in a resource poor setting.

Class I Graft-Versus-Host Mismatch Based on Predicted Indirectly Recognizable HLA Epitopes (PIRCHES) Is Associated with Worse Post-Transplant Outcomes in Patients Receiving Peripheral Blood, T-Cell Replete Haploidentical Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide

Introduction High dose post-transplant cyclophosphamide has improved the outcomes and expanded the use of haploidentical hematopoietic cell transplantation (haplo-HCT). The impact of HLA disparity in this setting, however, is unclear and is traditionally measured at the antigen or allele level. The Predicted Indirectly Recognizable HLA Epitopes (PIRCHES) model provides a novel tool to calculate the number of mismatched HLA peptides between donor and host that can be processed and presented by shared HLA antigens for T cell recognition. No data exist on the relationship between PIRCHES mismatch and clinical outcome in haplo-HCT with post-transplant cyclophosphamide. Methods 148 patients who received a peripheral blood, T-cell replete haplo-HCT with post-transplant cyclophosphamide at a single center between 2009 and 2016 were retrospectively analyzed. The PIRCHES mismatch load was calculated using the PIRCHES matching tool online and was categorized by class and vector. The primary outcome was incidence of relapse. The association between PIRCHES mismatch and outcome was analyzed using the Cox proportional hazard model or Gray's sub-distribution method for competing risk as appropriate. This study was approved by the Institutional Review Board. Results The median follow-up for survivors was 34.0 months (range, 14.5-78.3 months). One-hundred (67.6%) patients were deceased and 61 (41.2%) patients relapsed during follow-up. Class I graft-versus-host (GvH) PIRCHES mismatch had a median of 11 with a range of 0 to 56. Class II GvH PIRCHES mismatch had a median of 29 with a range of 0 to 122. Class I GvH PIRCHES mismatch was associated with worse acute graft-versus-host disease (aGvHD) (grades II-IV) (HR 1.021 per unit PIRCHES mismatch increase; 95% CI 1.001-1.040; p=0.036). Class I GvH PIRCHES mismatch was not associated with treatment-related mortality (TRM), but was associated with a trend towards worsened overall survival (OS) (HR 1.015 per unit PIRCHES mismatch increase; 95% CI 0.999-1.033; p=0.073). Class I host-versus-graft (HvG) PIRCHES mismatch was associated with worse relapse-free survival (RFS) (HR 1.018; 95% CI 1.001-1.035; p=0.036) and worse OS (HR 1.018; 95% CI 1.001-1.035; p=0.036) but not relapse. Class II PIRCHES mismatch was not associated with relapse, OS, RFS, TRM, or aGvHD. Both class I and II PIRCHES mismatch were not associated with chronic GvHD or engraftment. Discussion Class I GvH PIRCHES mismatch was associated with greater aGvHD and a trend towards worsened OS, while class I HvG PIRCHES mismatch was associated with worsened RFS and OS. Class II PIRCHES mismatch was not associated with outcomes and appears to be tolerated by this patient cohort. PIRCHES mismatch represents a novel strategy to predict clinical outcome in haplo-HCT. Further studies using registry data and prospective studies are needed to validate these findings.

HLA epitope mismatch in haploidentical transplantation is associated with decreased relapse and delayed engraftment

AbstractHLA disparity is traditionally measured at the antigen or allele level, and its impact on haploidentical hematopoietic cell transplantation (haplo-HCT) with high-dose posttransplant cyclophosphamide (PTCy) is unclear. To the best of our knowledge, the relationship between HLA eplet–derived epitope mismatch (EM) and clinical outcome has not been examined in haplo-HCT. We retrospectively analyzed 148 patients who received a peripheral blood, T-cell–replete haplo-HCT with PTCy at a single center. HLA EM was quantified using an HLAMatchmaker-based method and was stratified by class and vector. The primary outcome was incidence of relapse. The total number of mismatched epitopes (MEs) per patient-donor pair in our patient population ranged from 0 to 51 (median, 24) in the graft-versus-host (GVH) direction and 0 to 47 (median, 24) in the host-versus-graft (HVG) direction. Higher HLA class II EM in the GVH direction was associated with a significantly reduced risk of relapse (adjusted hazard ratio [HR], 0.952 per ME; P = .002) and improved relapse-free survival (adjusted HR, 0.974 per ME; P = .020). Higher HLA class II EM in the HVG direction was associated with longer time to neutrophil (adjusted HR, 0.974 per ME; P = .013) and platelet (adjusted HR, 0.961 per ME; P = .001) engraftment. In peripheral blood haplo-HCT patients, increased HLA EM was associated with a protective effect on the risk of relapse in the GVH direction but a negative effect on time to count recovery in the HVG direction. HLA EM based on the HLA Matchmaker represents a novel strategy to predict clinical outcome in haplo-HCT.

Review of Haploidentical Hematopoietic Cell Transplantation.

Use of haploidentical (haplo) donors for hematopoietic cell transplantation (HCT) has significantly increased in the last decade. The major advantage with this strategy is universal availability and faster acquisition of the donor, along with affordability and provision of immunotherapy in post-transplantation period. Historically, haplo-HCT was associated with compromised outcomes because of high rates of graft-versus-host disease and graft failure, but after the development of a post-transplantation high-dose cyclophosphamide strategy, which results in selective T-cell depletion, these issues have been addressed to a large extent. Nevertheless, graft failure, high treatment-related mortality due to graft-versus-host disease, infections, delayed immune reconstitution, and disease relapse remain significant concerns. As the experience with haplo-HCTs grows, the clinical outcomes are becoming more at par with those seen with fully matched unrelated donor allogeneic HCTs.

Post-Transplant Cyclophosphamide Versus MTX-CSA As Gvhd Prophylaxis in HLA-Identical Sibling HSCT

Background: Post-transplant high dose cyclophosphamide (PT-CY) effectively prevents graft-versus-host disease (GVHD) after HLA-haploidentical hematopoietic stem cell transplantation (HSCT). However, the use of PT-CY in HLA-identical HSCT is less explored. In this study, we analyzed the results of PT-CY as GVHD prophylaxis in HLA-identical sibling HSCT and compared them with those obtained after prophylaxis with methotrexate (MTX) plus cyclosporine (CsA).Methods: 107 HLA-identical sibling (10/10) HSCT from 2 Spanish centers have been analyzed: 50 performed consecutively between 2010 and 2015 using MTX-CsA as GVHD prophylaxis, and 57 performed consecutively between 2014 and 2018 using PT-CY.Results: Baseline characteristics and post-transplant complications are shown in Table 1. GVHD prophylaxis consisted in MTX days +1, +3, +6 and +11, and CsA from day -1 in the MTX-CsA group. The PT-CY group received cyclophosphamide 50 mg/kg/d on days +3 and +5 in 38 patients (65%), combined with CsA from day +5, and cyclophosphamide on days +3 and +4 in 19 patients (35%), followed by CsA and mycophenolate mofetil from day +5. Graft source was PBSC in 96% in the MTX-CsA group and 86% in the PT-CY group. Conditioning regimen was myeloablative in 64% and 40%, respectively. Neutrophil and platelet engraftment was significantly delayed in the PT-CY group (14.5 (11-27) vs 15.5 (13-37), p=0.02; 11.5 (8-180) vs 20.5 (10-43), p=0.02). After a median follow-up of 60 months for the MTX-CsA group and 15 months for the PT-CY group, 2-year overall survival (OS) was 56% (42-70) and 78% (67-90) (p=0.088), and event-free survival (EFS) was 48% (34-62) and 62.5% (42.5-82.5) (p=0.054), respectively. Cumulative incidence at 100 days of grade II-IV (52.2% vs. 22.6%, p=0.0015), and III-IV (24.4% vs. 8.8%, p=0.016) acute GVHD were significantly higher in the MTX-CsA group (Figure 1A). No differences were observed in the 2-year cumulative incidence of chronic moderate to severe GVHD (26% vs. 16.7% (p=0.306)). No differences were observed in the 2-years cumulative incidence of relapse (27% vs. 28% (p=0.47)). Non-relapse mortality (NRM) at 2-years showed a higher trend in the MTX-CsA cohort (24% vs. 8.8%, p=0.054). Finally, the composite endpoint of GVHD and relapse-free survival (GRFS) at 2-years was significantly better in the PT-CY group (48% vs. 24%, p=0.011) (Figure 1B).Conclusions: In our experience, GVHD prophylaxis using PT-CY combined with additional immunosuppression after HLA-identical sibling HSCT, using mostly peripheral blood as graft source, reduced the cumulative incidence of acute GVHD compared to standard prophylaxis with MTX-CsA, leading to an impact on GRFS. To our knowledge, this is the largest comparative retrospective cohort reported. Further prospective studies with longer follow-up are needed to confirm these observations. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Various Gvhd Prophylaxis Regimens Influence Differently T-Memory Cell Subsets Recovery after Allogeneic Stem Cell Transplantation in Leukemia Patients

Introduction. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative approach for most leukemia patients. It seems that the bone marrow (BM) resident T-memory cells are the main pool for reconstitution of adaptive immunity, providing graft-versus-leukemia effect after allo-HSCT. However it has been shown previously that T-naïve cell subsets are responsible for acute graft versus host disease (aGVHD) onset. Here we report an impact of different GVHD prophylaxis on the BM resident memory T-cells recovery after allo-HSCT.Patients and methods. Our study comprised 39 leukemia patients (AML-26, ALL - 13) with a median age of 36 years (17 - 60 years old) who underwent allo-HSCT. Classical immunosuppressive regimen with CsA+MMF+MTX was applied in case of matched related (n=9) and matched unrelated (n=13) donors. Post-transplant high dose Cyclophosphamide (PT-Cy) on day +3, +4 as GVHD prophylaxis was used if allo-HSCT was performed from unrelated mismatched donors (n=8) or haplo-donors (n=4). Alfa/beta T-cells depletion was used as GVHD prophylaxis in young patients with a median age of 19 years (17-57 y.o.) who underwent haplo-HSCT (n=5). Acute GVHD grade II-III was diagnosed in 6 patients (27%) from the group with classical immunosuppressive regimen, in 2 patients (16,6%) from PT-Cy group. Acute skin GVHD grade II was diagnosed in 1 patient (20%) after T-cells depletion. Leukemia relapse was diagnosed after the day +100 in 4 patients (18%) after classic immunosuppressive regimen and 1 patient (8,3%) after PT-Cy. All 5 patients after T-cells depletion stayed in complete remission during follow-up period in 34 months after allo-HSCT. Bone marrow (BM) samples were collected on day +30, +60 and +90 after allo-HSCT in EDTA-tubes. Flow cytometry analysis was performed on BD FACS Canto II (Becton Dickinson, USA) to define T-memory subsets: T-naive and T-stem cell memory (Tnv+Tscm) - CD8+/CD4+ CD45R0-CCR7+CD28+; T-central memory (Tcm) - CD8+/CD4+ CD45R0+CCR7+CD28+; T-transitional memory (Ttm) - CD8+/CD4+ CD45R0+CCR7-CD28+; T-effector memory (Tem) - CD8+/CD4+ CD45R0+CCR7-CD28-; T-terminal effector (Tte) - CD8+/CD4+ CD45R0-CCR7-CD28-. Mann-Whitney U test was used for nonparametric data analysis. A p-value less than 0,05 was considered as significant. All data analysis was conducted utilizing SPSS ver. 23. (IBM, Chicago, Ill., USA).Results. The data are presented in the picture 1. According to our data the number of BM resident Tnv+Tscm CD8+ or CD4+ cells are much lower after alternative regimes of GVHD prophylaxis (PT-Cy or T cells depletion) on day +30 after allo-HSCT. Moreover on day +60 Tnv+Tscm CD4+ T-cells are still extremely low after T-cells depletion comparing to PT-Cy (p=0,03) and classical regimen (p=0,034). We didn't found any correlation between the number of Tnv+Tscm, Tcm, Ttm, Tem, Tte and the development of leukemia relapse or acute GVHD.Conclusion. New immunosuppressive approaches are now available for GVHD prophylaxis for patients who undergoes allo-HSCT from mismatched or haplo- donors that provides comparable results with classical immunosuppression in case of matched allo-HSCT. However Tnv+Tscm is the progenitor subset for all memory T-cells and its prompt recovery after allo-HSCT seems to be crucial for graft-versus-leukemia effect. Here we show the lowest number of Tnv+Tscm after alternative GVHD prophylaxis regimens that can be explained by more sever immunoablation. Through this it may lead to delayed reconstitution of adaptive immunity after alternative immunosuppression in patients after allo-HSCT. DisclosuresNo relevant conflicts of interest to declare.

Incidence and Risk Factors of CMV Reactivation after Haploidentical Hematopoietic Cell Transplantation Using High-Dose Post-Transplant Cyclophosphamide - Possible Role of Donor KIR Genotypes

Haploidentical hematopoietic cell transplantation (HaploHCT) using high-dose post-transplant cyclophosphamide (PTCy) has been increasingly used in patients with hematologic disorders with promising results. However, limited data are available on the incidence, pattern, and risk factors including donor/recipient KIR genotypes for cytomegalovirus (CMV) reactivation after HaploHCT with PTCy. Furthermore, the impact of CMV reactivation on HaploHCT outcomes is not yet well-described. In this retrospective study, we evaluated a series of 119 consecutive patients who underwent HaploHCT with PTCy at City of Hope for hematological diseases, between January 2009 and December 2016. CMV reactivation was monitored by our institutional PCR assay (quantitative detection limit: 500 gc/ml, qualitative limit: 250 gc/ml) at least once a week for 100 days post-transplant, with preemptive anti-CMV therapy for positive PCR according to our institutional guidelines.The median age of the cohort was 43 years (range: 2 to 71 years); with 47 female and 72 male patients. CMV serostatus of donor/recipient was Donor−/Recipient− (D−/R−) in 7, D+/R− in 6, D−/R+ in 23, and D+R+ in 82 patients. Patients received fully ablative (n=46) or reduced intensity/non-myeloablative conditioning (n=73) followed by peripheral blood stem cell (n=81) or bone marrow (n=38) graft from sibling (n=42) or non-sibling haploidentical donors (n=77). Graft-versus-host disease (GVHD) prophylaxis was PTCy plus tacrolimus/mycophenolate mofetil. Diagnoses of these patients were acute leukemia (n=80), bone marrow failure (n=15), lymphoma (n=11), chronic leukemia (n=6), hemoglobinopathies (n=5), and multiple myeloma (n=2), and the HCT-comorbidity index was more than 2 in 42% (n=50) of patients.Cumulative incidence (CI) of CMV reactivation for the entire cohort was 68.1% (95%CI: 58.8-75.7%) at 100-days, with the median time to reactivation at 35 days (95%CI: 33-40); 76.2% in seropositive recipients and 7.7% in seronegative recipients (p<0.001). (Figure 1) Among 81 patients with any CMV reactivation; median initial viral load was 624 copies/mL (range: <500- 9930) and peak viral load was 2601 copies/mL (range: <500-166,865) with median CMV area under the curve (AUC) of 28,002 (range: 1671.0-2,149,929.5). In seropositive recipients (n=105), CI of CMV reactivation was 76.5% (95%CI: 66.9-83.6%) with the median onset of CMV reactivation at 33 days (95%CI: 30-36). Majority of patients (n=62) experienced only one reactivation episode with the median duration of 17 days (range=1-62) while 16 patients experienced more than one reactivation episodes with the median duration of 63.5 days (range: 33-78). Prolonged CMV exposure (>17days of CMV viremia) was seen in 47 patients.In univariate analysis; recipient CMV serostatus, recipient sex, and stem cell source were statistical significant factors, affecting CI of CMV reactivation, but only recipient CMV serostatus stood as an independent factor on multivariable analysis (HR=15.5, 95%CI: 2.3-106.3 for R+ compared to R−, p=0.005) (Figure 1). We also evaluated the effect of KIR status on the CI of CMV reactivation. Multivariable analysis indicated a trend towards decreased incidence of CMV reactivation in donors with 2DS5 and 3DS1 (HR= 0.71 for both donors; p value= 0.1). Donor-recipient KIR mismatch was also associated with a trend towards increased incidence of CMV reactivation (p=0.1) and statistically significant prolonged CMV reactivation (OR=2.48, 95%CI: 1.12-5.47, p=.025).With median follow up duration of 24.3 months (range: 10.3 to 99.2) and in univariate analysis, CMV reactivation, higher peak CMV PCR, time to CMV reactivation, or prolonged exposure to CMV were not associated with worse overall survival (OS), relapse-free survival (RFS), relapse incidence, or non-relapse mortality (NRM). Interestingly, the risk of extensive chronic GVHD was greater in patients who had no CMV reactivation than those who developed prolonged/recurrent CMV reactivations (41.9% vs. 26.2%, p= 0.046)In conclusion, recipient and not donor serostatus is predictive of CMV reactivation in HaploHCT with PTCy. With the current pre-emptive therapy approach, CMV reactivation did not translate into higher rate of CMV disease or worse survival outcome. Donor-recipient KIR match (KIR licensing) and donor activating KIR genes (2DS5 and 3DS1) may be involved with CMV control after HaploHCT. [Display omitted] DisclosuresDadwal:MERK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire: Research Funding; AiCuris: Research Funding; Gilead: Research Funding. Ali:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Salhotra:Kadmon Corporation, LLC: Consultancy. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding.

A Delayed Innate T Cell Reconstitution Is Associated with Epstein-Barr Virus Reactivation after Haploidentical Hematopoietic Stem Cell Transplantation Using Anti-Thymoglobulin and High-Dose Post-Transplant Cyclophosphamide

Background: Allogeneic hematopoietic stem cell transplantation (allo-HCT) using a haploidentical donor (haplo-HCT) using post-transplant high-dose cyclophosphamide (PTCy) is increasingly used for patients lacking a matched related or unrelated donor. We recently noticed a relatively high incidence of infectious complications, especially Epstein-Barr virus (EBV) reactivation after haplo-HCT. However, the mechanisms underlying the increased incidence of this complication in the haplo-HCT setting are unknown. We hypothesized that the use of PTCy may be associated with a deficit in innate-like effector T cells essential for preventing EBV reactivation.This study aimed to analyze immune reconstitution following haplo-HCT using peripheral blood stem cells (PBSC) grafts and to evaluate the correlations with EBV reactivation and outcomes.Patients and Methods: One hundred and twenty-three consecutive patients who underwent allo-HCT for hematological malignancies between 2013 and 2016 were included in this single-center retrospective study. All patients received G-CSF mobilized PBSC grafts and ATG 2.5-5 mg/Kg total dose. All patients received a combination of cyclosporine A and mycophenolate mofetil for GvHD prophylaxis, except for patients with a matched related donor (MRD) who received cyclosporine A alone and patients with an haploidentical donor who received PTCy (50mg/kg/d at d3+/-d5). α/β T cells (CD3+, CD4+ and CD8+), γ/δ T cells (pan γ/δ and Vδ2+), mucosal-associated T cells wich express a highly restricted TCR comprising a semi-variant Vα7.2-Jα33 (MAIT), invariant NK T cells, NK cells, B cells, Tregs, monocytes subsets and dendritic cells (myeloid DC, plasmacytoid DC and Slan-DC) were analyzed by multi-color flow cytometry at months (M) 1, 3, 6 and 12 following allo-HCT. Clinical data [acute GvHD (aGvHD), relapse incidence, chronic GvHD (cGvHD), viral reactivations, bacterial and fungal infections, non-relapse mortality (NRM), progression-free survival (PFS), refined GvHD-free and progression-free survival (GPFS), overall survival (OS)] were assessed together with sequential quantitative evaluation of immune subsets.Results: Median age was 55 (range, 17-70) years, with 32 male patients (26%) receiving a graft from a female donor. Diagnoses were myeloid malignancies (66%) or lymphoid malignancies (34%). Thirty-three patients (27%) received a graft from a MRD, 65 from an unrelated donor (MUD, 53%), and 25 from a haplo-identical donor (20%). Thirty patients (24%) with refractory disease received a sequential conditioning regimen while the remaining (n=93, 76%) received a RIC/RTC regimen based on fludarabine, busulfan +/- thiotepa. At d180, the cumulative incidences (CIs) of grade II-IV and grade III-IV aGvHD were 34% and 5%, respectively. The 2 years CIs of cGvHD, extensive cGvHD and relapse were 23%, 8% and 17%, respectively. At 2 years, NRM was 7%, PFS was 77%, GPFS was 66% and OS was 83%. The rate of EBV reactivation was significantly increased in haplo-HCT recipients as compared to fully-matched donor recipients (respectively, 68% versus 26%, P< .001).At one month after allo-HCT, the median counts of all immune cells subsets (except monocytes) was significantly lower in haplo-HCT recipients as compared to MRD or MUD recipients. At 3 months, α/β T cells, iNK T cells, NK cells, B cells, Tregs and Slan-DC reached similar median counts in haplo-HCT recipients as compared to MRD or MUD recipients. In contrast, Vδ2+ T cells and MAIT cells median counts remained significantly lower at 3, 6 and 12 months in haplo-HCT recipients compared to MRD or MUD recipients (at M1, M3, M6, M12, the median Vδ2+ T cells counts were 0.05/µL, 0.24/µL, 1.38/µL and 2.97/µL, and MAIT cells were 0.07/µL, 0.70/µL, 1.00/µL and 1.21/µL, respectively). Lower Vδ2+ T-cells and MAIT cells counts at one month was associated with a significantly increased CI of EBV reactivation (respectively, P=.04 and P<.0001) in landmark study.Conclusion: Immunological reconstitution of innate T cells is significantly delayed after haplo-HCT and low-dose ATG and PTCy. This prolonged deficiency is associated with an increased risk of EBV reactivation. Development of new strategies for innate-T cells expansion are necessary after haplo-HCT. DisclosuresMohty:MaaT Pharma: Consultancy, Honoraria.

Impact of High Donor-Derived CD4+ CCR7+ T Cell Count on Incidence of Grade II-IV Acute Graft-Versus-Host Disease Following Haploidentical Hematopoietic Cell Transplantation

IntroductionHistorically the administration of post-transplant high-dose Cyclophosphamide (PTCy) has led to haplo-HCT re-innovation.Although PTCy has a positive impact towards reducing severe acute graft-versus-host disease (aGVHD), this drug has serious adverse side effects and makes haploidentical-HCT more difficult in some patients-particularly in older patients and/or those presenting other comorbidities.Considering our previous published experience in the effect of graft lymphocyte composition, this work aims to explore the impact of infused T cell subsets on Overall Survival (OS), Event Free Survival (EFS) and acute GVHD in a retrospective cohort receiving allogeneic haplo-HCT.MethodsThis study retrospectively analyzed 29 adult patients who underwent first allogeneic haplo-HCT for hematologic malignancies at Lille University Hospital (CHRU Lille, France).Graft samples were analyzed by flow cytometry, and CD4 and CD8 T cell subsets were defined as follows: TN=naïve T cells; , TCM=central memory T cells; TEM=effector memory T cells; TTD =terminally differentiated T cells.ResultsThe median follow-up of patients was 11 months (0.4-44.3). The cohort median recipient age was 59 years old. Cumulative incidences of grade 2 to 4 aGVHD were 31%. The rate of grade 3 to 4 severe GVHD was 17%. Eleven patients died with 14% of deaths due to non-relapse mortality.We found a correlation between high percentage of donor-derived CD4+ CCR7+ T cells (>69.2% for CD4+ T cells-the median value in our study) and aGVHD (p=0.028) without any impact on OS and EFS (Table 1).In multivariate analysis, only high proportions of donor CD4+ CCR7+ T cells correlated significantly with aGVHD (HR=0.203, 95% CI [0,042-0,980], p=0,047) without any impact on OS and EFS (Figure 1).ConclusionNaïve and central memory T cells expressing CCR7 exhibit higher alloreactivity potential than CCR7- T cells. In this study, even with PTCy administration, we observed that a high percentage of donor-derived CD4+ CCR7+ T cells can be considered as a predictive indicator of grade II-IV aGVHD post Haplo-HCT. Thus, selective depletion of CD4+ CCR7+ T cells might be enough to prevent aGVHD in haplo-HCT, enabling the use of low doses of PTCy in order to reduce post haplo-HCT complications. DisclosuresNo relevant conflicts of interest to declare.

Achievement of High Concentration of Cyclosporine-a Is Associated with a Low Incidence of Acute Graft-Versus-Host Disease after Haploidentical Hematopoietic Cell Transplantation Using Post-Transplant Cyclophosphamide and Peripheral Blood Stem Cell Graft

Background: Allogeneic hematopoietic stem cell transplantation using a related haploidentical donor (Haplo-HCT) using post-transplant high-dose cyclophosphamide (PTCy) is increasingly used for patients lacking a matched related or unrelated donor. However, use ofperipheral blood stem cell graft (PBSC) is associated with an increased risk of acute GvHD (aGvHD) compared to bone-marrow graft. Therefore, while cyclosporine A (CsA) and mycophenolate mofetil (MMF) are traditionally initiated after completion of PT-Cy at day +5, we decided to initiate them at day -3 before transplant and to add a low dose of ATG to reinforce GvHD prophylaxis in those patients. With this background, we analyze retrospectively the impact of early initiation of CsA and of CsA concentration on patients' outcome in all patients who underwent Haplo-HCT with PBSC grafts and PTCy.Patients and Methods: Sixty-one consecutive patients who underwent Haplo-HCT for hematological malignancies between October 2013 and August 2017 were included in this retrospective single-center study. All patients received G-CSF mobilized PBSC as grafts and post-transplantation immunosuppression with CsA and MMF. CsA was administered at a dose of 3mg/kg by continuous intravenous infusion starting from D -3 and changed to twice daily oral dosing as soon as tolerated.MMF was administered at a fixed oral dose of 2g per day starting from day 6 without adjustment. In the absence of GvHD, MMF and CsA were tapered over 4 weeks starting from day 30 and day 60, respectively. CsA blood trough concentrations were monitored 3 times per week during the intravenous treatment and at least once per week after switch to oral dosing. CsA doses were adjusted to achieve blood levels between 200 and 300 ng/mL and to prevent renal dysfunction. The primary endpoint was to determine the impact of the CsA concentration on the risk of grade II-IV and III-IV aGvHD.Results: Median age was 53 (range, 15-72) years, with 16 male patients (26%) receiving a graft from a female donor. Diagnoses were myeloid (64%) or lymphoid malignancies (36%). According to the Disease Risk Index, patients were considered as low-risk, intermediate-risk, high-risk or very-high-risk (respectively 8%, 56%, 31% and 5%). Twenty-five patients (41%) with refractory disease received a sequential conditioning regimen while the remaining (n=36, 59%) received a RIC/RTC regimen based on fludarabine, busulfan and thiotepa. 51 patients (83%) received ATG (2.5-5 mg/Kg total dose) as part of the conditioning regimen. All patients received standard PTCy, nine at D+3 (15%) and 52 at D+3 and D+5 (85%). All patients engrafted at a median of 18 (range: 13-35) days after Haplo-HCT and the median follow-up among surviving patients was 21 (range: 13-53) months. The median concentrations of CsA at 1, 2, 3, and 4 weeks after Haplo-HCT were 272 (range: 114-911), 296 (range: 132-516), 251 (range: 111-485), and 246 (range: 36-375) ng/mL, respectively. At d180, the cumulative incidences (CIs) of grade II-IV and grade III-IV aGvHD were 39% and 18%, respectively. The CIs of chronic GvHD (cGvHD), extensive cGvHD and relapse were 41%, 19% and 35% at 18 months after Haplo-HCT, respectively. At 18 months after the transplant, the OS, PFS and GPFS rates were respectively 60%, 55% and 48%. In univariate analysis, patients having the lowest CsA concentration in the first week after Haplo-HCT had a significantly higher risk of grade II-IV aGvHD (49% vs 18%; P= .02), severe grade III-IV aGvHD (26% vs 0%; P = .03), cGvHD (P= .02) and extensive cGvHD (P= .04). We do not find statistically significant correlation between CsA concentration and relapse incidence, NRM, PFS, GPFS or OS. In multivariate logistic regression analysis, higher CsA concentration (> 301 ng/ mL; the cut-off value defined by ROC analysis) during the first week following Haplo-HCT was the only independent parameter significantly associated with a reduced risk of grade II-IV and grade III-IV aGvHD (respectively P = .04; RR .11; 95% CI, 0.05-0.94; and P < .0001; RR < .001; 95% CI, 0.000007-0.00006). There was no association with extensive cGvHD (P = .14; RR .11; 95% CI, 0.06-1.48).Conclusion: We conclude that achievement of high concentration of CsA early after Haplo-HCT using PBSC graft is associated with a low incidence of aGvHD and that CsA should be initiated at time of transplant with adequate monitoring during the engraftment period to reduce the risk of grade II-IV aGvHD. DisclosuresMohty:MaaT Pharma: Consultancy, Honoraria.

HLA Class II Epitope Mismatch Influences Relapse and Engraftment in Peripheral Blood Haploidentical Hematopoietic Cell Transplantation

Background: High dose post-transplant cyclophosphamide has improved and expanded the use of haploidentical hematopoietic cell transplantation (haplo-HCT). The impact of HLA disparity in this setting, however, is unclear and traditionally measured at the antigen or allele level. The HLA Matchmaker tool more precisely quantifies HLA disparity by calculating the number of mismatched three-dimensional amino acid patches, or epitopes, on the surface of two mismatched HLA antigens. Previous research has shown that class II epitope mismatch (EM), which includes the combination of DRB1 and DQB1 EM, is associated with reduced relapse and delayed engraftment in haplo-HCT (Rimando et al, ASBMT 2018 Abstract ID#53). The individual impact of DRB1 and DQB1 EM on clinical outcomes is currently unclear.Methods: 148 patients who received a peripheral blood T cell-replete haplo-HCT at a single center between July 2009 and November 2017 were retrospectively analyzed. All patients age ≥ 18 were included regardless of diagnosis. The HLA EM load for total class II disparity, DRB1, and DQB1 was quantified using the HLA Matchmaker software and a python script in a dose-dependent and vector-stratified fashion. The primary outcome was the incidence of relapse. The secondary outcomes included relapse-free survival (RFS), time to neutrophil engraftment, and time to platelet engraftment. The association between HLA EM and outcome was analyzed using the Cox proportional hazard model or Gray's sub-distribution method for competing risk as appropriate. The hazard ratios calculated report the hazard rate for a single unit increase in EM. This study was approved by the Institutional Review Board.Results: In this updated cohort, class II graft-versus-host (GvH) EM was again associated with reduced incidence of relapse (HR 0.966; 95% CI 0.938-0.995; p=0.023) and improved RFS (HR 0.978; 95% CI 0.957-0.999; p=0.037) (Table 1). Class II host-versus-graft (HvG) EM was again associated with delayed neutrophil (HR 0.976; 95% CI 0.955-0.997; p=0.027) and platelet (HR 0.971; 95% CI 0.950-0.993; p=0.010) engraftment. Neither DRB1 nor DQB1 GvH EM was independently associated with relapse or RFS. DRB1 HvG EM was associated with worse relapse-free survival (HR 1.038; 95% CI 1.002-1.076; p=0.040). DRB1 HvG EM was associated with delayed time to neutrophil engraftment (HR 0.965; 95% CI 0.934-0.997; p=0.033), while DQB1 HvG EM was not. DQB1 HvG EM was associated with delayed time to platelet engraftment (HR 0.967; 95% CI 0.938-0.997; p=0.032), while DRB1 HvG EM was not.Summary: HLA Matchmaker software enables the quantification of HLA EM in haplo-HCT patients. Neither DRB1 nor DQB1 GvH EM was independently associated with relapse or RFS. DRB1 HvG EM was associated with neutrophil but not platelet engraftment, while DQB1 HvG EM was associated with platelet but not neutrophil engraftment. HLA EM represents a novel strategy to predict clinical outcome in haplo-HCT. The mechanism for the divergent roles of DRB1 EM and DQB1 EM on neutrophil and platelet engraftment are currently unknown and warrant further investigation. DisclosuresNo relevant conflicts of interest to declare.

Steroid-Refractory Acute Gvhd in Children: Retrospective Analysis of the AIEOP HSCT Registry

Introduction. Severe acute graft-versus-host disease (GVHD) remains the most relevant complication after allogeneic HSCT. Although its incidence in the pediatric population is lower than in adults, children with severe acute GVHD and who do not respond to first-line treatment with systemic steroids still have a poor prognosis. The exact incidence of steroid-refractory acute GVHD in children is still not precisely defined, as well as the risk of non-relapse mortality (NRM) due to steroid-refractory acute GVHD. Aim of our study was to analyze the frequency of acute GVHD unresponsive to first-line steroid treatment in children and adolescents given allogenic HSCT, to describe the second line treatment employed, and the outcome of patient with this complication.Patients and methods. This retrospective study included patients younger than 18 years at the time of transplantation and given a first allogeneic HSCT between 2010 and 2015 in one of the HSCT Centers of the Italian Association for Pediatric Hematology / Oncology (AIEOP). Overall, 1608 patients (59% M and 41% F) were analyzed. Median age at HSCT was 8 years (range 0.2 - 18) 1084 (67%) were affected by malignant diseases and 524 (33%) by non-malignant disorders. The donor was an HLA-matched family donor (MFD) in 28% of cases, an unrelated donor (UD) in 52% and an HLA-haploidentical family donor in 20%. In MFD transplants Cyclosporine (CSA) was used as GVHD prophylaxis in 30% of cases and the combination of CSA + short-term methotrexate (MTX) in 48%. 75% of UD transplant recipients received CSA + MTX + anti-thymocyte globulin (ATG) as GVHD prophylaxis, and 25% other drug combinations. Ex vivo T-cell depletion of the graft was employed in most patients given a HLA-haploidentical HSCT (79% of transplants), and high-dose post-transplant cyclophosphamide in 11% of cases.Results. The cumulative incidence (CI) of grade II-IV acute GVHD was 31%, while that of grade III-IV acute GVHD was 10%. The overall incidence of chronic GVHD was 13% and that of extensive chronic GVHD was 6%. The CI of NRM was 14% for grade 0 acute GVHD patients, 9% for grade I, 11% for grade II, 26% for grade III and 68% for grade IV (P < 0.001). Of the 491 patients with grade II-IV acute GVHD, 250 (51%) required a second-line treatment after first-line steroid therapy (30% of grade II, of 75% grade III and 83% of grade IV patients). Acute GVHD requiring second-line treatment was more frequent in UD transplant recipients (21% of patients) than in matched sibling or haploidentical donor recipients (7% and 13% respectively, P < 0.01), while age at HSCT and diagnosis (malignant vs. non-malignant disease) were not associated with this complication. Second-line treatment was extracorporeal photochemotherapy in 60% of patients, mofetil mycophenolate (MMF) in 46%, mesenchymal stromal cells (MSC) in 12%, monoclonal antibodies (MoAbs) in 5% and other treatments in 28%; 32% of patients received more than one second line treatment. Overall NRM was 13% for patients with grade 0-I acute GVHD, 15% for grade II-IV responding to steroids, and 25% for grade II-IV patients requiring second-line therapy (P < 0.001). The addition of a second-line treatment partially decreased NRM only in patients with grade IV acute GVHD, but the difference was not statistically significant (66% vs. 78%; P = 0.313). In multivariable analysis, grade III (HR = 1.84; P = 0.044) and grade IV acute GVHD (HR = 7.07; P < 0.001), and the use of an UD (HR = 1.63; P = 0.007) were associated with an increased NRM, while the use of a second-line treatment did not decrease this risk (HR = 0.80; P = 0.368).Conclusions. Despite being less frequent than in adults, severe steroid-refractory acute GVHD is still associated with a very high NRM also in pediatric patients. Second or third-line treatments adopted so far have not been effective in improving control of the complication and in decreasing NRM. The prospective evaluation of acute GVHD biomarkers (such as ST2 and REG3α) could help in identifying patients at higher risk of NRM. Prospective studies are warranted to define new treatment modalities that could decrease the mortality rate associated with the most severe form of disease. DisclosuresZecca:Chimerix: Honoraria. Locatelli:bluebird bio: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria.

Haploidentical Transplantation Using High Dose Post-Transplant Cyclophosphamide for Patients with Aplastic Anemia : The European Group for Blood and Marrow Transplantation Experience

The outcome of patients with severe aplastic anemia (SAA) has greatly improved in recent years but is still poor for patients who failed or relapsed after immunosuppressive therapy (IST) and don't have a matched donor. Recent use of eltrombopag shows blood count improvements in 40% of cases, but most patients refractory to immunosuppressive therapy, are also unresponsive to eltrombopag. In this situation, hematopoietic stem cell transplantation (HSCT) using alternative donor sources (mismatched unrelated donors, cord blood, and haploidentical family donors) may be curative but are also associated with a high risk of morbidity and mortality. Moreover, ethnic minorities have limited access to an alternative donor, especially in the adult population. Haploidentical transplantation using post-transplant cyclophosphamide (Haplo-PTCy) has been shown to facilitate engraftment and shows GvHD rates comparable to those of matched sibling HSCT in hematologic malignancies. However, few papers have been published on Haplo-PTCy in the context of aplastic anemia.We conducted a retrospective analysis of 36 patients (72% male), who received an haplo-PTCy for aplastic anemia in 22 EBMT centers from June 2010 to March 2017. Haplo-PTCy was the first transplantation for 81% patients (second, 11%; third, 8%). The non-myeloablative preparatory regimen included anti-thymocyte globulin in 33% of patients and low dose TBI in 58% of patients. Donors were father (n=12, 35%), mother (n=12, 35%), brother (n=5, 15%), sister (n=3, 9%), cousin (n=1, 3%) and daughter (n=1, 3%). The stem cell source was mainly bone marrow (55%). All patients received cyclophosphamide 50mg/kg/day IV on days +3, and +4 post-transplant and 75% received tacrolimus or cyclosporine plus mycophenolic acid. The primary endpoint was the probability of OS. Secondary study endpoints included probability of neutrophil recovery (ANC 500/ μL for at least 3 consecutive days), platelet recovery (platelets 20 000/ μL for at least 3 consecutive days, and 7 days after the last transfusion), cumulative incidences of acute and chronic GVHD and relapse-free survival without Grade III-IV acute GvHD and without extensive chronic (GRFS).Thirty-two patients were diagnosed with moderate (7%), severe (52%) or very severe idiopathic aplastic anemia (41%), while 4 patients were transplanted for congenital aplastic anemia (3 Fanconi Anemia and 1 Diamond Blackfan). The median age was 19.4 years (range 2.5-45.4 years; 58% adults). Median disease duration before haplo-PTCy was 11.3 months (1.9-201.2). Thirty patients (83%) received pretreatment (77% anti-thymocyte globulin plus cyclosporine, 12% eltrombopag, and 1 patient (3%) received androgens). Cumulative incidence (CI) of neutrophil recovery at day 60 was 78% (64-91) with a median time of 21 days (18-26). Cumulative incidence (CI) of platelet recovery at day 60 was 60% (44-76) with a median time of 31 days (22-185). The CI of grade II-IV acute GvHD was 26% (12-41%) (grade II 19% (7-32%), grade III 6% (0-13%) and no grade IV). CI of chronic GvHD was 17% (5-30) at 1 year (6% (0-13%) extensive) and a CI of 22% (7-37) at 2 years (only limited, there was no new case of extensive cGvHD after one year). With a median follow-up of 24.6 months (15.9 - 38.2), the estimated probability of overall survival (OS) was 78% (64-91) at 1 year and 74% (60-89) at 2 years. Of note, among the 4 patients with inherited disorders, 2 died [1 infection (Diamond Blackfan) and 1 aGvHD (Fanconi Anemia)] and 2 are alive at month 12 and month 15 of follow-up, respectively. Nine patients died during the study. The main cause of death was infection (n=6, 67%). Finally, the GRFS (alive, full donor chimerism, without previous grade III-IV GvHD and without extensive cGvHD) was 58% (41-75) at 2 years.In conclusion, with a median follow-up of 2 years, Haplo-PTCy leads to 74% overall survival in 36 patients with aplastic anemia, with almost 60% of the patients being free from GvHD complication. In a population with no other therapeutic options, our data suggests haplo-PTCY is a feasible option. However, prospective well-designed trials are urgently needed before the inclusion of Haplo-PTCy in the treatment strategy of aplastic anemia. DisclosuresBloor:Janssen: Research Funding; AbbVie: Research Funding. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Tilly:Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Russell:Pfizer: Consultancy, Honoraria, Speakers Bureau; Jazz Pharma: Speakers Bureau; Daiichi Sankyo: Consultancy. Kerre:Celyad: Consultancy; BMS: Consultancy; Celgene: Consultancy, Research Funding. Peffault De Latour:Novartis: Consultancy, Honoraria, Research Funding; Pfizer Inc.: Consultancy, Honoraria, Research Funding; Amgen Inc.: Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding.

Post-Transplant High-Dose Cyclophosphamide Overcomes the Detrimental Effect of a Single-Locus HLA Mismatched in Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation

Background: Allogeneic hematopoietic stem cell transplantation (alloSCT) from unrelated donors mismatched (MMUD) at a single HLA-A, -B, -C, or -DRB1 locus (7/8) were previously reported to be associated with lower overall survival (OS) and disease-free survival (DFS), higher treatment-related mortality (TRM), and more acute graft-versus-host disease (GVHD) compared to 8/8 matched unrelated (MUD) allografts. Despite these risks, 7/8 MMUD grafts remain a viable option for alloSCT, particularly in patients who lack suitable donors or in those with aggressive hematologic malignancies for whom the risks of disease progression due to delays in identifying optimal donors is offset in part by the benefits of earlier transplantation with a 7/8 MMUD alloHCT. According to the published experience of post-transplant cyclophophamide (PTCy) in the context of haploidentical alloSCT, this GVHD prophylaxis strategy could potentialy overcome the detrimental effect of a single-locus HLA MMUD.Methods: We retrospectively analyzed 72 consecutive adult patients (median age 53y, range 18-69) who received 7/8 MMUD (n=44) or 8/8 MUD (N=28) alloSCT with PTCy in our institution. Unrelated donor selection was performed according to standard criteria, including high resolution typing for alleles at HLA-A, -B, -Cw, DRB1 and DQB1. For those patients in whom an 8/8 HLA-matched related or unrelated donor was not available, a search was performed based on a single HLA-mismatch.Results: Acute myeloid or lymphoblastic leukemia accounted for 51% of all hematologic diseases, myelodisplastic syndrome for 17%, chronic lymphoproliferative or myeloproliferative disorders for 28%, and severe aplastic anemia for 4%. Disease Risk Index (DRI) was intermediate in 51%, high 16% and very high 6%. Forty-four percent of patients had a HCT-CI ≥3. All patients, except 6 have received peripheral blood stem cells (PBSC). Fludarabine-based conditioning regimens were used in all patients (fludarabine-busulphan in 61%); of them, myeloablative (MAC) in 34 patients (47%) and RIC in 38 (53%). GVHD prophylaxis consisted on PTCy 50mg/kg IV on days 3 and 4 after transplant followed by one (tacrolimus or mycophenolate mofetil, MMF) (n=62, 86%) or 2 (n=10, 14%) immunossuppresor drugs. All but two patients engrafted and the median time to neutrophil (>500/mL) and platelet (>20,000/mL) recovery were 18 days (range 11-30) and 18 days (10-47), respectively. Thirteen patients (18%) developed an invasive pulmonary Aspergillosis, 20 (27%) had severe bacterial infection, 40 (56%) CMV reactivation, 5 (7%) cytomegalic disease and 3 EBV reactivation. The cumulative incidences of 1-year TRM, 100-days acute grade II-IV, 100-days grade III-IV GHVD, and 1-year moderate-severe chronic GHVD were 19%, 24%, 13%, and 11%, respectively. The cumulative incidence of relapse at 1-year was 16%. After a median follow-up for surviving patients of 12 months (2-60), 2-year OS, DFS, and survival free of moderate/severe chronic GVHD and relapse (cGRFS) were 64%, 61%, and 49%, respectively. Univariate analysis of variables that could influence OS, PFS, and cGRFS, including age, donor/patient sex, comorbidity, DRI, conditioning type, 1 vs. 2 immunosuppressors, and HLA 7/8 vs. 8/8 did not show any statistical differences. At 6 and 12 months after alloSCT, 42% and 73% of patients alive and without relapse were free of immunosuppressor drugs and prednisone.Conclusions: This study suggests that PTCy after unrelated PBSC alloSCT results in a low incidence of acute and chronic GVHD with encouraging survival outcomes even in the context of 7/8 HLA-mismatched transplant. An immunosuppressive schema of intermediate intensity such as PTCy followed by single-agent tacrolimus may provide an adequate GVHD prophylaxis and could be a good alternative to ATG in both MMUD and MUD transplants. Confirmatory and comparative studies are warranted to examine the effect of this approach on alloSCT outcomes. DisclosuresRosinol:Janssen, Celgene, Amgen, Takeda: Honoraria. Martinez:BMS: Research Funding; Takeda: Consultancy.

Clofarabine-based reduced intensity conditioning regimen with peripheral blood stem cell graft and post-transplant cyclophosphamide in adults with myeloid malignancies.

BackgroundThe Baltimore reduced-intensity conditioning (RIC) regimen using high-dose post-transplant cyclophosphamide (PTCY) is considered as a standard of care for haploidentical allogeneic stem cell transplantation (allo-SCT). However, it is associated with relatively low survivals and high incidence of relapse, especially when considering myeloid malignancies.ResultsThis retrospective study included 36 adults (males n = 18; median age: 60.5 years old; haplodonors n = 27; matched donors n = 8) with myeloid malignancies transplanted between March 2014 and March 2017 at the University Hospital of Nantes. Very encouraging results were observed with a 18-month overall survival (OS), disease-free survival (DFS) and relapse incidence (RI) of 72% ± 7.5%, 63.8 ± 8%, and 25 ± 6% respectively, and a GVHD relapse-free survival (GRFS) of 52.6 ± 8%. In univariate analysis, there were no differences regarding 18-month survivals between patients allografted: i) for acute myeloid leukemia vs myelodysplastic syndrome (OS 70 ± 11% vs 69.2 ± 13%, p = 0.3; DFS 64.7 ± 11% vs 61.5 ± 13%, p = 0.65), or ii) with haplo-identical vs other donors (OS: 66.2 ± 9% vs 88.8 ± 10.4%, p = 0.16; DFS 59 ± 9.5% vs 77.8%, p = 0.6).ConclusionThe “Clo-Baltimore regimen” is safe and feasible and provides good survivals for patients with myeloid malignancies and haplo-donors.MethodsHere, we report a variant of the Baltimore regimen, where 1) fludarabine was replaced by clofarabine, 2) bone marrow was replaced by peripheral blood stem cells, and 3) tacrolimus was replaced by cyclosporine, in a “Clo-Baltimore regimen”.

Haploidentical Transplants with Post-Transplant Cyclophosphamide for Relapsed or Refractory Hodgkin Lymphoma: The Role of Comorbidity Index and Pretransplant Positron Emission Tomography

Disease relapse remains an unmet medical need for patients with Hodgkin lymphoma (HL) receiving an allogeneic hematopoietic cell transplantation (HCT). With the aim of identifying patients at high risk for post-transplant relapse, we retrospectively reviewed 41 HL patients who had received haploidentical (haplo) nonmyeloablative (NMA) HCT with high dose post-transplant cyclophosphamide (PT-Cy) for graft-versus-host (GVHD) prophylaxis. Primary refractory disease, relapse within 6 months from autologous stem cell transplantation, age, pretransplant chemotherapy, HCT comorbidity index (HCT-CI), sex mismatch, tumor burden and pretransplant fluorodeoxyglucose positron emission tomography (FDG-PET) status, assessed by Deauville score, were analyzed as variables influencing outcomes. All but 1 patient engrafted: median time to neutrophil and platelet recovery was 15 (interquartile range, 13 to 23) days and 19 (interquartile range, 12 to 28) days, respectively. Cumulative incidence of severe (grade III to IV) acute graft-versus-host disease (GVHD) and 3-year moderate-severe chronic GVHD was 2.4% and 11.8%, respectively. The 3-year overall (OS), progression free (PFS), and graft relapse-free survival (GRFS) were 75.6%, 43.9%, and 39%, respectively. On multivariate analysis, 3-year OS was significantly worse in patients with HCT-CI ≥3 (hazard ratio [HR], 5.0; 95% confidence interval [CI], 1.1 to 21.8; P = .03). Three-year relapse rate, 3-year PFS, and 3-year GRFS were significantly worse in patients with HCT-CI ≥3 (HR, 3.5; 95% CI, 1.3 to 9.3; P = .01; HR, 3.3; 95% CI, 1.2 to 9.0; P = .02; and HR, 4.2; 95% CI, 1.7 to 9.9; P = .001, respectively) and in patients with a Deauville score ≥4 on pretransplant FDG-PET (HR, 4.4; 95% CI, 1.6-12.4; P = .005, HR, 3.8; 95% CI, 1.5 to 9.7; P = .005; and 3.2; 95% CI, 1.3 to 7.9; P = .01, respectively). On univariate analysis, 3-year NRM was significantly worse only in patients with a HCT-CI ≥3 (HR, 17.6; 95% CI, 1.4 to 221.0). Among relapsed or refractory HL patients undergoing haplo NMA HCT with PT-Cy, pretransplant FDG-PET with a Deauville score ≥4 and HCT-CI ≥3 identified patients at high risk of relapse. Moreover, an HCT-CI ≥3 was associated with higher NRM and lower OS.