Grade III-IV Acute Graft-versus-host Disease Research Articles

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 > 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.

CD34+ Cell Dose Influences Survival after Allogeneic Peripheral Blood Stem Cell Transplantation with Post-Transplant Cyclophosphamide

Introduction: Higher infused total nucleated cell dose (TNC) in allogeneic bone marrow transplant (BMT) with post-transplant cyclophosphamide (PTCy) resulted in improved overall survival (OS) in a recent report (McCurdy, et al. BBMT. 2018). As many centers prefer peripheral blood stem cell grafts (PBSCT) with PTCy, the optimal cell dose with this platform requires elucidation. Methods: We retrospectively evaluated 144 consecutive adult patients with hematologic malignancies treated at the Moffitt Cancer Center between 2012-2018 with allogeneic T-cell replete PBSCT followed by PTCy-based graft-versus-host disease (GVHD) prophylaxis. Data were extracted from the Moffitt BMT Research & Analysis Information Network (BRAIN) database. Both myeloablative (n=87) and reduced intensity (n=57) conditioning regimens were included. For analyses, CD34+ cell dose was stratified into low (<5 x106/kg), intermediate (5-10 x 106/kg) and high (>10x106/kg). TNC was stratified as higher or lower than the median. CD3+ T cell dose was evaluated as a continuous, linear variable. Associations with transplant related survival outcomes were assessed using univariate and multivariate Cox proportional hazard survival models. Fine and Gray regression models were used to assess associations of transplant related endpoints with competing risks. Kaplan Meier curves and cumulative incidence function curves were also plotted. RESULTS: The median follow-up for the entire cohort was 24 months. The median age at PBSCT was 58 (range: 21-76) years. Donors were haploidentical (n=72, 50%), matched unrelated (n=39, 27%), matched related (n=18, 13%), and mismatched unrelated (n=15, 10%). Median CD34+ cell dose was 8.12 x 106/kg (range: 2.27 - 22.4 x 106/kg). Stratified CD34+ dose was low for 16 patients (11.1%), intermediate for 93 patients (64.6%), and high for 35 patients (24.3%). Median CD3+ dose was 2.89 x 108 (range: 2.33 x 105 - 6.54 x 108/kg). Median TNC was 9.66 x 108/kg (range: 3.82 x 108 - 1.04 x 109/kg). Overall, successful neutrophil engraftment by day 30 was achieved in 94% (95% CI 91-98%) and platelet engraftment (>20,000/mL) by day 100 in 87% (95% CI 81-93%) of all patients. The likelihood of neutrophil recovery was similar in the high and low CD34+ cell groups, while it was higher for the intermediate CD34+ cell group (HR=1.52, 95% CI 1.0-2.2; p=0.03). Platelet recovery was similar in the intermediate and high CD34+ cell groups, but significantly lower in low CD34+ cell group (HR=0.38, 95% CI 0.2-0.8; p=0.01). CuI of grade II-IV acute GVHD at day 100 was 39% (95% CI 32-48%) and of grade III-IV acute GVHD was 10% (95% CI 6-17%). CuI of chronic GVHD at 2 years was 50% (95% CI 41-59%). The CD34+ cell dose had no significant impact on either acute or chronic GVHD. Nonrelapse mortality (NRM) at 1 year was 19% (95% CI 13-27%). By CD34+ cell dose, the rates of NRM for low, intermediate, and high dose were 46% (95% CI 25-85%), 15% (95% CI 10-25%), and 15% (95% CI 7-34%), respectively (p=0.002). Relapse rate was 30% at 2 years with no differences across dose levels. Progression free survival (PFS) probability at 2 years was 47% (95% CI 39-57%) for the entire group, 0% (95% CI 0%) for the CD34+ low group, 53% (95% CI 42-65%) for the intermediate group and 51% (95% CI 35-73%) for the high dose group (p=0.0003). Two-year OS for the entire group was 57% (95% CI 49-67%), and was inferior in the low group (0%, 95% CI 0%) with no difference between the intermediate (61%, 95% CI 50-73%) and high (67%, 95% CI 52-87%) CD34+ cell dose groups (p=0.0002). In multivariable modeling, the low CD34+ cell dose group was associated with worse NRM (HR=4.1, 95% CI 1.2-14.5, p=0.03), PFS (HR=2.9, 95% CI 1.3-6.5, p=0.01), and OS (HR=3.2, 95% CI 1.4-7.6, p=0.01) compared with the high group, while there were no differences between the high and intermediate groups. Increasing CD3+ dose was also associated with improved NRM (HR=0.8, 95% CI 0.69-0.97, p=0.02), PFS (HR=0.7, 95% CI 0.5-0.9, p=0.02), and OS (HR=0.7, 95% CI 0.5-0.9, p=0.004). TNC had no impact on survival outcomes. CONCLUSION: In patients receiving allogeneic PBSCT with PTCy, CD34+ cell doses below 5 x 106 cells/kg yielded inferior OS and PFS, attributable to higher NRM. Doses of 5-10 x 106 cells/kg and >10 x 106 cells/kg resulted in comparable outcomes. Higher CD3+ dose/kg was also associated with improved survival outcomes. Overall, this study supports targeting a CD34+ dose of >5 x 106 cells/kg for allogeneic PBSCT with PTCy. Disclosures Nishihori: Novartis: Research Funding; Karyopharm: Research Funding. Bejanyan:Kiadis Pharma: Other: advisory board.

Steep Neutrophil Recovery Following Unrelated Bone Marrow Transplantation Is a Major Risk Factor for the Development of Acute Graft-Vs-Host Disease

Background: Neutrophil recovery following allogeneic hematopoietic cell transplantation (allo-HCT) varies widely among patients. Some cases have a rapid increase in neutrophils and early engraft, while others show slow increase after neutrophils appearance and take time until engraftment. Such differences in neutrophil recovery may reflect the composition of the graft and affect the complications or prognosis after allo-SCT, though it has not been well documented in the literature. In this study, we retrospectively analyzed the influence of the slope of neutrophil recovery (N slope) following allo-HCT on post-transplant complications and prognosis. Methods: This study was a retrospective analysis of 120 patients with hematopoietic diseases who undergone first unrelated bone marrow transplantation at Jichi Medical University between January 2009 and December 2018. Patients who failed to achieve engraftment or did not receive granulocyte-colony stimulating factor were excluded. The N slope was defined as the increase of neutrophil counts from the last day of lowest neutrophil count after transplantation to the date of neutrophil engraftment. We evaluated the predictive value of N slope for acute graft-versus-host disease (GVHD) using the area under the receiver operating characteristic (ROC) curve and determined the cut-off value to maximize the sum of the sensitivity and specificity. Results: The median N slope was 205.5 /µL/day (range 26.4-7574). An ROC analysis showed that a cut-off value of N slope for grade II-IV acute GVHD was 207.5 /µL/day (sensitivity 0.73, specificity 0.6, AUC = 0.67, 95 % confidence interval (CI) = 0.59-0.79). Then, we classified patients into the low (n = 59) and high (n = 61) N slope groups according to the cut-off value of 200 /µL/day. The high N slope group correlated with older patients, RIC regimen, higher infused CD34+ cells ≥ 1.5 × 106/kg, and former transplantation between 2009 and 2013 compared with the low N slope group (p = 0.028, p = 0.003, p = 0.036 and p = 0.025, respectively). Cumulative incidence of grade II-IV acute GVHD at day 100 was significantly higher in the high N slope group than the low N slope group (44.3 % vs. 16.9%, p = 0.0007). With regard to the risk factors for grade II-IV acute GVHD, male, donor age ≥ 40 years, N slope ≥ 200 /µL/day and former transplantation between 2009 and 2013 were significant in univariate analysis. In multivariate analysis, donor age ≥ 40 years, N slope ≥ 200 /µL/day and former transplantation were identified as significant independent risk factors (hazard ratio (HR) 3.6, 95%CI 1.7-7.7, p = 0.001; HR 2.8, 95%CI 1.5-5.3, p = 0.002; HR 3.0; 95%CI 1.5-6.1, p = 0.02;, respectively). Cumulative incidence of grade III-IV acute GVHD at day 100 and chronic GVHD at 2 years did not differ in the high and low N slope groups (10.8 % vs. 5.1 %, p = 0.328; 63.3 % vs. 50.1 %, p = 0.12, respectively). In addition, there was no difference in relapse, non-relapse mortality and overall survival between the two groups (p = 0.76, p = 0.32, p = 0.65, respectively). Conclusion: The current study showed that a steeper slope of neutrophil recovery following HCT was associated with increased acute GVHD, though it did not affect relapse, NRM and OS. Early diagnosis and therapeutic intervention for acute GVHD may improve the outcome of patients with rapid neutrophil recovery. Disclosures Kanda: Chugai: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Ono: Consultancy, Honoraria, Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Ono: Consultancy, Honoraria, Research Funding; Nippon-Shinyaku: Research Funding; Takara-bio: Consultancy, Honoraria; CSL Behring: Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; CSL Behring: Research Funding; Mochida: Consultancy, Honoraria; Eisai: Consultancy, Honoraria, Research Funding; Taisho-Toyama: Research Funding; Otsuka: Research Funding; MSD: Research Funding; Takara-bio: Consultancy, Honoraria; Shionogi: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding; Nippon-Shinyaku: Research Funding; MSD: Research Funding; Asahi-Kasei: Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Tanabe Mitsubishi: Research Funding; Celgene: Consultancy, Research Funding; Mochida: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Dainippon Sumitomo: Consultancy, Honoraria, Research Funding; Asahi-Kasei: Research Funding; Pfizer: Research Funding; Alexion: Consultancy, Honoraria; Sanofi: Research Funding; Celgene: Consultancy, Research Funding; Otsuka: Research Funding; Taiho: Research Funding; Novartis: Research Funding; Taiho: Research Funding; Taisho-Toyama: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Dainippon Sumitomo: Consultancy, Honoraria, Research Funding; Tanabe Mitsubishi: Research Funding; Sanofi: Research Funding; Novartis: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding.

Fast CMV and EBV Reactivations after Ruxolitinib for Graft-Versus-Host Disease Treatment

Introduction: Corticosteroid-refractory graft-versus-host disease (GVHD) remains a serious complication of hematopoietic stem cell transplantation (HSCT) with high morbidity and mortality rates. Unfortunately, no standard therapy exists for this setting. Ruxolitinib (ruxo), an oral selective Janus-associated kinase (JAK) inhibitor, achieved good results for corticoresistant acute and chronic GVHD in preclinical and clinical studies, with 80% overall response rates. Recent studies showed an increased risk of infections in patients treated with ruxo, especially Epstein-Barr virus (EBV) and cytomegalovirus (CMV) reactivations. Patients and methods: In order to assess the efficacy and the safety of ruxo, we reviewed here the outcome of 57 patients who received ruxo for corticosteroid-refractory GVHD (in case of digestive tract involvement or in the absence of available ongoing clinical trials) or as a steroids-sparing medication. EBV and CMV reactivation risks were also assessed in the 137 consecutive patients received HSCT between January 1, 2012 and December 31, 2017 and who presented acute or chonic GVHD (57 of whom received ruxo). For this purpose, each reactivation were analyzed separately as a competing risk with death in a cause specific Cox model of survival after the first GVHD occurrence and the onset of ruxo therapy was coded as time dependent covariate. Results: The median age of 57 patients with ruxo was 55 years (range, 49 to 61). Indication for HSCT was acute myeloid leukemia for 25% patients, lymphoma for 30%, acute lymphoblastic leukemia for 11%, myeloproliferative neoplasm for 14% and myelodysplastic syndrome for 7%. Only 9% of this patients received ruxo before HSCT. Unrelated donor was used for 60% patients and main source of hematopoietic stem cells was peripheral stem cells (93%). T cell depletion with polyclonal anti-thymocyte globulin was performed for 89% of patients. Conditioning with high doses cyclophosphamide was used for 21% patients. A lymphopenia <1G/L persisted at day 100 for 42/51 patients evaluated. In these 57 patients, ruxo was given for 62 episode of GVHD (acute: 21 [which 95% for an acute grade III-IV GVHD]; chronic: 36; overlap syndrome: 5). Response rates to ruxo were 48% for acute GVHD, 60% for overlap syndrom and 58% for chronic GVHD. The overall GVHD related-death rate was 33% (19% for acute GVHD and 14% for chronic GVHD). Our median follow-up was 30 months (range, 9 to 42) after HSCT. Main non-infectious adverse events were cytopenias (17/57) and hepatic cytolysis (6/57) leading to discontinuation or tapering of ruxo in 12 patients. EBV reactivation (> 4 log or increasing viral charge of 0.5 log) occurred in 19 patients after ruxo with a 6-weeks cumulative incidence (6WCuI) of 22% (95CI [95% confidence interval]: 15-34). It was the first reactivation in 13 patients. CMV reactivation (> 3 log) occurred in 8 patients after ruxo with a 6WCuI of 4% (95CI: 7-25). It was the first reactivation in 3 patients (Figure 1). The distribution of first reactivation before ruxo and in the remaining 80 patients is shown in Table 1. Thus, 6WCuI of first EBV and CMV reactivation after the first episode of GVHD was 24% (95CI: 19-31) and 20% (95CI: 15-25) respectively. Finally, onset of ruxo coded as time dependent covariates retained a significant adverse prognostic value for the competing risks of death and first episode of EBV reactivation (HR [Hazard Ratio]: 2,657, p<0,05) as well as first episode of CMV reactivation (HR: 1,747, p<0,05) after first episode of GVHD. Discussion /Conclusion: Ruxo initiation coded as a time-dependent covariate was significantly associated with the overall risk of viral reactivation after the first episode of GVHD and the viral reactivations incidences after ruxo were similar with the incidence of reactivation at the onset of GVHD. Thus, it might be linked to the immuno-compromised state induced by both HSCT and GVHD. Furthermore, as we used ruxo for serious gastro intestinal GVHD, we could have selected patients with a more severe GVHD, requiring multiple immunosuppressive therapy, worsening immune reconstitution. To our knowledge it is the first study to assess the competing risk of CMV and EBV reactivation during ruxo treatment for GVHD. Given its effectiveness in corticoresistant GVHD, ruxo use must not be limited by the fear of viral reactivation at the light of our data, conditioned upon a close monitoring of viral loads in the first weeks. Disclosures No relevant conflicts of interest to declare.

Use of Thymoglobulin with Lower Dose of Busulfan Results in Less Acute Gvhd Following Unrelated Donor Allogeneic Stem Cell Transplantation for AML without Affecting Relapse-Free and Overall Survival

Introduction: Post-transplant relapse and GVHD are two major barriers of success of allogeneic hematopoietic stem cell transplantation (AHSCT) for AML. These outcomes are often dependent on the complex interaction between the post-transplant immunosuppression and the conditioning regimen. We as well as others have used rabbit thymoglobulin for the reduction of both acute and chronic GVHD in unrelated transplant in AML. The interaction between different conditioning regimens and thymoglobulin may play an important role in the outcomes, but it has not been fully investigated. In this study, we compared outcomes of patients undergoing unrelated donor AHSCT for AML using thymoglobulin with either a myeloablative or reduced intensity conditioning regimen. Patients received busulfan/fludarabine (Bu/Flu)-based myeloablative conditioning (MAC) regimen with 4 days of busulfan or reduced intensity conditioning (RIC) regimen using 2 days of busulfan with fludarabine. Since 2 days of busulfan as RIC may have a higher relapse rate, we added low dose TBI (200cGY) to the RIC regimen (Bu/Flu/TBI). Methods: We retrospectively evaluated outcomes of adult AML patients who underwent unrelated donor AHSCT utilizing tacrolimus, mycophenolate (MMF) and thymoglobulin as GVHD prophylaxis. All patients received either a Bu/Flu/TBI-based RIC or a Bu/Fu-based MAC regimen. Thymoglobulin was administered at a total dose of 4.5mg/kg in divided fashion (0.5mg/kg on day-3, 1.5mg/kg on day -2, 2.5mg/kg on day -1). Tacrolimus and MMF were started on day -3. The objectives were to determine the rates of acute and chronic GVHD, overall survival (OS), relapse free survival (RFS) and non-relapse mortality (NRM) using Cox proportional hazard regression and competing risk models. Results: One hundred twenty-two patients with AML received unrelated donor AHSCT between January 2005 and December 2017. Of these, 88 (72%) patients had de-novo and 34 (28%) had secondary AML. Sixty-four patients received Bu/Flu/TBI-based RIC, and 58 received Bu/Flu as MAC regimen. All patients received peripheral blood stem cells. The patients receiving RIC regimen were older (median age 66 vs 53 years, p<0.001), had higher proportion of patients with normal cytogenetics (47% vs 31%, p=0.02) and 8/8 HLA match (88% vs 64%, p=0.004) as compared to MAC regimen. The 6-month cumulative incidence rate (CIR) of grade III-IV acute GVHD (aGVHD) was 6% in RIC and 26% in MAC regimen (p=0.004). The 2-year CIR of chronic extensive GVHD was 35% and 29% in RIC and MAC regimen, respectively (p=0.50). Median follow-up of surviving patients after RIC and MAC regimen was 4.4 years and 4 years, respectively. Two-year OS after RIC and MAC regimen was 50% and 49%, respectively (p=0.69). Two-year relapse rate with RIC and MAC was 37% and 24%, respectively (p=0.25), whereas two-year NRM with RIC and MAC was 21% and 31%, respectively (p=0.41). Two-year RFS was 43% with RIC and 45% with MAC regimen (p=0.80). In all, CMV and EBV reactivation rates were 34% and 7%, respectively. Eight patients (7%) developed gastrointestinal CMV disease. Multivariable analysis revealed that relapsed and refractory AML at AHSCT was associated with adverse OS (HR 1.71, p=0.04), RFS (HR 1.84, p=0.01) and higher NRM (SHR 2.96, p=0.006) compared to first complete remission. Secondary AML was associated with higher NRM (HR 2.44, p=0.02). No impact of HLA matching and conditioning regimen on OS, relapse, NRM and RFS was observed. Subgroup analysis showed that HLA matching had an interaction with the conditioning regimen for RFS (p=0.03). Otherwise, none of the factors appeared to have any significant interaction with the conditioning regimen for survival outcomes. Conclusion: Our study shows that thymoglobulin when used with lower dose of busulfan (in the form of Bu/Flu/TBI-based RIC regimen) provided significantly lower rate of acute GVHD compared to Bu/Flu-based MAC in AML patients undergoing unrelated donor AHSCT without affecting leukemia-free and overall survival. Disease status at transplant remains a significant predictor of post-transplant outcomes. Disclosures Deol: Novartis: Other: Advisory board; Kite: Other: Advisory board; Agios: Other: Advisory board.

Absolute Lymphocyte Count (ALC) Less Than 100 Predicts Adverse Transplant Outcomes with Rabbit Thymoglobulin in Patients Undergoing Matched Unrelated Allogeneic Hematopoietic Stem Cell Transplantation

Introduction: Rabbit thymoglobulin, an in-vivo T-cell depleting agent, is widely used as a part of GVHD prophylaxis regimen. Current dosing of thymoglobulin is often weight based and does not consider patient related factors. This results in highly variable exposure of thymoglobulin. Although higher doses (>7mg/kg) of thymoglobulin have shown to reduce the risk of GVHD, it is associated with increased rate of opportunistic infections and disease recurrence. Conversely, lower dose (2.5mg/kg) of thymoglobulin is associated with increased risk of GVHD. Thus, optimum dosing of thymoglobulin remains undefined. We hypothesized that recipient peripheral blood ALC on the first day of thymoglobulin infusion would interact with the dose of thymoglobulin administered and predict post-transplant outcomes. We plan to identify association of thymoglobulin dose with the ALC on the first day of thymoglobulin. Methods: We retrospectively evaluated clinical outcomes of adult patients (pts) who underwent matched unrelated donor AHSCT and received tacrolimus, mycophenolate (cellcept) and thymoglobulin as GVHD prophylaxis. Thymoglobulin was given at a total dose of 4.5mg/kg in divided fashion (0.5mg/kg on day -3, 1.5mg/kg on day -2 and 2.5mg/kg on day -1). The objectives were to determine rate of GVHD, overall survival (OS), relapse-free survival (RFS), relapse rate and non-relapse mortality (NRM) following AHSCT using Cox proportional hazard regression and competing risk models. Results: Between January 2005 and December 2017, 217 pts underwent AHSCT. The most common indications for AHSCT were AML (n=95, 44%), MDS (n=57, 26%), non-Hodgkin's lymphoma (n=23, 11%), and ALL (n=22, 10%). Median age of pts was 60 years (range, 18-79). All pts received peripheral blood stem cells. Ninety-eight pts (45%) received full intensity conditioning regimen and 119 pts (55%) received reduced intensity regimen. The median ALC on the first day of thymoglobulin administration was 200 K/cubic millimeter. The 6-month cumulative incidence rate (CIR) of grade III-IV acute GVHD was 14.8% and the 2-year CIR of chronic extensive GVHD was 35.4%. With a median follow up of 3.82 years for surviving patients, the 2-year RFS, OS, relapse and NRM were 50%, 57.1, 20.1%, and 30.2%, respectively. CMV and EBV reactivation rates were 37% and 11%, respectively. Four pts developed CMV disease. By our lowest ALC cutoff of 100 K/cubic millimeter, pts were divided into two groups (ALC ≤ 100 vs. ALC > 100). Multivariable analysis revealed that ALC > 100 was associated with significantly superior OS (HR 0.51, 95% CI 0.33-0.79, p=0.002), RFS (HR 0.49, 95% CI 0.33-0.74, p=0.001) and lower NRM (SHR 0.57, 95% CI 0.34-0.97, p=0.038) and marginally lower relapse rate (SHR 0.57, 95% CI 0.31-1.05, p=0.070). In addition, higher infused total nucleated cells was associated with higher NRM (SHR 1.70, 95% CI 1.02-2.83, p=0.041). No impact of disease risk index, KPS, conditioning regimen, infused CD34 cells on NRM, relapse, RFS or OS was observed. Conclusion: Our study indicates that ALC ≤ 100 is associated with adverse post-transplant outcomes when thymoglobulin dose of 4.5mg/kg is used for in-vivo T cell depletion. This finding may indicate that in pts with lower ALC, thymoglobulin dose may need to be adjusted to optimize its efficacy and avoid toxicities. In the future prospective studies, which evaluate dose reduction of thymoglobulin in pts with low ALC need to be planned to confirm these results. Disclosures Deol: Agios: Other: Advisory board; Novartis: Other: Advisory board; Kite: Other: Advisory board.

Fludarabine Melphalan Versus Fludarabine Treosulfan As Reduced Intensity Conditioning Regimens in Allogeneic Hematopoietic Stem Cell Transplant - a Retrospective Analysis

Introduction Allogeneic hematopoietic stem cell transplantation (AHSCT) has evolved as a curative therapy for various hematological malignancies. Regimen-related toxicity and transplant-related mortality (TRM) preclude the use of myeloablative conditioning (MAC) regimens in older and unfit patients. Reduced intensity conditioning (RIC) regimens have enabled AHSCT in such patients. There is a recent rise in use of RIC regimens even in younger patients in view of decreased toxicity and equal efficacy as reported in some studies. Fludarabine + Melphalan (FM) and Fludarabine + Treosulfan (FT) are 2 such regimens. There are no prospective randomised comparisons between these regimens. We retrospectively analysed these 2 regimens for toxicities and outcomes. Methods This is a retrospective single centre analysis of all consecutive patients with haematological cancers who received either FM or FT from April 2008 to December 2018. The entire cohort was divided into two groups - Matched Sibling Donor (MSD)/Matched Unrelated Donor (MUD) and Haploidentical (Haplo) transplants for analysis. We compared patient characteristics, toxicities and outcomes in both the groups based on conditioning regimen. The FT regimen consisted of fludarabine (30 mg/m2 on days − 6 to − 2) combined with treosulfan (12-14 gm/m2 on days − 6 to − 4) with or without 2 Gy TBI on day-1. The FM regimen consisted of fludarabine (30 mg/m2 on days − 7 to − 3) combined with melphalan (140 mg/m2 on day -1).Prophylaxis for GVHD consisted of calcineurin inhibitor (CNI) plus methotrexate (MTX)or mycophenolate mofetil (MMF) in MSD/MUD. Rabbit ATG (2.5-5 mg/kg) was used for MUD. Haplo transplant patients received post-transplant cyclophosphamide with CNI and MMF. Comorbidities were scored according to the HCT-CI. Disease Risk Index(DRI) and EBMT score were recorded for all patients. Neutrophil (NE) and platelet engraftment (PE) were defined as per standard criteria. Early toxicity after AHCT was graded according to CTCAE version 4. Total parenteral nutrition (TPN) was used in patients as per the physician's discretion. Acute GVHD and chronic GVHD were recorded according to standard criteria. All patients underwent chimerism studies at day 15, 30 and then monthly for 1 year. Mixed chimerism was defined as > 5% to < 95% donor chimerism. The toxicities in various arms were compared by Chi-square test or Fisher exact test, while OS was calculated by Kaplan Meier method and the survival probabilities were compared using log-rank test. Competing risk analysis was used to calculate cumulative incidence of relapse and TRM. Results The study included 138 patients, 98 males and 40 females. The diagnoses were AML- 53, ALL- 30, MDS/MPN- 49 and lymphoma -6. Patient characteristics are outlined in Table 1. MSD/MUD transplants were 105 (FM- 94; FT-11); 33 were Haplo (FM-17; FT-16) transplants. PBSC was the stem cell graft in 136 (99%) patients. In both MSD/MUD and Haplo groups, there were no significant differences in median age, gender, pre transplant CMV status, HCT-CI and EBMT score between the two conditioning regimens. In MSD/MUD group, significantly more patients had high/very high DRI in FT arm (45% vs 17%; P=0.056) Comparison of engraftment and toxicity variables of both FM and FT arms are outlined in Table 2. In MSD/MUD group, 44 (47%) patients in FM arm had grade 3/4 oral mucositis compared to 1 (9%) in FT arm (P=0.02). Corresponding numbers were 7 (41%) and 1 (6%) in Haplo group (P=0.039). Grade 3/4 diarrhoea was higher in the FM vs FT arm of Haplo group (41% vs 6%; P=0.039) but not in the MSD/MUD cohort. More patients received TPN in the FM arms of both MSD/MUD and Haplo groups (Table 2). Incidence of grade III-IV acute GVHD was higher in FT vs FM in MSD/MUD group (27% vs 17%; P=0.04). The median follow up of entire cohort was 4.8 years. The OS (figure 1) at 5 years was 62% in FM arm of MSD/MUD group vs 53% in FT arm (P=NS). Similarly OS (figure 2) at 5 years was 41% and 28 %( P=NS) in FM and FT arms respectively of Haplo group. The cumulative incidence of TRM and relapse at 2 years were not different in FM and FT arms of both MSD/MUD and Haplo groups (Table 2). Conclusion Grade 3 and 4 oral mucositis and diarrhoea were significantly less with FT than FM in both MSD/MUD and Haplo groups. FT provided comparable outcomes to FM in the MSD / MUD group in spite of having higher proportions of patients with high / very high DRI. Prospective randomised studies are required to compare various RIC regimens. Disclosures No relevant conflicts of interest to declare.

Risk Adapted Antifungal Strategy in Allogeneic Stem Cell Transplantation. Should We Change the Current Guidelines?

Background: Current guidelines recommend the use of antifungal prophylaxis during, at least, the first three months post allogeneic stem cell transplantation (allo-SCT). However, these drugs are not exempt of adverse effects due to their own toxicity or drug-drug interactions. In addition, breakthrough mold infections seem to be emerging as a new problem in this setting. Objectives: The aim of this study was to analyze the benefit of a strategy in which allo-SCT patients were not routinely prescribed antifungal drugs except for the case of the development of neutropenic fever and/or exposure to high dose of corticosteroids. Main objectives were 1) requirement and time of exposure to antifungal treatment and 2) cumulative incidence (CI) of proven or probable IFI at 1, 3 and 6 months after transplant. Other objectives were IFI description and overall survival (OS). Patients and methods: 319 patients who underwent a first allo-SCT at our center between 2010 and 2017 and were not under antifungal prophylaxis at the moment of transplant were included. 181 patients (57%) were males and median age was 51 years, range (4-74). Acute myeloid leukemia (35%) was the most frequent diagnosis and myeloablative conditioning regimen was mostly used (69%). 99 patients (31%) received the stem cells from a mismatched donor and BM was the preferred stem cell source (72%). Fourteen patients (4%) did not engraft. The median length of neutropenia <0.5x109/L and <0.1x109/L were 12 days and 6 days, respectively. Forty-two patients (14%) developed acute GVHD grade III-IV. Post-mortem study was performed in 28 of the deceased patients (43%). Results:Thirty-one 31 patients (9.7%) did not receive antifungal drugs along the course of the transplantation, 58 patients (18%) required it for less than 1 week and only 24% were on therapy more than 3 weeks. The median total days on antifungal drugs was 13 days (0-175) for the entire population and 11 days (0-109) in patients who did not develop fungal infection and/or acute GVHD II-IV. Fluconazole (61%) was the main antifungal drug used during the neutropenic phase, followed by caspofungin (27%). Time on fluconazole was significantly shorter than caspofungin, 8 vs. 11 days, p=0.001. A change on antifungal therapy was needed in 130 (45%) patients and was more frequent in those who were receiving fluconazole (57%) compared to those who were receiving caspofungin (20%), p<0.0001. The CI of proven or probable IFI at day 30, 90 and 180 after transplant was 2.5%, 5.1% and 5.5%, respectively. Very importantly, none of the 106 patients who did not receive antifungal drugs or received less than one-week developed IFI. Twelve mold infection, 4 in the postmortem study, and 5 yeast infection were diagnosed. Microbiological identification was obtained in 9 patients; C. parapsilosis (3), Rhizopus (2), C. orthopsilosis (1), Criptococo laurentii (1), A. fumigatus (1), Alternaria spp. (1). The restricted administration of antifungal drugs did not affect the overall survival, Figure 1. Conclusion: In our experience, a restrictive strategy for the use of antifungal drugs in the setting of allo-SCT is feasible and effective. It results in similar cumulative incidences of fungal infection than the recommended policy. Moreover, it allows almost 10% of patients to remain free of antifungal treatment throughout the procedure and one fourth of them being exposed for less than a week. This data supports the change in the antifungal prophylactic paradigm for allo-SCT patients. Figure 1 Disclosures No relevant conflicts of interest to declare.

GVHD prophylaxis by tacrolimus and mini-MTX in single-unit CBT: a single institute experience.

Tacrolimus (TAC) combined with short-term methotrexate (MTX) is widely used to prevent graft-versus-host disease (GVHD) in cord blood transplantation (CBT). As short-term MTX aggravates mucositis and delays engraftment, we reduced the dose of MTX, as previously reported in the non-CBT setting. Here, we retrospectively analyze outcomes of 20 patients who received CBT from April 2017 to December 2018. All patients received TAC with mini-MTX as GVHD prophylaxis. Mini-MTX was administered at a dose of 5mg/m2 of MTX on days 1, 3 and 6 after CBT. Median age was 54.5years. Median follow-up time in surviving patients was 396days. The primary disease was acute leukemia (n = 12) or malignant lymphoma (n = 8). Three patients and 17 patients received myeloablative and reduced-intensity conditioning, respectively. Rate and median time to engraftment of neutrophils were 90.0% and 20.5days, respectively. Cumulative incidences of grade II-IV and grade III-IV acute GVHD were 35.0% and 5.0%, respectively. At one year after CBT, the overall survival rate was 80.5%, cumulative incidence of relapse/progression was 15.0%, and non-relapse mortality rate was 5.0%. In conclusion, TAC with mini-MTX may be a promising GVHD prophylaxis regimen in single-unit CBT.

Ex Vivo T Cell-Depleted Hematopoietic Stem Cell Transplantation for Adult Patients with Acute Myelogenous Leukemia in First and Second Remission: Long-Term Disease-Free Survival with a Significantly Reduced Risk of Graft-versus-Host Disease.

Large series of patients with acute myelogenous leukemia (AML) after ex vivo T cell-depleted (TCD) allogeneic hematopoietic stem cell transplantation (allo-HSCT) have not been reported previously. We retrospectively analyzed the outcomes of 266 patients (median age, 54 years) with AML who received CD34-selected TCD allo-HSCTs while in first (75%) or second (25%) complete remission (CR1/CR2) at a single institution. The conditioning regimens were all myeloablative, and no additional graft-versus-host disease (GVHD) prophylaxis was given. The cumulative incidences of grade II-IV and grade III-IV acute GVHD at 180 days were 14% (95% confidence interval [CI], 10% to 18%) and 3% (95% CI, 1% to 5%), respectively. The cumulative incidence of chronic GVHD at 3 years was 3% (95% CI, 1% to 6%). The 3-year cumulative incidence of nonrelapse mortality was 21% (95% CI, 16% to 26%) and that of relapse was 21% (95% CI, 17% to 27%). Overall survival (OS) and disease-free survival (DFS) at 1, 3, and 5 years were 75%, 61%, and 56% and 68%, 57%, and 53%, respectively. There were no significant differences in OS, DFS, and relapse rates for patients who underwent transplantation in CR1 and those who did so in CR2. However, patients with high-risk cytogenetics at diagnosis had significantly poorer outcomes. The OS and DFS rates compare favorably with those for unmodified allo-HSCT, but with considerably lower rates of GVHD.

Interleukin-6 as Biomarker for Acute GvHD and Survival After Allogeneic Transplant With Post-transplant Cyclophosphamide.

Background: Although the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) has dramatically improved in the past decade, it is still compromised by transplant-related mortality (TRM), mainly caused by Graft-vs. -Host Disease (GvHD).Methods: We conducted a prospective observational study to ascertain the potential of serum interleukin-6 (IL6) levels, measured before conditioning and 7 days after allo-HSCT, in predicting acute GvHD, TRM and survival after allo-HSCT with Post-Transplant Cyclophosphamide (PT-Cy) based GvHD prophylaxis.Results: Between April 2014 and June 2017, we collected samples from 166 consecutive allo-HSCT patients. By ROC analysis, we identified a threshold of 2.5 pg/ml for pre-transplant IL6 and 16.5 pg/ml for post-transplant IL6. Both univariate and multivariate analyses confirmed the ability of high baseline IL6 levels to predict worse OS (HR 4.3; p < 0.01) and grade II–IV acute GvHD (HR 1.8; p = 0.04), and of high post-transplant IL6 to identify patients with worse OS (HR 3.3; p < 0.01) and higher risk of grade II–IV (HR 5; p < 0.01) and grade III–IV acute GvHD (HR 10.2; p < 0.01). In multivariate analysis, both baseline (HR 6.7; p < 0.01) and post-transplant high IL6 levels (HR 3.5; p = 0.02) predicted higher TRM.Conclusions: IL6 may contribute to the risk stratification of patients at major risk for aGvHD and TRM, potentially providing a window for additional prophylactic or preemptive strategies to improve the quality of life in the early post-transplant phase and the outcome of allo-HSCT.

Investigation of TGFB1 -1347C>T variant as a biomarker after allogeneic hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapeutic option for malignant hematopoietic diseases. Cytokines including transforming growth factor β1 (TGFβ1) play a pivotal role in immune reconstruction, and the development of graft versus host disease (GvHD) or infections. The aim of this study was to investigate the role of TGFB1 gene -1347C>T variant in the outcome of HSCT in a cohort of 409 adult recipient-donor pairs. TGFB1 variant was analysed from genomic DNA with LightCycler hybridisation probe method. In case of myeloablative conditioning, donor TGFB1 genotype correlated with overall survival (60-month OS for CC: 62.1 ± 4.8%; CT: 46.8 ± 4.8%; TT: 35.6 ± 9.3%; p = 0.032), which was independent of age, donor type and GvHD prophylaxis in multivariate analysis (HR:2.35, 95%CI:1.35-4.10, p = 0.003). The cumulative incidence of acute GvHD grade III-IV [CC:10%; CT:17%; TT:24%], and non-relapse mortality was higher in TT-carriers (24-month NRM: CC:24%; CT:26%; TT:46%, p = 0.035). We did not find any association between recipient TGFB1 -1347C>T polymorphism and HSCT outcome. Our results suggest that donor TGFB1 -1347C>T may exert an adverse influence on the outcome of myeloablative conditioning transplantation.

Graft versus host disease in unmanipulated haploidentical marrow transplantation with a modified post-transplant cyclophosphamide (PT-CY) regimen: an update on 425 patients.

This is an update on acute and chronic graft-versus-host disease (GvHD) in 425 patients with hematologic malignancies, undergoing an unmanipulated haploidentical (HAPLO) graft from related donors, with a modified post-transplant cyclophosphamide (PT-CY) regimen. All patients received a myeloablative conditioning regimen, either based on thiotepa busulfan fludarabine (TBF), or on full-dose total body irradiation (TBI). The cumulative incidence of acute GvHD-grade II-IV was 29%, and the CI of GvHD-grade III-IV was 4%. We found older donors and older patients to have higher rates of grade II-IV acute GvHD; female donors, diagnosis, disease phase, year of transplant, and the conditioning regimen had no predictive effect on acute GvHD. There was no impact of grade II GvHD, but a significant impact of grade III-IV acute GvHD, on overall survival. The CI of moderate-severe chronic GvHD was 18%: the major predictor was a previous acute GvHD, followed by combined donor and recipients age. In conclusion, PT-CY given on days+3 + 5 results in a relatively low, but not insignificant risk of acute and chronic GvHD, in patients grafted from the related HAPLO donors. The use of young donors appears to reduce this risk.

PF751 POST-TRANSPLANT CYCLOPHOSPHAMIDE AND SIROLIMUS IN HAPLOIDENTICAL TRANSPLANT WITH PBSC GRAFTS: RESULTS IN 151 PATIENTS

Background: The use of haploidentical hematopoietic stem cell transplantation (HSCT) with post- transplant cyclophosphamide (PT-Cy) and calcineurin inhibitors (CNI) as graft-versus-host disease (GVHD) prophylaxis is rapidly increasing. Aims: Herein we describe long-term outcomes of haploidentical HSCT from PBSC grafts, using intensified myeloablative conditioning, and GVHD prophylaxis with PT-Cy and sirolimus. Methods: From 2012 to 2017, 151 adult patients received haploidentical HSCT for high-risk hematological malignancies, mainly acute myeloid leukemia (n = 92). Disease risk index (DRI; Armand et al) was low-intermediate in 52, high in 64 and very high in 35 patients. At HSCT, 58% of patients were not in CR; 25% of patients received a previous allogeneic HSCT. Conditioning was myeloablative in 123 and reduced-intensity in 28 patients. It was based on treosulfan-fludarabine, and 116 patients receive a regimen intensified by a 2nd alkylating agent (melphalan or thiotepa). The majority of patients (n = 148) received unmanipulated PBSCs. All pts received PT-Cy (50 mg/kg/day) on days 3 and 4. Sirolimus was given from day 5, and withdrawn 3 months after HSCT. Mycophenolate mofetil (MMF) was initiated on day 5, and withdrawn on day 30. All patients were treated according to current institutional programs upon written informed consent for transplant procedures and for the use of medical records for research. Results: Median follow up was 26 months (3–68). Median PBSC graft CD34+ and CD3+ cell doses were respectively 6x10^6/Kg (range, 5–8) and 2x10^8/Kg (range, 0.8–4.8). The majority of patients reached the neutrophil (86%) and platelet (77%) engraftment within 30 and 90 days after HSCT, respectively. Post-HSCT recovery of lymphocyte subsets was broad and fast, reaching more than 100/ml CD3+ T cells within a median of 33 days (20–799). Clinically relevant CMV and HHV-6 infections occurred in 63 and 60 patients, respectively. Invasive fungal diseases were reported in 14 cases. The cumulative incidence of grades II-IV and III-IV acute GVHD at 100 days was 35% and 20%, respectively. The cumulative incidence of chronic GVHD was 42% at 3 years; we observed severe chronic GVHD only in 16% of pts. The cumulative incidences of relapse and non-relapse mortality (NRM) were respectively 35% and 27% at 3 years. Three-year overall survival (OS) was 44% and progression free survival (PFS) 38%. The composite end point of GVHD-free/relapse-free survival (GRFS) was 24% at 3 years. Multivariate analysis confirmed the effect of DRI on transplant outcomes, with worse PFS in high and very high compared to low-intermediate DRI population. Summary/Conclusion: Extended follow-up in 151 high-risk patients confirms that Sirolimus and PT-Cy association as GvHD prophylaxis is feasible in haploidentical HSCT based on unmanipulated PBSC graft; DRI is still a major issue for transplant long-term outcome.

Post-transplant cyclophosphamide in matched and haploidentical transplant recipients receiving myeloablative timed sequential busulfan conditioning regimen: Results of a phase II study.

7007 Background: Myeloablative stem cell transplants have a lower rate of relapse than reduced intensity regimens. Timed sequential busulfan (TSB) with fludarabine (Flu) is a promising myeloablative regimen for patients undergoing matched sibling (MSD) or unrelated (MUD) donor transplantation (HCT) with low non-relapse mortality (NRM) (Popat et al Lancet Haematology 2018), but was not tested in haploidentical (haplo). Also, whether this approach can be used with post-transplant cyclophosphamide (PTCy) in MSD, MUD and haplo HCT is unknown. To address these issues, we conducted a prospective phase II study. Methods: Patients with hematological malignancies with MSD, MUD or haplo donor were eligible. They received fixed doses of Busulfan(BU) 80mg/m2 either on day -13 and -12 (n=45) or on -20 and -13 (n=10). Then, Flu 40mg/m2 was given on day -6 to -2 followed by Bu dosed to achieve target area under the curve (AUC) of 20,000 umol/min for the whole course based on pharmacokinetic studies. Thiotepa 5mg/kg was given on day -7 to haplo group. GVHD prophylaxis was PTCy 50mg/kg on day 3 and 4 and tacrolimus. Haplo and later MUD recipients also received mycophenolate mofetil. Results: 55 patients with a median age of 47 (15-65) years were enrolled. 30 patients had AML or MDS, 9 CML or MPD, 5 lymphoma, 5 myeloma and 6 ALL. About half had haplo 26 (47%); others had MUD 18 (33%) or MSD 11(20%). Disease risk index was high in 18 (32%), intermediate in 32 (58%), and low in 5 (9%) patients. Comorbidity score was ≥3 in 22 (40%) patients. With a median follow up of 17 months (5-28), 1-year OS, PFS, NRM and relapse rates were 71% (60-84%), 63% (51-77%), 20% (9-31%), and 17% (7-27%), respectively [Table]. There were no graft failures. Day 100 grade II-IV and III-IV acute GVHD rates were 38% (25-51%) and 9% (95% CI 1-17%), respectively; 1-year chronic GVHD and extensive chronic GVHD rates were 10% (2-28%) and 8% (0-15%), respectively. 1-year OS in MSD, MUD and haplo groups were 91% (75-100%), 72% (54-96%), and 62% (45-83%) respectively (P=0.11). Conclusions: Myeloablative TSB with PTCy is feasible in MSD, MUD and haplo HCT. It lowers the incidence of severe acute and chronic GVHD without apparent increase in relapse. Clinical trial information: NCT02861417. [Table: see text]

GRFS and CRFS in alternative donor hematopoietic cell transplantation for pediatric patients with acute leukemia

AbstractWe report graft-versus-host disease (GVHD)-free relapse-free survival (GRFS) (a composite end point of survival without grade III-IV acute GVHD [aGVHD], systemic therapy–requiring chronic GVHD [cGVHD], or relapse) and cGVHD-free relapse-free survival (CRFS) among pediatric patients with acute leukemia (n = 1613) who underwent transplantation with 1 antigen–mismatched (7/8) bone marrow (BM; n = 172) or umbilical cord blood (UCB; n = 1441). Multivariate analysis was performed using Cox proportional hazards models. To account for multiple testing, P < .01 for the donor/graft variable was considered statistically significant. Clinical characteristics were similar between UCB and 7/8 BM recipients, because most had acute lymphoblastic leukemia (62%), 64% received total body irradiation–based conditioning, and 60% received anti-thymocyte globulin or alemtuzumab. Methotrexate-based GVHD prophylaxis was more common with 7/8 BM (79%) than with UCB (15%), in which mycophenolate mofetil was commonly used. The univariate estimates of GRFS and CRFS were 22% (95% confidence interval [CI], 16-29) and 27% (95% CI, 20-34), respectively, with 7/8 BM and 33% (95% CI, 31-36) and 38% (95% CI, 35-40), respectively, with UCB (P < .001). In multivariate analysis, 7/8 BM vs UCB had similar GRFS (hazard ratio [HR], 1.12; 95% CI, 0.87-1.45; P = .39), CRFS (HR, 1.06; 95% CI, 0.82-1.38; P = .66), overall survival (HR, 1.07; 95% CI, 0.80-1.44; P = .66), and relapse (HR, 1.44; 95% CI, 1.03-2.02; P = .03). However, the 7/8 BM group had a significantly higher risk for grade III-IV aGVHD (HR, 1.70; 95% CI, 1.16-2.48; P = .006) compared with the UCB group. UCB and 7/8 BM groups had similar outcomes, as measured by GRFS and CRFS. However, given the higher risk for grade III-IV aGVHD, UCB might be preferred for patients lacking matched donors.

Haploidentical CD3 or α/β T-cell depleted HSCT in advanced stage sickle cell disease.

Despite significant improvements in the supportive care, sickle cell disease (SCD) leads to significant morbidity and mortality. Allogeneic hematopoietic stem cell transplantation (HSCT), the only curative option, is limited due to matched donor availability. This could be met with T-cell-depleted haploidentical HSCT. Twenty advanced-stage SCD patients, median age 15 years, and 9 patients, median age 14 years, were transplanted with CD3/CD19- or TCRαβ/CD19-depleted grafts and from matched sibling donors (MSDs). The conditioning consisted of ATG, thiotepa, fludarabine, and treosulfan. The median follow-up in the T-haplo-HSCT and the MSD patients was 21 (9-62) and 25 (7-60) months, respectively. The OS in the T-haplo-HSCT and MSD was 90% and 100%, respectively. In the T-haplo-HSCT group, two patient succumbed to a CMV pneumonitis and a macrophage activation syndrome (MAS). One patient in the T-haplo-HSCT group requires renal replacement therapy because of BK virus nephritis. None developed grade III-IV acute GvHD. In the T-haplo-HSCT and in the MSD, 20% and 22%, respectively, developed a mild or moderate chronic GvHD. These results demonstrate the feasibility, safety, and efficacy of T-haplo-HSCT also for adult advanced stage SCD patients.

PCN291 ACUTE GRAFT VERSUS HOST DISEASE (GVHD), CHRONIC GVHD AND NON-RELAPSE MORTALITY (NRM) ASSOCIATED WITH MISMATCHED ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION (ALLO-HSCT): A SYSTEMATIC REVIEW

When HLA-matched stem cell grafts are unavailable, mismatched sources may be used, which are often associated with increased risk of serious complications. We reviewed published evidence to assess complications associated with mismatched allo-HSCT in acute myeloid leukemia (AML) patients by graft source. Embase®, MEDLINE®, Cochrane databases and conference abstracts (ASCO, ASH) were systematically reviewed in November 2018. Main inclusion criteria: studies from 2008-2018, AML patients, allo-HSCT, mismatched, interventional prospective studies which reported complications. Main exclusion criteria: non-interventional, retrospective studies. Two analysts reviewed each abstract and publication using PICOS (Patient, Intervention, Comparators, Outcomes, Study Design) criteria and all results were recorded using preferred reporting items for systematic reviews and meta-analyses (PRISMA) diagram. Rates of acute GVHD, chronic GVHD, and NRM were extracted and compared. A total of 1,335 records were reviewed and 8 studies satisfied inclusion criteria. The incidence of grade III-IV acute GVHD events was 10.0% among patients receiving UM171-expanded umbilical cord blood (UCB) grafts, 12.2% with NiCord®-expanded-UCB, 19.4% with StemEx®-expanded-UCB and ranged from 3.2-21.2% with other mismatched allo-HSCT (majority mixed bone marrow/peripheral blood). Incidence of moderate-severe chronic GVHD was found to be 0.0% with UM171-expanded-UCB at 24 months, 11.5% with NiCord®-expanded-UCB at 12 months, 19.0% in unmanipulated-UCB grafts at 12 months and ranged from 6.5-10.6% in mismatched allo-HSCT assessed at time points between 12-24 months. GVHD prophylaxis regimens varied across studies. NRM at 24 months was 4.7% with UM171-expanded-UCB, 20.3% with NiCord®-expanded-UCB, 19.0% with unmanipulated-UCB and 23.0-30.0% with alternate graft sources. Patients treated with UM171-expanded-UCB grafts experienced the lowest rates of NRM and moderate-severe chronic GHVD at 24 months relative to UCB and other mismatched graft sources identified in the SLR. Additionally, rates of grade III-IV acute GVHD were lower in UM171-expanded-UCB grafts compared to most, but not all, other sources identified.

The role of checkpoint blockade after allogeneic stem cell transplantation in diseases other than Hodgkin's Lymphoma.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment option for many malignant high-risk hematological diseases. The Graft-vs.-Tumor (GvT) effect is the major hallmark of this treatment approach. However, disease relapse remains a major limitation. Boosting the GvT effect by checkpoint inhibitors (CI) is an attractive option in this desperate situation although potentially triggering Graft-vs.-Host Disease (GvHD). Early reports in patients with Hodgkin's lymphoma support the idea that CI therapy after HSCT is feasible and effective. We have retrospectively analyzed CI therapy for treatment of disease recurrence after allo-HSCT other than Hodgkin's lymphoma including 21 patients from eight German transplant centers. The median follow-up was 59 days. The overall response rate (ORR) was 43%. Patients receiving donor lymphocyte infusion (DLI) in combination with CI had superior response (ORR 80%). Severe acute GvHD grade III-IV and moderate to severe chronic GvHD were observed in 29% of all patients. Taken together, CI therapy in relapsed patients after HSCT, especially in combination with DLI, is effective but induces severe GvHD in a considerable proportion of patients. Thus, prospective trials or EBMT registry-based validation of different dosing and application schedules including immunosuppressive regimens in those patients are urgently needed.

Trasplante haploidéntico de progenitores hematopoyéticos en pacientes con diagnóstico de leucemia mieloide aguda

Introducción: En pacientes con leucemia mieloide aguda (LMA) el trasplante de progenitores hematopoyético (TPH) es el único tratamientoz curativo. El objetivo de este estudio es presentar la experiencia y resultados del trasplante haploidéntico en pacientes adultos con LMA en la Fundación Valle del Lili, Cali – Colombia.Materiales y métodos: Estudio de cohorte retrospectivo de pacientes que recibieron trasplante haploidéntico entre 2013 y 2017, con acondicionamiento mieloablativo y ciclofosfamida postrasplante, en Fundación Valle del Lili, Cali (Colombia).Resultados: Se realizaron 47 trasplantes en pacientes con leucemia mieloide aguda en la fecha de estudio, se incluyeron en el análisis 21 pacientes con donante haploidéntico, a 3 años tanto la supervivencia global y libre de eventos fue del 38%. La incidencia acumulada de mortalidad relacionada al trasplante fue del 26% a 100 días y del 38,3%, a 38 meses de seguimiento. La incidencia acumulada de recaída a 38 meses fue del 19%. Con respecto a la enfermedad injerto versus huésped (EICH) se encontró que la incidencia acumulada de EICH aguda grado II-IV, grado III-IV y EICH crónico fue del 19%, 5% y 19% respectivamente.Conclusión: Los resultados de este estudio sugieren que el trasplante haploidéntico es una alternativa factible como tratamiento para pacientes con diagnóstico de LMA en nuestro medio.