Incidence Of Acute GVHD Grade Research Articles

Outcomes of Tcrαβ and CD19-Depleted Hematopoietic Stem Cell Transplantation from Matched, Mismatched Unrelated and Haploidentical Donors for Pediatric Patients with Hematological Malignancy: A Meta-Analysis

Introduction: TCR αβ+/CD19+ depletion in hematopoietic stem cell transplantation (HSCT) is an emerging graft manipulation technique to help overcome the HLA barrier in the mismatched or haploidentical transplant setting and reduce or prevent graft-versus-host disease. Limited research has explored the impact of various donor sources, and type of malignancy on the outcomes of TCR αβ+/CD19+ depleted HSCT for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and myelodysplastic syndrome (MDS). Therefore, we performed a comprehensive meta-analysis of published clinical studies using individual patient data (IPD) to address this scientific gap. Methods: This meta-analysis combined patient-level data from studies involving AML/MDS and ALL patients treated with TCR αβ+/CD19+ depleted HSCT. By utilizing the IPDfromKM technique, we reconstructed time-to-event data from aggregated Kaplan-Meier curves, specifically focusing on overall survival (OS), disease-free survival (DFS), and GVHD-free, relapse-free survival (GRFS). Additionally, we conducted parallel meta-analyses to calculate the pooled incidences of GVHD, graft failure, mortality, as well as CMV and EBV reactivation, and sinusoidal obstruction syndrome (SOS) using aggregate data. All analyses were performed using STATA software. Our comprehensive literature search included publications up to May 2023, excluding studies with significant sample overlap. Results: The meta-analysis incorporated 817 children with AML/MDS or ALL from 12 studies. Successful primary engraftment was observed in 95% of patients (95% CI: 92 - 98), with an average time to neutrophil and platelet engraftment of 12 days. The incidence of acute GVHD grades I-II was 24% (95% CI: 14 - 34), while grades III and IV were 11% (95% CI: 3.0 - 0.18). Chronic GVHD was observed in 19% of patients (95% CI: 11 - 28). The relapse and graft failure rates were 25% (95% CI: 19 - 32) and 6% (95% CI: 2.0 - 9.0), respectively. The all-cause mortality was 34% (95% CI: 29 - 38), with HSCT-related mortality at 11% (95% CI: 8.0 - 13), while relapse-related mortality accounted for 22% (95% CI: 17 - 28). At a median follow-up of 2.55 years, the 1-year and 5-year OS rates were 74.7% (95% CI: 60.6 - 78.3) and 64.4% (95% CI: 59.9 - 68.5), respectively. No significant differences in OS were found between ALL and AML/MDS patients (HR= 0.99, 95% CI: 0.48 - 2.02, P=0.98) or between different donor types (Figure 1A). The DFS rates at 1- and 5-year were 72.8% (95%CI: 67.6 - 77.3) and 61.8% (95%CI: 56.1 - 67.0), respectively. No significant differences in DFS were observed between ALL and AML/MDS patients (HR = 0.74 95%CI: 0.48 - 1.14, P=0.17) or between different donor types (Figure 1B). The overall 1- and 5-year GRFS rates were 71.1% (95% CI: 64.1 - 77.4) and 63.0% (95% CI: 55.3 - 69.8), respectively. The overall incidence of CMV and EBV reactivation was 33% (95% CI: 19 - 46) and 16% (95% CI: 0 - 38), respectively. Conclusions: Our meta-analysis confirms the effectiveness and safety of TCRαβ and CD19-depleted HSCT for hematological malignancies, demonstrating high engraftment success, low graft failure, and a manageable incidence of acute and chronic GVHD. The consistently favorable outcome data across different donor types and malignancies support the broad applicability of this form of graft manipulation.

Cord blood transplantation for nonmalignant disorders: early functional immunity and high survival.

There is no consensus on the best donor for children with nonmalignant disorders and immune deficiencies in the absence of a matched related donor (MRD). We evaluated the 2-year overall survival (OS) after umbilical cord blood transplantation (UCBT) in patients with nonmalignant disorders from 2009 to 2020 enrolled in a prospective clinical trial using either 5/6 or 6/6 UCB as the cell source. Patients receive a fully ablative busulfan, cyclophosphamide, and fludarabine without serotherapy. Fifty-five children were enrolled, median age 5 months (range, 1-111 months); primary immune deficiency (45), metabolic (5), hemophagocytic lymphohistiocytosis (1), and hematologic disorders (4). Twenty-six patients had persistent infections before transplant. Nineteen of them (34%) were 6/6 matched, and 36 (66%) were 5/6 human leukocyte antigen-matched. The OS at 2 years was 91% (95% cumulative incidence, 79-96), with a median follow-up of 4.3 years. The median time to neutrophil and platelet recovery were 17 days (range, 5-39 days) and 37 days (range, 20-92 days), respectively. All but one evaluable patient achieved full donor chimerism. The cumulative incidence of acute GVHD grades 2-4 on day 100 was 16% (n= 9). All patients with viral infections at the time of transplant cleared the infection at a median time of 54days (range, 44-91 days). All evaluable patients underwent correction of their immune or metabolic defects. We conclude that in the absence of MRD, UCBT following myeloablative conditioning without serotherapy is an excellent curative option in young children with nonmalignant disorders. This trial has been registered at www.clinicaltrials.gov as NCT00950846.

Gvhd Prophylaxis Incorporating Methotrexate in Allo-HCT for Chronic Myeloid Malignancies and sAML: A Retrospective Analysis from the Cmwp of the EBMT

Introduction: Methotrexate (MTX) given on days 1, 3, 6 (and 11) after allogeneic haematopoietic cell transplantation (allo-HCT) along with calcineurin inhibitors (CNI) was established as effective GVHD prophylaxis decades ago when myeloablative conditioning was standard. Mycophenolate mofetil (MMF) replaced MTX initially in minimal intensity conditioning protocols and then became increasingly popular due to its favorable toxicity profile. Although MMF was associated with more severe GVHD in some reports, similar survival outcomes were reported for both regimens in most randomized trials. However, two large retrospective studies from the CIBMTR reported inferior outcomes of MMF-based regimens in allo-HCT standard indications. Taking advantage of a very large sample size within the EBMT registry, the aim of this retrospective study was to determine outcome differences after allo-HCT between MTX- and MMF-based GVHD prophylaxis regimens considering subgroup heterogeneity. Patients and Methods: Eligible were patients from the EBMT registry with select chronic myeloid malignancies (CML, CMML, MDS, myelofibrosis, secondary AML) who were transplanted from matched related, matched unrelated and mismatched unrelated donors between 2007 and 2017 and received either MTX or MMF prophylaxis in combination with a CNI. Endpoints were overall (OS) and relapse-free survival (RFS), relapse incidence, non-relapse mortality (NRM), and cumulative incidence of grade 2-4 acute GVHD. Multivariable Cox regression analyses included age, conditioning intensity, TBI, diagnosis, disease stage, ATG, graft source, donor type, gender match, CMV (recipient), year of transplantation, and Karnofsky index. We tested whether the association between the type of prophylaxis and the outcome was different in patient subgroups by including interaction terms in multivariable analyses between prophylaxis type (MTX/MMF) and ATG, age, Tacrolimus, conditioning intensity, use of TBI, diagnosis, disease stage and recipient CMV status. Finally, we studied the association between the same set of variables and OS, relapse and NRM in patients after aGvHD and separately in a landmark analysis at 3 months in patients without aGvHD. Results: Overall, 13699 patients from 321 centers were included. Diagnoses were MDS (44%), Myelofibrosis (18%), CML (11%), CMML (6%), atypical CML (1%) and secondary AML (21%). The conditioning / prophylaxis combination was RIC/MMF in 34%, RIC/MTX in 22%, MAC/MMF in 12% and MAC/MTX in 32%. CNI prophylaxis was Tacrolimus (n=1248), ciclosporin (n=12286), both (n=165). Median follow up was 42.8 months (IQR 19.8-74.5 months). Unadjusted analyses demonstrated significantly better outcomes with MTX in all subgroups of patients (TBI/no TBI, RIC/MAC, diagnoses except myelofibrosis, ATG/no ATG, age at allo-HCT < or ≥60 years). Figure 1a shows OS curves for conditioning/prophylaxis combinations. The cumulative incidence of acute GVHD grade 2-4 was lower in in particular RIC patients (Figure 1b). MTX was associated with significantly reduced overall mortality (HR 0.88, 95%CI 0.81-0.95, p<0.001) and NRM (HR 0.87, 95% CI 0.78-0.96, p=0.008) in multivariable analyses in the whole cohort. In contrast, MTX prophylaxis was not significantly associated with relapse (HR 1.02, 95% CI 0.92-1.12, p=0.72) and relapse-free survival (RFS) (HR 0.94, 95% CI 0.88-1.01, p=0.11). Notably, there was no significant interaction effect between prophylaxis type and any of the eight variables (ATG, age, tacrolimus, conditioning intensity, use of TBI, diagnosis, disease stage and CMV status in recipients) tested for OS and NRM, except that the beneficial association of MTX on OS was weaker for patients with Myelofibrosis. OS after acute GVHD was significantly lower with MTX prophylaxis and this was similar in RIC and MAC. MTX did not significantly associate with improved outcome in a landmark analysis in patients without aGvHD at 3 months after allo-HCT. Conclusion: Compared to MMF, MTX-complemented calcineurin inhibitor prophylaxis was associated with favorable early OS and NRM, and in particular with favorable OS after aGVHD, in this large cohort of patients with chronic myeloid malignancies or sAML transplanted in a recent time period. This effect was observed across various subgroups. These results may have future impact on clinical practice and trial design. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Myeloablative Fractionated Busulfan Conditioning Regimen with Venetoclax in Patients with AML/MDS: Prospective Phase II Clinical Trial

Background: Myeloablative conditioning can be given safely to older patients by simply administering busulfan over a longer period (fractionated busulfan regimen) than the standard four-day regimen (Popat et al Lancet Haematology 2018). This longer duration of conditioning regimen allows addition of targeted agents like Venetoclax, which may be synergistic with conditioning chemotherapy and may further improve disease control with this regimen. We therefore added Venetoclax to our ongoing prospective clinical trial with f-Bu-Flu-Cladribine conditioning (NCT02250937). After enrolling 83 patients, the study was amended and venetoclax was added for the next 33 patients. Here we report the safety and preliminary efficacy of venetoclax and fractionated busulfan regimen.Methods: Between 2/2019 and 3/2021, 33 patients with AML (n=21) or MDS (n=10) up to 70 years of age with adequate organ function and 8/8-HLA matched related or unrelated donor were enrolled on a prospective trial. The conditioning regimen was f-Bu to target an area under the concentration vs time curve (AUC) of 20,000 ± 12% μmol.min given over a period of 2-3 weeks. The first two doses of busulfan (80 mg/m2 IV each) were administered either consecutively (days -13 and -12) or with further fractionation, one week apart (days -20 and -13) on outpatient basis. Then, inpatient fludarabine 10 mg/m 2, and cladribine 10 mg/m 2 were given followed by Bu on days -6 to -3. Venetoclax 400mg daily was given from day -22 to -3. Azoles were avoided during this period. GVHD prophylaxis was PTCy 50mg/kg on days 3 and 4 and tacrolimus from day 5.Results: The median age was 59 years (range, 23-69); High or very high disease risk index was present in 21%; Comorbidity index score of >3 was present in 45%; Donor was a sibling in 39%; and peripheral blood stem cells was the graft source in 100%.The median follow up was 8 months. At 1-year, overall survival was 84% (95% confidence interval, 71-100), progression-free survival 77% (64-94), relapse 13% (1-25), and non-relapse mortality 10% (0-20) [Table 1, Figure 1]. Incidence of acute GVHD grade 2-4 was 28% (12-43) and grade 3-4 acute GVHD was 3% (0-9) at day 100. All patients engrafted. The median time to neutrophil engraftment was 15 days (13 -19) and median time to platelet engraftment was 23 days (11-85). Full donor chimerism at day 30 was noted in 76%. Common grade 3 or 4 toxicity were neutropenic fever (58%), mucositis (18%) and pulmonary toxicity in 21%.Conclusion: Venetoclax can be safely added to the fractionated busulfan regimen. Early data on efficacy appear promising. [Display omitted] DisclosuresPopat: Bayer: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding. Mehta: CSLBehring: Research Funding; Syndax: Research Funding; Incyte: Research Funding; Kadmon: Research Funding. Hosing: Nkarta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Gulbis: EUSA Pharma: Other: Advisory board participation. Rezvani: AvengeBio: Other: Scientific Advisory Board ; Pharmacyclics: Other: Educational grant, Research Funding; GemoAb: Other: Scientific Advisory Board ; Navan Technologies: Other: Scientific Advisory Board; Bayer: Other: Scientific Advisory Board ; Caribou: Other: Scientific Advisory Board; Takeda: Other: License agreement and research agreement, Patents & Royalties; Virogin: Other: Scientific Advisory Board ; GSK: Other: Scientific Advisory Board ; Affimed: Other: License agreement and research agreement; education grant, Patents & Royalties, Research Funding. Qazilbash: Bristol-Myers Squibb: Other: Advisory Board; Oncopeptides: Other: Advisory Board; Amgen: Research Funding; Angiocrine: Research Funding; NexImmune: Research Funding; Biolline: Research Funding; Janssen: Research Funding. Kadia: Cure: Speakers Bureau; Novartis: Consultancy; Dalichi Sankyo: Consultancy; Cellonkos: Other; Ascentage: Other; Genfleet: Other; Sanofi-Aventis: Consultancy; Genentech: Consultancy, Other: Grant/research support; Astellas: Other; Liberum: Consultancy; BMS: Other: Grant/research support; Amgen: Other: Grant/research support; Aglos: Consultancy; Pfizer: Consultancy, Other; AstraZeneca: Other; AbbVie: Consultancy, Other: Grant/research support; Pulmotech: Other; Jazz: Consultancy. Konopleva: Calithera: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Ascentage: Other: grant support, Research Funding; Cellectis: Other: grant support; Ablynx: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; AstraZeneca: Other: grant support, Research Funding; Stemline Therapeutics: Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Forty Seven: Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; KisoJi: Research Funding. Shpall: Axio: Consultancy; Magenta: Consultancy; Novartis: Consultancy; Bayer HealthCare Pharmaceuticals: Honoraria; Adaptimmune: Consultancy; Navan: Consultancy; Takeda: Patents & Royalties; Novartis: Honoraria; Affimed: Patents & Royalties; Magenta: Honoraria.

Mesenchymal stromal cells for the prophylaxis and treatment of graft-versus-host disease\u2014a meta-analysis

BackgroundGraft-versus-host disease (GvHD) is the main life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT). Thirty to 80% of GvHD patients do not respond to first-line treatment and a second-line treatment is not universally established. Based on their immunomodulatory properties, mesenchymal stromal cells (MSC) have been proposed for the prevention and the treatment of GvHD in patients undergoing HSCT. Unfortunately, previous studies reported conflicting results regarding the prophylactic and therapeutic effects of MSC for GvHD. Consequently, we carried out a meta-analysis to clarify whether MSC administration can improve the dismal outcome of these patients.MethodsWe carried out a systematic review and selected studies (2004–2019) reporting data about the administration of allogeneic MSC for the prevention (n = 654 patients) or treatment of acute (n = 943 patients) or chronic (n = 76 patients) GvHD after HSCT. Our primary outcome was overall survival at the last follow-up. The secondary outcomes were the response and development of GvHD. Subgroup analyses included age, MSC dose, first infusion day after HSCT, number of organs and organ-specific involvement, acute GvHD grade (I–IV), and chronic GvHD grade (limited or extensive).ResultsPatients infused with MSC for GvHD prophylaxis showed a 17% increased overall survival (95% CI, 1.02–1.33) and a reduced incidence of acute GvHD grade IV (RR = 0.22; 95% CI, 0.06–0.81) and chronic GvHD (RR = 0.64; 95% CI, 0.47–0.88) compared with controls. Overall survival of acute GvHD patients (0.50; 95% CI, 0.41–0.59) was positively correlated with MSC dose (P = 0.0214). The overall response was achieved in 67% (95% CI, 0.61–0.74) and was complete in 39% (95% CI, 0.31–0.48) of acute patients. Organ-specific response was higher for the skin. Twenty-two percent (95% CI, 0.16–0.29) of acute patients infused with MSC developed chronic GvHD. Sixty-four percent (95% CI, 0.47–0.80) of chronic patients infused with MSC survived; the overall response was 66% (95% CI, 0.55–0.76) and was complete in 23% (95% CI 0.12–0.34) of patients.ConclusionsOur meta-analysis indicates that allogeneic MSC could be instrumental for the prophylaxis and treatment of GvHD. Future trials should investigate the effect of the administration of MSC as an adjuvant therapy for the treatment of patients with GvHD from the onset of the disease.

T-Cell Replete Haploidentical Stem Cell Transplantation with Post-Transplantation Cyclophosphamide (PTCy) for Pediatric Patients with Primary Immunodeficiencies (PID) - a Survey of the Pediatric Transplantation Working Group of the Brazilian Society of Bone Marrow Transplantation (SBTMO)

Introduction Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for several primary immunodeficiencies. In the absence of a matched sibling or a well matched unrelated donor, the use of an haploidentical family donor can be considered. Historically, most part of haploidentical HSCT were performed with in vitro T-cell depletion techniques that aren't worldwide available, especially in middle or low income countries. The use of T-cell replete haploidentical HSCT with PTCy in children with PID has been described in only a few case-series. Objectives To report the outcomes of haploidentical HSCT with PTCy for children with severe PID Methods Retrospective chart review of 73 patients with PID who underwent haploidentical HSCT with PTCy from July 2012 to May 2019 at 9 centers in Brazil. Results Fifty-five patients received first allogeneic transplants, and 18 were rescued after graft failure of a previous transplant. Median age was 1.6 years (2 months to 19 years). Most patients were male (n=54) and had active infection at the time of transplant (n=50). Diagnoses were: severe combined immunodeficiency (n=34), Wiskott-Aldrich Syndrome (n=14), chronic granulomatous disease (n=10) and other PID (n=15). Donors were father (N=46), mother (N=24), or siblings (N=3); and cell source was predominantly bone marrow (94% of patients). Conditioning regimen was non-myeloablative (fludarabine 150mg/m2 + cyclophosphamide 29mg/Kg + TBI 200cGy) in 35 patients; and myeloblative in 38 patients (most part receiving: bussulfan + fludarabine 160mg/m2 + ATG 4-7,5 mg/Kg or alemtuzumab 0,5-1mg/Kg). GVHD prophylaxis was PT-Cy, CsA or Tacrolimus and MMF. The median follow-up of surviving patients was 24 months. Four patients died before 28 days and were not evaluable for engraftment. Sixty-one patients engrafted in a median of 15 days. The 100-day incidence of acute GVHD grades II–IV was 33% and grades III–IV, 14%. The incidence of Chronic GVHD at 1 year was 16%. Twenty-two patients died, most of them due to infection (n=15). The two-year overall survival was 66%. There was no difference in OS between patients receiving first allogeneic or rescue transplants, suggesting survival bias. Patients transplanted for WAS or SCID had a better OS compared to those transplanted for CGD (p=0,02). Conclusion In conclusion, 66% of Brazilian children with severe PID and no matched donor could be cured with haploidentical HSCT with PTCy. The high proportion of patients in our cohort transplanted with an active infection (70%) may have had a major impact in our results. The optimal conditioning regimen for these patients and long term follow up data are the objective of our ongoing studies.

Prophylactic or Preemptive Low-Dose Azacitidine (AZA) and Donor Lymphocyte Infusion (DLI) Prevent Disease Relapse Following Allogeneic Transplantation in High Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome

Introduction: Despite therapeutic advances in recent years, disease relapse is still observed in up to 50-60% of the patients (pts) receiving allogeneic transplantation for high risk AML and MDS. In an initial Phase II trial of 30 pts treated with prophylactic low-dose AZA and escalated doses of DLI to prevent relapse, we reported that such prophylactic treatment can be safely administered and compared favorably to patients receiving no post-transplant maintenance. We here update 16 pts from our center, included in that protocol, as well as a larger cohort of additional patients treated with combined epigenetic and cellular therapy and the resultant effect on their event-free survival and their overall survival. Patients and methods: Fifty-nine pts (median age 59 yrs (range, 37-70); 30 M/29 F), comprising 40 pts with AML and 19 pts with MDS, were treated. Among the AML pts (ELN classification FAV n=2, INT n=17, ADV n=21), high risk criteria were as follows: 15 had complex karyotypes, 7 Flt3-ITD, 1 MECOM (EVI1) rearr., 3 monosomies, 2 t(9;11), and 1 t(11;19)); 9 were in CR≥2, 4 were refractory, and 13 had 2ary AML to MDS/chemotherapy/or MPS. Among the MDS pts, high risk criteria included 6 pts with complex caryotypes, 2 monosomies, 1 MECOM (EVI1) rearr., and 4 had 2ary MDS. IPSS-R median was 5.5 (3 - 7.5). MDS pre-transplant status included 7 CR1, 1 CR2, 5 PR, 1 relapse, 4 upfront, and 1 refractory. The therapeutic protocol administered to the initial 16 pts consisted of AZA, starting between d56 and d100 post-transplant, at a dose of 32 mg/m²/d SC, for 5 consecutive days, every 28 days, for up to a total of 12 cycles followed by DLI commencing after 3 cycles of AZA and 4 weeks following discontinuation of immunosuppressive prophylaxis. Two additional DLI were scheduled every 8 weeks following the 1st DLI. The doses of DLI 1, 2 and 3 were, respectively, 5x106, 1x107, and 5x107 CD3+ cells/kg for matched related donor (MRD), and 1x106, 5x106, and 1x107 CD3+ cells/kg for unrelated donor (UD). In the extended patient cohort, presented here, we slightly modified the schedule: DLI could be given earlier (after one or two cycles of AZA) and haploidentical pts could receive AZA/DLI as well, with DLI at the escalated doses of 1x105, 5x105, and 1x106 CD3+ cells/kg. Immunosuppression included cyclosporine A (CsA) in case of MRD, CsA and mycophenolate mofetil (MMF) in case of UD or haplo. MMF was progressively reduced during the first 2 months. CsA was tapered starting at day 60-100 post-transplant. Patients could start AZA while they were still receiving CsA. The conditioning regimens consisted of MAC for 5 pts, RIC for 46 pts and sequential for 8 pts. Donors were MRD, MUD, UD 9/10, and haplo for 20, 30, 1 and 8 pts respectively. Results: The median number of cycles AZA was 7 (range 1-12), 17 pts received 12 cycles of AZA, while 42 pts (71%) received at least one DLI. The median number of DLI was 1 (range 0-4), 15 pts received ≥ 3 DLI. The median time for the first post-transplant AZA injection was 83 days (range 56-145 d) and the median time post-transplant for those pts who received a first DLI was 148 days (range 78-245 d). The median pt-follow-up was 17 months (range 2-83). Eight pts (13%) relapsed (7 AML and 1 MDS). The cumulative incidence of relapse and NRM at 1 year was 12% and 11.5% respectively. Fifteen pts (25%) died. Causes of death included relapse in 6 pts, infection in 7 pts, myocardial infarction in 1 pt, and GvHD in 1 pt. Overall survival and event free survival for the entire group at 2 years was 71% (95% CI 54-82%) and 67% (95% CI 50-80%) respectively. The cumulative incidence of acute GvHD grade 1-4 and chronic GvHD were 32% (95% CI 16-49%) and 39% (95% CI 20-58%). Among the 8 pts who developed grade 3 acute GvHD, 4 occurred in pts who had received DLI. One pt died from grade 4 digestive GvHD post-AZA alone. Conclusion: We conclude that, despite their very high risk disease, prophylactic/preemptive low-dose AZA and DLI can be readily and safely administered with an acceptable incidence of subsequent GvHD to the AML and MDS pts described here. Significantly, in the poor-prognosis pts under study, the incidence of relapse is lower than expected. Furthermore, considering the immune escape mechanisms prophylactic or pre-emptive either AZA or DLI might be associated to additive non-cross reactive interventions, such as checkpoint inhibitors, in order to further decrease disease relapse and increase overall survival. Disclosures Peterlin: Jazz Pharma: Consultancy; Astellas: Consultancy; Daiichi-Sankyo: Consultancy; AbbVie Inc: Consultancy. Orvain:Novartis: Honoraria; Incyte: Honoraria. Chevallier:Jazz Pharmaceuticals: Honoraria; Daiichi Sankyo: Honoraria; Incyte: Consultancy, Honoraria.

αβ-T-cell-depleted haploidentical hematopoietic stem cell transplantation in children with chemorefractory acute myeloid leukemia

Primary refractory and relapsed refractory acute myeloid leukemia remains an unresolved problem in pediatric oncology. Children with AML who fail to achieve complete remission on high-dose cytarabine and antracyclines have no chance for survival without allogeneic hematopoietic stem cell transplantation. We evaluated the outcome of αβ-T-cell-depleted haploidentical transplantation in a cohort of children with chemorefractory acute myeloid leukemia. Thirty-six patients with either primary refractory (n = 14) or relapsed refractory (n = 22) acute myeloid leukemia in active disease status received a transplantation from haploidentical donors. The preparative regimen included cytoreduction with fludarabine and cytarabine and subsequent treatment with treosulfan and either melphalan or thiophosphamide. Serotherapy consisted of antithymocyte globuline in 14 pts and targeted immunomodulation with tocilizumab +/- abatacept in 22 pts. Grafts were PBSCs engineered by TCR-αβ/CD19 depletion. Posttransplant preemptive therapy included modified donor lymphocyte infusions with or without hypomethylating agents. Complete remission was achieved in 30 (83%) рts. The cumulative incidence of acute GVHD grade II–IV was 25%, and the cumulative incidence of chronic GVHD was 18%. Transplant-related mortality was 6%, and relapse incidence was 48%. Event-free survival was 46%, and overall survival was 41% at 2 years. Good early recovery of NK cells was associated with significantly improved survival and decreased relapse incidence. Our data suggest that αβ-T-cell-depleted haploidentical HSCT provides a reasonable chance of cure in a cohort of children with chemorefractory acute myeloid leukemia and creates a solid basis for further improvement. The study was approved by the Independent Ethics Committee of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology.

PF759 ALLOGENEIC STEM CELL TRANSPLANTATION FOR HEMATOLOGICAL MALIGNANCIES FROM HLA IDENTICAL SIBLINGS OR HAPLOIDENTICAL DONORS: A COMPARISON

Background:Allogeneic stem cell transplantation (HSCT) from an HLA identical sibling donor(SIB) remains standard of care. When a SIB donor is lacking, HLA mismatched related donors (HAPLO) are a valid alternative source of stem cells. The outcome of SIB and HAPLO transplant have been evaluated and often found to be comparable.Aims:The aim of the present study is to compare the outcome of patients allografted from HAPLO or SIB donors in two transplant Units between 2010 and 2017, in terms of engraftment, GvHD, non relapase mortality (NRM), relapse and survival.Methods:678 patients were eligible for this study: 195 patients (29%) grafted from SIB donors and 483 (71%) from HAPLO donors. The main diagnosis were acute leukemias (55%) and myelodysplastic syndromes (20%), followed by lymphomas and myelofibrosis. The two groups were comparable in terms of recipients age (p = 0.3), donors age (p = 0.8) and status of disease at the time of HSCT; 401 patients were in CR1–2 (123 vs 288, p = 0.4) and 266 patients were beyond CR2 (72 vs 194). The stem cell source was bone marrow for all patients grafted from HAPLO donors; it was peripheral blood in 43% SIB grafts and 47% in bone marrow grafts. The conditioning regimen was full dose total body irradiation in 27% and 16% (SIB vs HAPLO), thiotepa, busulfan, fludarabine, in 69% vs 72% and a non myeloablative regimen in 3% vs 11% (p &lt; 0.001).GvHD prophylaxis was cyclosporin (CyA) and methotrexate (MTX) for SIB grafts and CyA+ mycophenolate (MMF)+ post transplant cyclophosphamide (PT‐CY) for HAPLO grafts.Results:Neutrophils engraftment was achieved in SIB vs HAPLO grafts at a median day of 17 (10–71) and 18 (13–64) days respectively (p = 0.6). Platelet recovery was faster after SIB grafts with platelet counts of 132x10^9/L vs 88 x10^9/L on day +50 after HSCT (p &lt; 0.00001). The cumulative incidence of acute GVHD grade 3–4 and chronic GVHD moderate to severe was higher in SIB vs HAPLO grafts: respectively 9% vs 3% (p = 0.001) and 32% vs 21% (p = 0.002). Platelet counts were significantly higher on day +50 in SIB vs HAPLO grafts, when stratified for acute GvHD grade 0‐I (141x10^9/L vs 95 x10^9/L) or acute GvHD grade II (104x10^9/L vs 57x10^9/L; p = 0.008). We found no difference in terms of transplant‐related mortality (TRM) (17% vs 19%, p = 0.5), 5 years survival (55% vs 54% p = 0.4) and relapse (32% vs 28%, p = 0.4).In a multivariate Cox analysis predictors of survival were advanced disease (RR 1.9, p &lt; 0.00001), recipients age &gt; 40 years (RR 1.4, p = 0.03) and over 60 years (RR 1.8, p = 0.003). The only predictor of NRM was patients age, and the only predictor of relapse was advanced disease.Summary/Conclusion:This study suggests that major transplant outcomes, are comparable in SIB vs HAPLO grafts, namely mortality, relapse and survival. GvHD is somewhat greater in SIB patients, but GvHD prophylaxis is less intense. Hematologic recovery is faster and more robust in patients receiving SIB transplants, also after stratifying for GvHD. HAPLO grafts remain a valid alternative source of stem cells in the absence of an HLA identical SIB.image

Impact of ruxolitinib pretreatment on outcomes after allogeneic stem cell transplantation in patients with myelofibrosis.

Ruxolitinib is the first approved drug for treatment of myelofibrosis, but its impact of outcome after allogeneic stem cell transplantation (ASCT) is unknown. We reported on 159 myelofibrosis patients (pts) with a median age of 59years (r: 28-74) who received reduced intensity ASCT between 2000 and 2015 in eight German centers from related (n=23), matched (n=86) or mismatched (n=50) unrelated donors. Forty-six (29%) patients received ruxolitinib at any time point prior to ASCT. The median daily dose of ruxolitinib was 30mg (range 10-40mg) and the median duration of treatment was 4.9months (range 0.4-39.1months). Primary graft failure was seen in 2 pts (4%) in the ruxolitinib and 3 (2%) in the non-ruxolitinib group. Engraftment and incidence of acute GVHD grade II to IV and III/IV did not differ between groups (37% vs 39% and 19% vs 28%, respectively), nor did the non-relapse mortality at 2years (23% vs 23%). A trend for lower risk of relapse was seen in the ruxolitinib group (9% vs 17%, P=.2), resulting in a similar 2year DFS and OS (68% vs 60% and 73% vs 70%, respectively). No difference in any outcome variable could be seen between ruxolitinib responders and those who failed or lost response to ruxolitinib. These results suggest that ruxolitinib pretreatment in myelofibrosis patient does not negatively influence outcome after allogeneic stem cell transplantation.

Two Doses of Antithymocyteglobulin As Graft-Versus-Host Disease Prophylaxis in Haploidentical Allogeneic Stem Cell Transplantation: A Multicenter Prospective Study

BackgroundGraft-versus-host disease (GVHD) is an important complication after haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Antithymocyteglobulin (ATG) has been widely used for GVHD prophylaxis. However, the delay of T-cell reconstitution causes by ATG may increase the risk of opportunistic infections. In this multicenter prospective study, we compared the outcomes of the patients undergoing haplo-HSCT who received 7.5 mg/kg ATG or 10 mg/kg ATG as GVHD prophylaxis.MethodsA total of 368 consecutive patients undergoing haplo-HSCT were randomized in 5 hospitals between May 2013 and March 2016. ATG with a total dosage of 7.5 mg/kg were administered in 184 patients and 10 mg/kg ATG were administered in 181 for GVHD prophylaxis. Three patients did not received allocated intervention and transplantation due to leukemia relapse before transplant or toxicity of conditioning regimens. The primary endpoint was the incidence of acute GVHD grade II to IV on day 100. Noninferiority of 7.5mg/kg ATG against 10mg/kg ATG was established if the difference of the 95% confidence interval (CI) in acute GVHD grade II to IV between the two groups was within 15%.ResultsThe incidences of acute GVHD grade II to IV on day 100 were 31.5% and 28.2% in 7.5 mg/kg and 10 mg/kg ATG (P=0.485), respectively. The difference between these two groups was 3.3% with 95% CI of -6.1% to 12.7%, which indicated that 7.5 mg/kg ATG was not inferior to 10 mg/kg ATG. The incidences of acute GVHD grade III to IV were similar in the two groups (8.2% in 7.5 mg/kg group vs. 5.0% in 10 mg/kg group, P=0.220). No difference in chronic GVHD was found in the two groups (21.2% in 7.5 mg/kg arm vs. 19.8% in 10 mg/kg arm, P=0.748). More patients developed EBV viremia in 10 mg/kg group (37.5±3.8%) than those in 7.5 mg/kg group (25.2±3.3%, P=0.018). The 2-years overall survival were 69.5±4.3% and 66.7±4.0% for 7.5 mg/kg and 10 mg/kg group (P=0.356). And the 2-year disease-free survival were also comparative in the two groups (66.3±5.7% in 7.5 mg/kg arm vs. 66.6±3.8% in 10 mg/kg arm, P=0.288).ConclusionCompared with 10 mg/kg ATG, the 7.5mg/kg ATG applied in haplo-HSCT appears not to increase GVHD and might reduce the risk of EBV infection after transplantation. DisclosuresLin:National Natural Science Foundation of China 81400141: Research Funding; National Natural Science Foundation of China 81270647: Research Funding; Science and technology planning project of Guangdong Province 2014B020226004: Research Funding; The project of health collaborative innovation of Guangzhou City 201400000003-4: Research Funding.

Impact of Pre-Transplant Ruxolitinib in Myelofibrosis Patients on Outcome after Allogeneic Stem Cell Transplantation

▪IntroductionRuxolitinib is the first approved drug for treatment of myelofibrosis. Major effects are reduction in spleen size and improvement of constitutional symptoms. Because spleen size and constitutional symptoms may influence outcome after allogeneic stem cell transplantation (ASCT), ruxolitinib is recommended before stem cell transplantation in order to reduce therapy-related morbidity and mortality and improve outcome (EBMT/ELN recommendation, Leukemia 2015) The aim of this retrospective study was to evaluate the impact of pretreatment with ruxolitinib in comparison to transplantation of ruxolitinib-naïve MF patients with regard to outcome after ASCT.Patients and methodsWe included 171 myelofibrosis patients (pts) with a median age of 59 years (r: 28 - 74) who received ASCT between 2000 and 2015 from related (n = 25), matched (n=94) or mismatched (n=52) unrelated donor. Stem cell source were more peripheral blood stem cells (n = 167) than bone marrow (n = 4). All patients received busulfan-based reduced intensity conditioning. While 113 pts (66%) did not receive ruxolitinib, 58 pts (34%) received ruxolitinib at any time point prior to ASCT. The median daily dose of ruxolitinib was 30mg (range 10-40mg) and the median duration of treatment was 28 days (range 12-159 days). In 11 pts ruxolitinib was stopped before stem cell transplantation because of no response or loss of response, while in 35 pts ruxolitinib was given until start of conditioning and in 12 pts ruxolitinib was given until stable engraftment. GvHD prophylaxis consisted of CNI plus short course MTX or MMF and anti-lymphocyte globulin. According to dynamic IPSS (DIPSS) (n = 170) the patients were either low (n = 2), intermediate-1 (n = 37), intermediat-2 (n = 81), or high risk (n = 38). 74 patients (43%) were transfusion dependent.ResultsAs the median follow up was shorter for patients treated with ruxolitinib (15 vs 73 months, p<0.001), we analyzed only 2 years RFS, OS, NRM and relapse incidence. Primary graft failure was seen in 2 pts in the ruxolitinib and 3 in the non-ruxolitinib group. The median leukocyte engraftment was 13 days (r., 9-32) in the ruxolitinib and 14 days (r., 7-34) in the non ruxolitinib group (p=0.7). The median age in the ruxolitinib group was slightly older ( 62 vs 58 years , p= 0.09). The incidence of acute GvHD grade I to IV was significantly lower in the ruxolitinib group (49% vs 64%, p=0.05), while aGvHD grade II-IV (33% vs 44%, p=0.14) and grade III/IV (23% vs 25%, p=0.48), did not differ significantly. The CI of NRM at 1 year was 18% (95% CI: 6-30%) for the ruxolitinib group and 22% (95% CI: 14-30%) for the non-ruxolitinib group (p=0.58), and the CI of relapse at 2 years was 8% (95% CI: 0-16%) vs 20% (95%CI: 12-28%, p=0.25). The 2 years RFS and OS was 66% (95%CI: 50-82%) and 69% (95%CI: 51-87) for the ruxolitinib group and 59% (95% CI: 49-69%) and 70% (95% CI:62-78%) for the non-ruxolitinib group (p=0.29 and p=0.45, respectively). Within the ruxolitinib group (n=53), 24 pts responded to ruxolitinib (more than 25% spleen size reduction), while 29 pts did not respond or lost response prior to stem cell transplantation. Here, no significant difference could be seen between the responding and non-responding group for NRM (19% vs 17%, p=0.69), Relapse (4% vs 13%, p=0.62), RFS (61% vs 72%, p=0.81) and OS (63% vs 75%, p=0.89). In a multivariate analysis including ruxolitinib treatment as variable there was a non-significant trend in favor for ruxolitinib pretreatment regarding NRM (HR 0.79; 95%CI: 0.38-1.66, p=0.54), relapse (HR 0.48; 95%CI: 0.18-1.31, p=0.15), RFS (HR 0.55; 95%CI: 0.29-1.03, p=0.06) and OS (HR 0.83; 95%CI: 0.41-1.67, p=0.61).ConclusionsThese results suggest that ruxolitinib pretreatment in myelofibrosis patient does not negatively influence outcome after allogeneic stem cell transplantation. To confirm the observed favorable trend in outcome after ruxolitinib treatment more patients and a longer follow-up is needed. DisclosuresCrysandt:Novartis: Other: Travel grant. Stelljes:Pfizer: Consultancy. Kröger:Novartis: Honoraria, Research Funding.

Similar Outcomes of Allogeneic Hematopoietic Cell Transplantation from Matched Sibling Donor and Haploidentical Donor for Refractory/Relapsed Acute Myeloid Leukemia

Allogeneic hematopoietic stem cell transplantation (allo-HCT) is the only effective, even curative treatment for refractory/relapsed AML patients. Unmanipulated haploidentical HCT (haplo-HCT) resulted in encouraging outcomes for treatment of hematologic malignancies and become an alternative option in case of lacking HLA matched sibling donor (MSD). Unmanipulated haplo-HCT from G-CSF mobilized bone marrow and peripheral blood stem cell (PBSC) has shown similar results as that from MSD-HCT in leukemia. Here, we report the results of a cohort study on the efficacy and toxicity of haplo-PBSCT compared with MSD-PBSCT for treatment of refractory/relapsed AML.PATIENTS AND METHODSAmong 419 newly diagnosed AML patients, 69 patients relapsed during CR1 and were planned to receive allo-HCT after re-induction. The order of preference of donors was MSD, matched unrelated (HLA 10/10 or 9/10 loci matched), or haploidentical donor. Thirty patients received haplo-PBSCT and 13 patients MSD-HCT (July, 2007 ~ June, 2014) at our unit. There was no difference of the characteristics of demography, disease or transplantation between these two groups (Table 1).High-resolution DNA techniques were used to evaluate the HLA-A, B, DRB1, DQB1, and C loci. Donors were treated with rhG-CSF (5 mg.kg-1.day-1) for consecutive days. The PBSCs were collected on day 5 - 6 and infused on the day of collection.The conditioning regimen consisted of Bu (9.6 mg.kg-1, intravenously, days -10 ~ -8), Carmustine, (250 mg.m-2, day -5), cytarabine (8 g.m-2, days -7 ~ -6), CY (120 mg kg-1, days -4 ~ -3), and ATG (rabbit; 10 mg.kg-1, days -5 ~ -2). MSD-HCT patients had the same conditioning regimen without ATG. All transplant recipients received cyclosporine A, mycophenolate mofetil, and short-term methotrexate for GVHD prophylaxis. The endpoint of the last follow-up for all surviving patients was June 30, 2015.RESULTSSustained myeloid engraftment with full donor chimerism was achieved in both groups (100%) at a median of 16 (10 - 26) days. Twenty-six patients (86.7%) in haplo-PBSCT group and all patients in MSD-PBSCT group achieved platelet recovery. There was no difference of the cumulative incidence of acute GVHD grade 2-4 (Fig. 1), chronic GVHD (20% vs 33.3%, P =0.581), transplantation-related mortality (TRM) (16.7% vs 0%, P = 0.121), relapse (33.3% vs 38.5%, P = 0.578, Fig 2) between haplo-PBSCT and MSD-PBSCT group. Donor age of 41yr and older was an independent risk factor for inferior leukemia-free-survival (27.8% vs 37.2%, P = 0.004).CONCLUSIONIn this cohort study, haplo-PBSCT showed similar outcomes in patients with refractory/relapsed AML compared with MSD-PBSCT. It suggested the feasibility of G-CSF-primed PBSC as a graft source in unmanipulated haplo-HCT under myeloablative conditioning, which was effective and tolerable for treatment of poor risk leukemia.Table 1Characteristics of patients and donorsHaploidentical donorMatched sibling donorP valueCases%Cases%Gender, n (%)ReceiptMale2273.3861.50.485DonorMale2273.3753.80.292Age,y, median(range)Patient≤40 y, n (%)2170646.20.178Donor≤41 y, n (%)1343.3538.51.000AML, n (%)1.000CR2516.7215.4NR/beyond CR22583.31184.6Time to transp0.51≥7m1446.7861.5Conditioning Regimen, n (%)0.675BuCy2273.2969.2TBIcy413.317.7FB413.3323.1CD34+ in graft (106/kg)0.499≥4.771756.7541.7 [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Comparison of Post-Allogeneic Hematopoietic Cell Transplantation (HCT) Outcomes after Matched Related Donor Versus Matched Unrelated Donor HCT in Adults with Acute Lymphoblastic Leukemia

Allogeneic hematopoietic cell transplantation (HCT) is a potentially life-saving treatment for patients with acute lymphoblastic leukemia (ALL). About one-third of patients have a human leukocyte antigen (HLA) matched related donor (MRD), while the remaining two-thirds have either a fully HLA-matched (HLA-A, -B, -C, -DRB1 [8/8]) unrelated donor (MUD) or a MUD with a single HLA mismatch (7/8). Previous analyses by the CIBMTR have shown that MRD and MUD transplants produce similar survival outcomes for patients with acute myelogenous leukemia (AML) (Blood 2012; 119(17):3908-16), while donor source was an important predictor of outcomes in patients with myelodysplastic syndrome (MDS) (Blood 2013; 122(11):1974-82). Given that ALL represents the second most common indication for HCT, and recognizing the disease-specific nature of the impact of donor source on post-HCT outcomes previously described, we performed an analysis of outcomes after MRD versus MUD HCT in 1458 patients with ALL who underwent allogeneic HCT from 2000-2011 (MRD n=440, 8/8 MUD n=729, 7/8 MUD n=289). Median age was 37 years (18-69). Thirty-four percent were Philadelphia chromosome positive.Ten percent received reduced intensity conditioning (RIC). Twenty-three percent were transplanted in second complete remission (CR2).Seventy-four percent received peripheral blood stem cells. At 100 days post-HCT, the incidence of acute GVHD Grade B-D was significantly lower in MRD recipients than in 8/8 MUD or 7/8 MUD recipients (26%, 45%, 50%, respectively; p<0.001). In multivariate analysis, 8/8 MUD recipients had similar rates of transplant-related mortality (TRM) and overall survival (OS) (hazard ratio [HR] 1.16, p=0.225and HR 1.01, p=0.93, respectively) compared to MRD recipients; 7/8 MUD recipients had inferior TRM and OS when compared to both MRD recipients (HR 1.92, p<0.001 and HR 1.29, p=0.01, respectively) and 8/8 MUD recipients (HR 1.66, p<0.001 and HR 1.28, p=0.008, respectively).Recipients of peripheral blood transplants had inferior long-term survival (>24 months post-HCT) (HR=2.13, p=0.003) compared to bone marrow transplants. Compared to MRD, 8/8 MUD recipients had superior relapse rates (HR 0.77, p=0.02), while 7/8 MUD recipients had no difference (HR 0.75, p=0.05). There were no differences in leukemia-free survival (LFS) comparing 8/8 MUD recipients (HR 0.95, p=0.55) and 7/8 MUD recipients (HR 1.20, p=0.07) to MRD recipients (Table 2, Figure 1).Differences in survival were likely due to higher rates of acute GVHD and TRM in the 7/8 MUD group. We conclude that MRD and 8/8 MUD recipients have similar survival outcomes post-HCT, while 7/8 MUD recipients suffer inferior survival, demonstrating that donor source plays a large role in the quality of outcomes. While MRD remains the ideal donor source due to its lower incidence of acute GVHD,HCT from an 8/8 MUD is a good alternative to MRD transplant, given its comparable long-term survival outcomes. [Display omitted] [Display omitted] [Display omitted] DisclosuresSandmaier:Gilliad: Honoraria; ArevaMed: Honoraria; Jazz Pharmaceutical: Honoraria; Seattle Genetics: Honoraria; Abmit: Research Funding; Bellicum: Research Funding.

Prevention of Chronic GvHD after HLA-Identical Sibling Peripheral Hematopietic Stem Cell Transplantation with or without Anti-Lymphocyte Globulin (ATG). Results from a Prospective, Multicenter Randomized Phase III Trial (ATGfamilystudy)

IntroductionAllogeneic stem cell transplantation is a curative and increasingly used treatment approach for a variety of hematological malignancies. Late complications such a chronic graft-versus-host disease (cGvHD) is a major risk factor, which significantly influences morbidity and mortality after allogeneic stem cell transplantation (ASCT). The incidence of cGvHD is higher when peripheral blood stem cells are used as stem cell source. There is a strong need for preventing cGvHD after ASCT without increasing the risk of relapse.Patients and MethodsWe performed a multicenter, multinational, open-label, randomized study comparing anti-lymphocyte globulin (ATG-Neovii®) 10mg/kg on day -3,-2 and -1 with no ATG in 155 patients with acute myeloid (n=110) or lymphoblastic leukemia (n=45) in 1st complete remission (CR; n= 139) or 2nd CR (n=16) who received peripheral blood stem cells from their HLA-identical sibling (n=148) or relatives (n=7) after standard TBI (12Gy)/Cyclophosphamide (120mg/kg) or Busulfan (16mg/kg)/Cy (120mg/kg) based myeloablative conditioning regimen and sufficient organ function. Standard GvHD prophylaxis consisted of cyclosporine A and a short course of MTX (10mg/m² on day +1,+3,+6 and +11). Major inclusion criteria were: acute myeloid or lymphoblastic leukemia in 1st or 2ndCR, age 18-65 years, HLA-identical sibling or relatives, peripheral blood stem cell as stem cell source, and a myeloablative conditioning regimen. The primary study aim was to compare the cumulative incidence of cGvHD at 2 years after ASCT.ResultsOut of 161 randomized patients from 27 centers and 4 nations, 6 were withdrawn before conditioning and ASCT due to leukemia progression, or cancellation of the donor. 155 patients were analyzed for safety and efficacy; 83 were randomized to ATG and 72 to non-ATG. The treatment groups were comparable regarding recipient and donor age and sex, CMV serostatus, disease (AML vs ALL), 1st or 2ndCR. The median time to leukocyte (>1.0x10e9/l) and platelet (> 20x 10e9/l) engraftment was significantly delayed in the ATG group (18 vs 15 days, p< 0.001 and 20 vs 13 days, p<0.001). The incidence of acute GvHD grade I-IV was 25% for the ATG arm and 36% for the non-ATG arm (p=0.32) and for severe grade III/IV acute GvHD 2% and 7%, respectively (p=0.2). Regarding the primary endpoint, the cumulative incidence of cGvHD at 2 years was 36% % (95% CI 26-51%) in the ATG and 73% (95% CI 63-84% ) in the non-ATG arm (p<0.0001). In the ATG group 74% of the patients with any cGvHD had only limited episodes and 26% had an extensive episode, compared to 49% and 51% for non-ATG (p=0.04). There was no higher rate of infectious complications (58% for ATG vs 54% for non-ATG), CMV reactivation (22 vs 24%) and of EBV reactivation (2.4 vs 1.4%). The cumulative incidence of therapy related mortality at 2 years was 13% (95% CI 7-22%) for the ATG arm and 10% (95% CI 5-20%) for the non-ATG arm (p=0.57), resulting in 2 year relapse-free and overall survival of 59%% (95%CI 49-70%) and 75% (95% CI 66-85%) for the ATG group and of 65% (95% CI 52-77%) and 79% (95% CI 69-89%) for the non-ATG group (p=0.44 and p=0.20, respectively).ConclusionThis randomized cGvHD prevention study provides evidence that ATG-Neovii® 3x 10mg/kg within a myeloablative preparative conditioning regimen for HLA-identical sibling peripheral blood stem cell transplantation is highly effective in preventing limited and extensive cGvHD without obvious increase of infectious complications and relapse, resulting in similar overall survival rates. DisclosuresKröger:Neovii: Research Funding.

Synergy of Unrelated Donor and Full Intensity Conditioning Breaks the Control of Graft Versus Host Disease By Alemtuzumab

Many variables influence the risk of graft versus host disease following hematopoietic stem cell transplantation. Comparison between preparative regimens is hampered by the use of many different combinations of chemotherapy and radiotherapy, varying intensity of conditioning, use of T cell depletion and donors who are either siblings or unrelated volunteers. Many reduced intensity regimens also incorporate enhanced GVHD prophylaxis with in vivo T cell depletion. Here we describe a cohort of patients prepared in a modular fashion with either reduced or full intensity conditioning combined with a uniform GVHD prophylaxis regimen for all transplants with sibling donors (alemtuzumab 30mg) and for all with unrelated donors (UD; alemtuzumab 60mg). Thus it was possible to dissect independently the effect of conditioning intensity and sibling or UD type upon GVHD risk in this settig of in vivo T cell depletion.Patients and analysis: the study was a retrospective analysis of 258 sequential transplants performed in adults with hematological malignancy between September 2005 and September 2013 at a single UK institution. Reduced intensity conditioning (n = 221) included fludarabine 150mg/m2 plus melphalan 140mg/m2 or fludarabine 150mg/m2 plus busulfan 9.6mg/kg. Full intensity transplants (n = 37) received 12Gy TBI plus melphalan 140mg/m2, 12Gy TBI plus cyclophosphamide 120mg/kg, or busulfan 16mg/kg plus cyclophosphamide 120mg/kg. All patients with sibling donors received 30mg alemtuzumab and those with UD received a 60mg of alemtuzumab. UD matching was similar in both reduced intensity and full intensity cohorts (92.2% and 86.5% 10/10 matches, respectively) but patients receiving reduced intensity were older than those receiving full intensity conditioning (median age 51 vs 31; p < 0.001). Outcome was analyzed according to EBMT guidelines. Relapse, non-relapse mortality and cGVHD were treated as competing risks and analysed as cumulative incidence.Outcome: the incidence of acute GVHD grades I-IV was comparable between reduced intensity and full intensity sibling transplants (45% vs 45%; p = NS) indicating a lack of effect of conditioning intensity upon GVHD risk in this setting. There was a slight increase in the risk of GVHD between reduced intensity UD compared with reduced intensity sibling donor transplants (57% vs 45%; p = NS) but a marked synergistic increase between UD transplants performed with full intensity compared with reduced intensity conditioning (100% vs 57%; p = < 0.001). The incidence of grades III-IV acute GVHD was also higher in full intensity UD transplants (16%) compared with reduced intensity UD transplants (5%). The incidence of chronic GVHD was also highest in full intensity UD transplants but both conditioning intensity and UD contributed in an additive manner: the rate of chronic GVHD progressed from 33% to 44% in reduced intensity and full intensity sibling transplants respectively and from 57% to 75% for reduced and full intensity UD transplants, respectively. Two year overall survival was comparable in all groups, ranging from 55% to 70%. In keeping with the higher rates of acute GVHD in full intensity transplants performed with UD, this group experienced the lowest relapse risk (15% vs 29% for all the other groups combined; p = 0.04) but the highest non-relapse mortality, reaching 41% at 2 years compared with 28% for all the other groups combined (p = 0.08).Conclusion: these results show that alemtuzumab provides good protection from acute GVHD in reduced intensity transplantation from sibling and UD. In sibling transplants given identical GVHD prophylaxis, full intensity conditioning does not increase the risk of GVHD. In contrast, a slight increase in GVHD risk with UD transplants seen with reduced intensity conditioning, is amplified in a synergistic manner by full intensity conditioning. This is associated with a high non-relapse mortality, even though the median age of full intensity patients is more than 20 years younger than those receiving reduced intensity conditioning. DisclosuresNo relevant conflicts of interest to declare.

Reduced Relapse Risk In Patients With AML After Hhcmv-Replication Post Transplantation-First Results Of a Prospective Registration Trial

AbstractAbstract 5503 IntroductionEarly detection of inapparent replicative human cytomegalovirus (HCMV) infection together with its preemptive antiviral treatment has led to a marked reduction of life-threatening HCMV disease after allogeneic hematopoietic stem cell transplants (alloSCT). A new aspect of HCMV reactivation and pretransplant HCMV serostatus has recently emerged by an earlier retrospectively performed report from us showing that the occurrence of a HCMV-reactivation after transplant reduces the risk for relapse in patients with AML and NHL. This idea was supported by a study by Scheper and co-worker (Leukemia, 2013) reporting recently, that gamma-delta T cells elicited by HCMV reactivation after alloSCT cross-recognize HCMV and leukemia. Here we evaluate the potential impact of early HCMV replication in a prospectively performed observational study about the occurrence of a HCMV- reactivation after T cell repleted alloSCT on the risk for leukemic relapse in patients with AML (Registration Trial DRKS00004300). Patients and MethodBetween January 2012 and March 2013 we enrolled in this trial 83 patients with AML who were consecutively transplanted at the University Hospital of Essen. 48 of 83 patients received a myeloablative (TBI based conditioning n=27, chemotherapy based conditioning n=23) and 35 patients a RIC regimen. Patients were transplanted in 1.CR (n=40), 2.CR (n=23) or more progressive disease stages (n=20) from HLA-identical sibling donor (n=17) or HLA-identical unrelated donor (URD) (n=42) or mismatched unrelated donor (n=24). The median age of patients was 53 years (range 18-72) and that of the donors 38 years (range 12-61). GVHD prophylaxis was performed with MTX and CSA, or CSA and MMF with or without ATG (n=64) (30-60mg total dose). The incidence of acute GVHD grade 2-4 was statistically not different in both groups (78% versus 85%). ResultsHCMV status of recipient (R) or donors (D) were in 29% R-/D-, 8% R-/ D+; 34% D+/R- and 29% R+/D+. Patients with a documented HCMV-reactivation (HCMV-R) had an estimated relapse incidence (CIR) at 1-year after transplant of only 8% compared to 43% in patients without a HCMV-R (p=0.03). Patients in more progressive disease phase of AML (N=43) benefit more from a HCMV-R in regard of CIR than patients in 1.CR of AML (0% versus 55% estimate for relapse at 1-year after transplant for patients with HCMV-R compared to patients without HCMV –R, p=0.028). One-year overall survival was statistically not different in both groups. Non relapse mortality was greater in patients with HCMV reactivation 37.8% versus 12.5%, p=0.1)ConclusionThe first result of this prospective study confirms an independent advantageous effect of early HCMV replication on the leukemic relapse risk in patients with AML after transplant, which was more pronounced in patients in progressive disease phase of AML than patients in 1.CR of AML. Disclosures:Off Label Use: The off-label use of HCG will be presented here for the first tiem for treatment of chronic GVHD and will clearly marked as off-label use.

Early Recovery Of Absolute Lymphocyte Counts ≥ 0.2x109/L At Day 21 Can Predict Reduced Risk Of Relapse In Acute Lymphoblastic Leukemia Following Allogeneic Stem Cell Transplantation

IntroductionPredicting transplant's outcome has been an important issue. Many factors have been elucidated. We evaluated impact of lymphocyte counts on transplant outcome including relapse in patients with acute lymphoblastic leukemia. MethodsA total of 117 patients with acute lymphoblastic leukemia receiving hematopoietic stem cell transplants (HSCTs) between year 1999 and 2012 at Princess Margaret Hospital, Toronto, Canada were evaluated for the occurrence of early recovery of absolute lymphocyte counts (ALC) and their impact on transplant's outcome. Patients who received T cell depletion were excluded from analysis, a total of 94 cases were finally included in the analysis. ALCs were regularly monitored on daily basis for first 28 days. ResultsSixty two patients (66%) were matched related donor and 31 (33%) were female. Seventy one patients (75%) were in 1st complete remission (CR1) versus 23 (25%) beyond CR1. Thirty four patients (64%) were Philadelphia chromosome positive. GVHD prophylaxis was CSA/MMF (n=28, 30%), CSA/MTX (n=64, 68%), other (n=2, 2%). Conditioning regimen was myeloablative in 91 patients (97%) versus reduced intensity in 3 patients (3%). Fifty eight patients received peripheral blood stem cells as a stem cell source. Different cut offs of ALCs including 0.2, 0.3, 0.5 and 1.0x109/L at day 21 and day 28 were evaluated for transplant outcomes in order to select the best cut off of ALC recovery. We selected ALC 0.2x109/L at day 21 as a cutoff of ALC recovery based on the p-value.With a median follow-up of 60 months for survivors (range 2 to 116.5 months), 71 patients (75%) showed early recovery of ALC at day 21 (i.e. patients with ALC ≥ 0.2 x109/L at day 21), while 23 patients did not reach 0.2x109/L of ALC at day 21 (i.e. patients with ALC ≤ 0.2 x109/L at day 21). The overall survival (OS) and non-relapse mortality (NRM) were not significantly different between the groups: for 3 years OS rate, 47% in early ALC recovery group vs 35% in late ALC recovery group (p=0.35 ); for 3 year NRM rate, 38% in early ALC recovery group vs 26% in late ALC recovery group (p =0.33 ). However, a lower incidence of relapse was observed in early ALC recovery group (17%) compared to late ALC recovery group (39% at 3 years; p=0.005).The cumulative incidence of acute GVHD grades 2 to 4, grades 3/4 at day 120 and overall chronic GVHD at 2 years was 62%, 32% and 45% for patients with ALC ≥ 0.2 x109/L versus 65%, 25% and 39% for those with ALC ≤ 0.2 x109/L at day 21. CMV viraemia rate was 44% versus 43% in early versus late ALC recovery groups. The median time to neutrophil and platelet engraftment was 16 and 12 days in early ALC recovery group versus 23 and 21 days in late ALC recovery group.In multivariate analysis, ALC ≥ 0.2 x109/L at day 21 was an independent favorable risk factor for relapse (p=0.017, Hazard ratio [HR] 0.183) together with chronic GVHD (p≤0.001, HR 0.058). For overall survival, acute GVHD grade 3-4 (p=0.03, HR 2.857), chronic GVHD (p=0.001, HR 0.103) and age as continuous variable (p=0.05, HR 1.04) were independent factors. For NRM acute GVHD grade 3-4 was the only independent prognostic factor (p=0.006, HR 6.896) ConclusionEarly recovery of absolute lymphocyte counts ≥0.2x109/L at day 21 can predict reduced relapse risk in ALL patients following allogeneic stem cell transplantation. The impact of lymphocyte counts on overall survival and non-relapse mortality was not statistically significant.▪ Disclosures:No relevant conflicts of interest to declare.

Decitabine Plus Mini Fludarabine and Busulfan Yields Durable Engraftment with Low Relapse Rates in Elderly or Medically Infirm Patients with Myeloid Malignancies

Abstract 1936 Background:Stem cell transplantation (SCT) is an effective treatment for myeloid malignancies but is often limited to younger patients without comorbidities. Reduced intensity conditioning (RIC) regimens offer this potentially curative treatment option to elderly or medically infirm patients but are often associated with increased relapse rates. Decitabine (DAC) has been effective in the primary treatment of MDS and may be useful in “debulking” prior to transplant. However, the role of DAC immediately prior to allografting (as part of the conditioning regimen) has not yet been determined. The combination of RIC fludarabine (FLU) and busulfan (BU) along with DAC is hypothesized to increase the anti-leukemic effect and produce durable engraftment while maintaining the reduced-intensity regimen toxicity profile. Methods:This was a single-institution, phase I study of DAC in combination with FLU/BU as a RIC regimen for myeloid malignancies. Subjects were evaluated to assess stability of engraftment, toxicity, disease response, PFS and OS. Patients received decitabine 20 mg/m2 IV daily × 5 from day -15 through day -11 followed by fludarabine 30 mg /m2 IV daily × 5 on days -7 to -3 and busulfan 130 mg/m2 IV daily on days -4 and -3. Thymoglobulin was given at a dose of 2 mg/kg IV daily on days -4, -3 and -2. Hematopoietic stem cells were infused on day 0. GVHD prophylaxis consisted of tacrolimus starting on day -2 and methotrexate 5 mg/m2 IV on days +1, +3, +6, and +11. Results:Eighteen patients were enrolled between 8/4/2009 and 5/2/2012. Median age was 67 years (range 49–79). Diagnoses included AML in CR1 (n = 4), CR2 (n = 4), or primary induction failure (n = 3); or MDS/MPD (n = 7). Eleven (61%) were male. Ten (56%) patients had unrelated donors as stem cell source; 8 (44%) had sibling donors; 17 (94%) received PBSCs; 1 received BM. Median number of CD34+ stem cells infused was 4.01 ×106 cells/kg (range 2.1 ×106 to 4.92 ×106).All patients engrafted. The median duration of neutropenia (ANC <1000) was 13 days. The median CD3 donor engraftment at day 56 and day 84 (+/− 7 days) was 73% (n=14) and 81% (n=11) respectively. Seven patients (of 12 evaluated) achieved >90% donor chimerism at day 84. The actuarial OS at 31 months was 43% (Kaplan Meier). Median OS has not yet been reached. Five of the nine evaluable patients (56%) not in a CR at the time of transplantation entered CR at three months post-SCT. For the entire cohort, at 3 months 10 of 14 evaluable patients (71%) were in remission. During follow up, five patients (27%) relapsed (1 pt with MDS; 3 pts with AML CR1; 1 pt with AML CR2) with a median time to relapse of 107 days. Four patients (22%) died of treatment related complications (TRM). Cause of death was GVHD (n=2), infection or other causes (n = 2), and relapse (n = 3). Four patients received DLI at a median of 173 days after SCT for either disease relapse (n = 2) or falling chimerism (n = 2). The incidence of acute GVHD grade I-II and III-IV were 44% and 22% respectively. Chronic GVHD was seen in 8 patients (44%). Conclusions:Combining DAC with reduced intensity FLU/BU appears to be a well-tolerated transplant conditioning regimen in elderly or infirm populations with myeloid malignancies. Successful engraftment was attained in 100% of patients at day 28, and 94% of patients remain alive at day +100. The toxicity profile is acceptable and the relapse rate appears favorable. Future investigation should involve DAC in combination with mini-FLU/BU in the preparative regimen for patients with myeloid malignancies who are otherwise ineligible for myeloablative therapy. [Display omitted] Disclosures:Off Label Use: Pretransplant use of decitabine. Goldberg:Eisai: Speakers Bureau. Mato:Celgene, Milennium, Genentech, Seattle Genetics: Speakers Bureau. McKiernan:Novartis: Speakers Bureau.

Effects of different serum-levels of ATG after unrelated donor umbilical cord blood transplantation

We determined total rabbit-IgG (r-ATG) levels in serum samples before (day 0) and after (day 11 and day 25) unrelated donor umbilical cord blood transplantation (UCBT). Most patients (27/41) suffered from a haematological malignancy. There were 25 children and 16 adults. All patients received rabbit anti-thymocyte globulin (ATG) at a total dose of 6 or 8mg/kg as part of the conditioning. No correlation between the dose of ATG and serum r-ATG levels post UCBT was found. The cumulative incidence of acute GVHD grades III–IV in patients given the 6 and 8mg/kg ATG dose was 15% and 13% (ns), respectively. Patients with r-ATG≤40μg/mL 11days after UCBT (n=19) had a higher incidence of grades III–IV acute GVHD (32% vs. 0%, p<0.01), higher TRM (69% vs. 7%, p=0.005), less relapse (17% vs. 82%, p<0.01) but similar relapse-free survival (RFS) (10% vs. 18%, p=0.4) compared to those with r-ATG>40μg/mL (n=17). Low serum-levels of r-ATG early after transplantation seem to be a strong predictor for acute GVHD grades III–IV, TRM and a low incidence of relapse in patients treated with thymoglobulin before unrelated donor UCBT.