Thiotepa-busulfan-fludarabine Research Articles

Thiotepa, busulfan and fludarabine conditioning-regimen is a promising approach for older adult patients with acute lymphoblastic leukemia treated with allogeneic stem cell transplantation.

For acute lymphoblastic leukemia (ALL) patients, total body irradiation (TBI)- based conditioning regimens are the first choice specially in young population. However, several studies have shown an equivalence in clinical outcomes with thiotepa-based conditioning regimen. We performed a retrospective study to evaluate the outcome of adult ALL patients who received allogeneic hematopoietic stem cell transplantation (allo-HCT) with a thiotepa-busulfan-fludarabine (TBF) myeloablative conditioning regimen with reduced toxicity. Fifty-five patients received a TBF regimen. The median age of the patients was 51 years (range, 17 to 72.4). Most patients had a diagnosis of B-ALL (93%) with 7% having T-ALL. Two - and 5-year overall survival was 73.2% and 64%, respectively. At 2 years, leukemia-free survival and GVHD-free, relapse-free survival were 59.5% and 57.6%, and at 5 years, 53.4% and 51.8%, respectively. The 5-year non-relapse mortality was 15%. The day 180 cumulative incidence (CI) of grade II-IV acute GVHD and grade III-IV acute GVHD were 38.2% and 5.5%, respectively. At 2 years, the CI of chronic GVHD and extensive chronic GVHD was 16.9% and 1.9%, respectively. Our study results do suggest that using TBF as the conditioning regimen in adult ALL patients is a promising option with acceptable toxicity.

Thiotepa-Busulfan-Fludarabine in Comparison to Busulfan-Cyclophosphamide As Myeloablative Conditioning Regimen Pre Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia: A Study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT)

Background. Busulfan plus Cyclophosphamide (BuCy) is the traditional myeloablative conditioning (MAC) regimen pre allogeneic stem cell transplantation (SCT) for acute myelogenous leukemia (AML). The Thiotepa, Busulfan, Fludarabine (TBF) protocol was initially developed for cord blood SCT and subsequently employed in haploidentical SCT; however, there is limited data assessing the TBF regimen in SCT from sibling (MSD) and unrelated donor (URD) for AML and no comparison between the two preparative protocols has been performed.Patients and methods. We analyzed transplantation outcomes of 2523 adult patients (pts) with AML in remission (CR1, CR2+) aged 18-50 years that underwent a first SCT from MSD or URD between 2007 and 2015 and reported to the ALWP of the EBMT. One hundred and three patients received TBF and 2370 pts received BuCy. Pts who received oral busulfan, manipulated grafts, or transplant from <=8/10 HLA-matched donor were excluded. All pts received MAC regimen (defined by Busulfan dose>=9.6 mg/kg). As compared to BuCy, the TBF group included significantly older pts, who were transplanted more recently, had longer interval from diagnosis to transplant, and were more likely to have received BM as stem cell source and URD as donor type. In order to minimize the bias due to differences in pts characteristics, a 1:3 pair-matched analysis was performed. One hundred and forty-six pts receiving TBF were compared with 438 pts receiving BuCy; matching factors included age, year of SCT, disease status at SCT, interval from diagnosis to SCT, donor type, CMV serostatus of both the donor and patient, stem cell source, GVHD prophylaxis and use of anti-thymocyte globulin.Results. With a median follow-up of 22 months, incidence of grade II-IV and III-IV aGVHD after TBF vs BuCy was 29% vs 23% (p=0.23) and 15% vs 8% (p=0.04), respectively. The 5-year cumulative incidence of cGVHD and severe cGVHD was 36% vs 43% (p=0.66) and 16% vs 22% (p=0.72) for TBF vs BuCy, respectively. The 1-year and 5-year non-relapse mortality (NRM) rates were 10% and 22% for TBF vs 9% and 13% for BuCy, respectively (p=0.36). The 1-year and 5-year relapse incidence (RI) rates were 17% and 25% for TBF vs 21% and 37% for BuCy, respectively (p=0.32). No significant difference was observed in leukemia-free survival (LFS), being the 1-year and 5-year LFS rates 73% and 53% for TBF vs 70% and 50% for BuCy, respectively (p=0.56). Overall survival (OS) was also similar, being 80% and 54% for TBF vs 79% and 59% for BuCy, respectively (p=0.88). The composite endpoint graft-vs-host disease-free, relapse-free survival (GRFS) at 5 years was 48% for TBF and 40% for BuCy (p=0.48). Notably, when the analysis was restricted to pts in CR1, a significant difference in RI rate was observed (1-year and 5-year RI: 10% and 18% for TBF vs 20% and 38% for BuCy, respectively, p=0.003) leading to a trend for better LFS for TBF as compared to BuCy (1-year and 5-year LFS: 78% and 57% for TBF vs 72% and 50% for BuCy, respectively, p=0.07), with no difference in OS. When examining separately pts receiving SCT from MSD or URD, no significant difference was observed between TBF and BuCy regimens in terms of transplant outcome. In multivariate analysis, TBF was associated with lower RI compared to BuCy (HR 0.6, p=0.02), while no difference was observed in terms of NRM, LFS, OS and GRFS (HR 0.8, p=0.12 for GRFS). TBF was also associated with lower incidence of cGVHD (HR 0.7, p=0.04) and a trend for lower incidence of severe cGVHD (HR 0.6, p=0.1); on the contrary we observed a trend for higher incidence of grade III-IV aGVHD following TBF as compared to BuCy (HR 1.79, p=0.06).Conclusions. These results suggest that TBF is a valid myeloablative conditioning pre MSD or URD SCT for AML pts < 50 years of age and in remission, with similar transplantation outcome as compared to the traditional BuCy preparative regimen. These data may serve as the scientific background for a well designed randomized two arm study comparing TBF to BuCy as MAC pre SCT in AML pts below the age of 50 years in CR. [Display omitted] DisclosuresSavani:Jazz Pharmaceuticals: Speakers Bureau.

Thiotepa-busulfan-fludarabine (TBF) conditioning regimen in patients undergoing allogeneic hematopoietic cell transplantation for myelofibrosis: an outcome analysis from the Chronic Malignancies Working Party of the EBMT.

Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative option in MF. There is no consensus on the optimal conditioning regimen. We report outcomes of 187 patients with MF transplanted between 2010 and 2017 conditioned with TBF. Median age was 58 years. Median interval from diagnosis to allo-HCT was 44 months. Donors were haploidentical (41%), unrelated (36%) or HLA-identical siblings (23%). Stem cell source was PB in 60%. Conditioning was myeloablative in 48% of cases. Antithymocyte globulin (ATG) was used in 41% of patients. At 100 days, neutrophil and platelet engraftment were 91% and 63% after a median of 21 and 34 days, respectively. Grade II-IV and III-IV acute GVHD occurred in 24% and 12%, while at 3 years, all grade chronic GVHD and chronic extensive GVHD had been diagnosed in 38% and 11%. At 3 years, OS, RFS and GRFS were 55%, 49% and 43%, respectively. RI and NRM were 17% and 33%. On multivariate analysis, poor KPS and the use of unrelated donors were associated with worse GRFS and a higher grade II-IV acute GVHD, respectively. Neither donor type nor intensity of the conditioning regimen influenced survival outcomes. TBF is a feasible conditioning regimen in allo-HCT for MF in all donor settings although longer term outcomes are required.

Comparable outcomes of haploidentical transplant with TBF conditioning versus matched unrelated donor with fludarabine/busulfan conditioning for acute myeloid leukemia.

We compared transplant outcomes of 708 acute myeloid leukemia (AML) patients receiving haploidentical allogeneic hematopoietic-cell transplantation using thiotepa/busulfan/fludarabine (TBF) conditioning with posttransplant cyclophosphamide (ptCy), to 2083 patients receiving matched unrelated donor (MUD) transplantation using fludarabine/busulfan (FB) conditioning and in vivo T-cell depletion. For intermediate cytogenetic risk AML transplanted in first complete remission (CR1), multivariate analysis revealed that haplo-TBF significantly increased nonrelapse mortality (NRM) (HR 2.1; p = 0.0006) but did not affect relapse incidence (RI), leukemia-free survival (LFS), overall survival (OS), or graft-versus-host disease-free, relapse-free survival (GRFS). For high cytogenetic risk AML transplanted in CR1, haplo-TBF significantly increased NRM (HR = 2.7; p = 0.02), decreased RI (HR = 0.45; p = 0.03) but had no influence on LFS, OS, or GRFS. For AML transplanted in CR2, haplo-TBF significantly increased NRM (HR = 2.36; p = 0.008), decreased RI (HR = 0.38; p = 0.005), but had no influence on LFS, OS, or GRFS. Finally, for AML patients transplanted with active disease, haplo-TBF had no influence on transplant outcomes. In conclusion, compared to MUD-FB, haplo-TBF increased NRM, reduced RI in high-risk AML in CR, resulting in similar LFS, OS, and GRFS. These results comparing two different approaches support the use of a haploidentical family donor for high-risk AML patients lacking a matched sibling donor.

Effect of the Thiotepa Dose in the TBF Conditioning Regimen in Patients Undergoing Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia in Complete Remission: A Report From the EBMT Acute Leukemia Working Party

BackgroundAllogeneic stem cell transplantation is a potentially curative therapy for patients with acute myeloid leukemia (AML) after achieving complete remission (CR). The aim of this study is to evaluate the optimal dose of thiotepa, administered as part of the thiotepa-busulfan-fludarabine (TBF) conditioning regimen for allogeneic stem cell transplantation in adults with AML in CR. Patients and MethodsIn a retrospective multicenter analysis, we identified 240 patients allotransplanted from matched related or unrelated donors or T replete haplo-identical donors. We compared the transplantation outcomes of patients who received 5 mg/kg thiotepa and 2 days of intravenous busulfan at 6.4 mg/kg (T1B2F) versus those who received 10 mg/kg thiotepa with 2 days of intravenous busulfan at 6.4 mg/kg (T2B2F). The median follow-up was 20 months. ResultsOn univariate analysis, the incidence of acute graft versus host disease (GVHD) grade II to IV was significantly lower in the T1B2F group (19%) versus 32% in the T2B2F group (P = .029). This result was confirmed on multivariate analysis; acute GVHD was higher for patients receiving T2B2F (hazard ratio, 2.22; P = .024). No significant change in non-relapse mortality, progression-free survival, or overall survival was observed between the 2 groups. ConclusionT2B2F is associated with a higher incidence of acute GVHD compared with T1B2F. These results suggest that a lower dose-intensity of thiotepa and busulfan in the TBF regimen may yield better results in patients with AML in CR.

Full Donor Chimerism after Allografts for Myelofibrosis: The Role of Conditioning Regimen

Background : The conditioning regimen for patients with myelolfibrosis undergoing an allogeneic HSCT is usually composed of a combination of fludarabine (FLU) with one alkylating agent, busulkfan (BU), thiotepa (THIO) or melphalan. In a recent prospective randomized study comparing BU-FLU versus THIO-FLU, the proportion of patients with full donor chimerism at 6 months, was respectively 63% and 65% (Patriarca et al, BBMT 2019). Aim of the study. Assess the rate of full donor chimerism in patients with myelofibrosis, after conditioning with one or two alkylating agents. Methods. We analyzed 113 patients with myelofibrosis, for whom chimerism data were available on day +30 . There were two groups: 35 patients were conditioned with either thiotepa-cyclophosphamide , thiotepa-fludarabine or busulfan-fludarabine (ONE-ALK), whereas 78 patients were prepared with thiotepa, busulfan, fludarabine (TBF). Patients receiving TBF were older (57 vs 52 years, p=0.008), were less frequently splenectomized pre-HSCT (30% vs 54%, p=0.03), had more frequently intermediate-2/high DIPSS scores (89% vs 74%, p=0.04) , and had comparable transfusion burden pre-HSCT (p=0.7). Chimerism was assessed via STR (PowerFlex-Promega) Results. The proportion of patients with full donor chimerism on day +30 in the TBF vs the ONE-ALK group was 87% vs 51% (p=0.00002); on day +60 these figures were 93% vs 13% (p&lt;0.0001) and on day +90 , the figures were 90% vs 21% (p&lt;0.00001). Full donor chimerism on day+30 was achieved in 81% of patients with DIPSS int1 (n=16), 74% of patients with int2 DIPSS, and 70% of patients with high risk DIPSS (p=0.6). Acute GvHD grade II-IV occurred in 27% vs 37% of patients in the two groups (p=0.7), and moderate severe chronic GvHD in 20% and 21% (p=0.8). The 5 year cumulative incidence of relapse was 8% in the TBF group, versus 50% for the ONE-ALK group (p&lt;0.0001), whereas the CI of TRM was 25% vs 11% (p=0.1). The 5 year actuarial disease free survival (DFS) was respectively 65% for TBF and 38% for the ONE-ALK group (p=0.004). Complete chimerism day+30. When looking at whether patients had (n=84) or not (n=29) full donor chimerism on day +30, the CI of relapse was respectively 44% vs 15% (p=0.002), the CI of TRM 18% vs 15% (p=0.5), and the 5 year DFS 65% vs 32% (p=0.001). Conclusions. Early full donor chimerism is a prerequisite for long term control of disease in patients with myelofibrosis undergoing an allogeneic HSCT. The combination of 2 alkylating agents in the conditioning regimen, provides a significantly higher chance of achieving full donor chimerism on day+30, and thus long term disease control. Figure Disclosures Angelucci: Vertex Pharmaceuticals Incorporated, and CRISPR Therapeutics: Other: Partecipation in DMC; Roche: Other: Local advisory board; Jazz Pharmaceuticals: Other: Local advisory board; BlueBirdBio: Other: Local advisory board; Novartis: Honoraria, Other: Chair Steering Committee TELESTO protocol; Celgene: Honoraria, Other: Partecipation in DMC.

Impact of KIR/HLA Incompatibilities after Posttransplant Cyclophosphamide Based T Cell-Replete Haploidentical Hematopoietic Stem Cell Transplantation

Introduction: Posttransplantation cyclophosphamide (PTCy) based T cell-replete haploidentical (haplo) hematopoietic stem cell transplantation (HSCT) is a valid option for patients with indication for allogeneic HSCT without a human leucocyte antigen (HLA) matched donor. However, selection criteria to determine the optimal among several available haplo donors are still a matter of debate. Especially, the impact of killer cell immunoglobulin-like receptor (KIR)/human leukocyte antigen (HLA) incompatibilities (inc) in the setting of PTCy T cell-replete haplo HSCT is unclear. PTCy has been reported to eliminate most mature donor NK cells infused with the graft, including single KIR+ NK cells, thereby blunting NK cell alloreactivity in this setting (Russo et al., Blood 2018). Willem et al. (J Immunol 2019) reported (i) a significant loss of KIR2DL2/3+ NK cells at day +30 in patients with inhibitory KIR/HLA incompatibility (inc.) suggesting that PTCy might target responsive KIR NK cells and (ii) a correlation of genetic KIR2DL/HLA inc. with less relapse, but more graft-versus-host-disease (GvHD). Similarly, NK alloreactivity defined as KIR receptor-ligand mismatch or group B KIR haplotype with the presence of KIR2DS2 has been correlated with improved survival (Salomon et al., BBMT 2018). Aims of our study were to evaluate the impact of (i) HLA/KIR inc, (ii) donor KIR genotype and (iii) HLA-DP mismatch status on survival and incidence of relapse, acute and chronic GvHD in our homogeneously treated, independent patient cohort. Patients and methods: We retrospectively analyzed the outcome of 51 consecutively transplanted patients (AML/MDS (n=28/5), ALL (n=9), HD (n=2), NHL (n=5), CML (n=1), PMF (n=1)) receiving a PTCy based T cell-replete haplo HSCT between 01/2011-12/2018. All patients received a myeloablative conditioning regimen (fludarabine/total body irradiation (FTBI) or thiotepa/busulfan/fludarabine (TBF)) with unmanipulated bone marrow (98%) as the preferred graft (median CD34+ cells: 3.02 x 106/kg (range, 1.50-6.90) and median CD3+ T cells: 3.54 x 107/kg (range 1.52-43.74)). GvHD prophylaxis with ciclosporin A started on day 0, mycophenolate-mofetil on day +1, PTCy was applied on day +3 and +5. Results: Patient, donor and transplant characteristics as detailed in table 1 were well balanced between the inh. KIR/HLA inc. group (n=29) vs. no inh. KIR/HLA inc. group (n=22) with the exception of the median donor age (41.7 (range, 23.4-73.7) vs. 33.6 years (range, 19.0-56.2), resp. All patients engrafted. At day +28 (range, 20-29; n=26) CD3+ cells were 88.5/nL (range, 3-665), CD3+CD4+ cells 22.5/nL (range, 0-277.0), CD3+CD8+ cells 117.0/nL (range, 7-478), CD19+ cells 1.0/nL (range, 0-12), CD56bright cells 74.4/nL (range11.1-93.4), CD56dim cells 25.5/nL (range, 6.4-88.9) measured by flow cytometry and without differences between the inh. KIR/HLA inc. group vs. no inh. KIR/HLA inc. group. Cytomegalovirus (CMV) reactivation occurred in 73.3% of patients at risk and median time of occurrence was 32 days (range, 12-97) without difference between groups. Median follow-up for surviving patients was 26.1 months (range, 2.8-92.8) and we found no significant differences in 2-year overall survival (OS; 65.3±10.3 vs. 89.6±7.0, p=0.311), 2-year relapse-free survival (RFS; 66.0±9.4 vs 77.8±10.2, p=0.235), GvHD- and relapse-free survival (GRFS; 48.4±9.8 vs 60.5±12.0, p=0.182) as well as cumulative incidence (CI) of relapse (23.3% vs 16.2%, p= 0.283), acute GvHD grade 2-4 (27.6% vs 31.8, p=0.563), moderate-severe chronic GvHD (22.2% vs. 9.9%, p=0.227) and NRM (16.3% vs 5.3%, p=0.283) between the inh. KIR/HLA inc. group vs. no inh. KIR/HLA inc. group. This was also the case for donor KIR genotype AA vs AB (n=46; 2-y OS: 74.9±13.0% vs. 73.0±9.9%, p=0.844; 2-y RFS: 60.0±14.8% vs 74.5±8.4%, p=0.645) and HLA-DP-identical/permissive mismatch (MM) vs non permissive MM (n=45; 2-y OS: 70.7±10.0% vs 72.7±13.4%, p=0.945; 2-y RFS: 73.2±8.2% vs 63.6.0±14.5%, p=0.798) Conclusion: Our outcome data support the hypothesis of PTCy eliminating mature donor NK cells infused with the graft and thereby reducing the impact of alloreactivity in this setting. However, our patient number is quite small and the findings need to be validated in larger cohorts and preferably prospective studies. Disclosures Lindner: Celegene, Sanofi, Neovii: Honoraria, Research Funding. Berg:Riemser Pharma GmbH: Consultancy, Honoraria; Incyte, Abbvie, Astellas, Alexion and Celgene: Other: travel support. Bug:Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene Neovii: Other: travel grant; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; Hexal: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Sanofi: Other: travel grants. Schwaeble:Uniqure BV: Research Funding. Ullrich:CellGenix: Honoraria, Research Funding; Novartis: Research Funding.

Thiotepa and antithymocyte globulin-based conditioning prior to haploidentical transplantation with posttransplant cyclophosphamide in high-risk hematological malignancies.

We report results of a thiotepa-based conditioning in haploidentical stem cell transplantation (haplo-SCT) with posttransplant cyclophosphamide (PT-CY) and antithymocyte globulin (ATG), for unmanipulated peripheral blood stem cell (PBSC) transplants, in 80 patients with hematological malignancies. Patients in complete remission (CR) received a thiotepa-busulfan-fludarabine (TBF) regimen, while patients with relapsed/refractory (R/R) malignancies received a sequential regimen consisting of thiotepa-etoposide-cyclophosphamide (TEC) and reduced-intensity conditioning (RIC). The median age was 52 (range, 17-72) years, 44% patients had R/R disease at transplant, and the median follow-up was 417 (range, 180-1595) days. The median days to neutrophil engraftment was 17 (range, 12-34). The cumulative incidences (CI) of acute graft-versus-host disease (GVHD) grade III to IV, severe chronic GVHD, nonrelapse mortality (NRM), and relapse were 16%, 16%, 26, and 26%, respectively. The 2-year overall survival (OS) and disease-free survival (DFS) were 53% and 47%, respectively. There were no significant differences between the patients in CR and R/R patients in terms of engraftment, GVHD, NRM, relapse, OS, or DFS. We conclude that thiotepa-based regimen with PT-CY can be modified with PBSC and ATG, still providing low toxicity, protection against GVHD, and low relapse incidence. Particularly encouraging are the results with the modification to sequential regimen in R/R patients.

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.

Fludarabine-treosulfan compared to thiotepa-busulfan-fludarabine or FLAMSA as conditioning regimen for patients with primary refractory or relapsed acute myeloid leukemia: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT)

BackgroundLimited data is available to guide the choice of the conditioning regimen for patients with acute myeloid leukemia (AML) undergoing transplant with persistent disease.MethodsWe retrospectively compared outcome of fludarabine-treosulfan (FT), thiotepa-busulfan-fludarabine (TBF), and sequential fludarabine, intermediate dose Ara-C, amsacrine, total body irradiation/busulfan, cyclophosphamide (FLAMSA) conditioning in patients with refractory or relapsed AML.ResultsComplete remission rates at day 100 were 92%, 80%, and 88% for FT, TBF, and FLAMSA, respectively (p = 0.13). Non-relapse mortality, incidence of relapse, acute (a) and chronic (c) graft-versus-host disease (GVHD) rates did not differ between the three groups. Overall survival at 2 years was 37% for FT, 24% for TBF, and 34% for FLAMSA (p = 0.10). Independent prognostic factors for survival were Karnofsky performance score and patient CMV serology (p = 0.01; p = 0.02), while survival was not affected by age at transplant. The use of anti-thymocyte globulin (ATG) was associated with reduced risk of grade III–IV aGVHD (p = 0.02) and cGVHD (p = 0.006), with no influence on relapse.ConclusionsIn conclusion, FT, TBF, and FLAMSA regimens provided similar outcome in patients undergoing transplant with active AML. Survival was determined by patient characteristics as Karnofsky performance score and CMV serology, however was not affected by age at transplant. ATG appears able to reduce the incidence of acute and chronic GVHD without influencing relapse risk.

The Optimal Alternative Donor Transplant for Pediatric Patients with Acute Leukemia: A Comparison between Alfa-Beta T-Cell and B-Cell Depleted Haplo-SCT and UCBT

▪Children with acute leukemia (AL) in need of an allograft and lacking an HLA-identical sibling and an HLA-matched unrelated donor, could benefit either from unrelated cord blood transplantation (UCBT) or T-cell depleted haploidentical (haplo) stem cell transplantation (SCT).Different techniques of T-cell depletion have been developed for improving immune reconstitution and for enhancing the graft-versus-leukemia (GvL) effect. Locatelli et al. (Blood 2017) reported remarkable results for children with AL given haplo-SCT after a novel method of graft manipulation based on selective, negative depletion of alfa-beta T and B cells.On behalf of Eurocord, CTIWP, and PDWP of EBMT, we compared outcomes of patients < 18 years with AL undergoing either single-UCBT (n=444) or haplo-SCT after alfa-beta T-cell and B-cell-depletion (n=99) from 2012 to 2016 using a myeloablative conditioning regimen (MAC).Median age at SCT was 6 (range 0.3-18) and 8 (range 0.6-18) years, and median follow-up was 36 and 14 months (p<0.05) for UCBT and haplo-SCT recipients, respectively. Compared to UCBT, haplo-SCT were performed more recently (median year 2016 vs 2012, p<0.05). Acute lymphoblastic leukemia (ALL) was the most frequent diagnosis (62% versus 55%), while 38% and 45% of patients had acute myeloid leukemia (AML) in the UCBT and haplo-SCT group, respectively. Cytogenetics was mainly at intermediate risk for UCBT (54%) and haplo-SCT (73%, p<0.05); 49% and 54% of patients were in CR1 at time of the allograft in UCBT and haplo-SCT group, respectively (p=0.45). In vivo T-cell depletion with ATG was more frequently adopted in haplo-SCT recipients (90% versus 81%, p=0.05). For UCBT recipients, HLA compatibility was 6/6 matched for 19% of patients, 5/6 for 58% and 4/6 for 23%. Cord blood graft contained a median TNC count at cryopreservation of 7.02x10e7/Kg (range 2.63-43) and at infusion of 5.3x10e7/Kg (range 0.3-39).Conditioning regimen varied according to the type of transplant: for haplo-SCT recipients Fludarabine+TBI (28%) and Thiotepa+Busulfan+fludarabine (TBF) (24%) were the most frequent MAC. In UCBT, Busulfan+Cyclophosphamide (Cy), or Cy+Fludarabine+TBI or TBF were used in 19%, 15% and 13% of patients, respectively.Haplo-SCT recipients did not receive any additional pharmacological post-transplant graft-versus-host disease (GvHD) prophylaxis, while CyclosporineA (CSA)+ steroids and CSA+mycophenolate mofetil were used in 38% and 32% of UCBT recipients.The 60-day probability of neutrophil engraftment was 91% vs 93% (p<0.05) for UCBT and haplo-SCT. The cumulative incidence (CI) of grade II-IV and grade III-IV acute (a) GvHD was 38% vs 12% (p<0.05) and 17% vs 4% (p<0.05) in UCBT and haplo-SCT recipients, respectively. The 2-year CI of relapse (RI) was similar following from UCBT and haplo-SCT (22% vs 25%, p=0.75), as well as non-relapse mortality (NRM) (18% vs 10%, p=0.07), respectively. Disease recurrence was the most common causes of death in both groups, with infections and GvHD being the most frequent transplant-related fatalities.According to donor type, no differences were found in overall survival (OS) (65% vs 68%, p=0.17) and leukemia-free survival (LFS) (61% vs 65%, p=0.24), while a lower GvHD-free, relapse-free survival (GRFS) was observed in UCBT compared to haplo-SCT (49% vs 60%, p<0.05). OS was 67% and 58% for patients with AML and ALL respectively, p=0.11.In multivariate analysis, UCBT was associated with higher risk of NRM (HR 2.36, p<0.05), while RI was not associated with type of allograft. Higher risk of grade II-IV aGVHD was observed in UCBT (HR 2.81, p<0.05), with no difference for cGVHD among the two groups (HR 0.68, p=0.31). OS (HR 1.52, p=0.10) and LFS (HR 1.28, p=0.28) were comparable between UCBT and haplo-SCT, while GRFS resulted lower for UCBT (HR 1.58, p<0.05). No others factors were associated with outcomes.Our results showed that RI, LFS, OS and cGVHD were comparable between UCBT and haplo-SCT recipients, while better NRM, aGVHD and GRFS were observed in patients transplanted from a family donor. These data confirm that alfa-beta T-cell and B-cell depleted haplo-SCT is a valid alternative for patients in need of an urgent allograft. Costs of manipulation in the haplo-SCT setting and costs of cord blood procurement should be further investigated. Technical expertise with this refined approach of graft manipulation and center experience are important to optimize patient's outcome. DisclosuresLocatelli:Miltenyi: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zecca:Chimerix: Honoraria. Bader:Medac: Patents & Royalties, Research Funding; Cellgene: Consultancy; Neovii: Research Funding; Riemser: Research Funding; Novartis: Consultancy, Speakers Bureau.

Thiotepa-busulfan-fludarabine compared to busulfan-fludarabine for sibling and unrelated donor transplant in acute myeloid leukemia in first remission.

BackgroundA preparatory regimen consisting of thiotepa-busulfan-fludarabine (TBF) has been associated with reduced relapse in patients with haematological malignancies after haploidentical and cord blood transplants; however, few data exist regarding TBF conditioning in sibling (MSD) and unrelated donor (URD) transplants for AML.ResultsAmong patients receiving a myeloablative (MAC) regimen, TBF-MAC was associated with significantly lower relapse (HR 0.47, p = 0.005) however higher non-relapse mortality (NRM, HR 2.69, p < 10–4) as compared to BF. This led to similar leukemia-free (LFS) and overall survival (OS) between the two regimens (LFS: p = 0.6; OS: p = 0.27). When we selected TBF-MAC patients receiving busulfan 9.6 mg/kg, NRM resulted still higher but no more significantly different as compared to BF-MAC with busulfan 12.8 mg/kg (HR 1.53, p = 0.12); despite the lower busulfan dose, relapse remained inferior with TBF-MAC (HR 0.45, p = 0.01), however no difference in survival could be demonstrated (LFS: p = 0.31; OS: 0.82). Among patients receiving a reduced-intensity (RIC) regimen, similar outcome was observed with TBF-RIC and BF-RIC (LFS: p = 0.77; OS: p = 0.88).ConclusionsTBF-MAC as conditioning regimen for transplant from MSD and URD in AML patients in first remission provided stronger anti-leukemic activity but higher NRM as compared to BF-MAC, thus leading to similar survival. TBF-MAC with busulfan 9.6 mg/kg was associated with low relapse and acceptable NRM, however again with no survival benefit. TBF-RIC and BF-RIC resulted in comparable outcome.MethodsWe conducted a registry-based study comparing outcomes of patients with AML in first remission undergoing transplant from MSD or URD prepared with either TBF (n = 212) or BF (n = 2698) conditioning.

Busulfan Fludarabine (BU-FLU) Compared to Thiotepa Busulfan Fludarabine (TBF) for Allogeneic Transplants in Acute Myeloid Leukemia (AML) or Refractory Anemia with Excess Blasts (RAEB) in Remission

▪INTRODUCTION The combination of Busulfan and fludarabine (BU-FLU) is considered a standard conditioning regimen for patients with acute myeloid leukemia undergoing an allogeneic hemopoietic stem cell transplant (HSCT) , especially in patient older than 40 years of age. However, in a recent prospective study, designed for patients in first or second remission (CR1 or CR2) the incidence of leukemia relapse at 3 years was 38%, both for patients receiving BU-FLU as well as for patients randomized to BU-CY (Lancet Oncol 2015;16:1525). The addition of thiotepa to a BU-FLU regimen (referred to as TBF) has shown promising control of leukemia, and has emerged as a standard regimen in cord blood (CB) transplants (BMT 2012; 47: 1287). The question is whether this holds true also for transplants other than CB grafts.Aim of the study : to compare Bu-FLU with TBF in patients with AML or RAEB, grafted in remission from related or unrelated donors.Methods: Eligible for this study were patients allografted between January 2008 and April 2017 with AML or RAEB in hematologic remission . Seventy-eight patients received the BU-FLU regimen (busulfan 3.2 mg/kg/day x4; and fludarabine 40 mg/m^2/day x4), and 127 received TBF(thiotepa 5mg/kgx2, busulfan 3.2 mg/kg/dayx3, fludarabine 50 mg/m^2x3). Graft-versus-host disease (GVHD) prophylaxis was as follows: in HLA identical sibling transplants , cyclosporin (CyA) and Metothrexate (MTX); in unrelated donor transplants CyA+MTX+ antithymocyte globulin (ATG) and for family haploidentical donors (HAPLO) , CyA, mycophenolate mofetil (MMF) and cyclofosphamide 50mg/kg given on day +3 and +5, after transplantation (PT-CY) . Supportive care and infectious disease prophylaxis, or pre-emptive therapy, were provided as per Institutional protocols. Clinical characteristics are shown in Table 1.Results: With a median follow up of 481 and 551 days (range, 8-2625 and 2-2277 respectively) after transplantation, the 5-year cumulative incidence of TRM was 25% and 9% for BU-FLU and TBF (p = 0.007); the 5-year cumulative incidence of leukemia relapse related deaths (RRD) was 33% and 9% (P = 0.008). TBF showed an advantage over BU-FLU, also after exclusion of HAPLO, both in TRM (p=0.08) and RRD (p=0.04). The 5-year actuarial survival was 41% (26-56%) and 82% (74- 90%) (p=0.000) respectively for the BUFLU and the TBF group. The survival advantage was seen also when looking only at HLA identical siblings and UD, excluding HAPLO grafts (51% vs 82%,p=0.05).In a multivariate Cox analysis, after correcting for patients age, interval diagnosis transplant, first or second remission , and donor type, the use of TBF reduced the risk of death as compared to BU-FLU (RR 0.3 , range 0.10-0.89, p=0.01) . This was true also when running a Cox model on TRM (RR 0.17 for TBF vs BU-FLU, p=0.02) . TRM was 4% vs 14% in patients receiving TBF vs Bu-FLU aged < 50 years (p=0.09), and 9% vs 32% in patients receiving TBF aged > 50 years (p=0.01). In a Cox analysis on RRD, TBF showed a reduced risk (RR 0.41) but this did not reach statistical significance (p=0.1)Conclusions: Superior survival of patients receiving TBF , as compared to BU-FLU appears to be a combination of reduced toxicity and reduced relapse. The survival advantage is independent of donor type, and therefore of GvHD prophylaxis. [Display omitted] DisclosuresLaurenti:Roche: Other: Advisory Board; Gilead: Other: Advisory Board; Janssen: Other: Advisory Board; Abbvie: Other: Advisory Board. Angelucci:Celgene: Honoraria, Other: Advisory: research project ; Novartis Oncology Swiss: Other: Invited speakers sponsored satellite meeting during ; Novartis Oncology: Other: Advisory board: iron toxicity; Jazz: Other: Advisory board: AML; Roche: Other: Advisory board: biosimilars; Bluebird Bio: Other: Advisory board: Gene therapy in Thalassemia; Celgene: Other: protocoll ACE 536 B-Thal 001: DMC Chair; Novartis Oncology: Other: Protocol Telesto: sterring committee Chair.

Haploidentical, G-CSF Primed, Unmanipulated Bone Marrow Transplantation with Anti-CD25 Monoclonal Antibody As Part of the Gvhd Prophylaxis for Patients with High-Risk Acute Myeloid Leukemia

Background. During the last years, hematopoietic stem cell transplant from haploidentical donor is increasing by using the unmanipulated graft. We report the results of allogeneic bone marrow transplantation (BMT) from haploidentical donor primed with G-CSF in patients (pts) with high-risk acute myeloid leukemia (AML), who received an uniform TBF (Thiotepa, Busulfan, Fludarabine) conditioning regimen including antitymocyte globulin and an identical GVHD prophylaxis combining MTX+CSA, MMF and an anti-CD25 monoclonal antibody (Basiliximab).Patients and Methods. Since August 2005 to December 2014, 165 pts with high-risk hematological malignancy underwent unmanipulated BMT from fully haploidentical donor primed with 4µg/kg/day of G-CSF over 7 days. Of these 165 pts, 71 (median age 49 yrs, (range5-66) were affected by high-risk AML and were in early (CR1 and CR2: n=58) or advanced (>CR2 or active disease: n=13) phase at time of transplant. All pts received the same myeloablative (MAC: n=47) or reduced intensity (RIC: n=24) TBF conditioning regimen including antithymocyte globuline for 4 days (days-4 through -1) and an identical graft-versus-host disease (GVHD) prophylaxis consisting of the classical association of MTX+CSA combined with MMF from day +7 to day +100 and the administration of 20 mg of Basiliximab at days 0 and +4. The donor were represented by: son (n=25); brother (n=18), mother (n=11), daughter (n=8), sister (n=6) and father (n=3). Anti-infective management, supportive care and transfusion policy were identical for all pts. The experience was conducted at 2 Institutions: Stem Cell Transplant Unit at University Tor Vergata of Rome (n=45) and at Civil Hospital of Pescara (n=26), Italy.Results. All pts engraftedwith full donor chimerism: median time 20 days (range, 11-35) and CI 94±3%. With a median follow-up (FU) of 3.9 yrs (range, 0.7-7.4), the 7-yrs probability of overall survival (OS) and disease free survival (DFS) for all pts was 45±6% and 43±6%, respectively. OS calculated by disease status at transplant was 53±7% at 7 yrs for 58 pts transplanted in early phase and 0.0% at 4 yrs for 13 transplanted in advanced phase (p=0.0027), DFS was 49±7% and 15±10% at 7 and 2 yrs (p=0.007), respectively.TBF-MAC Regimen: 47 pts (median age 43 yrs, range 5-63), in early (n=38) or advanced (n=9) phase at transplant received a TBF-MAC regimen. For all these pts the CI of engraftment was 94±4% at a median of 20 days (range, 12-35). The 100 day CI of acute GVHD (AGVHD) grade II-IV and III-IV was 32±7% and 6±4%, respectively. The CI of extensive chronic-GVHD (CGVHD) was 19±7%. In the patients transplanted in early phase the CI of transplant related mortality (TRM) at 6 months and 7 yrs was 21±7 and 27±7%, respectively. The CI of relapse at 1 and 7 yrs was 16±6% and 24±7%, respectively. With a median FU of 3.9 yrs (range, 1.3-7.4), the 7-yr probability of OS and DFS was respectively 60±8% and 52±8% with a plateau of the curve from 2 yrs after transplant. None of the 15 variables considered in multivariate analysis (Cox and Fine and Gray models) influenced significantly the outcomes.TBF-RIC Regimen: 24 pts (median age 61.5 yrs, range 41-66) were conditioned with TBF-RIC. All pts engrafted with full donor chimerism (CI 96±6%). The 100 day CI of AGVHD grade II-IV and III-IV was 33±10% and 13±7%, respectively. The CI of extensive CGVHD was 8±8%.Four pts were in advanced and 20 in early phase at transplant. For these last pts, the CI of TRM at 6 months and 6 yrs was 15±8% and 25±10%, respectively. The CI of relapse at 1 and 6 yrs was 15±8% and 27±11%, respectively. With a median FU of 4.1 yrs (range, 0.8-6), the 6-yr probability of OS and DFS was respectively 42±12% and 41±12% with a plateau of the curve from 2 yrs after transplant. In multivariate analysis, no significant factor was identified.Conclusions. Although the number of pts does not allow an extensive analysis of the results, the homogeneity of our series in terms of diagnosis, patient selection, conditioning regimen and GVHD prophylaxis supports the conclusion that haploidentical, G-CSF primed, unmanipulated BMT is a valid alternative for high-risk AML pts lacking an HLA identical sibling. The regimen of GVHD prophylaxis is highly effective and can be proposed in alternative to the use of post-transplant cyclophosphamide, proposed by the Baltimore group. Finally, TBF-RIC regimen can be confidently offered to unfit or older AML pts candidate to an haploidentical transplant. DisclosuresNo relevant conflicts of interest to declare.

Unrelated Cord Blood Versus Non-T Cell Depleted Haploidentical Stem Cell Transplantation: Comparable Results in Adults with Acute Leukemia, a Eurocord and ALWP-EBMT Study

Unrelated cord blood transplantation (UCBT) and related Haploidentical non T-cell depleted stem cell transplantation (Haplo) are alternative options to treat patients with high risk acute leukemia. Both techniques have shown encouraging results.The current retrospective analysis aimed to compare the outcomes of both approaches in adults with ALL and AML receiving either UCBT (n=928) or Haplo (n=518) reported to EBMT centres between 2007 and 2011.Diagnosis was ALL for 716 patients (Haplo=158 and UCBT=558) and AML for 730 (Haplo=360, UCBT=370). Haplo grafts were not T-cell depleted, with 236 patients receiving unmanipulated bone marrow (BM), 253 receiving peripheral blood stem cells (PBSC) and 29 receiving BM+PBSC. For UCBT, 431 patients were treated with a single unit, while 497 received double unit UCBT.Compared with recipients of UCBT, Haplo recipients were more likely to have AML (69% versus 40%, p=<0.001), and were transplanted more recently (2011 versus 2009, p=0.001), had a longer median interval from CR1 to transplant (139 versus 126 days, p=0.07), and had more frequently advanced phase of disease at time of transplant (35% versus 17%, p=0.001).Median follow-up was 19 months and 25 months, (p=0.007) for Haplo and UCBT, respectively. The type of conditioning regimen (MAC or RIC) was similar between both groups, with MAC representing 60% and 56% for Haplo and UCBT, respectively.For Haplo, the most frequently used regimens were Thiotepa-Busulfan-Fludarabine (TBF) for MAC and Treosulfan-based regimens for RIC. Graft versus host disease (GVHD) prophylaxis included CsA+MMF (41%), Sirolimus (15%), while 163 patients received post-transplant Cyclophosphamide (Cy). For UCBT cases, the most common MAC regimens were TBF for 33% of cases, CyFluTBI-12Gy for 27% and CyTBI12Gy for 17%. The most frequently used RIC was CyFluTBI-2Gy in 72% of the cases. GVHD prophylaxis was CsA+MMF in 70% of cases.In univariate analysis, cumulative incidence (CI) of neutrophil engraftment was 92% vs 84% (p=<0.001) for Haplo and UCBT; CI of acute GVHD was 27% vs 32% (p=0.11) and for chronic GVHD it was 30% vs 25% (p=0.06) for Haplo and UCBT. For non-relapse mortality (NRM), relapse incidence (RI) and leukemia-free survival (LFS) outcomes were analyzed separately according to disease status, and no statistically significant differences were observed between Haplo and UCBT.According to disease status, for patients in CR1 (n=610), 2 years RI was 27% versus 28%, p=0.67; NRM 26% versus 29%, p=0.30; and 2 years LFS 48% versus 43%, p=0.16; for Haplo and UCBT, respectively.For patients in CR2 (n=502), 2 years RI was 33% versus 28%, p=0.51; NRM 33% versus 33%, p=0.93; and 2 years LFS 34% versus 39%, p=0.61, for Haplo and UCBT, respectively.For patients in advanced disease status (n=334), 2 years LFS was 11% versus 14%, p=0.92 for Haplo and UCBT, respectively.Infections and GVHD were the most common causes of transplant-related deaths in both groups, (infection 30% in both groups, GVHD 15% and 9%, after Haplo and UCBT, respectively), and 40% of deaths were due to disease recurrence in both Haplo and UCB recipients.In multivariate analysis, UCBT was associated with lower incidence of chronic GVHD (HR= 0.62; p<0.001) and higher NRM (HR= 1.28; p=0.04) when compared to Haplo. No statistically significant differences were observed between Haplo and UCBT for RI (HR= 0.87; p=0.24) and LFS (HR= 1.06; p=0.47). Factors independently associated with lower LFS were disease status at transplant (HR 2.69, p=<0.001), and use of ATG (HR 1.28, p=0.001).In conclusion, in this retrospective analysis, non TCD Haplo and UCBT showed similar RI, NRM, and LFS, highlighting that both approaches are valid for this population of patients. Longer follow-up, more homogeneous transplant strategies (stem cell source, type of conditioning regimen and GVHD prophylaxis) are needed for further evaluation. While waiting for the results of the BMT CTN trial on non TCD Haplo using post-transplant Cy and double UCBT both in the RIC setting, the choice of the specific approach for Haplo or UCBT should be likely based on transplant centre expertise and policy. DisclosuresNo relevant conflicts of interest to declare.

Post-Transplant Cyclophosphamide Following a Myeloablative Conditioning For Hematologic Malignancies Receiving An Unmanipulated Haploidentical Bone Marrow Transplant

BackgroundUnmanipulated family haploidentical transplants are becoming increasingly used in patients lacking an HLA identical family donor, or a well matched unrelated donor. Aim of the studyThis is an updated analysis of our program of haploidentical bone marrow transplant (hBMT) , followed by post-transplant high dose cyclophosphamide (PT-CY) in 95 patients with hematoloigic malignancies receiving a myeloablative conditioning. MethodsThe conditioning regimen consisted of thiotepa, busulfan, fludarabine (TBF) (n=47) , thiotepa melphalan fludarabine (n=5) , or 9.9-12 Gy TBI + fludarabine (n=43). The patients' median age was 49 years (17-74); the disease status at the time of transplant, was first complete remission (CR1, n=29) , CR2 (n=23), or active disease (n=38,40%). The diagnosis was AML (35%), ALL (24%), MDS (12%) myeloproliferative disorders (12%), other malignancies (17%). The total nucleated cell dose infused was 3.37 (1.4-9.17). The median follow up for surviving patients is 440 days (90-930). Graft versus host disease (GvHD) prophylaxis consisted in PT-CY on day+3 and +5 , cyclosporine (from day 0) , and mycophenolate (from day +1).▪ ResultsThe cumulative incidence of neutrophil (PMN) engraftment was (90%) and all surviving patients on day +30 had full donor chimerism. The median day for neutrophil engraftment was day +17 (11-32). The cumulative incidence (CI) of grade II-III acute GvHD was 14%, and of moderate chronic GvHD 8%, severe cGvHD 9%. The CI of transplant related mortality (TRM) is respectively 7%, 17%, 26% for patients in CR1, CR2, or with active disease. The CI of relapse is respectively 17%, 30%, 37% for patients in CR1, CR2, or with active disease. The overall actuarial survival is respectively 75%, 44%, 32% for patients in CR1, CR2, or with active disease (p=0.002) (Fig.1). The most frequent cause of death was leukemia (26%) followed by infections (9%). ConclusionsThese data confirm our first report on 50 patients and support the use of myeloablative conditioning regimens, followed by h-BMT with PT-CY. The risk of acute and chronic GvHD seems relatively low , as well as the overall transplant related mortality. We have not seen the excess relapse rate reported when patients are given a non myeloablative regimen, and disease control has been satisfactorily both for patients in remission, as well as for patients with active disease at the time of transplants. Disclosures:No relevant conflicts of interest to declare.