Incidence Of cGVHD Research Articles

Ruxolitinib for Steroid-Refractory Acute Graft-Versus-Host Disease: A Single Centre Retrospective Study

BackgroundAcute graft-versus-host disease (aGVHD) is the major cause of non-relapse morbidity and mortality after allogeneic hematopoietic stem cell transplantation(allo-HSCT). But only 40% of the patients will respond to first-line therapies Corticosteroids. Ruxolitinib, a selective Janus kinase (JAK) 1/2 inhibitor, reduces the incidence and severity of GVHD while preserving graft-versus-leukemia effects in preclinical models. The retrospective study evaluated the efficacy of ruxolitinib compared with other second-line therapies for steroid-refractory aGVHD (SR-aGVHD) in a single-center.MethodsA total of 90 patients who developed SR-aGVHD after HSCT were evaluated in this retrospective study.They were treated with ruxolitinib (n=45) or other salvage-therapies (n=45) including MTX, basiliximab, etanercept and MSC at our institution. The primary endpoint was the overall response rate (ORR) at Day 28. Additional endpoints included overall survival (OS), cumulative incidence rates of failure-free survival (FFS), relapse, non-relapse mortality (NRM) and cGVHD. Treatment failure was defined as 1) addition of new systemic therapy for aGVHD, 2) NRM, 3) relapse, 4) progression of hematologic disease. FFS and OS were calculated from the day of starting the use of second-line treatments for aGVHD.ResultsThe median age was 34 years (range 14-69). At the time of enrollment 25 patients had grade Ⅱ disease, 39 with grade Ⅲ disease, 26 with grade IV disease. The skin was involved in 54.4%, lower gastrointestinal (GI) tract in 78.9% and liver in 20.2%. With a median follow-up of 1.33 years, the ORR at day 28 was higher in ruxolitinib group than non-ruxolitinib group (62.2% [95% CI, 47.5%-77.0%] vs. 26.7% [95% CI, 13.2%-40.1%], P=0.001) (Table 1). The 1-year OS was 64.4 % and 45.5% in the two groups, respectively (P=0.0382). Ruxolitinib treatment also improved the 1-year cumulative incidence of FFS (57.8% vs. 26.6%, P=0.002), while the 1-year cumulative incidence of relapse did not differ significantly (9.6% vs. 20.0%, P=0.195). The 1-year cumulative incidence of NRM was lower in the ruxolitinib group than the non-ruxolitinib group (24.4% vs. 45.3%, P=0.023). The 1-year and 3-year cumulative incidence of cGVHD were 17.8% vs. 33.3% and 26.8% vs. 44.4% between the ruxolitinib group and non-ruxolitinib group (P=0.10 and P=0.04).ConclusionsOur study demonstrated that ruxolitinib is effective than other second-line treatments in patients with SR-aGVHD due to the higher response rates and the improvement of prognosis. Furthermore, ruxolitinib could reduce the incidence and severity of chronic GVHD in aGVHD patients.Keywords: Ruxolitinib; Steroid-refractory; Acute graft-versus-host disease; Haploidentical hematopoietic stem cell transplantation [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Chimerism of Blood T-Cells and Leukemia Lineage Cells Following Myeloablative Hematopoietic Cell Transplantation Is a Risk Factor for Relapse and Chronic Graft-Versus-Host Disease

Background: Mixed chimerism of blood leukemia lineage cells has been reported to be highly predictive of relapse (Mattsson J et al. Leukemia 2001), but the utility of T-cell chimerism is controversial.Methods: Chimerism of T-cells (CD3 +) and leukemic lineage cells (CD13 +/CD33 + for myeloid malignancies and CD19 + for B-lymphoid malignancies) was measured in the peripheral blood for 600 hematopoietic cell transplant (HCT) recipients at 3-months post-transplant. Conditioning was myeloablative (fludarabine+busulfan+4GyTBI) and GVHD prophylaxis was with ATG+CsA+MTX.Results: Mixed (<95% donor) chimerism was present in 6% of patients in the leukemic lineage and 16% of patients in T-cells. Compared to patients with complete chimerism (≥95%), mixed chimerism predicted a significantly greater incidence of relapse (52% vs. 27%, P=0.044), and surprisingly, also a greater incidence of cGVHD (43% vs. 23%, P=0.028). Patients with mixed leukemic lineage chimerism also had poorer cGRFS (7% vs. 39%, P<0.001) and OS (29% vs. 55%, P<0.001). Mixed T-cell chimerism predicted a significantly greater incidence of relapse (46% vs. 24%, P<0.001) and lower cGVHD incidence (9% vs. 31%), with no difference in cGRFS or OS. The sensitivity/specificity/positive predictive value (PPV)/negative predictive value (NPV) of mixed leukemic lineage and T-cell chimerism for relapse were 65%/55%/35%/81% and 66%/57%/60%/79%, respectively. Sensitivity/specificity/PPV/NPV was similarly poor for cGVHD. In patients with complete leukemic lineage chimerism at 3-months, a ≥5% drop in donor chimerism at any future timepoint had sensitivity/specificity/PPV/NPV of 82%/79%/79%/82% for subsequent relapse.Conclusion: In the setting of myeloablative conditioning and ATG-based GVHD prophylaxis, mixed chimerism at 3-months post-transplant is a risk factor for subsequent relapse. However, the utility of these measurements in guiding medical interventions may be limited by insufficient predictive values. Nevertheless, patients with mixed chimerism may be candidates for more intensive surveillance. DisclosuresStorek: Atara Biotherapeutics: Other: Site PI, Research Funding.

Mesenchymal Stromal Cells Plus Anti-CD25 Antibody and Calcineurin Inhibitors for Steroid-Resistant Acute Graft-Versus-Host Disease: A Multicenter, Randomized, Phase 3 Trial

INTRODUCTION Steroid-resistant (SR) acute graft-versus-host disease (aGVHD) lacks standard second-line treatment. Mesenchymal stromal cells (MSCs) have potential efficacy in SR aGVHD. To assess efficacy and safety of MSCs combined with anti-CD25 antibody and calcineurin inhibitors as second-line therapy for SR aGVHD.METHORDS A randomized phase 3 trial involved 203 SR aGVHD patients at 10 centers in China (September 2014-March 2019). Final follow-up was on June 30, 2020. Participants were randomized in a 1:1 ratio to receive second-line therapy (anti-CD25 antibody combined with calcineurin inhibitors) with MSCs (n=101) or without MSCs (n=102). The primary endpoint was overall response (OR) at day 28 with a predefined threshold of -20%. Secondary and safety endpoints included durable OR at day 56, failure-free survival, overall survival (OS), chronic GVHD (cGVHD), infection, haematological toxicity and relapse.RESULTS Of 203 patients, 198 (97.5%; mean age, 30.1years; 40.4% women) completed the study. OR at day 28 was higher in the MSCs group than in the control group (82.8% [82 patients] vs 70.7% [70]; odds ratio, 2.00; 95% confidence interval [CI], 1.01-3.94; P=.043). Durable OR at day 56 was also higher in the MSCs group (78.8% [78 patients] vs. 64.6% [64]; odds ratio, 2.02; 95% CI, 1.08-3.83; P=.027). The median failure-free survival was longer in the MSCs group compared with control group (11.3 months vs. 6.0 month; hazard ratio (HR) 0.68; 95% CI, 0.48-0.95, P=.024). The 2-year cumulative incidence of cGVHD was 39.5% (95% CI, 29.3%-49.4%) and 62.7% (51.4%-72.1%) in the MSCs and control groups (HR 0·55, 95% CI, 0·36-0·84; P=0·005). Within 180 days after study treatments, the most common grade 3 and 4 adverse events were infections (65 [65.7%] in the MSCs group vs 78 [78.8%] in the control group), haematological toxicity (37 [37.4%] vs 53 [53.5%]).CONCLLUSIONS MSCs plus second-line treatments may increase the efficacy of SR aGVHD, decrease drug toxicity of second-line therapy and cGVHD development, and are well tolerated. DisclosuresNo relevant conflicts of interest to declare.

Graft-Versus-Host Disease Prophylaxis Using Low-Dose Antithymocyte Globulin in Peripheral Blood Stem Cell Transplantation—A Matched-Pair Analysis

Antithymocyte globulin (ATG) decreases chronic graft-versus-host disease (cGVHD) in peripheral blood stem cell transplantation (PBSCT); however, the optimal ATG dose has not been elucidated. We conducted a matched-pair analysis to evaluate whether low-dose ATG could inhibit cGVHD in HLA-matched PBSCT after myeloablative conditioning. A total of 70 patients who were enrolled in the JSCT-ATG15 study, a multicenter phase II clinical trial of 2 mg/kg of ATG (thymoglobulin) given on days −2 and −1, were compared with 210 patients not receiving ATG, who were matched for age, sex, disease, and calcineurin inhibitor selected from the database in Japan. The primary endpoint, cumulative incidence of extensive cGVHD at 2 years was significantly less in the ATG group than that in the non-ATG group (8.7% [95% CI, 3.5%-16.8%] versus 26.2% [95% CI, 20.3%-32.5%], P = .002). ATG significantly reduced the incidence of overall cGVHD and inhibited multiple organ involvement. The ATG group had favorable outcome compared to the non-ATG group in GVHD-free, and relapse-free survival at 2 years. In conclusion, low-dose ATG effectively inhibits chronic GVHD in PBSCT.

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.

Promising Results at 1 Year Follow-up Following Familial Haploidentical (FHI) T-Cell Depleted (TCD) with CD34 Enrichment and T-Cell (CD3) Addback Allogeneic Stem Cell Transplantation in Patients with High-Risk Sickle Cell Disease (SCD) (IND 14359)

AlloSCT from HLA-matched MSD has been successful for high-risk SCD, and is the only known curative therapy (Talano/Cairo et al EJH, 2014). We have recently demonstrated 100% EFS and absence of sickle cell symptoms following reduced toxicity conditioning in HLA matched sibling donor (MSD) or cord blood AlloSCT (Bhatia/Cairo et al BMT, 2014). However, 5 out of 6 children lack an HLA MSD without SCD. Only 19% of recipients of African descent will identify a well-matched unrelated donor (MUD) and results after unrelated UCBT are poor (Radhakrishnan/Cairo et al BBMT, 2013). Recent results utilizing matched unrelated donors in a multi-center trial showed unacceptable rates of cGVHD at 62% (95% CI 41-77) (Shenoy et al Blood, 2016). We demonstrated CD34+ selection followed by T-cell addback from MUD in pediatric recipients led to 100% engraftment with minimal aGVHD (Geyer/Cairo et al BJH, 2011). Limitations in the past of various T-cell depletion methods have included a higher incidence of graft failure, delayed immune reconstitution, opportunistic fungal infection and higher incidence of cGVHD. FHI TCD AlloSCT utilizing the approach of CD34+ enrichment and T-cell addback could expand the donor pool and improve outcomes for patients with high risk SCD and have similar outcomes to AlloSCT from HLA MSD.This SCD consortium trial (www.sicklecelltransplantconsortium.org) (NCT01461837) is investigating the safety, feasibility, EFS, donor chimerism, graft failure, aGVHD and cGVHD after FHI TCD AlloSCT in high-risk SCD patients.High risk included: ≥1 CVA, ≥2 ACS, ≥3 VOC in past 2 years, or 2 abnormal TCDs. Patients (2-<21 yrs) who have ≥1 high-risk SCD features were eligible. Patients received hydroxyurea and azathioprine, day -59 - day -11, fludarabine (150mg/m2), busulfan (12.8mg/kg) (targeted trough Css of 600-900), thiotepa (10 mg/kg), cyclophosphamide (200mg/kg), R-ATG (8mg/kg), and TLI (500cGy) followed by FHI T-cell depleted AlloSCT. AGVHD prophylaxis: tacrolimus. We utilized the CliniMACS to enrich for peripheral blood HPC's; target dose of 10 x 106 CD34+ cells/kg with a fixed dose of 2 x 105 CD3+ T cells/kg. The Child Health Rating Inventories (CHRIs) was used to serially collect parent proxy-rated health-related quality of life (HRQL).Twenty-one patients have been enrolled. Nineteen patients have received AlloSCT to date. Fifteen patients utilized maternal donors and 4 patients utilized paternal donors. Two donors encountered thrombocytopenia that resolved spontaneously. The mean ± SD CD34+ enrichment prior to cryopreservation was 12.66 ± 3.3 x 106/kg and log T-cell depletion was 4.8 ± 0.58. Evaluable pts had early neutrophil engraftment (median day +9), and ≥95% whole blood and RBC (CD71) donor chimerism at 1yr. Probability of aGVHD n=17, 7.1% (CI95: 0-70.0); cGVHD n=17, 20% (CI95: 0.7-59.6) (Figure 1A and 1B). Probability of 1-Year Overall Survival (OS) n=17; 88.2% (CI95: 60.6-96.9) (Figure 1C). Immune reconstitution was robust with 1 yr NK, CD3, CD4 and CD8 204±37 cells/μL, 795±168 cells/μL, 408±102 cells/μL and 375±90 cells/μL, respectively. Two-yr PFT results were also robust with % predicted FVC, FEV1, TLC and DLCO of 89%, 84%, 82%, and 68%, respectively. All survivors are free of SCD symptoms and without signs of progression of multi-organ toxicity. One patient developed late hepatic SOS and died at day +59; one patient died at day +390 due to complications of CGVHD, and one patient died at day +141 of steroid refractory aGVHD, the remainder are alive and free of SCD symptoms with a median follow-up of +711 days (range, +231 to +1684 days). Most importantly, mean + SD HRQL score (0-100) reported at 1 yr for emotional, physical functioning, role, and global scores were 82.9±9.7 points, 82.8±15.8 points, 89.6±13.3 points, and 86±8.2 points, respectively.Early results indicate promising results in 1 yr OS, stable donor chimerism, and low incidence of acute and/or cGVHD after FHI HCT utilizing CD34 enrichment and CD3/MNC addback in high-risk SCD patients who lack a MSD or URD. A longer term follow-up is needed to assess long-term safety and outcomes. This research was supported by RO1FD004090-01A1. [Display omitted] DisclosuresWalters:AllCells, Inc: Other: Medical Director; bluebird bio: Research Funding; Sangamo Therapeutics: Consultancy; ViaCord Processing Lab: Other: Medical Director. Cairo:Jazz Pharmaceuticals: Speakers Bureau.

Long-Term Follow-up of Adult Double Unit Cord Blood (CB) Transplantation (dCBT) Recipients Reveals High Rates of Progression-Free Survival after a Novel Cy/ Flu/ Thio/ TBI 400 Intermediate Intensity Conditioning Regimen

Background: CB transplantation (CBT) can be associated with the advantages of low rates of chronic GVHD & relapse. These benefits, however, can be offset by early post-transplant transplant-related mortality (TRM). Therefore, we have investigated CBT after a novel intermediate intensity, reduced toxicity myeloablative cyclophosphamide 50 mg/kg, fludarabine 150 mg/m2, thiotepa 5-10 mg/kg, 400 cGy TBI regimen in an effort to reduce early organ toxicity while also maximizing engraftment & disease control.Methods: We analyzed CBT outcomes, including patient (pt) & graft characteristics associated with TRM, relapse and progression-free survival (PFS), in adult CBT recipients transplanted with this approach. Eligible pts were first allograft recipients </= 65 yrs transplanted for acute leukemia/ MDS/ MPD (</= 10% blasts pre-CBT), B-cell NHL or Hodgkin lymphoma. Graft-versus-host disease (GVHD) prophylaxis was with cyclosporine-A/ mycophenolate mofetil (no ATG).Results: 139 consecutive pts [74 (53%) non-European, 84 (60%) CMV seropositive, median age 51 yrs (range 23-65), median weight 83 kg (range 49-136)] were transplanted 10/2007-12/2016. Diagnoses included 102 acute leukemia, 22 MDS/ MPD, 15 B-cell NHL/ HL. All received double unit grafts [median donor recipient 8-allele HLA-match 5/8 (range 2-8), median infused CD34+ dose 1.0 x 105/kg/unit (range 0.2-8.6)]. 54 (39%) CB grafts were supplemented with haplo-identical CD34+ cells as a myeloid bridge. The incidence of CB engraftment was 96% (95%CI: 91-99). Day 180 incidence of grades II-IV & III-IV aGVHD was 78% (95%CI: 70-84) & 21% (95%CI: 15-28), respectively. 1-yr cGVHD was 8% (95%CI: 4-14). Cumulative incidence of day 180 TRM was 12% (95%CI: 7-17) & 21% (95%CI: 14-29) at 3 yrs. 11% (95%CI: 6-18) of pts relapsed by 3 yrs post-CBT. With a median survivor follow-up of 2.7 yrs (range 6.5 months-9.5 yrs), the 3-yr overall survival is 71% (95%CI: 63-80) & PFS is 67% (95%CI: 59-76). 3-yr PFS in 75 acute leukemia CR1 pts is 66% versus 74% in 27 other disease status pts (p = 0.574). 3-yr PFS in 23 FLT-3 mutated AML pts is 83%. The 3-yr PFS is 62% in 22 MDS/ MPD pts & 67% in 15 NHL/ HD pts. The revised disease risk index (rDRI) was not associated with TRM, relapse or PFS (Figure, Table). By contrast, pts with an age adjusted hematopoietic cell transplant-comorbidity index (aaHCT-CI) 0-2 (n = 54) had very low day 180 TRM [4% (95%CI: 1-11)] & high PFS [81% (95%CI: 71-94)] whereas the 85 pts with high aaHCT-CI (median 4, range 3-9) had a day 180 TRM of 17% (95%CI: 10-25) & 3-yr PFS of 58% (95%CI: 48-71). In multivariate analysis of TRM, aaHCT-CI had a HR of 4 (95%CI: 1.4-11.6, p = 0.01) whereas age alone was not significant [HR 1.9 (95%CI: 0.8-4.5), p = 0.12]. In multivariate analysis of PFS, aaHCT-CI HR was 2.4 (95%CI: 1.2-4.7, p = 0.01) whereas for recent pts (CBT 2014-2016) HR was 0.6 (95%CI: 0.3-1.2) although this was not significant (p = 0.17)Conclusions: The 3-yr PFS in this older (median 51 yrs) intermediate intensity dCBT population is very promising. The incidences of cGVHD & relapse are low & DRI was not associated with TRM, relapse or PFS. Notably, addition of haplo-identical cells & better CB HLA-match was not associated with better PFS, & older age (51-65 yrs), CMV sero-positivity & non-European ancestry did not adversely affect PFS. Notably, day 180 TRM in recent pts is 9%. While high aaHCT-CI pts require additional strategies to reduce early post-CBT complications, given PFS is excellent in low aaHCT-CI CBT recipients (39% of pts in this analysis), survival comparisons of intermediate intensity dCBT in this population versus all other HSC sources is warranted. CB can also be attractive in pts with high risk disease given its rapid availability. [Display omitted] Disclosuresvan den Brink:Seres: Research Funding; Therakos Institute: Other: Speaking engagement; PureTech Health: Consultancy; Jazz Pharmaceuticals: Consultancy.

Bortezomib Consolidation after Nonmyeloablative Allogeneic Transplant Is Safe and Leads to a High Incidence of Immunophenotypic Complete Response in High-Risk or Young Myeloma Patients

▪Introduction: Allogeneic stem cell transplantation (alloSCT) is the only curative treatment for newly diagnosed multiple myeloma (NDMM) patients but is hampered by a high incidence of relapse and chronic graft-versus-host disease (cGVHD). We hypothesized that bortezomib (BTZ) in consolidation after tandem autologous stem cell transplantation (ASCT) and nonmyeloablative (NMA) alloSCT could decrease the incidence of cGVHD while improving quality of response.Method: NDMM patients ≤65 years with high-risk (HR) disease (defined as HR cytogenetics [del17p, t(4;14), t(14;16), t(14;20), del1p or gain 1q], ISS 3 or plasma cell leukemia) or ≤ 50 year regardless of risk status with an 8/8 HLA identical sibling or unrelated donor are eligible to participate in this prospective trial. After triplet BTZ-based induction chemotherapy and ASCT, outpatient NMA alloSCT is performed with either fludarabine 30 mg/m2 and cyclophosphamide 300 mg/m2 for 5 days (sibling donor) or fludarabine 30 mg/m2 for 3 days and total body irradiation 2 Gy (unrelated donor) followed by peripheral blood stem cell infusion. Acute GVHD (aGVHD) prophylaxis consists of tacrolimus and mycophenolate mofetil (MMF). BTZ is started on day +120 post-transplant at 1.3 mg/m2 every 2 weeks for 1 year. Response evaluation is based on IMWG criteria. Bone marrow minimal residual disease (MRD) evaluation is performed with highly sensitive (≥10-5) next-generation flow cytometry using 8-color Euroflow protocol before alloSCT, before BTZ, every 3 months for 2 years and at relapse. Immunophenotypic complete response (iCR) is defined as stringent CR in addition to 2 consecutive negative MRD results. aGVHD and cGVHD are evaluated according to modified Glucksberg and NIH criteria, respectively.Results: As of 07/10/2017, 33 NDMM patients (16 males) have been enrolled; median age is 55 (range: 35-64) years. ISS 3 is found in 39%, Durie-Salmon stage 3A or 3B in 85%, HR cytogenetics in 58% (12% del17p, 15% t(4;14), 33% gain 1q21, 9% del1p and 12% with >1 HR cytogenetics). Induction consisted of CyBorD (79%) or VTD (21%) for a median of 4 (range: 4-7) cycles followed by ASCT. Median times from induction to ASCT and from ASCT to alloSCT are 5.7 and 4.4 months, respectively. Sibling donor transplants were performed in 42%. With a median follow-up of 15 months after alloSCT, 23 patients have started BTZ and received 96% of planned doses. No dose reduction was needed for toxicity. Consolidation BTZ improve depth of response, increasing ≥CR rate from 55% to 80% and iCR rate from 17% to 67% (Table 1), regardless of cytogenetic abnormalities. Median progression-free survival (PFS) is not reached; 12-month PFS is 87% (CI: 66-96) (Fig. 1). The cumulative incidence of progression at 12 months is 8%. Median overall survival (OS) is also not reached and 12-month OS is 91% (CI: 68-98). In 23 patients followed ≥6 months, cumulative incidences of grade II-IV and grade III-IV aGVHD are 30% and 15%, respectively. In 18 patients followed ≥12 months, the cumulative incidence of all grade and moderate-severe cGVHD at 12 months are 58% and 40%, respectively, with mostly mouth, skin and liver involvement. There is no clear association between time of occurrence of cGVHD and improvement of response. Three patients died, one from myeloma progression and 2 from grade III aGVHD, with a non-relapse mortality at 12 months of only 5%. Observed grade ≥3 non-hematologic toxicities possibly/related to BTZ include diarrhea (n=1), viral hemorrhagic cystitis (2 adenovirus, 1BK virus) and subclinical EBV reactivations (n=4).Conclusion: Tandem ASCT-NMA alloSCT and BTZ consolidation result in a remarkably high rate of CR or better including iCR. Despite a HR NDMM population, a low relapse rate is observed. BTZ following alloSCT is safe and may contribute to decrease both the incidence of cGVHD or its severity. [Display omitted] DisclosuresSebag:Celgene, Janssen: Consultancy. Cohen:University of Montreal: Patents & Royalties: royalties.

Ixazomib for Chronic Graft-Versus-Host Disease (cGVHD) Prophylaxis in Patients Undergoing Allogeneic Transplantation (alloHCT): Preliminary Results of a Phase I/II Study

Ixazomib for Chronic Graft-Versus-Host Disease (cGVHD) Prophylaxis in Patients Undergoing Allogeneic Transplantation (alloHCT): Preliminary Results of a Phase I/II Study

Influence of VDR Polymorphisms on the Outcome of Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) within the Alovita Trial.

BackgroundVitamin D (VD), due to its interaction to vitamin D receptor (VDR), has a potent immunomodulator effect. Some retrospective studies have shown that VDR polymorphisms (which determine the affinity of VDR towards VD) can influence on the outcome and the incidence of GVHD after allo-HSCT. We have recently described in a phase I/II prospective trial (ALOVITA) that the use of VD in the post-transplant setting decreases the risk of overall and moderate-severe chronic GVHD (Caballero-Velazquez, Clin Cancer Res 2016).ObjectiveTo analyze the effect of VDR polymorphisms on post-transplant outcomes and on the effect of VD on cGVHD incidence in patients included in the ALOVITA clinical trial.MethodsPatients and donors with genomic DNA, extracted from peripheral or bone marrow blood prior to transplant, available were analyzed. A group of patients who received 1000 UI/day or 5000 UI/day of VD (n=71), and a control group (n=36) were included. Overall, 107 patients and 93 donors were selected. The polymorphisms FokI C>T, BsmI A>G, ApaI T>G, TaqI T>C were detected by TaqMan SNP genotyping assay.ResultsBaseline characteristics of patients are shown in table 1.The median follow-up was 453 days (13-1256d). The frequencies of genotypes coincided with that of the European population as described in international databases.There were no statistically significant differences in terms of NRM depending on polymorphisms for FokI, BsmI ApaI or TaqI neither in patients nor in donors, although a trend towards a decreased NRM was observed in patients whose donors were ApaI GG (10%) as compared to TG+TT (27.8%), (p=0.07).A higher relapse incidence (RI) was observed in patients with TaqI CC genotype (42.9%) vs those with TC+TT genotype (20.6%), p=0.02 as well as in patients with BsmI GG (37.5%) vs AA+GA (21%), p=0.04. Also, patients whose donors had an ApaI GT+TT genotype had a higher RI (26,8) as compared to GG (7,1), p=0.05.A trend towards a better EFS was observed for BsmI AA in donors (75.6%) vs GA+GG (48.7%), p=0.06. Regarding OS, significant differences were observed depending on the genotype of the patients for FokI: CT (84%) vs CC+TT (62,1%), p=0.03. .We analyzed BsmI, ApaI and TaqI haplotypes in 95 patients. The most frequent combination within our series were AAGGTT (group 1: n=23) and GATGTC (group 2: n=23). We named ‘group 3‘ to include the rest of the combinations (n=49). We observed significant differences in terms of OS: 73% vs 51.1% vs 81.6% for groups 1, 2 and 3, respectively (p=0.02).As far as cGVHD is concerned, data are shown in Table 2/3. The following patient genotypes influenced on the efficacy of VD as cGVHD prophylaxis, the incidence of overall cGVHD being: FokI, CT (22.5% vs 80%, p=0.0004); ApaI, GG (23% vs 60%, p=0.009); TaqI, TT (20% vs 64.7%, p=0.001), BsmI, AA (18.2% vs 73.3%, p=0.0004) for those patients receiving or not VD. These differences were also observed for moderate-severe cGVHD. The same analysis was performed for donors' genotypes, and differences in overall and moderate-severe cGVHD were observed for the following genotypes: FokI, CC; ApaI, TT; TaqI, TC; BsmI, AA, (table 2).We also evaluated the benefit of GVHD prophylaxis with VD regarding patients' haplotype. Group 1 haplotype had the greatest benefit from receiving VD in terms of cGVHD: overall cGVHD: 75% vs 15.4% for patients who did and did not receive VD, p=0.008, and moderate-severe cGVHD: 75% vs 14.3%, respectively; p=0.01.Conclusion:Patient VDR polymorphisms influence on outcome after transplantation. The VDR genotypes from either the donor or the patient modulate the effect of VD used post-transplant on the risk of cGVHD, thus suggesting that genomic changes in VDR can modify its interaction to VD. [Display omitted] DisclosuresSanchez-Guijo:Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria.

Use of G-CSF after Haploidentical Peripheral Blood Stem Cell Transplantation with Post-Transplantation Cyclophosphamide

IntroductionT-repleted haplotype mismatched (haplo) hematopoietic stem cell transplant (haplo-HSCT) from a relative has emerged during the last decade as a new modality of allogeneic transplant (allo-HSCT). The use of post-transplant high-dose cyclophosphamide (PT-HDCY) has been successfully introduced by the Johns Hopkins team. Initially this modality encompassed with non-myeloablative conditioning (NMAC) and bone marrow (BM) as stem cell source followed by post-transplantation GCSF (PT-GCSF) until engraftment. Then some teams investigated alternatives with more intensive preparation, either reduced intensity (RIC) or myeloablative (MAC) conditionings as well as the use of peripheral blood stem cells (haplo-PBSCT). In the latter situation, GCSF was usually kept contrary to what is usually done after HLA-matched PBSCT. In a cohort of 58 successive patients treated with haplo-PBSCT followed with PT-HDCY we did not administer any in-vivo GCSF. In this retrospective study, we compared the results of this cohort with an historical control group of 173 haplo-PBSCT treated with PT-GCSF.Materials and methodsThe goal of the study was to assess the impact of PT-GCSF on neutrophil and platelet recovery, and to evaluate the impact on overall survival (OS), progression-free survival (PFS), non-relapse mortality (NRM), incidence of relapse (IR) and incidence of acute/chronic GVHD. Patients' characteristics of both cohorts are resumed in Table 1.Median time to neutrophils recovery (ANC >500 x106/L) was d+ 25 (range 15-43) in the group not treated with PT-GCSF, versus d+21 (range 13-112) in the control group (p .006) while platelet recovery (PLT > 20 G x 109/L) was achieved at d+29.5 (range 13-169) and d+32 (range 10-394), respectively (p 0.03). One-year OS and PFS in the study group were 63% and 65% respectively, versus 71% and 64% in the historical cohort (OS: p 0.2; PFS: p 0.8). The analysis of 1-year NRM (27% vs18%, p 0.3) or incidence of relapse (7% vs17%, p 0.3) showed no significant difference.One-year cumulative incidence of grade II-IV aGVHD was 26% in the study group versus 20% in the control cohort (p 0.2) while the incidence of moderate-severe cGVHD was 10% versus 19%, respectively (p 0.05).ConclusionsWe conclude that PT-GCSF post haploidentical PBSCT significantly enhances the time for neutrophils recovery.These results, however, doesn't seem having any significant impact on OS, PFS, NRM, IR or acute GVHD incidence.Despite de small number of patients and the limitations of a retrospective study, we found a trend in cGVHD incidence, with patients who never received GCSF support experiencing a slightly higher rate of moderate-severe cGVHD.These results, however, need to be further confirmed in larger studies or, possibly, randomized clinical trials. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Risk Factors and Outcomes According to Age at Transplant with an HLA Identical Sibling for Sickle Cell Disease

Background: Hematopoietic stem cell transplant (HSCT) from an HLA identical (HLAid) sibling donor is a well-established curative therapy for sickle cell disease (SCD). However, the ideal age to perform HSCT in SCD patients remains controversial. We report the outcomes after HLAid sibling HSCT for SCD according to patient's age at the time of HSCT as well as their pre-transplant characteristics.Methods: We retrospectively analyzed 727 HLAid sibling HSCTs performed between 1986 and 2015 in 98 EBMT centres. Patients were divided in three groups according to their age at the time of HSCT: <5 year-old (n=176): group 1, 6-15 year-old (n=431): group 2 and >15 years old (n=120): group 3. Primary endpoint was probability of 3-year overall survival (OS) according to age group.Results: Median follow-up was 46 (range: 0.5-346) months. Median age at HSCT was 4 (range: 0.9-5) years in patients <5 years, 10 (range: 6-14) years in patients 6-15 years and 17 (range: 15-39) years in patients >15 years. Gender distribution did not significantly differ among the three groups. The most common SCD genotype was homozygous (SS) in the three groups (95% vs 92% vs 84%, p=0.004). Positive cytomegalovirus (CMV) serology was less frequent in group 1 (63% vs 79% vs 83%, p<0.001. Also, patients in group 1 were less treated with hydroxyurea (37% vs 60% vs 77%, p<0.001), received less than 20 red blood cell units transfusions (32% vs 43% vs 58%, p=0.002) and presented less than 3 SCD complications before HSCT (11% vs 19% vs 39%, p<0.001). For all age groups, vaso occlusive crisis (VOC), acute chest syndrome (ACS) and cerebral vasculopathy were the most reported SCD complications, and the main indications for HSCT were VOC, cerebral vasculopathy, ACS and nephropathy.The proportion of patients with Karnofsky performance status (KPS) <80 did not differ between groups. Graft source distribution was bone marrow (BM) in 74%, cord blood (CB) in 23% and peripheral blood (PBSC) in 3% of cases in group 1; BM in 85%, CB in 11% and PBSC in 4% of cases in the group 2; BM in 79%, CB in 1% and PBSC in 20% of cases in group 3 (p<0.001). Conditioning regimen was myeloablative in 97% of cases in group 1, 96% in group 2 and 83% in group 3 (p<0.001), and included in vivo T cell depletion, mostly antithymocyte globulin (ATG), in 74%, 86% and 90% of the cases, respectively (p<0.001). In all groups, graft versus host disease (GvHD) prophylaxis was mainly cyclosporine- A with methotrexate±mycophenolate mofetil. ABO and gender match between donor and recipient did not significantly vary among groups.Neutrophil engraftment at day +60 was 96%+1 in the first group, 98%+1 in the second group and 95%+2 in the third group (p=0.009). Four patients in group 1, 10 patients in group 2 and 6 patients in group 3 had primary graft failure. The first group experienced less acute GvHD (aGvHD) within 100 days after HSCT (9%+2 vs 18%+2 vs 17%+4, p=0.022) and less chronic GvHD (cGvHD) within 3 years after HSCT (9%+2 vs 12%+2 vs 20%+4, p=0.006). Three-year OS was significantly better in group 1 (99%+1 vs 95%+1 vs 88%+3, p<0.001) as well as 3-year event free survival (EFS) (96%+2 vs 92%+1 vs 84%+4, p=0.001). In a subset of patients with available chimerism data (n=405), in group 1 and group 2 65% were full donor, 32% mixed chimeras and 3% autologous reconstitution whereas in group 3 46% were full donor, 49% mixed chimeras and 5% autologous reconstitution. A univariate risk factor survival analysis was performed for group 3 (only group with sufficient events for analysis), but no patient, donor or HSCT risk factors influencing OS were identified.Conclusion: Patients transplanted at a young age have a better 3-year OS and 3-year EFS, with lower incidence of aGvHD and cGvHD. These findings outline the importance of early referral to HSCT for SCD patients. Strategies to further evaluate pre HSCT, HSCT and donor factors that may influence survival and adverse outcomes could help improve HSCT results. Disclosuresde la Fuente:Jazz Pharmaceuticals: Honoraria; bluebird bio: Consultancy; HCA: Consultancy. Bader:Novartis, Medac, Amgen, Riemser, Neovii: Consultancy, Honoraria, Research Funding.

An EBMT Analysis of Matched Sibling, Mismatched Family or Matched Unrelated Donors for Allogeneic Stem Cell Transplants in MDS

An EBMT Analysis of Matched Sibling, Mismatched Family or Matched Unrelated Donors for Allogeneic Stem Cell Transplants in MDS

The Use of Anti-Thymocyte Globulin Is Associated with Decreased Risk of Chronic Graft-Versus-Host Disease without Impact on Survival after Allogeneic Peripheral Blood Stem Cell Transplantation for Adults with Philadelphia-Positive Acute Lymphoblastic Leukemia: An Analysis By the Acute Leukemia Working Party of the EBMT

BACKGROUNDAllogeneic hematopoietic stem cell transplantation (allo-SCT) is the standard of care for adults with Philadelphia-positive acute lymphoblastic leukemia (Ph-pos ALL). During the last decade mobilized peripheral blood stem cells (PBSCT) have become predominant source of graft for allo-SCT. However, as compared to bone marrow, PBSCT is associated with increased risk of chronic graft-versus-host disease (cGVHD). Attempts to reduce the cGVHD rate include the addition of anti-thymocyte globulin (ATG) to the conditioning regimen. The goal of this registry-based, retrospective study was to analyze the effect of ATG on results of allo-PBSCT in adults with Ph-pos ALL. PATIENTS AND METHODS1055 patients, aged 18-76 years, with Ph-pos ALL, treated with unmanipulated allo-PBSCT in first complete remission between 1997-2014 were included in the analysis. Conditioning regimen was myeloablative in 769 (72%) cases and based on total body irradiation in 608 (58%) cases. Among 590 transplantations from matched sibling donors, ATG was used in 95 (16%) patients. While, in the 8/8 HLA-matched unrelated setting 304/465 (65%) patients were treated with ATG. RESULTSIn a univariate analysis the use of ATG was associated with decreased incidence of the overall cGVHD (32% vs. 48%, p<0.001) and extensive cGVHD (14% vs. 22%, p=0.002) as well as a tendency to increased probability of survival free from grade III-IV acute GVHD, cGVHD and relapse (GRFS, 43% vs 36%, p=0.07). No significant difference could be demonstrated with regard to the incidence of grade II-IV acute GVHD (34% vs. 33%, p=0.59), grade III-IV acute GVHD (12.5% vs. 13%, p=0.68), relapse (25.5% vs. 27%, p=0.86) and non-relapse mortality (NRM, 19% vs. 18.5%, p=0.21), as well as probability of leukemia-free survival (LFS, 55% vs. 54.5%, p=0.95) and overall survival (OS, 68% vs. 67%, p=0.57). Among patients treated with ATG, original disease was the most frequent cause of death (40%) followed by infections (24%) and GvHD (21%). Respective proportions among those not treated with ATG were 36%, 23%, and 28%.In a multivariate model adjusted for other potential risk factors, the use of ATG was associated with reduced risk of the overall cGVHD (HR=0.53, p<0.001) and extensive cGVHD (HR=0.53, p<0.001) while increased risk of relapse (HR=1.34, p=0.03). No significant effect was found with regard to the risk of NRM (HR=0.78, p=0.15), a chance of LFS (HR=1.01, p=0.49) and OS (HR=0.87, p=0.27). CONCLUSIONSPatients with Ph-pos ALL treated with allo-PBSCT benefit from the use of ATG in terms of reduced risk of cGVHD without impact on survival. Increased risk of relapse, as shown in a multivariate model implicates the need for strict monitoring of minimal residual disease and either prophylactic or pre-emptive use of tyrosine kinase inhibitors after transplantation. Further studies are needed to explore potential role of the ATG brand and dose. DisclosuresMohty:Sanofi: Honoraria, Speakers Bureau.

Identifying Risk Factors for Acute and Chronic Graft-Versus-Host Disease in T-Replete HLA-Haploidentical Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide

Introduction: Acute(aGVHD) and chronic graft-versus-host disease (cGVHD) cause significant morbidity and mortality in patients post hematopoietic cell transplantation (HCT). The use of T-replete HLA-haploidentical transplantation (HIDT) with post-transplant cyclophosphamide has become a common donor source for patients lacking a suitably matched donor. In spite of the increase in HIDT, there is paucity of data describing aGVHD and cGVHD outcomes and potential risk factors for developing graft-versus-host disease after HIDT.Methods: The outcomes and the characteristics of 203 patients undergoing first allogeneic transplantation using HIDT with post-transplant cyclophosphamide between 2005 and 2016 were retrospectively assessed to identify the incidence and risk factors for aGVHD and cGVHD. Variables included in the analysis included patient related (age, sex, race, karnofsky, HCT-CI), disease related (diagnosis, disease type, disease risk index DRI, CIBMTR risk status) and transplant related (graft source as marrow vs peripheral blood, donor age, donor/recipient relationship, donor/recipient gender match, donor/recipient CMV match, conditioning intensity, high dose TBI in conditioning intensity, CD34 cell dose, CD3 cell dose and year of transplant). Univariate analysis with Gray's test and log-rank was carried for cumulative incidence and survival respectively. The proportional hazard cox model was used with backward elimination to select significant covariates. Multivariate analyses for developing GVHD, overall survival (OS), disease free survival (DFS), and relapse were conducted.Results: The median age was 51 years (range 19, 75) with a median follow up for survivors of 37 months. Seventy patients (34%) received bone marrow as graft source and 43% had Myeloablative conditioning. All patients received GVHD prophylaxis consisting of post-transplant cyclophosphamide on Days +3 and +4, MMF till day +35 and tacrolimus till day +180. The cumulative incidence for aGVHD grade II-IV and grade III-IV were 45% and 12% respectively. The common organs involved in aGVHD were skin (76% of cases, 39% stage 3 /4), gut (58% of cases, stage 3 /4 11%) and liver (7% of cases, stage 3 /4 of 1%). Subsequent aGVHD flare developed in 6 patients (5 with gut GVHD and 1 skin GVHD). The cumulative incidences of all grade cGVHD and moderate-severe cGVHD were 32% and 24% respectively (table 1). Conditioning intensity was the only risk factor associated with developing grade 2-4 aGVHD (p=0.04). Patients that received myeloablative regimens as compared to those who received a reduced intensity or non-myeloablative regimen had statistically higher rates of grade 2-4 aGVHD (hazard ratio [HR] of 1.52 (95% CI, 1.01-2.29, p=0.04). Risk factors for cGVHD showed that race and hematopoietic cell transplantation-comorbidity index (HCT-CI) had a statistically significant bearing on the likelihood of developing all-grade cGVHD (p=0.004 and 0.01 respectively). Graft source (marrow vs Peripheral blood) was a significant risk factor for developing moderate-severe cGVHD (p=0.03). Multivariate analysis on OS, DFS and relapse showed that Patients aged 55 or older (HR of 1.91, 95% CI 1.22-2.99, p =.005) and High/very high DRI risk (HR 2.06, CI 1.05-4.00, p=0.03) had worse overall survival rates. Older age, not developing chronic GVHD and receiving a transplant between 2005 and 2010 were all associated with a worse DFS (P<0.01 for all). High/very high DRI, male gender and not developing cGVHD were all significant factors for a higher relapse rate.Conclusions: This single center analysis of GVHD incidence and risk factors after HIDT using post-transplant cyclophosphamide showed that conditioning intensity, graft source and HCT-CI to be factors affecting incidence of GVHD. Higher disease risk and older patient age were associated with worse overall survival. [Display omitted] DisclosuresSolh:Amgen: Speakers Bureau; ADC Therapeutics: Research Funding; Celgene: Speakers Bureau.

RIC Allogeneic Stem Cell Transplantation for High Risk CLL Followed By Preemptive MRD-Based Immunointervention - Final Results from the Phase II ICLL03 Ricac-Pmm Trial (FILO - SFGM-TC French intergroup)

RIC Allogeneic Stem Cell Transplantation for High Risk CLL Followed By Preemptive MRD-Based Immunointervention - Final Results from the Phase II ICLL03 Ricac-Pmm Trial (FILO - SFGM-TC French intergroup)

Allogeneic Hematopoietic Stem-Cell Transplantation for GATA2 Deficiency Using a Busulfan-Based Regimen

Background: GATA2 deficiency is an increasingly recognized bone marrow failure syndrome responsible for: MonoMAC, monocytopenia with atypical mycobacterial infection (MAC); DCML, dendritic cell, monocyte and lymphoid cell deficiency; Emberger syndrome with lymphedema and monosomy 7; and familial myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML). GATA2 deficiency can be reversed by hematopoietic stem cell transplantation (HSCT). However, the intensity of conditioning required to ensure engraftment and reverse the myelodysplastic syndrome (MDS) characteristic of the disease remains controversial.Methods: We carried out a prospective study of allogeneic HSCT in 22 patients (mean age 26 years; range 17 to 45 years) with GATA2 deficiency, or the MonoMac syndrome, using a myeloablative, busulfan-based conditioning regimen. All 22 patients had MDS and two had AML. Eleven patients had clonal cytogenetic changes in the bone marrow. There were two matched related donor (MRD) recipients, 13 matched unrelated donor (URD) recipients, and 7 haploidentical related donor recipients. MRD and URD recipients received conditioning with 4 days of busulfan (days -6 to -3) to target an AUC between 3600 and 4800 min*microm/L and 4 days of fludarabine 40 mg/m2/day (days -6 to -3). Haploidentical related donor recipients received low-dose cyclophosphamide for two days (days -6 and -5), fludarabine 30 mg/m2/day for 5 days (days -6 to -2), 2-3 days of busulfan depending upon cytogenetics, along with 200 cGY total body irradiation (TBI) on day -1. MRD and URD recipients received tacrolimus and short course methotrexate for post-transplant graft-versus-host disease (GVHD) prophylaxis, whereas haploidentical recipients received high-dose post-transplant cyclophosphamide (PT/CY) followed by tacrolimus and mycophenolate mofetil for GVHD prophylaxis.Results: Nineteen of the 22 patients are alive with resolution of the clinical phenotype and correction of the bone marrow MDS with eradication of the cytogenetic changes at a median follow-up of 23 months (range, 6 to 48 months) giving an overall disease-free survival of 86 percent. The three deaths all occurred in the URD group. Of the three deaths, one resulted from refractory acute myelogenous leukemia (AML), and two from complications related to treatment for GVHD. There was a 26 percent incidence of grade III-IV acute GVHD (aGVHD) in the MRD and URD groups, and no grade III-IV aGVHD in the haploidentical related donor cohort. Similarly, there was a 46 percent incidence of chronic GVHD (cGVHD) in the MRD and URD cohort, whereas two of the 7 (28 percent) of the haploidentical related donor recipients had cGVHD.Conclusions: Despite overall disease-free survival of 86 percent with eradication of the clonal cytogenetic abnormalities in the bone marrow, GVHD remains a limitation in the MRD and URD cohorts treated with standard post-transplant tacrolimus/methotrexate prophylaxis for GVHD. We are currently de-escalating the busulfan dosing based on the AUC in all cohorts and incorporating PT/CY in the MRD and URD cohorts to decrease toxicity and reduce the incidence of aGVHD and cGVHD. Together with our previous studies using a nonmyeloablative regimen, it appears that when GATA2 deficiency patients are transplanted when they have a hypocellular bone marrow with MDS and without cytogenetic changes, a nonmyeloablative regimen results in reliable engraftment in GATA2 deficiency since the GATA2 deficient marrow has a proliferative disadvantage. However, with clonal progression and unfavorable cytogenetic changes and/or a hypercellular marrow, where the malignant clone has a proliferative advantage, a higher dose regimen results in more reliable engraftment and eradication of the clone. Studies to identify the precise level of conditioning for the stages of the disease are ongoing. DisclosuresNo relevant conflicts of interest to declare.

Safety and Efficacy of Extracorporeal Photopheresis for Acute and Chronic Graft-Versus-Host-Disease

IntroductionAcute and chronic graft-versus-host disease (GVHD) remain severe complications of allogeneic hematopoietic cell transplantation (alloHCT). Corticosteroids and conventional intensified immunosuppressive therapy for steroid-refractory GVHD increase morbidity, mortality and relapses without improving survival. Extracorporeal photopheresis (ECP) has been introduced as an alternative treatment in many centers. We studied the safety and efficacy of extracorporeal photopheresis (ECP) as second or third line treatment in acute and chronic GvHD.MethodsWe enrolled consecutive patients that received ECP post alloHCT from 2003 to 2016. All patients with unrelated or haploidentical donors received thymoglobulin (ATG) 5mg/kg as prophylaxis. GVHD prophylaxis included cyclosporine-methotrexate in myeloablative and cyclosporine-mycophenolate mofetil in reduced toxicity or intensity regimens. ECP was commenced after assessment of response to 7 days of steroid treatment in acute (aGVHD): 2 sessions/week for 1 month, 1 session/2 weeks for 3 months, evaluation of response and 1 session/month for 6 months. In chronic (cGVHD), ECP was mostly administered as third line treatment with a similar protocol that was less intensified in the 1st month (1 session/week).ResultsWe studied 21 patients with acute, 81 with chronic and 7 with induced GVHD post Donor Lymphocyte Infusion (DLI) for relapsed disease. Only 2 patients with acute, 5 with chronic and 1 with induced GVHD received 4 or less ECP sessions because of severe GVHD-related morbidity and were excluded from further analysis. There were no ECP-related adverse events.AGVHD was observed at day +18 (8-50) in 15 patients, late-onset at + 130 (110-160) in 4 patients. Skin, intestine and liver involvement was evident in 6 patients, skin and intestine in 9 and skin only in 4 patients. Seven patients were steroid-dependent and 12 steroid-refractory. ATG was administered simultaneously with ECP initiation in 8 refractory patients. The majority of patients presented partial (6), very good (9) or complete (1) response to ECP. Immunosuppression was reduced in 10/19 and ceased in 1. Clinically significant bacterial infections were found in 17 patients, fungal in 2 and viral in 15 patients. Cumulative incidence (CI) of cGVHD was 86.6 at 1-year. 1-year CI of aGVHD-related mortality was 17.6% and was associated with lack of response to ECP (p=0.026) and steroid-refractoriness (p<0.001). With a follow-up of 17.5 (1.8-58.3) months, 1-year overall survival (OS) was 52.5%. Improved OS was associated with response to ECP (0.032), number of ECP sessions (p=0.005), aGVHD grade (p=0.018) and reduction of immunosuppression (p=0.009). In the multivariate analysis, number of ECP sessions were independently associated with improved OS (p=0.037).Regarding cGVHD, 52 patients presented with cutaneous sclerosis manifestations, 53 mucocutaneous disease, 31 liver, 37 visceral and 12 lung involvement. The majority of them (59/82) received mycophenolate mofetil, cyclosporine or ATG as a second line treatment and ECP as third line. Bacterial infections were observed in 26 patients, viral in 24 and fungal in 8 patients. Eligible for evaluation of response were 72 patients. Only 12 patients did not show response. Significantly higher rates of response presented in patients with cutaneous sclerosis manifestation (p=0.031) and later post-transplant GVHD diagnosis (p=0.001). With a follow-up of 68.1 (5.4-283.1) months, 5-year CI of cGVHD-related mortality was 24.1% and was associated only with number of ECP sessions (p=0.002). 5-year OS was 64.5% and was associated with HLA matching (p=0.030), cutaneous lesions (p=0.041), higher number of ECP sessions (p<0.001), later initiation of ECP post-transplant (p=0.004) and no relapse (p=0.027). In the multivariate analysis, cutaneous lesions (p=0.013), number of ECP (p<0.001) and days of ECP initiation post-transplant (p=0.015) predicted OS.ConclusionOur data indicate that ECP is safe and effective for both acute and chronic GVHD. Steroid-dependence in aGVHD and cutaneous manifestations in cGVHD predict improved survival with low toxicity. Therefore, ECP should be considered early in the course of GVHD, before significant irreversible end organ damage has been established. Optimal timing of intervention, frequency, duration and tapering schedule of ECP remain important unanswered questions. DisclosuresGavriilaki:European Hematology Association: Research Funding.

Intermediate Post-HCT Exposure to Thymoglobulin Minimizes Mortality and High Exposure Minimizes the Composite of Death, Relapse or Chronic Graft-Versus-Host Disease

IntroductionGraft-versus-host disease (GVHD) remains a major problem after allogeneic-HCT as it is associated with high mortality, morbidity and poor quality of life. Rabbit anti-T cell globulin (ATG, Thymoglobulin) reduces GVHD without increasing relapse or mortality (Walker I: Lancet Oncol 2016). At multiple centers, including ours, ATG has become a standard component of conditioning. However, the efficacy of ATG is limited- at our center 40% patients still develop grade 2-4 aGVHD or moderate-severe cGVHD; 10% die of it and 25% survive with poor quality of life. We hypothesize that one of the reasons for the limited efficacy of ATG is suboptimal dosing (leading to low ATG levels in a fraction of recipients). Here we set out to determine the effect of pre- and post-HCT ATG exposure (area under the curve, AUC) on clinical outcomes and the factors influencing the AUCs in adult HCT recipients.MethodsA total of 141 patients receiving first allo-HCT in Calgary with a peripheral blood stem cell graft after conditioning with fludarabine (250 mg/m2), busulfan (~12.8 mg/kg) +/- TBI (4 Gy) and GVHD prophylaxis with rabbit ATG (0.5 mg/kg on day -2, 2 mg/kg on day -1 and 2 mg/kg on day 0 before graft infusion), methotrexate and cyclosporine were included. Serum was collected at the end of the last ATG infusion, immediately pre-graft infusion, 30 minutes after the end of graft infusion and days 7, 14 and 28.Serum levels of ATG capable of binding to lymphocytes were determined using a flow cytometric assay as previously described (Podgorny PJ: Biol Blood Marrow Transplant 2010). Pre-HCT ATG AUC was estimated from ATG levels at the end of the last ATG infusion and pre-graft infusion. Post-HCT ATG AUC was estimated from the ATG levels pre-graft infusion, 30 minutes post graft infusion and on days 7, 14 and 28. AUCs were split into terciles, quintiles and deciles for analysis.Multivariate Cox regression was used to determine if ATG AUC was associated with mortality due to any cause or a composite outcome of death, relapse or moderate-severe chronic GVHD (the inverse of chronic GVHD relapse free survival, cGRFS). Multivariate competing risks regression was used to determine whether ATG AUC was associated with the cumulative incidence of cause-specific outcomes.ResultsPre-/post-HCTAUC and Clinical OutcomesIntermediate post-HCT AUC appeared to be associated with lower mortality than low or high post-HCT AUC (Figure 1). This was significant when comparing the second tercile with the first tercile (HR=0.37, p=0.027) and the second with the third tercile (HR 0.38, p=0.032). However, high post-HCT AUC appeared associated with the lowest composite incidence of death, relapse or cGVHD (Figure 2). This was significant when comparing deciles 7-10 with deciles 1-6 (HR 0.60, p=0.047). The incidence of relapse was similar in all post-HCT AUC terciles/quintiles/deciles. As compared to deciles 1-6, deciles 7-10 were associated with a lower incidence of grade 2-4 aGVHD (HR 0.42, p=0.017) and moderate-severe cGVHD (HR 0.45, p=0.045), while GVHD-associated non-relapse mortality (NRM) (NRM preceded at any time by diagnosis of grade 2-4 aGVHD or moderate-severe cGVHD) trended towards a lower incidence (HR 0.28, p=0.097). Non-GVHD-associated NRM (NRM not preceded by diagnosis of grade 2-4 aGVHD or moderate-severe cGVHD) appeared to increase from the lowest to highest AUCs; however, there were too events for a meaningful statistical analysis.Pre-transplant AUC did not appear to influence any of the above outcomes.Factors influencing post-HCT AUCGiven that there appears to be an ideal (intermediate or high) post-HCT AUC and that low post-HCT AUC is deleterious, we next determined factors influencing the post-HCT AUC. The factors associated with (presumably influencing) the post-HCT AUC were body mass index (BMI) (Spearman correlation coefficient r = 0.24, p=0.005), day -2 (pre-ATG) blood lymphocyte count (r = -0.30, p<0.001) and possibly graft lymphocyte content (r = -0.14, p=0.081).ConclusionLow post-HCT ATG AUC is associated with the highest mortality and the highest composite of death, relapse or cGVHD. From the perspective of mortality, intermediate AUC may be ideal. In contrast, from the perspective of cGRFS, high AUC may be ideal. The post-HCT AUC appears influenced by BMI (when ATG is dosed per kg), pre-ATG blood lymphocyte count and graft lymphocyte content. We aim to develop a formula for ATG dosing that will avoid low post-HCT AUC. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Post-Transplantation Cyclophosphamide and Short-Term Methotrexate for Tolerance Induction in HLA-Haploidentical Transplantation for Severe Aplastic Anemia

Background. Haploidentical related donors (HIDs) are attractive donors for patients with severe aplastic anemia (SAA) because they are readily available for nearly all the patients. Bone marrow transplant (BMT) using post-transplant cyclophosphamide (PTCy) has been shown effective to cross the immune barriers between the recipients and their HIDs. Short-term low dose of methotrexate (ST-MTX) has long been adopted either alone or combined with calcineurin inhibitors to get across the immune barrier in hematopoietic stem cell transplant (HSCT).Aim of the study. We presented the outcome of 15 patients with SAA who underwent haploidentical transplant (HIT) using T-cell-replete peripheral graft and combination of PTCy with ST-MTX.Patients and grafts. We analyzed the medical records of 15 patients with SAA between Jan 2015 and July 2017. The transplants were either upfront (8/15) or rescue treatment (7/15). The median age of the patients was 16 (range 5-39) years and 66.7% (10/15) were male. All the patients received granulocyte colony-stimulating factor (G-CSF) mobilized peripheral graft from haploidentical related donors. The median mononuclear cells (MNCs) was 12.4 × 108 cells/kg recipient ideal body weight (IBW) with the range of (7.0-22.0) × 108 cells/kg, the CD34+ cell was 7.5 × 106 cells/kg with the range of (5-23) × 106 cells/kg and the CD3+ cells was 2.7 × 108 cells/kg with the range of (1.8-5.0) × 108 cells/kg.Conditioning regimen and GvHD prophylaxis. We used a TBI-free transplantation platform named FBC+PTCy/ST-MTX. Fludarabine was administered at 40 mg/m2 IV daily for 5 days. Busulfan was delivered in a total dose of 6.4mg/kg. Cyclophosphamide was given 14.5 mg/kg daily for 2 days. PTCy was administered at 60mg/kg/day IV on days +3 and +4 post-transplant. Low doses of MTX were delivered on days +1, +2 and +5 post-transplant at 15mg/m2, 10mg/m2 and 10mg/m2. Cyclosporine was given from day +6 through day +180 with the target through level 150~180ng/ml and then was tapered until 12 months post transplant. Mycophenolate mofetil (MMF) was given from day +6 to +35 days for the first 3 patients and then was eliminated for the following patients.Results.Neither primary nor secondary graft failure (GF) was seen in this study. Neutrophil engrafted at 15 days (range, 13-18 days). Platelets engrafted at 19 days (range, 14-36 days) and recovered over 100 × 109/L at 38 days (range, 14-77 days). The time to total lymphocytes recovery over 0.5 × 109/L for 3 consecutive days was 34 days (range, 25-72 days). The accumulated engraftment of neutrophil and platelets were both 100% at +40 days. (Figure 1-A, B.)The cumulative incidence of aGvHD at 100 days was 20.0%(3/15). Two patients had grade I skin aGvHD and the other one had grade II skin aGvHD. No grade III-IV aGvHD was seen. 12 patients were evaluable for the incidence of cGvHD and none of them developed moderate or sever cGvHD with a median of 150 (102-806) days post transplant. (Figure 1-C, D.) During the follow-up, one patients had skin cGvHD and received systemic therapy with corticoid. The treatment was discontinued after 8 months post transplant. All 3 patients, who survived beyond 12 months post transplant at the end of our follow-up, were off immunosuppress.With a median follow-up of 230 days (range 41-806 days), all the patients are alive. They are transfusion independent with karnofsky performance status scale (KPS) scores 100.Conclusion.This study shows that haploidentical related transplant can be successfully applied using T-cell-repleted peripheral grafts. ST-MTX may facilitate PTCy to achieve a stable engraftment with a minimal risk of GvHD in HIT for patients with SAA. Our approach should expand the donor pool for patients with SAA. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.