Abstract: Osteopetrosis (OP) is a genetic disease characterized by increased bone density due to osteoclast dysfunction, leading to life-threatening multi-systemic complications in early childhood. Haematopoietic stem cell transplantation (HSCT) is the only curative approach for most children with OP and can effectively prevent serious complications such as blindness, bone fractures, hydrocephalus and cranial nerve compression. Since timing of transplant is critical in OP, umbilical cord blood is an attractive stem cell source, due to its prompt availability. We analysed the outcomes of unrelated umbilical cord blood transplantation (UCBT) in 45 children with osteopetrosis transplanted in EBMT centers between 1996 and 2012, using data reported to Eurocord. Median age at UCBT was 6 months (1.1 month - 7.4 years). Donor-recipient pairs were matched at HLA-A and -B (antigen level) and DRB1 (allelic level) in 14 or HLA mismatched at 1 (n= 23) or 2 (n= 7) loci. Information on conditioning regimen was available for 42 patients; it was myeloablative (mostly busulfan-based) in 40 children and reduced intensity in 2 patients. GvHD prophylaxis consisted mainly of cyclosporine combined with either prednisolone (n= 20), or methotrexate (n=6), or mycophenolate mofetil (n=3). Anti thymocyte globulin (ATG) or alemtuzumab was given to 37/40 patients. Median number of infused total nucleated cell (TNC) and CD34+ was 13x107/kg and 3.4x105/kg, respectively. Median follow-up for survivors was 44 (range 4-144) months. Neutrophil recovery with donor chimerism was documented in 27/45 patients; 19/25 evaluable patients presented full donor engraftment, while 6 children presented mixed donor chimerism. Median time to neutrophil recovery was 20 (range 10-60) days. Eighteen patients experienced graft failure and 3/18 are alive at last follow up. Information on treatment post-graft failure was available 7/18 children: 6 patients underwent a second HSCT and 3 of them survived. Stem cell dose was associated with a trend for a better probability of donor engraftment: the cumulative incidence of donor engraftment was 46% in patients who received a CD34+ cell dose 〈 2 x 105/kg, versus 71% in children receiving a CD34+ cell dose ≥2x105/kg (p = 0.09). Eleven patients developed grade II-IV acute graft-versus-host disease (aGvHD: n=6 grade II, n=4 grade III, n=1 grade IV) and 5 patients chronic GVHD (cGvHD: n=3 limited, n=2 extensive). Overall survival (OS) at 3 years was 45+8%. Twenty-four patients died after UCBT due to: infections (n=13), acute respiratory distress syndrome (n=2), veno occlusive disease (VOD), (n=2) hemorrhage (n=2), or other causes (n=5). VOD was observed in 7/26 evaluable patients. Stem cell dose and HLA disparity were the only predictors of superior outcome in univariate analysis. The 3-year probability of OS was 50% in patients who received grafts with a CD34+ cell dose 〉 2x105/kg versus 0% in children receiving grafts with a CD34+ cell dose 〈 2x105/kg (p=0.001). According to HLA disparities, 3-year probability OS was 54% versus 58% versus 0% in patients receiving a 6/6, 5/6 and 4/6 HLA-mismatched graft, respectively (p=0.01). Interestingly, 4/4 children receiving a treosulfan-based myeloablative regimen achieved donor engraftment and 3 children are alive at last follow up. These data suggest that transplantation of unrelated UCB is a valid alternative for children with OP without a matched sibling or a suitable matched unrelated adult donor. The use of CB units mismatched at 〉 1 HLA locus should be avoided due to worse survival. The incidence of primary graft failure was high and therefore the optimization of the conditioning regimen and/or the use of CB units containing a high TNC and CD34+ cell dose must be considered in this setting. The use of treosulfan-based conditioning regimens is worth further investigation, as well as the use of defibrotide prophylaxis to reduce the risk of VOD in this population of high risk patients. Disclosures: No relevant conflicts of interest to declare.

Abstract: The current results suggest that, at least for secondary acute promyelocytic leukemia (APL), evolving strategies in the treatment of cancers have modified the primary tumors and the drugs involved in leukemogenesis, but without reducing their incidence. These findings also confirm prospectively that patients with secondary APL have characteristics and outcomes similar to those of patients with de novo APL.

Abstract: Rationale and Aim: In patients with Myeloma, early relapse following Autologous Haematopoietic Cell Transplantation (Auto-HCT) is a poor prognostic marker. Two groups have published scoring systems to predict early relapse. The CIBMTR score is based on cytogenetics, the bone marrow plasma cell percentage at the time of Auto-HCT and serum albumin. The GIMEMA Simplified early relapse in multiple myeloma (S-ERMM) score is a cumulative score based on a raised serum lactate dehydrogenase (LDH), t(4;14), del17p, low albumin, bone marrow plasma percentage & gt;60%, and lambda light chain. The aim of the current study was to develop a scoring system to predict early relapse post-Auto-HSCT-1 using readily available variables. Study design and statistics: Within the EBMT database, there were 8,206 patients meeting the following eligibility criteria: First auto transplant 2014-2019, Known sex, ISS at diagnosis, cytogenetics analysis at diagnosis, disease status at Auto-HCT, Interval diagnosis-Auto-HCT & gt; 1 month and & lt;= 12 months, conditioning with Melphalan 200 mg/m2 and known information on relapse; tandem auto-allo patients were excluded. The analysis consisted of two steps: (1) Training: modeling based on 4,389 patients (611 events for PFS12) transplanted between 2014 and 2017, with internal validation carried out by bootstrapping; and (2) Testing: the models obtained were applied to 3,817 patients (346 events for PFS12) transplanted in 2018 and 2019 for external validation. The characteristics of the two cohorts are first reported separately and then together (Table 1). Possible adjustment factors analyzed for the prognostic model included Age at Auto-HCT, Known sex, ISS at diagnosis, disease status at Auto-HCT, and time from diagnosis to Auto-HCT. Complete cytogenetic information was not available at the time of this analysis and will be included in the later analysis. The shape of the effect of age and of time from diagnosis to Auto-HCT was investigated both by the analysis of residuals and by applying boot-strap backward selection among different alternatives. The final results were confirmed in a robustness analysis excluding patients undergoing tandem Auto-HCT. Results: Comparison of the training and validation cohorts revealed no relevant differences (Table 1). Importantly, OS and PFS of both cohorts were overlapping with the probability of PFS at 12 months being 83.3% and 86.8%, respectively. The cumulative incidence of relapse at 12 month was 15.7% and 12.1%, respectively. Among patients who relapsed early, this occurred at a median of 6.64 months (0.56-11.99) in the first cohort, and at 5.85 months (0.1- 11.99) in the second cohort. The final model included (1) disease status at Auto-HCT, (2) age at Auto-HCT, and (3) ISS at diagnosis. Considering the order of magnitude of the coefficients, the points attributed in the risk score were: 0 for CR or VGPR; 1 for PR or SD/MR; 3 for Rel/Prog; 0 / 1/ 2 respectively for ISS I / II / III and -1 for Age & lt;=55 yrs; -2 for Age (55-75 yrs]; -3 for Age & gt;=75 yrs. The Hazard Ratio for a +1 point is 1.52 i.e. the risk of early relapse/death increased on average by 52% for each additional point in the score. The distribution of risk scores was as follows: Score= -2 (n=757), -1 (n=1,481), 0 (n=1,358), 1 (n=647), and 2 (n=146). The score allows separation of the PFS12 curves (Figure 1), with the lowest risk group (N=757) having a PFS at 12 months of 91%, and the highest risk group (N=146) having a PFS at 12 months of 65%. Despite some minor differences in the risk factors between the training and validation cohorts, the score has a similar average effect (HR=1.48 i.e. + 48% hazard for each additional point) and worked well in separating the curves, in particular in identifying the patients at high risk of early relapse. Discussion and conclusion: The new EBMT score to predict early relapse post-Auto-HCT uses the easily available variables of age and ISS stage at diagnosis as well as the dynamic variable of response to induction. With this simple approach, we were able to clearly identify patients at high risk of early relapse. To our surprise, older age emerged as a protective factor against relapse. This may reflect a relative selection bias in that older patients with higher risk disease may not have been selected for transplant. Impact of cytogenetics will be presented at the Congress. In conclusion, this novel scoring system is robust and easy to use in routine daily practice. Figure 1 Figure 1. Disclosures Beksac: Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Oncopeptides: Consultancy. Blaise: Jazz Pharmaceuticals: Honoraria. Leleu: Karyopharm Therapeutics: Honoraria; AbbVie: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; Merck: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria; Carsgen Therapeutics Ltd: Honoraria; Oncopeptides: Honoraria; Janssen-Cilag: Honoraria; Gilead Sciences: Honoraria; Celgene: Honoraria; Pierre Fabre: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Other: Non-financial support. Forcade: Novartis: Consultancy, Other: Travel Support, Speakers Bureau; Gilead: Other: Travel Support, Speakers Bureau; Jazz: Other: Travel Support, Speakers Bureau; MSD: Other: Travel Support. Rabin: Janssen: Consultancy, Honoraria, Other: Travel support for meetings; BMS / Celgene: Consultancy, Honoraria, Other: Travel support for meetings; Takeda: Consultancy, Honoraria, Other: Travel support for meetings. Kobbe: Celgene: Research Funding. Sossa: Amgen: Research Funding. Hayden: Jansen, Takeda: Other: Travel, Accomodation, Expenses; Amgen: Honoraria. Schoenland: Pfizer: Honoraria; sanofi: Research Funding; janssen,Prothena,Takeda,: Consultancy, Honoraria. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria.

Abstract: Introduction Current consensus identifies translocations t(4;14), t(14;16), t(14;20), and del(17/17p) as high-risk cytogenetics in newly diagnosed multiple myeloma (NDMM). However, evidence on outcome of specific abnormalities according to types of transplant as first-line treatment is limited. We analyzed NDMM patients with del(17) and/or t(4;14) reported to the European Society for Blood and Marrow Transplantation (EBMT) registry undergoing either upfront single autologous (auto), tandem autologous (auto-auto) or tandem autologous/reduced-intensity allogeneic (auto-allo) stem cell transplantation. Methods Upfront transplantation was defined as first autologous transplant within 12 months from MM diagnosis and tandem transplant was defined as a second transplant (autologous or allogeneic) within 6 months from first transplant. Survival and cumulative incidence were calculated from date of first transplant (95% confidence interval) and analyses were performed using a landmark approach of patients who were alive and relapse-free by month 6. End points were progression-free survival (PFS), overall survival (OS), relapse and non-relapse mortality (NRM). Results Patients. Within the EBMT registry, 498 NDMM patients with del(17) (n=224), t(4;14) (n=229) or both (n=45) could be analyzed between 2000-2015. First-line auto was received by 337, auto-auto by 99 and auto-allo by 62 patients. Frequencies of del(17)/t(4;14)/or both were 39/51/10% in auto, 58/36/6% in auto-auto, and 55/35/10% in auto-allo (p=0.01). Median age was 60 years in auto and auto-auto, and 52 years in auto-allo (p 〈 0.001) and more than half of patients were male (53% in auto, 63% in auto-auto, 52% in auto-allo). Median time from diagnosis to transplant was 5 months in all groups. 85% received at least 200mg/m2 melphalan conditioning for first autologous transplant. Most patients had IgG subtype (51% in auto, 60% in auto-auto, 58% in auto-allo). Disease stage according to ISS I/II/III was 23/55/22% in auto, 18/69/13% in auto-auto, and 14/63/23% in auto-allo. More patients receiving auto were in complete remission (CR) at time of first transplant (21%) compared with auto-auto (11%) and auto-allo (7%; p=0.01). Posttransplant outcome and cytogenetics. The median follow-up of all patients was 57 months (55 months for auto, 57 months for auto-auto, and 64 months for auto-allo). 5-year PFS according to transplant was 18% (12-23) for auto, 32% (22-43) for auto-auto, and 32% (19-45) for auto-allo (p=0.11) and 5-year OS was 47% (41-54) for auto, 51% (40-63) for auto-auto, and 65% (51-78) for auto-allo (p=0.28). Relapse incidence was 82% (77-87) for auto, 63% (53-74) for auto-auto, and 58% (44-72) for auto-allo (p=0.002) while NRM was 1%, 4%, and 10%. PFS and OS according to cytogenetics was 24% and 58% for del(17), 22% and 42% for t(4;14), and 19% and 55% for presence of both. When stratified according to cytogenetics and transplant, PFS in del(17) was 21% (12-29) for auto, 26% (13-39) for auto-auto, and 30% (13-47) for auto-allo (p=0.78) while OS was 56% (45-67) for auto, 56% (41-70) for auto-auto, and 67% (50-84) for auto-allo (p=0.74). Relapse incidence and NRM were 79% and 1% for auto, 70% and 4% for auto-auto, and 64% and 6% for auto-allo. Single autologous transplant showed significantly worse PFS in t(4;14) resulting in 15% (8-22) compared with 45% (26-63) for auto-auto, and 39% (16-61) for auto-allo (p=0.05). OS was 39% (30-48) for auto, 37% (13-60) for auto-auto, and 63% (38-88) for auto-allo. Relapse incidence was also significantly higher in auto showing 84% (77-91) in comparison with 49% (30-67) for auto-auto and 52% (29-75) for auto-allo (p=0.004). Multivariable analysis. A Cox regression was fitted to compare types of transplant after adjusting for cytogenetics, sex, age, ISS, and remission status. Subsequently, auto-auto (hazard ratio, 0.66) and auto-allo (hazard ratio, 0.58) were associated with better PFS while auto-allo appeared to result in better OS (hazard ratio, 0.71) in comparison with single autologous transplant. Both auto-auto and auto-allo were significantly associated with lower incidence of relapse after fitting a Fine and Gray model (p 〈 0.001, respectively). Conclusion In NDMM patients undergoing upfront transplantation, PFS and relapse incidence were improved in patients specifically with del(17) and t(4;14) receiving tandem autologous or autologous/reduced-intensity allogeneic transplant. Disclosures Leleu: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Kobbe:Amgen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Celgene: Honoraria, Other: Travel Support, Research Funding. Rambaldi:Novartis: Consultancy; Italfarmaco: Consultancy; Celgene: Consultancy; Roche: Consultancy; Pfizer: Consultancy; Omeros: Consultancy; Amgen Inc.: Consultancy. Garderet:Amgen: Consultancy; Takeda: Consultancy; Celgene: Consultancy. Kroeger:Novartis: Honoraria, Research Funding; Sanofi: Honoraria; Riemser: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Neovii: Honoraria, Research Funding; JAZZ: Honoraria.

Abstract: To compare a reduced-intensity conditioning regimen (RIC) with a myeloablative conditioning regimen (MAC) before allogeneic transplantation in patients with myelodysplastic syndrome (MDS) within a randomized trial. Patients and Methods Within the European Society of Blood and Marrow Transplantation, we conducted a prospective, multicenter, open-label, randomized phase III trial that compared a busulfan-based RIC with MAC in patients with MDS or secondary acute myeloid leukemia. A total of 129 patients were enrolled from 18 centers. Patients were randomly assigned in a 1:1 ratio and were stratified according to donor, age, and blast count. Results Engraftment was comparable between both groups. The CI of acute graft-versus-host disease II to IV was 32.3% after RIC and 37.5% after MAC ( P = .35). The CI of chronic graft-versus-host disease was 61.6% after RIC and 64.7% after MAC ( P = .76). The CI of nonrelapse mortality after 1 year was 17% (95% CI, 8% to 26%) after RIC and 25% (95% CI, 15% to 36%) after MAC ( P = .29). The CI of relapse at 2 years was 17% (95% CI, 8% to 26%) after RIC and 15% (95% CI, 6% to 24%) after MAC ( P = .6), which resulted in a 2-year relapse-free survival and overall survival of 62% (95% CI, 50% to 74%) and 76% (95% CI, 66% to 87%), respectively, after RIC, and 58% (95% CI, 46% to 71%) and 63% (95% CI, 51% to 75%), respectively, after MAC ( P = .58 and P = .08, respectively). Conclusion This prospective, randomized trial of the European Society of Blood and Marrow Transplantation provides evidence that RIC resulted in at least a 2-year relapse-free survival and overall survival similar to MAC in patients with MDS or secondary acute myeloid leukemia.