Patients Achieved Platelet Engraftment Research Articles

Clinical outcomes of allogeneic hematopoietic stem cell transplantation from matched sibling donor for myelofibrosis

Objective: To evaluate the efficacy and safety of matched sibling donor allogeneic hematopoietic stem cell transplantation (allo-HSCT) for the treatment of myelofibrosis (MF). Methods: In this case series, the clinical data of 18 patients with MF who received allo-HSCT in the Department of Hematology, Peking University People's Hospital from December 2008 to December 2023 were retrospectively studied. Kaplan-Meier survival analysis and competitive risk model were used to evaluate the probabilities of 3-year overall survival (OS), disease-free survival (DFS), cumulative incidence of relapse (CIR), and transplant related mortality (TRM). The transplant related complications were also analyzed. Results: Among the 18 patients included, there were 12 males and 6 females, with a median age of 50 (range: 28-64) years. All 18 patients achieved neutrophil engraftment, and the time of neutrophil engraftment [M (Q1, Q3)] was 16.0 (11.8, 18.0) days. Twelve patients achieved platelet engraftment, and the platelet engraftment time was 21.0 (16.2, 43.2) days. Six patients had grade Ⅱ to Ⅳ acute graft-versus-host disease (GVHD), and six patients had chronic GVHD. The 3-year OS rate and DFS rate after transplantation were 62.2% and 52.2%, respectively. The 3-year CIR and TRM were 29.7% and 24.6%, respectively. Four patients died during follow-up, with the main cause of death being infections. Conclusion: Matched sibling allo-HSCT is a feasible option for the treatment of MF.

A Modified Busulfan/Cyclophosphamide Preconditioning Regimen Incorporating Selinexor for Allogeneic Hematopoietic Stem Cell Transplantation in Relapsed/Refractory Hematologic Malignancies

Objective: To investigate the safety and efficacy of a modified busulfan (Bu)/cyclophosphamide (Cy) conditioning regimen incorporating Selinexor for allogeneic hematopoietic stem cell transplantation in relapsed/refractory hematologic malignancies. Methods: We retrospectively evaluated the clinical outcomes of patients with hematologic malignancies who had received allo-HSCT with conditioning incorporating Selinexor at the Institute of Hematology and Blood Disease Hospital. Results: Between September 2022 and June 2023, 13 adult patients with high-risk hematologic malignancies were enrolled including 6 males and 7 females with a median age of 49 (13-58) years. There were 7 patients with acute myeloid leukemia (AML), 4 with myelodysplastic syndromes (MDS)/AML, 1 with multiple myeloma (MM) and 1 with extramedullary plasmacytoma. Six patients were in complete remission (CR), four in CR1, two in ≥CR2, five in non-remission (NR), and two patients were in a progressive disease status (PD) prior to conditioning. Three patients received matched-sibling donors transplant, while ten received related haploid hematopoietic stem cell transplantation. All patients had received myeloablative conditioning regimen incorporating Selinexor. Eleven patients received the conditioning: Bu (3.2mg/kg/d*2d); Melphalan (Mel, 60mg/m 2/d*2d), Fludarabine(Flu 30mg/m 2/d*3d) or CLA (5mg/m 2/d*3d), Cy (40mg/kg/d*2d), Selinexor 60mg/d*2d. The other 2 patients received the conditioning: Decitabine (DAC, 20mg/m 2/d*5d), Bu (3.2mg/kg/d*3d), Cy (40mg/kg/d *2d), Flu 30mg/m2/d*3d, Selinexor 60mg/d*2d. The median amount of infused mononuclear cell and CD34 + stem cell were 11.72×10 8/kg(range, 9.66 to 14) and 2.92×10 6/kg(range, 2.35 to 9.61), respectively. All the 13 patients achieved neutrophil engraftment with a median time of 12 (range, 9 to 18) days and 9 patients achieved platelet engraftment with a median time of 13 (range, 11 to 30) days. Four patients were still experiencing prolonged isolated thrombocytopenia. All patients achieved complete donor chimerism and minimal residual disease (MRD) negative at 30 days post-transplantation.The cumulative incidence of cytomegalovirus (CMV) reactivation was 15.4%, while Epstein-Barr virus (EBV) reactivation was not observed. Six patients (46.2%) experienced mucosal barrier injury, comprising three cases of oral mucosal ulcer, one case of digestive tract hemorrhage, and two cases of hemorrhagic cystitis. The cumulative incidence of II-IV and III-IV acute GVHD was 23.1% and 15.4%. The median follow-up for all the participants was 93 (40-316) days after transplantation. Only one patient was dead due to Thrombotic Microangiopathy (TMA) 78 days after transplant. One patient experienced molecular relapse 156 days after transplant, and another patient experienced hematology relapse 20 days after transplant. The two relapsed patients had received donor lymphocyte infusions after chemotherapy. The other 10 patients were still in CR with complete donor chimerism and MRD negative. The cumulative transplant-related mortality (TRM) and relapse rates are 7.7% (1 case) and 15.4% (2 cases), respectively. Conclusions: Incorporating Selinexor into the modified BU/CY conditioning regimen for allogeneic HSCT in patients with relapsed/refractory hematologic malignancies demonstrated a favorable safety profile. Ongoing prospective trials will provide valuable insights into the potential benefits of Selinexor in patients undergoing HSCT.

Haematopoietic Progenitor Cell Mobilisation Following Blinatumomab Therapy

Background: Our institution routinely performs autologous back-up haematopoietic progenitor cell (HPC) harvest prior to unrelated donor transplantation, particularly in the post-pandemic era, or in other circumstances if there is risk of graft failure. This practice is influenced by our relative geographical isolation and significant challenges in obtaining emergency allogeneic products. As the treatment landscape for paediatric acute lymphoblastic leukaemia (ALL) has expanded to incorporate immunotherapy, many patients proceeding to transplant receive the bispecific T-cell engager blinatumomab. Little is known about HPC mobilisation outcomes in patients following blinatumomab therapy. Here we report our experience with HPC mobilisation for autologous back-up harvest in paediatric patients with ALL treated with blinatumomab. Methods: We reviewed HPC mobilisation attempts in patients with ALL at The Children's Hospital at Westmead, Sydney, Australia from 1 January 2012 to 30 June 2022. Patients were analysed in two groups: those mobilised following blinatumomab and those mobilised following chemotherapy or from steady state. Patients were mobilised according to our institutional practice. Following chemotherapy or blinatumomab, granulocyte-colony stimulating factor (G-CSF) was given subcutaneously at a dose of 5 µg/kg/day after chemotherapy, or 10 µg/kg/day after blinatumomab or from steady state haematopoiesis. Records were assessed retrospectively for demographics, mobilisation strategy, G-CSF days, apheresis days, final HPC yield in CD34+ cells/kg, transplant characteristics, and outcomes. Successful mobilisation was defined as proceeding to apheresis and successful harvest at the patient level by achieving an HPC yield of at least 2 x 106 CD34+ cells/kg. Results: Over the 10.5 year (y) study period, 30 patients with ALL underwent 34 HPC mobilisation attempts for the purpose of autologous back-up HPC harvest prior to allogeneic transplant; 7 (23%) after blinatumomab and 23 (77%) after chemotherapy. Mobilisation and apheresis characteristics of the two groups are summarised in Table 1. There were no differences in age, weight, gender, disease status or prior exposure to radiotherapy between the blinatumomab and chemotherapy groups. Successful mobilisation was less likely in the blinatumomab group with 5/8 (63%) proceeding to apheresis vs 24/26 (92%) in the chemotherapy group, P=.037. In 29 successful mobilisations, the blinatumomab group had a lower median number of days of G-CSF (6 (range 5-7) vs 11 (3-24), P=.006), and greater utilisation of plerixafor (2/5 (40%) vs 0/24 (0%), P=.001). On day 1 of apheresis, the blinatumomab group had a lower median CD34+ count x 106/L (27 (20-32) vs 57 (13-636), P=.021) and a higher median white cell count x 109/L (37.4 (24.5-79) vs 15.6 (1.3-63.5), P=.015). Although the median total HPC yield of CD34+ cells x 106/kg was significantly lower in the blinatumomab group (2.2 (2-4.7) vs 5.6 (1.4-35.2), P=.033), there was no difference in the proportion of patients achieving the collection target of 2 x 106 CD34+ cells/kg (5/5 (100%) vs 21/23 (91%), P=.494). With a median follow up of 1.6y for the blinatumomab group and 7y for the chemotherapy group, there was no difference in 2y relapse-free (83% vs 57%, P=.310) or overall (83% vs 67%, P=.5903) survival between the groups. Of 28 patients who proceeded to transplant, 3 (11%) required autologous HPC reinfusion for secondary graft failure, 2/3 after 9/10 matched unrelated donor transplants without serotherapy, and all from the chemotherapy group. Neutrophil engraftment for these 3 patients occurred at a median of 13 days (range 11 - 14). One patient died 35 days after salvage reinfusion without achieving platelet engraftment. The 2 surviving patients achieved platelet engraftment at 18 and 29 days post reinfusion and remain alive in continuous complete remission more than 3y following HPC re-infusion. Conclusions: HPC mobilisation for autologous back-up harvest is feasible for ALL patients following blinatumomab. However, these patients are at risk of failed mobilisation and may benefit from pre-emptive strategies such as the use of plerixafor to optimise mobilisation success. Our relatively high rate of salvage reinfusion of autologous HPCs in ALL patients underlines the utility of universal back-up harvests for patients undergoing unrelated donor transplant. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A risk score system for stratifying the risk of relapse in B cell acute lymphocytic leukemia patients after allogenic stem cell transplantation.

BackgroundFor patients with B cell acute lymphocytic leukemia (B-ALL) who underwent allogeneic stem cell transplantation (allo-SCT), many variables have been demonstrated to be associated with leukemia relapse. In this study, we attempted to establish a risk score system to predict transplant outcomes more precisely in patients with B-ALL after allo-SCT.MethodsA total of 477 patients with B-ALL who underwent allo-SCT at Peking University People's Hospital from December 2010 to December 2015 were enrolled in this retrospective study. We aimed to evaluate the factors associated with transplant outcomes after allo-SCT, and establish a risk score to identify patients with different probabilities of relapse. The univariate and multivariate analyses were performed with the Cox proportional hazards model with time-dependent variables.ResultsAll patients achieved neutrophil engraftment, and 95.4% of patients achieved platelet engraftment. The 5-year cumulative incidence of relapse (CIR), overall survival (OS), leukemia-free survival (LFS), and non-relapse mortality were 20.7%, 70.4%, 65.6%, and 13.9%, respectively. Multivariate analysis showed that patients with positive post-transplantation minimal residual disease (MRD), transplanted beyond the first complete remission (≥CR2), and without chronic graft-versus-host disease (cGVHD) had higher CIR (P < 0.001, P = 0.004, and P < 0.001, respectively) and worse LFS (P < 0.001, P = 0.017, and P < 0.001, respectively), and OS (P < 0.001, P = 0.009, and P < 0.001, respectively) than patients without MRD after transplantation, transplanted in CR1, and with cGVHD. A risk score for predicting relapse was formulated with the three above variables. The 5-year relapse rates were 6.3%, 16.6%, 55.9%, and 81.8% for patients with scores of 0, 1, 2, and 3 (P < 0.001), respectively, while the 5-year LFS and OS values decreased with increasing risk score.ConclusionThis new risk score system might stratify patients with different risks of relapse, which could guide treatment.

Phase I Dose-Finding, Safety, and Tolerability Trial of Romiplostim to Improve Platelet Recovery After UCB Transplantation

Platelet recovery is delayed after umbilical cord blood transplant (UCBT). Romiplostim is a thrombopoietin receptor agonist that has the potential to improve platelet engraftment after UCBT. The purpose of this study was to determine the safety profile and maximum tolerated dose (MTD) of romiplostim and to investigate whether romiplostim accelerates platelet recovery post-UCBT. It was a single-center, dose-finding, safety and tolerability phase I trial of weekly romiplostim in 20 adult patients who failed to achieve an un-transfused platelet count of 20×109/L by day +28 post-UCBT. Romiplostim was administered at the assigned dose as 6 weekly injections beginning by day +42 post-UCBT. Four dose levels (4, 6, 8, and 10 µg/kg per dose) were evaluated. The MTD of romiplostim was determined by the continual reassessment method, with a goal to identify a dose level with desired toxicity rate of ≤20%. Median age of the patients was 59.5 years, and 60% were female. Eleven patients received nonmyeloablative (NMA) double UCBT, seven patients received myeloablative single UCBT, and two patients received NMA single UCBT. Two patients received 4 µg/kg per dose, two received 6 µg/kg per dose, four received 8 µg/kg per dose, and the remaining 12 received 10 µg/kg per dose. Only five patients completed the full six doses of treatment. Of the 15 patients who received fewer than six doses, 12 were due to a platelet count of >100×109/L, two were due to platelet count of >400×109/L, and one was due to right upper extremity edema without thrombosis. All romiplostim-treated patients achieved platelet engraftment to 20×109/L at a median of 45 days post-UCBT compared to 90% of controls at a median of 45 days (P=.08). Similarly, 90% of romiplostim-treated patients achieved platelet engraftment to 50×109/L at a median of 48 days compared to 75% of controls at a median of 52 days (P=.09). All dose levels were effective with low toxicity; therefore, the MTD of romiplostim was 10 µg/kg per dose, and romiplostim is a safe and potentially effective therapy to counter delayed platelet recovery post-UCBT.

Romiplostim Improves Platelet Recovery after UCB Transplant

Background Prolonged thrombocytopenia after hematopoietic stem cell transplant is a common complication, especially after umbilical cord blood transplant (UCBT). Romiplostim is a thrombopoietin receptor agonist that is FDA approved for chronic ITP. Its effect on platelet recovery after UCBT remains unknown. Objectives The primary objective of the study was to determine the maximum tolerated dose (MTD) of romiplostim in patients who failed to achieve platelet recovery by day +28 after UCBT. Secondary objectives were to determine if romiplostim influences the speed of platelet recovery, decreases the risk of thrombocytopenia related complications or affects the incidence of bone marrow fibrosis or relapse. Methods This was a single center dose escalation trial of weekly romiplostim in patients >18 years who failed to achieve an untransfused platelet count (PLT) of 20 × 109/L by day +28 after myeloablative (MA) or non-myeloablative (NMA) UCBT. A total of 20 patients were enrolled. Romiplostim was administered at the assigned dose as 6 weekly injections beginning by day +42 post UCBT with an end date by day +100. Four dose levels (4, 6, 8, and 10 mcg/kg/dose) were evaluated. There was no intra-patient dose escalation. The MTD of romiplostim was determined by the Continual Reassessment Method, with a goal to identify a dose level with desired toxicity rate of ≤ 20%. Historical controls were selected from our database based on age, gender, underlying disease, and transplant type (1:1 matching). Results Median age of the patients was 59.5 years and 40% were male. Ten patients had AML, 5 ALL, 3 MDS, 1 NHL and 1 MM. Two patients received 4, two 6, four 8 and the remaining 12 received 10 mcg/kg/dose. Only 5 patients completed the full 6 doses. Of the 15 patients who received less than 6 doses, 12 were due to a PLT>100, 2 due to PLT>400 (× 109/L), and 1 was due to the subject developed right upper extremity edema (no thrombosis). All romiplostim treated patients achieved platelet engraftment to 20 × 10^9/L at a median of 45 days post UCBT compared to 85% of controls at a median of 49 days (p=0.07). Similarly, 90% of romiplostim treated patients achieved platelet engraftment to 50 × 10^9/L at a median of 48 days compared to 70% of controls at a median of 52 days (p=0.04) (fig 1). Three patients experienced serious AEs requiring discontinuation of the drug: 2 had a PLT>400 × 109 /L and 1 developed right upper extremity edema. Bleeding episodes or transfusions improved with the use of the drug. All dose levels appear to be effective with low toxicity. Therefore, the MTD of romiplostim was 10mcg/kg/dose. There were no BM findings suggestive of increased fibrosis or relapse by day +100. Conclusion Our results indicate that romiplostim is safe and potentially effective therapy to improve platelet recovery after UCBT, with the MTD being 10mcg/kg/dose. Further studies in larger numbers of patients are needed to confirm these observations.

Allogeneic CD34-Selected HSCT Following CAR T-Cells Is Associated with Low TRM and Favorable OS in Pediatric/Young Adult Patients with Relapsed/Refractory B-ALL

Background: Chimeric antigen receptor (CAR) T-cells have transformed the therapeutic options for patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). The tolerability and outcome of allo-HSCT following CAR T-cell therapy is yet to be defined. Methods: We retrospectively reviewed pediatric and young adult patients with R/R B-ALL who received allo-HSCT following CAR T-cells. Outcomes of interest were overall survival (OS), cumulative incidence of relapse, and transplant-related mortality (TRM). These were estimated using log-rank analysis. Variables of interest were disease status at time of allo-HSCT, time from CAR T-cell therapy to start of allo-HSCT, conditioning regimen, graft source and manipulation, GVHD prophylaxis, donor HLA matching, neutrophil/platelet engraftment, relapse and cause of death. Results: Sixteen patients, with a median age of 13 (range 1-20), at time of allo-HSCT were included. All patients achieved MRD-negative complete remission (CR) following CAR T-cells and proceeded to allo-HSCT as definitive therapy. CR status included CR1 (n=6), CR2 (n=5), CR3 (n=4), and CR4 (n=1). The median time from CAR T-cells to the start of allo-HSCT conditioning was 46.5 days (range 20 -126). Conditioning was TBI-based (n=13) or chemotherapy only (n=3). Graft source included PBSC (n=8) or BM (n=8). Graft manipulation included CD34-selected T-cell depleted (TCD) (Miltenyi) (n=9) or an un-modified HSCT (n=7). Donors were HLA-matched related (n=8), HLA-matched unrelated (n=3), or HLA-mismatched unrelated (n=5). GVHD prophylaxis in the non-manipulated grafts included a calcineurin inhibitor (CNI) plus MTX (n=5), CNI plus MMF (n=1) or post-transplant cyclophosphamide (n=1). Available data included: 15/15 patients achieved neutrophil engraftment (median 12 days; range 9-29) and 13/15 patients achieved platelet engraftment (median 30 days; range 16-265). The 12-month cumulative incidence of relapse was 0% in patients receiving CD34-selected transplant, versus 25% [95% CI: 0 to 67%] in patients receiving un-modified transplant (log-rank p=0.80) and the 24-month cumulative incidence of relapse for the whole cohort was 25% [0-47%]. Late relapse (&gt;12 months from allo-HSCT) occurred in three (n=3) patients in the CD34-selected TCD cohort with a median time to relapse from allo-HSCT of 24.2 months (range 16.3 - 24.7 months). Two (n=2) patients achieved subsequent MRD-neg/CR following additional CD19-specific CAR T-cell infusions (CRs ongoing at 12.4 and 1.4 months). The other patient (n=1) experienced a CD19-negative relapse and is awaiting infusion of CD22-specific CAR T-cells. Early relapse occurred in one (n=1) patient (4.7 months from allo-HSCT) following un-modified allo-HSCT with subsequent MRD-neg/CR following treatment with CD19-specific CAR T-cells (CR ongoing at 5.2 month). Three (n=3) patients in the un-modified cohort died due to TRM (24-month TRM = 46% [7-86%]), including veno-occlusive disease (multi-organ failure/infection) (n=2) and GVHD (n=1), while no TRM was noted in the CD34-selected TCD cohort (p=0.03). The TRM for the entire cohort was 19% at 24 months [0-39%]. The 24-month OS for the entire cohort was 81% [61 -100%], with 100% OS in CD34-selected TCD recipients and 54% in the un-modified recipients (p=0.03). Conclusion: CAR T-cells when followed by a CD34-selected TCD allo-HSCT resulted in less TRM and favorable OS when compared to un-modified allo-HSCT. Disease control is not impacted by the type of allo-HSCT and late relapse was seen following CD34-selected TCD. Successful re-treatment with CAR T-cells to induce remission is possible and analysis as to the durability of this response is ongoing. Disclosures Margossian: Novartis: Membership on an entity's Board of Directors or advisory committees. Prockop:Atara Biotherapeutics: Other: Support for industry sponsored trails ; Mesoblast: Other: Support for industry sponsored trails . Shah:Jazz pharmaceuticals: Speakers Bureau. Boelens:Takeda: Consultancy; Magenta: Consultancy; Bluerock: Consultancy; Avrobio: Consultancy. Curran:Juno Therapeutics: Consultancy, Research Funding; Novartis: Consultancy.

Romiplostim Improves Platelet Recovery after UCB Transplant

Background: Prolonged thrombocytopenia after hematopoietic stem cell transplant is a relatively common complication associated with intricate mechanisms including impaired thrombopoiesis and increased platelet turnover. Platelet recovery is particularly delayed after umbilical cord blood transplant (UCBT). Romiplostim is a thrombopoietin receptor agonist that is FDA approved for the treatment of chronic ITP. Although an increasing number of studies recently show promising results on the use of romiplostim in chemotherapy induced thrombocytopenia, the effect of romiplostim on platelet recovery in patients with persistent thrombocytopenia after UCBT remains unknown. Objectives: The primary objective of the study was to determine the maximum tolerated dose (MTD) of romiplostim in patients who failed to achieve platelet recovery by day +28 after UCBT. Secondary objectives were to determine if romiplostim influences the speed of platelet recovery, decreases the risk of thrombocytopenia related complications or affects the incidence of bone marrow (BM) fibrosis or relapse. Methods: This was a single center dose escalation trial of weekly romiplostim in patients &gt;18 years who failed to achieve an untransfused platelet count (PLT) of 20 x 109/L by day +28 after myeloablative (MA) or nonmyeloablative (NMA) UCBT. A total of 21 patients were enrolled from April 2015 to December 2018. One patient withdrew and was replaced so 20 patients are included in the analysis. Romiplostim was administered at the assigned dose as 6 weekly injections beginning by day +42 post UCBT with an end date by day +100. Four dose levels (4, 6, 8, and 10 mcg/kg/dose) were evaluated. There was no intra-patient dose escalation. The MTD of romiplostim was determined by the Continual Reassessment Method, with a goal to identify a dose level which corresponds to the desired toxicity rate of £ 20%. Toxicities of interest included thrombosis, PLT&gt;400x109/L and any grade 4-5 adverse event (AE) attributed to romiplostim. The comparison group were historical controls selected from our prospectively collected database based on age, gender, underlying disease, conditioning intensity and transplant type (1:1 matching). Results: Median (range) age of the patients was 59.5 (18-68) years and 60% were female. Ten patients had AML, 5 ALL, 3 MDS, 1 NHL and 1 MM. Of those, 11 received NMA double UCBT, 7 MA single UCBT and 2 received NMA single UCBT. Two patients received 4 mcg/kg/dose, two 6 mcg/kg/dose, four 8 mcg/kg/dose and the remaining 12 received 10 mcg/kg/dose. Only 5 patients completed the full 6 doses of treatment. Of the 15 patients who received less than 6 doses, 12 were due to a PLT&gt;100×109/L, 2 due to PLT&gt;400×109/L, and 1 was due to physician choice after the subject developed right upper extremity edema (without thrombosis). As shown in figure 1, 100% of romiplostim treated patients achieved platelet engraftment to 20 x 10^9/L at a median of 45 days post UCBT compared to 85% of controls who achieved platelet engraftment at a median of 49 days (p=0.07). Similarly, 90% of romiplostim treated patients achieved platelet engraftment to 50 x 10^9/L at a median of 48 days compared to 70% of historical controls who achieved platelet engraftment at a median of 52 days (p=0.04). The most common AEs were insomnia (30%), arthralgia (25%), myalgia (20%), headache (20%), dizziness and abdominal pain (15%). Only three patients experienced serious AEs requiring discontinuation of the drug: two had a PLT&gt;400x109 /L (without complications) and one developed right upper extremity edema. Bleeding episodes improved with the use of the drug as well as need of transfusions (patients vs controls, p&lt;0.05). All dose levels appear to be effective with overall low toxicity. Therefore, the MTD of romiplostim was 10mcg/kg/dose. All study patients were evaluated for BM fibrosis and relapse at regular intervals. There were no BM findings suggestive of increased fibrosis or relapse by day +100, and peripheral blood morphology was normal (no significant dacryocytosis, normal platelet morphology). Conclusion: Our study showed that romiplostim was well tolerated and accelerates platelet engraftment in patients undergoing UCBT, with the MTD being 10mcg/kg/dose. These results indicate that romiplostim is safe and potentially effective therapy to improve platelet recovery after UCBT. Further studies in larger numbers of patients are needed to confirm these observations. Disclosures Wagner: BlueRock: Research Funding; Rocket Pharmaceuticals: Consultancy; Novartis: Research Funding; Magenta: Consultancy, Research Funding; Gadeta: Membership on an entity's Board of Directors or advisory committees. Brunstein:Gamida: Research Funding; Magenta: Research Funding; Astex: Research Funding. Bejanyan:Kiadis Pharma: Other: advisory board. Smith:Amgen: Research Funding; Jazz Pharmaceuticals: Research Funding. OffLabel Disclosure: Romiplostim (Nplate) is an FDA approved drug for chronic ITP. In this study (phase I trial) we aimed to evaluate the safety and effectiveness of romiplostim on platelet recovery following UCBT.

Cord Blood Transplantation Is an Effective Treatment Option in Patients with Myelodysplastic and Myeloproliferative Syndromes

Background: Few registry studies have investigated the use of cord blood transplantation (CBT) for treatment of patients with myelodysplastic syndrome (MDS) and myeloproliferative disorders (MPN). To date, the outcomes reported have been not encouraging with excess of graft failures [1] and poor disease-free survival (DFS) [2]. The major obstacle to the success of CBT in this high-risk population has been related to the high rate of non-relapse mortality (NRM) due to the delayed time to engraftment. In this single-center study we retrospectively investigated clinical outcomes in patients with MDS and MPN undergoing a CBT. Methods: We reviewed clinical outcomes in 65 consecutive patients with either MDS (n=42) or MPN (n=23) who received a CBT at our institution between 2006 and 2018. The conditioning regimens used consisted of Cyclophosphamide (CY), Fludarabine (FLU), and total body irradiation (TBI) 13.2 Gy (n=16); Treosulfan, FLU, and TBI 2 Gy (n=26); Busulfan, CY, and FLU (n=6); or CY, FLU, and TBI (2 to 4 Gy) (n=17). All patients received Cyclosporine and Mycophenolate Mofetil for graft-versus-host disease (GVHD) prophylaxis. Cord blood units were HLA-typed at the antigen level for HLA-A and B, and high resolution for HLA-DRB1. Disease risk was classified as low to intermediate (n=37) and high to very high (n=28). Cytogenetics risk at diagnosis was favorable, intermediate and unfavorable in 11 (17%), 33 (51%) and 21 (32%) patients, respectively. Among patients with MDS, the R-IPSS score was low in 6 (14%), intermediate in 18 (43%), high in 8 (19%), and very-high in 10 (24%). Engraftment, relapse, NRM, and acute GVHD were calculated using cumulative incidence estimates adjusting for the appropriate competing risks. DFS and overall survival (OS) were assessed using the Kaplan-Meier method. Results: Patient characteristics are shown in Table 1. Median follow-up was 4.2 years (range, 0.5-12). The median age and weight were 46 years (range, 1-71) and 71 kg (range, 10-116). Six (9%) patients had failed a prior HCT. 56 (86%) patients received 2 cord blood units to achieve the required cryopreserved cell dose. The median cell doses infused were 2.6 x 107 (range, 1.4-15) TNC/kg and 0.12 x 106 (range, 0.02-0.78) CD34+ cells/kg. Neutrophils (&gt;500 for 3 days) and platelet (&gt;20x109/L for 7 days transfusion free) engraftment occurred at a median time of 20 days (range, 6-89) and 35 days (range, 13-85), respectively. There were only 4 (6%) cases of primary graft failure, 2 of which were patients with MDS and 2 patients with MPN, and no cases of secondary graft failures. 76% of MDS patients and 52% of MPN patients achieved platelet engraftment by day 100. OS at 3 years was 60% (95% Confidence Interval, CI: 47-71) and specifically was 63% (95% CI: 47-76) for MDS patients and 55% (95% CI: 32-73) for MPN patients. Disease free survival at 3 years was 54% (95% CI: 41-66) with a cumulative incidence of relapse of 21% (95% CI: 11-32). The cumulative incidence of NRM at day 100 and at 3 years were 9% (95% CI: 4-17) and 25% (95% CI: 15-36), respectively. No differences in DFS, relapse incidence, and NRM were seen between MDS and MPN patients (Table 2). The cumulative incidence of acute GVHD grade II-IV and III-IV were 74% (95% CI: 61-82) and 21% (95% CI: 12-32), respectively. Seventeen (26%) patients developed late acute GVHD at a median time of 186 days (range, 101-379), and 10 (15%) had overlap syndrome. Twenty-three (35%) patients were diagnosed with classical chronic GVHD: 18 (27%) with mild, 3 (5%) with moderate, and only two (3%) with severe grade. Conclusions: The results presented herein demonstrate that in patients with MDS and MPN undergoing CBT sustained engraftment was achievable without excessive graft failures. The rates of OS and DFS at 3 years were extremely encouraging and similar to what was observed after matched related and unrelated donors' transplants. [3,4]. Overall, our data suggest that CBT should be considered as a valid option for this high-risk population in case of lack of conventional donors. Disclosures Delaney: Biolife Solutions: Membership on an entity's Board of Directors or advisory committees; Nohla Therapeutics: Employment, Equity Ownership. Milano:ExCellThera: Research Funding; Amgen: Research Funding.

S140 RESULTS FROM THE PHASE 3 NORTHSTAR‐3 STUDY EVALUATING LENTIGLOBIN GENE THERAPY IN PATIENTS WITH TRANSFUSION‐DEPENDENT β‐THALASSAEMIA AND A β0 OR IVS‐I‐110 MUTATION AT BOTH ALLELES OF THE HBB GENE

Background:LentiGlobin gene therapy in transfusion‐dependent β‐thalassaemia (TDT) contains autologous CD34+ haematopoietic stem cells (HSCs) transduced ex vivo with the BB305 lentiviral vector (LVV) encoding β‐globin with a T87Q amino acid substitution. Patients with β0/β0 genotypes generally have the most severe phenotype and require higher production of transgenic haemoglobin (Hb) to fully ameliorate symptoms. In the phase 1/2 Northstar study (NCT01745120), 3/8 patients with TDT and β0/β0 genotypes became free from red blood cell (RBC) transfusions and 5/8 patients had a 55% median reduction in annualised RBC transfusion volume. The LentiGlobin drug product (DP) manufacturing process was then refined to improve clinical outcomes.Aims:To evaluate refined LentiGlobin gene therapy in patients with TDT and β0 or β+ IVS‐I‐110 (G→A) mutations on both HBB alleles in the ongoing, international, single‐arm, phase 3 Northstar‐3 study (HGB‐212; NCT03207009).Methods:Patients with TDT undergo HSC mobilisation with G‐CSF and plerixafor. CD34+ HSCs, collected via aphaeresis, are transduced with BB305 LVV. Patients undergo myeloablative, single‐agent, pharmacokinetic‐adjusted conditioning with busulfan and are infused with the transduced cells. The primary endpoint is transfusion reduction (≥60% reduction in transfused RBC volume post‐DP infusion compared to pre‐DP infusion). Patients are followed for 2 years and offered participation in a long‐term follow‐up study.Results:As of 14 September 2018, 10 patients have completed HSC mobilisation and DPs have been manufactured for 7 patients. Three patients (aged 7, 17, 26 yrs) have been treated with LentiGlobin (follow‐up 9.2, 4.2, 1.4 months). In treated patients, the median DP cell dose was 6.1 (min‐max: 5.9–12.9) x106 CD34+ cells/kg, the median DP vector copy number (VCN) was 3.3 (min‐max: 2.9–3.9) vector copies/diploid genome, and the median transduction rate was 82% (min‐max: 78–85%).The median time to neutrophil engraftment was 34 (min‐max: 14–38) days. Two patients achieved platelet engraftment at 28 and 50 days. Patient 3 had not achieved platelet engraftment as of the datacut (day +42). The first patient treated (β0/β0) has not had any RBC transfusions since DP infusion, maintaining a total Hb of 12.8 g/dL, which consisted of 11.6 g/dL (91%) gene therapy‐derived Hb, HbAT87Q, at month 9.Investigator reported data available as of 19 November 2018 was also analyzed. Patient 1's month 12 total Hb was 13.8 g/dL. Patient 2 (β0/IVS‐I‐110) has been transfusion‐free for 4 months with a total Hb of 10.1 g/dL at month 6. Patient 3 (IVS‐I‐110/IVS‐I‐110) was last transfused 1.4 months after DP infusion and had a total Hb of 11.6 g/dL at month 3. Longer follow‐up and results obtained in additional patients will be presented.Non‐haematologic grade ≥3 adverse events (AEs) following DP infusion as of 19 November 2018 included stomatitis (67%) and one AE each of anal inflammation, epistaxis, febrile neutropenia, and pharyngeal inflammation. There were no serious AEs or DP‐related AEs following DP infusion.Summary/Conclusion:Early data from Northstar‐3 suggest that improvements in DP manufacturing are resulting in improved DP VCN, HbAT87Q production, and total Hb levels after treatment with LentiGlobin gene therapy for TDT. The 2 patients with ≥6 months follow‐up have stopped RBC transfusions and total Hb levels are &gt;10 g/dL. Longer follow‐up and data from additional patients are needed to demonstrate whether the manufacturing refinements ultimately translate into improved clinical outcomes for patients with TDT and β0/β0 genotypes.

Assessment of Safety and Efficacy of PBSC Mobilization with G-CSF and CD34+ Enrichment and Pbmnc (CD3+) Addback in Familial Haploidentical (FHI) Adult Donors with Sickle Cell Disease Trait (SCDT) Prior to Allogeneic HSCT of High-Risk SCD Patients

Background We and others have previously reported the safety of allogeneic stem cell transplantation in children with SCD without sibling HLA matched bone marrow donors who commonly have SCDT. The majority of the sibling donors donated bone marrow and received G-CSF mobilized PBSCs (Bhatia/Cairo et al, BMT 2014; Gluckman et al, Blood 2017). Furthermore, only 14-18% of siblings can serve as donors based on HLA match and presence of SCD (Mentzer, Am J Ped Hem/Onc 1994; Walters, BBMT 1996). Unrelated cord blood as a donor source for SCD patients was associated with unacceptable primary graft failure rates (Radhakrishnan/Cairo, BBMT 2013). MUD HSCT resulted in unacceptably high rates of CGVHD (Shenoy et al, Blood 2016). Parental FHI SCDT PBSCs represent an alternative donor source. However, little is known about G-CSF PBSC mobilization in older donors with SCDT. GCSF mobilization of PBSC in homozygous SCD patients in the past has been reported to be associated with major toxicity and death (Adler et al, Blood 2001). Objective To determine if FHI PBSC mobilization in older adult donors with SCDT is safe and effective. Methods Eighteen FHI donors with SCDT received 15mg/kg/d GCSF divided BID x4 days. PBSC leukapheresis on day 5, repeating qd until 10 × 106 CD34/kg and 2 × 105 CD3/kg (minimum) were cryopreserved. CD34+ enrichment utilized the CliniMACS® System (generously provided by Miltenyi), with 2 × 105 CD3/kg T-cell add-back before HSCT as we have previously described (Geyer/Cairo, BJH 2011). Donor chimerism assays for whole blood CD3, CD71, and CD56 were performed post-HSCT. Results Fifteen female/3 male FHI donors with SCDT were mobilized: mean age 41 yrs (30-55). The most common donor side effect was grade 1 bone pain (n = 11). Other side effects were grade 1 nausea/vomiting (n = 3), grade 1 headache (n = 2), grade 1 dizziness (n = 1), grade 1 fatigue (n = 2), grade 1 abdominal pain (n = 2), grade 3 bone pain (n = 1), and grade 3 thrombocytopenia (n = 1). The mean ± SEM cryopreserved CD34 count was 12.9 ± 0.8 × 106/kg recipient wt with the mean ± SEM yield 533.69 ± 48.9 × 106. Mean ± SD log T-cell (CD3) depletion was 4.84 ± 0.58 (Fig. 1). 100% of patients achieved neutrophil engraftment at a median of 9 days (range 6-13), and 92.1% of patients achieved platelet engraftment at a median of 19 days (range 8-90) (Fig 2A/2B, respectively). Mean ± SEM Blood and CD71+ (RBC) donor chimerism was 97 · 1 ± 1.4 and 96 · 4 ± 2.0%, respectively. Conclusion These data suggest that adult FHI stem cell donors with SCDT undergoing GCSF mobilization for PBSC collection is safe and well-tolerated with only minor temporary adverse events. PBSC collection and CD34 enrichment was effective and resulted in successful SCD recipient engraftment and long-term donor chimerism. Further studies are needed to evaluate the long-term outcome of high-risk SCD patients undergoing FHI AlloHSCT R01FD004090.

A New Prediction System for Platelet Recovery after Autologous Stem Cell Transplantation in B-Cell Non-Hodgkin Lymphomas

Transient thrombocytopenia is common after autologous peripheral blood stem cell transplantation (auto-PBSCT). Although patients underwent auto-PBSCT usually show the recovery of peripheral leukocytes and platelets counts within a couple of weeks after auto-PBSCT, delayed platelet engraftment (DPE) is occasionally observed despite prompt neutrophil engraftment. However, there are few studies evaluating the risk factors for DPE. In this study, to investigate the association between clinical characteristics and duration required for post-auto-PBSCT platelet engraftment, we retrospectively analyzed 144 patients with B-cell non-Hodgkin lymphomas who underwent auto-PBSCT between January 2000 and December 2017 at 5 independent institutes involved in the Kyoto Clinical Hematology Study Group. Platelet recovery was defined as a recovery of platelet count greater than 50.0 × 109/L without transfusion support for 3 consecutive days, and the first day of 3 consecutive days was regarded as the day of platelet engraftment. The median observation period was 930 days (range, 25 - 5272 days). Median age at auto-PBSCT was 61, and 144 patients included 109 diffuse large B cell lymphoma, 11 follicular lymphoma, 22 mantle cell lymphoma. Ninety one patients were in complete remission at the time of auto-PBSCT. The mobilization regimens for stem cell collection were chemotherapy such as high-dose VP16 (46.5%), CHASE (cyclophosphamide, AraC, VP16, and dexamethasone) (40.3%), and high-dose AraC (8.3%) followed by G-CSF. All 144 patients except one achieved neutrophil engraftment with the median engraftment day of 10 days (range, 4-41 days), and 139 patients achieved platelet engraftment with the median engraftment day of 19 days (range, 10-1125 days). Multivariate analysis showed that infused CD34-positive cell number (≥ 2.0 × 106/kg vs. < 2.0 ×106/kg: HR 3.06: P < 0.001), pre-apheresis absolute lymphocyte count (PA-ALC), which was the mean number of lymphocytes during aphaeresis procedure (≥ 1.0 × 109/L vs. < 1.0 × 109/L: HR 2.62: P < 0.001), and the days required for apheresis procedure (≥ 3 days vs. 1 or 2 days: HR 0.49: P = 0.02) were independently associated with the duration for platelet engraftment after auto-PBSCT. Age, gender, diagnosis, Ann Arbor stages, previous history of bone marrow infiltration, performance status, international prognostic index (IPI)-defined disease risk, disease status at the time of transplant, the number of chemotherapy regimens, and mobilization regimen were not associated with platelet engraftment period. On the basis of these results, we next tried to create a new prediction system for post-transplant platelet recovery by incorporating the three factors, i.e., infused CD34-positive cell number, PA-ALC, and days required for apheresis procedure. Risk groups were determined by the sum of predictive factors for platelet recovery: favorable (3 factors), intermediate (2 factors), unfavorable (1 factor), and very unfavorable (no factor). As the results, the median duration for platelet engraftment with favorable, intermediate, unfavorable, and very unfavorable groups were 15, 19, 31, and 148 days, respectively (P < 0.001) (Figure). Furthermore, 14 of 144 patients did not achieve platelet engraftment by day 80 after auto-PBSCT. We defined those as patients with DPE. Median duration for platelet engraftment in patients with DPE was 137 days (range, 82-1125 days), while that for neutrophil engraftment was 11 days. Intriguingly, PA-ALC was less than 1.0 × 109/L in all 14 patients with DPE, while 6 required apheresis for ≥3 days, and 5 received <2.0 ×106/kg CD34-positive cells for transplantation. Collectively, the newly developed scoring system which incorporates infused CD34+ cell dose ≥ 2.0 × 106/kg, PA-ALC ≥ 1.0 × 109/L, and number of apheresis procedures ≤2 days, is an useful tool for predicting platelet recovery after auto-PBSCT. Especially, patients with low PA-ALC are high risk of DPE after auto-PBSCT. This study was conducted in accordance with the ethical principles of the Declaration of Helsinki, and was approved by the Institutional Review Board of our institutes. [Display omitted] DisclosuresKuroda:Chugai Pharma: Honoraria, Research Funding.

Clinical outcome of allogeneic hematopoietic stem cell transplantation with FLAG sequential busulfan/cyclophosphamide conditioning regimen for refractory/relapsed acute myeloid leukemia

Objective: To investigate the therapeutic effects of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with FLAG sequential busulfan/cyclophosphamide(Bu/Cy) conditioning regimen for refractory/relapsed acute myeloid leukemia. Methods: From February 2012 to June 2017, 21 patients with refractory/relapsed acute myeloid leukemia underwent allo-HSCT with FLAG sequential Bu/Cy conditioning regimen. Transplantation-related complications and clinical outcome were retrospectively analyzed. Results: After conditioning, no hepatic veno-occlusive disease (VOD) and grade Ⅲ hemorrhagic cystitis occurred. 76.2% (16/21) patients had fever with 4 septicemia. One patient died of septic shock before engraftment. Twenty patients achieved neutrophil engraftment with a median time of 13 days (range, 10 to 21 days). Seventeen patients achieved platelet engraftment with a median time of 18 days (range, 9 to 25 days). The cumulative incidence of acute graft-versus-host disease (aGVHD) was 39.5%, and 3 patients developed grade Ⅲ-Ⅳ aGVHD. Of 19 patients who survived more than 100 days after transplantation, 4 had local chronic graft-versus-host disease (cGVHD). Of 21 patients, the median survival time was 15 months (range, 0.5 to 67 months) post-transplantation. Transplantation-related mortality rate was 28.7%. Leukemia relapse occurred in 4 patients with a median time of 4 months (range, 3 to 8 months) after transplantation. The cumulative relapse rate at 1 year was 21.4%. The 1-year and 3-year overall survival (OS) rates were 60.7% and 54.9% respectively. Log-rank analysis revealed that bone marrow blasts ≥ 20% or extramedullary leukemia before transplantation, poor platelet engraftment and grade Ⅲ-Ⅳ aGVHD were significantly related to shortened OS (P<0.05). Conclusions: Allo-HSCT with FLAG sequential Bu/Cy conditioning regimen in patients with refractory/relapsed myeloid leukemia has acceptable transplantation-related risk and relapse rate. The 1-year and 3-year OS rates are comparable with those in remission patients.

Moving Average Of Immature Platelet Fraction Predict Late Platelet Engraftment After Reduced-Intensity Cord Blood Transplantation: A Single-Institutional Study

Introduction Platelet engraftment is an important marker of successful allogeneic stem cell transplantation and platelet is the last to be regenerated in bone marrow after stem cell transplantation. Especially, platelet engraftment is far slower in reduced-intensity conditioning regimen(RIC) in cord blood transplant(CBT). Early prediction of platelet engraftment in RIC-CBT can be helpful to proper treatment. Recent retrospective studies suggested immature platelet fraction(IPF) can be useful to predict platelet engraftment. However, the role of IPF in RIC-CBT is not be sufficiently investigated. In addition, these studies included patients undergoing bone marrow or peripheral blood transplantation. Therefore, we analyzed cases in our database to evaluate the impact of IPF and Reticulocyte count(RET%) on the outcome of platelet engraftment in consecutive patients who were treated with RIC-CBT over the past 4 years at our institution in Tokyo, Japan. Patients and Methods We included 53 consecutive patients treated at our institution between April 2008 and May 2013. The study population consisted of 29 male and 23 female patients with a median age of 57 years old (range: 36-69). Patient in this cohort underwent RIC-CBT as a part of therapy for myeloid malignancies(N=28) and lymphoid malignancies (N=24). 21 patients were treated with Flu+Cy+TBI(2gy), and 31 patients were treated with Flu+Bu+TBI(2Gy). All patients received calcineurin inhibitor plus MMF for GVHD prophylaxis. Due to the influence of blood transfusion on IPF and RET% and overall estimation of IPF and RET% movement, IPF and RET% were assessed by using the 5-day moving average ,and then we compared movement of the fifth moving average between patients with platelet engraftment and patients without platelet engraftment. The fifth moving average was calculated from the time of day4 after transplantation until the date of platelet engraftment or death from any cause or the date on which the patient was received next chemotherapy. Platelet engraftment was defined as independent from platelet transfusion. Result Among 53 patient, 29 patieunt achieved platelet engraftment. The median time of platelet engraftment was day +42 (range:24-203day), and median time of follow up periods of patients without platelet engraftment was 47 days. 16 patients achieved platelet engraftment after day +40. Baseline characteristics according to patients who achieved platelet engraftment, or did not achieve were similar among RIC-regimen, patient diagnosis. Patients' age, sex, total cell count andCD34 cell count in donor cord blood has no impact on pletelet engraftment. Maximum value of IPF did not have significant impact on platelet engrafment. As shown figure 1, The mean of the 5-day moveing average in IPF show similar curve from day +4 to day +30 between patient with platelet engraftment and without, and after +30 days the curve of patient with platelet engraftment gradually highter than the curve of patient without platelet engraftment. The difference of these curves was larger after day +50. In the RET% case, it was almost same. the 5-day moveing average of IPF and RET% in platelet engraftment patient were raising after day +40, while those in non-engraftment patient were decreasing in this period. Provided the 5-day moving average of IPF are blow 6.0 from day +40 to day +50, It is highly likely that platelet engraftment can't be expected (p=0.001 in univariate analyses). Likewise, provided the 5-day moving average RET% are blow 1.5 from day +40 to day +50, platelet engraftment significantly can't be expected (p=0.002). Conclusion The results of the present study highlighted the importance of the fifth-moving average of IPF and RET% after day +40, and IPF and RET% can be useful tools to predict platelet engraftment in RIC-CBT. Disclosures: No relevant conflicts of interest to declare.

Seuqential Intensive Chemotherapy (FLAG-IDA) Followed by Reduce-toxicity Conditioning (FLU-BU) for Refractory Acute Myeloid Leukemia: An Interim Analysis of Phase II Trial

Abstract 4509Allogeneic stem cell transplantation (Allo-SCT) is the most effective treatment for a variety of hematological malignancies. For high-risk or refractory AML, the outcome of allo-SCT with standard conditioning regimen remains poor. There are successful reports of 40∼50% DFS with sequential conditioning regimen for patients with high risk AML consisting of cytoreductive chemotherapy (FLAMSA) followed by reduced intensity (RIC) conditioning and prophylactic transfusion of donor lymphocytes infusion (DLI). But for very refractory patients such as patients with more than 2 cycles of previous chemotherapy, the outcome remain unsatisfactory (∼15%). Beside the treatment mortality, the important issue is the early relapse (usually less than 6 months). In this phase II trial (NCT01496547), we designed a preparation regimen including an intensive chemotherapy (FLAG-IDA) followed by a sequential (with interval of 7 days) reduced-toxicity regimen including (Fludarabine 30mg/m2 for 5 days + intravenous busulfan 3.2mg/kg for 3 days) and allo-SCT. The aim of study is to evaluate the efficacy and safety of such intensive regimen in young adults with refractory AML which has a very dismal prognosis (survival <10% in our history control series after allo-SCT with Bu-Cy conditioning). The inclusion criteria were as follow: primary refractory patients (non-remission after 2 cycles of induction chemotherapy); refractory relapsed patients or patients relapse very early during the consolidation therapy. Here we reported the outcome of the first 8 patients (all female, age 16∼39). All 8 patients had refractory disease with 3∼10 cycles (median 4) previous chemotherapy and blasts in bone marrow remained at 18∼90%. After the transplantation, 7 patients achieved neutrophils engraftment at 12∼17 days, in which 5 patients achieved platelet engraftment at 17∼28 days. One patient (UPN 7) died of infection before engraftment documented. In the remaining 7 patients, bone marrow blasts were cleared in all cases. Among these 7 patients, 1 died in remission due to CNS bleeding after recovering from grade III aGVHD. One patient relapsed 7 months after transplantation and died of disease 4 months later. Up to the last follow-up at 1st Aug 2012, 5 patients remain alive in continuous remission for 4+, 10+, 13+, 15+, 19+ months respectively. Based on our pilot study, we suggested that the sequential intensive cytoreduction chemotherapy (FLAG-IDA) followed by Flu-Bu conditioning regimen can be effective in refractory AML patients and achieved continuous remission for more than 6 months, thus providing an important treatment platform for further improvement such as prophylaxis DLI to enhance the graft-versus leukemia effect. Further enrolled of patients and longer follow-up is warranted.TablePatients' characteristics and outcomeUPNTime of TxDiagnosisDonorSexAgeDisease-status*Blasts in BMNo cycles chemoConditioningPost-Tx BMGVHDCurrent StatusLeukemia-free (months) after Tx12010–12AMLMUDF16Ref-Rel90%4FLAG-IDA/FLU-BuCR/Alive in CR19+22011–3AMLMUDF38E-Rel29%4FLAG-IDA/FLU-BuCR/Alive in CR15+32011–7AMLMUDF34P-Ref25%4FLAG-IDA/FLU-BuCRp/Death ″C relapse742011–5AMLMUDF39P-Ref18%5FLAG-IDA/FLU-BuCR/Alive in CR13+52011–10AMLSibF19Ref-Rel85%6FLAG-IDA/FLU-BuCRcGVHD liver/skinAlive in CR10+62012–3AMLHaploF16Ref-Rel90%10FLAG-IDA/FLU-BuCRpIII aGVHDDeath ″C TRM **1.872012–4AMLMUDF25P-Rel80%3FLAG-IDA/FLU-Bu//Death ″C TRM ***/82012–4AMLMUDF37P-Rel18%4FLAG-IDA/FLU-BuCRII aGVHD/cGVHD skinAlive in CR4+*Ref-rel: refractory relapse; E-rel: early relapse during consolidation; P-Ref: Primary refractory.**Recover from III aGVHD involving skin, liver and intestine and eventually died of CNS bleeding because of low platelet.***Died of infection (sepsis). Disclosures:No relevant conflicts of interest to declare.

Allogeneic Hematopoietic Cell Transplantation for Consolidation of Vgpr or Cr in Myeloma

Abstract 4581 Allogeneic hematopoietic cell transplantation (HCT) from HLA-identical siblings has been shown to prolong survival of patients with multiple myeloma in some studies. However, all published clinical trials of up front allogenic transplant for myeloma were conducted before thalidomide, lenalidomide and bortezomib became available; as such, less than 10% of the patients were in complete remission (CR) at time of transplantation. With contemporary therapy incorporating novel agents, more than 50% of patients achieve very good partial response (VGPR) or better (VGPR or CR). We summarize our experience with the safety and efficacy of allogeneic transplantation for patients achieving VGPR or better following induction therapy containing novel agent(s). Thirteen myeloma patients with first VGPR or CR received allogeneic HCT between July 2007 and January 2011. Median age at transplant was 45 years (range, 25 – 59), median time from initial therapy to transplant was 236 days (range, 122 – 410). Six patients (46%) have high-risk cytogenetics/FISH. Five patients received bortezomib plus lenalidomide induction therapy and eight patients received bortezomib-induction. Three patients (23%) underwent autologous HCT with melphalan plus bortezomib conditioning (melphalan 100 mg/m 2 for 2 days followed by bortezomib 1.3 mg/m 2 ) subsequent to induction therapies to achieve further cytoreduction prior to allogeneic HCT. Median number of prior therapies was 2 (range, 1–2). Disease status at the time of allogeneic HCT was stringent CR (n=5), CR (n=3), and VGPR (n=5). All patients received unmanipulated peripheral blood stem cell grafts from HLA-matched sibling donors (n=5) and HLA-matched unrelated donors (n=8). Six patients received fludarabine 30 mg/m 2 for 4 days and melphalan 70 mg/m 2 for 2 days followed by a single dose of bortezomib 1.3 mg/m 2 (Flu/Mel/Vel). Seven patients received fludarabine 40 mg/m 2 for 4 days and melphalan 70 mg/m 2 for 2 days (Flu/Mel). Graft-versus-host disease (GVHD) prophylaxis constitutes tacrolimus/methotrexate (n=5), tacrolimus/mycophenolate mofetil (n=4), and tacrolimus/sirolimus (n=4). All patients achieved neutrophil engraftment after a median of 17 days (range, 11 – 19), and all patients achieved platelet engraftment after a median of 17 days (range, 12 – 21). All patients established stable donor cell chimerism. Best responses after allogeneic HCT were sCR (n=10), CR (n=2) and VGPR (n=1). The cumulative incidence of grades 2–4 acute GVHD at day 100 was 57% (95% CI 0.30 – 1.00) with Flu/Mel conditioning and 33% (95% CI 0.11 – 1.00) for Flu/Mel/Vel conditioning, respectively (p=0.24). This observation suggests that a single dose of bortezomib 48 hours before HCT may prevent GVHD. One patient died of GVHD complications, 1 had disease progression and 11 remain alive, progression free with a median follow-up of one year (range 4 months to 4 years). The one year progression-free survival estimate is 90% (95%CI 0.71 – 1.00). These initial data indicate that allogenic transplant for myeloma in VGPR or CR is well tolerated. Longer follow-up is required to assess the efficacy of allogeneic HCT in the era of novel agents in preventing progression of the disease. Disclosures: Baz: Millenium: Research Funding, Speakers Bureau; Celgene: Research Funding. Alsina: Millennium: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Allergan: Research Funding.

Allogeneic Hematopoietic Cell Transplantation for Consolidation of VGPR or CR In Myeloma

Abstract 4581Allogeneic hematopoietic cell transplantation (HCT) from HLA-identical siblings has been shown to prolong survival of patients with multiple myeloma in some studies. However, all published clinical trials of up front allogenic transplant for myeloma were conducted before thalidomide, lenalidomide and bortezomib became available; as such, less than 10% of the patients were in complete remission (CR) at time of transplantation. With contemporary therapy incorporating novel agents, more than 50% of patients achieve very good partial response (VGPR) or better (VGPR or CR). We summarize our experience with the safety and efficacy of allogeneic transplantation for patients achieving VGPR or better following induction therapy containing novel agent(s). Thirteen myeloma patients with first VGPR or CR received allogeneic HCT between July 2007 and January 2011. Median age at transplant was 45 years (range, 25 – 59), median time from initial therapy to transplant was 236 days (range, 122 – 410). Six patients (46%) have high-risk cytogenetics/FISH. Five patients received bortezomib plus lenalidomide induction therapy and eight patients received bortezomib-induction. Three patients (23%) underwent autologous HCT with melphalan plus bortezomib conditioning (melphalan 100 mg/m2 for 2 days followed by bortezomib 1.3 mg/m2) subsequent to induction therapies to achieve further cytoreduction prior to allogeneic HCT. Median number of prior therapies was 2 (range, 1–2). Disease status at the time of allogeneic HCT was stringent CR (n=5), CR (n=3), and VGPR (n=5). All patients received unmanipulated peripheral blood stem cell grafts from HLA-matched sibling donors (n=5) and HLA-matched unrelated donors (n=8). Six patients received fludarabine 30 mg/m2 for 4 days and melphalan 70 mg/m2 for 2 days followed by a single dose of bortezomib 1.3 mg/m2 (Flu/Mel/Vel). Seven patients received fludarabine 40 mg/m2 for 4 days and melphalan 70 mg/m2 for 2 days (Flu/Mel). Graft-versus-host disease (GVHD) prophylaxis constitutes tacrolimus/methotrexate (n=5), tacrolimus/mycophenolate mofetil (n=4), and tacrolimus/sirolimus (n=4). All patients achieved neutrophil engraftment after a median of 17 days (range, 11 – 19), and all patients achieved platelet engraftment after a median of 17 days (range, 12 – 21). All patients established stable donor cell chimerism. Best responses after allogeneic HCT were sCR (n=10), CR (n=2) and VGPR (n=1). The cumulative incidence of grades 2–4 acute GVHD at day 100 was 57% (95% CI 0.30 – 1.00) with Flu/Mel conditioning and 33% (95% CI 0.11 – 1.00) for Flu/Mel/Vel conditioning, respectively (p=0.24). This observation suggests that a single dose of bortezomib 48 hours before HCT may prevent GVHD. One patient died of GVHD complications, 1 had disease progression and 11 remain alive, progression free with a median follow-up of one year (range 4 months to 4 years). The one year progression-free survival estimate is 90% (95%CI 0.71 – 1.00). These initial data indicate that allogenic transplant for myeloma in VGPR or CR is well tolerated. Longer follow-up is required to assess the efficacy of allogeneic HCT in the era of novel agents in preventing progression of the disease. Disclosures:Baz: Millenium: Research Funding, Speakers Bureau; Celgene: Research Funding. Alsina:Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Allergan: Research Funding.

Safety of Recombinant Human Thrombopoietin in Adults after Related Donor Haploidentical Haematopoietic Stem Cell Transplantation

Delayed recovery of platelets can be found in recipients of related donor haploidentical haematopoietic stem cell transplantation (HSCT). The objective of this study was to evaluate the safety of recombinant human thrombopoietin (rhTPO) administration prior to engraftment in patients who received related donor haploidentical HSCT. Nineteen patients with haematological malignancies received rhTPO prior to platelet engraftment after related donor haploidentical HSCT. Safety and tolerability levels together with the influence of rhTPO on the outcome of transplantation were evaluated. Slight elevations in ALT and/or AST were observed in five patients; in two other patients, bilirubin levels increased slightly. No significant changes in routine examination findings and no allergic reactions were observed during the study period. Eighteen patients achieved platelet engraftment at a median of 16 (range 11-34) days. The cumulative ± SD incidence of acute graft-versus-host disease (GVHD) grade 1-4 at +100 days was 68.4 ± 10.7%, and that of chronic GVHD at 3 years was 24.7 ± 10.7%. Nine (47.4%) patients survived free of relapse, with a median follow-up of 1631 (1550-1734) days after transplantation. Early administration of rhTPO prior to engraftment was safe and well tolerated in patients receiving related donor haploidentical HSCT.

Collection of Stem Cell Early In the Disease Course of Multiple Myeloma Is Associated with Early Engraftment.

AbstractAbstract 4518 Introduction:Autologous stem cell transplant (PBSCT) is an integral part of the management of Multiple Myeloma (MM). Available data suggest that the timing of PBSCT has no effect on overall outcome. Some patients currently opt to delay their transplant, especially in this era of proteosome inhibitors and iMIDs. In such patients the best time for stem cell collection is unknown. We conducted a retrospective study looking at early stem collection and storage compared to stem cell collection at the time of transplant in patients who opt to be transplanted at a later date. Method:All patients who had PBSCT performed more than one year from the time of diagnosis were reviewed. Two groups of interest were then evaluated. Early collection (ET): those who had stem cells collected within 6 months of diagnosis, and Late collection (LT): those who had stem cells collected more than 1 year from diagnosis and within 3 months of PBSCT. Results:Table 1 shows some patient characteristics. 334 patients were identified, ET (85) and LT (249). Gender distribution, Durie Salmon stage, immunoglobulin subtype and cytogenetic abnormalities were similar in both groups. The LT group was older 60 yrs compared to ET 56.6 yrs, P=0.02. More patients in the ET (77%) group were mobilized with cyclophosphamide compared to LT (51%) p<0.0001. Stem cell yield was similar in both groups 9.26 × 10(6) CD34/kg in ET and 8.19 × 10(6) in LT, P=0.16. Median number of collections was 3 in both. More patients in the LT (67%) received Melphalan 200 mg/m2 conditioning compared to ET (59%) p=0.03. Neutrophil engraftment occurred at day + 11 ET and +12 (LT) p<0.0001. ET patients achieved platelet engraftment on day + 13 compared to + 15 (LT) p=0.002. Complete response rates were similar 30% (ET) and 34% (LT). Duration of response after PBSCT was not different 12.6 months (ET) and 11.6 months (LT). Median overall survival from diagnosis was 70.5 months (ET) and 74.5 months (LT) p=0.5. Similarly there was no difference in overall survival post PBSCT 33.5 month (ET) and 32.2 months (LT). Conclusion:Stem cell collection and storage early in the disease course of multiple myeloma results in early engraftment compared to stem cell collection at the time of transplant in patients who opt for a delayed transplant. More studies looking at cost analysis will however be need to determine the cost effectiveness of early versus late stem cell collection.Table 1Early Collection (ET)Late Collection (LT)P value# patients85249Median time to collection (months)513.5Median time from collection to PBSCT (months)284# Prior Regimen before PBSCT22Stem cell yield CD34/kg9.26 × 10(6)8.19 × 10(6)0.16Stem cell dose CD34/kg5.68 × 10(6)4.23 × 10(6)<0.0001Median time from diagnosis to PBSCT (months)32.4290.16 Disclosures:Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Gertz:Celgene: Honoraria; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Improved Outcomes Using Tacrolimus/Sirolimus for Graft-versus-Host Disease Prophylaxis with a Reduced-Intensity Conditioning Regimen for Allogeneic Hematopoietic Cell Transplant as treatment of Myelofibrosis

Allogeneic hematopoietic cell transplantation (HCT) using reduced-intensity conditioning (RIC) regimens is a potentially curative treatment for patients (patients) with myelofibrosis (MF), as we and others have reported. Nonrelapse mortality (NRM) from graft-versus-host disease (GVHD) and other complications has limited the success of this approach. As part of an ongoing prospective research study at City of Hope, a combination of tacrolimus/sirolimus +/- methotrexate (MTX) for GVHD prophylaxis has become the standard treatment for our allogeneic HCT patients. In this report, we present results for 23 consecutive patients, including extended follow up for 9 patients previously reported who received cyclosporine (CsA)/mycophenolate moffetil (MMF)+/-MTX, and the current series of 14 patients who received tacrolimus/sirolimus+/-MTX, and evaluate the impact of the GVHD prophylaxis regimen on the outcomes. Median follow-up for alive patients was 29.0 months (9.5-97.0). The estimated 2-year overall survival (OS) for the CsA/MMF cohort was 55.6% (confidence interval 36.0, 71.3), and for the tacrolimus/sirolimus cohort it was 92.9% (63.3, 98.8) (P=.047). The probability of grade III or IV acute GVHD (aGVHD) was 60% for the CsA/MMF patients, and 10% for the tacrolimus/sirolimus group (P=.0102). No significant differences were seen for grade II to IV aGVHD in the 2 groups. We conclude that the combination of tacrolimus/sirolimus+/-MTX for GVHD prophylaxis in the setting of RIC HCT for MF appears to reduce the incidence of severe aGVHD and NRM, and leads to improved OS compared to CSA/MMF+/-MTX.