Reduced-intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation Research Articles

Clinical Features of Acute Kidney Injury in the Early Post-Transplantation Period Following Reduced-Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation

Allogeneic hematopoietic stem cell transplantation (HCT) is a potentially curative therapy for patients with hematologic malignancies but is associated with acute kidney injury (AKI). To date, few studies have examined risk factors for AKI at engraftment, or the relationship between AKI and clinical outcomes. This study examined the incidence and risk factors for periengraftment AKI, as well as the association between AKI and overall survival (OS) and nonrelapse mortality (NRM). We conducted a retrospective analysis of adult patients undergoing reduced-intensity conditioning (RIC) allogeneic HCT at the Dana-Farber Cancer Institute between 2012 and 2019. Periengraftment (day 0 to day 30) AKI incidence and severity were defined using modified KDIGO (Kidney Disease: Improving Global Outcomes) criteria. Factors associated with periengraftment AKI risk were examined using Cox regression analysis. The impact of periengraftment AKI on OS and NRM (defined as death without recurrent disease after HCT), was evaluated using Cox regression and the Fine and Gray competing risks model, respectively. Kidney recovery, defined as a return of serum creatinine (SCr) to within 25% of baseline or liberation from kidney replacement therapy (KRT), was examined at day 90 post-HCT. Periengraftment AKI occurred in 330 of 987 patients (33.4%) at a median of 13 days (interquartile range, 4 to 30 days) post-transplantation. Factors associated with a higher multivariable-adjusted risk of AKI were supratherapeutic rapamycin (hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.20 to 2.03; P < .001), fludarabine/melphalan conditioning (HR, 1.35, 95% CI, 1.01 to 1.81; P=.05, compared to fludarabine/busulfan and fludarabine, cyclophosphamide, and total body irradiation), HCT Comorbidity Index ≥4 (HR, 1.43; 95% CI, 1.14 to 1.79; P=.002), albumin <3.4 g/dL (HR, 2.04; 95% CI, 1.33 to 3.12; P=.001), hemoglobin ≤12 (HR, 1.96; 95% CI, 1.38 to 2.78; P < .001), supratherapeutic tacrolimus (HR, 1.45; 95% CI, 1.07 to 1.95; P=.02), and baseline SCr >1.1 mg/dL (HR, 1.87; 95% CI, 1.48 to 2.35; P < .001). Periengraftment AKI was associated with worse OS (HR, 1.40; 95% CI, 1.16 to 1.71; P < .001) and NRM (subdistribution HR, 2.10; 95% CI, 1.52 to 2.89; P < .001). Kidney recovery occurred in 18%, 15%, and 30% of patients with stage 1, stage 2, and stage 3 AKI without KRT, respectively, and 4 of 16 patients (25%) were liberated from KRT. Periengraftment AKI is common among RIC allogeneic HCT recipients. We identified several important risk factors for periengraftment AKI. Its association with worse OS and NRM underscores the importance of timely recognition and management.

Differential Impact of Conditioning Intensity on Post-Transplant Outcome of FLT3 -Mutated and FLT3 Wild Type AML in First Remission, a Report from Taiwan Bone Marrow Transplant Registry (TBMTR)

AML with FLT3 -internal tandem duplication mutation (FLT3-ITD) has a very high relapse rate when patients were treated with chemotherapy alone. Allogeneic hematopoietic stem cell transplantation (HSCT) as soon as possible once remission is achieved is generally recommended. Nevertheless, the best conditioning regimen, specifically the myeloablative (MAC) or reduced intensity conditioning (RIC), for FLT3-ITD AML remains unknown. Of the two largest series reported so far, vast majority of the patients received myeloablative regimen (100% in EBMT report, 87% in CIBMTR report). In this study, we utilize the Taiwan Bone Marrow Transplant Registry (TBMTR) database to analyze the impact of conditioning intensity on the post-transplant outcome of FLT3 -mutated and FLT3 wild type AML.TBMTR is a research collaboration affiliated to the Taiwan Society of Blood and Bone Marrow Transplantation. It comprises all the 14 transplantation centers in Taiwan that contribute detailed information on HSCT. In this study, only adults aged ≥ 18 years with a diagnosis of de novo AML who received allogeneic peripheral blood stem cell transplantation (PBSCT) at the first complete remission (CR1) and with known FLT-ITD mutation status in the registry were included. Patient characteristics and transplant outcome following MAC or RIC allogeneic PBSCT were compared. Kaplan-Meier estimates were used to calculate the probability of LFS and overall survival (OS). Cumulative incidence of relapse and non-relapse mortality (NRM) was calculated from the time of transplant to the time of event. NRM was considered a competing risk for relapse and vice versa. Multivariable analyses for LFS and OS were performed using Cox proportional hazards model.146 patients who met the eligibility criteria were enrolled for analysis. The median follow-up of survivors was 21 months (range, 1-73 months). Of the 146 patients, 49 (33.6%) were positive and 97 (66.4%) were negative for FLT3-ITD mutation. 32.7% and 35.1% of FLT3-ITD mutated and FLT3 WT AML received RIC regimen respectively. FLT3-ITD mutated patients had significantly higher WBC count (51.7 x 109/L) and more normal (64.9%) karyotype at diagnosis comparing to patients without FLT3 mutation (11.8 x 109/L WBC count and 42% normal karyotype). Patients who received RIC regimen were significantly older than patients who received MAC regimen (53.196±12.107 vs 38.327±11.788, p<0.001, for FLT3-ITD mutated AML; 52.084±12.533 vs 39.181±10.704, p<0.001, for FLT3 WT AML).In multivariable analysis, FLT3 mutation status did not negatively impact the transplant outcome in term of both overall survival (OS) and leukemia free survival (LFS). However, RIC regimen is associated with a significant poor LFS (HR 1.754, p=0.0476) and higher relapse rate (HR 2.184, p=0.015). The impact of conditioning intensity is even more prominent in patients of FLT3 WT AML (Figure 1, left, p=0.0468 for LFS, log rank test). For FLT3-ITD mutated AML, the LFS and relapse rate were almost the same after either MAC or RIC conditioning (Figure 1, right, p=0.768 for LFS, log rank test). For NRM and cumulative incidence of acute and chronic GVHD, the differential impact of conditioning intensity was not seen in FLT3-ITD mutated AML and FLT3 WT AML.In conclusion, conditioning intensity has a differential impact on post-transplant outcome of FLT3-ITD mutated AML and FLT3 WT AML. Reduced intensity conditioning is associated with a lower LFS and higher relapse rate for FLT3 WT AML. For patients of FLT3-ITD mutated AML, RIC is just as good as MAC, even though patients who received RIC were almost 15 years older than patients who received MAC. RIC allogeneic HSCT should be a viable option for elderly or unfit AML with FLT3-ITD mutation. [Display omitted] DisclosuresYao:Celgene International Sàrl: Research Funding. Tang:Celgene International Sàrl: Research Funding.

Outcomes of reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation for 10 patients with myelofibrosis

目的评价减低强度预处理异基因造血干细胞移植（allo-HSCT）治疗骨髓纤维化患者的疗效。方法回顾性分析接受减低强度预处理allo-HSCT的10例骨髓纤维化患者的临床资料。结果全部10例患者中男6例、女4例，中位年龄为28.5（22~54）岁。采用以氟达拉滨/白消安+全身照射为主的预处理方案。9例患者移植后获得造血重建，中性粒细胞、血小板的中位植入时间分别为13.5（10~22）、16.5（13~40）d。4例患者发生急性移植物抗宿主病，5例患者发生慢性移植物抗宿主病。中位随访时间17（6~109）个月，预期3年总生存率为（90.0±8.5）%。1例患者死亡。结论以氟达拉滨/白消安+全身照射为主的减低强度预处理allo-HSCT是骨髓纤维化的有效治疗方法。

Higher Donor Apheresis Blood Volumes Are Associated with Reduced Relapse Risk and Improved Survival in Reduced-Intensity Allogeneic Transplantations with Unrelated Donors

Allogeneic hematopoietic stem cell transplantation (HSCT) with reduced-intensity conditioning (RIC) offers a curative option for patients with hematologic malignancies who are unable to undergo myeloablative conditioning, but its success is limited by high rates of relapse. Several studies have suggested a role for T cell doses in peripheral blood stem cell grafts in RIC HSCT. Because T cell dose is typically not known until after the collection, and apheresis blood volume is easily modifiable, we hypothesized that higher donor apheresis blood volumes would improve transplantation outcomes through an effect on graft composition. Thus, we analyzed the relationships between apheresis volume, graft composition, and transplantation outcomes in 142 consecutive patients undergoing unrelated donor allogeneic RIC HSCT. We found that apheresis volume ≥15 L was associated with a significantly decreased risk of relapse (adjusted hazard ratio [aHR], .48; 95% confidence interval [CI], .28 to .84]; P = .01) and improved relapse-free survival (aHR, .56; 95% CI, .35 to .89; P = .02) and overall survival (aHR, .55; 95% CI, .34 to .91; P = .02). A high apheresis volume was not associated with increased rates of acute or chronic graft-versus-host disease. These results demonstrate that an apheresis volume of at least 15 L is independently predictive of improved transplantation outcomes after RIC allogeneic HSCT.

Reduced-Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation for Multiple Myeloma in Relapse after Autologous Transplantation: A Single Institution Experience with Matched Related Donors

INTRODUCTIONRelapse in Multiple Myeloma (MM) comprises a dismal prognosis. The proteasome inhibitors and immunomodulators increased the median overall survival (OS) in relapse from 12 to 24 months. For relapsing patients, high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (HSCT) and also allogeneic HSCT have been considered valid options in recent consensus statement. The major concern about allogeneic HSCT is the high transplant-related mortality (TRM) even with Reduced Intensity Conditioning (RIC). AIMSSingle institution retrospective evaluation of RIC allogeneic HSCT from matched related donors, in a cohort of MM patients relapsing after autologous HSCT. RESULTSBetween 1998 and 2016, 43 MM patients received allogeneic HSCT. From this group, a cohort of 29 MM patients relapsing after autologous HSCT was selected, based on supracited inclusion criteria. The median age at allogeneic HSCT was 51 (33-62) years. Before allogeneic HSCT, 55,7% (N=16) were treated wih salvage chemotherapy alone, whereas 20,7% (N=6) received chemotherapy plus autologous HSCT. For allogeneic HSCT, the conditioning was fludarabine plus bussulphan. Acute graft-versus-host disease (GVHD) prophylaxis was cyclosporine plus mycophenolate mophetil in 25 (86,2%) and in vivo antithymocyte globulin plus cyclosporine in 4 (13,8%). All patients recieved matched related peripheral blood grafts. Responses to salvage treatment previous to allogeneic HSCT were: progressive/stable disease (PD/SD) 24,1%, partial response (PR) 41,4%, very good partial response/complete remission (VGPR/CR) 13,7%, unknown 20,7%. Best responses after allogeneic HSCT were: PD/SD 15,7%, PR 24,1%, VGPR/CR 58,6%, unknown 10,3%. Engraftment was achived in 86,2% (N=25) and full donor chimerism was observed, at least once, in 72,4% (N=21). The overall reported incidence of grade II-IV acute GVHD was 48,3% (N=14) and moderate/severe chronic GVHD was 34,5% (N=10). Cytomegalovirus (CMV) reactivation ocurred in 44,8% (N=13) and hemorrhagic cystitis in 10,3% (N=3). The median progression free survival (PFS) and overall survival (OS) was 24 (0-61) and 176 (0-376) months, respectively. The incidence of relapse/progression was 48% (N=14). In this setting, 42,9% (N=6) were treated with chemotherapy alone and 35,7% (N=5) with donor lymphocyte infusion (DLI). After DLI, 80% (N=4) achieved CR. The overall mortality and TRM were 48,3% (N=14) and 17,2% (N=5), respectively. Best response after allogeneic HSCT was the only factor that improved PFS and OS (p<0,05). CONCLUSIONIn our cohort, the allogeneic HSCT as salvage treatment for MM relapsing after autologous HSCT showed ability to deepen responses after salvage chemotherapy/autologous HSCT and also to prolong OS. The diferences between PFS and OS probably reflect the increasing therapeutical options to rescue patients after progression/relapse (chemotherapy, immunossupression tapper and DLI). The scarce data concerning the cytogenetic risk and the short dimension of this cohort are major limitations to define the MM relapsing patients who benefit most of allogeneic HSCT. DisclosuresNo relevant conflicts of interest to declare.

Host Lymphocyte Depletion as a Strategy to Facilitate Early Full Donor Chimerism after Reduced-Intensity Allogeneic Stem Cell Transplantation

Reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (RIC-alloHSCT) is associated with lower toxicity but higher rates of prolonged mixed chimerism than myeloablative conditioning. Decreased pretransplantation host T cell numbers are associated with less graft rejection and early full donor chimerism. To compensate for variability in pretransplantation host lymphocyte numbers and facilitate the achievement of rapid full donor chimerism, we tested a strategy of targeted lymphocyte depletion (TLD) using chemotherapy at conventional doses to provide cytoreduction and lymphocyte depletion before RIC-alloHSCT. In our study, 111 patients with advanced hematologic malignancies received 1 to 3 cycles of conventional-dose chemotherapy to reduce circulating lymphocytes to a predetermined level. Patients then underwent RIC-alloHSCT from HLA-matched siblings. Patients received a median of 2 cycles of TLD chemotherapy, resulting in a median 71% decline in CD4+ count. All patients engrafted; there were no late graft failures. By day +14, median CD3+ chimerism was 99% donor and was significantly associated with lower post-TLD CD4+ counts (P = .012). One- and 5-year treatment-related mortality were 15% and 21%, respectively. At 1-year follow-up, 66% of patients had achieved complete remission (CR) of which 92% were not in CR at the time of transplantation. Overall survival at 1 and 5 years post transplantation were 66% and 47%, respectively.

Targeting Histone Deacetylases As a New Strategy for Graft Versus Host Disease Prevention

AbstractAbstract ▪740▪This icon denotes a clinically relevant abstract Introduction:Graft-versus-host disease (GVHD) precludes an effective utilization of allogeneic hematopoietic stem cell transplantation (HSCT). Histone deacetylase inhibitors (HDACi) are an important class of anti-cancer agent and have recently been shown by us and others to attenuate experimental GVHD in multiple murine models. They suppress proinflammatory cytokine production, modulate antigen presenting cells (APCs), and enhance T regulatory cell (Treg) numbers and functions. We have translated our experimental observations from murine models in a first-in-human clinical trial to test the hypothesis that HDAC inhibition will be safe and reduce the severity of GVHD in patients undergoing matched related donor (MRD) reduced intensity conditioning (RIC) allogeneic HSCT. Methods:From March 2009 through June 2012, we enrolled 45 patients at two centers, the University of Michigan and Washington University, in a phase I/II trial that combined the HDACi, vorinostat, with standard GVHD prophylaxis regimen consisting of tacrolimus and mycophenolate mofetil (MMF) and compared them with historical controls. The primary endpoint was the cumulative incidence of grade 2–4 acute GVHD (aGVHD) with a target risk of 25%, which would represent a statistically significant improvement over the 42% risk experienced by historical controls, assuming a type I error rate of 5%. The controls comprised of patients who underwent MRD RIC allogeneic HSCT and received standard GVHD prophylaxis with tacrolimus and MMF. Study eligibility included adult patients with a hematological malignancy for which RIC HSCT was considered appropriate and had an available 7/8 or 8/8-HLA-MRD. Specifically, patients with CLL and lymphoma must have been in CR, PR or had stable disease. Patients with myelodysplasia, acute leukemia or CML must have had < 20% blasts on the bone marrow examination. Study subjects received fludarabine 40 mg/m2 for 4 days, busulfan 3.2 mg/kg for 2 days, MMF for 29 days, and tacrolimus levels were maintained between 8–12 ng/mL through day (D) 56, and then tapered off by D180 (in the absence of GVHD). The investigational agent, vorinostat, was administered orally from D-10 to D100. Results:The median age of the study patients (vorinostat-treated) was 58 years (range, 43–69 years). There have been no cases of graft failure or excessive toxicity or death attributable to vorinostat. The median time to neutrophil and platelet engraftment was similar between study and controls (12 vs 11 days, respectively, for both groups). Bone marrow chimerism analyses for study patients showed the percent of myeloid (CD33+) engraftment to be 94%, 100% and 100%, and whole T cell (CD3+) engraftment to be 74.5%, 75%, and 100% at D30, D100 and D365, respectively. In the 45 study patients, the cumulative incidence of D100 grade 2–4 aGVHD was significantly lower compared to controls (22% vs 42%, respectively, P=0.04). Severe grade 3–4 aGVHD at D100 (4% vs 19% controls) and transplant-related mortality at 1 year (13% vs 19% controls) were also reduced. The incidence of aGVHD was globally diminished in all target organs, and all but one patient responded rapidly to standard steroid therapy. The incidence of relapse was similar between the study and controls (17% vs 20%, respectively). Infectious complications were not different between the groups. We performed several correlative analyses with patient samples to understand the putative mechanisms based on murine studies. Peripheral blood mononuclear cells (PBMCs) from study patients demonstrated enhanced histone (H3) acetylation at D30 compared with PMBCs from controls (P<0.03). Consistent with experimental data, there was greater acetylation of STAT-3 and increased percent and total numbers of CD4+CD25+CD127− Tregs in PBMCs in study patients compared to control or normal healthy patients (P=0.03 and P=0.04, respectively). Ex vivo stimulation of PBMCs from the study patients with TLR agonist (LPS) demonstrated reduced secretion of proinflammatory cytokines (TNF-α and IL-6) when compared with controls or healthy volunteers. Conclusions:The data herein demonstrate translation of our experimental observations into a proof of concept first-in-human phase I/II clinical trial in prevention of GVHD. More importantly, the data suggest that administration of vorinostat in MRD RIC allogeneic HSCT may be a safe and effective strategy to reduce aGVHD. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Reduced-Intensity Conditioning Allogeneic Stem Cell Transplantation in Pediatric Patients and Subsequent Supportive Care

To determine if children undergoing reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation (RIC-AlloHSCT) have lower incidence of acute toxicities and, subsequently, require less supportive care than is required with myeloablative conditioning (MAC)-AlloHSCT. An additional purpose is to examine later outcomes by comparing 100-day transplantation-related mortality (TRM). Retrospective chart and electronic medical records review. A pediatric care center in the northeastern United States. 86 patients who underwent AlloHSCT from January 2004 through March 2008. Charts were retrospectively reviewed. The comparison between groups was done by t test (continuous variables) and chi-square test (categorical variables). The logistic regressions, Kaplan-Meier product-limit estimator, log rank test, and Cox proportional hazards model were used. Days requiring total parenteral nutrition (TPN), patient-controlled analgesia (PCA), incidence of mucositis, days with fevers, number of infections, transfers to pediatric intensive care unit (PICU), blood product infusions, and 100-day TRM, all for 30 days post-transplantation. When comparing pediatric patients undergoing RIC-AlloHSCT (n = 43) versus MAC-AlloHSCT (n = 43) in the first 30 days post-transplantation, a statistically significant decreased incidence was noted for mucositis, infections, transfers to PICU, days on TPN and PCA, and days with fever, as well as 100-day TRM. For pediatric patients, RIC-AlloHSCT is associated with significantly lower acute post-transplantation toxicities and TRM than MAC-AlloHSCT. For nurses to correctly educate their patients and family members, and to aid nurses in anticipating patient's needs, an understanding of the potential different acute toxicities and supportive care between pediatric patients undergoing RIC- versus MAC-AlloHSCT is vital.

Impact of anti-HLA antibodies on allogeneic hematopoietic stem cell transplantation outcomes after reduced-intensity conditioning regimens

Anti-human leukocyte antigen (HLA) antibodies are associated with several complications in solid organ transplantations, but their impact after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is not yet well defined. To evaluate the relevance of anti-HLA antibodies, we have retrospectively analyzed 107 peripheral blood allo-HSCTs after reduced-intensity conditioning regimen between 2005 and 2010. Acute myeloid leukemia and multiple myeloma were the most frequent malignancies in the cohort. The detection of anti-HLA antibodies was systematically performed in all patients before transplantation. Anti-HLA antibodies were present in 24 patients (22%). There was no significant impact of anti-HLA antibodies on engraftment, incidence of relapse, and incidence of acute graft-vs-host disease. The presence of anti-HLA antibodies was associated with significantly worse overall survival (p = 0.006) and event-free survival (p = 0.024) after stratification on sex. The 3-year probability of overall survival was 34% without anti-HLA antibodies and 16% in their presence. Patients with anti-HLA antibodies had a higher transplant-related mortality associated with life-threatening vascular complications. Our study supports that anti-HLA antibodies should be tested and considered as an important impacting factor for transplantation outcomes after reduced-intensity conditioning allo-HSCT. We recommend its consideration before allo-HSCT in the donor-recipient selection parameters.

Dose-Adjusted EPOCH-Rituximab Combined With Fludarabine Provides an Effective Bridge to Reduced-Intensity Allogeneic Hematopoietic Stem-Cell Transplantation in Patients With Lymphoid Malignancies

There is currently no standard chemotherapy regimen for patients with lymphoid malignancies being considered for reduced-intensity conditioning allogeneic hematopoietic stem-cell transplantation (RIC-alloHSCT). The ideal regimen would provide disease control and result in lymphocyte depletion to facilitate engraftment. To this end, we developed a novel regimen by adding fludarabine to dose-adjusted continuous-infusion etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus with or without rituximab (DA-EPOCH-F/R). One hundred forty-seven patients with lymphoid malignancy (median age, 50 years) who had heavily pretreated (median prior regimens, three) and chemo-refractory (47%) disease were treated with DA-EPOCH-F/R before RIC-alloHSCT. Patients received one to three consecutive cycles until achieving lymphocyte depletion (CD4(+) count < 200/μL) or progressive disease. Overall response rate was 41%; 39% of patients had stable disease. Toxicity included grade 4 neutropenia in 65% and thrombocytopenia in 25% of patients. DA-EPOCH-F/R resulted in lymphocyte depletion (P < .001), which was inversely associated with serum interleukin (IL) 7 and IL-15 levels. Of 147 patients, 143 patients proceeded to RIC-alloHSCT. Patients with lower CD3(+) (P < .001), CD4(+) (P < .001), and CD8(+) (P < .001) T-cell counts after DA-EPOCH-F/R were more likely to achieve full donor lymphoid chimerism by day +14 after transplant. Relative to nonresponders to DA-EPOCH-F/R, patients with complete and partial response had increased event-free survival (77.4 v 4.8 months; P < .001) and overall survival (98.5 v 16.2 months; P < .001). DA-EPOCH-F/R safely provides tumor cytoreduction and lymphocyte depletion, thereby offering a bridge to RIC-alloHSCT in patients with aggressive lymphoid malignancies.

A Simple Prognostic Score to Predict Short and Long-Term Survival Following ICU Admission in Critically Ill Adult Allogeneic Hematopoietic Stem Cell Transplant Recipients: Improved Survival Following Reduced Intensity Conditioning

Abstract 146▪▪This icon denotes a clinically relevant abstractTransplant-related complications necessitate intensive care unit (ICU) admission in a significant proportion of patients undergoing allogeneic hematopoietic stem cell transplantation (Allo-HSCT). Historically patients requiring ICU admission for transplant related toxicities have fared extremely poorly with very high ICU mortality rates. Although recent reports have indicated improvements in short-term survival for Allo-HSCT patients admitted to ICU there are little data on the subsequent long-term survival of ICU survivors and the impact of reduced intensity conditioning regimens in this cohort of patients. Methods:A retrospective analysis of data collected from 164 consecutive adult Allo-HSCT recipients admitted to ICU (with a total of 214 ICU admissions), at a single centre, University College London Hospitals NHS Foundation Trust (UCLH) between June 1996 and December 2007 (11.5 year study period) was performed. Follow-up of surviving patients was recorded until 31 March 2011. Results:29% of all patients undergoing Allo-HSCT at our centre during the study period required one or more ICU admission. The ICU admission rate was significantly lower for patients undergoing reduced intensity conditioning (RIC) than myeloablative conditioning (17% vs. 38%, p<0.001). The median age of RIC-Allo recipients was significantly older than patients who received myeloablative conditioning (47 vs 36 years, P<0.0001). The most frequent reasons for ICU admission were sepsis (67%) and respiratory failure (55%), not mutually exclusive. Mechanical ventilation (MV) was required in 53% of admissions, inotropic support was required in 47%. Median acute physiology and chronic health score (APACHEII) was 23 (range 0–51). Overall ICU survival for all admissions was 48% (n=214). 35 patients (21%) had more 1 or more ICU admissions. Survival by patient (measured at discharge from final ICU admission) was 32%. ICU survival was significantly better after RIC Allo-HSCT than following myeloablative conditioning (OR 3.27, p=0.023). There was no difference in ICU outcome by stem cell source (sibling vs. unrelated). Patients who did not require ventilatory support (non-invasive ventilation and/or MV) had significantly better ICU outcome (OR 12.7, p<0.001). Multivariate analysis by Cox regression revealed raised urea, inotropic support and MV as independent determinants of death on ICU. Long term survival was significantly better for patients who underwent RIC Allo-HSCT (p=0.0055) (Figure 1). The subsequent long term survival for patients who survived ICU admission was excellent; 1, 2, and 5 year survival rates were 60%, 55%, and 50% respectively (median follow-up 3 years, 7 months).A simple prognostic scoring system has been derived which is predictive of both ICU survival and long term outcome (Table 1). Patients with 2 or more of the following factors: myeloablative conditioning, MV, elevated serum urea, score 1. Patients with <2 of these factors score 0. In our patient population, this binary index has been shown to be predictive of both death on ICU (OR 7.24, p=0.001) or poorer overall survival after ICU discharge (OR 3.04, p=0.01). [Display omitted] Table 1:Prognostic score for prediction of short and long term outcome for allo-HSCT patients admitted to ICU. Score 1 if 2 or more of the following factors are present: Myeloablative conditioning, mechanical ventilation, elevated serum urea.ScoreSurvival to discharge2y OS from discharge5y OS from discharge061%71%65%118%35%26% Conclusion:In this study we report favourable ICU survival following allogeneic HSCT and for the first time report significantly better short and long-term outcome for patients who underwent RIC Allo-HSCT compared to those treated with myeolablative conditioning regimens despite a higher median age in the patients undergoing RIC transplants. For patients surviving ICU admission, subsequent long-term overall survival was excellent at 50% at 5 years, comparing favourably with other critically ill non-surgical patients admitted to ICU. A simple prognostic score has been generated which can be used to predict outcome in critically ill patients admitted to ICU following Allo-HSCT. Disclosures:No relevant conflicts of interest to declare.

Reduced-intensity Allogeneic Hematopoietic Stem Cell Transplantation for Multiple Myeloma: A Concise Review

Reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (HSCT) can result in reliable donor engraftment, relatively low treatment-related mortality, and sustained remissions in the treatment of multiple myeloma. However, substantial cytoreduction pre-allografting is often necessary because of a variable graft-versus-myeloma effect. The use of RIC allogeneic HSCT immediately after autologous HSCT provides a temporal separation between tumor reduction by high-dose chemotherapy and the graft-versus-myeloma effect. There are currently a number of prospective trials attempting to address the issue of whether this strategy leads to decreases in relapse and/or improvement in overall survival as compared with double autologous transplants. Unfortunately, similar to autografting, relapse remains the major cause of treatment failure after RIC allogeneic HSCT. To improve treatment results with allografting, consideration should be given to incorporating immunomodulatory drugs and targeted treatments to enhance pretransplantation remission status, as posttransplantation maintenance therapy, or in combination with donor lymphocyte infusions for refractory or relapsed disease. Studies exploring these strategies are ongoing.

Donor Stem Cell Source Does Not Impact Outcome of High Risk (HR) Acute Myeloblastic Leukaemia (AML) Patients After Reduced Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation (RIC-ALLO).

Abstract 4339Allogeneic Stem Cell Transplantation (ASCT) offers a potential curative treatment approach of HR AML patients (pts). Over years, the use of umbilical cord blood (UCB) has become an attractive alternative stem cell source for those pts lacking a suitable HLA matched related or unrelated donor.The aim of this analysis was to assess the outcome of 50 pts who received a RIC-ALLO in our centre between 2005 and 2008 with a special focus on three different donor sources: identical sibling, unrelated donor or UCB.All pts had HR AML in complete remission (CR) at time of transplant. HR features were defined as at least one of the following criteria: CR1 with unfavourable cytogenetics, secondary AML, more than one induction chemotherapy for obtaining CR or CR2 and above. Reasons for RIC regimen were older age, unfit physical condition, comorbidities or prior autologous transplant. All pts received a Fludarabine-based RIC regimen with GVHD prophylaxis consisting in CSA alone or CSA and MMF.The median age of all pts was 51 (range, 19-70) years. 28 pts had identical sibling donors, 7 pts had a matched 10/10 (5 pt) or mismatched 9/10 (2 pt) unrelated donors and 15 pt received a single or double UCBT. Pts characteristics were comparable between the three groups but for pt age [identical sibling group: 52 (range, 35-70) years; unrelated donor group: 61 (range, 50-66) years; UCB group: 44 (range, 19-61) years].After a median follow-up of 886 (range, 336-1528) days, 20 pts have died (disease=6, treatment related=14) and 8 pts have experienced relapse. Four year OS and EFS for all pts were 57% and 54%, respectively with no significant difference between the 3 groups (2 year OS: 61%, 54% and 66%; 2 year EFS: 59%, 54% and 45% respectively). One year TRM was 20% for the entire group and did not significantly differ between the 3 groups.Despite the obvious limitations of this small series, results seem to indicate that in this population, donor type does not highly influence outcome. This is quite encouraging as most of the pts lack a compatible sibling donor. This may invite to consider privileging a rapid identification of an alternative donor rather than a given donor type when a match sibling is not available. Thus concomitant search for both graft type should be undertaken in order to perform allo SCT in a larger number of pts otherwise not treated because of early progression as illustrated in the underrepresentation of alternative transplant as compared with familial transplant in this retrospective study (28 familial vs 22 alternative). Disclosures:No relevant conflicts of interest to declare.

Cyclosporine a and Mycophenolate Mofetil Vs Cyclosporine a and Methotrexate as Gvhd Prophylaxis in Reduced Intensity Conditioning Hematopoietic Stem Cell Transplantation from HLA-Identical Sibling Donor.

J.L.Piñana is supported by grants from the Instituto de Salud Carlos III (expedient CM06/00139, Ministerio de Sanidad)Background: Cyclosporine A (Csa) with methotrexate (MTX) is the most common prophylactic regimen against acute graft versus host disease (aGVHD). Although some studies show that Mycophenolate Mofetil (MMF) in combination with Csa for patients undergoing allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is associated with early hematologic recovery, less toxicity as mucositis and no diferencies in terms of aGVHD. Limited data is available comparing these two combinations in reduced intensity conditioning Allo-HSCT (Allo-RIC). In this case-control study from two Spanish BMT centers, we retrospectively analyzed the introduction of MMF as GVHD prophylaxis in comparison with a short course of MTX in a large series of patients who underwent HLA identical sibling donor Allo-RIC.Patients and methods: We include 145 consecutive Allo-RIC patients, who received peripheral blood (PB) as source of stem cells, between April 2000 and August 2007. The median follow-up for the whole group was 514 days (8 to 3170 days). The study group included 91 males and 54 females. Median age was 55 years (range 18 to 71 years). Diagnoses were acute leukemia/myelodisplastic syndrome/myeoloproliferative disorders) (n=37/15/13), multiple myeloma (n= 32), Hodgkin lymphoma (n= 6), chronic lymphocytic leukemia (n=15) and non-Hodgkin lymphoma (NHL) (n= 27). GVHD prophylaxis consisted of CsA/MMF in 52 and CsA/MTX in 93 patients. The conditioning regimen was based on fludarabine in combination with busulfan (59 recipients) or melphalan (86 cases).Results: The occurrence of mucositis grade 2–4 was higher in the CsA/MTX group than in the CsA/MMF group (57% vs 23% p= 0.001). No significant differences were found between CsA/MMF and CsA/MTX groups in time to neutrophil recovery (15 +/−3 days vs 15 +/− 2days) (p= 0.5). Cumulate incidence of acute GVHD were 50% (95% C.I., 38–65) for CsA/MMF group and 48% (95% C.I. 39–60%) for CsA/MTX group (p= 0.9). Although chronic GVHD was also similar [71% (95% C.I. 58–86%) in CsA/MMF group vs 68% (95% C.I. 57–80%) in Csa/MTX group (p= 0.7)], we observed that the development of chronic GVHD was delayed in the CsA/MMF group [174 days (range 100–365) vs 134 days (range 84–302) p= 0.008)]. Non relapse mortality (NRM) at 100 days was higher in MTX group (6% vs 18%, p=0.04). However, relapse and overall survival at median follow-up were still similar between groups (25% vs 18%, p= 0.4 and 52% vs 51%, p=0.7, respectively).Conclusion: We conclude that the combination Csa/MMF appears to be at least equivalent to the standard Csa/MTX GVHD prophylaxis in HLA identical sibling donor Allo-RIC. The toxicity profile of Csa/MMF was better, reflected by a significantly less incidence of mucositis.

Predictive factors for outcomes after reduced intensity conditioning hematopoietic stem cell transplantation for hematological malignancies: a 10-year retrospective analysis from the Société Française de Greffe de Moelle et de Thérapie Cellulaire

This retrospective study analyzed the impact of demographic and transplantation variables on outcomes of 1108 patients who have undergone allogeneic hematopoietic stem cell transplantation after reduced intensity conditioning (RIC HSCT) for hematological malignancies and were reported to the Société Française de Greffe de Moelle et de Thérapie Cellulaire registry between November 1994 and December 2004. Only 442 patients (40%) were in complete remission (CR) at time of transplantation. Peripheral blood stem cells were used in the majority of patients (n = 878; 79%), 255 patients received fludarabine and low-dose total body irradiation, while 465 patients (42%) fludarabine and busulfan with rabbit anti-thymocyte globulins (ATG). The impact of demographic and transplant variables was studied on overall (OS) and event-free survival (EFS) in univariate and multivariate analysis. With a median follow-up of 21 months, 3-year probability of OS and EFS was 42% and 30%, respectively, and treatment-related mortality was 15% at 2 years. The multivariate analysis showed a significant negative impact on OS and EFS of the absence of CR status before transplantation; conditioning regimen, including >10 mg/kg ATG; and minor ABO incompatibility. In conclusion, this study highlights the major impact on RIC HSCT outcome of disease status before transplantation, ATG dose and ABO incompatibility.

Reduced Intensity Conditioning (RIC) with FLU-BU-ATG and Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Pediatric Malignancies.

RIC regimens are increasingly used for the treatment of adults with malignancies, relying predominantly on graft-vs-tumor cellular therapy. RIC reduces the risk for regimen related morbidity (RRM) and mortality in adults. Pediatric experience with RIC protocols has been limited despite the potential benefit for reduced long-term morbidity. We report the experience of 35 RIC HSCT for malignancies in pediatric patients (pts), 31 were at very high-risk for complications of full-intensity conditioning due to disease state, prior HSCT (7 allo, 8 auto) and/or co-morbid medical conditions. The RIC regimen was comprised of fludarabine, 30 mg/m2 for 6 consecutive days (days -10 through -5), followed by intravenous busulfan (days -5 and -4), 0.8 - 1 mg/kg for 8 doses (n=15) or targeted AUC 4000 microMol*min for 2 doses (n=20) and ATG days -4 through -1, (equine 40 mg/kg/d or rabbit, 2 mg/kg/d). RIC was followed by allogeneic HSCT. Diagnoses included: recurrent ALL (15, ≥CR3 in 8), AML (5, refractory in 4), refractory neuroblastoma (5), recurrent Non-Hodgkin’s Lymphoma (4), CML (3) or treatment-related myelodysplastic syndrome (3). There were 21 males, 14 females, ages 2 to 17 yrs, median 9.14. Stem cell sources included 22 unrelated donors (URD), 11 matched sibs and 2 mis-matched relatives. 31 of 35 stem cell donations were G-CSF mobilized peripheral blood. The median cell doses infused were 5.05 × 108 MNC/kg and 4.6 × 106 CD34+ cells/kg. Graft-versus-host disease (GVHD) prophylaxis was cyclosporin A (CsA) alone in the first 12 pts, CsA and mycophenolate mofetil (MMF) in the subsequent 23 pts. Significant (&gt;80%) donor chimerism was achieved in 32 pts with a median time to reach an ANC &gt;500/μl of 18 days (range 9–62). Three pts with URD failed to engraft and another 3 had graft loss. An unsupported platelet count &gt; 20,000/μl was achieved in 29 of 35 pts at a median of 15 days (7–228). Six pts developed Gr III–IV acute GVHD, 7 of the 25 pts surviving more than 100 days developed chronic GVHD (4 limited, 3 extensive). Since addition of MMF, only one pt developed chronic GVHD (limited). While there was no immediate RRM, 10 pts (8 URD, 4 prior HSCT) died of infection (4), infection + GVHD (3), GVHD (2) or veno-occlusive disease after a subsequent HSCT (day + 146 post RIC HSCT). Infections included 4 probable fungal, 2 viral and one bacterial infection. Sixteen pts have relapsed from 25 to 427 days post HSCT for an event-free-survival of 22%. Because RIC HSCT creates a platform for cellular immuno-therapy, early post-HSCT relapse or persistent disease was treated by withdrawal of GVHD prophylaxis (n= 11) and/or donor leukocyte infusions (n=3). 4 pts responded to immune modulation and 3 remain in remission. Thus, the projected three-year overall survival in this very high-risk group of pts is 44%. Our results indicate RIC allogeneic HSCT has a role for pediatric pts at high-risk for complications after conventional HSCT.

Reduced Intensity Conditioning Hematopoietic Stem Cell Transplantation (HSCT) with Mesenchymal Stem Cells (MSC) Infusion for Treatment of Metachromatic Leukodystrophy (MLD): A Case Report.

Background: Patients (pts) with MLD have neurological and musculo-skeletal defects with a limited survival. HSCT has been reported as an effective treatment to stabilize or improve defects associated with this disease. Koç and colleagues reported that donor allogeneic MSC infusion is safe and may be associated with reversal of the disease pathophysiology in some tissues (Bone Marrow transplant, 2002). We decide thus to perform a non myeloablative familial HSCT in adult pt with a symptomatic MLD in order to evaluate the safety and the benefit allogeneic HSCT with MSC infusion in a patient with MLD. An informed consent was obtained from the pt.Patient: a 23 years old women who presented an adult form of MLD for three years was admitted in our department. The most important symptoms associated with the disease were dizziness, proximal weakness of the lower limbs, difficulty to walk, disorder of the memory and urinary incontinence. The reduced intensity conditioning was preferred to decrease the morbidity and mortality of the procedure. MSC were isolated and amplified from the BM-mononuclear cells of the HSC donor. MSC expansion was made in a commercial serum-free medium (UltraCulture, Cambrex, Walkersville, MD) supplemented with a serum substitute (Ultroser, Pall Biosepra, Cergy-Saint-Christophe, France) as previously reported by our group (Eur J Haematol, 2006). Ex vivo expanded allogeneic MSC were intravenously infused at the dose of 1×106 MSC/kg of recipient body weight. The conditioning regimen of the HSCT consisted in Fludarabine and ATG combination and 5× 106 CD34 cells were infused concomitantly with 1.106 MSC cells. We did not observed any immediate or delayed side effects after the MSC infusion. The patient did not presented any complications after the HSCT. At day 8 of the transplantation she had an normal hematological recovery. The platelet nadir was 72.000/mm3 and she did not need any transfusion. With regards of her neurological status, since 22 months the patient had no new deterioration and we observed a stabilisation of the clinical manifestations.Conclusions: This case report suggests the feasibility and the potential efficacy of reduced intensity conditioning allogeneic HSCT with MSC infusion for patient with MLD. A larger trial is required to confirm this observation.

Conventional versus reduced‐intensity conditioning regimen for allogeneic stem cell transplantation in patients with hematological malignancies

Allogeneic hematopoietic stem cell transplantation (HSCT) from human leukocyte antigen (HLA)-compatible sibling donors is a potential curative treatment for hematological and non-hematological malignancies. Nevertheless, high mortality rates may be associated with this therapy, especially in older patients, those with other comorbidities or who receive a second HSCT. We analyzed the factors associated with transplant-related mortality (TRM) and overall survival in 157 consecutive adult patients (104 males and 53 females) who received a HSCT [29 bone marrow (BM) transplantation and 128 peripheral blood (PB) transplantation] from a HLA-identical sibling between January 1995 and March 2002 in our institution. One hundred patients received a standard conditioning prior to HSCT (STAND) and 57 patients received a reduced-intensity conditioning (RIC) HSCT. Fifty-eight patients were in an early phase at transplant and 99 in a non-early phase. Median age was 46 yr (16-66), and 90 patients (57%) were >45 yr of age. Patients in the RIC group were older than those in the STAND group, and had a higher proportion of non-early disease phases including a prior autologous HSCT in 39%. Median follow-up for survivors was 28 and 15 months in the STAND and RIC groups (P < 0,001), respectively. Cumulative incidence of TRM at 2 yr was 30% [95% confidence interval (CI) 22-41%] for the STAND group and 22% (95% CI 13-37%) for the RIC group [non-significant (NS)]. Factors associated with a higher TRM in multivariate analysis were: STAND vs. RIC conditioning regimen [relative risk (RR) 5.4; 95% CI 2.3-12.8; P < 0.001]; age > or =45 yr vs. <45 yr (RR 5; 95% CI 2.4-10.8, P < 0.001); second vs. first HSCT (RR 2.8, 95% CI 1.3-6.3, P = 0.01) and non-T-cell-depleted vs. T-cell-depleted graft (RR 2.7, 95% CI 1.3-5.8, P = 0.009). Overall survival (OS) at 2 yr was 52.5 +/- 10.4% for STAND group and 59 +/- 16.8% in RIC group. Factors associated with poorer OS in multivariate analysis were: STAND vs. RIC conditioning regimen (RR 3.4, 95% CI 1.7-6.9, P = 0.001); age > or =45 vs <45 yr (RR 2.5, 95% CI 1.4-4.5, P = 0.002) and diagnosis [other than chronic myeloid leukemia (CML) vs. CML] (RR 2.6, 95% CI 1.2-5.7 P = 0.02). Our results indicate that the introduction of RIC allogeneic HSCT for patients at high risk for TRM (advanced age, prior HSCT and non-T-cell depletion) leads to a reduction in the TRM and improvement in the OS.

Stable mixed chimerism after T cell-depleted allogeneic hematopoietic stem cell transplantation using conditioning with low-dose total body irradiation and fludarabine.

Although reduced intensity conditioning (RIC) before allografting is associated with low treatment-related morbidity and mortality, graft-versus-host disease (GVHD) remains a significant complication of hematopoietic stem cell transplantation (HSCT). T cell depletion (TCD) has been successfully used in conventional allotransplantation to reduce the incidence of GVHD, but was associated with an increased rate of engraftment failure. In a small cohort of six patients at high risk of developing GVHD we have determined whether sustained engraftment could be achieved using reduced intensity conditioning and T cell depletion in combination. All patients engrafted and 5/6 developed high levels (i.e. > or =95%) of donor chimerism, even though mismatched related or matched unrelated donors were used. Only one patient developed acute GVHD, as he received donor lymphocyte infusions (DLI) for relapse. In summary, TCD might be a useful prophylactic tool in RIC allogeneic HSCT. Although TCD after RIC might be associated with high relapse rate, as 5/6 patients are not in remission, this combined strategy might be appropriate for patients with less aggressive malignant or non-malignant diseases in which high transplant-related morbidity and mortality is not acceptable.