Matched Unrelated Donor Transplantation Research Articles

Improved survival in matched unrelated donor transplant for childhood ALL since the introduction of high-resolution matching at HLA class I and II

We present the first detailed study analysing OS in BMT for paediatric ALL following the introduction of high-resolution (HR) HLA matching. A total of 356 consecutive paediatric ALL stem cell transplants performed between 1988 and 2007 were reviewed; 80 of them were performed following the introduction of HR HLA class I and class II matching to the transplant programme in 2002. Comparisons of matched unrelated donor (MUD) transplant outcomes before and after this period were made. Matching at the HR level for HLA-A, -B, -C, -DRB1 and -DQB1 (HR-MUD) correlated with a greater than 25% improvement in 2- and 5-year OS in paediatric ALL patients transplanted with MUDs (P=0.009, P=0.005, respectively). Two-year OS for contemporaneous HLA-matched sibling transplants (80.8%) and HR-MUD transplants (78.8%) was equivalent. At 6%, non-relapse mortality (NRM) in MUD transplants since 2002 was significantly reduced compared with previous epochs. Changes in treatment and epoch-dependent improvements in outcome were reviewed for possible confounders to the influence of HR typing using univariate and multivariate analysis.

Low Levels of 25-Hydroxyvitamin D Prior to Allogeneic Transplantation Correlate with the Development of Chronic Graft-Versus-Host Disease

Abstract 4063 Graft-versus-host disease (GVHD) remains a significant cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation. GVHD is mediated by the activation and expansion of donor derived alloreactive lymphocytes stimulated in part by residual host dendritic cells (DCs) and donor DCs with cross presentation of alloantigens. Vitamin D is a hormone essential for calcium homeostasis and exhibits potent immunomodulatory characteristics. We have demonstrated that vitamin D exposure inhibits DC maturation and DC mediated stimulation of allogeneic T cells. As such, we hypothesized that vitamin D deficiency may result in the enhanced capacity of DCs to induce GVHD. In this study, we performed a retrospective case-control study to evaluate whether monohydroxyvitamin D levels measured in serum samples obtained from patients prior to allogeneic transplantation were predictive of the risk for GVHD. Fifty-three patients aged 18–60 who underwent a myeloablative matched related or matched unrelated donor transplant between December 2000 and December 2009 at Dana Farber Cancer Institute (DFCI) were included in the analysis. 25-OH vitamin D concentrations were measured by an ELISA assay on serum samples that had been cryopreserved between one and three months prior to transplantation. All patients were alive and evaluable at day 100. The median 25-OH vitamin D level was 21.9 ng/mL (range 7.8–45.7). Patients were divided into two cohorts based on a vitamin D level: < 25 ng/mL (32 patients) or ≥25 ng/mL (21 patients). There was no difference between the groups with respect to patient or donor age, donor type (matched related versus unrelated donor), cell source (peripheral blood versus bone marrow), patient-donor sex matching, myeloid versus lymphoid malignancy, risk status, patient/donor CMV status, conditioning regimen, or GVHD prophylaxis regimen. The cumulative incidence of grades II-IV acute GVHD at 100 days was 53.1% in the group with vitamin D level <25 versus 33.3% in the group with vitamin D≥25 (p=0.13). Remarkably, the cumulative incidence (CI) of chronic GVHD (cGVHD) at 2 years in patients with 25-OH vitamin D <25 was 63.8%, compared to 23.8% in patients with vitamin D levels ≥ 25 (p=0.009). Similarly the 2 year CI of extensive cGVHD was significantly greater in patients with vitamin D levels <25 compared to those with ≥25 (54.5% versus 14.3%, p=0.005). This result is consistent in multivariable competing risks model for which patient and transplant related factors mentioned above were adjusted (HR 5.26, p=0.02). [Figure 1][1] represents the CI of cGVHD with death and relapse as a competing risk. Three-year progression-free survival and overall survival were similar between the two groups (51% vs. 47%, p=0.61; and 53% vs. 50%, p=0.57 respectively). In summary, vitamin D deficiency prior to allogeneic transplantation is associated with a significantly increased risk of chronic GVHD. A prospective clinical trial evaluating the use of vitamin D for the prevention of chronic GVHD is planned. ![Figure 1:][2] Figure 1: Cumulative Incidence of cGVHD with Death/Relapse as a Competing Risk Disclosures: No relevant conflicts of interest to declare. [1]: #F1 [2]: pending:yes

T Cell–Depleted Partial Matched Unrelated Donor Transplant for Advanced Myeloid Malignancy: KIR Ligand Mismatch and Outcome

To evaluate the applicability of high-dose conditioning, CD34 selection, and enhanced natural killer (NK) cellalloreactivity reported as promising after haploidentical transplantation, we tested the same strategy for patients with advanced/high-risk myeloid leukemia lacking either related or well-matched unrelated donors (URD). In a prospective multicenter clinical trial using pretransplantation conditioning of thiotepa (5 mg/kg/day × 2), fludarabine (40 mg/mg/M(2)/day × 5), and total body radiation (800 cGy) plus thymoglobulin (2.5 mg/kg/day × 2), as well as a CD34 selected filgrastim stimulated peripheral blood graft from a partial matched URD, we treated 24 patients. The patients (median age 40 [range: 22-61]) were mismatched at 1-3 of 10 HLA loci with their donors; all were mismatched at HLA-C. Thirty-seven percent were ethnic or racial minorities. Twenty-one of 24 engrafted promptly with 1 primary graft failure and 2 early deaths. The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) (34%, 95% confidence interval [CI], 14-54%), chronic GVHD (20%, 95% CI, 2%-38%), and relapse (26%, 95% CI, 8%-84%) were unaffected by KIR ligand donor:recipient mismatch (n = 5) versus KIR ligand match (n = 19). Only 3 (12%) had grade III-IV GVHD. Nonrelapse occurred in 17% (95% CI, 30%-31%) by 100 days and in 35% (95% CI, 15%-55%) by 1 year. Two-year survival and leukemia-free survival were each 40% (95% CI, 21%-59%) and was similar in KIR ligand matched or mismatched patients. Infections, mostly in the first 2 months, were frequent, and were the cause of death in 5patients (35% of deaths). T cell recovery and NK cell proliferation and functional maturation were not altered by KIR ligand match or mismatch status. For these high-risk patients, this high intensity regimen and T depleted approach yielded satisfactory outcomes, but logistical difficulties in arranging URD grafts for patients with high-risk, unstable leukemia limited accrual. Improvements in peritransplantation disease control and additional measures to augment the allogeneic graft-versus-leukemia effect are still required.

Donor-specific anti-HLA Abs and graft failure in matched unrelated donor hematopoietic stem cell transplantation

AbstractAnti-HLA donor-specific Abs (DSAs) have been reported to be associated with graft failure in mismatched hematopoietic stem cell transplantation; however, their role in the development of graft failure in matched unrelated donor (MUD) transplantation remains unclear. We hypothesize that DSAs against a mismatched HLA-DPB1 locus is associated with graft failure in this setting. The presence of anti-HLA Abs before transplantation was determined prospectively in 592 MUD transplantation recipients using mixed-screen beads in a solid-phase fluorescent assay. DSA identification was performed using single-Ag beads containing the corresponding donor's HLA-mismatched Ags. Anti-HLA Abs were detected in 116 patients (19.6%), including 20 patients (3.4%) with anti-DPB1 Abs. Overall, graft failure occurred in 19 of 592 patients (3.2%), including 16 of 584 (2.7%) patients without anti-HLA Abs compared with 3 of 8 (37.5%) patients with DSA (P = .0014). In multivariate analysis, DSAs were the only factor highly associated with graft failure (P = .0001; odds ratio = 21.3). Anti-HLA allosensitization was higher overall in women than in men (30.8% vs 12.1%; P < .0001) and higher in women with 1 (P = .008) and 2 or more pregnancies (P = .0003) than in men. We conclude that the presence of anti-DPB1 DSAs is associated with graft failure in MUD hematopoietic stem cell transplantation.

Low Levels of 25-Hydroxyvitamin D Prior to Allogeneic Transplantation Correlate with the Development of Chronic Graft-Versus-Host Disease,

Abstract 4063Graft-versus-host disease (GVHD) remains a significant cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation. GVHD is mediated by the activation and expansion of donor derived alloreactive lymphocytes stimulated in part by residual host dendritic cells (DCs) and donor DCs with cross presentation of alloantigens. Vitamin D is a hormone essential for calcium homeostasis and exhibits potent immunomodulatory characteristics. We have demonstrated that vitamin D exposure inhibits DC maturation and DC mediated stimulation of allogeneic T cells. As such, we hypothesized that vitamin D deficiency may result in the enhanced capacity of DCs to induce GVHD. In this study, we performed a retrospective case-control study to evaluate whether monohydroxyvitamin D levels measured in serum samples obtained from patients prior to allogeneic transplantation were predictive of the risk for GVHD. Fifty-three patients aged 18–60 who underwent a myeloablative matched related or matched unrelated donor transplant between December 2000 and December 2009 at Dana Farber Cancer Institute (DFCI) were included in the analysis. 25-OH vitamin D concentrations were measured by an ELISA assay on serum samples that had been cryopreserved between one and three months prior to transplantation. All patients were alive and evaluable at day 100. The median 25-OH vitamin D level was 21.9 ng/mL (range 7.8–45.7). Patients were divided into two cohorts based on a vitamin D level: < 25 ng/mL (32 patients) or ≥25 ng/mL (21 patients). There was no difference between the groups with respect to patient or donor age, donor type (matched related versus unrelated donor), cell source (peripheral blood versus bone marrow), patient-donor sex matching, myeloid versus lymphoid malignancy, risk status, patient/donor CMV status, conditioning regimen, or GVHD prophylaxis regimen. The cumulative incidence of grades II-IV acute GVHD at 100 days was 53.1% in the group with vitamin D level <25 versus 33.3% in the group with vitamin D≥25 (p=0.13). Remarkably, the cumulative incidence (CI) of chronic GVHD (cGVHD) at 2 years in patients with 25-OH vitamin D <25 was 63.8%, compared to 23.8% in patients with vitamin D levels ≥ 25 (p=0.009). Similarly the 2 year CI of extensive cGVHD was significantly greater in patients with vitamin D levels <25 compared to those with ≥25 (54.5% versus 14.3%, p=0.005). This result is consistent in multivariable competing risks model for which patient and transplant related factors mentioned above were adjusted (HR 5.26, p=0.02). Figure 1 represents the CI of cGVHD with death and relapse as a competing risk. Three-year progression-free survival and overall survival were similar between the two groups (51% vs. 47%, p=0.61; and 53% vs. 50%, p=0.57 respectively). In summary, vitamin D deficiency prior to allogeneic transplantation is associated with a significantly increased risk of chronic GVHD. A prospective clinical trial evaluating the use of vitamin D for the prevention of chronic GVHD is planned. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Outcomes in Allogeneic Hematopoietic Stem Cell Transplant Patients ≥ 60 Years of Age with a Novel Reduced Intensity Conditioning Regimen Incorporating Extracorporeal Photopheresis,

Abstract 4153The optimal preparative regimen for older patients undergoing hematopoietic stem cell transplantation (HSCT) is unclear. We routinely employ a reduced intensity conditioning regimen consisting of extracorporeal photopheresis (ECP) on days −6 and −5, Pentostatin 4 mg/m2/day by continuous infusion on days −4 and −3, and 600 cGy total body irradiation in 3 divided fractions on days −2 and −1 (“PPT regimen”) for patients greater than 60 years of age (Bone Marrow Transp 2004; 33:881). We now report outcomes of 38 consecutive patients ≥ 60 years old (median 62, range 60–70) (M 22, F 16) transplanted at our center between 1/1/00 and 4/1/11 for hematologic malignancies: AML (n=23), MDS (n=10), ALL (n=1), CLL (n=1), NHL (n=2) and MM (n=1). Twenty-six (68.4%) received matched related and 12 (31.6%) 6/6 matched unrelated donor (MUD) grafts. Twenty-five (65.8%) received marrow and 13 (34.2%) peripheral blood stem cell grafts. Median time to neutrophil engraftment was 16 days (3–25). Survival at day 100 was 84% (32/38), with a 13% TRM (5/38) and 3% (1/38) incidence of relapse-related death. Actuarial 1-year overall survival (OS) for all patients was 45% (95% CI 28 – 61%), and median OS in all patients was 10.6 months (95% CI 4.6 – 25.7 months). Estimated 1-year event-free survival, defined as freedom from relapse, progression, or death from any cause, was 44% (95% CI 27 – 59%). Median event-free survival for the entire cohort was 7 months (95% CI 3.6 – 25.6 months).Grade II and grades III/IV acute GvHD (aGvHD) occurred in 8 (21%) and 2 (5%) patients respectively within 1 to 8 weeks of HSCT (median 16 days). After day 100, 6 patients had died, 1 was missing data, and 23 (74% of remaining patients and 60% of the original cohort) had symptoms of GvHD. Fourteen met NIH consensus criteria for chronic GvHD (cGvHD) including 6 with severe classic or overlap cGvHD while 6 had recurrent, 2 persistent and 1 delayed aGvHD. Of those with aGvHD after day 100, 2 patients exhibited ≥ grade III disease. Median time to onset of cGvHD was 4.1 months (3.3 – 11.7). Among patients who received marrow as their stem cell source (n=25), incidence of grades II-IV aGvHD was 32% (24% grade II, 8% grade III/IV), and incidence of any GvHD from day 100 up to date of death or last follow-up was 68%. Among those who received blood stem cells (n=13) incidence of grades II-IV aGvHD was 15% (all grade II) and incidence of GvHD from day 100 until date of death or last follow-up was 83%. There was no statistically significant difference between those who received marrow versus blood stem cells with respect to incidence of either grade II-IV aGvHD or GvHD after day 100 (P =0.27 and 0.36). For those who received MUD transplants (n=12), incidence of grades II-IV aGvHD and of any post-day 100 GvHD were 42% (33% grade II, 8% grade IV) and 75% respectively, and in those who received related donor transplants (n=26) were 19% (15% grade II, 4% grade IV) and 74%, respectively. There was no statistically significant difference between MUD HSCT versus related donor HSCT patients with regard to grade II-IV aGvHD or GvHD after day 100 (P =0.14 and 0.94). In conclusion, our approach was well tolerated by HSCT patients > 60 years old, provided prompt myeloid recovery and had an acceptable incidence of post-day 100 severe chronic (19%) or > grade II late acute GvHD (6%). Disclosures:Off Label Use: Pentostatin and Extracorporeal photopheresis are not FDA approved for conditioning prior to allogeneic transplant. Comenzo:Elan: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Neotope: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Allogeneic Stem Cell Transplantation Is Associated with Prolonged Disease Control in Chemosensitive Aggressive Histology Lymphoma Patients When Done Early

Abstract 4525 IntroductionAllogeneic stem cell transplantation (Allo-SCT) is a treatment option in aggressive histology lymphoma (AG-NHL) patients who have either failed or relapsed after autologous SCT (ASCT) or if the potential for long term disease control after ASCT is limited. There is limited data in literature regarding the long term outcome of allo-SCT in AG-NHL. MethodsWe did a retrospective analysis of all aggressive histology patients who underwent Allo-SCT between 1989 and 2009 at our centre. A total of 41 patients with AG-NHL [diffuse large B cell lymphoma (DLBCL) and variants, follicular lymphoma grade 3 (FL3), biopsy proven aggressive transformation of indolent lymphoma (TRIL)] underwent Allo-SCT. All patients were in a chemosensitive remission at time of transplantation. The conditioning regimen was BU-CY in the majority (36 or 88%) of patients and 3 patients had reduced intensity transplantation (RIC) with fludarabine-based regimens. GVHD prophylaxis was cyclosporine and methotrexate until 2009 and was cyclosporine and mycophenolate mofetil after that. Alemtuzumab was used in matched unrelated donor (MUD) transplants in 5 (12%) cases. ResultsThere were 22 (54%) males and 19 (46%) females. The median age at BMT was 48 years (range: 20–65). Fifteen (37%) had DLBCL, 19 (46%) had TRIL and 7 (17%) had FL3. Fifteen (37%) patients had received 2 or less lines of chemotherapy and 26 (63%) had received more than 2 lines of therapy at time of transplantation. The median number of chemo regimens was 3 (range: 1–7). The chemotherapy regimens included prior anthracyclines in 40 (98%), prior platinum in 26 (63%) and prior mini BEAM in 19 (46%). Six (15%) patients had received Rituximab and 9 (22%) had received prior RT. Seven (17%) patients had prior ASCT. Thirty-five (85%) of patients received matched related donor transplant whereas 5 (12%) received MUD transplant. The graft source was bone marrow in 33 (80%) and peripheral blood stem cells in 8 (20%). Grade 1–2 acute GVHD was seen in 53% and grade 3–4 in 9%. Chronic GVHD was seen in 51% patients. With a median follow up of 49 months and 96 months in those who are alive, five (12%) patients have relapsed, 20 (49%) patients are alive and in remission. Non relapse mortality (NRM) was 16/41 (39%) and predominantly related to infection. The overall survival (OS) and progression free survival (PFS) of the entire cohort at 60 months was 55% (Fig-1). Patients, who had achieved CR pre-allo-SCT (compared to PR) had a statistically significantly improved PFS and OS (100% survival for those who were in CR). In multivariate analysis, number of chemotherapy regimens (≤2) was associated with improved OS (p=0.015) and presence of chronic GVHD showed a trend towards significant OS (p=0.052) ConclusionsWith a median follow up of 96 months in survivors, myeloablative allo-SCT is associated with durable remission in patients with chemosensitive AG-NHL. Results are less favourable in patients who have received multiple prior regimens. NRM remains a significant concern with myeloablative regimens. We believe there is a role for myeloablative regimens and research should focus on ways to reduce NRM in this setting. Disclosures:Gupta:Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. [Display omitted]

Alemtuzumab-Based Conditioning Protocols for Paediatric Matched Unrelated Donor Transplants for Severe Aplastic Anaemia: An Important Alternative to TBI Containing Regimens

Alemtuzumab-Based Conditioning Protocols for Paediatric Matched Unrelated Donor Transplants for Severe Aplastic Anaemia: An Important Alternative to TBI Containing Regimens

Allogeneic hematopoietic cell transplantation for hematologic malignancy: relative risks and benefits of double umbilical cord blood

AbstractEffectiveness of double umbilical cord blood (dUCB) grafts relative to conventional marrow and mobilized peripheral blood from related and unrelated donors has yet to be established. We studied 536 patients at the Fred Hutchinson Cancer Research Center and University of Minnesota with malignant disease who underwent transplantation with an human leukocyte antigen (HLA)–matched related donor (MRD, n = 204), HLA allele–matched unrelated donor (MUD, n = 152) or 1-antigen–mismatched unrelated adult donor (MMUD, n = 52) or 4-6/6 HLA matched dUCB (n = 128) graft after myeloablative conditioning. Leukemia-free survival at 5 years was similar for each donor type (dUCB 51% [95% confidence interval (CI), 41%-59%]; MRD 33% [95% CI, 26%-41%]; MUD 48% [40%-56%]; MMUD 38% [95% CI, 25%-51%]). The risk of relapse was lower in recipients of dUCB (15%, 95% CI, 9%-22%) compared with MRD (43%, 95% CI, 35%-52%), MUD (37%, 95% CI, 29%-46%) and MMUD (35%, 95% CI, 21%-48%), yet nonrelapse mortality was higher for dUCB (34%, 95% CI, 25%-42%), MRD (24% (95% CI, 17%-39%), and MUD (14%, 95% CI, 9%-20%). We conclude that leukemia-free survival after dUCB transplantation is comparable with that observed after MRD and MUD transplantation. For patients without an available HLA matched donor, the use of 2 partially HLA-matched UCB units is a suitable alternative.

Superior Outcomes with Matched Unrelated Donors Compared with One Human Leukocyte Antigen Mismatched Related Donors In Allogeneic Hematopoietic Stem Cell Transplantation

AbstractAbstract 907Most candidates for hematopoietic stem cell transplantation lack a human leukocyte antigen (HLA)-identical sibling donor; however, many patients may have a related donor with whom they are mismatched at one antigen/allele. It is not known whether such a match is preferable to a matched unrelated donor (MUD). We hypothesized that, in transplantation using related donors, adding a single HLA antigen/allele mismatch, identified through high resolution HLA typing at HLA-A, -B, -C, -DRB1 and -DQB1, would be associated with worse outcomes than transplantation using matched unrelated donors. Patients and Methods:To test this hypothesis, we analyzed outcomes (survival, relapse, non-relapse mortality) of 367 patients who received transplants from either a 10/10 MUD (n=318) or a one-antigen/allele mismatched related donor (MRD) by 7/8 HLA typing (n=49) treated during the same period of time (1995-2009) at our institution. All patients had intermediate/high-resolution HLA typing at all 5 loci either prospectively or retrospectively, if treated after or before year 2002. Of the 49 patients treated with mismatched related donors, 28 patients (57%) had one antigen/allele mismatched at HLA class I or II loci (or 9/10), 18 patients (37%) had 2 alleles mismatched (or 8/10), and 3 patients (6%) had 3 alleles mismatched (or 7/10). From the 28 patients with a one-allele mismatch, 24 had class I mismatches at either HLA-A or -B loci, and 4 had class II mismatches at either HLA-DR or -DQ loci. Characteristics between the MUD group and 9/10 MRD group were similar [median age 53 vs. 47 years (p=0.08); AML/MDS diagnosis 84% vs. 82% (p=0.5); active disease at transplant 59% vs. 57% (p=0.9); myeloablatie conditioning 63% vs. 75% (p=0.2); bone marrow stem cells 58% vs. 70% (p=0.2); pentostatin use 14% vs. 11% (p=0.4); median year of transplant 2006 vs. 2004, respectively] except more patients in the MUD group received ATG (96% vs. 68%, p=0.02). Results:Outcomes at 3-years were analyzed for the 28 consecutive patients who had received a transplant from a 9/10 MRD based on 5-loci (including -DQB1) HLA typing. Graft failure was more common in patients treated from 9/10 related donors than from MUD. The incidences of primary and secondary graft failure for the 9/10 MRD were 7% and 14%, respectively, whereas none of the MUD transplant recipients had either primary or secondary graft failure (p= 0.02). Cumulative incidence of progression was 40% vs. 25% (p=0.02, HR 1.9, CI 1.1–3.9), non-relapse mortality 40% vs. 26% (p=0.05, HR 1.9, CI 1.0–3.6) and grade II-IV a GVHD was 27% vs. 38% (p=0.4, HR 0.7, CI 0.3–2.5) for the two groups, respectively. Median survival was 6 months for the 9/10 MRD vs. 18 months for the MUD group. The overall survival and progression-free survival rates were 19% and 45% (p=0.007, HR 1.8, CI 1.2–2.9) and 19% vs. 42% (p=0.006, HR1.8, CI 1.2–2.9), respectively. Outcomes for 9/10 MRD transplant patients with class I mismatches (n=24) were significantly worse than outcomes in those with MUD transplants (n=318). The 2-year actuarial OS rate was 27% for the 9/10 MRD and 48% for the MUD transplant group (HR 1.9; 95% CI 1.1 – 3.1; p=0.01). Conclusion:These results indicate that transplant outcomes for patients treated from a one-antigen/allele mismatch related donor are significantly worse than from a MUD, primarily due to increased non-relapse mortality. Patients receiving transplants form a 9/10 related donors, at least with a class I mismatch, should be treated on investigational protocols. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

The Equilibration of Peripheral Blood and Tissue CD3+ T Cell Engraftment Is Influenced by Graft Versus Host Disease Following Reduced Intensity Conditioning Stem Cell Transplantation

AbstractAbstract 2546Alemtuzumab-containing reduced intensity transplantation regimens frequently induce a state of partial T cell chimerism in the blood of the recipient. It has been widely shown that partial T cell chimerism is associated with freedom from graft versus host disease (GVHD) and that the occurrence of GVHD is often associated with rapidly rising donor T cell engraftment. The mechanism by which this occurs remains unknown and recipient cells may be killed, out-competed for homeostatic niches or simply diluted out by expanding donor T cells. The skin, a target organ of GVHD, normally contains T cells which enter from the blood in the steady state. Studies in mice have highlighted the gate-keeping function of inflammation in allowing trafficking of host-reactive donor T cells into tissues during conversion from mixed to full donor chimerism in blood. This implies that the equilibration of donor engraftment in the blood and tissue may occur more rapidly in patients at risk for GVHD. To test this hypothesis, we set out to define the relationship between skin and blood donor T cell engraftment in patients with and without GVHD. Methods:We studied a group of 51 patients receiving fludarabine melphalan (FM) conditioning with alemtuzumab 30mg for matched related donors and 60mg for matched unrelated donors. Skin biopsies were obtained at 28 and 100 days post transplant, dermal T cells isolated by migration and chimerism assessed in sex-mismatched transplants by combined immunofluorescence/in situ hybidization for XY chromosomes. Peripheral blood myeloid (CD15+) and T cell (CD3+) chimerism was determined by short tandem repeat amplification at monthly intervals after transplantation. All patients gave consent for clinical follow up and post transplant blood and skin sampling for research purposes, according to protocols approved by the local research ethics committee of Northumberland and North Tyneside. Results:All patients achieved >95% myeloid engraftment by day 100. Median (range) T cell engraftment was variable and significantly higher after MUD transplants: 70% (9-99%) than MRD transplants: 21% (5-85%; Mann Witney p <0.05). The incidence of acute GVHD was also greater after MUD transplantation at 47% (grade I or II) compared with 11% (grade I only) for MRD recipients. Overall a positive correlation was observed between donor T cell engraftment in skin and blood at all time points (r = 0.5792; P 0.0187) and at 100 days (r = 0.6570; P 0.0281). Analysis of the data with respect to GVHD showed a further interesting finding. Patients who developed GVHD had the closest correlation between blood and skin donor engraftment, even when they were in a state of partial T cell chimerism prior to the onset of GVHD. Patients who did not develop GVHD but nonetheless eventually achieved full donor engraftment in the blood tended to show lower levels of donor T cell engraftment in the dermis at day 100. Individual examples of patients who did not develop GVHD are: blood 77%, dermis 37%; blood 77%, dermis 6%; blood 92%, dermis 25%, compared with patients who did develop GVHD: blood 55%, dermis 56%; blood 90%, dermis 75%; blood 100%, dermis 100%. Conclusion:This analysis supports the hypothesis that the equilibration of blood and tissue donor T cells is influenced by GVHD and may offer a means to predict patients at risk of GVHD after withdrawal of immunosuppression or donor lymphocyte infusion. Disclosures:No relevant conflicts of interest to declare.

A Study of Factors Influencing Outcome In Patients with Haematological Malignancy Requiring High Dependency Support In a Large UK Haematology and Bone Marrow Transplant Centre

AbstractAbstract 4732 Introduction:Controversy surrounds the decision to admit a patient with Haematological malignancy to receive treatment in a Level 2- High Dependency Unit with patients needing single organ support or Level 3 – intensive care with patents requiring two or more organ support setting. Little is known regarding factors influencing outcome of such patients when admitted to such a setting. Methodology:We performed a retrospective case note review supplemented by computer database analysis of all patients admitted to the High Dependency Unit (HDU) at Christie Hospital, Manchester between October 2008 and January 2010. Results:53 episodes in 53 patients (Median age 60 (IQR 44–66) years; 36 (68%) male) with known haematological malignancy were studied. The underlying diagnoses included AML (40%), NHL/HCL (13%), CLL (11%), Multiple Myeloma (11%), ALL (9%) and CML (6%). 51% (27/53) had undergone Stem Cell Transplantation; 15% (8/53) Allogeneic from a Matched Unrelated Donor, 23% (12/53) Sibling and 13% (7/53) Autologous. Of the 20 Allogeneic transplants, 7 (35%) had Full Intensity and 11 (55%) had Reduced Intensity conditioning. 25% had Graft versus Host disease (GVHD) at the time of HDU admission.The trigger leading to HDU admission was septic shock (46%), bacterial pneumonia (24%), cardiac decompensation (10%) and other causes in 20% (viral pneumonia, infective colitis and neurological). Admission APACHE score in the overall cohort was 21 (IQR 17–25); 32% (17/53) required CPAP whilst 40% received inotropic support. Pre admission observations noted to be associated with subsequent increased mortality were tachycardia (heart rate>100), tachypnoea (respiratory rate > 20 per minute), systolic hypotension (SBP < 70mm Hg), acidaemia (pH < 7.4) and septic shock requiring ionotropic support. Of note is that neutropenia (absolute neutrophil count <1) at the time of HDU admission did not seem to affect outcome.In-hospital HDU mortality in the overall sample was 13% (7 of 53 patients) with median length of stay being 4 (IQR 2–7) days. 38% (20/53) were alive at 1 month and 31% (16/53) were still alive by 6 months post HDU discharge. 28% (15/53) were transferred from HDU for Level 3 support and all these patients were intubated and mechanically ventilated. Of these transfers, 40% (6/15) survived to discharge.Patients receiving Allogeneic Sibling donor transplants exhibited improved 1 and 6 month survival when compared to Allogeneic Matched Unrelated Donor transplant recepient (p=0.011) although no statistically significant difference in short and long term survival or in length of stay on HDU were noted between those who had received Full Intensity Conditioning compared to Reduced Intensity Conditioning. Using Kaplan-Meier Survival analysis, median survival in those with an underlying diagnosis of MDS/AML was 11 months compared to 3 months in NHL and CLL. Conclusion:Patients with Haematological conditions do not necessarily exhibit a uniformly poor outcome when admitted for Level 2 (High Dependency) care with 87% surviving the episode. This is further emphasized by the fact that 40% patients requiring intubation and invasive mechanical ventilation survived to discharge. Matched unrelated donor transplants fared worse compared to Sibling and Autologous transplant cases. Interestingly, patients receiving Full and Reduced Intensity conditioning regimes showed no difference in admission mortality and length of stay. Disclosures:No relevant conflicts of interest to declare.

The Outcome of the Combination of Tacrolimus, Sirolimus, and ATG for GvHD Prophylaxis on Allogeneic Stem Cell Transplantation From Matched Unrelated Donors

AbstractAbstract 2345 Background:Graft-vs-Host Disease (GvHD) remains a significant complication of allogeneic stem cell transplantation from matched unrelated donors (MUD). Compared to MTX-based regimen, Tacrolimus/Sirolimus was found to decrease the incidence of acute GvHD (Keil et al, Biol Blood Marrow Transplant. 2009;16(2):S319, and Cutler et al, Blood. 2007;109:3108–14), whereas, the incorporation of Antithymocyte globulin (ATG) into MTX-based regimen decreases the incidence of chronic GvHD (Bacigalupo et al, Biol Blood Marrow Transplant. 2002;8(12):656–61). There are no reports of the outcome of the combination of Tacrolimus/Sirolimus and ATG. We compared the results of MUD using tacrolimus and sirolimus (day-3 to day +180) combined with ATG (2.5 mg/kg day −3,−2, and −1) (TSA) prophylaxis in consecutive patients treated at our institution from September 2006 to March 2009, with those using MTX-based prophylaxis without ATG in consecutive patients treated from January 2000 to August 2006. The primary endpoints were incidence of acute and chronic GvHD, lethal infectious complications, relapse, and survival. Result:Between 1/2000 and 3/2009, 71 MUD stem cell transplants were performed. 27 patients received TSA regimen as GvHD prophylaxis and 44 patients received traditional MTX-based prophylaxis without ATG. More patients in the TSA group received PBSC compared to the MTX group (63% vs. 36%; P=0.029), otherwise both groups were matched for age, sex, underline malignancies, disease risk per ASBMT criteria, degree of HLA-match, CMV serology, and conditioning regimens. The cumulative incidence of Grade II-IV classic acute GvHD at day +100 was significantly lower in the TSA group compared to control group (11.7% vs. 41.6%; Gray's test P =0.008). However, the cumulative incidence of aGvHD at day +365 was not statistically significant between both groups (33.1% vs. 44.4%; Gray's test P=0.154); this was due to an increase rate of delayed-onset aGvHD in TSA group (18.5%) compared to MTX group (2.3%). The rate of limited cGvHD was 7.1% vs. 30% in the TSA group and MTX group, respectively (Fisher's P= 0.12). 23% of patients surviving beyond day +100 in MTX group developed extensive/overlap cGvHD, whereas, there were no cases in the TSA group. The rate of CMV infection in patients not receiving corticosteroid treatment for GVHD was higher in the TSA group, although not statistically significant (36.8% vs. 16%, P=0.27). The rate of invasive fungal infections was similar (10.7% vs. 11.8%). The cumulative incidence of relapse at 2 years was 38.5% vs. 22.8% in the TSA and MTX groups, respectively (Gray's test P=0.18). Non-relapse mortality at 2 years was similar in both groups (42% vs. 48%; Grays's test P=0.8). Day +100 mortality was 14.4% and 27.3% in TSA and MTX group respectively. The median survivals were 251 days (95% CI, 170–332) vs. 349 days (95% CI, 236–462) for TSA and MTX groups, respectively. The 1- and 2-year overall survival were 42.3% and 31.7% for TSA group vs. 47.7% and 34.1% for MTX group, respectively (P=0.704). While the mortality rate from bacterial sepsis were equivalent, more patients in the TSA group who were not receiving corticosteroid treatment for aGvHD died from viral and fungal infection (14.3% vs. 0% at 12 months, Fisher's P=0.014). Summary:This is the first report of the combination of TSA for GvHD prophylaxis in MUD transplants. This regimen resulted in a significant decrease in classic aGvHD as previously reported for combination of Tacrolimus/Sirolimus, and decrease in incidence of cGvHD as reported previously in the studies incorporated ATG in MTX-based regimens. Hence, this did not translate into benefit in overall survival due to an increased rate of relapse and lethal viral and fungal infections with TSA regimen. Our study does not demonstrate an appreciable benefit for the addition of ATG, at the dose used, to sirolimus and tacrolimus for GvHD prophylaxis. Further studies directed at optimizing the dose of ATG to lower the rate of lethal infections may result in an overall benefit. Disclosures:No relevant conflicts of interest to declare.

Donor Selection for Allogeneic Stem Cell Transplantation In Elderly Patients with Advanced MDS: Younger Matched-Unrelated Donor or HLA-Identical Sibling ?

AbstractAbstract 912Allogeneic stem cell transplantation from related and unrelated donors is now a reasonable treatment option for elderly patients with advanced MDS. Retrospective studies have shown that donor age is an independent risk factor for outcome of allogeneic stem cell transplantation. By nature there is a strong correlation between patient's age and age of an HLA-identical sibling. Therefore we investigated whether a young matched unrelated donor should be preferred as donor to an elderly HLA-identical sibling in elderly MDS patients who underwent allogeneic stem cell transplantation. We extracted from the MDS-registry of the EBMT 871 patients who received allogeneic stem cell transplantation between 1986 and 2009 and fulfilled the following criterias: 1. patient's age > 50 years, 2. advanced MDS: RAEB, RAEB-t, CMML or sAML, 3. HLA-identical sibling or fully matched unrelated donor transplantation. From those 871 patients with a median age of 57 years (r., 50–73) 706 received stem cells from an HLA-identical sibling and 168 from a matched unrelated donor, either after standard conditioning (n = 387) or after reduced intensity conditioning (n = 481). After a median follow-up of 30 months, the estimated 3 years overall survival did not differ between patients who received stem cells from HLA-identical sibling or from matched unrelated donor (36 % vs. 34 %, p = 0.8).However, the median donor age was significantly higher for HLA-identical sibling than for MUD transplantation: 56 years (r: 35 – 81 y) vs. 34 years (r: 19 – 64) (p < 0.001). While age as continuous variable did not influence survival in HLA-identical sibling transplantation (HR: 1.002, p = 0.8), but did in MUD transplantation (HR: 1.03, p = 0.009), we performed 4 groups according to donor age: HLA-identical sibling transplantation with donor age > 50 years (n = 535) and donor age 30 – 50 years (n = 169) and matched unrelated transplantation with donor age < 30y (n = 60) and donor age > 30y (n = 107). These groups were well balanced according to disease-status, abnormal cytogenetics, and intensity of the conditioning regimen.The estimated 5 years OS for MUD (donorage < 30y) was 41 % and better than for HLA-identical (donor > 50y) with 31 % (p = 0.03) and HLA-identical (donor 30 – 50 y) with 33 % (p = 0.06), but worse than MUD (donor > 30 y) 24 % (p = 0.003). For overall survival, younger donors (< 30y) remained an independent factor for improved survival in a multivariate Cox model: HR: 0.66 (p = 0.03). Other factors influencing survival were disease status (sAML: HR: 1.31, p = 0.03), standard myeloablative conditioning (HR: 1.40, p = 0.002), and abnormal cytogenetic (HR: 1.26, p = 0.07). In comparison to HLA-identical sibling transplantation the hazard ratio for survival remained less than 1 for matched unrelated donors aged 20–35 years (HR: 0.66–0.99), but the hazard ration increased >1 if matched unrelated donor age becomes greater than 35 years.We conclude that for elderly patients (> 50 years) with advanced MDS who need allogeneic stem cell transplantation a younger unrelated donor should be preferred to an HLA-identical sibling donor. Disclosures:No relevant conflicts of interest to declare.

Brain Natriuretic Peptide (BNP) Elevations In Allogeneic Stem Cell Transplant (ASCT) Recipients at the Time of WBC Engraftment. Correlation with Engraftment Syndrome and Cardiac Dysfunction.

AbstractAbstract 1309Engraftment syndrome (ES) may occur in ASCT recipients at the time of neutrophil recovery and is suspected to reflect increased capillary permeability due to increases in proinflammatory cytokines. Clinical features of ES may include fever, weight gain, rash, hypoxia and pulmonary infiltrates, which are by definition non-cardiogenic and non-infectious in origin. We have observed elevations in BNP in ASCT recipients at the time of WBC engraftment who appear to meet clinical criteria for ES and therefore chose to monitor BNP at the time of hospital admission, on day + 0, and at engraftment to further characterize the relationship between conditioning intensity, ES and cardiac dysfunction.A retrospective review was conducted of pretransplant cardiac features and transplant course in 139 patients undergoing ASCT between January, 2007 and April, 2010. Informative data was available for 122 transplants in 121 pts (74 males, 48 females). Median follow up of survivors was 266 days (minimum 100 days). Median age was 52 yrs (range 17–72). Transplant indication was AML 80 (66%), NHL 20 (16%), other 22 (18%). There were 58 (48%) matched related (MRD) and 64 (52%) unrelated donor (MUD) transplants. Graft source was PBSC (118) and BM (4). High dose (HD) therapy (Busulfan/Fludarabine or TBI/Cyclophosphamide [Cy]) was used in 61 transplants (50%), and reduced intensity (RI) conditioning (Busulfan/Fludarabine based or Pentostatin/TBI based) was used in 61 (50%). Tacrolimus and Mycophenolate were used for GVHD prophylaxis in 104 (85%), and Tacrolimus, Sirolimus, and Methotrexate were used in 18 (15%) mismatched transplants. Filgrastrim was routinely used from day +7 to engraftment. Forty pts (33%) had a history of HTN, CAD, CHF, or arrhythmias, 28 (25%) had received a high cumulative anthracycline dose (≥300 mg/m2 adriamycin equivalent), and 22 (18%) received HD Cy in the conditioning regimen. Results were analyzed according to a clinical diagnosis of ES noted in the medical record as well as by fulfillment of two or more diagnostic criteria (fever, rash, weight gain >2.5%, hypoxia/pulmonary infiltrate of noncardiac and noninfectious origin) present within 96 h of engraftment, as noted by Gorak et al. (BBMT 11:542, 2005).Median admission BNP (nl<100pg/ml) was 57 pg/ml (range 40–386, n=99). Median Day 0 BNP was 59.50 pg/ml (range 40–2580, n=120). Median engraftment BNP was 216 pg/ml (range 40–11200, n=122). Abnormal BNP at admission, on day 0, and at engraftment was seen in 24%, 45% and 76% of pts respectively, with engraftment BNP>400 in 37%. The incidence of ES was 11% by clinical impression and 25% by definition criteria. Ninety four percent of pts with ES had abnormal BNP at engraftment and 61% had BNP >400. Seventy percent of pts with no evidence of ES or overt cardiac complications were noted to have abnormal BNP at engraftment, and 53% had BNP >400. Weight gain occurred in 27% of all pts and of these 90% had elevation in BNP. Six pts experienced acute cardiac complications at the time of WBC engraftment with markedly elevated BNP. There were no primary cardiac deaths.A high cumulative anthracycline dose was associated with elevated BNP on day 0 and at WBC engraftment. High BNP on day 0 was also associated with reduced intensity conditioning but not with age. There was no correlation between cardiac history or HD Cy with elevations in BNP at any point. Elevated BNP at engraftment as well as presence of ES were significantly more common in MUD recipients. No correlation was observed between elevated engraftment BNP or presence of ES with acute GVHD or survival. One-year non relapse mortality was higher in pts with high anthracycline dose (28 vs. 18%%), high BNP at engraftment (22 vs. 7%), or MUD transplant (22 vs. 13%); High anthracycline dose was the only significant predictor of NRM in multivariate analysis. However, in the group of patients with normal BNP on day 0, a BNP >400 at engraftment was an independent predictor of both NRM and OS.Conclusions: Elevations in BNP following ASCT are common and are associated with anthracycline exposure and MUD source. Marked elevations were noted in patients with or without ES or evidence of cardiac compromise and are of uncertain etiology. The high frequency of abnormal BNP in pts with ES and the prognostic value of a de novo elevation in BNP at the time of engraftment suggest the physiologic stress of WBC engraftment following ASCT has important cardiac consequences which deserve further study. Disclosures:No relevant conflicts of interest to declare.

AML Patients In First CR with Intermediate Risk Cytogenetic and High Level of CD34+ Mobilization Have Better DFS After Allogeneic Transplantation.

AbstractAbstract 4563AML patients having a high apheretic yield in CD34+ cells during mobilization have a poor prognosis, independently from cytogenetic risk (Feller 2004, Keating 2004). It is however not known if prognostic value of PBSC mobilization is retained after different post remissional treatment and clinical usefullness of this prognostic information in dealing with intermediate cytogenetic group patients, the more represented AML subgroup in which post remissional therapy is still a controversial issue. METHODSA group of 64 AML adult patients in 1st CR was prospectively studied. PBSC mobilization was attempted following first consolidation course. Cytogenetic assessment at diagnosis was available in 95% of patients. Post remissional treatment was chosen based on cytogenetic risk, sibling donor availability and presence of others prognostic factors, MUD transplants were proposed in cytogenetic high risk patients or in selected young patients with intermediate cytogenetic, Autologous HSC Transplantation was proposed when allogeneic transplant was felt not indicated, no further therapy was administered in patients deemed ineligible for any kind of transplantation. Prognostic significance of CD34+ cells was evaluated measuring DFS in groups of patients identified from value of CD34+ peak in respect to 50th percentile (CD34 peak: 65×10e6/L) and 75th percentile (197×10e6/L). Those patients having a CD34+ cell peak below median value (65×10e6/L) were categorised as LOW MOBILIZER, those having a CD34+ peak between 65 and 197 ×10e6/L were categorised as GOOD MOBILIZER, and those having a CD34+ peak over 75th percentiles (197 ×10e6/L) were categorised as SUPERMOBILIZER. RESULTSIn our serie 40% of patients received an Allogeneic transplant after a myeloablative treatment, 49% an autologous transplant while 11% no further chemotherapy. Disease Free Survival (DFS) was 60%. CD34+ peak during mobilization, evaluated as a continuous variable, in a Cox regression model resulted important for DFS (hazard ratio:1.001; p=0.01). Importance of CD34+ peak was maintained also when the stratum of patients with intermediate cytogenetic risk was analysed (DFS: p=0.002). POOR MOBILIZER, GOOD MOBILIZER and SUPERMOBILIZER patients had statistically different DFS when cases were analysed as a whole (DFS: POOR M.: 70%; GOOD M. 50%; SUPER M: 30%; log rank: p=0.05); mobilizing efficiency was important for DFS also in intermediate cytogenetic group (DFS: POOR M. 70%; GOOD M. 40% DFS; SUPER M. 28%; log rank p= 0.02), importance was maintained also in patients treated by allogeneic transplantation or with autologous transplantation (fig.1).When allogeneic transplantation was compared to the group of patients receiving autologous transplantation or other post remissional strategies both in the cases as a whole and in the stratum of intermediate cytogenetic (table 1), the group of POOR mobilizer had after autologous transplants results non different from patients receiving allogeneic transplantation, however, the group of GOOD mobilizer patients had after allogeneic transplants a DFS significantly better compared to other treatment while SUPER mobilizer patients had poor results also when allogeneic transplantation was employed.In conclusion in AML in 1st CR, evaluation of CD34 peak during mobilization is a parameter providing prognostic informations useful also within intermediate cytogenetic group.INTERMEDIATE CYTOGENETIC RISK (n.42)DFS (All patients) (n.42)DFS (Autologous Tx Group) (n.16) or no Tx (n.6)Log rankDFS (Allogeneic Tx Group) (n.20)CD34+ LOW MOBILIZER70%65%NS80%CD34+ GOOD MOBILIZER40%0%p=0.0275%CD34+ SUPER MOBILIZER28%0%NS30%Log rankp=0.02p=0.005p=0.04 [Display omitted] Disclosures:No relevant conflicts of interest to declare.

A Phase II Study of Yttrium-90-Ibritumomab Tiuxetan In Combination with a Fludarabine-Based Reduced Intensity Regimen Followed by Allogenic Stem Cell Transplantation In Patients with Relapsed or Chemorefractory CD 20 Positive Non-Hodgkin's Lymphoma.

AbstractAbstract 4565 Background:The outcome of patients with relapsed or refractory non-Hodgkin's lymphoma (NHL) is very poor despite aggressive treatments or novel therapeutic agents. Allogenic STC (allo-STC) remains the only curative approach with an interesting reduced treatment-related-mortality (TRM) commonly associated with reduced intensity conditioning regimens (RIC).Radio immunotherapy (RIT) as part of conditioning regimen for autologous stem cell transplantion (ASCT) as well as for allo-SCT has demonstrated its safety and many studies are now suggesting an improved outcome.This phase II study (ClinicalTrials.gov: NCT 00607854) evaluated the safety and efficacy of Yttrium-90 ((90)-Y)-ibritumomab tiuxetan in combination with a fludarabine-based RIC followed by allo-SCT in patients with relapsed or chemorefractory CD 20 positive non-Hodgkin's lymphoma. Patients and Method:Patients with relapsed or refractory CD 20 positive NHL where eligible for the study if they had a sensitive disease (at least partial response) to the last salvage regimen and a suitable donor: related (RD) or unrelated donor (MUD or with a C or DQ mismatch).Each patient received a single dose of ((90)-Y)-ibritumomab tiuxetan (0,4 mci/Kg on day -14) followed from day -6 by a combination of fludarabine (30 mg/m2 d -6 to d -2), busilvex ((3,2 mg/Kg d -5 and d -4) and antithymocyte globulin (2,5 mg/Kg d -1). GVH prophylaxis was based on cyclosporine (CsA) alone or in combination with methotrexate (Mtx) in case of mismatched unrelated donor.The trial was designed to enroll 30 evaluable pts and the study started on January 2008. At time of this writing, 27 pts have been included and we report the preliminary results of the first 14 consecutive pts.The primary objective (PO) of the study was to evaluate the day 100 TRM. Secondary objectives were response (CR, PR) and event-free survival at 1 year. RESULTS:Fourteen pts are evaluable for the PO. The median age was 55 years (35-60), and the sex ratio (M/F) 10/4. Prior disease was DLBCL (5), MCL (4), FL (5). Pts received a median number of 2 previous treatment regimens and all pts had undergone ASCT before. Median time between diagnosis and allo-SCT and between ASCT and allo-SCT were 39 mo (range 8 – 106) and 14, 5 mo (range 3–52) respectively. At time of transplant 10 pts were in CR and 4 in PR. There were 10 RD and 4 MUD transplants. All pts received peripheral blood stem cells transplantation and GVH prophylaxis with CsA alone.Two pts died from a-GVH at day 40 and 117 post-transplant respectively with a TRM at day 100 of 7%. Both were in CR. The median time to ANC engraftment (ANC > 500/mm3) was 17 days (range 12 – 22) and time to platelets engraftment (Plt > 20.000/mm3) was 11 days (range 0–16). Acute GVH occurred in 7 pts with only 3 pts with grade ≥ 2. At day 100 after transplantation, 8 out of the 10 (80%) evaluable pts achieved a complete T-cell donor chimerism.With a median follow-up of 10 month (range 6 – 26), 12 pts are alive and in CR. The estimated event-free survival at 1year is 86% (CI 78% - 94%). CONCLUSION:((90)-Y)-ibritumomab tiuxetan is safe and well tolerated when used in combination with a fludarabine-based RIC regime. Preliminary data suggest that the TRM is not increased by adding RIT in this conditioning regimen. Disclosures:Bouabdallah:Bayer Healthcare: The Trial has been partially sponsored by Bayer Healthcare. Off Label Use: Zevalin is off-label use in conditioning regimen in France.

Reduced Intensity Conditioning (RIC) Transplantation In Acute Leukemia: The Effect of Source of Unrelated Donor Stem Cells on Outcomes

AbstractAbstract 908Peripheral blood progenitor cells (PBPC) are the preferred graft source for RIC transplantation. As in other settings, if a suitable unrelated adult donor is not available, primarily HLA mismatched unrelated cord blood (CB) is increasingly utilized, including the co-infusion of two CB units to overcome the cell dose limitation. We here report the relative efficacy of double CB (dCB, n=161) transplantation vs. PBPC whether from an 8/8 HLA matched (MUD, n=313) vs. 1 allele mismatched (MMUD, n=111) unrelated donor in patients with acute myeloid (AML, n=523) and lymphoblastic leukemia (ALL, n=62) transplanted between 2000 and 2009. Patients were aged 21 – 69 years. dCB recipients were more likely to be younger (median age: 54 vs. MUD 59 vs. MMUD 58 years, p<0.001), to have ALL (20% vs. MUD 6% vs. MMUD 10%, p<0.001) and to be in 1st or 2nd complete remission (83% vs. MUD 74% vs. MMUD 65%, p<0.001). Transplant conditioning regimens differed between dCB and PBPC transplants. Approximately 75% of dCB recipients received TBI 200 cGy + cyclophosphamide + fludarabine (TCF) ± ATG, 20% received melphalan or busulfan (Bu) or cyclophosphamide (Cy) + fludarabine ± ATG and the remaining 5%, TBI + fludarabine ± alkylating agent ± ATG. In contrast, approximately 75% of PBPC recipients received melphalan or Bu or Cy + fludarabine ± ATG. While there were no differences in overall survival by conditioning regimen in PBPC recipients, conditioning regimen influenced survival in recipients of dCB with the best survival in those treated with TCF. Therefore, 4 groups were created for multivariate analysis comparing transplant outcomes: dCB after TCF, dCB after other RIC regimens, MUD and MMUD; results are shown in the Table below. Compared to dCB after TCF, grade 2–4 but not grade 3–4 acute GVHD was lower in those with a MUD and chronic GVHD was higher in those with either a MUD or MMUD. Compared to dCB after other RIC regimens, transplant-related mortality (TRM) and overall mortality were lower after MUD and dCB after TCF transplants but similar to those after MMUD transplants. The 2-year probabilities of TRM in recipients of dCB after TCF, dCB after other RIC regimens, MUD and MMUD transplants are 19%, 52%, 21% and 28%, respectively. The corresponding probabilities for overall survival, adjusted for disease status and performance score were 38%, 19%, 44% and 37%. These data support dCB after TCF for adults with acute leukemia where a transplant is indicated but a suitably HLA matched unrelated adult donor is not available or when transplant is needed urgently. Although a center-effect could not be demonstrated statistically (p=0.2), a substantial proportion of dCB patients treated with TCF were done at a single center. Results of an ongoing multi-center phase II trial evaluating dCB after TCF will verify the reproducibility of these results. Disclosures:No relevant conflicts of interest to declare.

Similar Overall Survival and Toxicity After CB Transplanation with Co-Infusion of CD34+ Cells From a Third Party Donor Compared to Myeloablative MUD Stem Cell Transplantation In High Risk Patients

AbstractAbstract 3532In the absence of an HLA matched sibling donor, an unrelated adult donor matched (MUD) at 8 of 8 alleles for HLA A, B, C, DRB1 is considered as first alternative. However, only 50% of patients in Europe have an available suitable donor in a median time of 4 months. For those patients without a suitable MUD, we have adopted CB (cord blood) stem cell transplantation with the co-infusion of CD34+ cells from a third party non HLA-identical donor (Dual transplantation). The objective of this study was to analyze toxicity and overall survival (OS) rates of patients who underwent this procedure and compare them with a cohort of patients who received a myeloablative MUD transplantation in a single centre and during a similar period of time. Patients:Between 2005 and 2010, 16 consecutive patients with high risk disease underwent a total of 18 dual transplants and 17 patients, with similar pre-SCT characteristics recieved a myeloablative MUD transplantation with 12/12 HLA identity in a single centre (Table 1). Transplants performed before 2005, those with manipulated grafts and with HLA mismatches were excluded. [Display omitted] Results:There were no significant differences in age, gender, pre-SCT disease status and previous therapy lines between both groups. Three cases among the dual group showed primary graft failure (2 of them showing third party donor cells engraftment) who were rescued by a second CB transplant in two cases and a MUD in one case (succesfull in 2). There were no graft failures in the MUD group. GVHD rates are shown in table 1. OS was 50% in the dual group and 53% in the MUD group with a median follow-up of 33 (1-67) y 13 months (1,1-48,5) respectively (Figure 1). The cumulative relapse incidence at 2 years was 54% in the dual group and 53% in the MUD group. There were no relpses after 2 years in both groups. All the transplant related deaths (TRM) took place within the first year after transplantation with no significant differences in cumulative incidence between both groups (p=0,69). [Display omitted] Conclusions:In our experience, CB transplantion together with the co-infusion of CD34+ cells from a third party HLA-mismatched donor offers OS and DFS rates comparable to those from myeloablative HLA 12/12 MUD trasnplantation with an acceptable TRM. Therefore, dual transplantion is still our first choice for patients without an available MUD or for whom trasplant is urgent. Disclosures:No relevant conflicts of interest to declare.

Outcomes of Patients with Myeloid Malignancies Treated with Allogeneic Hematopoietic Stem Cell Transplantation from Matched Unrelated Donors Compared with One Human Leukocyte Antigen Mismatched Related Donors Using HLA Typing at 10 Loci

Most candidates for hematopoietic stem cell transplantation (HSCT) lack a human leukocyte antigen (HLA)-identical sibling donor. Some patients may have a related donor with whom they are mismatched at 1 antigen/allele. It is not known whether such a match is preferable to a matched unrelated donor (MUD). We evaluated the outcomes (survival, relapse, nonrelapse mortality [NRM]) of all 28 patients with a single HLA antigen/allele mismatch identified through high-resolution HLA typing at HLA-A, -B, -C, -DRB1, and -DQB1, and all 318 patients with myeloid malignancies who received transplants from a 10/10 MUD treated during the same period of time at a single institution. Overall, outcomes for patients treated from a 1-antigen/allele mismatch related donor were significantly worse than from a MUD, primarily because of increased NRM. Overall survival (OS) rates at 3 years for 1-antigen/allele mismatched related donor and MUD transplant recipients were 19% and 45% (P = .007), and NRM rates were 40% and 26% (P = .05), respectively. Patients with class I mismatches appeared to have poorer OS than did patients with class II mismatches. A higher incidence of graft rejection was identified in the mismatched related donor group (P = .02). These results indicate that transplant outcomes are better with a MUD than with a 1 antigen/allele-mismatched related donor.