Unrelated Donor Hematopoietic Cell Transplantation Research Articles

Late Effects in Hematopoietic Cell Transplant Recipients with Acquired Severe Aplastic Anemia: A Report from the Late Effects Working Committee of the Center for International Blood and Marrow Transplant Research

With improvements in hematopoietic cell transplant (HCT) outcomes for severe aplastic anemia (SAA), there is a growing population of SAA survivors after HCT. However, there is a paucity of information regarding late effects that occur after HCT in SAA survivors. This study describes the malignant and nonmalignant late effects in survivors with SAA after HCT. A descriptive analysis was conducted of 1718 patients post-HCT for acquired SAA between 1995 and 2006 reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). The prevalence and cumulative incidence estimates of late effects are reported for 1-year HCT survivors with SAA. Of the HCT recipients, 1176 (68.5%) and 542 (31.5%) patients underwent a matched sibling donor (MSD) or unrelated donor (URD) HCT, respectively. The median age at the time of HCT was 20 years. The median interval from diagnosis to transplantation was 3 months for MSD HCT and 14 months for URD HCT. The median follow-up was 70 months and 67 months for MSD and URD HCT survivors, respectively. Overall survival at 1 year, 2 years, and 5 years for the entire cohort was 76% (95% confidence interval [CI]: 74-78), 73% (95% CI: 71-75), and 70% (95% CI: 68-72). Among 1-year survivors of MSD HCT, 6% had 1 late effect and 1% had multiple late effects. For 1-year survivors of URD HCT, 13% had 1 late effect and 2% had multiple late effects. Among survivors of MSD HCT, the cumulative incidence estimates of developing late effects were all <3% and did not increase over time. In contrast, for recipients of URD HCT, the cumulative incidence of developing several late effects exceeded 3% by 5 years: gonadal dysfunction 10.5% (95% CI: 7.3-14.3), growth disturbance 7.2% (95% CI: 4.4-10.7), avascular necrosis 6.3% (95% CI: 3.6-9.7), hypothyroidism 5.5% (95% CI: 2.8-9.0), and cataracts 5.1% (95% CI: 2.9-8.0). Our results indicated that all patients undergoing HCT for SAA remain at risk for late effects, must be counseled about, and should be monitored for late effects for the remainder of their lives.

MHC-Resident Variation Affects Risks After Unrelated Donor Hematopoietic Cell Transplantation

Blood malignancies can be cured with hematopoietic cell transplantation from human leukocyte antigen (HLA)-matched unrelated donors; however, acute graft-versus-host disease (GVHD) affects up to 80% of patients and contributes to increased mortality. To test the hypothesis that undetected patient-donor differences for non-HLA genetic variation within the major histocompatibility complex (MHC) could confer risks after HLA-matched transplantation, we conducted a discovery-validation study of 4205 transplants for 1120 MHC region single-nucleotide polymorphisms (SNPs). Two SNPs were identified as markers for disease-free survival and acute GVHD. Among patients with two or more HLA-matched unrelated donors identified on their search, SNP genotyping of patients and their potential donors demonstrated that most patients have a choice of SNP-matched donors. In conclusion, the success of HLA-matched unrelated donor hematopoietic cell transplantation depends on non-HLA MHC region genetic variation. Prospective SNP screening and matching provides an approach for lowering risks to patients.

Immune Recovery in Adult Patients after Myeloablative Dual Umbilical Cord Blood, Matched Sibling, and Matched Unrelated Donor Hematopoietic Cell Transplantation

Immunologic reconstitution after allogeneic hematopoietic cell transplantation is a critical component of successful outcome. Umbilical cord blood (UCB) transplantation in adult recipients is associated with slow and often inadequate immune recovery. We characterized the kinetics and extent of immune recovery in 95 adult recipients after a dual UCB (n=29) and matched sibling donor (n=33) or matched unrelated donor (n=33) transplantation. All patients were treated with myeloablative conditioning. There were no differences in the immune recovery profile of matched sibling donor and matched unrelated donor recipients. Significantly lower levels of CD3+, CD4+, and CD8+ T cells were observed in UCB recipients until 6 months after transplantation. Lower levels of regulatory T cells persisted until 1 year after transplantation. Thymopoiesis as measured by TCR rearrangement excision circle was comparable among all recipients by 6 months after transplantation. In a subset of patients 1 year after transplantation with similar levels of circulating T cells and TCR rearrangement excision circle, there was no difference in TCR diversity. Compared to HLA-identical matched sibling donor and matched unrelated donor adult hematopoietic cell transplantation recipients, quantitative lymphoid recovery in UCB transplantation recipients is slower in the first 3 months, but these differences disappeared by 6 to 12 months after transplantation.

Secondary breast cancer (s-BC) after hematopoietic cell transplantation (HCT) for leukemia: Role of total body irradiation (TBI).

1592 Background: s-BC after conventional chest radiation for histologically distinct cancer is well-recognized, and has resulted in radiologic screening recommendations by American Cancer Society. However, risk of s-BC after TBI is not well-defined. Methods: We determined the risk of s-BC in 648 consecutive females transplanted for leukemia (ALL [19%], AML/MDS [57%], CML [24%]) between 1976 and 2008 with a post-HCT survival of ≥2 years. The study was restricted to leukemia to understand the role of TBI without the influence of pre-HCT chest radiation. Near-complete ascertainment of s-BC was assured by combining institutional follow-up with California Cancer Registry data. Results: Median age at HCT was 38 years (range, 0-71); 14% had received autologous HCT, 64% related and 22% unrelated donor HCT; 70% had received TBI for myeloablative conditioning. After 5,675 person-years of observation, 16 patients developed s-BC (14 after TBI). Median latency from HCT to s-BC was 16y (2-27). Median age at s-BC was 50y (29-66). Cumulative incidence of s-BC was 6% at 20y after HCT, contributed to largely by TBI (s-BC incidence after TBI: 5.7%). Among TBI-exposed, 8.6% were projected to develop s-BC by age 65y (1.6% among non-TBI-exposed, p=0.03). TBI-exposed patients were 2.4 times more likely to develop s-BC compared with general population (p=0.001); non-TBI exposed were not at increased risk (SIR=0.9, p=0.9). Multivariate analysis (adjusted for age at HCT, follow-up and primary diagnosis) revealed a 4.7-fold (p=0.068) increased risk of s-BC among TBI-exposed. Conclusions: Risk of s-BC after TBI as the sole source of radiation to breast is increased. Nearly 9% of those exposed to TBI will develop s-BC by age 65y. Identification of vulnerable sub-populations among the TBI-exposed patients is underway to create targeted screening strategies for early detection of s-BC.

Anti-thymocyte globulin for conditioning in matched unrelated donor hematopoietic cell transplantation provides comparable outcomes to matched related donor recipients

Rabbit anti-thymocyte globulin (ATG) is used as prophylaxis against GVHD following allogeneic hematopoietic cell transplantation (HCT). At our institution, ATG is exclusively used in the conditioning of matched unrelated donor (URD) transplant recipients. A total of 50 URD HCT recipients who received ATG (ATG group) were retrospectively compared with 48 matched related donor (MRD) HCT recipients who did not receive ATG (no ATG group). There were no significant differences between the groups in rates of day 100 mortality, acute GVHD or relapse. Chronic GVHD incidence was significantly lower in the ATG group (P = 0.007). At a median follow-up of 36 months in the entire cohort, 50% patients are alive in the ATG group and 63% of the patients are alive in the no ATG group (P = 0.13). We conclude that the administration of ATG to patients undergoing URD HCT preserves the anti-leukemia benefit of the transplant, while reducing the risk of developing GVHD, resulting in OS rates that are comparable to MRD HCT recipients.

Outcomes after matched unrelated donor versus identical sibling hematopoietic cell transplantation in adults with acute myelogenous leukemia

AbstractApproximately one-third of patients with an indication for hematopoietic cell transplantation (HCT) have an HLA-matched related donor (MRD) available to them. For the remaining patients, a matched unrelated donor (MUD) is an alternative. Prior studies comparing MRD and MUD HCT provide conflicting results, and the relative efficacy of MRD and MUD transplantation is an area of active investigation. To address this issue, we analyzed outcomes of 2223 adult acute myelogenous leukemia patients who underwent allogeneic HCT between 2002 and 2006 (MRD, n = 624; 8/8 HLA locus matched MUD, n = 1193; 7/8 MUD, n = 406). The 100-day cumulative incidence of grades B-D acute GVHD was significantly lower in MRD HCT recipients than in 8/8 MUD and 7/8 MUD HCT recipients (33%, 51%, and 53%, respectively; P < .001). In multivariate analysis, 8/8 MUD HCT recipients had a similar survival rate compared with MRD HCT recipients (relative risk [RR], 1.03; P = .62). 7/8 MUD HCT recipients had higher early mortality than MRD HCT recipients (RR, 1.40; P < .001), but beyond 6 months after HCT, their survival rates were similar (RR, 0.88; P = .30). These results suggest that transplantation from MUD and MRD donors results in similar survival times for patients with acute myelogenous leukemia.

Peripheral Blood or Marrow: Is One Better Than the Other?

A study by Bertz et al. [1] in this issue of Biology of Blood andMarrow Transplantation shows that the results of unrelated donor hematopoietic stem cell transplant for adults with acute myelogenous leukemia or myelodysplastic syndrome are better with transplantation of peripheral blood progenitor cells (PBPCs) compared to bone marrow (BM). Overall mortality risks were lower after transplantation of PBPC compared to BM. With a median follow-up of 10 years, event-free survival rate after PBPC transplants was 55% and significantly higher compared to 28% after BM transplants. This is in contrast to the findings of a randomized multicenter trial of unrelated donor PBPC vs BM for hematologic malignancies in North America [2]. That trial randomized 273 patients to receive PBPC and 278 patients to receive BM. With a median follow-up of 3 years, event-free survival rates were not significantly different after PBPC and BM transplants, 47% and 44%, respectively [2]. However, the incidence of chronic graft-versus-host disease (cGVHD) was more after transplantation of PBPC compared to BM grafts (53% vs 40%; P 5 .02) and without significant differences in non-relapse mortality rates between the 2 treatment groups [2]. Bertz et al. [1] also report more cGVHD after PBPC compared to BM transplants, but the observed difference was not statistically significant (52% vs 33%; P 5 .11). The probability estimates reported by Bertz et al. [1] and Anasetti et al. [2] are similar. Relatively few events in the small patient population in the report by Bertz et al. [1] are the most likely explanation for their inability to detect statistically significant differences in cGVHD rates between the 2 graft sources. The reported higher event-free survival rate in the PBPC group with a median follow-up of 10 years is intriguing. Several groups have reported on the

Excellent outcome of matched unrelated donor transplantation in paediatric aplastic anaemia following failure with immunosuppressive therapy: a United Kingdom multicentre retrospective experience

We retrospectively analysed the outcome of consecutive children with idiopathic severe aplastic anaemia in the United Kingdom who received immunosuppressive therapy (IST) or matched unrelated donor (MUD) haematopoietic stem cell transplantation (HSCT). The 6-month cumulative response rate following rabbit antithymocyte globulin (ATG)/ciclosporin (IST) was 32·5% (95% CI 19·3-46·6) (n = 43). The 5-year estimated failure-free survival (FFS) following IST was 13·3% (95% confidence interval [CI] 4·0-27·8). In contrast, in 44 successive children who received a 10-antigen (HLA-A, -B, -C, -DRB1, -DQB1) MUD HSCT there was an excellent estimated 5-year FFS of 95·01% (95% CI 81·38-98·74). Forty of these children had failed IST previously. HSCT conditioning was a fludarabine, cyclophosphamide and alemtuzumab (FCC) regimen and did not include radiotherapy. There were no cases of graft failure. Median donor chimerism was 100% (range 88-100%). A conditioning regimen, such as FCC that avoids total body irradiation is ideally suited in children. Our data suggest that MUD HSCT following IST failure offers an excellent outcome and furthermore, if a suitable MUD can be found quickly, MUD HSCT may be a reasonable alternative to IST.

Unrelated Donor Cord Blood Transplantation for Children with Severe Sickle Cell Disease: Results of One Cohort from the Phase II Study from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN)

The Sickle Cell Unrelated Donor Transplant Trial (SCURT trial) of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) is a phase II study of the toxicity and efficacy of unrelated donor hematopoietic cell transplantation in children with severe sickle cell disease (SCD) using a reduced-intensity conditioning regimen. Here we report the results for the cord blood cohort of this trial. Eight children with severe SCD underwent unrelated donor cord blood transplantation (CBT) following alemtuzumab, fludarabine, and melphalan. Cyclosporine or tacrolimus and mycophenolate mofetil were administered for graft-versus-host disease (GVHD) prophylaxis. Donor/recipient HLA match status was 6 of 6 (n = 1) or 5 of 6 (n = 7), based on low/intermediate-resolution molecular typing at HLA -A, -B, and high-resolution typing at -DRB1. Median recipient age was 13.7 years (range: 7.4-16.2 years), and median weight was 35.0 kg (range: 25.2-90.2 kg). The median pre-cryopreservation total nucleated cell dose was 6.4 × 10(7) /kg (range: 3.1-7.6), and the median postthaw infused CD34 cell dose was 1.5 × 10(5) /kg (range: 0.2-2.3). All patients achieved neutrophil recovery (absolute neutrophil count >500/mm(3)) by day 33 (median: 22 days). Three patients who engrafted had 100% donor cells by day 100, which was sustained, and 5 patients had autologous hematopoietic recovery. Six of 8 patients had a platelet recovery to >50,000/mm(3) by day 100. Two patients developed grade II acute GVHD. Of these, 1 developed extensive chronic GVHD and died of respiratory failure 14 months posttransplantation. With a median follow-up of 1.8 years (range: 1-2.6), 7 patients are alive with a 1-year survival of 100%, and 3 of 8 are alive without graft failure or disease recurrence. Based upon the high incidence of graft rejection after unrelated donor CBT, enrollment onto the cord blood arm of the SCURT trial was suspended. However, because this reduced-intensity regimen has demonstrated a favorable safety profile, this trial remains open to enrollment for unrelated marrow donor transplants. Novel approaches aimed at improving engraftment will be needed before unrelated CBT can be widely adopted for transplanting patients with severe SCD.

Analysis of non-HLA genomic risk factors in HLA-matched unrelated donor hematopoietic cell transplantation for chronic myeloid leukemia

Allogeneic hematopoietic cell transplantation is the main curative therapy for patients with chronic myeloid leukemia who do not respond to tyrosine kinase inhibitors. It has been proposed that non-human leukocyte antigen gene polymorphisms influence outcome after hematopoietic cell transplantation and could be used alongside traditional patient-donor and transplant characteristics to create a recipient risk profile associated with allogeneic hematopoietic cell transplantation. A previous study from the European Group for Blood and Marrow Transplantation showed that the absence of recipient tumor necrosis factor receptor II, absence of donor interleukin 10 ATA/ACC and presence of donor interleukin 1 receptor antagonist allele 2 genotypes were associated with decreased survival and increased non-relapse mortality in adult patients with chronic myeloid leukemia undergoing myeloablative human leukocyte antigen-identical sibling transplantation. To explore these associations in unrelated donor transplantation, these polymorphisms were genotyped in 383 adult patients with chronic myeloid leukemia who underwent hematopoietic cell transplantation from unrelated donors matched for 10/10 human leukocyte antigens. The polymorphisms were not associated with overall survival, non-relapse mortality, relapse or acute graft-versus-host disease in the unrelated donor cohort. Comparison of the unrelated donor and human leukocyte antigen-identical sibling cohorts showed differences in survival and clinical characteristics. We did not confirm that non-human leukocyte antigen polymorphisms were associated with outcomes in myeloablative unrelated donor hematopoietic cell transplantation for chronic myeloid leukemia, possibly because of the strong association between clinical variables and outcome which masked more subtle genetic effects.

Late Effects in Hematopoietic Cell Transplant Recipients with Acquired Severe Aplastic Anemia: A Report from the Late Effects Working Committee of the Center for International Blood and Marrow Transplant Research (CIBMTR)

With improvements in hematopoietic cell transplantation (HCT) for severe aplastic anemia (SAA), there is a growing population of SAA survivors of HCT. However, there is a paucity of information regarding late effects in SAA HCT survivors. We analyzed the burden of malignant and non-malignant late effects in HCT survivors with acquired SAA. A descriptive analysis of 1,718 patients post-HCT for acquired SAA between 1995-2006 reported to the CIBMTR was conducted. Cumulative incidences (CI) of selected late effects are reported for among “condition-free” (i.e. survivors without a previous diagnosis of the specified late effect) HCT survivors with SAA. One-year overall survival for the recipients of related donor HCT was 83% (80-85) and 62% (58-66) for the recipients of unrelated donor HCT. Of the HCT recipients, 1176 (68.5%) patients with a median age at HCT of 20 years (<1-65) utilized a related donor and 542 (31.5%) patients with a median age at HCT of 20 years (<1-67) utilized an unrelated donor. The median interval from diagnosis to transplant was 3 months (<1-348) for related donor HCT and 14 months (1-318) for unrelated donor HCT. Radiation (of any type) was utilized in 6% and 78% of related and unrelated donor HCT cases; respectively. Cy-TBI (68%) was a commonly utilized conditioning regimen for unrelated donor HCT. The median follow-up is 70 months (1-160) and 67 months (3-182) for related and unrelated donor HCT; respectively. The 2-year CI of chronic GVHD was 20% (18-22) and 37% (32-41) in related and unrelated donor HCT; respectively. Table 1 demonstrates that among 1-year condition-free survivors, the CI of late effects is greater among unrelated donor HCT survivors and continues to increase. These findings suggest that HCT survviors with SAA are a robust and healthy group in general. However, subgroups of patients undergoing HCT for SAA are at-risk for late effects and must be educated about and should be monitored for late effects. Subgroups of survivors may be at-risk group for a greater burden of specific late effects. Ongoing analyses in our cohort will explore selected risk-factors for late effects after HCT for SAA.Table 1Interval specific cumulative incidence of select late effects among 1-year condition free survivors following related and unrelated donor HCT for acquired SAA between 1995 and 2006 reported to the CIBMTRHealth conditions post transplantN (at risk)Related DonorN (at risk)Unrelated DonorCumulative Incidence % (95% CI)Cumulative Incidence % (95% CI)Strokes/SeizuresOver next 2 years7071.7 (0.9-2.7)2831.3 (0.3-2.8)Over next 5 years4161.8 (1.0-2.9)1182.8 (1.2-5.1)Gonadal DysfunctionOver next 2 years7092.6 (1.6-3.8)2736.2 (3.8-9.1)Over next 5 years4193.0 (2.0-4.3)10810.5 (7.3-14.3)Renal FailureOver next 2 years7151.1 (0.5-1.9)2871.9 (0.7-3.6)Over next 5 years4251.4 (0.7-2.3)1272.4 (0.9-4.5)Avascular NecrosisOver next 2 years7241.4 (0.7-2.3)2763.2 (1.5-5.4)Over next 5 years4261.8 (1.0-2.8)1176.3 (3.6-9.7)CataractsOver next 2 years7340.6 (0.2-1.2)2842.2 (0.9-4.1)Over next 5 years4331.1 (0.5-1.9)1185.1 (2.9-8.0)Growth DisturbanceOver next 2 years7350.2 (0.0-0.7)2861.9 (0.7-3.6)Over next 5 years4330.5 (0.1-1.2)1137.2 (4.4-10.7)HypothyroidismOver next 2 years7310.7 (0.3-1.4)2860.6 (0.1-1.8)Over next 5 years4321.2 (0.5-2.1)1195.5 (2.8-9.0)Solid TumorsOver next 2 years8200.6 (0.2-1.1)2760.7 (0.1-1.9)Over next 5 years5280.7 (0.2-1.3)1211.4 (0.4-3.0) Open table in a new tab

Comparison of Survival and Incidence of Graft Versus Host Disease in Fully Matched, Single C Mismatched and Other Mismatched Unrelated Donor Hematopoietic Stem Cell Transplants in a Pediatric Population

Comparison of Survival and Incidence of Graft Versus Host Disease in Fully Matched, Single C Mismatched and Other Mismatched Unrelated Donor Hematopoietic Stem Cell Transplants in a Pediatric Population

HLA-DPA1 Mismatch Is Associated with Decreased Overall Survival Following Unrelated Donor Hematopoietic Stem Cell Transplantation

HLA-DPA1 Mismatch Is Associated with Decreased Overall Survival Following Unrelated Donor Hematopoietic Stem Cell Transplantation

Outcomes after matched unrelated donor versus identical sibling hematopoietic cell transplantation in adults with acute myelogenous leukemia

Outcomes after matched unrelated donor versus identical sibling hematopoietic cell transplantation in adults with acute myelogenous leukemia

Alternate Donor Hematopoietic Cell Transplantation (HCT) in Non-Hodgkin Lymphoma Using Lower Intensity Conditioning: A Report from the CIBMTR

We analyzed the outcomes of 248 (61% male) adult recipients of HLA-matched unrelated and HLA-mismatched related donor hematopoietic cell transplantation (HCT) for non-Hodgkin lymphoma (NHL) after reduced or lower intensity conditioning (RIC), reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) from 1997 to 2004. Median age was 52 (range: 18-72 years); 31% had a Karnofsky performance score <90. Follicular NHL (43%) was the major histology. Incidence of grades II-IV acute graft-versus-host disease (aGVHD) was 43% at 100 days; and chronic GVHD (cGVHD) was 44% at 3 years. Treatment-related mortality (TRM) at 100 days was 24%. Three-year overall survival (OS) and progression-free survival (PFS) were 41% and 32%, respectively. In multivariate analysis, use of antithymocyte globulin (ATG) and HLA mismatch were associated with increased TRM. High-grade histology, ATG use, and chemotherapy resistance were associated with lower PFS. Older age, shorter interval from diagnosis to HCT, non-total body irridiation (TBI) conditioning regimens, exvivo T cell depletion, and HLA-mismatched unrelated donors were associated with mortality. GVHD did not influence relapse or PFS. Older age, aggressive histology, and chemotherapy resistance correlated with poorer survival. For selected patients with NHL, lack of an available sibling donor should not be a barrier to allogeneic HCT.

Randomized phase II trial comparing two dose levels of thymoglobulin in patients undergoing unrelated donor hematopoietic cell transplant

The optimal dose and schedule of thymoglobulin (ATG) for graft-versus-host disease prevention (GVHD) is unknown. We compared two doses of ATG (4.5 mg/kg and 7.5 mg/kg) in a Bayesian adaptively randomized fashion, and assessed whether ATG levels measured on days 0, 7, 14 and 28 were associated with clinical outcomes. Treatment success was defined as the patient being alive, engrafted, in remission and without acute GVHD at day 100. Twenty patients received ATG 4.5 mg/kg (n = 15) or 7.5 mg/kg (n = 5) with reduced-intensity conditioning followed by unrelated donor hematopoietic cell transplant. The first 10 patients were fairly randomized, but the next 10 patients were adaptively randomized to the arm with higher success rate (4.5 mg/kg arm in this trial). The posterior mean treatment success rates for the ATG 4.5 mg/kg and ATG 7.5 mg/kg arms were 0.73 and 0.45, respectively. The posterior probability that the success rate was greater in the 4.5 mg/kg arm than in the 7.5 mg/kg arm was 0.93. There was no difference in the overall survival (p = 0.607), relapse-free survival (p = 0.607), treatment-related mortality (p = 0.131) or incidence of acute (p = 0.303) or chronic GVHD (p = 0.999) between the two doses. ATG levels were not associated with clinical outcomes. Thus, our results favor the use of ATG 4.5 mg/kg over ATG 7.5 mg/kg in patients undergoing unrelated donor hematopoietic cell transplant with reduced-intensity conditioning regimens.

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.

Comparable Outcome After Single-Antigen Mismatched Versus Matched Unrelated Donor Hematopoietic Cell Transplantation,

Abstract 4165 Introduction:Hematopoietic cell transplantation (HCT) is the treatment of choice for many hematological malignancies and often the only curative option. Despite continuous expansion of unrelated donor registries worldwide, not all patients have a matched donor available and single antigen mismatched donors are used for patients at high risk of relapse or progression. However, it remains unclear whether or not single-antigen mismatched and matched unrelated donor transplantations generate comparable clinical outcomes. Here, we present the results of a unicentre analysis approaching this question. Patients and Methods:The outcome of all patients transplanted from unrelated donors between 2000 and 2009 at the University Hospital in Leipzig was analyzed. A total of 206 patients with a median age of 38 (range 18–58) years with acute leukemias, chronic myeloid leukemia, myelodysplastic syndrome or non Hodgkin‘s lymphoma were treated with a myeloablative regimen consisting of 12 Gy fractionated total body irradiation (n=189) or busulfan 16mg/m2 (n=17) in combination with cyclophosphamide. All patients received antithymocyte globulin during the conditioning regimen and graft-versus-host prophylaxis with cyclosporine and short course methotrexate. Donors were considered matched according to the typing available at the time of transplantation: Antigen typing in class I and allele typing in class II was available prior to 2006 and 10/10 4 digit HLA typing thereafter. Donors were considered matched if no HLA-antigen mismatch was detected. One hundred and fifty five patients were matched for the HLA loci A, B, C, DRB1 and DQB1 at the antigen level, while 39 patient/donor pairs had a single antigen mismatch and 12 a mismatch of two or more antigens. Disease stage, comorbidity index and Gratwohl score were well balanced in both groups. Results:After a median follow-up of 49 months, 54% of the 206 patients were alive. Most interestingly, there was no difference in overall survival (OS) at 5 years between HCT with matched and HCT with mismatched donors [52% vs 49% respectively (p=0.48)]. Also similar were event free survival (EFS) at 47% vs. 39% (p=0.44), relapse incidence (RI) 34% vs. 50% (p=0.22) and non-relapse mortality (NRM) 28% vs. 22% (p=0.81) in the matched versus mismatched donors. Acute graft versus host disease (GvHD) grade one or two occurred in 58% of all patients, while 14% had grade three or four and 28% had no signs of acute GvHD. The incidence of GvHD was comparable after antigen mismatched and antigen matched HCT. As expected, there was a significantly better OS, PFS and lower NRM for patients with early (n=104) vs. advanced disease (p=0.02) and patients with high resolution typing vs. low resolution typing (n=99; P=0.04). Even within these subgroups, however, the use of a single antigen mismatched donor did not worsen the results. Conclusion:In this unicenter analysis a comparable outcome was found after single antigen mismatched HCT compared to matched unrelated donor HCT. An antigen mismatched donor seems to be an acceptable option for patients with high risk malignant disease for whom no fully matched donor is available Disclosures:No relevant conflicts of interest to declare.

Unrelated Donor Hematopoietic Stem Cell Transplantation for the Treatment of Advanced Multiple Myeloma: The John Theurer Cancer Center Experience,

Abstract 4162Allogeneic hematopoietic stem cell transplantation has been associated with a graft-versus-myeloma effect and may be the only potentially curative option for patients with advanced multiple myeloma. Unfortunately, the majority of patients (pts) do not have an HLA-identical sibling. Unrelated donor transplantation is an alternative option for these patients. We conducted a retrospective analysis of patients with advanced multiple myeloma who received an unrelated donor (URD) hematopoietic stem cell transplant at our institution between 11/1997 and 11/2010. Analyses were done using Kaplan Meier survival and Cox regression on the SAS version 9.2 software.Between 11/1997 and 11/2010, 27 pts with multiple myeloma received an URD transplant. One patient was lost to follow-up and 26 pts are evaluable. Patient characteristics included: median age 52 years (range 37–64), male 58%, all patients had prior autologous transplant (23% of pts had 2 or more prior transplants), and 43% of pts had refractory or progressive disease at the time of transplantation. Transplant regimens were ablative (defined as melphalan dose > 140mg/m2) in 73% of pts. GVHD prophylaxis was tacrolimus-based in all. Hematopoietic cell source was peripheral blood for 92% of pts, 46% of pts received a 10/10 HLA matched URD and 54% had a least one allele mismatch. Results:With a median follow up of 3.4 years, 54% of patients are alive and 47% of patients are progression-free. The treatment-related mortality at day 100 was 15%. The incidence of acute graft-versus-host disease (GVHD) was 44% and chronic GVHD 25%. Univariate analysis of risk of progression or relapse and overall survival failed to show any significance for disease status at the time of transplantation, degree of donor match, transplant regimen, refractoriness to bortezomib or lenalidomide, acute or chronic GVHD. Conclusion:In this analysis, URD transplantation has an acceptable treatment related mortality, and leads to durable remissions even in patients with relapsed and/or refractory disease. The 3.4 year PFS is similar to the BMT CTN 0102 sibling data and compares favorably to related donor transplantation for relapsed disease. In comparison to the BMT CTN study, the preparative regimen in this current analysis was overall more intense and regimen intensity has been previously shown to be significant. Allogeneic transplantation is an effective treatment strategy in multiple myeloma. Unrelated donor transplantation should be offered to patients with advanced multiple myeloma who do not have an HLA-identical sibling. Disclosures:No relevant conflicts of interest to declare.

Anti-CD25 Monoclonal Antibody for Graft-Versus-Host Disease Prophylaxis Following Unrelated Donor Peripheral Blood Stem Cell Transplantation,

Abstract 4070 Introduction:Enhanced risk of graft-versus-host disease (GVHD) makes one of major critical barriers to successful unrelated donor hematopoietic stem cell transplantation (URD-HSCT). Antithymocyte globulin (ATG) has been combined to standard GVHD prophylaxis regimens and significantly reduced GVHD in URD-HSCT. But ATG is associated with increases of infections and post-transplant lympholiferative disease (PTLD). Thus it is valuable to find alternative immunosuppressive agent for GVHD prophylaxis in URD-HSCT. Basiliximab and daclizumab, two anti-CD25 monoclonal antibodies, prevent graft failure in renal transplantation, which also effectively treat steroid-refractory graft-versus-host disease (GVHD). However, only few researches report that anti-CD25 monoclonal antibodies prevent GVHD. Here we firstly retrospectively explored the prophylactic effects of basiliximab or daclizumab against GVHD in 93 patients with hematological malignancies following unrelated donor peripheral blood stem cell transplantation (URD-PBSCT). Patients/methods:Between April 2004 and May 2011, 93 patients with hematological malignancies received basiliximab or daclizumab additional to standard GVHD prophylaxis regimens and underwent URD-PBSCT in our department. Their clinical data were retrospectively collected and analyzed. All patients received GVHD prophylaxis regimen consisting of cyclosporine A, short-course methotrexate, mycophenolate mofetil and an anti-CD25 monoclonal antibody. Basiliximab was administrated to 71 patients at a dose of 20 mg, while daclizumab was given to 22 patients at a dose of 1 mg/kg on day 0 (2 hours before transplantation) and day +4. Eighteen patients were 8/8 identical, 41 were 7/8 identical and 34 were 6/8 identical at HLA-A,-B,-Cw and -DRB1. The median number of infused nucleated cells and CD34+ cells were 7.5×108/kg and 5.8×106/kg, respectively. Results:i) All the recipients achieved engraftment. The median time to neutrophil recovery and platelet recovery were 12 days and 15 days, respectively. The rates of grade II-IV and III-IV acute GVHD (aGVHD) were 35.5% and 18.3%, respectively. Chronic GVHD (cGVHD) developed in 43.4% of evaluable patients. The limited cGVHD rate was 27.6% and the extensive cGVHD rate was 15.8%. The transplantation-related mortality (TRM) was 19.4% while relapse rate (RR) was 10.8%. The 2-year overall survival (2-yr OS) reached 74.2% and disease free survival (2-yr DFS) accumulated to 69.6% during a median follow-up of 24 months.ii)The side effects of basiliximab and daclizumab were moderate and tolerable. The infectious rate was 66.7% including 44.1% bacterial infection, 10.8% probable or proven invasive fungal infection, and 11.8% mixed infection. The infection-related mortality was 7.5%. The CMV reactivation rate was 46.2% and only one patient suffered CMV pneumonia. Moreover there was no clinical evidence of PTLD.iii) There were no significant differences in aGVHD onset and survival between daclizumab and basiliximab group. However, basiliximab presented superior prophylactic effects on cGVHD than daclizumab (cGVHD rate, 31.1% versus 66.7 %, P=0.007).iiii) The aGVHD rate, cGVHD rate, RR, TRM, 2-yr OS and 2-yr DFS were compared among different HLA matching groups. There were significant differences in the occurrence of grade II-IV aGVHD (11.1% versus 36.6%, P=0.047) and cGVHD(18.8% versus 51.6%, P=0.03) between HLA 8/8 identical group and HLA 7/8 identical group. Comparing HLA 8/8 identical group versus HLA 6/8 identical group, there were not only significant decreases in the rate of grade II-IV aGVHD (11.1% versus 47.1%, P=0.01) and grade III-IV aGVHD (5.6% versus 32.4%, P=0.039), but also a significant increase in the RR (22.2% versus 2.9%, P=0.043). There were no significant differences between HLA 7/8 identical group and HLA 6/8 identical group. Interestingly, the survival was not significantly different among three HLA matching groups. Conclusion:Basiliximab or daclizumab prevents GVHD efficiently and feasibly following URD-PBSCT, especially in HLA identical or only one allele mismatched recipients. Furthermore, anti-CD25 monoclonal antibodies benefit the outcome, even for those recipients with two or more HLA disparities. Basiliximab has similar effects on aGVHD prophylaxis but superior effects on cGVHD prophylaxis than daclizumab. Further prospective and randomized control studies are needed. Disclosures:Off Label Use: Drug: basiliximab (Simulect, Novartis Pharmaceuticals); daclizumab (Zenapax, Roche Pharmaceuticals). Purpose: for graft-versus-host disease prophylaxis following unrelated donor peripheral blood stem cell transplantation.