Sibling Hematopoietic Cell Transplantation Research Articles

Impact of High Body Surface Area on AML Outcome in Younger Patients: A Goelams Study

▪In younger patients with acute myeloid leukemia (AML), standard intensive induction chemotherapy combines anthracyclins and cytarabine (Ara-C). While dosage is usually determined according to body-surface area (BSA), various chemotherapy adjustments are empirically performed in patients with high BSA from full dose administration to capping doses. The aim of the present study is to determine the outcome of younger AML patients with high BSA at diagnosis.Between November 2001 and April 2005, the prospective GOELAMS 2001 trial enrolled patients between 18 and 60 affected with non promyelocytic AML.1,2 Briefly, patients randomly received either daunorubicin or idarubicin in association with standard dose Ara-C during induction therapy. Height, weight and induction chemotherapy doses were registered at diagnosis. BSA was evaluated using the formula of Dubois and Dubois. BSA was categorized in low (BSA ≤1.5m2), intermediate (1.5<BSA<2), high (2<BSA<2.15) or very high BSA (BSA ≥2.15). In the course of consolidation therapy, patients with a matched related donor received an allogeneic stem cell transplantation. Patients without a matched related donor received either a single or tandem autologous bone marrow transplantation. Patients who did not achieve sufficient stem cell mobilization received chemotherapy-only consolidation.823 patients were eligible to induction therapy. 43 (5%), 638 (77%), 91 (11%) and 51 (6%) patients displayed low, intermediate, high or very high BSA at diagnosis, respectively. Median age, performance status, karyotype group were similar in all BSA groups. On the contrary, male gender was enriched in high and very high BSA groups (86% and 88%, respectively). During induction therapy, 20 patients (39%) with very high BSA were administered reduced dose (decrease of > 10% in anthracyclin or Ara-C dosing compared to full dose) versus 8%, 4% and 7% in low, intermediate or high BSA subgroups (p <10-5). Type of consolidation therapy - chemotherapy, autologous or allogeneic stem cell transplantation - was not significantly different in BSA groups.Compared to patients with intermediate BSA, patients with a low or high BSA displayed a similar OS and EFS. On the contrary, patients with a very high BSA displayed a decreased 5-year OS (27% (95% CI, 18-43) vs 47% (95% CI, 44-51), p= 0.006, figure 1A) and LFS (22% (95% CI, 13-36) vs 41% (95% CI, 37-45), p=0.004). Non-relapse mortality was similar in the very high or intermediate BSA groups, suggesting that intensive therapy was similarly tolerated in intermediate or very high BSA patients. Meanwhile, relapse incidence was increased in patients with a very high BSA compared to intermediate BSA patients (61% (95% CI, 46-73) vs 44% (95% CI, 40-48), p = 0.02, figure 1B).Conclusion: patients with a very high BSA display an adverse outcome, due to an increased relapse incidence. Meanwhile, non-relapse mortality is not significantly increased in very high BSA patients. These data suggest that patients with very high BSA should receive full dose induction chemotherapy.Bibliography;1. Recher C , Bene MC, Lioure B et al. Leukemia, Long-term results of a randomized phase 3 trial comparing idarubicin and daunorubicin in younger patients with acute myeloid leukaemia. Leukemia 2014; 28:440-3.2. Lioure B, Bene MC, Pigneux A et al. Early matched sibling hematopoietic cell transplantation for adult AML in first remission using an age-adapted strategy: long-term results of a prospective GOELAMS study. Blood 2012; 119: 2943–2948. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Comparable Leukemia-Free Survival after Autologous Hematopoietic Cell Transplantation Versus HLA-Identical Sibling Hematopoietic Cell Transplantation for Adult Acute Myeloid Leukemia in First Complete Remission: A Registry Study By the Adult AML Working Group of the Japan Society for Hematopoietic Cell Transplantation

Allogeneic hematopoietic cell transplantation (HCT) from a matched sibling donor (MSD) may provide a cure for acute myeloid leukemia in first complete remission (AML/CR1), although the procedure is associated with a higher rate of treatment-related mortality (TRM) than autologous HCT, and it remains uncertain which modality is preferable as post-remission treatment. We therefore conducted a retrospective registry-based analysis to compare the outcomes of patients with AML/CR1 receiving autologous peripheral blood (PB) grafts (n=398, median age: 47, range: 17-80) and those receiving allogeneic MSD bone marrow (BM) grafts (n=633, median age: 38, range: 16-73) or allogeneic MSD PB grafts (n=475, median age: 42, range: 16-74) between 1995 and 2011. Consequently, the 5-year overall survival (OS) rates for the autologous PB, allogeneic BM and allogeneic PB recipients were 62% (95% confidence interval [CI], 57-67%), 61% (95% CI, 57-65%; P=0.90) and 54% (95% CI, 49-59%; P=0.07), respectively (Fig. 1-A), and the 5-year leukemia-free survival (LFS) rates were 57% (95% CI, 52-62%), 58% (95% CI, 54-63%; P=0.49) and 51% (95% CI, 46-56%; P=0.12), respectively(Fig. 1-B). Meanwhile, the 5-year cumulative incidence of TRM was 8% (95% CI, 5-11%), 16% (95% CI, 13-19%; P=0.009) and 19% (95% CI, 15-23%; P=0.0001), respectively, while that of relapse was 35% (95% CI, 30-40%), 26% (95% CI, 22-29%; P=0.003) and 30% (95% CI, 26-35%; P=0.08), respectively. A multivariate analysis performed with autologous PB HCT as the reference showed a hazard ratio (HR) for OS of 0.93 (95% CI, 0.73-1.18; P=0.53) for allogeneic BM HCT and 1.08 (95% CI, 0.83-1.39; P=0.57) for allogeneic PB HCT and an HR for LFS of 0.86 (95% CI, 0.69-1.09; P=0.21) and 0.98 (95% CI, 0.77-1.24; P=0.85), respectively. Stratifying the patients according to cytogenetics (favorable, intermediate and poor) and age (<50 years and ≥ 50 years) did not influence the results. Accordingly, autologous PB HCT may be a viable alternative as post-remission therapy in patients with AML/CR1 in the absence of MSD. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Aplastic Anemia in Adolescents and Young Adults

Adolescent and young adult patient presentations of aplastic anemia require a particular perspective on both diagnosis and treatment. This unique age group necessitates a thorough diagnostic evaluation to ensure the etiology, acquired or inherited, is sufficiently determined. The treatment options include human leukocyte antigen-identical sibling hematopoietic cell transplantation or immunosuppressive therapy, and both require attention to the specific medical and social needs of these adolescents and young adults. Longitudinal surveillance throughout life for the development of late complications of the disease and treatment is mandatory.

Low CD34 Dose Is Associated with Poor Survival after Reduced-Intensity Conditioning Allogeneic Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndrome

Reduced-intensity conditioning/nonmyeloablative conditioning regimens are increasingly used in allogeneic hematopoietic cell transplantation (HCT). Reports have shown CD34+ dose to be important for transplantation outcome using myeloablative conditioning. The role of CD34+ dose of peripheral blood progenitor cells (PBPC) has not been previously analyzed in a large population undergoing reduced-intensity conditioning/nonmyeloablative HCT. We studied 1054 patients, ages 45 to 75 years, with acute myeloid leukemia or myelodysplastic syndrome who underwent transplantation between 2002 and 2011. Results of multivariate analysis showed that PBPC from HLA-matched siblings containing <4 × 106 CD34+/kg was associated with higher nonrelapse mortality (hazard ratio [HR], 2.03; P = .001), overall mortality (HR, 1.48; P = .008), and lower neutrophil (odds ratio [OR], .76; P = .03) and platelet (OR, .76; P = .03) recovery. PBPC from unrelated donors with CD34+ dose < 6 × 106 CD34+/kg was also associated with higher nonrelapse (HR, 1.38; P = .02) and overall mortality (HR, 1.20; P = .05). In contrast to reports after myeloablative HCT, CD34+ dose did not affect relapse or graft-versus-host disease with either donor type. An upper cell dose limit was not associated with adverse outcomes. These data suggest that PBPC CD34+ doses >4 × 106 CD34+/kg and >6 × 106 CD34+/kg are optimal for HLA-matched sibling and unrelated donor HCT, respectively.

Comprehensive Long Term Evaluation of End-Organ Function in Pediatric Patients Undergoing Matched Sibling Hematopoietic Cell Transplantation for Sickle Cell Disease

Comprehensive Long Term Evaluation of End-Organ Function in Pediatric Patients Undergoing Matched Sibling Hematopoietic Cell Transplantation for Sickle Cell Disease

HLA Disparity Is Associated with Improved Outcomes in Hematological Malignancies After Family HLA-Mismatched /Haploidentical HCT but Not URD

Abstract 2014▪▪This icon denotes a clinically relevant abstract Background:Previous reports have evidenced that donor-recipient HLA disparity is not associated with improved outcomes after URD hematopoietic cell transplantation (HCT). Some data indicates that Haploidentical (haplo) HCT may result in lower relapse and better outcomes than HLA-identical sibling transplantation in lymphoma. Unfortunately, HLA disparity coming along with severe GVHD and infectious diseases may counteract any benefits from this potentially intensive graft-versus-leukemia (GVL) effects. Here we investigate the impact of donor types on clinical outcomes in 233 patients with hematological malignancies from our single BMT Center. Patients and methods:The outcomes of 233 patients, median age 23 years (4–62), with leukemia undergoing HLA-matched sibling(MRD) (n=52), unrelated (URD) (n=52) and related HLA-mismatched/haploidentical (haplo) (n =129) HCT, performed during the same time period (2007–2012) in single Med Center were compared. Patients received either BUCY2 or BUFlu in HLA-identical sibling HCT, and BUCY + ATG or BUFlu +ATG in URD and haplo cohorts as conditioning regimens, followed by G-CSF mobilized unmanipulated marrow and/or peripheral blood (PB) transplantation. All HLA typing has been performed using high-resolution DNA techniques. In haplo cohort, a hundred-four patients were 3/6 identical, 4 were 4/6 identical and 21 were 5/6 identical at HLA-A,-B, and -DRB1. In URD cohort, thirty-one were 8/8 identical, 13 were 7/8 identical and 8 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. 100/129 haplo, 36/52 URD and 14/52 sibling HCT received HLA 3/6–5/6 matched unrelated CB or haplo BM co-transplantation on day –1 as “third party” cells. GVHD prophylaxis consisted of CSA, MMF and short-term MTX. Results:The median follow-up was 23 mon. (range, 2.5mon.-59.2mon.). All patients engrafted to ANC exceeding 0.5× 109/L at 13.5 d (range, 10–19 d) in matched HCT and URD vs. 125 patients engrafted in haplo patients at 13.5d (8–25d). All patients achieved platelet engraftments in both matched and URD cohorts, at 13.5 d (10–22 d) vs. 124 patients engrafted at 13.5d (9–36 d) in haplo, respectively. Univariate analyses showed that the probability of grades 1–4 acute GVHD at 100 days in MRD, URD and haplo were 42%((95% confidence interval [CI], 28%-56%) vs. 48% (CI, 34%-62%) vs. 63%(CI, 54%-71%, P=0.006), respectively. But aGVHD3-4 were only 10%(CI, 3%-21%) vs. 25%(CI, 14%-39%) vs., 19%(CI, 12%-26%, P=0.155), respectively. The 3-year relapse and TRM rates were 34.6% vs. 13% vs. 17.3%(P=0.0126) and 12.7% vs. 30.2 vs. 21%(P= 0.0496) for patients who underwent MRD, URD and haplo transplantation, respectively. The 3-year RRM rates were 29.2% vs. 24.7% vs. 11.6%(P=0.018)after matched vs. URD vs. haplo, respectively. The 3-year Over all survival(OS)probabilities were 61.8% (range, 48.5%-78.4%), 52.5% (38.6%-71.9%) and 69.8 % (61.6%-79.1%) after the matched, URD and haplo HCT, respectively. There were no differences in survival probabilities according to donor types (P= 0.2743). But further analyses indicated that the 3-year OS for patients with early/intermediate disease were 71.8%, 57.3% and 80.2%, P=0.0401, while patients with advanced disease were 36%, 31.8% and 44.2% (P=0.9633)after the matched, URD and haplo transplantation, respectively. Tests in the multivariate analyses indicated that diseases in advanced stage, long period between diagnoses and transplantation, as well as acute GVHD 3–4 were all correlated with lower survival. Conclusion:These data suggest that HLA disparity in Haplo HCT results in relatively lower relapse and RRM, accepted TRM and improvement of survival for hematological malignant patients, especially in early and intermediate disease. The GVL effect using family HLA mismatched donors may be superior to HLA-identical siblings HCT. URD HCT also have lower relapse but do not associated with improvement of OS because relatively high TRM. Family –mismatched /haploidentical HCT should not be the last choice for these patients with Hematological Malignancies. Choosing the best haploidentical donor and further reduction of relapse and infectious complications in the future will lead to better clinical outcomes. Studies with more patients enrolled are undertaken. Disclosures:No relevant conflicts of interest to declare.

Long-Term Follow-up of a Randomized Trial Comparing Cyclosporine and Short Course Methotrexate with Cyclosporine and Mycophenolate Mofetil for Graft Versus Host Disease Prophylaxis in Myeloablative HLA-Identical Sibling Hematopoietic Cell Transplantation.

AbstractAbstract 3073▪▪This icon denotes a clinically relevant abstractThe combination of a calcineurin inhibitor and methotrexate (MTX) is currently the gold standard for GVHD prophylaxis. MTX, however, is associated with toxicity including mucositis, delayed engraftment and other organ toxicity. We conducted a randomized trial comparing cyclosporine (CSA) and mycophenolate (MMF) with CSA and MTX for GVHD prophylaxis in recipients of myeloablative allogeneic hematopoietic cell transplants (HCT) with matched sibling donors (Bolwell et al, BMT 2004, 34:621). We showed reduced toxicity without an increased relapse rate in patients treated with MMF instead of MTX. Now, with a median follow up of almost 10 years, we report long-term outcomes of this study.From May 2001 until February 2003, 40 patients with hematologic malignancies were randomized to receive CSA (300mg/m2) and MMF (500mg three times daily) or CSA and short course MTX (5mg/m2 days 1, 3, 6, 11). Study endpoints included incidence of acute GVHD, severity of mucositis, time to engraftment of neutrophils and platelets and 100 day survival. Baseline variables were compared using the Wilcoxon rank sum tests or Chi square test. Outcomes were compared between MMF and MTX using the Pepe-Mori test. The two treatment arms were similar in patient characteristics such as age, disease, disease status, and CMV status. In total, 21 patients received MMF and 19 patients received MTX. The study was stopped early when an interim analysis demonstrated less mucositis, shorter length of stay and no difference in the incidence of GVHD or relapse with a median of 6 months of follow up. Currently, with a median follow up of 119 months (range 46–129 months) in survivors, there remains no difference in the incidence of or degree of acute (p≥0.35) or chronic GVHD (p≥0.53), overall survival (p=0.84) or relapse (p=0.41). There are 6 long term survivors in the MMF arm and 4 in the MTX arm. Of those that received MMF, 3 have mild chronic GVHD of the skin or upper GI tract and 1 has moderate chronic GVHD involving the skin, fascia, and vulva. Three of those who received MTX have mild chronic GVHD primarily of the skin. Only 3 patients (2 MMF and 1 MTX) remain off of all immunosuppression without evidence of GVHD. Eight patients (38%) died of relapse in the MMF arm versus 7 (37%) in the MTX arm which was also not statistically different (p=0.86). Death from GVHD was similar in both groups.Results from this updated analysis support our original conclusion that the combination of CSA and MMF results in decreased mucositis and more rapid engraftment compared with CSA and MTX, with no significant difference in GVHD, survival or relapse on long-term follow up. The primary limitation of this trial remains sample size and the ability to detect modest differences in survival. There remains limited data and virtually no long-term data comparing standard MTX based regimens with less toxic prophylaxis in myeloablative allogeneic HCT. Larger prospective studies with long-term follow up comparing GVHD prophylaxis regimens are warranted. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

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.

Early matched sibling hematopoietic cell transplantation for adult AML in first remission using an age-adapted strategy: long-term results of a prospective GOELAMS study

AbstractThe LAM2001 phase 3 trial, involving 832 patients with acute myeloid leukemia (AML; median: 46 years) proposed HLA-identical sibling allograft HSCT for all patients with an identified donor. The trial compared reduced-intensity conditioning (RIC) for patients older than 50 years of age (N = 47) and myeloablative conditioning for younger patients (N = 117). BM HSCT was performed in the younger patients, while the older ones received a consolidation course, followed by peripheral blood allo-HSCT using RIC. The incidence of grade II-IV acute GVHD, was 51.9% (95% confidence interval [CI]: 42.1-61.8) and 11.3% (1.6-21.2) after myeloablative or RIC, respectively (P < .0001) and that of chronic GVHD 45.8% (95% CI: 34.8-56.7) and 41.7% (24.7-58.6; NS). Cumulative incidence of nonrelapse mortality at 108 months was 15.8% (95% CI: 9.8-23.2) for myeloablative, and 6.5% (0.2-16.2) for RIC (NS). CI of relapse at 108 months was 21.7% (95% CI: 13.9-28.6) and 28.6% (16.5-43.4; NS). Overall survival at 108 months was 63.4% (95% CI: 54.6-72.2) and 65.8% (52.2-72.2), respectively, after myeloablative or RIC (NS). RIC peripheral blood stem cell allo-HSCT is prospectively feasible for patients between the ages of 51 and 60 years without excess of relapse or nonrelapse mortality, and compares favorably with myeloablative marrow allo-HSCT proposed to younger patients. This study was registered at clinicaltrials.gov as no. NCT01015196.

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

Outcomes from Unrelated Donor Hematopoietic Stem Cell Transplantation

Allogeneic hematopoietic cell transplantation (HCT) offers a curative treatment option for management of a variety of hematologic malignancies. While sibling donors have been the gold standard for adult patients in need of an HCT, not all patients have a suitable family donor. The availability of unrelated volunteer donor registries and alternative stem cell sources has expanded the wide application of this procedure. PubMed and MEDLINE were searched for human trials and the English language from 2001 to 2011. Factors influencing transplantation outcomes involving unrelated donors over the last decade are discussed, and feasible alternative stem cell sources when a matched unrelated donor is not available are reviewed. HCT using a matched unrelated donor offers outcomes comparable to sibling HCT due to current molecular-based HLA typing and improvements in conditioning regimens and/or supportive care. The primary factor that contributes to improved outcome is the degree of donor-to-recipient HLA matching. The selection of younger unrelated donors has also been associated with improved outcomes in HCT. Evidence supports the universal application of matched unrelated donors even in high-risk leukemia and/or older patients. In adult patients without a matched related donor, other promising options as stem cell source includes mismatched unrelated donors, umbilical cord blood units, and haploidentical donors. With current methodologies for molecular HLA typing and supportive care tools, outcomes of transplants with matched unrelated donors are comparable to those achieved with sibling donors. Alternative stem cell donors when a matched unrelated donor is not available are feasible expanding the stem cell donor pool.

The Impact of Donor Type In Patients with AML and High Risk Cytogenetic Aberrations

AbstractAbstract 2369 Objectives:Matched sibling (SIB) hematopoietic cell transplantation (HCT) has become an established treatment option in first complete remission of AML with high risk cytogenetic aberrations by donor versus no donor comparisons. Comparable evidence for matched unrelated donor (UD) HCT is lacking and selection of a matched UD has been considered as a risk factor based on retrospective studies. However, in some more recent studies, elderly patients and patients with high risk AML who had a matched UD had a trend to better survival compared to patients with matched sibling donors. This observation led to the hypothesis that elderly patients could even benefit from the selection of a young male UD compared to an old sibling donor – especially if an unfavourable sex mismatch is present. Therefore, we sought to determine the role of UD HCT in high risk AML by comparing the outcome of patients with SIB HCT to patients with matched or partially matched UD HCT. Methods:We performed a retrospective cohort analysis in patients with AML according to WHO criteria and high risk cytogenetic aberrations according to modified CALGB 2002 criteria who received allogeneic HCT between 01/2005 and 12/2008. Centers in which high resolution typing for HLA-A, -B, -C and DRB1 for all non-sibling HCTs was standard were invited to include patients. Patients who received a second allogeneic HCT or haploidentical HCT were excluded. Comorbidities at HCT were retrospectively assessed with the HCT-specific comorbidity index. We used multivariate Cox regression modelling for OS and PFS while competing event statistics were applied for NRM and RI. Besides donor type the potential confounders age, comorbidities (HCT-CI), Karnofsky performance status and delay between diagnosis and HCT were entered a priori into the multivariate models for OS and PFS. Additional variables were tested by stepwise backward selection based on the likelihood ratio test. Results:Six transplant centers contributed data on 301 patients with AML. The median age was 56 years (range, 21 to 77 years). 77% of the patients received allogeneic HCT as part of firstline treatment whereas 23% of patients were transplanted after relapse. At HCT 59% of the patients were in a morphologic leukemia-free marrow state and 31% of patients had residual blasts prior to start of the conditioning regimen. Donors were HLA-identical siblings in 27%, matched UD in 49% and partially mismatched UD in 24% of the patients. Patients with a matched sibling donor more often had an unfavourable sex mismatch (male recipient and female donor pairs, 25% in SIB HCT, 7% in matched UD HCT and 19% in partially matched UD HCT, p=0.001) but received ATG less frequently (27% in SIB HCT, 75% in UD-HCT and 67% in partially matched UD HCT, p<0.001). The median observation time at last follow-up was 28 months (range, 8 to 61 months). At 3 years overall survival (OS) was 40% (95% CI, 33% to 47%) and progression-free survival (PFS) was 38% (95% CI, 32% to 44%). The incidence of non-relapse mortality (NRM) at 3 years was 27% (95% CI, 22% to 32%) and relapse incidence (RI) was 35% (95% CI, 30% to 41%). The hazard ratios (HR) attributed to a matched UD was 1.0 (95% CI, 0.7 to 1.5) and to a mismatched donor 1.2 (95% CI, 0.7 to 1.8), compared to a matched sibling donor, respectively. Interestingly, when sex mismatch and CMV constellation were entered into the multivariate model the hazard ratios of UD HCT and partially matched UD HCT slightly increased to 1.1 (95% CI, 0.7 to 1.6) and 1.3 (95% CI, 0.8 to 2.0), respectively. This observation could be an indicator that selection of unrelated donors by gender and CMV status contributes to the good results of matched unrelated HCT. We did not find significant interactions between donor type and age, cytogenetic risk group or disease stage. Notably, having a matched unrelated donor neither significantly affected the risk of NRM (HR 0.7; 95% CI, 0.4 to 1.3) nor the risk of relapse (HR 1.4; 95% CI, 0.9 to 2.3). Conclusions:Matched UD HCT is not associated with a significantly different impact on survival compared to matched SIB HCT in high risk AML taking into account that the transplant strategies are different with respect to the use of ATG. The results confirm the current practice to consider matched siblings and unrelated donors for allogeneic HCT in high risk AML. Subgroups of patients for whom a matched UD should be preferred to a matched sibling donor could not be defined by transplant outcome. Disclosures:Bug: Celgene: Honoraria.

Impact of In Vivo T-Cell Depletion on Outcome of Reduced Intensity Conditioning (RIC) Hematopoietic Cell Transplantation (HCT) for Hematologic Malignanciesimpact of In Vivo T-Cell Depletion on Outcome of Reduced Intensity Conditioning (RIC) Hematopoietic Cell Transplantation (HCT) for Hematologic Malignancies

AbstractAbstract 2305HCT using RIC regimens has increased steadily over the past decade. In vivo administration of anti-T cell antibodies, such as alemtuzumab and anti-thymocyte globulin (ATG) preparations, is often employed to promote engraftment and limit graft-versus-host disease (GVHD). While these antibodies might reduce the severity and incidence of GVHD, they may also blunt the allo-immune graft-versus-tumor effect of HCT. Transplant outcomes after in vivo T-cell depletion (n=584 ATG; n=213 alemtuzumab) were compared to those after T-cell replete (n=879) RIC transplants for myeloid and lymphoid malignancies. Patients were aged 21–69 yrs and transplanted from 2000–2007. Median follow-up of patients is 3 years. Conditioning regimens consisted of an alkylating agent (melphalan, busulfan, or cyclophosphamide) with fludarabine. 792 patients (47%) received allografts from a HLA-matched sibling, 650 (39%) from an 8/8 and 234 (14%) from a 7/8 HLA-matched unrelated donor. In vivo T-cell depletion was used for 35% of matched sibling HCT, 57% of 8/8 and 64% of 7/8 HLA matched unrelated donor HCT. Results of multivariable analysis adjusted for age, disease and disease stage, donor, year of transplant, conditioning regimen, and GVHD prophylaxis are shown in Table below. Grade 2–4 acute GVHD was lower with alemtuzumab containing regimens (20%) than ATG containing (41%) or T replete (42%) regimens. Chronic GVHD occurred in 27% of recipients of alemtuzumab, 43% of ATG, and 57% of T replete regimens, respectively. Compared to T-cell replete regimens, relapse risks were higher with ATG and alemtuzumab containing regimens (38%, 49% and 51%, respectively) and non-relapse mortality, higher with ATG containing regimens only. Treatment failure (relapse or death) was higher with both ATG and alemtuzumab containing regimens compared to T replete regimens. Overall mortality was highest with ATG containing regimens. These observations are independent of disease, disease status and donor type including 7/8 HLA-matched HCT. The 3-year probabilities of disease-free survival (DFS) were 25%, 30% and 39% with ATG-containing, alemtuzumab-containing and T-cell replete regimens, respectively. Corresponding probabilities for overall survival were 38%, 50% and 46%. There were no differences in disease-free and overall survival at 3-years by ATG source or dose. The incidence of EBV-PTLD was higher with alemtuzumab and ATG containing compared to T-cell replete regimens (2% vs. 2% vs. 0.2%). These results suggest in-vivo T-cell depletion with RIC regimens containing an alkylating agent and fludarabine significantly lowers DFS despite lower GVHD. The routine use of in-vivo T-cell depletion in this setting warrants a cautious approach in the absence of a prospective randomized trial.Alemtuzumab vs. T-cell repleteATG vs. T-cell repleteAlemtuzumab vs. ATGHazard ratio, p-valueHazard ratio, p-valueHazard ratio, p-valueGrade 2-4 acute GVHD0.33, p<0.00010.88, p=0.120.38, p<0.001Grade 3-4 acute GVHD0.42, p<0.00010.86, p=0.200.48, p=0.001Chronic GVHD0.34, p<0.00010.69, p<0.00010.49, p<0.0001Non-relapse mortality1.04, p=0.851.34, p=0.010.78, p=0.19Relapse1.54, p=0.00011.53, p<0.00011.01, p=0.94Treatment failure1.40, p=0.00031.46, p<0.00010.96, p=0.67Overall mortality1.09, p=0.461.25, p=0.0020.87, p=0.22 Disclosures:No relevant conflicts of interest to declare.

Outcome of Allogeneic Hematopoietic Cell Transplantation from HLA-Identical Siblings for Severe Aplastic Anemia in Patients Over 40 Years of Age

Patients with severe aplastic anemia (SAA) over 40 years of age are often not offered treatment with hematopoietic cell transplantation (HCT) because of concerns about treatment-related morbidity or mortality. To evaluate this risk, we analyzed outcomes after allogeneic HCT from HLA-identical sibling donors for all older patients with SAA at our center since 1988. The 23 consecutive patients ranged in age from 40 to 68 years. The conditioning regimen was cyclophosphamide (200 mg/kg) and horse antithymocyte globulin. Methotrexate and cyclosporine were given for postgrafting immunosuppression. The cumulative incidences of grades II, III, and IV acute graft-versus-host-disease were 30%, 4%, and 0%, respectively; that for chronic GVHD was 26%. With a median follow-up of 9.1 years, overall survival was 65%. Documented infections within 1 month before HCT were significantly associated with risk of early treatment-related mortality (P < .001). The median time to discontinuation of posttransplant immunosuppression was 6.2 (range: 5.9-92.0) months. Three patients developed superficial basal cell carcinoma between 5.5 and 15 years after HCT. Our data favor a practice of extending HLA-identical sibling HCT for treatment of SAA in patients older than 40 years of age who are without significant medical comorbidities.

Relapse and Late Mortality in 5-Year Survivors of Myeloablative Allogeneic Hematopoietic Cell Transplantation for Chronic Myeloid Leukemia in First Chronic Phase

PURPOSE Allogeneic hematopoietic cell transplantation (HCT) is curative therapy for chronic myeloid leukemia (CML), but its long-term outcomes are not well described. We studied the long-term outcomes of CML patients in first chronic phase who receive an allogeneic HCT. PATIENTS AND METHODS Our study included 2,444 patients who received myeloablative HCT for CML in first chronic phase between 1978 and 1998 and survived in continuous complete remission for at least 5 years (median follow-up, 11 years; range, 5 to 25 years). Donor sources were human leukocyte antigen-matched siblings in 1,692 patients, unrelated donors in 639 patients, and other related donors in 113 patients. RESULTS Overall survival rates at 15 years were 88% (95% CI, 86% to 90%) for sibling HCT and 87% (95% CI, 83% to 90%) for unrelated donor HCT. Corresponding cumulative incidences of relapse were 8% (95% CI, 7% to 10%) and 2% (95% CI, 1% to 4%), respectively. The latest relapse was reported 18 years post-HCT. In multivariable analyses, history of chronic graft-versus-host disease increased risks of late overall mortality and nonrelapse mortality but reduced risks of relapse. In comparison with age-, race-, and sex-adjusted normal populations, the mortality of HCT recipients was significantly higher until 14 years post-HCT; thereafter, mortality rates were similar to those of the general population (relative mortality ratio at 15 years, 2.3; 95% CI, 0 to 4.9). CONCLUSION Recipients of allogeneic HCT for CML in first chronic phase who remain in remission for at least 5 years have favorable subsequent long-term survival, and their mortality rates eventually approach those of the general population.

A Prospective Study Of Donor Immuknow® As A Biomarker For Acute GvHD In Hematopoietic Cell Transplantation Recipients

Abstract 4646 Introduction Graft versus host disease (GvHD) occurs in ∼40% of allogeneic hematopoietic cell transplantation (HCT) recipients and is associated with substantial morbidity and mortality. The exact mechanisms underlying GvHD remain to be defined, but donor immune cells are thought to play a major role in the pathogenesis of GvHD. Depletion of donor lymphocytes reduces the risk of GvHD but to the expense of disease relapse and lower engraftment. Immunological parameters of donor cells that predispose a recipient to GvHD will be of great value. The Cylex” ImmuKnow® assay determines the strength of immune function by quantifying the amount of ATP released from phytohemagglutinin-stimulated peripheral blood CD4 + cells. The amount of ATP production is a measure of lymphocyte activity. In our current study, we utilized the ImmuKnow® to assess whether a donor9s immune response correlates with early outcomes in recipients post-HCT. Patients and Methods Twenty-six (26) donor-recipient pairs were included in our study (15 HLA identical sibling HCT and 11 haploidentical HCT). The median age of recipients at the time of transplantation was 49 years (range, 23-65). Twelve were female and 14 male. The median age of donors was 45 years (range, 18-67), and half of them were female. Recipients received an average cell-dose of 10.7 ± 4.9 × 10 6 CD34 + cells/kg. Twenty-one patients received nonmyeloablative, reduced intensity conditioning consisting of Fluarabine, Busulfan or melphlan, and alemtuzumab, and mycophenolate mofetil was given for GvHD prophylaxis in these recipients. Five patients received myeloablative conditioning with total body irradiation or Busulfan, and cyclophosphamide. Methotrexate with/without cyclosporine or tacrolimus alone was used for GvHD prophylaxis in myeloablative patients. Stem cell source was G-CSF-mobilized peripheral blood. Blood samples obtained prior to G-CSF mobilization and prior to stem cell collection (approximately 2 weeks apart) were assayed for ImmuKnow values and cell counts (WBC, ANC, ALC & CD34 + count). Results G-CSF mobilization led to a significant increase in ImmuKnow® ATP values from 342 to 728 ng/mL (p + cell dose) and GvHD. In haploidentical HCT, mobilized donor blood ImmuKnow® ATP values did not correlate with GvHD. However, donor ImmuKnow® values correlated with increased risk of acute GvHD in HLA identical sibling HCT. ROC analysis of mobilized donor samples showed that in HLA identical sibling HCT ATP values in excess of 747 ng/mL predicted grade II or higher GvHD with a likelihood ratio of 4.00 (2.9-5.5, 95% confidence), sensitivity of 100%, and specificity of 75% (AUC=0.889, p=0.003) . Conclusions In HLA identical matched sibling transplantation, very strong ATP values (>747 ng/mL) following mobilization correlated with the risks of developing grade II or higher GvHD during the first 90 days post-transplant. If confirmed in larger studies, these data suggest that ImmuKnow can serve as an independent predictor/biomarker for the development of GvHD in HLA identical HCT. Disclosures: No relevant conflicts of interest to declare.

A Prospective Study of Donor ImmuKnow® as a Biomarker for Acute GvHD in Hematopoietic Cell Transplantation Recipients.

Abstract 4646 IntroductionGraft versus host disease (GvHD) occurs in ∼40% of allogeneic hematopoietic cell transplantation (HCT) recipients and is associated with substantial morbidity and mortality. The exact mechanisms underlying GvHD remain to be defined, but donor immune cells are thought to play a major role in the pathogenesis of GvHD. Depletion of donor lymphocytes reduces the risk of GvHD but to the expense of disease relapse and lower engraftment. Immunological parameters of donor cells that predispose a recipient to GvHD will be of great value. The Cylex” ImmuKnow® assay determines the strength of immune function by quantifying the amount of ATP released from phytohemagglutinin-stimulated peripheral blood CD4+ cells. The amount of ATP production is a measure of lymphocyte activity. In our current study, we utilized the ImmuKnow® to assess whether a donor's immune response correlates with early outcomes in recipients post-HCT. Patients and MethodsTwenty-six (26) donor-recipient pairs were included in our study (15 HLA identical sibling HCT and 11 haploidentical HCT). The median age of recipients at the time of transplantation was 49 years (range, 23-65). Twelve were female and 14 male. The median age of donors was 45 years (range, 18-67), and half of them were female. Recipients received an average cell-dose of 10.7 ± 4.9 × 106 CD34+ cells/kg. Twenty-one patients received nonmyeloablative, reduced intensity conditioning consisting of Fluarabine, Busulfan or melphlan, and alemtuzumab, and mycophenolate mofetil was given for GvHD prophylaxis in these recipients. Five patients received myeloablative conditioning with total body irradiation or Busulfan, and cyclophosphamide. Methotrexate with/without cyclosporine or tacrolimus alone was used for GvHD prophylaxis in myeloablative patients. Stem cell source was G-CSF-mobilized peripheral blood. Blood samples obtained prior to G-CSF mobilization and prior to stem cell collection (approximately 2 weeks apart) were assayed for ImmuKnow values and cell counts (WBC, ANC, ALC & CD34+ count). ResultsG-CSF mobilization led to a significant increase in ImmuKnow® ATP values from 342 to 728 ng/mL (p<0.001) along with an increase in all measured cell counts. Average ImmuKnow® values from recipients were 108 ± 116 at 2-3 weeks post-transplant, 231± 221 at 4-5 weeks, and 104 ± 95 ng/mL at 8-10 weeks. Grade ≥ II acute GvHD occurred in 27% of haploidentical HCT recipients (3/11 patients) and 20% of HLA identical HCT recipients (3/15 patients). We found no correlations between recipient post-transplant ImmuKnow® values and GvHD. No correlations were observed between various donor cell counts (WBC, ANC, ALC or CD34+ cell dose) and GvHD. In haploidentical HCT, mobilized donor blood ImmuKnow® ATP values did not correlate with GvHD. However, donor ImmuKnow® values correlated with increased risk of acute GvHD in HLA identical sibling HCT. ROC analysis of mobilized donor samples showed that in HLA identical sibling HCT ATP values in excess of 747 ng/mL predicted grade II or higher GvHD with a likelihood ratio of 4.00 (2.9-5.5, 95% confidence), sensitivity of 100%, and specificity of 75% (AUC=0.889, p=0.003) . ConclusionsIn HLA identical matched sibling transplantation, very strong ATP values (>747 ng/mL) following mobilization correlated with the risks of developing grade II or higher GvHD during the first 90 days post-transplant. If confirmed in larger studies, these data suggest that ImmuKnow can serve as an independent predictor/biomarker for the development of GvHD in HLA identical HCT. Disclosures:No relevant conflicts of interest to declare.

Allogeneic hematopoietic cell transplant for multiple myeloma: Comparative results of planned therapy versus salvage therapy

7035 Background: Despite advances in therapy for multiple myeloma, the disease remains incurable using chemotherapy or immune-modulating agents alone. Several newer hematopoietic cell transplant (HCT) strategies including tandem HCT, and non- myeloablative (NMA) regimens have reported encouraging results. However, the appropriate timing for utilizing these strategies is not clear. Methods: We report outcomes in 51 patients with multiple myeloma who received an allogeneic HCT; either as salvage therapy (after failing a prior autologous HCT), n= 15 or as planned therapy, n= 36, between the years 1996 and 2008 at University of Minnesota. Results: Patients in salvage therapy group were significantly older than in planned therapy group (median age 58 versus 49 years) and had a longer interval from diagnosis to transplant (median 47 versus 10 months). Forty four patients received a HCT from a HLA-identical sibling. Five received umbilical cord blood (four in salvage therapy, one in planned therapy group) and two received unrelated donor HCT (one in each group). Thirteen patients in planned therapy group underwent a tandem transplant (planned autologous followed by NMA sibling HCT). All patients in salvage therapy group, and 50% in planned therapy group received NMA HCT. Patients in salvage therapy group were more heavily pre-treated, all having failed a prior autologous HCT. Complete response was seen in 34% versus 47% of recipients in the two groups, respectively. After a median follow-up of 24 and 41 months, similar relapse was seen, but transplant related mortality (TRM) was significantly higher in salvage therapy group, leading to significantly lower two year survival and disease free survival (DFS) in salvage group. Conclusions: Good overall survival and low transplant related mortality was seen in patients undergoing a planned allogeneic transplant. In heavily pre-treated patients, receiving allogeneic HCT as salvage therapy, despite lower relapse, the high TRM led to lower survival. [Table: see text] No significant financial relationships to disclose.

Alloantigeneic Reactions after Human Hematopoietic Cell Transplantation Induce Genomic Alterations in Epithelium: A Confirmation in Vivo and in Vitro Study and Implications to Secondary Neoplasia

We previously demonstrated frequent genomic alterations measured by microsatellite instability (MSI) in non-neoplastic epithelial tissues of pts who underwent allogeneic Hematopoietic Cell Transplantation (HCT) but not after autologous transplantation (Blood 2006; 107:3389–3396). Confirmation in a larger and independent patient cohort and demonstration in an in vitro system was needed. In total 176 buccal samples obtained from 71 unselected patients who underwent allogeneic HCT were analyzed for MSI with standard PCR for microsatellite markers (THO-1, SEE33, D14S120 and D1S80) and analysis by capillary electrophoresis. MSI was observed in 37 (52%) allo-transplanted pts but never in the 31 controls (16 healthy and 15 pts after auto-HCT, 47 samples). MSI+ pts were significantly older than MSI-pts (median age 60y vs 48y, p<0.05). Other clinical features were not significantly different between MSI+ and MSI− pts: gender, myeloid vs lymphoid disease, sibling vs unrelated HCT, myeloablative vs reduced intensity conditioning, sex mismatched transplantation, bone marrow vs mobilized peripheral blood graft, T-cell depletion of the graft, use of methotrexate for GvHD prophylaxis, number of CD3+ cells/kg b.w. infused, occurrence and grade of mucositis during neutropenia, CMV reactivation, median ferritin levels post-transplant and occurrence of GvHD vs no GvHD. When GVHD was analyzed according to its severity we found that there was a trend for increasing risk of MSI for pts who experienced severe GvHD (RR=1.8) as compared to pts with no GvHD (RR=1). Secondary malignancy (5 skin-, 1 adeno-Ca) was diagnosed in 5 (14%) of the MSI+ pts and only in 1 (3%) MSI− pts. In an in vitro model of mutation analysis we tested the hypothesis that an alloantigenic stimulus is substantially involved in the mutation process. Briefly, keratinocyte DNA-repair proficient HaCaT cells were transfected with a reporter plasmid and genomic instability (GI) was detected and measured as hygromycin resistant clones. Treatment of HaCaT cells with H2O2 resulted in a time and dose dependent GI induction (1.9–5.7 fold). Cytokines abundant in alloreactions such as IFN-γ, TNF-α, TGF-β didn't result in any GI in various concentrations and incubation times. Also, treatment with supernatants from different MHC non-matched Mixed Lymphocyte Cultures (MLC-SN) or with MLC separated from HaCaT cells with a semipermeable membrane didn't induce any significant GI. In contrast, exposure of HaCaT cells to the whole MLC which includes activated cellular components (measured as BrdU+) resulted in significant induction of GI in 6 out of 8 different cases (mean 2.4-fold). GI was also evaluated in terms of DNA strand break formation by using the neutral comet assay. Treatment of HaCaT cells with whole MLC resulted in significant increase of DNA strand breaks as compared to HaCaT cells exposed to MLC-SN (p=0.039) or untreated controls (p=0.048). Western blot analysis revealed no significant alterations in the levels of MMR proteins upon treatment with MLC or MLC-SN. Exposure of HaCaT cells to MLC or MLC-SN resulted in increase of intracellular ROS levels as compared to untreated cells. The MLC treatment caused significantly higher increase of ROS levels than MLC-SN. The results of the present study confirm that GI of epithelial cells is a frequent phenomenon in patients after allogeneic HCT and give in vivo and in vitro support that alloantigeneic processes can be the cause of such a phenomenon. Progress in understanding DNA damage and repair after allogeneic HCT can potentially provide molecular biomarkers and therapeutic targets.

Natural T-cell responses against minor histocompatibility antigen (mHag) HY following HLA-matched hematopoietic cell transplantation: what are the requirements for a ‘good’ mHag?

Allogeneic hematopoietic cell transplantation (HCT) represents a potentially curative treatment modality for several hematologic malignancies. Conventional myeloablative conditioning regimens are associated with high treatment-related mortality. To this end, the introduction of nonmyeloablative (NMA) conditioning implies that older and more frail patients can be offered HCT, and recent data suggest comparable outcome of conventional and NMA–HCT, both with regards to efficacy and side effects, at least for selected indications.1 The curative principle in allogeneic HCT with NMA conditioning is solely related to the graft-versus-leukemia (GVL) effect, and several lines of evidence strongly suggest that donor T cells are the main effectors. In human leukocyte antigen (HLA), identical sibling HCT, T-cell responses to minor histocompatibility antigens (mHags) are—at least in part—responsible for the GVL effect but also cause graft-versus-host disease (GVHD). GVHD represents a major side effect of HCT, and it is well established that there exists correspondence between the GVL effect and GVHD. As a consequence, increased knowledge concerning mechanisms at play and the targets recognized may set the stage for development of treatment strategies that focus on induction of GVL in the absence of GVHD.2 Obviously, increased insight into the cells, molecules and antigens involved with GVL and GVHD are important to possibly be able to control and direct these events more precisely.