Unrelated Donor Stem Cell Research Articles

Ofatumumab and High-Dose Methylprednisolone Is An Effective Salvage Treatment for Heavily Pretreated, Unfit or Refractory Patients with Chronic Lymphocytic Leukemia: Single Institution Experience

AbstractAbstract 4638High-dose methylprednisolone (HDMP) and the fully human monoclonal anti-CD 20 Ofatumumab each can produce partial responses in CLL, even though complete remissions are not often observed following treatment with either agent alone.Previously we have reported that the combination of Rituximab and HDMP is an effective non-myelosuppressive treatment combination for previously untreated CLL patients as well as in patients that are fludarabine refractory. We report here our single institution experience of treatment using the combination of HDMP and Ofatumumab in CLL patients that were not considered to be good candidates for chemotherapy treatment due to comorbidities, poor performance status, profound cytopenias or because refractory status to fludarabine and/or alemtuzumab.Eight patients with progressive, symptomatic CLL were treated with HDMP 1 g/m2 IV daily × 3 every 28 days for three consecutive cycles, and ofatumumab administered based on package insert instructions (300 mg dose # 1 followed by 11 doses of 2,000 mg over a 6 month period) along with prophylactic antimicrobial therapy. The main objectives were to determine the safety, toxicity and clinical efficacy of this regimen.All of the patients were males with a median age of 69 years (range 49–78). The median of prior treatments was 4.5 including 4 patients that have received previously HDMP and rituximab and two patients that underwent matched unrelated donor stem cell transplant. All patients have been previously treated with rituximab, 75% of the patients failed or were intolerant to fludarabine and/or aletuzumab and 88% had high-risk disease by the modified Rai classification. Most of the patients had bulky disease with median lymph node product of 42 cms2 and median splenomegaly of 6. 5 cm (range 0–17) below the left costal margin. The median lymphocyte count was 28,000 cells/mm3. 75% of the patients had high-risk prognostic markers including unfavorable cytogenetics, unmutated IgVH region genes or high expression levels of ZAP-70.All patients completed the planned therapy with no major side effects or toxicities. There was no evidence of marrow suppression and even patients with pancytopenia improved their peripheral blood counts with this salvage regimen. During treatment patients experience significant decrease in peripheral white blood cell counts, increase in hemoglobin, elevation of platelets and a dramatic reduction in lymphadenopathy and splenomegaly. Response assessment based on the IW-CLL 2008 criteria showed that the overall response rate was 50% (4 partial remissions), 25% of patients had stable disease and the remainder showed progressive disease.Overall, these data suggest that the combination of HDMP and Ofatumumab is a safe and effective salvage regimen for high-risk CLL patients that otherwise were not candidates for additional treatment. The response rates observed for the combination of HDMP and Ofatumumab in this group of patients appear to be favorable with the majority of patients achieving a response to therapy or experiencing disease stabilization. Moreover, HDMP and Ofatumumab treatment was not associated with bone marrow suppression, which is a major limiting factor for treatment administration, making this regimen a potential valid alternative for high-risk CLL patients. Additional clinical studies of this combination are warranted. Disclosures:No relevant conflicts of interest to declare.

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.

Matched Unrelated Donor Transplantation Is Curative In Selected Patients with Diffuse Large B Cell Lymphoma: A Report of the Lymphoma Working Party (LWP) of the European Group for Blood and Marrow Transplantation (EBMT)

AbstractAbstract 363Matched unrelated donor stem cell transplantation (MUD-SCT) has recently become a therapeutic option for patients with B cell diffuse large cell lymphoma (DLBCL) who fail other conventional therapies and do not have a matched sibling donor available. We present retrospective data of 473 DLBCL patients, 285 males and 188 females, aged 18 to 69 years (median 46 years), treated with matched sibling (n=301) or matched unrelated (n=172) SCT between January 2000 and December 2007 and reported to the EBMT registry. Median time from diagnosis to allograft was 25 months (range 2 – 203). Fifty-seven percent of the patients had failed previous autologous SCT, and 12% were transplanted in chemorefractory disease. After a median follow up of 41 months, the estimated 3-year non-relapse mortality (NRM), relapse rate (RR), progression free survival (PFS) and overall survival (OS) for the whole series were 37%, 32%, 31% and 40%, respectively. There were no statistically significant differences in patient age, disease status at transplantation, stem cell source and intensity of conditioning regimen between the Sib and the MUD cohorts (summarized in Table 1).However, a higher number of patients undergoing MUD have already failed an autograft (66% vs 52%, p=0.004), and T cell depleted grafts were more frequently used in the MUD cohort. Acute GvHD occurred in 48% of patients treated with a sib allograft vs 54% in those receiving a MUD (p=n.s). Interestingly, there were no statistically significant differences in NRM and RR between the Sib and the MUD groups (3 yr NRM=38% vs 37%, RR approached 38% vs 34%), resulting in a similar 3-year PFS and OS (32% vs 29% and 42% vs 35%, respectively). Multivariate analysis identified refractory disease (p = 0.001, RR 3.2; CI=1.3-3.5), poor performance status (p = 0.017, RR 1.9; CI=1.1-3.4) and age at transplantation > 50 years (p = 0.015, RR1.5; CI=1.1-2.1) as independent adverse prognostic factors for NRM and time from diagnosis to SCT < 36 months (p = 0.02, RR 1.5; CI=1.1-2.1), a previously failed autologous SCT (p = 0.026, RR .4; CI=1.1-1.9), refractory disease (p = 0.003, RR 2; CI=1.3-3.1), poor performance status (p = 0.0001, RR 3.5; CI=2.1-5.6) and T cell depletion (p = 0.001, RR 2; CI=1.3-2.9) as adverse prognostic factors for RR. A previous autologous SCT, poor performance status and refractory disease at transplantation were found to be significantly associated with a shorter PFS (p=0.04, RR 1.3; CI=1-1.6; p=0.0001, RR 2.4; CI=1.6-3.4; p=0.000,RR 2.1; CI=1.5-2.9, respectively) and refractory disease (p=0.0001, RR 2.2; CI=1.6-3.1) and poor performance status at the time of SCT (p=0.0001, RR 2.5; CI=1.7-3.6) with a shorter OS. Patients allografted from MUD tended to have a slightly increased risk of overall mortality in multivariate analysis, but this was not statistically significant (p=0.06, RR 1.2; CI=0.95-1.6). In conclusion, MUD SCT provides a curative option, not significantly inferior to that obtained with a matched sibling transplant, for selected patients with DLBCL who have failed conventional therapies, including autograft. Similarly, the type of conditioning regimen was not found to have a significant impact on patient outcome.Table 1Clinical characteristics Sib vs MUDSib (n = 301)MUD (n= 172)pAge (median, years)4645N.S.Previous ASCT48%33%0.004Refractory disease12%12%N.S.Poor P.S.13%7%0.06RIC/CC57%/43%56%/42%N.S.SC source BM/PB20%/80%22%/78%N.S.ATG/ALG15%46%<0.001in vivoüT-cellüdepletion12%20%0.03ex vivoüT-cellüdepletion5%12%0.03ASCT. Autologous stem cell transplantation; PS. Performance status; RIC. Reduced intensity conditioning; CC. Conventional conditioning; SC. Stem cell; BM. Bone marrow; PB. Peripheral blood; ATG/ALG. Anti-thymocyte globulin/ALG. Anti-lymphocyte globulin. Disclosures:No relevant conflicts of interest to declare.

Phase II Study Evaluating Busulfan and Fludarabine as Preparative Therapy In Adults with Hematopoietic Disorders Undergoing Matched Unrelated Donor Stem Cell Transplantation.

AbstractAbstract 1317 Introduction:Allogeneic stem cell transplantation offers potentially curative therapy for selected patients with hematopoietic malignancies or bone marrow failure states. Only 20–25% of transplantation candidates have compatible related donors, and thus the majority of patients require stem cells from unrelated individuals matching their human leukocyte antigen (HLA) genes. Unrelated donor transplantation (NMUDT) is associated with higher rate of acute and chronic graft versus host disease (aGVHD and cGVHD, respectively) resulting in significant treatment related morbidity and mortality. Severe aGVHD (grade III/IV) occurs in 30–40% of patients and many of these patients eventually die from the complications. The incidence of cGVHD following unrelated transplantation was reported to occur up to 80%. Treatment-related mortality in the first 100–180 days post-transplant ranges from 30–60% depending on the patient/donor age, disease status at time of transplant and HLA mismatch. This compares to a treatment-related mortality of approximately 20–30% for patients receiving sibling-donor transplants. More aggressive conditioning including total body irradiation is believed to result in severe organ toxicities fueling subsequent GVHD in the NMUDT patients. In this study we evaluated chemotherapy only based preparative therapy (busulfan and fludarabine) and tacrolimus plus methotrexate as the GVHD prophylaxis. Also the donors and recipients were matched with strict HLA compatibility. Patients and Method:Thirty-five patients meeting eligibility criteria for NMUDT were prospectively enrolled. Diagnoses included:14 AML, 6 NHL, 6 MDS, 5 ALL, 2 MPD, 2 CML. The median age was 46 years (18-61); 20 males and 15 females. Preparative therapy consisted of Fludarabine (F) 30mg/m2 daily for 5 doses, Busulfan (Bu) 0.8mg/kg IV q6 hrs for 16 doses. All patients received stem cells from allele-matched unrelated donors; 7/8 (n=1), 8/10 (n=1), 9/10 (n= 7) or 10/10 (n= 26) at HLA A, B, C, DR and DQ. 9 patients received bone marrow and 26 patients received G-CSF mobilized peripherial blood stem cells. All patients received TAC (target 5–10 ug/L), MTX (5mg/m2 d1,3,6,11) for GVHD prophylaxis. Infectious disease prophylaxis included; G-CSF, acyclovir, anti-bacterials, voriconazole, and CMV pre-emptive therapy. Results:The engraftment was documented as follows: ANC >1.0 median: day 12 (SD3.5), Plt >50×10e9/L median: day 16 (SD 7.2), Plt >100×10e9/L median: day 20 (SD 40.7). The frequent (>20%) toxicities included bone marrow suppression (grade 4 100%) mucositis (gr≥1 91%), enteritis (gr≥1 43%); elevated AST (gr 1 27%), elevated total bilirubin (gr 1 20%) and alkaline phosphatase (gr1 40%). Other significant toxicities (gr ≥3) included neutropenic fever (20%), bacteremia (11%), infections (including pneumonia, fungal pneumonia, CMV viremia) (26%), enteritis 6%, ARF 9%, rash 9%, respiratory failure 14%. The incidence of aGVHD (Gr II-IV) was 43%. The incidence of cGVHD was 60% (90% extensive cGVHD). The 100 day non-relapse mortality (NRM) was 9% (2 GVHD, 1 VOD). The late TRM (beyond 100 days) was 11% (3 GVHD, 1 infection). Cumulative relapse related mortality was 17% at 6 months, 26% at 9 months and 31% at 24 months. Overall mortality at 1 year was 44%. Overall survival is currently 40% with median follow-up of 4.4 years. Conclusions:In this prospective study of 35 patients undergoing matched unrelated donor transplantation, the busulfan/fludarabine preparative regimen is safe and resulting in reasonably low TRM and comparable GVHD rates. Disease relapse remains the most significant cause of death. Disclosures:No relevant conflicts of interest to declare.

A Comprehensive Comparison Immune Recovery In Adult Patients Following Allogeneic Umbilical Cord Blood, Matched Sibling and Matched Unrelated Donor Stem Cell Transplantation

AbstractAbstract 2313Immunologic reconstitution following stem cell transplantation (SCT) arises from thymic-independent peripheral expansion of memory T-cells transplanted with the stem cell graft, and thymic-dependent maturation of stem cell derived lymphoid progenitor cells. As a consequence of thymic involution, adult stem cell transplant recipients rely largely upon the thymic-independent pathway. This process is facilitated by a plentiful supply of mature T-cells contained within peripheral blood or bone marrow grafts. Umbilical cord blood (UCB) grafts contain predominantly naive T-cells thereby limiting the potential for thymic-independent immune recovery. Recent reports have documented slow immune recovery in adult UCB recipients, however it has yet to be described in the context of a comparable population of adult allogeneic matched sibling or unrelated donor SCT. Methods:Between 2007 and 2009, we characterized cellular immune reconstitution in a consecutive cohort of adult patients undergoing myeloablative SCT using either matched sibling (MSD), matched unrelated donor (MUD) peripheral blood stem cell (PBSC) or dual UCB donor grafts. Dual UCB transplant recipients were conditioned with TBI 1350cGy and fludarabine 160mg/m2 (Flu). PBSC recipients were conditioned with either TBI 1350cGy or IV busulfan 12.8mg/kg (Bu) and cyclophosphamide 120mg/kg, or Bu/Flu. PBSC grafts were allele-level matched at HLA-A, B, C and DRB1. UCB grafts were mismatched at no more than 2 class I or class II loci. Both cohorts received GvHD prophylaxis with Tacrolimus for at least 6 months. UCB recipients received mycophenolate mofetil 2g/day for at least 60 days instead of standard dose methotrexate GvHD prophylaxis for PBSC recipients. Quantification of the following lymphoid subsets were performed by flow cytometry on fresh peripheral blood prior to, and then at approximately 45, 100, 180, and 360 days following transplantation: NK and NKT cells, B-cells, plasmacytoid dendritic cells, CD3+, CD4+, CD8+, regulatory and na•ve T-cells. T-cell receptor excision circles (sjTREC) were quantified by real time PCR on DNA collected from an isolated fraction of CD3+ T-cells. Cumulative corticosteroid usage prior to day 100 (as determined by area under the curve) was determined as a method for comparing acute GvHD severity. The Kruskal-Wallis test with adjustments for multiple comparisons was used compare immune recovery values at 45, 100, 180 and 360 days post transplantation. The PearsonÕs Chi-square test was used to compare the CMV reactivation rate of UCB to MSD/MUD. Results:Forty-two recipients of allogeneic SCT (MSD-13, MUD-14, UCB-15) with successful donor engraftment and who survived a minimum of 6 months were evaluated. The MSD, MUD and UCB recipients had a median age of 41, 42 and 31 years, respectively (p = 0.13). There was no significant difference in corticosteroid administration before day 100 or chronic GvHD in the three cohorts (p=0.74). There were no differences in the kinetics of immune recovery between MSD and MUD recipients. At 45 days following transplantation, UCB recipients had significantly lower levels of CD4+ (figure), CD8+ and NKT-cells. By day 100, UCB recipients had similar numbers of CD4+ T-cells, but remained lower in the other major T-cell subsets. By day 180 however, all T-cell subsets except NKT cells (p=0.033) were similar to the MSD/MUD recipients. NK cell recovery was faster in the UCB recipients (figure). There was also no difference in B-cell recovery among the 3 cohorts. TREC levels were not significantly different in recipients of all graft types, but were uniformly low (figure). The slow recovery of T-cells in the UCB cohort corresponds with a higher Kaplan-Meier estimate of CMV reactivation compared to the MSD/MUD cohort (90% vs. 36%; p = 0.0078). Conclusion:Compared to HLA-identical MSD and MUD adult SCT recipients, quantitative lymphoid recovery in UCB transplant recipients is slower in the first two months, but these differences are erased by 4–6 months following transplantation. NK reconstitution is more rapid in UCB recipients. Reduction of early opportunistic infections affecting UCB transplant recipients may arise from effective techniques to boost early T-cell recovery. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Peripheral Blood Stem Cell (PBSC) Donors Experience Higher Levels of Pain and Toxicities Early On, While Bone Marrow (BM) Donors Experience Slower Recovery and More Late Pain: A Prospective Study of the National Marrow Donor Program (NMDP).

AbstractAbstract 1107Although PBSC has replaced BM as the most common unrelated donor stem cell product collected, a direct comparison of the PBSC vs. BM donation experiences has not been performed. We report a prospective study of 2726 BM and 6768 PBSC donors who underwent BM harvest at 83 centers or PBSC collection at 98 centers between January 2004 and July 2009. 340 donors who were randomized between PBSC and BM donation in a prospective clinical trial were excluded from this analysis. The proportions of donors of BM or PBSC were similar in regards to gender, race/ethnicity, age, body mass index (BMI), and year of donation. PBSC donors were collected using a median dose of 10 micrograms/kg/day of filgrastim for 5–6 days with 1–2 days of collection. Pain and toxicities were assessed using the common toxicity criteria (CTC) at baseline, daily during G-CSF administration and PBSC collection and within 48 hours of the bone marrow harvest. Peak levels of pain and toxicities of PBSC and BM donors were compared through the early collection period and at one week and one month after the procedure. Donors were followed weekly until they reported complete recovery. While the incidence of pain (80-90%) and common toxicities such as fatigue, insomnia, anorexia, nausea, dizziness, and site reactions (10-80%), was similar for both procedures, there were notable differences between donor experiences by type of donation. PBSC donors were at significantly increased risk of moderate, severe, and intolerable pain as well as ≥ grade 2 CTC toxicities during the peri-collection period (see table). In contrast, BM donors were more likely to experience ≥ grade 2 toxicities at 1 week after the procedure and moderate to severe pain at 1 week and one month, although these complaints were rare in both groups. BM donors reported a slower time to complete recovery compared to PBSC donors, with 3% of BM donors still not fully recovered at 24 weeks, while 100% of PBSC donors had recovered (see Figure). Unique aspects of BM donation included an overnight stay in 37% of donors (almost always routine) and a low risk (<1%) of requiring an allogeneic blood transfusion. PBSC donors experienced symptoms of hypocalcemia 45% of the time, and 11% required central line placement. In addition to risks associated with stem cell source donated, multivariate analysis showed that female gender, obesity, and increased age were associated with significantly increased risk of toxicity or pain. In summary, while the large majority of donors of BM and PBSC experience only mild to moderate symptoms and recover within a few weeks, PBSC donors experience more pain and toxicities in the early peri-donation period, while BM donors are more likely to experience discomfort for several weeks after the harvest, with a small fraction having persistent symptoms at 6 months. Women, obese, and older donors experience more pain and toxicity with the donation process independent of stem cell source donated. Prospective unrelated donors should be informed of the different risk profiles associated with BM vs. PBSC donation in order to assist them in making an informed decision.TimeCTC 2–4CTC 3–4Pain 2–4Pain 3–4d−5 to d+2PBSC28.0%2.1%56.6%6.4%BM15.6%0.8%30.7%1.6%Adjusted OR0.460.390.330.23p-value<0.001<0.001<0.001<0.0011 weekPBSC1.7%0.2%1.6%0.2%BM6.6%0.3%12.0%0.6%Adjusted OR4.07–8.47–p-value<0.001–<0.001–1 monthPBSC0.7%0.1%0.7%0.1%BM0.5%0.1%2.3%0.2%Adjusted OR0.75–3.23–p-value0.337–<0.001–OR indicates odds ratio [Display omitted] Disclosures:No relevant conflicts of interest to declare.

European Marrow Donor Information System: Concept and Praxis

Hematopoietic stem cell transplantation is an increasingly used treatment option for patients with severe disorders of hematopoiesis. In roughly two thirds of the cases, an unrelated donor must be sought in international databases. These searches would nowadays be unimaginable without the support of information technologies. Reliable communication and data transfer of donor and patient records between all partners in this huge network is one of the most important success factors in stem cell transplantation. The European Marrow Donor Information System (EMDIS) is an open computer network for data exchange among different unrelated hematopoietic stem cell donor registries that covers 85% of all potential unrelated stem cell donors and cord blood units worldwide. The network has spread also to North America, Australia, Asia, and Africa. The Czech Stem Cell Registry in Prague became a member of the EMDIS community at the end of 2003, when it manually processed about 300 preliminary search requests per year and exported 32 stem cell products to other countries. In 2008, it has automatically processed >14,000 preliminary requests with a doubled 63 number of exported stem cell products.

HLA-A, -B, -DR haplotype frequencies in the Thai Stem Cell Donor Registry

This study aimed to report antigen and haplotype frequencies (HFs) in the Thai Stem Cell Donor Registry (TSCDR). From 16,807 human leukocyte antigen (HLA)-A, -B, and -DR typed donors, 19 HLA-A, 41 HLA-B, and 13 HLA-DR antigens were found. HLA-A43, A80, B78, B82, B83, and DR18 were not observed. A total of 1921 haplotypes were estimated and 245 haplotypes were reliable and their cumulative HF was 75.74%. Similar to previous Thai subpopulation studies, the most common haplotypes were HLA-A33-B58-DR17 (4.54%), A2-B46-DR9 (4.11%), A33-B44-DR7 (2.85%), and A11-B75-DR12 (2.00%). To evaluate the probability in finding matched donors, from April 2002 to August 2008, 793 Thai patients were requested for unrelated stem cell donor searching. The number of patients with HLA-A, -B, -DR split matched donor found were 49%. Only 8% of the patients found matched donor within 1 month. However, high-resolution HLA-A, -B, -DR typing in TSCDR is suggested to accurately estimate HFs and evaluate the probability in finding a matched donor for patients in the future.

Unrelated hematopoietic stem cell donors as research subjects

Requests for participation of unrelated stem cell donors in research transplant protocols are becoming more frequent. World Marrow Donor Association calls on donor registries to participate in research activities. Here, we discuss various implications of research participation and make some recommendations as how to make this possible.

Monitoring the international use of unrelated donors for transplantation: the WMDA annual reports

The World Marrow Donor Association Annual Reports describe the current status of the use of unrelated hematopoietic cell products worldwide. In 2008, almost 1.7 million individuals were recruited into unrelated stem cell donor registries and almost 78 000 cord blood units were added to the inventory increasing the total number of available stem cell donors worldwide to over 14 million. In 2008, there were 10 481 adult stem cell donations (3221 BM and 7260 PBSC donations) provided from stem cell donor registries in 38 countries. In 2008, 3529 cord blood products were provided from 21 countries. Although the number of BM donations has been stable over the past 10 years, donations of PBSCs and umbilical cord blood are increasing.

Recipient‐derived HPA‐1a antibodies: a cause of prolonged thrombocytopenia after unrelated donor stem cell transplantation

Patients with human platelet antigen (HPA) specific antibodies in cases of neonatal alloimmune thrombocytopenia and platelet (PLT) refractoriness derive clinical benefit from the use of HPA-selected PLTs. This study describes three patients with underlying diagnoses of acute myeloid leukemia, chronic lymphocytic leukemia, and myelodysplasia, respectively, who underwent allogeneic bone marrow transplantation (BMT) with unrelated donors matched at the HLA-A, B, C, Dr, and DQ loci but who failed to achieve an adequate PLT count. Investigation using PLT immunofluorescence test, monoclonal antibody immobilization of PLT antigens assay, and genotyping revealed the presence of recipient-derived HPA-1a antibodies. In two patients, anti-HPA-1a was detected post-BMT and in the third patient, anti-HPA-1a was detected during pre-BMT chemotherapy. Despite apparent 100% engraftment of donor cells, the patients' PLT counts failed to recover 9-10 months posttransplant. The patients remained PLT-transfusion dependent and failed to achieve satisfactory increments following random donor or HLA-matched PLT transfusions. After the identification of HPA-1a antibodies, the patients were supported by HPA-1a(-) PLTs and satisfactory posttransfusion PLT increments were obtained. These cases illustrate that HPA-1a antibodies may remain detectable for 10 months following apparently successful donor engraftment and the disappearance of recipient-derived HLA antibodies. The prolonged persistence of recipient-derived PLT-specific antibodies following BMT has to our knowledge not been described previously. HPA-1a antibodies were associated with protracted PLT-transfusion dependence and significant hemorrhagic complications. Appropriate and timely laboratory investigation for HPA-specific antibodies followed by transfusion support with HPA-selected PLTs provided the cornerstone of the hemostatic management in these cases.

Family donor care management: principles and recommendations

The World Marrow Donor Association (WMDA) is an international organization fostering collaboration in clinical transplantation and promoting the interests of unrelated stem cell donors. The WMDA has developed standards for the recruitment, counseling, work-up and subsequent donations to protect the interests of donors. Although the care of family donors has been carefully considered and managed in transplant centers (TCs) internationally over numerous years (and increasingly TCs are facing accreditation programs, which address this issue) there is currently a lack of standardized guidelines for the management of family donors. The underlying principles of family donor care are in many ways identical to those concerning unrelated donors, although key ethical considerations differ. Although the WMDA is primarily involved in the field of unrelated donors, we believe that it is important to collaborate with those involved with family donors, to standardize the care. This document hopes to encourage increased collaboration between those caring for related and unrelated donors, and build on the extensive work, which has already been undertaken in this field to homogenize care. We recognize that there will be financial, regulatory and logistic differences in different countries and that the manner in which these principles are achieved may vary.

The Transplant Outcomes of a 10/10 Matched Unrelated Donor (MUD) Stem Cell Transplant (SCT) Is Similar to a HLA Identical Related Donor (RD) Transplant.

Abstract 4346 BackgroundAllogeneic SCT is a potential curative treatment for many hematological malignancies. Unfortunately, approximately 70% of patients who may benefit from an allogeneic SCT can not find a HLA identical related donor. Through National Marrow Donor Program, about 60-70% patients will be able to identify a suitable donor for transplant. However, prior studies suggested that MUD-SCT was associated with increased transplant related morbidity and mortality when compared with RD-SCT. Hence, many hematologists/oncologists were hesitant to recommend a MUD-SCT even when a matched related donor is not available. We hypothesized that through optimal HLA typing and using a 10/10 molecularly matched unrelated donor, the outcomes for a MUD-SCT will be similar to RD-SCT. MethodBeginning in 2004, we adopted a new policy in HLA typing and all patients and donors will be tested for HLA: A, B, C, DR, and DQ using molecular techniques. Here, we report the outcomes on 24 consecutive patients who revived a 10/10 MUD-BMT at our institution. ResultsBetween February, 2004 and April, 2008, 24 patients (8 males & 16 females) with various hematological malignancy and life threatening hematological disorders underwent a 10/10 molecularly matched MUD-SCT at Rush University Medical Center. Median age at SCT was 43 (range 18-67). Diagnoses included acute myeloid leukemia:11, myelodysplasia:3, non-hodgkin lymphoma:3, chronic myeloid leukemia:2, acute lymphoblastic leukemia:2, severe aplastic anemia:2 and hodgkin lymphoma:1. While 9/24 (38%) has early disease, 15/24 (62%) had advanced disease at SCT. All patients received a myeloablative conditioning regimen. Four patients (4/24, 17%) died before day 100 post-SCT from treatment related toxicity; all 4 pts > 55 years old. The 1-year survival was 62.5% with a minimal follow-up of 1 year for surviving patients. At last follow-up, 9 patients survived greater than 3 years post-SCT. The cumulative incidences of acute GVHD Grades ≥ 2 and 3 - 4 were 42% and 13% respectively. ConclusionWe conclude that the transplant outcomes of 10/10 matched unrelated donor stem cell transplant appears similar to matched related donor stem cell transplant. Thus, matched related donor stem cell transplant should be considered for patients lacking a HLA identical donor whenever an allogeneic SCT is clinically indicated. Disclosures:No relevant conflicts of interest to declare.

Reduced Relapse and Similar Progression-Free Survival After Double Umbilical Cord Blood Transplantation (DUCBT): Comparison of Outcomes Between Sibling, Unrelated Adult and Unrelated DUCB Hematopoietic Stem Cell (HSC) Donors.

Abstract 662For patients with hematologic malignancies who lack a matched or mismatched unrelated donor, UCBT is an alternative. However, only a minority of larger adolescents and adults are able to find a single UCB with an adequate cell dose. Double UCB unit grafts (DUCB) have previously been shown to extend this HSC option. In order to understand the relative merits of each HSC source, we combined the datasets at the University of Minnesota and Fred Hutchinson Cancer Research Center. Between 2001- and 2008, 536 patients with leukemia (AML, n=211; ALL, n=236; CML, n=70 and MDS, n=19) were transplanted with HSC from a matched sibling (SIB, n=204), 8/8- (MUD, n=152) or 7/8-HLA (MMUD, n=52) matched unrelated donor or DUCB (n=128). All patients received myeloablative conditioning with cyclophosphamide 120 mg/kg and total body irradiation 1200-1320cGy with fludarabine 75mg/m2administered prior to DUCB. All patients received GVHD immunosuppression with a calcineurin inhibitor and either methotrexate (SIB, MUD and MMUD) or mycophenolate mofetil (DUCB). While patient weight and sex distribution and proportion with standard risk disease (STD, AML and ALL in CR1-2, and CML in CP1) were similar, DUCB pts were younger (median age 25 yrs, SIB 40 yrs, MUD 31 yrs, MMUD 31 yrs; p<.01). The proportion of AML and ALL was similar among groups, although more CML patients received a MUD or MMUD. Recipient CMV seropositivity was lower among MUD (44%; SIB 58%; MMUD 60; DUCB 62%, p<.01). The median follow-up of survivors was 3.1 yrs (0.3-8.1). The univariate point estimates at the stated timepoints and multivariate outcomes are summarized in the Table.Outcomes after SIB vs. MUD vs. MMUD vs. DUCBSIB* Ref.MUD* RR (95%CI)MVA p-value†MMUD* RR (95%CI)MVA p-value†DUCB* RR (95%CI)MVA p-value†Neutrophil Recovery at day 4598% 1.097% 0.62 (0.50-0.78). . <0.0198% 0.63 (0.46-0.86). . <0.0187%; 0.29 (0.23-0.37). . <0.01Platelet Recovery at day 10086% 1.081% 0.83 (0.64-1.09). . 0.1875% 0.71 (0.48-1.04). . 0.0845% 0.22 (0.17-0.29). . <0.01Grade II-IV aGVHD at day 10065% 1.080% 1.68 (0.32-2.14). . <0.0185% 2.17 (1.46-3.23). . <0.0160% 1.01 (0.76-1.35). . 0.94cGVHD at 2 year47% 1.043% 1.04 (0.75-1.46). . 0.8048% 1.24 (0.77-2.0). . 0.3726% 0.73 (0.47-1.13). . 0.16TRM at 3 years24% 1.014% 0.92 (0.53-1.60). . 0.7627% 1.83 (0.97-3.42). .0.0634% 2.86 (1.81-4.51). . <0.01Relapse at 5 years43% 1.037% 0.83 (0.58-1.19). . 0.3235% 0.68 (0.39-1.20). . 0.1915% 0.27 (0.16-0.47). . <0.01PFS at 5 years33% 1.048% 0.83 (0.62-1.11). . 0.2038% 1.04 (0.70-1.53). . 0.8551% 1.00 (0.73-1.37). . 0.99*Results are shown as pointwise estimates, relative risk (RR) and the 95% confidence interval. SIB group was the reference (Ref) group for the multivariate analysis (MVA).†P-value shown relates to multivariate analysis.In summary, after a Cy/TBI based myeloablation, DUCB is associated with slower hematopoietic recovery compared to other HSC sources. While incidence of acute GVHD was similar to that observed after SIB, DUCB was associated with less acute and trend toward less chronic GVHD relative to unrelated donors. Despite reduced risk of GVHD after DUCBT, risk of relapse was remarkably low while TRM was elevated, resulting in similar PFS. In the absence of a SIB donor, using either MUD or DUCB yield encouraging PFS and are promising donor options. These results support a) the front line use of HLA 0-2 antigen mismatched DUCB in patients with hematological malignancy, b) development of new strategies to enhance hematopoietic recovery after DUCBT, potentially reducing the risk of TRM, c) studies to understand why relapse rates are reduced with DUCBT and d) quality of life assessments long term between HSC groups, as there appears to be less risk of acute and chronic GVHD after DUCBT. Disclosures:No relevant conflicts of interest to declare.

Oligoclonal T Cells Associated with Gvhd Following Allogeneic Stem Cell Transplantation Conditioned with Thymoglobulin and Reduced Intensity Total Body Irradiation.

Abstract 4662Patients undergoing unrelated donor stem cell transplantation following reduced intensity regimens are prone to acute graft vs host disease (GVHD). In vivo T cell depletion with rabbit anti-thymocyte globulin (r-ATG, Thymoglobulin, Genzyme inc. Cambridge MA) is consistently associated with reduced risk of acute GVHD however poor T cell reconstitution seen with current schedules results in a high incidence of opportunistic infections and relapse. We report data on immune reconstitution in patients participating in an ongoing clinical trial testing a novel conditioning regimen for allogeneic GCSF-mobilized blood stem cell transplantation. Patients were randomized to receive conditioning with either 7.5 or 5.1 mg/kg of r-ATG in divided doses between days -9 and -7, followed by 450 cGy total body irrradiation (TBI) in 3 fractions on day -1 and 0. GVHD prophylaxis was with tacrolimus (day -3 to 120) and mycophenolate mofetil (day 0-30). So far 10 heavily pre-treated (median number of prior therapies 4, prior autologous SCT n=5) patients have been transplanted; 6 from unrelated donors (1 bone marrow), 3 from matched related donors and 1 from an HLA-A mismatched sibling. Diagnosis includes MM (4), NHL (3), and CLL/PLL (3). Median patient age is 57 years. No patients have developed acute GVHD in the first 90 days. All patients achieved prompt engraftment of neutrophils and have demonstrated sustained complete myeloid donor chimerism (median <1% recipient DNA) at 3-6 months post transplant. NK cell recovery is prompt (mean±SD absolute CD56+ cell count 177±85/μL at day 30) and sustained (184±116 at day 90). T cell subset recovery is modest (absolute CD3+ cell count 861±934/μL at day 90) with predominantly cytotoxic T cells (CD3+/4+ cell count 143±116 and CD3+/8+ cell count 708±837). T cell chimerism at day 90 is mixed with either donor ('10% recipient DNA, n=5) or recipient dominance (>10% recipient DNA, n=3). Patients demonstrating dominant donor T cell chimerism at day 90 went on to develop either delayed onset acute GVHD (n=2/8 evaluable) or chronic GVHD (n=2/8) after withdrawal of immunosuppression. Patients demonstrating mixed T cell chimerism with recipient dominance did not develop chronic GVHD; one of these patients has relapsed, following an HLA-A mismatched SCT from his brother, and though he had predominantly recipient derived T cells, his granulocytes were completely donor derived indicating graft tolerance. T cell receptor beta locus was examined by RT-PCR for oligoclonality in all the donor-recipient pairs at baseline, day 90 and at onset of GVHD. Patients with GVHD demonstrated high level of expression of TCR V beta 23 and 24 (n=1/4), 11 (n= 1/4), 18 (n= 1/4), or 11 and 18 (n= 1/4) exclusively, in addition to TCR V beta 14, 16, 17, 22. The latter loci were also expressed in patients who had no GVHD with mixed T cell chimerism; this group of patients also expressed TCR V beta 4 (n=2/2), 13 and 19 (n=1/2) exclusively. All but one of the patients expressed the majority of TCR V beta loci at day 90 (with the exceptions noted above) indicating early polyclonal T cell recovery following transplantation. Asymptomatic CMV and EBV reactivation requiring therapy developed in one patient each. No patients have developed invasive fungal infections. In conclusion conditioning with Thymoglobulin and reduced intensity TBI results in stable myeloid engraftment in patients receiving unrelated and alternative donor transplants. In this small group of patients, GVHD appears to be associated with emergence of oligoclonal T cell populations which in the future may be selectively depleted ex vivo to allow engraftment without risk of chronic GVHD. Disclosures:McCarty:Celgene: Honoraria; Genzyme: Honoraria. Toor:Genzyme: Research Funding.

The Beneficial Impact of KIR-Ligand Mismatch and Absence of Donor-KIR2DS3 Gene On Outcome Following Unrelated Donor Stem Cell Transplantation for Myeloid Leukemia.

Abstract 3396Poster Board III-284 OBJECTIVE:Allogeneic hematopoietic stem cell transplantation (HSCT) is a successful curative therapy for a variety of hematological malignancies. The success of allogeneic HSCT partly depends on the graft-versus-leukemia (GVL) effect caused by donor lymphocytes. Apart from alloreactive T cells, alloreactive natural killer (NK) cells also play an important role in the induction of GVL effect after HSCT. However, the effect of NK cell alloreactivity on the outcome of unrelated hematopoietic stem cell transplantation is controversial. NK cell alloreactivity after allogeneic HSCT is regulated by killer cell immunoglobulin-like receptors (KIRs). So, our study is to investigate the impact of KIRs on the outcome after unrelated hematopoietic stem cell transplantation. METHODS:116 cases of unrelated transplants between Jan. 2001 to May. 2008 were involved in the study. The inhibitory KIRs identified with HLA ligands are as follows: KIR2DL2/KIR2DL3 bind HLA-C1; KIR2DL1 recognizes HLA-C2; and KIR3DL1 recognizes HLA-Bw4. KIR-ligand mismatch was defined as the absence of one or more recipient HLA epitopes for the corresponding donor-inhibitory KIRs. Samples containing either one or two group B haplotypes were assigned the genotype designation B/x. Samples that lacked all KIR B loci were assigned the genotype A/A. RESULTS:We found that KIR-ligand mismatch was significantly associated with a decreased leukemic relapse risk (p=0.019; HR=0.329, 95% CI 0.131-0.830), mainly in myeloid disease (p=0.003; HR=0.193, 95% CI 0.066-0.563). In myeloid disease, the cumulative risk of relapse was lower in the patients with KIR-ligand mismatch than KIR-ligand match (10.7% vs. 41.5%, p=0.002). This effect of the KIR-ligand mismatch on relapse was comparably significant between AML/MDS subgroup (12.6% vs. 40%, p=0.03) and CML subgroup (4% vs. 41.7%, p=0.008). For standard-risk myeloid leukemia, KIR-ligand mismatch resulted in a lower relapse rate than KIR-ligand match, although no statistical significance was reached. (11.3% vs. 26%, p=0.356). For high-risk myeloid leukemia, the risk of relapse in patients with KIR-ligand mismatch was significantly lower than that in patients with KIR-ligand match (9.1% vs. 71.4%, p=0.002). Furthermore, the impact of KIR-ligand mismatch was found mainly in the HLA-match group (13.9% vs. 62.5%, p= 0.001) and KIR haplotype, Bx group (11.5% vs. 55%, p=0.01). In myeloid disease, KIR-ligand mismatch also improved 5-year overall survival (OS) (p=0.034; HR=0.430, 95% CI 0.194-0.924) and disease-free survival (DFS) (p=0.024; HR=0.445, 95% CI 0.221-0.897). No effect was seen in patients with lymphoid disease. AA in the donor significantly decreased the cumulative incidence of relapse compared with Bx (12.9% vs. 28.6%, p=0.024). We further found that more activating KIR genes in the donor resulted in an increased relapse risk (p=0.005; HR=1.463, 95% CI 1.123-1.906). Meanwhile, the presence of donor activating KIR2DS3 gene was associated with increased relapse risk (p=0.003; HR=5.046, 95% CI 1.746-14.575) and decreased OS (p=0.004; HR=3.181, 95% CI 1.432–7.064) and DFS (p=0.003; HR=2.919, 95% CI 1.430-5.959) in myeloid disease. CONCLUSION:Our study indicated that, in unrelated HSCT for myeloid leukemia, selection of donors with KIR-ligand mismatch offered a lower relapse risk and a long-term survival advantage. The presence of KIR2DS3 in the donor was an important risk factor for myeloid leukemia. If donors carry low number of activating KIR genes, the risk of relapse is reduced. Disclosures:No relevant conflicts of interest to declare.

Matched unrelated donor stem cell transplant in 131 patients with follicular lymphoma: an analysis from the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation

Matched unrelated donor stem cell transplantation (MUD-SCT) provides the only curative option for patients with follicular lymphoma (FL) who fail conventional therapies and do not have a sibling donor. The purpose of this study was to analyse the outcome of patients with FL treated with MUD-SCT included in the European Group for Blood and Marrow Transplantation registry. 131 patients treated with reduced-intensity conditioning (RIC, n = 87) or conventional myeloablative (CONV, n = 44) MUD-SCT between 2000 and 2005 were included. Median time from diagnosis to MUD-SCT was 47 months and the median number of previous therapeutic regimens was 4 (previous autograft: 47%). RIC recipients were significantly older, with a longer interval from diagnosis to MUD-SCT and had failed a previous autograft more frequently than CONV recipients. Non-relapse mortality (NRM) was 24% and 30% at 100-d and 1-year, respectively. After a median follow-up of 36 months, 17% of the patients developed disease progression, the 3-year progression-free survival (PFS) being 47%. Three-year overall survival (OS) for the whole series was 51%. On multivariate analysis, RIC regimens were associated with at lower NRM and a significantly longer PFS and OS. This retrospective study demonstrated that MUD-SCT results, even in heavily pre-treated populations, in a meaningful PFS and OS.

Safety and efficacy of hematopoietic stem cell collection from mobilized peripheral blood in unrelated volunteers: 12 years of single-center experience in 3928 donors

AbstractWe present results of peripheral blood stem cell (PBSC) mobilization, collection, and follow-up from 3928 consecutive unrelated stem cell donors. Assessments were performed prospectively at baseline, leukapheresis, 1 month, 6 months, and annually after PBSC donation. During follow-up, side effects were recorded by return post questionnaires. The median CD34+ cell counts on day 5 were 67.5/μL in male and 51/μL in female donors. Bone pain and headache were the most common side effects of recombinant human granulocyte-colony stimulating factor. Central venous access was required for 23 donations (0.6%). Throughout the follow-up, the absolute neutrophil counts were slightly below the initial baseline values but remained within the normal range. The majority of the donors reported good or very good health. Malignancies occurred in 12 donors (0.3%), among whom were 1 case of acute myeloid leukemia, 1 case of chronic lymphatic leukemia, and 2 cases of Hodgkin disease. Only the incidence of Hodgkin lymphoma differed significantly from an age-adjusted population. In conclusion, 7.5 μg/kg per day lenograstim proved to be safe and effective for mobilizing hematopoietic stem cells for allogeneic transplantation. Long-term monitoring of healthy PBSC donors remains important to guarantee the safety standards of PBSC mobilization and collection.

173-P: Searching for matched unrelated stem cell donors – the Israeli experience

173-P: Searching for matched unrelated stem cell donors – the Israeli experience

168-P: Discrepancy of HLA typing results of unrelated stem cell donors between registry typing and confirmatory typing

168-P: Discrepancy of HLA typing results of unrelated stem cell donors between registry typing and confirmatory typing