ALBERT

Description: Previous randomized graft-versus-host disease (GVHD)-prophylaxis trials have failed to demonstrate reduced incidence and severity of chronic GVHD (cGVHD). Here we reanalyzed and updated a randomized phase 3 trial comparing standard GVHD prophylaxis with or without pretransplantation ATG-Fresenius (ATG-F) in 201 adult patients receiving myeloablative conditioning before transplantation from unrelated donors. The cumulative incidence of extensive cGVHD after 3 years was 12.2% in the ATG-F group versus 45.0% in the control group (P 〈 .0001). The 3-year cumulative incidence of relapse and of nonrelapse mortality was 32.6% and 19.4% in the ATG-F group and 28.2% and 33.5% in the control group (hazard ratio [HR] = 1.21, P = .47, and HR = 0.68, P = .18), respectively. This nonsignificant reduction in nonrelapse mortality without increased relapse risk led to an overall survival rate after 3 years of 55.2% in the ATG-F group and 43.3% in the control group (HR = 0.84, P = .39, nonsignificant). The HR for receiving immunosuppressive therapy (IST) was 0.31 after ATG-F (P 〈 .0001), and the 3-year probability of survival free of IST was 52.9% and 16.9% in the ATG-F versus control, respectively. The addition of ATG-F to standard cyclosporine, methotrexate GVHD prophylaxis lowers the incidence and severity of cGVHD, and the risk of receiving IST without raising the relapse rate. ATG-F prophylaxis reduces cGVHD morbidity.

Description: Abstract 3024FN2 Reduced-intensity conditioning (RIC) regimen followed by allogeneic stem cell transplantation (SCT) has become a reasonable treatment option for patients with multiple myeloma who are refractory or have relapse to an autograft. However, in comparison to standard myeloablative conditioning RIC resulted in higher risk of relapse. Maintenance therapy after autologous transplantation has shown to improve survival while after allogeneic SCT data are lacking so far. We here report the results of myeloablative toxicity-reduced allograft consisting of intravenous busulfan (12.2 mg/kg) and cyclophosphamide (120 mg/kg) followed by lenalidomide maintenance in 33 patients with multiple myeloma who relapsed to an autograft. A total of 32 patients had received one (n=16), two (n=15), or even three (n=1) autografts, and 1 patient was refractory to 2 induction therapies and failed to collect autologous stem cells. The median duration of remission after the autograft was 12 months. The primary endpoint of the study was non-relapse mortality at 1 year and secondary objectives were evaluation of response, incidence of acute and chronic graft-versus-host disease as well as progression and overall survival. To prevent graft-versus-host disease antithymocyte globulin (ATG Fresenius®) was given at a median dose of 20 mg/kg on day -3, -2, and -1. Lenalidomide was started earliest at day 120 after transplantation if there were no signs of infection or graft-versus-host disease. The median time between last autograft and allogeneic transplantation was 20 months. 19 patients were treated with fully HLA-matched unrelated donor, 8 patients had a mismatch donor, and 6 patients were transplanted from an HLA-identical sibling. 2 patients died of treatment-related complications resulting in a cumulative incidence of non-relapse mortality at 1 year of 6% (95% CI: 0–14%). After transplantation 27% developed grade II graft-versus-host disease, and severe grade III graft-versus-host disease was seen in 6% of the patients. Complete remission was noted in 46% of the patients, partial remission was seen in 48% and stable disease in 3%. The median interval between allogeneic transplant and start of lenalidomide was 168 days. The median starting dose was 5 mg (range 5–15 mg) without dexamethasone for 21 day followed by 1 week rest. 9 patients did not receive lenalidomide maintenance due to ongoing graft-versus-host disease, cytopenia or patient's wish. The median number of lenalidomide cycles was 6 (range 1–30). During follow-up 13 patients discontinued lenalidomide treatment due to progressive disease (n=6), GvHD (n=3), thrombocytopenia (n=2), or fatigue (n=2). In 10 patients lenalidomide dose could be increased to 10 or 15 mg, respectively. The major toxicities of lenalidomide were acute graft-versus-host disease grade I – III (21%), viral reactivation (12%), thrombocytopenia grade III-IV (12%), neutropenia grade III-IV (6%), peripheral neuropathy grade I-II (12%), or other infectious complications (6%). During follow-up 9 patients experienced relapse resulting in a cumulative incidence of relapse at 3 years of 42% (95% CI: 18–66%). The 3 year estimated probability of progression-free and overall survival was 52 % (95% CI: 28–76%) and 79 % (95% CI: 63–95%), respectively. In the current trial neither the deletion 13q14 nor the use of mismatch donor nor the chemosensitivity prior allogeneic SCT could be identified as risk factor for survival. This study showed that toxicity-reduced myeloablative conditioning regimen is feasible and highly effective in relapsed patients with multiple myeloma resulting in an acceptable treatment-related mortality. Lenalidomide as maintenance therapy is feasible early after transplantation but toxicity especially the induction of graft-versus-host disease should be considered. Disclosures: Kröger: Celgene: Research Funding. Kropff:Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.

Description: Abstract 1019 Allogeneic stem cell transplantation is the only curative treatment for myelofibrosis. Here we present a long–term follow up of patients with myelofibrosis treated with reduced-intensity allogeneic stem cell transplantation in the prospective multicenter study conducted by the MDS subcommittee of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT) (study registration NCT 00599547). From 2002 to 2007, a total of 103 patients with primary (63 pts) or post-polycythemia vera and –essential thrombocythemia myelofibrosis (40 pts) from seventeen transplantation centers in three nations were included in the study. There were 62 males and 41 females with a median age of 55 years (range, 32–68 years). Risk profile according to Lille score was low risk with constitutional symptoms (17%), intermediate risk (53%) and high risk (30%). All but three of the patients received peripheral stem cells as stem cell source from either related (n=33) or unrelated donor (n=70) and a conditioning with Busulfan (10mg/kg orally or 8mg/kg intravenously),Fludarabin (180 mg/m2) and antithymocyte-globulin (ATG-Fresenius®) according a previously published protocol. According to high-resolution HLA typing, 21 patients had at least one allele or antigen HLA mismatch. From 88 patients with a known JAK2V617F-status 63 harbored the mutation. After a median follow up of 60 months (range 9–109 months), 41 patients had chronic graft vs. host disease which was extensive in the half of cases. The 5-year and 8-year estimated overall survival (OS) was 68% and 65%, respectively with a stable plateau after 5,3 years follow up (Figure-1). Estimated 5-year disease-free survival was 40%. The cumulative incidence of relapse/progression at 3 and 5 years was 22% and 28% and the non-relapse mortality at 1 and at 3 years was 18% ands 21%, respectively.Figure-1Figure-1. Within the overall follow up period, relapse/progression occurred in 28 patients. Twenty one of them were treated with donor-lymphocyte infusions (DLI) and/or a second allogeneic transplantation (n=11). Sixteen of those were at the last follow up alive. The estimated OS of all relapsed patients after a median follow up of 46 months (range 4–62 months) beginning from the time of relapse was 55%. In multivariate analysis advanced age 〉55years (HR: 4.69, p=0.001), absence of JAK2V617F mutation (HR: 2.50, p=0.02), mismatched donor (HR: 3.62, p=0.002) were significant independent predictors for reduced OS. This update of a prospective trial using reduced intensity conditioning followed by allogeneic stem cell transplantation for myelofibrosis confirmed a very good long-term OS. Relapse still occurs in about 30% and remains the main problem after transplantation. However, with adoptive immunotherapy using DLI or even second allogeneic transplantation a second remission with long term survival can be induced in about 50% of the relapsed patients. Developing methods for remission monitoring and early prediction and treatment of relapse should be the focus of future studies. Disclosures: Kobbe: Celgene: Consultancy, Research Funding; Ortho Biotec: Consultancy. de Witte:Novartis: Consultancy, Honoraria, Speakers Bureau.

Description: Abstract 4555 Introduction: Activating and inhibitory killer immunoglobulin like receptors (KIR) are predominantly expressed on natural killer (NK) cells. KIR mismatch allogeneic stem cell transplantation (alloSCT) has been reported to provide beneficial effects for Multiple Myeloma (MM). However, their recovery in MM patients remains poorly understood. We, therefore, analysed KIR recovery in 90 MM patients after alloSCT. Methods: KIR expression (CD158a/h, CD158b/b2, CD158e1/e2) on NK cells and T cell subsets was measured by flow cytometry at different time points after alloSCT. Results: During the first 90 days after alloSCT NK cells represent the largest lymphocyte subset. Activating receptors like NKp30 and NKp44 showed a fluctuating expression while members of the KIR family were expressed at a constant rate (20% of NK cells). There was no significant difference in the early post transplantation period (day 0–90) compared to later time points (day 360). In contrast, T cells showed increased KIR expression during the first 30 days after alloSCT, which was highly significant for CD158e (p=0,0001). After 30 days the expression declined to baseline. Furthermore, T cell activation marker HLA-DR reached its highest expression between days 60 and 90 when KIR receptors were expressed at their lowest level (27% vs. 8%, p 〈 0,0001). Conclusions: We conclude that KIR receptors were differentially expressed on NK and T cells. Because KIR receptors are constantly expressed by NK cells and NK cells are the most frequent lymphocyte populations early after alloSCT, NK cells may be useful for KIR mismatch cellular therapy. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 148 Multiple Myeloma (MM) is considered to be an incurable disease, but in some patient long-term survival can be achieved after high dose chemotherapy followed by autologous or allogeneic stem cell transplantation. Those patients, who achieved molecular remission, have a high probability of long-term disease-freedom and of cure. More recently the introduction of dose-reduced conditioning and the use of auto-allo tandem approach has broaden the use of allogeneic stem cell transplantation in MM, but the results of prospective trials are controversial. We here investigated within a prospective protocol the incidence and impact of molecular remission on long-term outcome obtained after auto-allo tandem approach in MM. (study registration NCT 00781170). From 4/2000 to 10/2008, 73 patients with a median age of 50 years (r 29–64) and advanced stage II/III MM were included. The conditioning regimen for autologous transplantation consisted of melphalan 200 mg/m2 given divided over 2 days. After an interval of 2–3 months, the patients received a dose-reduced conditioning consisting of melphalan 140 mg/m2, fludarabine 180 mg/m2 and ATG Fresenius® (Fresenius, Bad Homburg, Germany) at a dose of 10 mg/kg for related and 20 mg/kg for unrelated donors on day -3, -2, and -1 followed by allogeneic stem cell transplantation. Remission was defined according to modified EBMT criteria. In 46 patients with CR or nCR minimal residual disease could be monitored by myeloma-specific primers (allele specific oligonucleotides, ASO) targeting IgH gene rearrangements (n=20) or by highly sensitive plasma cell chimerism using real-time PCR after magnet-activated cell sorting of CD138+ cells (n=26). The sensitivity of plasma cell chimerism was 10−4 using real-time PCR and donor/patient specific polymorphisms and 10−5 in case of Y-PCR. Sensitivity for nested PCR with myeloma-specific primers was 10−5. In 5 patients only 1 MRD measurement was available and those patients were excluded from MRD sub-analysis. Molecular complete remission was defined as by least two negative PCR results with ASO primers or achievement of at least two times ≥99.9 % donor chimerism of plasma cells by real-time PCR from bone marrow samples. Sustained MRD negativity was defined by at least 4 negative molecular results either by ASO primer or plasma-cell chimerism. Mixed MRD was defined by negative molecular markers for at least two times, but intermittent positivity was defined by myeloma-specific primers or plasma cell chimerism. Overall 44 patients (60 %) achieved a CR according to EBMT criteria with negative immunofixation. 8 % achieved a VGPR and 18 % a partial remission. 3 % had progressive disease and 11 % were not evaluable for determination of remission. Molecular remission was observed in 30 patients, in 15 patients the molecular markers were sustained negative while in 15 patients molecular markers were only intermittent negative, resulting in an overall complete molecular remission rate of 46 % and a stable sustained complete molecular remission rate of 23 %. After a median follow-up at 7 years the 5 year progressive-free survival was 29 % (95% CI: 17–41%). Patients without del(13q14) had a significantly better PFS than those with del(13q14) (5 y: 56% vs. 17%, p=0.02). Patients who achieved CR after transplantation had improved PFS in comparison to non-CR patients (5 y: 41% vs. 28%, p=0.008). Patients with sustained negative molecular remission had a 5 year PFS of 85 % vs. 31 % for mixed molecular remission (p= 0.003). The 5 year overall survival was 52 % (95% CI: 40–64%). Patients without del(13q14) had significantly improved 5 year survival (75% vs. 40%. p=0.02). Patients who achieved a sustained molecular remission had a 5 year OS of 91 % while those with mixed molecular remission resulted in a 5 year OS of 87 % (p=0.06). The study underlines the importance of the depth of remission and shows that achieving molecular remission as determined by myeloma-specific IgH gene rearrangements and plasma cell chimerism is associated with long-term freedom from disease and potential cure of MM in an auto-/allo SCT approach. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 4147 Introduction: AML is one of the most common indications for allogeneic hematopoietic stem cell transplantation (allo-HSCT). A matched sibling donor (matched related donor, MRD) is generally considered preferable to an unrelated donor (UD). It has been reported before that donor age may influence outcome of allo-HSCT. Sibling donors of older patients will generally be old as well. How a young unrelated donor compares with an old sibling donor is unclear. In this retrospective study we evaluate the influence of donor age on outcome of MRD and UD allo-HSCT and compare the impact of young unrelated donors vs. old related donors on overall survival (OS). Patients and Methods: We performed a retrospective analysis of 298 consecutive patients transplanted for AML at our center between January 2000 and December 2009. Median follow-up was 56 months. The median age of donors and patients were 39 and 50 yrs. respectively. These two ages were used as cut-off points for young and old donors and patients respectively. Accordingly, four donor aged groups were assigned: UD ' 39 years, UD 〉 39 yrs, MRD ≤ 39 yrs and MRD 〉 39 yrs. Analyses were performed in the more homogeneous population of patients in CR at time of transplant (n = 170) as well for patients older than 50 years and in CR at time of transplant (n = 77). Patient characteristics for the 170 Patients in CR are summarized in table 1. Results: In the cox-regression multivariate analysis of all 298 patients including factors significant in the univariate analysis (conditioning intensity, cytogenetic risk group, remission status at time of transplant and donor age) remission status (RR: 1.88, p 〈 0.001) and cytogenetic risk (RR: 5.50, p = 0.004) significantly impacted overall survival (OS). Donor age (p = 0.08) and patient age (p = 0.063) tended to influence OS in this group. In the more homogenous group of 170 patients who were in CR at time of transplantation the Kaplan Meier estimated 5 yr OS was 66% (95% CI: 54%-78%) for patients transplanted from UD ≤ 39 yrs, 41% (95% CI: 25–57%) for UD 〉39 yrs, 61% (41–81%) for MRD ≤ 39 yrs and 33% (19–47%) for MRD 〉 39 yrs (p =0.002 comparing all 4 groups), fig. 1. OS of patients with UD ≤ 39yrs was significantly better than for those with MRD 〉 39 yrs (66% vs. 33%, p = 0.001). In the multivariate cox-regression analysis (including donor age, patient age and cytogenetic risk) only donor age (p = 0.001) and cytogenetic risk (p = 0.011) significantly impacted OS whereby MRD 〉 39 yrs. was associated with poorer OS compared to UD ≤ 39 yrs (RR: 3.07, p〈 0.001). Further subgroup analyses of patients 〉 50 years old and in CR at time of transplant (n = 77) revealed similar findings with 5 yr OS of 62% for UD ≤ 39 yrs and 25% for MRD 〉39 yrs (p = 0.016). Conclusions: In patients undergoing allo-HSCT for AML our findings suggest that young unrelated donors may improve survival outcome as compared to old related donors. Further studies are necessary to confirm these findings and better define possible age limits for choosing young unrelated donors vs. older sibling donors. Disclosures: No relevant conflicts of interest to declare.