Disease relapse is the major causes of treatment failure after allogeneic stem cell transplantation (SCT) in patients with acute myeloid leukemia (AML). As well as demonstrating significant clinical activity in AML, azacitidine (AZA) upregulates putative tumor antigens, inducing a CD8+ T cell response with the potential to augment a graft-versus-leukemia effect. We, therefore, studied the feasibility and clinical sequelae of the administration of AZA during the first year after transplantation in 51 patients with AML undergoing allogeneic SCT. Fourteen patients did not commence AZA either because of transplantation complications or withdrawal of consent. Thirty-seven patients commenced AZA at a median of 54 days (range, 40 to 194 days) after transplantation, which was well tolerated in the majority of patients. Thirty-one patients completed 3 or more cycles of AZA. Sixteen patients relapsed at a median time of 8 months after transplantation. No patient developed extensive chronic graft-versus-host disease. The induction of a post-transplantation CD8+ T cell response to 1 or more tumor-specific peptides was studied in 28 patients. Induction of a CD8+ T cell response was associated with a reduced risk of disease relapse (hazard ratio [HR], .30; 95% confidence interval [CI], .10 to .85; P = .02) and improved relapse-free survival (HR, .29; 95% CI, .10 to .83; P = .02) taking into account death as a competing risk. In conclusion, AZA is well tolerated after transplantation and appears to have the capacity to reduce the relapse risk in patients who demonstrate a CD8+ T cell response to tumor antigens. These observations require confirmation in a prospective clinical trial.

PURPOSE Reduced-intensity conditioning (RIC) regimens have extended the curative potential of allogeneic stem-cell transplantation to older adults with high-risk acute myeloid leukemia (AML) and myelodysplasia (MDS) but are associated with a high risk of disease relapse. Strategies to reduce recurrence are urgently required. Registry data have demonstrated improved outcomes using a sequential transplant regimen, fludarabine/amsacrine/cytarabine-busulphan (FLAMSA-Bu), but the impact of this intensified conditioning regimen has not been studied in randomized trials. PATIENTS AND METHODS Two hundred forty-four patients (median age, 59 years) with high-risk AML (n = 164) or MDS (n = 80) were randomly assigned 1:1 to a fludarabine-based RIC regimen or FLAMSA-Bu. Pretransplant measurable residual disease (MRD) was monitored by flow cytometry (MFC-MRD) and correlated with outcome. RESULTS There was no difference in 2-year overall survival (hazard ratio 1.05 [85% CI, 0.80 to 1.38] P = .81) or cumulative incidence of relapse (CIR) (hazard ratio 0.94 [95%CI, 0.60 to 1.46] P = .81) between the control and FLAMSA-Bu arms. Detectable pretransplant MFC-MRD was associated with an increased CIR (2-year CIR 41.0% v 20.0%, P = .01) in the overall trial cohort with a comparable prognostic impact when measured by an unsupervised analysis approach. There was no evidence of interaction between MRD status and conditioning regimen intensity for relapse or survival. Acquisition of full donor T-cell chimerism at 3 months abrogated the adverse impact of pretransplant MRD on CIR and overall survival. CONCLUSION The intensified RIC conditioning regimen, FLAMSA-Bu, did not improve outcomes in adults transplanted for high-risk AML or MDS regardless of pretransplant MRD status. Our data instead support the exploration of interventions with the ability to accelerate acquisition of full donor T-cell chimerism as a tractable strategy to improve outcomes in patients allografted for AML.

BackgroundReduced intensity conditioning regimens permit the delivery of a potentially curative graft-versus-leukemia effect in older patients with acute myeloid leukemia. Although T-cell depletion is increasingly used to reduce the risk of graft-versus-host disease its impact on the graft-versusleukemia effect and long-term outcome post-transplant is unknown. Design and MethodsWe have characterized pre-and post-transplant factors determining overall survival in 168 patients with acute myeloid leukemia transplanted using an alemtuzumab based reduced intensity conditioning regimen with a median duration of follow-up of 37 months. ResultsThe 3-year overall survival for patients transplanted in CR1 or CR2/CR3 was 50% (95% CI, 38% to 62%) and 44% (95% CI, 31% to 56%), respectively compared to 15% (95% CI, 2% to 36%) for patients with relapsed/refractory disease. Multivariate analysis demonstrated that both survival and disease relapse were influenced by status at transplant (P=0.008) and presentation cytogenetics (P=0.01). Increased exposure to cyclosporine A (CsA) in the first 21 days post-transplant was associated with an increased relapse risk (P<0.0001) and decreased overall survival (P<0.0001). ConclusionsDisease stage, presentation karyotype and post-transplant CsA exposure are important predictors of outcome in patients undergoing a T-cell depleted reduced intensity conditioning allograft for acute myeloid leukemia. These data confirm the presence of a potent graft-versusleukemia effect after a T-cell depleted reduced intensity conditioning allograft in acute myeloid leukemia and identify CsA exposure as a manipulable determinant of outcome in this setting.Key words: reduced intensity conditioning, graft-versus-leukemia, acute myeloid leukemia. leukemia. Haematologica 2010;95:989-995. doi:10.3324/haematol.2009 This is an open-access paper. Citation: Craddock C, Nagra S, Peniket A, Brookes C, Buckley L, Nikolousis E, Duncan N, Tauro S, Yin J, Liakopoulou E, Kottaridis P, Snowden J, Milligan D, Cook G, Tholouli E, Littlewood T, Peggs K, Vyas P, Clark F, Cook M, MacKinnon S, and Russell N. Factors predicting long-term survival after T-cell depleted reduced intensity allogeneic stem cell transplantation for acute myeloid Factors predicting long-term survival after T-cell depleted reduced intensity allogeneic stem cell transplantation for acute myeloid leukemia

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Purpose: Azacitidine (AZA) is a novel therapeutic option in older patients with acute myeloid leukemia (AML), but its rational utilization is compromised by the fact that neither the determinants of clinical response nor its mechanism of action are defined. Co-administration of histone deacetylase inhibitors, such as vorinostat (VOR), is reported to improve the clinical activity of AZA, but this has not been prospectively studied in patients with AML.Experimental Design: We compared outcomes in 259 adults with AML (n ¼ 217) and MDS (n ¼ 42) randomized to receive either AZA monotherapy (75 mg/m 2 Â 7 days every 28 days) or AZA combined with VOR 300 mg twice a day on days 3 to 9 orally. Next-generation sequencing was performed in 250 patients on 41 genes commonly mutated in AML. Serial immunophenotyping of progenitor cells was performed in 47 patients.Results: Co-administration of VOR did not increase the overall response rate (P ¼ 0.84) or overall survival (OS; P ¼ 0.32). Specifically, no benefit was identified in either de novo or relapsed AML. Mutations in the genes CDKN2A (P ¼ 0.0001), IDH1 (P ¼ 0.004), and TP53 (P ¼ 0.003) were associated with reduced OS. Lymphoid multipotential progenitor populations were greatly expanded at diagnosis and although reduced in size in responding patients remained detectable throughout treatment.Conclusions: This study demonstrates no benefit of concurrent administration of VOR with AZA but identifies a mutational signature predictive of outcome after AZA-based therapy. The correlation between heterozygous loss of function CDKN2A mutations and decreased OS implicates induction of cell-cycle arrest as a mechanism by which AZA exerts its clinical activity.

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Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disease (PTLD) remains an important complication of allogeneic haematopoietic stem cell transplantation (allo-HSCT). We retrospectively analysed incidence and risk factors for EBV reactivation in 186 adult patients undergoing consecutive allo-HSCT with Alemtuzumab T-cell depletion at a single centre. The cumulative incidence of EBV reactivation was 48% (CI 41-55%) by 1 year, with an incidence of high-level EBV reactivation of 18% (CI 13-24%); 8 patients were concurrently diagnosed with PTLD. Amongst patients with high-level reactivation 31/38 (82%) developed this within only 2 weeks of first EBV qPCR positivity. In univariate analysis, age≥50 years was associated with significantly increased risk of EBV reactivation (HR 1.54, CI 1.02-2.31; P=0.039). Furthermore, a diagnosis of non-Hodgkin lymphoma (NHL) was associated with greatly reduced risk of reactivation (HR 0.10, CI 0.03-0.33; P=0.0001) and this was confirmed in multivariate testing. Importantly, Rituximab therapy within 6 months prior to allo-HSCT was also highly predictive for lack of EBV reactivation (HR 0.18, CI 0.07-0.48; P=0.001) although confounding with NHL was apparent. Our data emphasise the risk of PTLD associated with Alemtuzumab. Furthermore, we report the clinically important observation that Rituximab, administered in the peri-transplant period, may provide effective prophylaxis for PTLD.

myelodysplasia, 7 T cell non Hodgkin's lymphoma 6 aplastic leukaemia and 7 myelofibrosis At transplantation 40% (N=133) patients had normal and 60%(N=198) high BMI with 14% of patients being obese (BMI>30). After a median follow-up of 24 months (range:2-79), the mean overall survival(OS) in patients undergoing allograft with normal BMI was 31 months as compared to 39 with high BMI ( p:0.06). The mean progression free survival(PFS) in patients undergoing allograft with normal BMI was 33 months as compared to 38 with high BMI (p:0.13).16% of the patients in the high and obese BMI group developed acute GvHD with 8% grade III-IV and 28% in the normal BMI group with 14% grade III-IV acute GvHD.(p.0.11).17% of the patients in the high BMI group developed chronic GvHD and 30% of the patients in the normal BMI group (p:0.09).However higher infection rates and more days of inpatient stay in the first year post transplant were observed in the high BMI and obese patients but there was no difference in ITU admissions. This study shows that high BMI and obesity does not adversely impact on either OS or PFS in patients undergoing allogeneic transplantation for haematological malignancies but it does have a significant impact on infection rates and hospitalisation of high BMI and obese patients. We recommend patients with high BMI should not be excluded from allogeneic transplantation however good supportive care should be undertaken and careful patient selection on the basis of comorbidity index in order to avoid the risks from the increased rates of infection.Response to Reviewers: I am really grateful for your comments The changes suggested by the reviewer has been incorporated in the materials and methods and also in the table with the patient characteristics(disease status at transplant, disease type, related unrelated donor equally distributed between the two groups) I have also added the D+100 mortality as well as the 1st year mortality for both groups Disease split (myeloid vs lymphoid showed similar results in both groups) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Abstract Bone marrow transplantation is frequently used as a consolidation therapy in patients with haematological malignancies to improve outcome of these patients.Obese individuals have larger absolute lean body and fat masses than non-obese individuals of the same age, gender and height, which might lead to altered This study shows that high BMI and obesity does not adversely impact on either OS or PFS in patients undergoing allogeneic transplantation for haematological malignancies but it does have a significant impact on infection rates and hospitalisation of high BMI and obese patients. We recommend patients with high BMI should not be excluded from allogeneic transplantation however good supportive 1