Acute Myeloid Leukemia In First Complete Remission Research Articles

Extramedullary Disease at Diagnosis of Acute Myeloid Leukemia Does Not Influence Outcome of Patients Undergoing Allogeneic Hematopoietic Cell Transplant in First Complete Remission

Occurrence of extramedullary (EM) disease at diagnosis of acute myeloid leukemia (AML) has been associated with increased risk of relapse and worse outcomes post-chemotherapy. There is minimal data in the literature concerning the association with outcomes following allogeneic hematopoietic cell transplantation (HCT). The purpose of this single-centre study was to retrospectively investigate the impact of EM disease at diagnosis on the outcome of 303 patients with AML in first complete remission (CR1) that underwent HCT during the time period 2000-2013.Median age at HCT was 51 years (range 18-71), 151 (50%) patients were female. Myeloablative conditioning (MAC) was used in 202 (67%) patients, reduced-intensity (RIC) in 101 (33%) patients. Donors were related for 194 (64%) patients, unrelated for 109 (36%) patients. Grafts were peripheral blood stem cells (PBSC) in 253 (83%) patients and bone marrow in 50 (17%) patients. Median follow-up of patients alive was 63 months (range 12-168). Cytogenetics at diagnosis were available for 263 (87%) of patients, of which 16 (5%) were favorable, 185 (61%) were intermediate and 62 (20%) were unfavorable risk (MRC classification). Primary induction failure prior to achievement of CR was seen in 67 (22%) patients. In vivo T-cell depletion was performed in 71 (23%) patients. A total of 124 patients (41%) underwent HCT during the years 2000-2006 and 179 patients (59%) during the years 2007-2013. EM disease at diagnosis was seen in 39 patients (13%), of whom 11 patients had CSF disease, 7 patients had gingival infiltration and 5 patients had leukemia cutis.Univariate analysis for overall survival (OS) demonstrated that EM disease at diagnosis had no influence (HR=0.96 for EM, 95%CI=0.60-1.51, p=0.85, Figure 1). Multivariable analysis for OS including the previously described variables verified this observation. EM disease did not influence cumulative incidence of relapse (CIR) on univariate analysis (HR=0.94 for EM, 95%CI=0.45-1.96, p=0.86, Figure 2), and this also was confirmed on multivariable analysis. Moreover, EM disease did not influence cumulative incidence of non-relapse mortality on both univariate (HR=0.94 for EM, 95%CI=0.53-1.66, p=0.83) and multivariable analysis.In conclusion, EM disease at diagnosis of AML in patients achieving CR1, does not seem to influence outcomes post allogeneic HCT. This is significant in the consideration of allogeneic HCT for the treatment of this unfavorable subtype of AML. We are unable to comment on whether a similar percentage of patients with EM disease versus without EM disease, achieve CR1. [Display omitted] [Display omitted] DisclosuresKim:Bristol-Myers Squibb: Consultancy, Research Funding; Novartis Pharmaceuticals: Consultancy, Research Funding.

Prognostic Score for Adults with Acute Myeloid Leukemia in First Complete Remission

BackgroundCurrent prognostic scoring systems in acute myeloid leukemia (AML) help predict outcomes in newly diagnosed patients at the time of diagnosis. In AML, achievement of complete remission (CR) is essential for the success of treatment. Therefore, development of a prognostic score for patients who enter first CR would be an important tool for physicians to guide their decisions for further treatment at the time of CR.Patients and MethodsWe developed a prognostic score based on data from 938 newly diagnosed adult AML (non-APL) patients (median age 59 years, range [18 - 88]) diagnosed and treated at the University of Texas MD Anderson Cancer Center, USA between [1999-2012], who achieved 1st CR/CRp and were not transplanted in 1st CR. Median follow-up was 22.3 months [range 1.4-165.1 months]. Information on MRC 2010 classification was available for 896 patients (156 (17.4%) patients in favorable, 550 (61.4%) in intermediate, and 190 (21.2%) in adverse group); ELN classification could be determined for 478 patients (160 (33.5%) in favorable, 88 (18.4%) in intermediate-1, 103 (21.5%) in intermediate-2, and 127 (26.6%) patients in adverse risk group.For survival analysis Kaplan-Meier method was used. Survival distributions were compared using log-rank tests. Univariable and multivariable Cox regression analyses were performed to evaluate an impact of clinically significant prognostic variables (P<0.05). Each significant variable in the multivariate analysis was then assigned points based on the weight of the coefficient. A sum of the points led to a score that segregated patients into different prognostic subgroups (Table 1 and 2).ResultsBased on multivariable analysis, age and MRC/ELN subgroup were statistically significant prognostic factors (p<0.001) and were subsequently included in the prognostic score model. Since age (<60 and ≥60 years old) is an important prognostic factor not directly accounted for in the original MRC2010 and ELN classification systems, this was added to each of the new prognostic scores: "MRC+age" and "ELN+age".In "MRC +age" prognostic score four groups were identified: favorable, intermediate-1, intermediate-2 and poor (Table 1B). In "ELN+age" score five groups were identified: favorable, intermediate-1, intermediate-2, poor and very poor (Table 2B).According to "MRC+age" prognostic score, the 3- and 5-year overall survivals (OS), respectively were: 80% and 77% in the favorable group; 53% and 45% in the intermediate-1 group; 31% and 19% in the intermediate-2 group; and 8% and 6 % in the poor group. According to "ELN+age" prognostic score, the 3- and 5-year OS, respectively, were 78% and 77% in the favorable group; 68% and 50% in the intermediate-1 group; 46% and 37% in the intermediate-2 group; 27% and 22% in poor group; and 3% and 2% in the very poor group (Figure 1; A and B).ConclusionDespite the new discoveries in AML (DNA sequencing, genomic mutations, etc.) many clinics worldwide still don't have access to those tools and they stratify patients according to MRC or ELN classifications. The prognostic score presented above could be a powerful tool for physicians to risk-stratify patients with AML in first CR for post-remission therapy based on age and basic cytogenetic and/or molecular testing.Table 1Prognostic score for AML in 1st complete remission according to Age and MRC classificationPrognostic factorCoefficientPointsAge<6000≥600.5131MRC subgroupFavorable00Intermediate1.0702Adverse1.9574Table 2Prognostic score for AML in 1st complete remission according to Age and ELN classificationMRC + ageTotal scoreFavorable0Intermediate-11-2Intermediate-23Poor4-5Table 3Prognostic factorCoefficientPointsAge<60 years00≥60 years0.2240.5ELN subgroupFavorable00Intermediate - 11.5703Intermediate - 21.1282.5Adverse2.0134Table 4ELN + ageTotal scoreFavorable0Intermediate-10.5Intermediate-22.5Poor3Very poor3.5 - 4.5 [Display omitted] DisclosuresTamamyan:Conquer Cancer Foundation of the American Society of Clinical Oncology: Other: Long-term International Fellowship (LIFe). Cortes:Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding; BMS: Consultancy, Research Funding; BerGenBio AS: Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy. Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding.

Interleukin-2 as maintenance therapy for children and adults with acute myeloid leukaemia in first complete remission.

Acute myeloid leukaemia (AML) is a malignant cancer of hematopoietic stem cells. The treatment of AML consists of two treatment phases: the remission induction phase to achieve a rapid, complete remission (CR) and the consolidation phase to achieve a durable molecular remission. People in CR are at risk of AML relapse, and people with relapsed AML have poor survival prospects. Thus, there is a continuous need for treatments to further improve prognosis. Interleukin-2 (IL-2), an immune-stimulatory cytokine, is an alternative to standard treatment for people with AML to maintain the efficacy after consolidation therapy. Maintenance therapy is not an integral part of the standard treatment for AML. Studies have been conducted to evaluate the efficacy of IL-2 as maintenance therapy for people with AML in first CR, but the effect of IL-2 is not yet fully established. To evaluate the efficacy and safety of IL-2 as maintenance therapy for children and adults with AML who have achieved first CR and have not relapsed. We systematically searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library 2015, Issue 8), MEDLINE (1950 to August 2015), EMBASE (1950 to August 2015), LILACS (1982 to August 2015), CBM (1978 to August 2015), relevant conference proceedings (2000 to 2015), and metaRegister of Controlled Trials (since inception to August 2015) of ongoing and unpublished trials. In addition, we screened the reference lists of relevant trials and reviews. Eligible studies were randomised controlled trials (RCTs) comparing IL-2 with no treatment in people with AML who had achieved first CR and had not relapsed. We did not identify studies comparing IL-2 versus best supportive care or maintenance chemotherapy or studies comparing IL-2 plus maintenance chemotherapy versus maintenance chemotherapy alone. Two review authors independently screened studies, extracted data with a predefined extraction form, and assessed risk of bias of included studies. We extracted data on the following outcomes: disease-free survival, overall survival, event-free survival, treatment-related mortality, adverse events, and quality of life. We measured the treatment effect on time-to-event outcomes and dichotomous outcomes with hazard ratio (HR) and risk ratio, respectively. We used inverse-variance method to combine HRs with fixed-effect model unless there was significant between-study heterogeneity. We included nine RCTs with a total of 1665 participants, comparing IL-2 with no treatment. Six studies included adult participants, and three studies included both adults and children. However, the latter three studies did not report data for children, thus we were unable to conduct subgroup analysis of children. One Chinese study did not report any outcomes of interest for this review. We included six trials involving 1426 participants in the meta-analysis on disease-free survival, and included five trials involving 1355 participants in the meta-analysis on overall survival. There is no evidence for difference between IL-2 group and no-treatment group regarding disease-free survival (HR 0.95; 95% CI 0.86 to 1.06, P = 0.37; quality of evidence: low) or overall survival (HR 1.05; 95% CI 0.95 to 1.16, P = 0.35; quality of evidence: moderate). Based on one trial of 161 participants, IL-2 exerted no effect on event-free survival (HR 1.02; 95% CI 0.79 to 1.32, P = 0.88; quality of evidence: low). Adverse events (including thrombocytopenia, neutropenia, malaise/fatigue, and infection/fever) were more frequent in participants receiving IL-2, according to one trial of 308 participants. No mortality due to adverse events was reported. None of the included studies reported treatment-related mortality or quality of life. There is no evidence for a difference between IL-2 maintenance therapy and no treatment with respect to disease-free survival or overall survival of people with AML in first CR; however, the quality of the evidence is moderate or low, and further research is likely or very likely to have an important impact on the estimate or our confidence in the estimate. Adverse events seem to be more frequent in participants treated with IL-2, but the quality of the evidence is very low and our confidence in the estimates is very uncertain. Thus, further prospective randomised trials are needed before definitive conclusions can be drawn on these issues.

Natural Killer Cell Expression of Natural Cytotoxicity Receptors Determines Relapse Risk in Elderly Patients with Acute Myeloid Leukemia Receiving Immunotherapy with Histamine Dihydrochloride and Interleukin-2

Background: The insufficiency of natural killer (NK) cells in acute myeloid leukemia (AML) and the purported role of NK cells for prognosis have inspired the use of NK cell-based immunotherapies for relapse prevention, including the administration of NK cell-activating cytokines. A previous phase III trial using immunotherapy with histamine dihydrochloride and low-dose interleukin-2 (HDC/IL-2) was shown to significantly prevent relapse in patients who had achieved complete remission (CR) and completed the phase of consolidation chemotherapy (Brune et al., Blood108:88). Details regarding the mechanisms of relapse prevention are only partly understood.Trial design and methods: In a single-armed multicenter phase IV study (Re:Mission Trial, NCT01347996) we aimed at assessing the immunomodulatory effects of HDC/IL-2 with a focus on NK cell biology and to correlate NK cell markers with relapse risk. Eighty-four patients (age 18-79, median 61.2) with AML in first CR received post-consolidation immunotherapy with HDC/IL-2 for 18 months in ten 3-week cycles with 3 (cycle 1-6) or 6 week (cycle 7-10) intervals between cycles. NK cell counts in blood and natural cytotoxicity receptor (NCR) expression were determined by flow cytometry before and after cycles 1 and 3. The trial protocol specified separate analyses in younger (<60 years old, n=37) and elderly patients (>60 years old, n=47).Results: During cycle 1, CD56bright (CD3–/16–/56bright) and CD16+ (CD3–/16+/56+) NK cell counts increased in the blood (P=3x10-8 and P=2x10-5, respectively, paired t-test, n=47, all evaluable patients) along with an increased expression intensity of the NCRs NKp30 and NKp46 in the cytotoxic CD16+ subset (P=2x10-7 and P=6x10-8, respectively, paired t-test n=47). NK cell counts declined between the end of treatment cycle 1 and the start of cycle 3. CD56bright NK cell counts typically returned to pre-treatment levels whereas CD16+ NK cell counts remained modestly elevated at the onset of cycle 3 (P=.003, paired t-test; n=46). A renewed accumulation of CD56bright and CD16+ NK cells in the blood was observed during treatment cycle 3 (P=2x10-6 and P=.007, respectively, paired t-test, n=40). Young and elderly patients showed similar fluctuations in counts of CD56bright and CD16+ NK cell within and between treatment cycles. Also, significant induction of the expression intensity of NKp30 and NKp46 on CD16+ NK was observed in young and elderly patients.Among elderly patients, expression of NKp46 in CD16+ NK cells after the first treatment cycle was associated with favorable outcome (RFS for above-median NKp46 expression in CD16+ NK cells; P=.002, HR=4.1, CI: 1.7-10.0; logrank test). Similar results, with increased likelihood of RFS, were obtained in elderly patients with NK cells showing above-median expression of NKp30. The expression intensity of NKp30 and NKp46 did not predict relapse in younger patients.Conclusion: These results highlight the impact of NK cells and NCRs for AML prognosis and suggest that NK cell expression of NCRs may determine the efficacy of immunotherapy for remission maintenance in elderly patients. DisclosuresMartner:Study sponsor Meda Pharma GmbH & Co, Bad Homburg, Germany: Honoraria, Research Funding. Brune:Study sponsor Meda Pharma GmbH & Co, Bad Homburg, Germany: Consultancy, Honoraria. Foa:Study sponsor Meda Pharma GmbH & Co, Bad Homburg, Germany: Consultancy. Hellstrand:Study sponsor Meda Pharma GmbH & Co, Bad Homburg, Germany: Consultancy, Honoraria, related to the use of HDC/IL-2 in AML Patents & Royalties, Research Funding. Off Label Use: HDC/IL-2 is approved for use within the EU for AML patients in CR <60 years old. In the abstract we discuss the potential usefulness of the drug for patients >60 years old. Thorén:Study sponsor Meda Pharma GmbH & Co, Bad Homburg, Germany: Honoraria, Research Funding.

Impact of CD3+ and CD34+ Doses in the Mobilized Peripheral Blood Stem Cell Grafts on the Outcome of Reduced-Intensity Conditioning Allogenic Transplantation from Matched Unrelated Donors for Acute Myeloid Leukemia – an Analysis from the Acute Leukemia Working Party of the EBMT

Introduction:The impact of peripheral blood stem cell (PBSC) grafts composition on the outcome of reduced-intensity conditioning (RIC) allogenic transplantations (allo-SCT) is still controversial. Inconsistent results have been reported regarding the influence of CD3+ and CD34+ cells dose on incidence of GVHD, disease control and survival. These discrepancies may be at least in part explained by the differences in disease categories, disease status at transplant, donor type and conditioning.Aim and methods:This retrospective EBMT registry study aimed to analyze the impact of CD3+ and CD34+ cells dose in PBSC grafts on the outcome of RIC allo-SCT in patients with acute myeloid leukemia (AML) allografted from matched unrelated donors (MUD). Two hundred and three adults with AML in first complete remission (CR1) treated with RIC allo-PBSCT from MUD (10 of 10 match) between 2000 and 2012 (median 2011) were included. Ex-vivo T-cell depletion was an exclusion criterion. Median age was 58 (range, 21-73) years; gender: male-116, female-87; 142 had intermediate, 42 unfavorable, 4 favorable, and 15 unknown cytogenetic features; median time to achieve CR1 was 51 (range, 21-350) days, whereas time from CR1 to allo-SCT was 115 days (15-351). Median donor age was 34 (range, 19-61) years. The preparative regimen was based on chemotherapy in 143 (70%) of the RIC allo-CST (Flu-Bu:110; Flu-Mel:12; Flu-Treosulfan:14, other:7), whereas in 60 (30%) low dose TBI was applied (2 Gy:57; 4 Gy:3). In-vivo T-cell depletion (ATG or Campath) was used in 166 (82%) of the transplants. Median transplanted CD3+ and CD34+ doses were 250 (50-885) x 10^6 and 6.53 (1.34-413) per kg of recipient b.w., respectively. Follow-up was 22 months (3-105).Results:The engraftment rate equaled 99% (202 pts) and was not affected by CD3+ nor CD34+ counts. In univariate analysis, patients transplanted with the highest CD3+ doses (above the third quartile cut-off point value, >347 x 10^6/kg) had an increased incidence of acute (a) GVHD grade >2 (45% vs. 26%, p=0.007) and grade 3-4 (20% vs. 6%, p=0.003), respectively. In the quartile of pts transplanted with the highest CD34+ graft content (>8.25 x 10^6 /kg) increased incidence of grade 3-4 aGVHD (18% vs. 7%, p=0.02) was observed. Other risk factors for aGVHD were transplantation from CMV seropositive donors (grade >2; 44% vs. 24%, p=0.005) and from females to males (grade 3-4; 19% vs. 8%, p=0.04). There was no association between cellular composition of grafts and non-relapse mortality (NRM), AML relapse, incidence of chronic (c) GVHD and survival. There was also no significant correlation between CD3+ and CD34+ cells infused. In multivariate analysis, CD3+ dose was the only adverse predicting factor for aGVHD grade >2 (HR= 2.1; 95%CI: 1.25-3.55, p=0.005) and together with CD34+ dose for aGVHD grade 3-4 (CD3+, HR=3.6; 95%CI: 1.45-9.96, p=0.006; CD34+, HR=2.65; 95%CI: 1.07-6.57, p=0.04). Other factors that independently affected unfavorable outcome were: time from diagnosis to CR1 above median for NRM, transplantation without in-vivo T-cell depletion for cGVHD, time from CR1 to allo-SCT above median and unfavorable karyotype for leukemia-free and overall survival and unfavorable karyotype for relapse incidence.Conclusions:These results suggest that the incidence of severe acute GVHD post RIC allo-SCT, still a major cause of morbidity and mortality, is associated with the composition of the PBSC grafts, specifically higher numbers of infused CD3+ and CD34+ cells. As graft composition can be manipulated, careful assessing the CD3+ and CD34+ graft content and the cell dose infused may help in reducing severe aGVHD risk and improving transplantation outcome. DisclosuresNo relevant conflicts of interest to declare.

Contrasting Factors Determine the Kinetics of Disease Relapse after Allogeneic Stem Cell Transplantation (allo-SCT) for Acute Myeloid Leukaemia (AML): a Survey from the Acute Leukaemia Working Party of the EBMT

Disease relapse remains the major cause of treatment failure in patients allografted for AML. Post transplant interventions, such as donor lymphocyte infusion or adjunctive targeted therapies, represent novel strategies with the potential to reduce the risk of disease recurrence. Such approaches are however critically dependent on timely intervention prior to disease relapse. Whilst the factors predicting the overall risk of relapse have been well characterized determinants of the kinetics of disease relapse have not been extensively studied. We therefore performed a systematic analysis of factors determining the kinetics of disease relapse in patients allografted for AML.1052 patients who received an allo-SCT for AML in first complete remission (CR1) between 2000 and 2012 were studied. Median age was 50 (18-72) years. 544 patients were transplanted using a sibling donor and 508 from an adult matched-unrelated donor. 538 patients received a myeloablative and 514 a reduced intensity conditioning regimen. 923 patients had good/intermediate risk and 129 had adverse risk cytogenetics at diagnosis. A series of landmark analyses were performed at 3, 6 and 12 months in order to identify prognostic factors of relapse for patients alive and well at the beginning of each time interval. The probabilities of relapse were calculated by using the cumulative incidence estimator to accommodate for death as a competing risk. Factors predicting relapse were studied using Cox regression model including time dependent variables. A backward stepwise procedure was used for variable selection.With a median follow-up of 26 months, 244 patients relapsed. The 3 year cumulative incidence of relapse was 26% [95%CI: 23-28]. The cumulative incidence of relapse in the first three months post-transplant was 7.1% (95% CI: 5.6-8.8%), 8.3% (95% CI: 6.6-10.3) between 3-6 months, 8.3 (95% CI: 6.5-10.5) between 6 and 12 months and 3.8% (95% CI: 2.4-5.6) beyond 12 months post-transplant. Overall 84% of patients destined to relapse did so within the first year post-transplant. Factors predicting relapse for the whole population were: more than one course of chemotherapy to achieve CR1, FLT3 ITD positivity, adverse risk cytogenetics and a shorter interval from CR1 to transplant. The occurrence of acute GVHD grade II or greater (p=0.05) and chronic GVHD (p=0.03) were both associated with a lower risk of relapse.Of interest, using landmark analyses, the factors determining relapse at different stages post transplant were observed to differ. In the first 3 months post-transplant the significant factors determining relapse risk were, flt3 ITD positivity (p=0.002), adverse risk cytogenetics (p=0.02) patient age (p=0.03), and prolonged interval from diagnosis to CR1 (p=0.05) aswell as the use of in vivo T cell depletion (p=0.003). The only factor observed to determine relapse risk between 3 and 6 months post-transplant was the presence at diagnosis of adverse risk cytogenetics (p=0.04). In patients who relapsed between 6 and 12 months post-transplant more than one course of chemotherapy to achieve CR1 (p=0.02), adverse risk cytogenetics (p=0.05) and FLT3 ITD positivity (p=0.00002) all predicted for relapse. Finally only CMV positivity predicted for relapse risk for more than 12 months post-transplant (p=0.05).This study confirms the importance of factors previously demonstrated to increase the overall relapse risk in patients allografted for AML. Our data also demonstrate a complex interaction of disease specific and transplant factors contributing to the kinetics of disease recurrence at different times post-transplant. In addition to identifying the occurrence of a dynamic interplay between tumor biology and transplant factors in determining the pathobiology of disease relapse post-transplant the results of this analysis can be used to assist in the design of novel strategies with specific reference to the timing of post-transplant intervention. DisclosuresNo relevant conflicts of interest to declare.

CALGB 100801 (Alliance): A Phase II Multi-Center NCI Cooperative Group Study of the Addition of Azacitidine (AZA) to Reduced-Intensity Conditioning (RIC) Allogeneic Transplantation for High Risk Myelodysplasia (MDS) and Older Patients with Acute Myeloid Leukemia (AML): Results of a “test dose” Strategy to Target Busulfan Exposure

▪Relapse remains the major cause of death in older patients transplanted for AML in first complete remission (CR1) or for patients with advanced MDS at any age. Conventional myeloablative conditioning followed by allogeneic blood or marrow transplantation is associated with significantly less relapse compared with RIC when performed in younger patients with AML or MDS, but the toxicity of this approach in older patients is prohibitive. We hypothesized that pharmacokinetic targeting to optimize busulfan (Bu) exposure, combined with the administration of AZA post transplantation would mitigate the risk of relapse while avoiding non-relapse mortality (NRM) and ultimately improve progression free survival (PFS). Here we report the results of a Bu test dose strategy targeting daily Bu exposure as determined by the area under the plasma concentration versus time curve (AUC). The primary endpoint of the study was two year progression free survival (PFS). An important secondary objective was to determine whether administration of a test dose of Bu with post test sampling would enable achievement of a daily target Bu AUC level of 4000 uM*min in at least 80% of the recipients. We used this strategy as part of a RIC regimen on a prospective multi-center phase II trial conducted by the Alliance (formerly Cancer and Leukemia Group B (CALGB)). Eligibility included patients with AML in CR1 aged 60-74 years inclusive, MDS with IPSS risk > Int-2 with less than 10% marrow blasts and age <75, availability of a well matched sibling or volunteer unrelated donor (VUD), and absence of significant end-organ damage prior to transplantation. The study completed accrual in 10/2013. 67 patients were registered, and 63 transplanted with 39 receiving grafts from VUDs and 23 from matched siblings. The donor type was not documented at the time of this abstract for one patient. The median age was 63 (44-74), 18 had AML and 45 had MDS. Ten centers enrolled at least one patient. All patients were conditioned with a uniform regimen consisting of fludarabine IV (days -7 to -3), busulfan IV (Bu) targeted to a daily AUC of 4000uM*min (Days -6 to -3) following administration of a 25mg/m2 test dose on one day between Days -14 to -9, and antithymocyte globulin (days -6, -5 and-4 (two doses for matched sibs and three for VUDs only). Body surface area was calculated using a corrected weight formula in overweight individuals (ideal weight + 25% of the difference between ideal and actual weight). Beginning day +42, all patients were planned to receive up to six monthly cycles of AZA at 32mg/m2 subcutaneously x 5days. The proportion of patients who actually received AZA and the median number of cycles received will be reported at the time of abstract presentation. 58 patients received a test dose of Bu and had target validation samples drawn on day -6, following the first dose. Test dose was infused over 45 minutes and blood samples were drawn at end of infusion and 1, 2, 4, and 6 hours after test dose completion. Bu target level validation samples were then obtained at the same time points following the Day-6 dose of Bu. The validation results are depicted in the table:TableTest dose AUCBody surface area (median)Targeted daily Bu dose received(mg/m2) (median; range)Median AUC achieved on validation sample(median,range)Median AUC/4000927.5uM*min1.9m2107 (32-198)4170uM*min (3284-6642)1.04390% of patients were within 20% of the target AUC (95% CI=0.79-0.96) based on the validation sample. Maximum non-hematologic CTCAE v4.0 toxicity was grade 3 in 28 (50%), grade 4 in 6 (11%), and grade 5 in 5 (9%) of the 56 patients with available adverse event data. There were ten deaths within the first 100 days after transplant; six of these were due to NRM. With a median follow up of 564 days, the estimated overall survival at 2 years was 39 %. In conclusion, the preliminary results of this prospective multi-center trial suggest a strategy of targeting busulfan exposure to an AUC of 4000uM*min based on a prior “test dose” is successful in the majority of patients without causing excessive non-hematologic toxicity even in older patients. Further follow up is necessary to determine whether this results in less relapse and improved PFS. DisclosuresVij:celgene: Honoraria, Research Funding. Off Label Use: Busulfan, fludarabine, thymoglobulin: conditioning for transplant Azacytidine: post allogeneic transplant. Blum:Celgene: Consultancy. Shea:CALGB/Alliance: CALGB Board of Directors Other. Devine:sanofi: Research Funding.

Abstract 2545: Histamine dihydrochloride and interleukin-2 for relapse prevention in AML: Initial results of the Re:MISSION phase IV trial

Abstract BACKGROUND AND METHODS. Immunotherapy with histamine dihydrochloride and low-dose interleukin-2 (HDC/IL-2) has been approved within the EU for relapse prevention in the post-consolidation phase of acute myeloid leukemia (AML) (Blood 108:88). We have performed a phase IV trial (Re:MISSION) to assess the immunomodulatory properties of this regimen and to correlate potential biomarkers of immunity with outcome. Eighty-nine patients (age 19-80) with AML in first complete remission received HDC (0.5 mg sc bid) and human recombinant IL-2 (1MIU sc bid) in ten repeated three-week cycles for 18 months or until relapse. Mononuclear cells were analyzed for NK and T cell phenotypes by flow cytometry at onset and during cycles 1 and 3. INDUCTION OF NK CELLS AND NCR EXPRESSION DURING THERAPY. Treatment with HDC/IL-2 resulted in a 3-fold expansion of both CD56bright (CD56/CD16-) and CD16+ (CD56+/CD16+) NK cells during cycle 1 (CD56+, P= 10-6, n=47; paired samples t-test). During cycle 1, the median expression intensity of the natural cytotoxicity receptors (NCRs) NKp46 and NKp30 on CD16+ NK cells increased by 50% and 30%, respectively (P=6 x10-8 for NKp46; P=2 x10-7 for NKp30, n=56). For CD56bright cells, the results were discordant for the NCRs with pronounced induction of NKp30 (P=4 x10-13) during cycle 1 but no induction of NKp46 (P=0.51, n=56). ROLE OF NCR EXPRESSION FOR MAINTENANCE OF REMISSION. An interim analysis of immune markers vs. relapse-free survival (RFS) revealed a strong impact of NK cell NKp46 expression. Patients with NKp46 expression above the median after one 21-day cycle of HDC/IL-2 thus showed significantly higher RFS than those with lower expression (CD16+, P=0.003, HR=3.0, CI 1.4-6.4; CD56bright, P=0.002, HR=3.3, CI: 1.5-7.0; logrank test). High NK cell expression of NKp46 after a treatment cycle also identified a population of elderly patients (&amp;gt;60 years old) with favorable outcome (CD16+, P=0.002, HR=4.1, CI: 1.6-10.2; logrank test). We observed a pronounced expansion of CD4+/CD25+/Foxp3+ regulatory T cells during cycles that did not impact on relapse risk. CONCLUSION. These results highlight the role of NK cells and NCR expression for relapse-free survival in AML. Citation Format: Anna Martner, Anna Rydström, Rebecca Riise, Johan Aurelius, Mats Brune, Kristoffer Hellstrand, Fredrik Bergh Thorén. Histamine dihydrochloride and interleukin-2 for relapse prevention in AML: Initial results of the Re:MISSION phase IV trial. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2545. doi:10.1158/1538-7445.AM2014-2545

A cost-effectiveness analysis evaluating allogeneic hematopoietic cell transplantation (AHCT) versus consolidation chemotherapy for the treatment of acute myeloid leukemia (AML) in first complete remission.

6556 Background: The objective of this study was to determine which treatment strategy for AML in first complete remission (CR) is more cost-effective: consolidation chemo or AHCT. Methods: Simple ...

Prediction of non-relapse mortality in recipients of reduced intensity conditioning allogeneic stem cell transplantation with AML in first complete remission.

Non-relapse mortality (NRM) after allogeneic hematopoietic stem cell transplantation (alloHSCT) can be predicted by the hematopoietic cell transplantation comorbidity index (HCT-CI) and the European Group for Blood and Marrow Transplantation (EBMT) score, which are composed of different parameters. We set out to integrate the parameters of both scores in patients with acute myeloid leukemia (AML) in first complete remission (CR1) receiving reduced intensity conditioning (RIC) alloHSCT. All parameters from the HCT-CI and the EBMT-score with the addition of patient and donor cytomegalovirus serology were evaluated in 812 patients by multivariable analysis with end-point NRM at 2 years. Subsequently, 16 parameters were selected based on hazard ratio >1.2, and were incorporated into a novel score, which was further internally validated by bootstrapping. Both the HCT-CI and the EBMT-score showed relatively weak predictive value, whereas the integrated score allowed to identify three clearly distinct risk groups with 2-year NRM estimates of 8±2% (low-risk), 17±2% (intermediate-risk) and 38±4% (high-risk), which also translated in prediction of overall survival. Collectively, integration of the most dominant parameters from the HCT-CI and the EBMT-score allowed to develop a simple and robust, integrated score with improved prediction of NRM for AML patients proceeding to RIC alloHSCT in CR1.

Indications for allogeneic hematopoietic cell transplantation for acute myeloid leukemia in the genomic era.

Few choices in medical oncology are as stark as the decision of whether or not to proceed with allogeneic hematopoietic cell transplantation (HCT) in the treatment of acute myeloid leukemia (AML). Recent advances provide more information to inform the decision, including molecular studies of leukemia that predict tumor responsiveness, assays of minimal residual disease that measure early treatment outcome, and comorbidity indices that predict nonrelapse mortality. Although large prospective studies incorporating all of these factors are lacking, literature reviews and consensus statements exist that can help the clinician in this difficult choice. Allogeneic HCT should be considered for all patients younger than age 65, with an available donor, an acceptable comorbidity index, and whose had initial induction therapy has failed. Similarly, allogeneic HCT is appropriate therapy for all patients with AML in second remission younger than age 75, with an appropriate donor, and a comorbidity index of 5 or less. For patients younger than age 60 with AML in first complete remission (CR), there is little evidence that HCT benefits those with favorable-risk disease who achieve CR with one cycle of induction and have no evidence of minimal residual disease. Allogeneic HCT is indicated for essentially all other categories of patients. For those age 60 and older, few prospective studies are available on which to base recommendations, but, as in younger patients, the benefit of allogeneic HCT is questionable for patients with favorable-risk AML. For patients with higher-risk disease, allogeneic HCT is a reasonable option with the caution that the risk of HCT increases dramatically in those with a comorbidity index of 3 or higher.

Should Busulfan Now be Part of the Standard Treatment for Patients with Acute Myeloid Leukemia?

2014 Treatment of acute myeloid leukemia (AML) in nonelderly patients has followed the same paradigm of remission induction with cytarabine and anthracycline with or without a third cytotoxic drug for more than 40 years. These drugs produce complete remissions in the majority of patients, but cure requires intensive postremission treatment. Postremission therapies have also remained similar for many years, but better criteria for selection of postremission treatment for individual patients has improved results. Cytogenetic analysis and molecular markers predict risk of relapse more accurately than previously used factors. Patients at low risk of relapse, including those with core binding factor abnormalities and those with normal cytogenetics and an NPM-1 mutation without FLT3 mutations, are generally best treated with multiple doses of high-dose cytarabine as postremission therapy. Most other patients who have good performance status, minimal comorbidities and a well-matched sibling or unrelated donor, have better long-term survival with allogeneic hematopoietic cell transplantation (HCT) [1]. There is no doubt as to the potent antileukemic efficacy of HCT. This effectiveness, however, comes at the cost of significantly more nonrelapse mortality (NRM) compared with cytarabine. Thomas and colleagues employed a myeloablative regimen of cyclophosphamide and total body irradiation (Cy/TBI) as the preparative regimen for the first successful HCTs in relapsed and refractory acute leukemia. Subsequent patients with AML who underwent transplantation in first remission experienced sustained leukemia-free survival rates in excess of 50% [2]. A few years later, Santos et al. demonstrated the feasibility of a chemotherapy-only preparative regimen of busulfan and cyclophosphamide (BuCy). In a small group of patients with AML in first complete remission (CR1) treated with BuCy and sibling bone marrow grafts, no relapses occurred and the estimated 2-year survival was 44% [3]. This established BuCy as an alternative to Cy/TBI. This was of particular importance because TBI is not universally available, particularly in developing countries. Owing to the high NRM of the original BuCy study, the Cy dose was modified from 200 mg/kg over 4 days to 120 mg/kg over 2 days (BuCy2) in most subsequent studies and the modification appeared to decrease toxicity [4].

Phase I study of oral clofarabine consolidation in adults aged 60 and older with acute myeloid leukemia

Clofarabine has shown activity and tolerability in older patients with acute myeloid leukemia (AML). We investigated the safety and tolerability of an oral formulation of clofarabine for consolidation therapy of patients aged 60 and older with AML. In this phase I study, twenty-two patients older than 60 years with AML in first complete remission were treated once daily with oral clofarabine for 14 or 21 days of a 28-day cycle, for up to five cycles. Dose escalation from 1 mg to 6 mg daily using a 3 + 3 design was used to determine dose-limiting toxicities (DLT), the maximum tolerated dose (MTD), and tolerability of oral clofarabine. No DLTs or Grade 3-4 nonhematologic toxicities were observed. The primary toxicities were hematologic, including uncomplicated grade 3-4 neutropenia (50%) and thrombocytopenia (50%). Given that myelosuppression necessitating dose delays/reductions was observed more commonly at higher doses, the recommended phase II dose is 2 mg daily for 21 of 28 days. At doses equal to or greater than 2 mg, the median relapse-free survival was 28.35 months. Oral clofarabine was well-tolerated with encouraging activity in patients older than 60 years. Further investigation of oral clofarabine as a consolidation and/or maintenance therapy in AML for older individuals is warranted. (ClinicalTrials.gov:NCT00727766).

Recombinant interleukin‐2 in patients aged younger than 60 years with acute myeloid leukemia in first complete remission: Results from Cancer and Leukemia Group B 19808

Recombinant interleukin-2 (rIL-2) induces cellular cytotoxicity against leukemia blasts. Patients with acute myeloid leukemia (AML) in first complete remission (CR) may harbor minimal residual disease that is susceptible to rIL-2-activated effector cells. In the Cancer and Leukemia Group B (CALGB) 19808 study, patients with AML in first CR were randomly assigned after all planned chemotherapy to receive a 90-day course of subcutaneously administered rIL-2 or no further therapy. The primary objective was to compare disease-free survival (DFS) between the 2 treatment arms. A total of 534 patients achieved a CR, 214 of whom were randomized. Six courses of low-dose daily rIL-2 were given for the expansion of cytotoxic effector cells, each followed by 3-day high-dose boluses given to trigger cytotoxicity against minimal residual disease. On the protocol-specified intention-to-treat analysis, the hazards ratio for DFS was 0.75 (95% confidence interval, 0.52-1.09; P = .13); the 5-year DFS rate was 42% in the observation arm and 53% in the rIL-2 treatment arm. The hazards ratio for overall survival (OS) was 0.88 (95% confidence interval, 0.54-1.23; P = .34); the 5-year OS rate was 58% for the observation arm and 63% for the rIL-2 treatment arm. Twenty-five of the 107 patients randomized to treatment with rIL-2 either refused or were unable to initiate therapy and 30 patients did not complete their assigned therapy. However, significant toxicities were not commonly observed. The trial design did not anticipate the difficulties patients would encounter with protocol compliance. The efficacy of immunotherapy with rIL-2 administered after intensive postremission treatment was not assessed as planned because of unexpected refusals by patients and/or their physicians to comply with protocol-directed therapy. Neither DFS nor OS was found to be significantly improved.

Alternative Donor Hematopoietic Transplantation For Patients Older Than 50 Years With AML In First Complete Remission: Unrelated Donor and Umbilical Cord Blood Transplantation Outcomes

Post-remission allogeneic transplantation is increasingly used for treatment of the high-risk acute myeloid leukemia (AML) affecting older adults. We analyzed 740 adults over age 50 with AML in first complete remission (CR1) to compare the effectiveness of volunteer unrelated donor (URD) and umbilical cord blood (UCB) graft sources in providing a successful transplant. For prospective cases reported (2005-2010) to the Center for International Blood and Marrow Transplant Research and Eurocord, we evaluated 8/8 HLA allele matched (at HLA-A, -B, -C, -DRB1) n=441; 7/8 matched URD n=94 and UCB n=205 for the outcomes of engraftment, treatment related (non-relapse) mortality (TRM), relapse, leukemia free survival (LFS) and overall survival (OS) using the cumulative incidence and Kaplan-Meier estimators and multivariate Cox regression modeling. Patient age (median 58, range 50-75), gender and CMV serostatus were similar across the treatment groups. However, UCB recipients were less likely to achieve CR within 8 weeks, more likely to report Intermediate and unfavorable risk cytogenetics, more likely to receive reduced-intensity conditioning compared to myeloablative conditioning regimens, and receive cyclosporin rather than tacrolimus-based GVHD prophylaxis.After a median follow-up of 50, 61 and 37 months in 8/8 URD, 7/8 URD and UCB grafts, neutrophil and platelet recovery was slower in UCB compared to URD recipients; the day-42 incidence of neutrophil recovery in UCB recipients was 85% compared to 98% and 92% in 8/8 and 7/8 URD recipients. While there were no significant differences in rates of grade II to IV acute GVHD (35%, 36% and 44% in UCB, 8/8 URD and 7/8 URD recipients respectively), the 3-year incidence of chronic GVHD was significantly lower in UCB recipients (28% compared to 53% and 59% in 8/8 and 7/8 URD recipients. Compared to 8/8 URD transplants, multivariate analysis confirmed higher TRM after transplantation of UCB grafts, but only in the first 3 months (HR 2.83, p<0.0001) with similar risks thereafter (HR 1.00, p=0.99). Compared to 8/8 URD transplants, TRM was higher after 7/8 URD transplants (HR 1.73, p=0.005). There were no significant differences in relapse risks between the three groups; compared to 8/8 URD transplants, relapse risks after UCB and 7/8 URD transplants were HR 1.15, p=0.36 and HR 0.86, p=0.47, respectively. These hazards yielded higher adjusted 3-year LFS after 8/8 URD (39% [95% CI 34%-43%]) compared to 7/8 URD (34% [95% CI 24%-43%]) and UCB transplants (28% [95% CI 22%-35%]), p=0.015) and adjusted 3-year OS of 43% (95% CI 38%-48%), 37% (95% CI 27%-46%) and 30% (95% CI 23%-37%), respectively (p=0.003). Relapse risks were greater in patients with intermediate or unfavorable risk cytogenetics, independent of graft type and leukemia-free and overall survival were also worse in patients with unfavorable risk cytogenetics and in patients over age 60. For the older population with AML, allotransplantation in CR1 can provide extended leukemia-free survival for 30%-43% of patients using any of these graft sources. While 8/8 URD transplants are preferred for patients who can promptly obtain a well-matched URD, for ethnic or racial minorities, UCB grafts provide a meaningful chance of extended LFS, even though nearly all UCB grafts are HLA mismatched.Additionally, the rapid availability of UCB provides effective therapy for older patients with expected short initial remissions: settings where ongoing consolidation therapy has not been effective in limiting risks of relapse. Later TRM and relapse rates were similar, lower risks of chronic GVHD and the need for long-term immunosuppression and its morbidities may be of particular value for these older patients. These encouraging results suggest that allotransplantation need not be withheld from older patients and for clinically suitable AML patients, can produce extended and even curative long-term survival. Disclosures: GluckmanCord use: Honoraria; gamida: Honoraria.

Comparison Of Minimal Residual Disease As Outcome Predictor For AML Patients In First Complete Remission Undergoing Myeloablative Or Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation

BackgroundMinimal residual disease (MRD) has been recognized as a strong, independent predictor of increased relapse risk and poor outcome for patients with acute myeloid leukemia (AML) in first complete remission (CR) undergoing myeloablative (MA) allogeneic hematopoietic cell transplantation (HCT). As the relationship between MRD and outcome is less studied for AML patients undergoing nonmyeloablative (NMA) HCT, we herein conducted a comparative analysis to assess this association relative to that seen in MA HCT. Patients and MethodsWe studied 272 consecutive patients receiving NMA (n=63) or MA (n=209) HCT for AML in first CR or CR with incomplete blood count recovery (CRi) between May 2006 and May 2012. Pre-HCT bone marrow aspirates were obtained in all patients and analyzed by routine karyotyping and ten-color flow cytometry. MRD was identified as a cell population showing deviation from normal antigen expression patterns as compared with normal or regenerating marrow. Any level of residual disease was considered MRDpos. Data are current as of April 1, 2013. ResultsBaseline characteristics of the study cohort are summarized in Table 1. Patients undergoing NMA HCT were significantly older than those undergoing MA HCT (p<0.001), more often were male (p=0.03), had more comorbidities (p<0.001), more often had secondary leukemias (p=0.05), and more often had incomplete blood count recovery at the time of HCT (p<0.001). Sixteen NMA patients (25.4%) and 40 MA patients (19.1%) were MRDpos, with medians of 0.31% (range: 0.02-2.8%) and 0.29% (0.007-7.8%) abnormal blasts for MRDpos NMA and MA patients, respectively. Three-year estimates of relapse among NMA patients were 31% (18-44%) and 64% (35-82%) for MRDneg and MRDpos patients, respectively, and 21% (15-29%) and 53% (37-68%), respectively, among MA patients (Figure 1A). Among NMA patients, the 3-year estimates of OS were 53% (37-66%) and 49% (21-73%) for MRDneg and MRDpos patients, respectively; among MA patients, 3-year OS was estimated to be 74% (65-80%) and 36% (20-51%), respectively (Figure 1B). This unexpectedly similar outcome in OS for MRDneg and MRDpos NMA patients was largely accounted for by the considerably higher non-relapse mortality (NRM) in MRDneg patients (29% [17-42%]) compared to MRDpos patients (0%), which was the reverse of findings in MRDneg and MRDpos MA patients (8% [5-13%] vs. 21% [10-34%], respectively; Figure 1C). Hazard ratio analysis confirmed a highly statistically significant difference between MA and NMA patients in the association of MRD status with NRM (p<0.001), but not with relapse (p=0.45). There was also evidence of a differential association of MRD status with OS (p=0.03). After adjustment for HCT type (NMA vs MA), age, cytogenetic risk, type of AML, number of cycles of induction chemotherapy, type of consolidation therapy, pre-HCT karyotype, pre-HCT blood counts, and HCT-comorbidity index, being MRDpos was associated with increased risk of relapse (HR=3.31 [1.91-5.73], p<0.001).Table 1NMA HCTMA HCTMRDneg (n=47)MRDpos (n=16)MRDneg (n=169)MRDpos (n=40)Median Age at HCT (range), years62.2 (20.0-75.0)63.7 (33.1-74.0)44.7 (0.6-69.7)47.6 (2.5-66.8)Male Gender, %61.7%87.5%51.5%57.5%Cytogenetics, %Favorable6.7%0%4.2%0%Intermediate71.1%50.0%72.1%51.3%Adverse22.2%50.0%23.6%48.7%Secondary AML, %42.6%62.5%29.0%55.0%Pre-HCT Consolidation Therapy, %No8.5%25.0%16.0%37.5%Yes91.5%75.0%84.0%62.5%Median CR Duration (range), days115 (35-318)76.5 (35-356)121 (18-465)93 (16-383)Pre-HCT Peripheral Blood Counts, %Recovered72.3%68.9%91.7%85.0%Not recovered27.7%31.3%8.3%15.0%Pre-HCT Routine Cytogenetics, %Normalized karyotype51.1%37.5%52.7%47.5%Abnormal karyotype6.4%43.8%8.9%27.5%Missing/non-informative data42.6%18.8%38.5%25.0%Median HCT Comorbidity Index (range), days3 (0-11)4 (2-10)2 (0-6)2 (0-7)Unrelated Donor, %72.3%62.5%65.1%72.5% ConclusionThe negative impact of MRD on post-transplant relapse risk among AML patients in CR1 undergoing NMA HCT is similar to the negative impact seen in patients undergoing MA HCT. Because of the high rate of NRM among MRDneg NMA patients the survival difference between MRDneg and MRDpos patients was much larger in MA than NMA patients in this analysis.▪ Disclosures:No relevant conflicts of interest to declare.

Improving Survival in Acute Myeloid Leukemia: Pick the Best Subjects?

Improving Survival in Acute Myeloid Leukemia: Pick the Best Subjects?

Consolidation Chemotherapy for Adults With AML in First Remission: Is There a Best Choice?

Consolidation Chemotherapy for Adults With AML in First Remission: Is There a Best Choice?

A Phase II Study of Allogeneic Transplantation for Older Patients with AML in First Complete Remission Using a Reduced Intensity Conditioning Regimen: Results From CALGB 100103/BMT CTN 0502

AbstractAbstract 230▪▪This icon denotes a clinically relevant abstractThe prognosis for patients (pts) with acute myeloid leukemia (AML) who are aged 60 years or older at the time of initial diagnosis is poor. Even for pts achieving a first complete remission (CR1), prospects for long-term survival are poor due to the very high risk of relapse. Conventional myeloablative conditioning followed by allogeneic blood or marrow transplantation is associated with significantly less relapse compared with conventional chemotherapy when performed in younger pts with AML in CR1. However, the toxicity of this approach in older pts is prohibitive. A reduced intensity conditioning (RIC) regimen may mitigate the risk of early toxicity and while early results in older AML pts have been encouraging and suggest disease free survival (DFS) rates above 30% at 3 yrs (Farag et al, Biol Blood Marrow Transplant 2011), most data are retrospective and pts have not been treated uniformly. We therefore sought to determine the effectiveness of a uniform RIC regimen given to older pts with AML in CR1 on a prospective multi-center phase II trial conducted by the Alliance (formerly Cancer and Leukemia Group B (CALGB)) and the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). The study, activated in 2004, was initially limited to recipients of a matched related donor (MRD) graft but was amended in 2006 to include matched unrelated donor grafts (URD). The primary endpoint of the study was 2-year DFS. We hypothesized that DFS at 2-years would exceed 20% and powered the study to detect a 2-year DFS probability of 35% for URD recipients. We focused the primary analysis on URD recipients since the majority of older pts require an URD graft. Eligible pts were from 60–74 years old inclusive, had AML in CR1 following induction chemotherapy, availability of a 6/6 MRD or 8/8 URD, and absence of significant end-organ damage prior to transplantation. Adverse events (AE) were initially recorded according to NCI-CTCAE v3.0, amended to v4.0 in 10/2010. Accrual was completed in 12/2011. 132 pts were registered at 21 centers and 123 transplanted (MRD (47%); URD (53%). All donor grafts were mobilized and collected following G-CSF (PBSC). The median age of pts was 65 (range 60–74) and 76 pts (62%) were male. At diagnosis, 67% had an intermediate risk karyotype, 20% adverse risk, <1% favorable, and in 11% data were missing. More than 90% achieved CR following standard “7+3” based induction. CR1 was achieved after 1 (59%) or 2 (41%) induction cycles. Consolidation therapy was administered for one (50%) or two (24%) cycles and 17% received no consolidation with data missing in 9%. All but the initial 8 MRD recipients (who received fludarabine and busulfan alone) were conditioned with the same regimen containing fludarabine (30mg/m2/day × 5), busulfan (6.4mg/kg IV total dose), and antithymocyte globulin (ATG; thymoglobulin) (7.5mg/kg total dose). Only one case of primary graft failure was reported. With a median follow-up of 3.3 yrs, the results in the 123 transplanted pts are depicted below:EventCumulative incidence at 100 days* or 2yrs†95% CIAcute GVHD 2-49.4%*4.1–15%Acute GVHD 3-43.4%*1.2–6.7%Chronic GVHD26%†17–34%Relapse47%†37–57%Treatment related mortality (TRM)14%†7.2–21%EventProbability at 2 yrs95% CIDFS39%30–50%DFS URD only38%26–55%Overall survival (all pts)46%36–57%The rates of both acute and chronic GVHD as well as TRM were relatively low. There were 81 grade 3–5 non-hematologic AE recorded, including 7 grade 5 (4 infections, 1 each cardiac, pulmonary, and second malignancy). Relapse was the most common cause of death. In conclusion, the results of this first prospective US cooperative group trial conducted in a homogeneously treated group of older AML patients in CR1 demonstrate the feasibility and effectiveness of RIC allografting using MRD or URD PBSC grafts. DFS appears better following a RIC allograft compared to results achieved historically after conventional therapies, warranting prospective comparison in pts with contemporary cytogenetic and molecular disease characterization. Future research should also focus on preventing disease relapse after RIC allografting in this population. Disclosures:Devine:Sanofi: Honoraria, Research Funding. Off Label Use: Antithymocyte globulin for GVHD prophylaxis is included in the abstract. Vij:Millennium: Speakers Bureau. Shea:Otsuka: Research Funding.

Equivalent Outcome Between Older Siblings and Unrelated Donors After Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation for Patients Older Than 50 Years with Acute Myeloid Leukemia in First Complete Remission: A Report From the ALWP of EBMT

AbstractAbstract ▪961▪This icon denotes a clinically relevant abstract Background:Current data indicates that allogeneic hematopoietic stem cell transplantation (HSCT) provides identical long-term survival for patients (pts) with acute myeloid leukemia (AML) receiving grafts from matched 8/8 unrelated donor (MUD) or matched sibling donor (MSD) after reduced intensity conditioning (RIC) regimen. Given those results, one may question the requirement for an “older” MSD when a healthy younger MUD is available. This study assessed the impact of older age of MSD on outcomes post-HSCT for pts older than 50 years with AML in first complete remission (CR1) transplanted after a RIC regimen. Patients and methods:From January 2000 to December 2010, this retrospective multi-center study included 1102 pts with AML in CR1 who received PBSC after a RIC regimen, either from MSD (n=854) or from 8/8 HLA MUD (n=248). Conditioning regimen was fludarabine-based in 95% of the pts and Graft versus Host Disease (GvHD) prophylaxis consisted of cyclosporine plus MMF in 42% of cases. To address the role of donor age in our population, 3 groups of pts were defined: pts who were transplanted from a MUD (“MUD group”), pts who received their graft from a sibling aged less than 60 years old (“MSD<60 group”) and pts who were transplanted from a sibling aged of 60 years old or more (“MSD360 group”). Results:Patient characteristics were similar between the 3 groups for gender, disease distribution (FAB classification) and cytogenetic risks (MRC classification). Recipients were younger in the MSD<60 group (57 years versus 60 and 61 years for MUD and MSD360, respectively, p<0.001). Donors were younger for MUD (median age 35 years versus 53 years and 64 years for MSD<60 and MSD360 respectively, p<0.001). In the MUD group, pts were transplanted more recently (2009 versus 2006 and 2007 for MSD<60 and MSD360 respectively, p<0.001), with a longer time interval between diagnosis and HSCT (184 days versus 154 days and 151 days for MSD<60 and MSD360 respectively, p<0.001) and the conditioning regimen included more ATG (p< 0.0001). The median follow-up was 24 months (range, 2–122) for MUD, 42 months (range, 1.5–140) for MSD<60 and 33 months (range, 1–129) for MSD360. During evolution, the cumulative incidence (CI) of acute GvHD was 28% in MUD versus 20% and 17% in MSD<60 and MSD360, respectively (p=0.006) while the CI of chronic GvHD at 2 years was about 50% in each group (p=0.93). CI of treatment related mortality (TRM) and relapse as well as leukemia free survival (LFS) and overall survival (OS) were not different at 2 years between the 3 groups (Table 1). In multivariate analysis, TRM was decreased in pts who received ATG in the conditioning regimen (HR: 0.62; 95%CI 0.41–0.95; p=0.03). A longer interval between AML diagnosis and CR1 (>median) was the only factor associated with relapse (Hazard ratio - HR: 1.35; 95%CI 1.05–1.74; p=0.02). Two independent factors were associated with worse LFS: a longer delay between AML diagnosis and CR1 (HR: 1.34; 95%CI 1.09–1.64; p=0.01) and CMV donor seropositivity (HR: 1.28; 95%CI 1.02–1.6; p=0.04). For pts alive after 2 years post HSCT (n=454), a significant higher rate of TRM was found in pts transplanted from MUD compared with the 2 other groups (Landmark analysis, Table 2). Conclusion:These data suggest equivalence of outcome using MUD, MSD<60 or MSD360 in pts older than 50 years with AML in CR1 transplanted after a RIC regimen. Until prospective studies are completed, this study supports the recommendation to consider HLA-identical donors for HSCT even after 60 years of age (if eligible for donation) prior to younger 8/8 MUD for pts with AML older than 50 years in CR1 after a RIC regimen.Table 1:2-years Cumulative Incidences of TRM, relapse, LFS and OSTRMRelapseLFSOSMUD15±229±355±356±3Sib and donor age <60 years14±130±252±263±2Sib and donor age 36015±233±352±357±3Pvalue0.460.560.740.06Table 2:Landmark analysis after 2 yearsMUD (n=84)TRMRelapseLFSOS21±85±372±974±9Sib and donor age <60 (n=252)5±211±283±390±2Sib and donor age 360 (n=96)7±316±477580±5Pvalue0.0090.370.740.06 Disclosures:No relevant conflicts of interest to declare.