Leukemia In First Remission Research Articles

Impact of Chronic Graft-Versus-Host Disease on Long-Term Outcomes of Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation for Adults with High-Risk Acute Lymphoblastic Leukemia in First Remission

Background : The role of reduced-intensity conditioning allogeneic hematopoietic cell transplantation (RIC-HCT) in adult acute lymphoblastic leukemia (ALL) remains unclear because the interpretation of transplantation outcome is mainly limited by the small sample size, short follow-up duration, various regimens for conditioning and graft-versus-host disease (GVHD) prophylaxis, and the heterogeneity of the criteria used to select patients for RIC-HCT. Previously, we conducted a phase 2 trial of RIC-HCT in adults with high-risk ALL who were ineligible for myeloablative conditioning and showed the potential role of this strategy, especially in patients in first complete remission (CR1). Here, we report the long-term outcomes of RIC-HCT by analyzing 122 consecutive adults with high-risk ALL in CR1, particularly focusing on the prognostic relevance of chronic GVHD.Methods: During the period between 2000 and 2014, 122 patients in CR1 (median age, 52 years [range, 15-65 years]; 54 Ph-negative ALL and 68 Ph-positive ALL) were given an identical RIC regimen consisting of fludarabine (150 mg/m2 in total) and melphalan (140 mg/m2in total). The indications for RIC-HCT were advanced age (≥50 years; n=79; 64.8%) and comorbid conditions (n=43; 35.2%). Graft sources were peripheral blood stem cells (n=118; 66 matched sibling donor, 23 matched unrelated donor, 29 mismatched unrelated donor) and bone marrow (n=4; 1 matched sibling donor, 1 matched unrelated donor, 2 mismatched unrelated donor). The median time to transplantation was 155.5 days (range, 103-291 days). GVHD prophylaxis was attempted by administering calcineurin inhibitors (cyclosporine for sibling donor transplants, tacrolimus for unrelated donor transplants) plus methotrexate. Antithymocyte globulin was administered to the patients who received mismatched unrelated donor grafts. If residual leukemia was detected in the absence of GVHD at 3 months after transplantation, calcineurin inhibitors were rapidly discontinued.Results: The median time for neutrophil and platelet recovery was 12 days (range, 8-30 days) and 13 days (range, 5-60 days) after RIC-HCT. Sixty-two patients developed acute GVHD (53 grade II, 5 grade III, 4 grade IV). The cumulative incidence of acute GVHD at 1 year was 50.8% (42.6% for Ph-negative and 57.4% for Ph-positive, P=0.152). Except for 11 patients with early deaths within 100 days, 77 developed chronic GVHD (30 mild, 29 moderate, 18 severe), resulting in a 5-year cumulative incidence of 63.6% (69.1% for Ph-negative ALL and 58.8% for Ph-positive ALL, P=0.319). The median time to onset of chronic GVHD was 140 days (range, 37-843 days) after transplantation. Cytomegalovirus reactivation >10,000 copies/mL was observed in 40.2% (44.4% for Ph-negative ALL and 36.8% for Ph-positive ALL, P=0.447). After a median follow-up duration of 57.9 months (range, 17.7-206.8 months), the 5-year cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 27.5% (23.9% for Ph-negative ALL and 30.2% for Ph-positive ALL) and 19.0% (17.4% for Ph-negative ALL and 20.3% for Ph-positive ALL), respectively, and the 5-year disease-free survival (DFS) and overall survival (OS) rates were 53.5% (58.4% for Ph-negative ALL and 49.7% for Ph-positive ALL) and 59.8% (60.2% for Ph-negative ALL and 59.3% for Ph-positive ALL). In multivariate analysis, the presence of chronic GVHD lowered CIR (HR, 0.23; 95% CI, 0.10-0.48; P<0.001), but severe chronic GVHD increased NRM (HR, 8.76; 95% CI, 3.39-22.6; P<0.001). Thus, the presence of mild to moderate chronic GVHD was closely related to better outcomes in terms of DFS (HR, 0.45; 95% CI, 0.32-0.64; P<0.001) and OS (HR, 0.44; 95% CI, 0.30-0.64; P<0.001) in all patients as well as in both subgroups of patients. In Ph-positive ALL subgroup of patients, patients without achievement of major molecular response until the time of transplantation had also significantly higher CIR (HR, 7.42; 95% CI, 3.04-18.10; P<0.001) and poorer DFS (HR, 3.47; 95% CI, 1.48-8.14; P=0.004) and OS (HR, 2.58; 95% CI, 1.03-6.47; P=0.043).Conclusion: Our long-term follow-up data with a uniform treatment strategy suggest that RIC-HCT is a valid alternative choice for providing a long-term disease control for adult high-risk ALL patients in CR1. Minimal residual disease-based treatment strategies to reduce leukemia cell burden before HCT and to enhance the graft-versus-leukemia effect are needed in the future. DisclosuresKim:ILYANG: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Lee:Alexion Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Comparable Long-Term Outcomes of Reduced-Intensity and Myeloablative Conditioning Allogeneic Hematopoietic Cell Transplantation By Minimal Residual Disease Kinetics during the Tyrosine Kinase Inhibitor-Based Chemotherapy Courses in Adults with Philadelphia-Chromosome Positive Acute Lymphoblastic Leukemia in First Remission

Background: The use of tyrosine kinase inhibitor (TKI)-based chemotherapy has demonstrated improved complete remission (CR) rates and increased applicability to allogeneic hematopoietic cell transplantation (HCT), thus allowing better survival in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL). However, the sensitivity of Ph-positive ALL to reduced-intensity conditioning (RIC) versus myeloablative conditioning (MAC) by minimal residual disease (MRD) kinetics is not well established. Previously, we have confirmed that monitoring MRD kinetics is very important to predict long-term outcomes. Here, we examined a cohort of patients with Ph-positive ALL in CR1 and tried to compare the long-term outcomes of RIC-HCT vs MAC-HCT according to pre-HCT MRD kinetics.Methods: During the period between 2000 and 2014, 173 adults (median age, 39 years [range, 16-65 years]) with Ph-positive ALL were included in this analysis. All patients received allogeneic HCT (68 RIC [fludarabine 150mg/m2 + melphalan 140mg/m2] and 105 MAC [total body irradiation 13.2Gy + cyclophosphamide 120mg/kg]) in CR1 following two courses of first-line TKI (138 imatinib and 35 dasatinib)-based chemotherapy and had data on prospectively determined quantitative MRD kinetics. A total of 52 patients were excluded because of >CR1 pre-HCT status (n=26), transplants receiving umbilical cord blood grafts (n=14), and no TKI use before HCT (n=12). All but one RIC transplants received peripheral blood stem cells as a graft source (40 matched sibling donor, 11 matched unrelated donor, 17 mismatched unrelated donor), while MAC transplants used either bone marrow (n=73; 57 matched sibling donor, 8 matched unrelated donor, 6 mismatched unrelated donor) or peripheral blood stem cells (n=32; 2 matched sibling donor, 20 matched unrelated donor, 10 mismatched unrelated donor). The median time to transplant was 154 days (range, 119-291 days) in RIC transplants and 141 days (range, 112-280 days) in MAC transplants, respectively. Calcineurin inhibitors (cyclosporine for sibling donor transplants, tacrolimus for unrelated donor transplants) and methotrexate was used for graft-versus-host disease (GVHD) prophylaxis and antithymocyte globulin was administered to the patients who received mismatched unrelated donor grafts. If residual leukemia was detected in the absence of GVHD at 3 months after transplantation, calcineurin inhibitors were rapidly discontinued. MRD monitoring was centrally evaluated by real-time quantitative PCR (4.5 log sensitivity) through handling of bone marrow samples.Results: After a median follow-up of 70.4 months (range, 16.0-176.8 mo), RIC regimen showed comparable 5-year cumulative incidence of relapse (CIR; 30.2% vs 27.9%, P=0.750), non-relapse mortality (NRM; 20.3% vs 15.5%, P=0.318), disease-free survival (DFS; 49.7% vs 56.6%, P=0.296), and overall survival (OS; 59.3% vs 62.1%, P=0.540) compared to MAC regimen. We further analyzed the impact of conditioning intensity on CIR and DFS according to MRD kinetics. Based on the MRD kinetics during the pre-HCT TKI-based chemotherapy courses, we classified patients into 3 subgroups: early-stable molecular responders (EMR, n=59), late molecular responders (LMR, n=57), and poor molecular responders (PMR, n=53). In all MRD-based subgroups of patients, no significant difference in CIR (EMR: 16.3% vs 6.2%, P=0.280; LMR: 10.5% vs 21.4%, P=0.334; PMR: 63.6% vs 59.4%, P=0.372) or DFS (EMR: 68.1% vs 78.1%, P=0.381; LMR: 49.6% vs 59.5%, P=0.369; PMR: 27.3% vs 34.2%, P=0.250) was observed between RIC and MAC. In multivariate analysis, LMR (HR, 2.36; 95% CI, 0.81-6.86; P=0.114) or PMR (HR, 9.05; 95% CI, 3.40-24.1; P<0.001) had higher relapse risk than EMR. Consequently, compared with EMR, LMR (HR, 2.02; 95% CI, 1.01-4.02; P=0.046) or PMR (HR, 3.79; 95% CI, 1.92-7.50; P<0.001) had poorer DFS. The presence of chronic GVHD, especially mild to moderate grade, was also independently associated with better DFS (HR, 0.28; 95% CI, 0.14-0.53; P<0.001). In addition, patients older than 40 years had higher risk of treatment failure in terms of NRM (HR, 4.25; 95% CI, 1.69-10.6; P=0.002).Conclusion:RIC-HCT showed comparable long-term outcomes to MAC-HCT in all MRD-based subgroups of patients with Ph-positive ALL in CR1. Our data suggest that RIC-HCT is worthy of further investigation in prospective trials of adult Ph-positive ALL. DisclosuresKim:ILYANG: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Autologous stem cell transplantation for adult acute myelocytic leukemia in first remission-Better outcomes after busulfan and melphalan compared with busulfan and cyclophosphamide: A retrospective study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT).

Autologous stem cell transplantation (ASCT) for adult acute myelogenous leukemia (AML) is a valid therapeutic option for patients with good-risk and intermediate-risk disease. The authors used the registry of the European Society for Blood and Marrow Transplantation to compare combined busulfan and melphalan (BUMEL) with combined busulfan and cyclophosphamide (BUCY) before transplantation. From 2005 to 2013, 853 patients with available cytogenetics underwent ASCT in first remission, including 257 after receiving BUMEL and 596 after receiving BUCY. The proportion of patients with good-risk AML was lower in those who received BUMEL (14% vs 20%; P = .02). More patients who received BUMEL underwent autograft in molecular remission (89% vs 78%; P = .02). Three years after transplantation, the relapse incidence (RI) was 48.7%, the leukemia-free survival (LFS) rate was 47.7%, the overall survival (OS) rate was 66.2%, and the nonrelapse mortality (NRM) rate was 3.6%. Patients who underwent an autograft after receiving BUMEL fared better than those who underwent an autograft after receiving BUCY with a lower RI (39.5% vs 52.2%; hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.49-0.87; P = .003) a better LFS (55.4% vs 44.6%; HR, 0.69; 95% CI, 0.53-0.89; P = .005), and a better OS (73.8% vs 63%; HR, 0.62; 95% CI, 0.47-0.82; P = .0007). There was no difference in the NRM rate (BUMEL vs BUCY, 4.5% vs 3.2%, respectively). Among 74 patients in the BUMEL group and 187 in the BUCY group who underwent autograft in molecular remission, the RI was 30% versus 51%, respectively (univariate analysis; P = .01), and the LFS rate was 66% versus 47%, respectively (univariate analysis; P = .03). In patients with AML in first complete remission who undergo ASCT, the BUMEL combination is a better preparative regimen. Cancer 2017;123:824-31. © 2016 American Cancer Society.

Allogeneic transplantation is not superior to chemotherapy in most patients over 40years of age with Philadelphia-negative acute lymphoblastic leukemia in first remission.

Survival of patients ≥40years of age with Philadelphia-negative acute lymphoblastic leukemia (ALL) remains poor with current therapeutic approaches. It is unknown whether allogeneic hematopoietic stem-cell transplantation (HSCT) in first remission confers a survival benefit compared to a chemotherapy-only approach. We retrospectively compared the outcome of patients >40years treated with HSCT or chemotherapy alone in first remission (n=40 in each cohort). Three-year overall survival (OS) and disease-free survival (DFS) were not significantly different between the chemotherapy-only and HSCT groups (OS, 46% [31-68] vs. 40% [27-59], P=0.35; DFS, 31% [18-52] vs. 40% [27-59], P=0.98). The 3-year cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 61% [41-76] and 9% [2-21] for the chemotherapy-only group and 28% [15-43] and 32% [17-47] for the transplant group (CIR, P=0.011; NRM, P=0.014). Allogeneic transplantation for patients ≥40years with Ph-negative ALL in first remission is associated with a lower CIR, but this benefit is offset by considerable NRM as compared with chemotherapy-only approach. HSCT may be beneficial in patients with high-risk disease features. Am. J. Hematol. 91:793-799, 2016. © 2016 Wiley Periodicals, Inc.

Low Socioeconomic Status, Adverse Gene Expression Profiles, and Clinical Outcomes in Hematopoietic Stem Cell Transplant Recipients.

Low socioeconomic status (SES) is associated with adverse outcomes among unrelated donor hematopoietic stem cell transplant (HCT) recipients, but the biologic mechanisms contributing to this health disparity are poorly understood. Therefore, we examined whether social environment affects expression of a stress-related gene expression profile known as the conserved transcriptional response to adversity (CTRA), which involves upregulation of proinflammatory genes and downregulation of genes involved in type I IFN response and antibody synthesis. We compared pretransplant leukocyte CTRA gene expression between a group of 78 high versus low SES recipients of unrelated donor HCT for acute myelogenous leukemia in first remission. Post hoc exploratory analyses also evaluated whether CTRA gene expression was associated with poor clinical outcomes. Peripheral blood mononuclear cells collected pre-HCT from low SES individuals demonstrated significant CTRA upregulation compared with matched HCT recipients of high SES. Promoter-based bioinformatics implicated distinct patterns of transcription factor activity, including increased CREB signaling and decreased IRF and GR signaling. High expression of the CTRA gene profile was also associated with increased relapse risk and decreased leukemia-free survival. Low SES is associated with increased expression of the CTRA gene profile, and CTRA gene expression is associated with adverse HCT clinical outcomes. These findings provide a biologic framework within which to understand how social environmental conditions may influence immune function and clinical outcomes in allogeneic HCT.

Autologous Stem Cell Transplantation for Adult Acute Myelocytic Leukemia in First Remission: Better Outcome Following Busulfan and Melphalan Compared to Busulfan and Cyclophosphamide : A Retrospective Study from the Acute Leukemia Working Party of the EBMT

RationaleAutologous stem cell transplantation for adult acutemyelogenousleukemia (AML) is a therapeutic option for good and intermediate risk patients. New compounds and new formulations in conjunction with pre andpost transplant targeted therapy may improve outcome.A recent EBMT retrospective survey investigating on Busulfan administered IV (Nagler A et al:Haematologica. 2014 ) pre autologous stem cell transplantation (ASCT) suggested that the combination of Busulfan and High dose Melphalan (BUMEL) was associated with the best overall survival. To address this question, we compared this regimen with the historical Busulfanand Cyclophosphamide (BUCY) association.MethodsEligibilitycriteria consistedof all adult patients (age >18 years) with AMLautograftedin CR1, following a preparative regimen consisting of either BUCY or BUMEL, reported to the EBMT registry in the period from January 2005 to December 2013. The doses of Busulfan were either oral at 16 mg/kg over 4 days or IV at 12.8 mg/kg over 4 days. High dose Melphalan was 140mg/m². The data came from 231 centers 23 ofwhich usedboth regimens. The relationships between outcomes and patient, disease and transplant characteristics was evaluated in multivariate analyses using the Cox model.Results1120 patients received BUCY and 436 BUMEL prior to autografting in first remission. Patients receiving BUMEL were older (median 52 years versus 50 years, p=0.01) with less good risk diseases by cytogenetics (16% versus 28%, p=0.001). They were autografted with a longer interval from CR1 to autografting (120 days versus 104 days, p=0.001) and they were more frequently in a negative minimal residual disease (MRD) status by molecular biology (89% versus 82%, p= 0.03).The nature of the pretransplant regimen interacted with the interval from diagnosis to autografting on both relapse incidence (p=0.005) and leukemia free survival (p= 0.02): the outcome post BUMEL was superior to BUCY only in patients transplanted within less than six months post diagnosis. In these patients, following BUMEL and BUCY respectively, the RI was 35%versus 50.6% (p< 10-3), the LFS 61.1% versus 46.2% (p< 10-3) and the OS 79.4% versus 64.8% (p= 0.003). There was no difference for NRM.When considering only patients autografted at the time when MRD detection was negative, the LFS at two years was 75.8% for 134 patients receiving BUMEL and 58.6% in the 371 patients receiving BUCY, with no significant difference (p= 0.1). The major cause of death in the two groups was leukemia recurrence.ConclusionWe conclude that the BUMEL combination pre ASCT in AML CR1 is superior to BUCY when the transplant is performed less than 6 months after diagnosis. These registry data should be confirmed in a well designed two arm study assessing the role of ASCT in good risk and possibly intermediate -1 risk adult patients with AML.TablepHR95% CINRMBUMEL vs BUCY0.4501.3760.5993.16Age atTx/ 10years0.0011.0641.0251.10Time from diagnosis to Transplant.0.9000.9990.9841.01Cytogenetics :Intermediatevs good0.6100.7090.1912.63Poor versus good0.7100.7080.1124.46Missing0.4200.5910.1642.11centre (frailty)0.360RIBUMEL vs BUCY0.0010.6020.4450.816Age at Transplant / 10years0.0051.0121.0031.020Time from diagnosis to Transplant:0.7201.0000.9961.004Cytogenetics : Intermediatevs good0.5101.1450.7641.714Poor versus good0.0311.7991.0553.067Missingversus good0.4801.1500.7791.699centre (frailty)0.110OSBUMEL vs BUCY0.0020.6140.4490.841Age at Transplant / 10years<10-41.0251.0141.036Time from diagnosis toransplant0.940.9990.9951.004Intermediatevs good0.881.0360.6491.653Poor versus good0.111.6320.9012.956Missingversus good0.811.0580.6721.665centre (frailty)0.29LFSBUMEL vs BUCY0.0020.6490.4900.858Age at Transplant / 10years<10-41.0151.0061.023Time from diagnosis to Transplant0.7401.0000.9961.004Cytogenetics : Intermediatevs good0.5901.1100.7551.630Poor vs good0.0461.6791.0082.796Missingversus good0.5901.1060.7631.604centre (frailty)0.170Multivariate analyses of prognostic factors in patients autografted within 6 months [Display omitted] DisclosuresNemet:Celgene: Honoraria; Pliva: Honoraria; Amgen: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria; Janssen: Honoraria. Mohty:Janssen: Honoraria; Celgene: Honoraria. Nagler:Biokine LTD: Consultancy.

Cytomegalovirus (CMV) Serostatus: High Importance of Choosing Seropositive Donors for Seropositive Patients When Using Rabbit Antithymocyte Globulin (ATG)

Introduction: In published studies that included mostly hematopoietic cell transplants (HCTs) not using in vivo T cell depletion by ATG, there is a substantial survival difference between D-R- and D+R- patients, and a very small or no survival difference between D-R+ and D+R+ patients. We set out to determine the impact of donor CMV serostatus on survival after HCTs using ATG.Methods: A total of 919 patients underwent myeloablative HCT for hematologic malignancies in Alberta between 1999 and 2014, with a uniform graft versus host disease (GVHD) prophylaxis using ATG (4.5 mg/kg given between day -2 and 0) in addition to methotrexate and cyclosporine. Monitoring for CMV reactivation was performed until at least day 100 after transplant using pp65 antigenemia (before 2008) or CMV DNAemia by quantitative polymerase chain reaction (since 2008). Preemptive therapy typically with ganciclovir was started whenever pp65 antigenemia exceeded 10 to 20 positive cells/200,000 granulocytes or CMV DNAemia exceeded 25,000 IU/mL plasma. Significance of survival difference between patient groups was tested using Cox proportional hazards analysis. Significance of difference in nonrelapse mortality (NRM) or cumulative incidence of relapse (CIR) was tested using Fine-Gray analysis (nonrelapse death was a competing risk of relapse and vice versa, in addition to graft failure and second malignancy). In all analyses, covariates included patient age (>45 vs ≤45), disease stage (acute leukemia in first remission, chronic myeloid leukemia in first chronic phase and myelodysplasia with <5% marrow blasts were considered good risk, all others poor risk), graft type (marrow vs PBSCs) and donor type (human leucocyte antigen [HLA] matched sibling vs other [typically matched unrelated]).Results: D-R- and D+R- patients had similar survival (no significant difference) (blue vs orange curve, figure 1). D-R+ patients had a substantially lower survival than D+R+ patients with an estimated 5 year survival of 41% versus 60% respectively (Hazard Ratio [HR], 1.6; P = 0.001; 95% confidence interval[CI], 1.22-2.09) (red vs green curve, figure 1). This was due to higher NRM (sub hazard ratio [SHR], 1.76; P = 0.003; 95% CI, 1.212-2.58), not CIR. This appeared to be due to higher GVHD-associated mortality. We then compared D-R+ HLA matched sibling transplants with D+R+ HLA matched unrelated donor transplants to assess whether for a CMV seropositive patient with a CMV seronegative HLA matched sibling, search for a CMV seropositive HLA matched unrelated donor could be justified. D-R+ HLA matched sibling transplant recipients had a substantially lower survival than D+R+ 8/8 HLA allele matched unrelated donor transplant recipients with an estimated 5 year survival of 45% versus 66% respectively (HR, 1.7, P = 0.01, 95% CI, 1.10-2.89) (green vs orange curve, figure 2). This suggests that in the scenario of a seropositive patient with a seronegative matched sibling, unrelated donor search is justified.Conclusion: Contrary to recommendations for HCTs not using ATG, choosing a seronegative donor for a seronegative patient is unimportant, whereas choosing a seropositive donor for a seropositive patient is very important (~20% absolute 5 year survival gain). Even if a seronegative HLA matched sibling donor is available for a seropositive patient, it is better to select a seropositive HLA matched unrelated donor. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Comparison of the efficacy of chemotherapy and allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia in first remission in adults

The aim of the study was to compare the efficacy of allogeneic hematopoietic stem cell transplantation (alloHSCT) and chemotherapy (CT) of acute myeloid leukemia (AML) in first remission (CR1), to identify factors influencing the results. We compare the efficacy alloHSCT in CR1 (n = 70) and CT (n = 52). Patients were stratified by age, the level of leucocytes, the origin of AML, cytogenetic risk group and response to induction CT. Five-years overall and disease-free survival (OS and DFS) were higher in the group alloHSCT (67 and 65 % vs 46 and 30 % (p = 0.02 and p = 0.001)). Benefits of DFS after alloHSCT was in standard and high-risk cytogenetic groups (78 % versus 29 % (p = 0.001), and 34 % vs 17 % (p = 0.007)). The risk of relapse (RR) was 24 % in patients after alloHSCT vs. 57 % for CT (p = 0.003). Comparing the RR after alloHSCT and CT depending on the cytogenetic risk groups: standard (HR0.2(CI95 %0.07 - 0.56) p = 0.002), and high (HR0.27(CI95 %0.08-0.86) p = 0.03). Additional factors affect the RR were the origin of AML (de novo) (HR0.47 (CI95 %0.3-0.74) p = 0.001), the hyperleukocytosis (HR1.91 (CI95 %1.09 - 3.32) p = 0.02), and no remission after the first course CT (HR3.32(CI95 %1.57-7.0) p = 0.002). The efficacy of alloHSCT compared with CT is higher both in standard and high-risk cytogenetic group.

Using multiple timescale models for the evaluation of a time-dependent treatment.

In survival analysis, the absolute measure of cumulative risk provided by the Kaplan-Meier estimator is still the most used quantity for its easy calculation and direct interpretability. However, for describing the survival after an intervention that may occur at different times from baseline observation, the Kaplan-Meier estimator generally yields to biased results if intervention is considered as fixed at baseline. The main focus of the present paper is to extend the use of a multiple timescale model in the presence of a time dependent intervention. The aim is to obtain 1) an estimate of treatment effect in terms of hazard ratios by flexible modeling, 2) a valid prediction tool, i.e. estimate of prognosis for a patient who changes treatment later in time, and 3) an appropriate graphical representation of survival in the presence of a time dependent treatment change, accounting for different timescales. We will show the advantages of this approach on the comparison of chemotherapy versus transplant in children with high-risk acute lymphoblastic leukemia in first remission. We considered a model with two timescales that accounts for the change in treatment at different times in the disease course. An alternative approach to survival estimates is also proposed which has some advantages over the traditional landmark approach: it uses all the data available to plot survival from the date of remission, it avoids the arbitrary choice of a landmark time and explicitly models the change in hazard due to transplant.

Comparable outcomes post allogeneic hematopoietic cell transplant for patients with de novo or secondary acute myeloid leukemia in first remission.

Secondary AML (sAML) has a poor prognosis with conventional chemotherapy alone. Allogeneic hematopoietic cell transplantation (HCT) is beneficial for high-risk AML. Data comparing outcomes of transplants for patients with de novo and sAML are limited. We compared outcomes of patients transplanted for de novo and sAML in first complete remission and investigated the effect of age, HCT comorbidity index (HCT-CI) and karyotype in both groups. A total of 264 patients with de novo (n=180) and sAML (n=84) underwent allogeneic HCT between 1999 and 2013. Median age at transplant was 51 years (range 18-71), median follow-up of survivors was 77 months. Evaluation of all patients demonstrated no significant difference between de novo and sAML for overall survival (P=0.18), leukemia-free survival (P=0.17), cumulative incidence of relapse (P=0.51) and non-relapse mortality (P=0.42). Multivariable and propensity score analyses confirmed the comparable outcomes between de novo and sAML post transplant. Although sAML demonstrates outcomes inferior to de novo AML treated with chemotherapy alone, outcomes following allogeneic HCT are comparable between the two groups.

Post-Remission Treatment with Allogeneic Stem Cell Transplantation Improves Outcome in Patients Aged 60 Years and Older with Acute Myeloid Leukemia in First Remission

While allogeneic hematopoietic stem cell transplantation (alloHSCT) has extensively been studied in patients with AML <60 years of age, AML predominantly affects older individuals (median age at diagnosis of 71 years). The majority of older patients receiving intensive induction treatment may obtain a first complete remission (CR1), but the probability of relapse is very high necessitating effective post-remission treatment (PRT). AlloHSCT is the most effective PRT to prevent relapse, although non-relapse mortality (NRM) may compromise that beneficial effect, especially in the elderly. The development of reduced intensity conditioning (RIC) regimens, however, has enabled the application of alloHSCT in older patients with acceptable NRM. In the present study, we set out to compare alloHSCT following RIC with other PRTs including no further chemotherapy by time-dependent analysis in patients with AML aged 60 years and older.A total number of 640 patients with newly diagnosed AML were included, with a median age of 66 years, who participated in consecutive, prospective HOVON-SAKK phase II/III trials (AML42/42A, AML43, AML81, and AML92) between May 2001 and February 2010 and who obtained CR1 after induction chemotherapy. PRT consisted of RIC alloHSCT (n=97), gemtuzumab ozogamicin (n=110), chemotherapy (n=38), autologous HSCT (autoHSCT) (n=23), or no further treatment (n=372). RIC regimens contained either busulfan and fludarabine, or 2.0 Gy total body irradiation preceded by fludarabine. Endpoints of this study were 5 year overall survival (OS), relapse-free survival (RFS), relapse and non-relapse mortality (NRM) measured from start of consolidation. Patients were classified by leukemia risk, based on the latest European Leukemia NET (ELN) risk classification. To perform a time-dependent statistical analysis of alloHSCT versus non-alloHSCT, a multivariable cox regression model with time-dependent covariates autoHSCT and alloHSCT was applied with adjustment for the different types of non-alloHSCT treatment, leukemia risk, white blood cell count at diagnosis, late CR, age, sex, and year of consolidation.Recipients of alloHSCT were significantly younger as compared to patients who were not consolidated with alloHSCT (64 (range: 60-74) versus 67 (range: 60-82) years, respectively, p<0.001). Leukemia risk, white blood cell count at diagnosis, karyotyping, and CR reached after first or second cycle of chemotherapy, was not significantly different between the two groups. A trend towards improved OS was found for RIC alloHSCT recipients as compared to patients receiving no alloHSCT (35±5% versus 23±2% at 5 years, respectively, p=0.09), while OS was significantly improved in patients with adverse risk AML receiving an alloHSCT (34±10% versus 8±3% at 5 years, p=0.002). Recipients of RIC alloHSCT showed improved relapse-free survival (RFS), as compared to non-transplant approaches (32±5% versus 17±2% at 5 years, p=0.02), which effect was similarly exerted among intermediate and adverse risk AMLs. Following multivariable analysis with adjustment for covariates, RIC AlloHSCT was associated with better OS (HR 0.68, p=0.006), better RFS (HR 0.59, p<0.001), and less relapse (HR 0.44, p<0.001) as compared to non-transplant approaches (Figure 1). The cumulative incidence of NRM was 18±4% in the present study, demonstrating the feasibility of RIC alloHSCT in elderly patients. In the non-transplanted patients the estimated cumulative incidence of NRM was 10±1%.Collectively, these results indicate that RIC alloHSCT significantly improves survival in elderly patients with AML in CR1 who are eligible for PRT upon achieving remission following induction chemotherapy. Subgroup analysis showed that, similar to results in younger patients, alloHSCT was not associated with better outcome in favorable risk patients, but both OS and RFS appeared improved in intermediate and poor risk patients. Our findings suggest that RIC alloHSCT is a feasible and effective PRT in elderly patients. Future studies including comorbidities and geriatric assessment may more reliably give insight into eligibility criteria other than age for alloHSCT in elderly patients. Our results underscore the importance of a prospective randomized study such as currently is being performed in Europe (http://clinicaltrials.gov/show/NCT00766779). [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

PCN47 - Budget Impact Model of Ceplene® As Maintenance Therapy in Adult Patients with Acute Myeloid Leukemia in First Remission

PCN47 - Budget Impact Model of Ceplene® As Maintenance Therapy in Adult Patients with Acute Myeloid Leukemia in First Remission

Childhood high-risk acute lymphoblastic leukemia in first remission: results after chemotherapy or transplant from the AIEOP ALL 2000 study

AbstractThe outcome of high-risk (HR) acute lymphoblastic leukemia patients enrolled in the AIEOP-BFM ALL 2000 study in Italy is described. HR criteria were minimal residual disease (MRD) levels ≥10−3 at day 78 (MRD-HR), no complete remission (CR) at day 33, t(4;11) translocation, and prednisone poor response (PPR). Treatment (2 years) included protocol I, 3 polychemotherapy blocks, delayed intensification (protocol IIx2 or IIIx3), cranial radiotherapy, and maintenance. A total of 312 HR patients had a 5-year event-free survival (EFS) of 58.9% (standard error [SE] = 2.8) and an overall survival of 68.9% (SE = 2.6). In hierarchical order, EFS was 45.9% (4.4) in 132 MRD-HR patients, 41.2% (11.9) in 17 patients with no CR at day 33, 36.4% (14.5) in 11 patients with t(4;11), and 74.0% (3.6) in 152 HR patients only for PPR. No statistically significant difference was found for disease-free survival in patients with very HR features [MRD-HR, no CR at day 33, t(4;11) translocation], given hematopoietic stem cell transplantation (HSCT) (n = 66) or chemotherapy only (n = 88), after adjusting for waiting time to HSCT (5.7 months). Patients at HR only for PPR have a favorable outcome. MRD-HR is associated with poor outcome despite intensive treatment and/or HSCT and may qualify for innovative therapies. The study was registered at www.clinicaltrials.gov as #NCT00613457.

Prognostic significance of flow cytometric residual disease, dysregulated neutrophils/monocytes, and hematogones in adult acute myeloid leukemia in first remission

Fifty-one consecutive non-M3 acute myeloid leukemia (AML) patients who had achieved morphologic complete remission (mCR) after induction chemotherapy were enrolled in the present study. Three characteristics of bone marrow (BM) composition analyzed by flow cytometry were combined to determine the prognostic impact. A standardized panel of reagents was used to detect residual disease of aberrant myeloid progenitor cells (RD), identify neutrophils/monocytes with dysregulated immunophenotype (dysregulated neutro/mono) and quantify the appearance of CD34(+) B-progenitor-related cluster (hematogones) simultaneously in post-induction BM of adult AML patients. Patients who had detectable RD ≥0.2 % exhibited significantly lower median leukemia-free survival (LFS) than those who did not (13.5 vs. 48.0 months; P = 0.042). Dysregulated neutro/mono abnormalities assessed by this flow cytometric scoring system (FCSS ≥2) predicted shorter LFS (8.0 vs. 39.0 months; P = 0.008). While B-progenitor-related cluster size ≥5 % predicted improved outcome, with longer LFS (not reached vs. 13.5 months; P = 0.023) and better overall survival (not reached vs. 24.0 months; P = 0.027). The proposed RD/dysregulated neutro/mono/hematogones score showed a new risk groups with different LFS in the overall patients (P = 0.0006) as well as in the subgroup of intermediate cytogenetic risk (P = 0.001). The RD/dysregulated neutro/mono/hematogones score assessed by flow cytometry for adult AML in mCR may offer a rapid and practical risk assessment providing better refinement in risk-adapted management after induction chemotherapy.

Is Timing Everything?

Is Timing Everything?

Stem Cell Transplant Versus Chemotherapy in Older Adults with Acute Myelogenous Leukemia In First Remission

▪ IntroductionOptimal therapy for older adults with acute myelogenous leukemia (AML) who achieve remission following induction chemotherapy has not been determined. Options include consolidation chemotherapy (CC) or stem cell transplant (SCT) if an appropriate donor is identified. In order to determine whether SCT improved overall survival (OS) or whether associated toxicity was increased, we performed a retrospective study comparing SCT with CC in this older age group. MethodsAll adult patients ages 60 to 75 years with AML in 1st remission (CR1) who underwent a SCT at MSKCC between 2001 and 2013 were reviewed and compared to age-matched patients with AML who achieved CR1 and received CC. A landmark analysis at 3 months following CR1 was used to compare OS for the 2 patient groups. Only SCT patients transplanted by landmark time were included in the analysis. Overall survival was compared using Kaplan-Meier methodology. ResultsSixty-eight patients were identified for the SCT group. Thirty-two patients were identified for the CC group (Table). Stem cell sources included: peripheral blood (n=63), cord blood (n=4) and bone marrow (n=1). Fifty-six patients received a T cell depleted transplant (32 with ClinMACsTM and 24 with IsolexTM ) and 12 received an unmodified product. Conditioning regimens were busulfan/melphalan/ fludarabine (n=54), melphalan/fludarabine (n=4), cyclophosphamide/fludarabine/thiotepa/ TBI (n=4), fludarabine/busulfan (n=3), busulfan/melphalan (n=2) and thiotepa/fludarabine/TBI (n=1). Donors included matched unrelated (n=28), matched related (n=25), mismatched unrelated (n=11) and mismatched cord blood (n=4). For patients in the CC group, induction chemotherapy included cytarabine in combination with either idarubicin (n=21), daunorubicin (n=10), or mitoxantrone plus etoposide (n=1). Forty-four patients received their transplant by the 3 month landmark and 30 patients in the CC group were alive at the landmark and were included in the OS analysis.Patient Characteristics:SCTCCNumber of patients6832Median age at SCT or CC65 (60-75)65 (60-69)Males/Females41/2718/14Median F/U in mos (range)19 (1-83)22 (11-75)Number of deaths within 100 days of SCT or 1st cycle CC6 (9%)2 (6%) [Display omitted] Deaths in the SCT group included 4 patients from infection, 1 from treatment-related toxicity, and 1 from relapsed disease. The estimated OS at 2 years in the landmark groups were 64% in the SCT group and 42% in the CC group (p=0.04). ConclusionsRecognizing the inherent bias when retrospective studies compare SCT and CC, these data support the use of SCT for older patients with AML in CR1 who have an appropriate donor. Despite the older age, there was a statistically significant better OS with low 100 day mortality for those patients who underwent SCT. Disclosures:No relevant conflicts of interest to declare.

Cost-effectiveness and clinical outcomes of double versus single cord blood transplantation in adults with acute leukemia in France

Double cord blood transplantation extends the use of cord blood to adults for whom a single unit is not available, but the procedure is limited by its cost. To evaluate outcomes and cost-effectiveness of double compared to single cord blood transplantation, we analyzed 134 transplants in adults with acute leukemia in first remission. Transplants were performed in France with reduced intensity or myeloablative conditioning regimens. Costs were estimated from donor search to 1 year after transplantation. A Markov decision analysis model was used to calculate quality-adjusted life-years and cost-effectiveness ratio within 4 years. The overall survival at 2 years after single and double cord blood transplants was 42% versus 62%, respectively (P=0.03), while the leukemia-free-survival was 33% versus 53%, respectively (P=0.03). The relapse rate was 21% after double transplants and 42% after a single transplant (P=0.006). No difference was observed for non-relapse mortality or chronic graft-versus-host-disease. The estimated costs up to 1 year after reduced intensity conditioning for single and double cord blood transplantation were € 165,253 and €191,827, respectively. The corresponding costs after myeloablative conditioning were € 192,566 and € 213,050, respectively. Compared to single transplants, double cord blood transplantation was associated with supplementary costs of € 21,302 and € 32,420 up to 4 years, but with increases in quality-adjusted life-years of 0.616 and 0.484, respectively, and incremental cost-effectiveness ratios of € 34,581 and €66,983 in the myeloablative and reduced intensity conditioning settings, respectively. Our results showed that for adults with acute leukemia in first complete remission in France, double cord transplantation is more cost-effective than single cord blood transplantation, with better outcomes, including quality-adjusted life-years.

The superiority of allogeneic hematopoietic stem cell transplantation from unrelated donor over chemotherapy for adult patients with high-risk acute lymphoblastic leukemia in first remission

For adult patients with acute lymphoblastic leukemia (ALL), allogeneic hematopoietic stem cell transplantation(allo-HSCT) from HLA-matched related donors(MSD) is recommended for standard and high-risk patients. The role of unrelated donor transplantation (URD) in first remission has not been fully determined. We sought to compare directly the outcome of URD allo-HSCT and chemotherapy in patients with high-risk ALL. In this single center retrospective analysis, we included 74 consecutive adult patients with high-risk ALL in first complete remission(CR) and without a sibling donor, in which 32 patients received URD allo-HSCT in CR1 with busulfan-cyclophosphamide preparation regimen and in vivo T-cell depletion with anti-T-lymphoglobulin (ATG). The remaining 42 patients received chemotherapy consolidation and maintenance only in first remission. With median follow-up of 18 months, in the URD allo-HSCT group, the relapse rate(RR) was 30.6 ± 11.4 % which was significantly lower than that of the chemotherapy group (80.5 ± 10.1 %,p < 0.001), while non-relapse mortality (NRM) was higher(16.4 ± 6.7 % vs. 0, p = 0.028). Overall, 3-year leukemia free survival (LFS) was superior in the URD allo-HSCT group compared to chemotherapy group (57.8 ± 10.6 vs.19.5 ± 10.5 %, p = 0.002), as was 3-year overall survival(OS, 63.5 ± 13.3 vs. 31.6 ± 10.6 %, p = 0.016). URDHSCT was the only factor associated with improved OS, LFS and reduced RR in multivariate analysis. Based on our data, URD allo-HSCT significantly reduced the relapse in high-risk ALL and the benefit translated into improvement in both LFS and OS. Prospective studies based on availability of HLA-matched URD are warranted to evaluate the precise role of URD transplantation in adult ALL.

Acute Myeloid Leukemia in First Remission: To Choose Transplantation or Not?

A 42-year-old woman presented with bruising and fatigue. Her WBC count was 10,370/μL, with a differential showing 5% polys, 5% monos, 10% lymphocytes, and 80% myeloid-appearing blasts, some of which contained Auer rods (Fig 1). Bone marrow examination revealed 90% infiltration with myeloid-appearing blasts, and flow cytometry analysis confirmed the diagnosis of acute myeloid leukemia (AML) with expression of CD33, CD13, and CD117. Cytogenetics revealed a normal female karyotype; molecular testing for NPM1, FLT3-ITD, and CEBPαmutations revealed wild-type status for each gene. The patient received induction therapy with daunorubicin 90 mg/m(2) per day for 3 days and continuous-infusion cytarabine 100 mg/m(2) per day for 7 days. After an induction course complicated by Gram-negative bacterial sepsis, her counts recovered by day 32, and bone marrow examination 6 weeks after diagnosis showed a complete remission. One week later she feels well and has normal physical and laboratory examinations. She is an only child (but has a common HLA type) and presents for discussion of postremission therapy options.

High-risk childhood acute lymphoblastic leukemia in first remission treated with novel intensive chemotherapy and allogeneic transplantation

Children with acute lymphoblastic leukemia (ALL) and high minimal residual disease (MRD) levels after initial chemotherapy have a poor clinical outcome. In this prospective, single arm, Phase 2 trial, 111 Dutch and Australian children aged 1-18 years with newly diagnosed, t(9;22)-negative ALL, were identified among 1041 consecutively enrolled patients as high risk (HR) based on clinical features or high MRD. The HR cohort received the AIEOP-BFM (Associazione Italiana di Ematologia ed Oncologia Pediatrica (Italy)-Berlin-Frankfurt-Münster ALL Study Group) 2000 ALL Protocol I, then three novel HR chemotherapy blocks, followed by allogeneic transplant or chemotherapy. Of the 111 HR patients, 91 began HR treatment blocks, while 79 completed the protocol. There were 3 remission failures, 12 relapses, 7 toxic deaths in remission and 10 patients who changed protocol due to toxicity or clinician/parent preference. For the 111 HR patients, 5-year event-free survival (EFS) was 66.8% (±5.5) and overall survival (OS) was 75.6% (±4.3). The 30 patients treated as HR solely on the basis of high MRD levels had a 5-year EFS of 63% (±9.4%). All patients experienced grade 3 or 4 toxicities during HR block therapy. Although cure rates were improved compared with previous studies, high treatment toxicity suggested that novel agents are needed to achieve further improvement.