Transplantation In First Complete Remission Research Articles

Dexrazoxane Does Not Negatively Impact Survival Outcomes in Children and Young Adults with Acute Myeloid Leukemia (AML)

Introduction: Acute myeloid leukemia (AML) comprises 5% of pediatric cancers and reports 5 year event free survival (EFS) of approximately 50% and overall survival (OS) of 60-70% following intensive multi-agent chemotherapy. Anthracyclines have been the cornerstone in upfront treatment of AML since the 1960's and continue to be used today in upfront trials for AML. Anthracycline induced cardiotoxicity remains a significant contributor to late morbidity/mortality in children and young adults with AML. The cardioprotectant dexrazoxane (Zinecard) can be used as prophylaxis to diminish the risk for cardiomyopathy but whether it affects the risk of relapse in pediatric AML is unproven. Our institution adopted the use of dexrazoxane prior to administration of any non-liposomal anthracycline for all patients in 2011. We are therefore reporting the differences in cardiac and treatment outcomes in children and young adults with AML treated with and without dexrazoxane from 2008 to 2013.Methods: We performed a retrospective chart review of children ages 0 to 21 years who received their therapy for AML at the Children's Hospital of Wisconsin (CHW) between January 1, 2008 and December 31, 2013. This study was approved by the CHW institutional review board prior to our data collection. Descriptive statistics were used to describe the study population. Echocardiogram statistics were generated with each model based on the least squares means and then transformed back to its original unit. A log rank test was used to detect differences between populations. Based on number of patients, a hazard ratio of 3 will achieve 85% power to detect a significant difference between groups.Results: Forty-four patients with AML were treated at CHW during 2008 - 2013 with 28 (64%) receiving dexrazoxane cardioprotectant and 16 (36%) did not. The median age at diagnosis was 8.1 years (5 months - 21.7 years) and 55% (n=24) were female. Six (14%) patients underwent transplantation in first complete remission and 6 (14%) underwent transplantation following relapse. No patients had history of cardiac disease, cardiac surgery or hypertension prior to treatment.We identified no statistical difference in relapse free survival (RFS) p>0.40), EFS (p>0.48) or OS (p>0.53) between groups. However, there was a significant decrease in the ejection fraction (EF %) (p=0.0018) and a significant decrease in shortening fraction (SF %) (p=0.0108) trends over time in the non-dexrazoxane group compared to patients who received dexrazoxane (Figures 1 & 2).Conclusion: Utilization of the cardioprotectant dexrazoxane prior to anthracycline chemotherapy in pediatric patients with AML demonstrated no significant difference in RFS or OS relative to our institutional controls and appeared to improve cardiac function. Further studies are needed to confirm these findings. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

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.

Addition of Rituximab Improves the Outcome of Adult Patients with CD20-Positive, Ph-Negative, B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL): Results of the Randomized Graall-R 2005 Study

▪Purpose: The use of rituximab, a chimeric monoclonal antibody to CD20, has led to significant improvement in the treatment of B-cell non-Hodgkin's lymphoma and mature B-cell ALL. CD20 is expressed in 30 to 50% of adult BCP-ALL patients. Although some single arm studies suggested that adding rituximab to chemotherapy could improve the outcome of these patients, no randomized study has been reported so far.Methods: To evaluate the potential benefit of adding rituximab, we conducted a multicenter randomized trial comparing the pediatric-inspired GRAALL protocol to the same regimen plus rituximab, in patients aged 18-59 years old with newly diagnosed CD20-positive Ph-negative BCP-ALL enrolled in the GRAALL 2005 trial. CD20 positivity was defined as expression of CD20 in more than 20% of leukemia blasts. Rituximab (375 mg/m2) was given during induction (day 1 and 7), salvage reinduction when needed (day 1 and 7), consolidation blocks (6 infusions), late intensification (day 1 and 7) and first year of maintenance (6 infusions) for a total of 16 to 18 infusions. Allogeneic stem cell transplantation (SCT) was offered in first complete remission (CR) to patients with one or more conventional high-risk criteria and a donor. The primary study objective was event-free survival (EFS). A study sample size of 220 patients was estimated in order to detect a 20% gain in EFS at 2 years (two-sided test, power 85%, type 1 error 5%). A sensitivity analysis was performed after censoring patients allografted in first CR at transplant time. This trial was registered at http://www.clinicaltrials.gov as #NCT00327678.Results: From 2005 to 2014, 220 patients from 56 centers were randomized. Eleven patients had non-eligibility criteria (n=5 Ph+ ALL; n=3 CD20-negative ALL; n=1 HIV infection) or withdrew their consent (n=2) and were accordingly excluded from this modified ITT analysis that dealt with 209 patients (105 in the rituximab arm and 104 in the control arm). Median age was 40 years. Both randomization arms were well balanced for pretreatment characteristics including age, ECOG status, WBC, and central nervous system (CNS) involvement (6% of the whole cohort). After induction ± salvage reinduction, CR rate was 92% and 91% in rituximab and control arm, respectively. In patients who reached CR after first induction and were evaluated for Ig/TCR minimal residual disease level (MRD), the rates of patients with MRD<10-4 in the rituximab vs control arm were 65% vs 61% (p=0.82) and 91% vs 82% (p=0.31), after induction and first 3 consolidation blocks respectively. A higher proportion of patients received allogeneic SCT in first CR in the rituximab arm (34% vs 20% in the control arm; p=0.029). With a median follow-up of 30 months, patients treated in the rituximab arm had a lower cumulative incidence of relapse (CIR) (2-year CIR, 18% [95% CI, 10-26] vs 30.5% [95% CI, 21-40] in control arm; p=0.02), while no significant difference was observed regarding non-relapse mortality (NRM) between both arms (2-year NRM, 12% [95%CI, 5-18] vs 12% [95%CI, 5-18] in control arm; p=0.80). This translated into longer EFS in patients treated in the rituximab arm (2-year EFS, 65% [95% CI, 56-75] vs 52% [95% CI, 43-63] in control arm; HR= 0.66 [0.45-0.98]; p=0.038; Figure 1) but no longer overall survival (OS) (2-year OS, 71% [95% CI, 62-80] vs 64% [95%CI, 55-74] in control arm; HR= 0.70 [0.46-1.07]; p=0.095). Other factors impacting EFS were age, CNS involvement and WBC at diagnosis. Together with the randomization arm, all these factors remained significantly associated with EFS in multivariate analysis, even when adjusting on allogeneic SCT in first CR as a time-dependent covariate. When censoring patients who received allogeneic SCT in first CR at transplant time, EFS and OS were longer in the rituximab arm (2-year EFS, 66% [95% CI, 56-78] vs 53% [95% CI, 44-65] and 2-year OS, 74% [95% CI, 65-85] vs 63% [95%CI, 54-74]; HR= 0.59 [0.37-0.93] and 0.55 [0.34-0.91] and p=0.021 and 0.018, respectively). Finally, 71 and 55 infection-related SAEs were reported in non-transplanted patients in the rituximab and control arm, respectively, without significantly higher incidence in the rituximab arm, at any treatment phase.Conclusions: In adults with CD20-positive, Ph-negative, BCP-ALL, the addition of rituximab to the pediatric-inspired GRAALL protocol improves EFS; it also prolongs OS when ignoring patient's outcome after transplantation in first CR. [Display omitted] DisclosuresOff Label Use: Rituximab is not currently approved for this indication.. Chalandon:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Monosomal karyotype as an adverse prognostic factor in patients with acute myeloid leukemia treated with allogeneic hematopoietic stem-cell transplantation in first complete remission: a retrospective survey on behalf of the ALWP of the EBMT.

Despite the overall benefit from allogeneic hematopoietic stem cell transplantation observed in patients with poor cytogenetic risk acute myeloid leukemia in first complete remission, the precise effect of this procedure for different poor-risk subtypes has not been fully analyzed. This retrospective analysis was performed to investigate whether allogeneic hematopoietic stem cell transplantation performed in first complete remission in patients with monosomal karyotype can overcome the adverse prognosis associated with these patients. Of the 4635 patients included in the study, 189 (4%) harbored a monosomal karyotype. The presence of a monosomal karyotype was associated with a worse outcome, with an inferior leukemia-free survival and overall survival (5-year leukemia-free survival and overall survival: 24 ± 3% and 26 ± 3% vs. 53 ± 1% and 57 ± 1% in monosomal-karyotype and non-monosomal-karyotype, respectively; P<0.0001) and higher relapse risk after transplantation (cumulative incidence of relapse at 5 years: 56 ± 4% in monosomal-karyotype vs. 28 ± 1% in non-monosomal-karyotype; P<0.0001). The adverse negative impact of monosomal karyotype cytogenetics was confirmed in the entire cohort in a multivariate analysis [Hazard Ratio (HR): 1.88, 95% Confidence Interval (CI):1.29-2.73, P=0.001 for relapse incidence; HR:1.71, 95%CI:1.27-2.32, P<0.0001 for leukemia-free survival; HR:1.81, 95%CI:1.32-2.48, P=0.0002 for overall survival], and was independent of the presence of other poor-risk cytogenetic subtypes. In summary, monosomal karyotype arises as a strong negative prognostic feature in acute myeloid leukemia also in patients who undergo allogeneic hematopoietic stem cell transplantation in first complete remission, stressing the need to develop additional pre- and post-transplantation strategies aimed at improving overall results. Nonetheless, allogeneic hematopoietic stem cell transplantation in early phase is currently the best therapy for this very poor-risk acute myeloid leukemia subtype.

Role of allogeneic stem cell transplantation in adult patients with Ph-negative acute lymphoblastic leukemia

AbstractBecause a pediatric-inspired Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) protocol yielded a markedly improved outcome in adults with Philadelphia chromosome–negative ALL, we aimed to reassess the role of allogeneic stem cell transplantation (SCT) in patients treated in the GRAALL-2003 and GRAALL-2005 trials. In all, 522 patients age 15 to 55 years old and presenting with at least 1 conventional high-risk factor were candidates for SCT in first complete remission. Among these, 282 (54%) received a transplant in first complete remission. At 3 years, posttransplant cumulative incidences of relapse, nonrelapse mortality, and relapse-free survival (RFS) were estimated at 19.5%, 15.5%, and 64.7%, respectively. Time-dependent analysis did not reveal a significant difference in RFS between SCT and no-SCT cohorts. However, SCT was associated with longer RFS in patients with postinduction minimal residual disease (MRD) ≥10−3 (hazard ratio, 0.40) but not in good MRD responders. In B-cell precursor ALL, SCT also benefitted patients with focal IKZF1 gene deletion (hazard ratio, 0.42). This article shows that poor early MRD response, in contrast to conventional ALL risk factors, is an excellent tool to identify patients who may benefit from allogeneic SCT in the context of intensified adult ALL therapy. Trial GRAALL-2003 was registered at www.clinicaltrials.gov as #NCT00222027; GRAALL-2005 was registered as #NCT00327678.

Effect of Allogeneic Hematopoietic Cell Transplant in First Complete Remission on Post-Relapse CR Rate and Survival in Acute Myeloid Leukemia

Purpose. Several studies have shown that allogeneic hematopoietic cell transplant (HCT) in first complete remission (CR1) reduces risk of relapse and improves relapse-free survival in patients with intermediate- and poor-risk AML. Benefits in overall survival (OS) are less obvious. One possible explanation is that once relapse occurs previous receipt of allogeneic HCT in CR1 is associated with shorter survival, with a lower CR rate following salvage therapy for relapse being a possible contributing factor. The aims of our study were to analyze the specific effect of allogeneic HCT in CR1 on (a) second CR rate and (b) OS from first salvage therapy.Patients and Methods. We identified 166 consecutive patients with AML (APL excepted, but including MDS with 10-19% blasts) who after achieving CR1 with initial treatment relapsed and subsequently received first salvage therapy between 2005 and 2013 at our institution. We used chart reviews to collect data on: (1) age, (2) CR1 duration, (3) ECOG performance status at relapse, (4) cytogenetic category (ELN criteria for adverse, intermediate, "favorable", and "missing") at relapse, (5) allogeneic HCT in CR1 (yes vs. no, and then myeloablative vs. reduced intensity vs. no) and (6) intensity of salvage therapy: with high-dose cytarabine containing therapy or myeloablative HCT considered "high intensity", 3+7 +/- other drugs as average intensity, and other salvage treatments as low intensity.CR was defined using conventional criteria. OS was measured from date of first salvage therapy to death from any causes analyzed using the Kaplan-Meier method. Multivariable regression analysis was performed using logistic and Cox models, adjusted for the 6 covariates noted in the preceding paragraph.Results. The median age of the 166 patients was 53.5 years (20 - 80 years). The three groups differed regarding this variable (p < 0.001): a median of 47 years (22 - 66) in the 27 patient myeloablative group, 61 years (21 - 75) in the 20 patient reduced intensity group and 54 years (20 - 82) in the 119 patient no-HCT group. The median CR1 duration was 7.9 months, and CR1 duration did not differ statistically (p = 0.46) in the three groups: 11.5 months myeloablative group, 8.8 months reduced intensity group, and 6.4 months no-HCT group. Cytogenetic data were missing in 22 patients; in the remaining 144, 8% had "favorable", 67% intermediate, and 25% adverse risk cytogenetics with no statistically significant differences in distribution between the three groups (p = 0.27 considering all patients). The median PS was 1, with 19% of patients having PS ≥ 2. Patients in the reduced intensity group more often had PS ≥ 2 (40% vs. 19% for myeloablative and 16% for no-HCT) (p = 0.07). 52% received high intensity salvage therapy (including 4 who received myeloablative allogeneic HCT), 18% received average intensity, and 30% received low intensity. The three groups differed regarding intensity of salvage therapy (p = 0.04). 25% of reduced intensity patients received high intensity salvage vs. 44% of myeloablative and 59% of no-HCT. In contrast, 26% of no-HCT patients received low intensity salvage vs. 37% myeloablative group and 40% reduced intensity group. The CR2 rate was 37.9%. The median survival after first salvage was 7.8 months.A multivariable analysis showed that HCT in CR1 had no significant effect on CR2 rate (OR 1.33, p = 0.50) or OS (HR 0.87, p = 0.55). In contrast, shorter CR1 duration and low intensity salvage were independently associated with a lower CR2 rate with favorable cytogenetic at relapse associated with a higher CR2 rate, while PS ≥ 2, low intensity salvage, and, to a lesser extent, shorter CR1 duration were similarly associated with poorer survival with favorable cytogenetic at relapse associated with better survival. An analysis of myeloablative vs. reduced intensity vs. no-HCT led to similar conclusions: myeloablative HCT p = 0.98 and reduced intensity HCT p = 0.29. Together with the Kaplan-Meier plots (Figure 1, log rank p = 0.90) the data suggest that neither myeloablative nor reduced intensity HCT in CR1 has an adverse effect on OS after first salvage.Conclusion.There was no evidence that preceding allogeneic HCT in CR1 was associated with lower probabilities of CR2 or OS after first salvage therapy. We believe our results should encourage use of allogeneic HCT in CR1 with some confidence that this will not unfavorably affect CR2 rate and OS should post HCT relapse occur. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Achieving Early Remission By Induction Therapy Predicts a Favorable Outcome in Patients with Acute Myeloid Leukemia and an Intermediate Risk Karyotype Undergoing Allogeneic Stem Cell Transplantation in First Complete Remission

Purpose: Acute myeloid leukemia (AML) is a highly heterogeneous disease. In addition to patient-related factors (co-morbidities, age, physical performance) and disease-specific variables (genetic risk profile) response to treatment is an important prognostic factor. In particular, the rapid achievement of hematologic remission by induction therapy was shown to predict overall outcome irrespective of the type of post-remission therapy employed. Here, we specifically investigated the impact of achieving early remission (ER), i.e. absence of leukemic blasts in the bone marrow at the end of the first course of induction therapy, as compared to delayed remission (DR) on the outcome of patients with AML who underwent allogeneic stem cell transplantation (alloSCT) in first complete remission (CR1) at our center.Patients and Methods: We retrospectively analyzed 132 consecutive patients (ER: N=79, DR: N=53) with AML and an intermediate risk karyotype transplanted at our center between 1994 and 2013. Median age at alloSCT was 48 years. Before referral to transplantation, all patients were treated in a German multicenter AML trial. Patients aged <60 years were treated according to a double induction strategy, which consisted of one course of “7+3” followed by one course of high-dose cytarabine (HD-AraC) (3000 mg/m²). Patients aged ≥60 years were treated with a single course of “7+3”. In case of residual leukemic blasts, i.e. 5% or more in the bone marrow on day +16, first induction was followed by either one additional course of the same regimen or one course of HD-AraC (1000 mg/m2). Depending on the timing of alloSCT, one (N=78) or two (N=7) additional courses HD-AraC consolidation were given. For transplantation, myeloablative conditioning (MAC) (N=58) consisted of 12 Gy total body irradiation (TBI) and 120 mg/m2 cyclophosphamide (CY). Reduced-intensity conditioning (RIC) (N=74) consisted of fludarabine (FLU) 150 mg/m2, oral busulfan (BU) 8 mg/kg and anti-thymocyte globulin (ATG)(Fresenius®) 40 mg/kg. Transplants were from related (N=60) or unrelated (N=72) donors and were HLA-matched (10/10 antigens) (N=119) or HLA-mismatched (N=13) according to high-resolution molecular typing. Immunosuppression consisted of short course methotrexate (MTX) and cyclosporine in patients treated with MAC or cyclosporine and mycophenolate mofetil (MMF) in patients treated with RIC prior to alloSCT.Results: After a median follow-up of 56 (4-220) months for the surviving patients, 87 patients (66%) are alive and in CR. 26 patients (20%) relapsed after a median interval of 8 (1-133) months, whereas 19 patients (14%) died from NRM. Projected overall survival (OS) of the entire cohort after 1, 3, 5 and 10 years was 81%, 68%, 65%, and 61%. At the same time points the cumulative incidence of relapse (CI-R) or non-relapse mortality (CI-NRM) was 12%, 19%, 22%, and 22% or 13%, 13%, 13%, and 17%. In contrast to patients showing DR, patients achieving ER had a significantly higher 3-year OS and disease-free survival (DFS) of 76% versus 54% (p=0.03) and 76% versus 53% (p=0.03). Likewise, 3 years after alloSCT the CI-R was significantly lower in the ER subgroup as compared to patients achieving DR, i.e. 10% versus 35% (p=0.004). In contrast, NRM did not differ significantly between the ER and the DR subgroup. Multivariate analysis identified DR as an independent prognosticator for an inferior DFS (HR 3.37, p=0.002) and a higher CI-R (HR 3.55, p=0.002). Notably, there was no significant difference in OS, DFS, or CI-R between patients treated with MAC versus RIC in the ER or the DR subgroup.Conclusions: Taken together, these data indicate that rapid achievement of remission may predict a favorable outcome in patients with intermediate risk AML undergoing alloSCT in CR1. In turn, the adverse effect of DR may not be necessarily overcome by alloSCT. DisclosuresNo relevant conflicts of interest to declare.

Pediatric Acute Megakaryoblastic Leukemia without Down Syndrome: A Retrospective Study by the International Berlin-Frankfurt-Munster Study Group (I-BFMSG)

Acute megakaryoblastic leukemia (AMKL) comprises up to 10% of childhood acute myeloid leukemia (AML) cases. However, no large-scale studies have comprehensively evaluated the clinical characteristics and outcomes of patients with AMKL. We performed a large-scale international retrospective study of pediatric patients (diagnosed at age ≤18 years) with de novoAMKL without Down syndrome treated from 1989 to 2009.The study included 490 patients with AMKL, which comprises 7.9% of the pediatric AML patients treated by 19 members of the I-BFMSG. At diagnosis, the median age of patients was 1.5 years (range, 0.0–16.5 years), median white blood cell count was 12.0×109/L (range, 0.6–188.0×109/L), 23 (4.7%) patients showed central nervous system involvement, and both sexes were equally represented. Complete remission (CR) was achieved in 417 (85.1%) patients, and 5-year event-free (EFS) and overall survival (OS) rates were 43.7%±2.7% and 49.0%±2.7%, respectively. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) was performed in 206 (42.0%) patients. The 5-year disease-free survival and OS rates for patients who received allo-HSCT in first CR (n=112, 56.3%±5.2%, and 57.7%±5.2%, respectively) and for those who did not receive transplantation in first CR (n=298, 50.2%±3.6% and 55.2%±3.5%) were not significantly different (P=0.12 and P=0.57).Complete cytogenetic data were available for 372 (75.9%) patients: diploid (n=49, 13.2%), hypodiploid (n=18, 4.8%), pseudodiploid (n=119, 32.0%), 47–50 chromosomes (n=142, 38.2%), and >50 chromosomes (n=44, 11.8%). Chromosome gain occurred in 195 (52.4%) patients: +21 was the most common (n=106, 28.5%), followed by +19 (n=93, 25.0%), and +8 (n=77, 20.7%). Losses occurred in 65 cases (17.5%), in the decreasing order of –7 (n=13, 3.5%), –9 (n=9, 2.4%), –13, and –15 (n=7 each, 1.9%). Structural chromosomal aberrations were observed in 278 (74.7%) patients, most commonly t(1;22) (n=51, 13.7%) and 11q23 rearrangements (n=38, 10.2%) with t(9;11) in 21 patients. Other abnormalities included 7p (n=43, 11.6%) and 13q (n=31, 8.3%; 16 with deletions) breakpoints. Patients with t(1;22) were significantly younger at diagnosis (P<0.001; median 0.6 years, range 0.0–6.3 years) and more often female (P=0.05; 64.7%) while those with –7 were significantly older (P=0.006; median 4.2 years, range 0.4–15.0 years) than those with other cytogenetic subgroups.Multiple regression analysis for EFS and OS with clinical and cytogenetic features showed that treatment period (1989–1999 vs. 2000–2009), normal cytogenetics, –7, t(9;11), 13q-, and –15 were associated with significantly worse outcomes than those for other subgroups, whereas abnormalities in 7p were associated with better outcomes (Table). Patients with –13 and 9p abnormalities other than t(9;11) had a poorer EFS and OS, respectively. Patients with +21 or t(1;22) did not show a significant difference in survival rates.This international study on the largest cohort of AMKL patients analyzed to date shows heterogeneity in cytogenetic findings and identifies some subgroups with a particularly dismal outcome. The advent of newer methods to evaluate genetic lesions can help identify therapeutic targets for improving the outcome in this subgroup of patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Higher Doses of Antithymocyte Globulin (ATG) Increase the Risk of Relapse in Acute Myeloid Leukemia (AML) Patients Undergoing Matched Related Donor Allogeneic Transplantation in First Complete Remission (CR1): An Analysis from the Acute Leukemia Working Party of EBMT

The use of ATG as part of the reduced-intensity conditioning regimen for AML is still controversial especially in the setting of matched related donor (MRD) allogeneic hematopoietic stem cell transplantation (alloHSCT). A previous study suggested that the use of ATG reduced the incidence of graft versus host disease (GVHD) but increased the risk of relapse when a MRD is used, leading to worse outcome compared to patients who did not receive any in vivo T-cell depletion (CIBMTR data, Soiffer et al., Blood 2011). In contrast, the EBMT series, focused on AML patients undergoing alloHSCT from MRD in CR1, showed that the use of ATG reduced the incidence of GVHD without increasing the risk of relapse (Baron et al., BMT 2014). These discordant conclusions could be explained by the different median doses of ATG used, 7 and 5 mg/kg in the CIBMTR and EBMT studies, respectively. Thus, we hypothesized that the dose and the type of ATG are critical issues and could be a major determinant of outcome after alloHSCT. Here, we investigated the impact of ATG (Thymoglobulin) dose on cumulative incidences of GVHD, non-relapse mortality (NRM), relapse (CIR), leukemia-free (LFS) and overall survival (OS).Data of patients with the following criteria were collected from the EBMT registry: alloHSCT between January 2000 and February 2013; AML in CR1; peripheral blood stem cells from MRD as graft source; RIC regimen; use of ATG (Thymoglobulin) as part of the RIC regimen.We analyzed 334 consecutive patients with a median age of 56 years (range, 19-70). Fifty-eight (17%) patients had unfavorable cytogenetics and 238 (71%) received a busulfan-based RIC regimen. Most patients (95%) received cyclosporine A as GVHD prophylaxis, while mycophenolate mophetil (MMF) was added to 99 patients (30%). ATG was given at the dose of 6 mg/kg or more (high dose group, median dose: 7.5 mg/kg, range: 6-10.5) in 71 patients (21%) while 263 patients (79%) received less than 6 mg/kg total dose (low dose group, median dose: 5 mg/kg, range: 2-5.5). Patients in the higher dose group were more frequently transplanted before 2009, received more frequently a RIC regimen without busulfan and were more frequently given MMF in GVHD prophylaxis. Age, time from diagnosis to alloHSCT and cytogenetic risk groups were equally distributed according to both high and low ATG dose groups.In multivariate analysis after adjustment for age (<=55 vs. >55 years), transplant period (2000-08 vs. 2009-13), cytogenetics (unfavorable vs. other), RIC regimen (busulfan-based vs. other) and GVHD prophylaxis (MMF vs. no MMF) showed no significant impact of high ATG dose (low dose was considered as the reference group) on the incidence of both grade II-IV acute (OR=0.996 [95%CI, 0.561-1.767]; p=0.989) and chronic GVHD (HR=0.977 [95%CI, 0.543-1.759]; p=0.939). Similarly, ATG dose did not influence the cumulative incidence of NRM (HR=1.202 [95%CI, 0.467-3.093]; p=0.703). With a median follow up of 36 months, high ATG dose significantly increased the CIR (HR=2.298 [95%CI, 1.328-3.977]; p=0.003, Figure A), leading to significantly shorter both leukemia-free (HR=1.904 [95%CI, 1.186-3.058]; p=0.008) and overall survival (HR=1.711 [95%CI, 1.030-2.844]; p=0.038, Figure B).In conclusion, these results suggest that ATG dose is a determinant factor for outcome. ATG total dose below 6 mg/kg is likely sufficient for GVHD prophylaxis, with no additional benefit for using the higher ATG doses. In contrast, a higher ATG dose (6 mg/kg and more) will likely impair outcome of patients due to a significant increase of the relapse risk. Therefore, in the setting of CR1 AML patients undergoing RIC alloHSCT from MRD, lower ATG doses (<6 mg/kg total dose) could be safely used and can allow for better GVHD control without impairing the overall outcome. These results may differ in patients transplanted for other diseases than CR1 AML. Further comparative prospective studies could be helpful to better identify the optimal ATG dose in different setting of AML. [Display omitted] DisclosuresBaron:sanofi: Honoraria. Blaise:Sanofi: Honoraria, Research Funding. Mohty:Sanofi: Honoraria, Research Funding.

Log Reduction Levels of WT1 mRNA Expression in BM after Chemotherapies Are Predictive Markers of Good Prognosis in AML Patients Achieved CR after Induction Therapy

IntroductionWhile some prognostic factors such as chromosome or gene mutations in acute myeloid leukemia (AML) have been reported, the indication of allogeneic stem cell transplantation in first complete remission (CR) of AML patients is still controversial. Evaluation of minimal residual disease (MRD) during chemotherapy is considered as one of the predictive markers for the prognosis of AML patients. Detection of leukemia-specific chimeric genes by real-time quantitative polymerase chain reaction is the most sensitive method to quantify MRD. However, because over 50% of AML patients lack suitable leukemia-specific chimeric genes for the detection of MRD, other gene markers for assessing MRD are necessary for a greater proportion of AML patients. Wilms tumor gene 1 (WT1) mRNA transcript levels in peripheral blood have been reported as a suitable molecular marker of MRD for the prediction of relapse in most AML patients. In contrast, in acute lymphoblastic leukemia (ALL) patients, it remains to be elucidated whether early and/or deep reduction of tumor burden predicts a good prognosis in AML patients achieved CR.AimsIn this study, we focused on the clinical relevance of the log reduction levels of WT1 mRNA transcript in bone marrow (BM) as MRD during chemotherapies, and also the association between WT1 mRNA transcript levels and outcomes in adult AML patients achieved CR.Patients and methodsFrom 2007 to 2011, 48 AML patients who received chemotherapy at hospitals in our study group were enrolled in this study. Written informed consent was obtained from each patient before starting induction chemotherapy. We analyzed transcript levels of WT1 mRNA in BM at diagnosis, after induction therapy and after final consolidation therapy. WT1 mRNA levels were determined using the WT1 mRNA Assay Kit (Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan) and normalized with GAPGH.ResultWe analyzed the expression levels of WT1 mRNA in 48 patients at diagnosis. Quantification of WT1 mRNA expression in BM at diagnosis was associated with neither disease-free survival (DFS) nor overall survival (OS). Twenty-eight of 32 patients who achieved CR could be analyzed for the expression levels of WT1 mRNA in BM after induction therapy. Expression levels of WT1 mRNA in BM after induction therapy were not associated with DFS and OS. Log reduction levels of WT1 mRNA transcript in BM after induction therapy were associated with DFS (P=0.0066) and OS (P=0.0074). Twenty-three CR patients could be examined for the expression levels of WT1 mRNA in BM after final consolidation therapy. Expression levels of WT1 mRNA in BM after final consolidation therapy were not associated with DFS and OS. Log reduction levels of WT1 mRNA transcript in BM after final consolidation therapy were associated with DFS (P=0.015) and OS (P=0.012). We analyzed the effect of log scales of WT1 mRNA expression levels in BM at diagnosis and the impact of log reduction levels of WT1 expression in BM by multivariate analysis adjusting stepwise p-values. Factors were adjustment for age, sex, SCT in 1CR and chromosome. The log scales of WT1 mRNA expression levels in BM at diagnosis were not associated with DFS and OS. We used Wd/i_log and Wd/c_log to assess the value of reduction of tumor burden. Wd/i_log was defined as a log scale of WT1 mRNA transcript level in BM at diagnosis divided by that after induction therapy. Wd/c_log was defined as a log scale of WT1 mRNA transcript level in BM at diagnosis divided by that after final consolidation therapy. Wd/i_log and sex were associated with DFS and only Wd/i_log was associated with OS. Hazard ratios of Wd/i_log for DFS and OS were 0.37 (P=0.0031) and 0.34 (P=0.0035), respectively, by every shallow remission level in log scale. Wd/c_log was also associated with DFS and OS. Hazard ratios for DFS and OS were 0.48 (P=0.0012) and 0.41 (P=0.022), respectively, by every shallow remission level in log scale.ConclusionLog reduction levels of WT1 mRNA expression in BM after induction therapy are suitable predictive markers for DFS and OS in AML patients achieved CR. It is suggested that early treatment response is important for AML patients such as ALL patients. Furthermore, log reduction levels of WT1 mRNA expression in BM after final consolidation therapy may be a predictive marker of good prognosis in AML and may be useful for the decision to proceed with allogeneic stem cell transplantation. DisclosuresNo relevant conflicts of interest to declare.

Decreased Nonrelapse Mortality after Unrelated Cord Blood Transplantation for Acute Myeloid Leukemia Using Reduced-Intensity Conditioning: A Prospective Phase II Multicenter Trial

A prospective phase II multicenter trial was performed with the aim to obtain less than 25% nonrelapse mortality (NRM) after unrelated cord blood transplantation (UCBT) for adults with acute myeloid leukemia (AML) using a reduced-intensity conditioning regimen (RIC) consisting of total body irradiation (2 Gy), cyclophosphamide (50 mg/kg), and fludarabine (200 mg/m2). From 2007 to 2009, 79 UCBT recipients were enrolled. Patients who underwent transplantation in first complete remission (CR1) (n = 48) had a higher frequency of unfavorable cytogenetics and secondary AML and required more induction courses of chemotherapy to achieve CR1 compared with the others. The median infused total nucleated cells (TNC) was 3.4 × 107/kg, 60% received double UCBT, 77% were HLA mismatched (4/6), and 40% had major ABO incompatibility. Cumulative incidence of neutrophil recovery at day 60 was 87% and the cumulative incidence of 100-day acute graft-versus-host disease (II to IV) was 50%. At 2 years, the cumulative incidence of NRM and relapse was 20% and 46%, respectively. In multivariate analysis, major ABO incompatibility (P = .001) and TNC (<3.4 × 107/kg; P = .001) were associated with increased NRM, and use of 2 or more induction courses to obtain CR1 was associated with increased relapse incidence (P = .04). Leukemia-free survival (LFS) at 2 years was 35%, and the only factor associated with decreased LFS was secondary AML (P = .04). In conclusion, despite the decreased NRM observed, other RIC regimens with higher myelosuppression should be evaluated to decrease relapse in high-risk AML. (EUDRACT 2006-005901-67).

The evolution of clinical trials for infant acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) in infants has a significantly inferior outcome in comparison with older children. Despite initial improvements in survival of infants with ALL since establishment of the first pediatric cooperative group ALL trials, the poor outcome has plateaued in recent years. Historically, infants were treated on risk-adapted childhood ALL protocols. These studies were pivotal in identifying the need for infant-specific protocols, delineating prognostic categories and the requirement for a more unified approach between study groups to overcome limitations in accrual because of low incidence. This subsequently led to the development of collaborative infant-specific studies. Landmark outcomes have included the elimination of cranial radiotherapy following the discovery of intrathecal and high-dose systemic therapy as a superior and effective treatment strategy for central nervous system disease prophylaxis, with improved neurodevelopmental outcome. Universal prospective identification of independent adverse prognostic factors, including presence of a mixed lineage leukemia rearrangement and young age, has established the basis for risk stratification within current trials. The infant-specific trials have defined limits to which conventional chemotherapeutic agents can be intensified to optimize the balance between treatment efficacy and toxicity. Despite variations in therapeutic intensity, there has been no recent improvement in survival due to the equilibrium between relapse and toxicity. Ultimately, to improve the outcome for infants with ALL, key areas still to be addressed include identification and adaptation of novel prognostic markers and innovative therapies, establishing the role of hematopoietic stem cell transplantation in first complete remission, treatment strategies for relapsed/refractory disease and monitoring and timely intervention of late effects in survivors. This would be best achieved through a single unified international trial.

T(6;9)(p22;q34)/DEK-NUP214-rearranged pediatric myeloid leukemia: an international study of 62 patients

Acute myeloid leukemia with t(6;9)(p22;q34) is listed as a distinct entity in the 2008 World Health Organization classification, but little is known about the clinical implications of t(6;9)-positive myeloid leukemia in children. This international multicenter study presents the clinical and genetic characteristics of 62 pediatric patients with t(6;9)/DEK-NUP214-rearranged myeloid leukemia; 54 diagnosed as having acute myeloid leukemia, representing <1% of all childhood acute myeloid leukemia, and eight as having myelodysplastic syndrome. The t(6;9)/DEK-NUP214 was associated with relatively late onset (median age 10.4 years), male predominance (sex ratio 1.7), French-American-British M2 classification (54%), myelodysplasia (100%), and FLT3-ITD (42%). Outcome was substantially better than previously reported with a 5-year event-free survival of 32%, 5-year overall survival of 53%, and a 5-year cumulative incidence of relapse of 57%. Hematopoietic stem cell transplantation in first complete remission improved the 5-year event-free survival compared with chemotherapy alone (68% versus 18%; P<0.01) but not the overall survival (68% versus 54%; P=0.48). The presence of FLT3-ITD had a non-significant negative effect on 5-year overall survival compared with non-mutated cases (22% versus 62%; P=0.13). Gene expression profiling showed a unique signature characterized by significantly higher expression of EYA3, SESN1, PRDM2/RIZ, and HIST2H4 genes. In conclusion, t(6;9)/DEK-NUP214 represents a unique subtype of acute myeloid leukemia with a high risk of relapse, high frequency of FLT3-ITD, and a specific gene expression signature.

TP53 Mutations In Patients With High-Risk Acute Myeloid Leukemia Treated With Allogeneic Hematopoietic Stem Cell Transplantation

PurposeThe treatment success in patients (pts) with acute myeloid leukemia (AML) is very heterogeneous. Cytogenetic and molecular alterations present at diagnosis are strong prognostic factors, which have been used to individualize treatment. As shown by several groups, the subgroup of pts with deletion of the short arm of chromosome 17 are at high risk for treatment failure (e.g. Seifert, Leukemia 2009), which persists even after allogeneic hematopoietic stem cell transplantation (HSCT) (Middeke, Blood 2012; Mohr, Br J Haematol 2013). Besides allelic loss of TP53 located on the short arm of chromosome 17, other mechanisms of inactivation have been shown for this key tumor suppressor gene, most importantly missense point mutations or small deletions. These alterations have also been linked to poor outcome in AML after chemotherapy (Grossmann, Blood 2012). Here, we studied the impact of TP53 mutations on the outcome of AML pts with adverse cytogenetic risk treated with HSCT. Patients and MethodsWe selected AML pts with complex karyotype (CK), monosomy 7, monosomy 5/del5q and/or abnl(17p) who had received HSCT within 3 randomized controlled trials (NCT numbers 00180115, 00180102, and 00180167). All pts were treated with intensive induction chemotherapy and HSCT according to a risk adapted strategy.Complete sequencing of the TP53coding region was done using next generation sequencing (NGS) on a 454 GS Junior instrument (Roche) using the IRONII-study amplicon panel. Amplicons were generated from genomic DNA isolated at the time of diagnosis. Data analysis was done using the Sequence Pilot software package (JSI Medical Systems), a 10% cut-off was used for mutation calling.Nonsynonymous mutations were classified into bi-allelic TP53 mutations if detected allelic frequency as determined by NGS was >50% and mono-allelic TP53 mutations for frequencies between 10% and 50%. All samples with synonymous mutations or no detectable mutations according to the predefined cut-off of 10% were classified as TP53wild type (wt).Overall survival (OS), event-free survival (EFS), cumulative incidence of relapse (CIR) and non-relapse-mortality (NRM) after HSCT were analyzed according to the mutational status. ResultsSamples from 97 pts with AML were analysed, the median age was 51 years (range 18 to 67), 83% suffered from de novo AML, while 13% had sAML and 3% therapy-related myeloid neoplasms. CK and monosomal karyotype (MK) were present in 61% and 42% of the pts, respectively. Twenty-nine pts (30%) had abnl(17p) detected by conventional karyotyping or FISH analysis. Twenty-six pts (27%) were treated with standard myeloablative conditioning (MAC) regimens while the remaining pts received reduced intensity conditioning (RIC). Donors were siblings in 36 pts (37%) and matched or mismatched unrelated donors in all other pts.Overall, TP53 mutations were found in 40 pts (41%). Twenty-eight (29%) pts had a bi-allelic TP53 mutation while 12 (12%) pts had a mono-allelic TP53 mutation. We identified 15 pts with TP53 mutations without abnl(17p). Four pts with abnl(17p) had wt TP53. Pts with TP53 mutations were significantly older than pts with wt TP53 AML (median age 55 vs. 43, p=.004). Donor type, type of conditioning and the rate of transplantation in first complete remission were not statistically different among pts with or without TP53mutations.With a median follow up of 67 months the three-year probabilities of OS and EFS for pts with wt TP53 were 33% (95% CI, 21% to 45%) and 24% (95% CI, 13% to 35%) compared to 10% (95% CI, 0% to 19%) and 8% (95% CI, 0% to 16%) (p=.002 and p=.007) for those with mutated TP53, respectively. CIR at three years was 42% for pts with wt TP53 and 60% for those with mutated TP53 (p=.05). NRM was not different in both groups. In multivariate analysis including age, donor type (sibling vs. all other), type of conditioning (RIC vs. MAC) and disease status (CR1 vs. advanced disease) only the TP53-mutation status had a significant influence on EFS (HR=1.72; p=.03). In our analysis, classification according to MK did not significantly influence OS, EFS, CIR or NRM. ConclusionIn this cohort of pts with cytogenetic adverse risk abnormalities, who had received HSCT, TP53 mutations were present in 41% of the pts. OS and EFS were significantly worse in pts with mutated TP53. Mutational analysis of TP53 might be an important additional tool to predict outcome after HSCT in pts with adverse karyotype AML. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Impact Of Cytarabine Dose In The Induction Regimen On The Outcome Of Patients With Newly Diagnosed Acute Myeloid Leukemia With Or Without NPM1 and/Or FLT3 Mutations: A SWOG and MD Anderson Cancer Center Report

BackgroundThe value of “high dose” cytarabine (HDAC) during initial induction therapy for patients with newly diagnosed AML remains controversial with some prior reports suggesting improved relapse-free survival (RFS) but not complete remission (CR) or overall survival (OS) (Kern and Estey, Cancer 2006; 107: 116-24), and others finding no benefit (Lowenberg, Blood 2013; 121:26-28). The benefit of HDAC in the management of more favorable subsets of AML (such as core binding factor AML) is well-established, demonstrating higher sensitivity of this group to cytarabine. It is commonly acknowledged that AML is several diseases that may respond differently to a given therapy. With the increasing use of NPM1 and FLT3-ITD to stratify patients, it seemed plausible that the value of HDAC during induction might vary according to patient's genotype as defined by NPM1 and FLT3-ITD mutation status. In particular, patients with normal cytogenetics/ NPM1 mutated/FLT3-ITD negative AML clearly have more favorable outcomes and, hence, are potentially a group that might benefit from HDAC therapy. Herein we examine this possibility. MethodsWe analyzed 1080 patients (median age 53, range 17-88) with newly diagnosed AML. The standard dose cytarabine (SDAC) group comprised 531 patients who received 7 days of cytarabine at 100 mg/m2 daily + 3 days of daunorubicin (3+7) on SWOG protocols (S0106 N=368, S9031 N=73, S9333 N=46, S9500 N=44). The HDAC group consisted of 549 patents treated on various MD Anderson (MDA) induction protocols, each of which administered cytarabine at either 1.5g/m2 daily X 4 days by continuous infusion or at 1-2 g/m2 daily X 5 days, most commonly combined with idarubicin, fludarabine, or clofarabine +/- other agents. Once in CR, both the SDAC and HDAC groups received HDAC consolidation. Only 16% of patients at MDA received allogeneic transplant in first CR (off-protocol transplant data not available for SWOG). We used log-rank tests to compare RFS and OS in the SDAC and HDAC groups and multivariate Cox regression to adjust for other potential prognostic covariates: numerical age, sex, performance status (0-1 vs. >2-4), numerical WBC count, platelets, % marrow blasts, and cytogenetics (SWOG criteria). Results15% of the 1080 patients were positive for NPM1 mutation (N+)/negative for FLT3-ITD (F-) (13% MDA, 17% SWOG), 10% N-/F+ (9% MDA, 11% SWOG), 10% were N+/F+ (9% MDA, 11% SWOG), and 65% were N-/F-(69% MDA, 61% SWOG). CR rates were similar in each of the 4 groups regardless of the cytarabine dose (interaction p=0.42). On multivariate analysis, among N+/F- patients, OS was superior in the SDAC group (HR=0.50, p=0.02)). Multivariate analysis indicated that OS was similar between SDAC and HDAC in each of the other cohorts and that RFS was similar in all four cohorts. , When we restricted the analysis to the 545 patients age 60 with de novo AML treated since 2000 (N+/F- 15%, N-/F+ 9%, N+/F+ 10%, N-/F- 65%) there was no evidence that SDAC or HDAC was associated with CR, RFS or OS. When we restricted the analysis to the 418 patients with normal cytogenetics (N+/F- 27%, N-/F+ 13%, N+/F+ 20%, N-/F- 40%), on multivariate analysis, among N-/F- patients, OS and RFS were superior in the SDAC group (OS: HR=0.4, p=0.001; RFS: HR=0.48, p=0.02). SDAC and HDAC were similar with respect to OS and RFS in the other three cohorts and had similar CR rates in all four cohorts. ConclusionOur data do not suggest that higher doses of cytarabine during induction improve response, RFS or OS in any of the 4 subsets defined by NPM1 and FLT3 mutations in newly diagnosed AML, overall. This may be at least partly due to the use of HDAC in consolidation in both groups. Disclosures:Faderl:Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kantarjian:Sanofi-Aventis: Research Funding.

Differential Clinical Impact Of Gene Mutations and Their Combinations In Primary Cytogenetically Normal Acute Myeloid Leukemia (CN-AML)

In CN-AML, mutations of specific genes have prognostic significance and are used for treatment guidance. However, these mutations are in general not mutually exclusive and CN-AML patients (pts) frequently harbor mutational combinations with unclear prognostic significance because of the concurrent presence of mutations with favorable (CEBPA, NPM1) and unfavorable (ASXL1, DNMT3A, IDH1, IDH2, FLT3-ITD, MLL-PTD, RUNX1, TET2, WT1) impact on outcome. Here, we report the frequency and clinical significance of isolated mutations and their combinations in 364 CN-AML pts. Younger [<60 years (y); n=163] and older (≥60 y; n=201) pts were intensively treated on frontline CALGB/Alliance protocols and, per protocol, did not undergo allogeneic stem cell transplantation in first complete remission (CR). Median follow-up for pts alive was 8.7 y. Pts were analyzed centrally for mutations in the ASXL1, CEBPA, DNMT3A, IDH1, IDH2, NPM1, RUNX1, TET2, and WT1 genes and the presence of FLT3-ITD, FLT3-TKD and MLL-PTD. We found that 99% of pts had ≥1 and 88% ≥2 of the 12 mutations. Specifically, 11% of pts had 1 gene mutated (n1), 40% had 2 (n2), 31% 3 (n3), and 18% harbored ≥4 mutated genes (n4). The distribution of the different n groups in younger and older pts was similar (Fig 1). The expected frequency of each mutated gene in every numerical (n) group was calculated as follows: [no. of pts with the mutated gene] x [total no. of mutations in the n group] / [total no. of mutations in all pts], and compared with the observed frequency. CEBPA, IDH2, NPM1, and RUNX1 mutations were overrepresented in the n1 and n2 groups (P<.001, P<.001, P=.002, P=.02, respectively) and thus likely represent “early” events in leukemogenesis. In contrast, DNMT3A, FLT3-ITD, and TET2 mutations were more frequent in the n3 and n4 groups (P=.008, P<.001, P=.02, respectively) suggesting that they are likely “late” events. The distribution among age groups and clinical impact of the “early” mutations (i.e., CEBPA, NPM1, IDH2) presenting as isolated mutations or in combination with other mutations were then investigated. Isolated RUNX1 mutations could not be evaluated due to small sample size. Younger pts were more likely to harbor an isolated “early” mutated gene than older pts (21% v 12%, P=.03). Specifically, isolated CEBPA and NPM1 mutations were more frequent in younger pts compared with the older (7% v 2%, P=.007; 7% v 3%, P=.07, respectively). In pts with isolated CEBPA mutations, these were always bi-allelic. Single “early” mutated genes varied in their impact on CR achievement (CEBPA: 100%, NPM1: 94%, IDH2: 67%), and overall survival (OS; 3-y OS: CEBPA: 87%, NPM1: 69%, IDH2: 22%). Acquisition of additional mutations adversely modified the prognostic significance of favorable “early” mutations in the CEBPA (Fig 2A) and NPM1 (Fig 2B) genes, but left unchanged the unfavorable effect of IDH2 mutations (Fig 2C). Two mutational combinations were exceptions to this: younger pts with both NPM1 and DNMT3A mutations (8 pts) had an excellent prognosis with 3-y OS of 100%; and older pts with concurrent NPM1 and IDH2 mutations (9 pts; all IDH2 mutations were in codon R140) had a high 3-y OS rate of 67%. We conclude that CEBPA and NPM1 mutations mainly define pts with favorable prognosis when they present as single markers, whereas mutated IDH2 predominantly associates with adverse outcome. The NPM1+DNMT3A and NPM1+IDH2 mutational patterns may define novel favorable molecular subtypes in younger and older CN-AML pts, respectively, but these results require corroboration in larger pt cohorts. [Display omitted] [Display omitted] Disclosures:Mrózek:AMERICAN SOCIETY OF HEMATOLOGY: I will review abstracls submitted for presentation at the 55th ASH Annual Meeting in the 611 category Other. Eisfeld:AMERICAN SOCIETY OF HEMATOLOGY: I will review abstracls submitted for presentation at the 55th ASH Annual Meeting in the 608 category Other.

In Adult Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia, The Negative Prognostic Impact Of IKZF1, CDKN2A/B and PAX5 Deletions Is Not Abrogated By Allogeneic Stem Cell Transplantation In First Complete Remission

Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) is traditionally considered the subtype with the worst prognosis, despite recent improvements in long-term survival brought about by the use of tyrosine kinase inhibitors (TKI) such as imatinib or dasatinib. Allogeneic stem cell transplantation (aSCT) remains the most effective curative post-remission therapy in adults but appears to be less critical in children, indicating a substantial clinical and biological heterogeneity within the subgroup of Ph+ ALL. The ability to segregate Ph+ ALL into subgroups with different prognosis on the basis of reductions of BCR-ABL1 transcript levels during therapy lends further support to the heterogeneity of this type of leukemia, for which the genetic basis is not known. Microarray-based genome-wide profiling studies conducted predominantly in pediatric ALL patients have recently revealed novel recurrent submicroscopic aberrations of genes involved in B-cell development and cell cycle regulation, such as CDKN2A/B, IKZF1, PAX5, ETV6, RB1, BTG1 and EBF1. Deletions of IKZF1, CDKN2A/B and PAX genes have received the most attention due to their high frequency particularly in BCR-ABL1-positive ALL and their association with an inferior prognosis in the setting of combined TKI and chemotherapy. Their prognostic relevance in the setting of allogeneic SCT for adult or pediatric high risk BCP-ALL is not known. We therefore examined whether the negative prognostic role of IKZF1 aberrations and other frequent microdeletions of genes associated with B-cell development can be overcome by allogeneic SCT in CR1.A total of 137 newly diagnosed Ph+ ALL pts. (median age 42 years, range 18-64y, 79 male 58 female) treated within the prospective multicenter GMALL study 07/03 were analyzed. 96 of these patients underwent aSCT in first complete remission (CR), 8 pts. were primary refractory, 12 CR pts. did not undergo aSCT and relapsed, 11 pts. died during induction. Genome-wide copy number analysis in search for acquired copy number alterations (CNA) was performed with Affymetrix SNP 6.0 arrays with anonymous references. Copy number polymorphisms were excluded from the data by comparison with known copy number polymorphisms registered in the UCSC genome browser http://genome.ucsc.edu/, (hg-18). Putatively acquired CNAs were validated by multiplex ligation-dependent probe amplification (MLPA) and germline matched SNP array analysis of n=20 samples within the study.Of the 96 pts. transplanted in CR1, 48 remain in CR (CCR), 30 pts. relapsed after aSCT and 7 died of treatment related causes, survival data only are available for one patient. CDKN2A/B genomic alterations were identified in 41% (40/97) of patients, deletions of IKZF1 and PAX5 were observed in 61% (59/97) and 39% (38/97) of pts., respectively.Univariate analysis of the complete cohort revealed that deletion of CDKN2A/B was the only aberration with a statistically significant negative effect on overall survival (OS) (p=0.003). Among patients transplanted in CR1, IKZF1-deletions were associated with inferior median time to relapse after SCT (56 mos vs. n.r., p=0.01), DFS from SCT (15.6 mos. vs. n.r.; p=0.024) and OS (median 40 mos. vs. not reached (n.r.) p=0.04) compared with the IKZF1 wildtype cohort. Similarly, the prognosis of pts. with CDKN2A/B deletions was inferior in terms of DFS (median 10.6 mos. vs. n.r.; p=0.022) and OS (median 25 mos. vs. n.r.; p=0.01), but not of remission duration from SCT. PAX5 (p=0.07) but not the combination of all three lesions (p=0.14) showed a trend to a worse prognosis. Of the more uncommon genetic aberrations BTLA, EBF1, ETV6, RB1 and BTG1, only the latter was associated with a lower probability of remaining in CR (0% vs. 67% at 5 years; p=0.012) or DFS (0% vs. 52% at 5 years; p=0.043), with a trend towards shorter OS (median 35 mos. vs. 87 mos; p=0.078).In conclusion, genomic lesions of IKZF1, CDKN2 and PAX5 identify a subgroup of Ph+ ALL pts. who have an inferior survival despite undergoing aSCT in CR1. Their poor outcome is attributable primarily to a high relapse rate after SCT, emphasizing the need to introduce additional treatment elements prior to and after aSCT. Disclosures:No relevant conflicts of interest to declare.

Detection of MRD may predict the outcome of patients with Philadelphia chromosome–positive ALL treated with tyrosine kinase inhibitors plus chemotherapy

AbstractFrom 2001 to 2011, 122 patients with newly diagnosed Philadelphia chromosome–positive acute lymphoblastic leukemia were treated with chemotherapy + imatinib (n = 54) or + dasatinib (n = 68). One hundred fifteen (94%) achieved complete remission (CR) including 101 patients who achieved it with only 1 induction course and had at least 1 minimal residual disease (MRD) assessment; 25 patients underwent an allogeneic stem cell transplant in first CR and were excluded, leaving 76 patients as the subject of this report. MRD monitoring by multiparameter flow cytometry (MFC) and real-time quantitative polymerase chain reaction (PCR) was performed at the end of induction and at ∼3-month intervals thereafter. Median age was 54 years (range, 21-84 years). There was no difference in survival by achievement of at least a major molecular response (MMR; BCR-ABL/ABL < 0.1%) at CR (P = .22). Patients achieving MMR at 3, 6, 9, and 12 months had a better survival (P = .02, .04, .05, and .01, respectively). Negative MFC at CR did not predict for improved survival (P = .2). At 3 and 12 months, negative MRD by MFC was associated with improved survival (P = .04 and .001). MRD monitoring by PCR and MFC identifies patients who benefit from treatment intensification in first CR.

Usefulness of allogeneic hematopoietic stem cell transplantation in first complete remission for pediatric blastic plasmacytoid dendritic cell neoplasm with skin involvement: A case report and review of literature

No standard treatment has been established in childhood blastic plasmacytoid dendritic cell neoplasma (BPDCN) because of its rarity. We treated with acute lymphoblastic leukemia-type regimen for a child with BPDCN with skin and leukemic involvement. She has been disease-free for 4 years after allogeneic bone marrow transplantation in first complete remission. In 33 cases of pediatric BPDCN, the over survival was significantly lower in the patients with skin manifestation than those without cutaneous involvement. Accordingly, it is important to determine whether allogeneic hematopoietic stem cell transplantation should be applied to first complete remission in the patients with poor prognosis.

Comparable long‐term outcomes after reduced‐intensity conditioning versus myeloablative conditioning allogeneic stem cell transplantation for adult high‐risk acute lymphoblastic leukemia in complete remission

The role of reduced-intensity conditioning (RIC) in adult acute lymphoblastic leukemia (ALL) remains unclear because of the small sample size, short follow-up duration, various regimens for conditioning and graft-versus-host disease (GVHD) prophylaxis, and the heterogeneity of selection criteria for transplantation. We compared long-term outcomes of 60 consecutive RIC transplants (fludarabine plus melphalan) with 120 myeloablative conditioning (MAC) transplants (total body irradiation plus cyclophosphamide) for adult high-risk ALL in first or second complete remission. All transplants received a uniform strategy of pretransplant chemotherapy and GVHD prophylaxis. Compared to MAC transplants, RIC transplants had older age (46 years vs. 33 years, P < 0.001) and higher proportions of transplantation using peripheral blood (93.3% vs. 13.3%; P < 0.001) but otherwise showed similar characteristics. After a median follow-up of 67 months, RIC transplants showed comparable nonrelapse mortality (21.2% vs. 24.3%) and disease-free survival (50.8% vs. 54.9%) to MAC transplants, although relapse risk was higher (34.2% vs. 26.4%; HR, 2.07; P = 0.019) in multivariate analysis. Other independent factors associated with better outcomes were the presence of chronic GVHD and transplantation in first complete remission. Interestingly, the negative impact of RIC on relapse risk was seen only for Philadelphia-positive ALL transplants (32.7% vs. 19.6%; HR, 3.46; P = 0.020), while no difference was found between RIC and MAC for Philadelphia-negative ALL transplants (35.0% vs. 32.1%; HR, 1.39; P = 0.429). RIC can be considered as a reasonable choice for providing a sufficient long-term graft-versus-leukemia effect for adult high-risk ALL patients ineligible for MAC.