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The indication for performing an allogeneic hematopoietic stem cell transplantation (allo-HCT) in patients with isolated trisomy 8 AML in first complete remission (CR) is still debated. Here, we compared outcomes of such patients given either allo-HCT or autologous (auto)-HCT. Inclusion criteria consisted of adult patients with de novo AML, isolated trisomy 8, first HCT between 2000 and 2018, CR1 at transplantation, and either auto-HCT or allo-HCT with a HLA-identical sibling donor (MSD) or a 10/10 HLA-matched unrelated donor (UD 10/10). A total of 401 patients met the inclusion criteria. They underwent an auto-HCT (n = 81), allo-HCT with a MSD (n = 186) or allo-HCT with a 10/10 UD (n = 134). At 3 years, relapse incidence, nonrelapse mortality and leukemia-free survival (LFS) were 59%, 5%, and 37%, respectively, in auto-HCT recipients; 31% (P

The theoretical generalization and experimental confirmation of the features of the progression of myelodysplastic syndrome are presented in the article. The purpose of the study was to identify the available clinical parameters that may be suitable for assessing of the course of MDS and predicting the risk of transformation of this pathology into acute leukemia. The subject of the study was a group of patients with different subtypes of myelodysplastic syndrome according to the FAB classification. The statistical analysis was performed using the application software package STATISTICA for Windows 5.0 and NCSS. Leukemia-free survival was evaluated using the Kaplan-Meier method. To compare survival rates in two groups, the log-rank test and the Cox F-criterion were used. Cox proportional hazard regression was used to determine the most significant independent prognostic factors influencing the survival rate. The obtained results indicate that the process of leukemic transformation of the low and high risk myelodysplastic syndrome is different, confirming the presence of different predictive risk factors for the transformation in these patients. It is statistically confirmed that the main predictors that shorten the leukemia free survival in patients with low-risk myelodysplastic syndrome are the age of patients above 60 years, multilineage dysplasia of bone marrow cells and serum TNF-α level above 10 pg/ml. Instead, in patients with high-risk myelodysplastic syndrome, besides the older age and multilineage dysplasia of bone marrow cells, with a shorter leukemia-free survival are also significantly associated: the presence of thrombocytopenia, increased blasts in bone marrow and the IL-6 concentration above 50 pg/ml. Permanent search for prognostic factors and the development of new, more advanced prognostic scales that could cover not only demographic, laboratory or cytogenetic parameters, but also pathogenetic markers, are not only of scientific but also of a great practical importance, since they provide the opportunity to start therapy in patients with a high probability of transformation on time, thereby increasing the time to progression of the disease, in patients with MDS both low and high risk

Background Autologous stem cell transplantation (ASCT) is a potential consolidation therapy for acute myeloid leukemia (AML). This study was designed to develop a prediction model for leukemia-free survival (LFS) in a cohort of patients with de novo AML treated with ASCT during their first complete remission. Methods This was a registry study of 956 patients reported to the European Society for Blood and Marrow Transplantation. The primary outcome was LFS. Multivariate Cox regression modeling with backward selection was used to select variables for the construction of the nomogram. The nomogram's performance was evaluated with discrimination (the area under the receiver operating characteristic curve [AUC]) and calibration. Results Age and cytogenetic risk (with or without FMS-like tyrosine kinase 3 internal tandem duplication) were predictive of LFS and were used for the construction of the nomogram. Each factor in the nomogram was ascribed points according to its predictive weight. Through the calculation of the total score, the probability of LFS at 1, 3, and 5 years for each patient could be estimated. The discrimination of the nomogram, measured as the AUC, was 0.632 (95% confidence interval [CI], 0.595-0.669), 0.670 (95% CI, 0.635-0.705), and 0.687 (95% CI, 0.650-0.724), respectively. Further validation with bootstrapping showed similar AUCs (0.629 [95% CI, 0.597-0.657], 0.667 [95% CI, 0.633-0.699], and 0.679 [95% CI, 0.647-0.712], respectively), and this suggested that the model was not overfitted. Calibration was excellent. Patients were stratified into 4 incremental 5-year prognostic groups, with the probabilities of LFS and overall survival ranging from 25% to 64% and from 33% to 79%, respectively. Conclusions The Auto-AML nomogram score is a tool integrating individual prognostic factors to provide a probabilistic estimation of LFS after ASCT for patients with AML.

Context Purine analogue therapy remains the standard of care in hairy cell leukemia (HCL) management. Despite high remission rates, many patients subsequently relapse and require re-treatments. Objective The aim of this study is to compare the effectiveness and safety of cladribine vs. cladribine followed by rituximab consolidation as first-line therapy of HCL. Design This is a retrospective study including all consecutive patients with classical HCL treated and followed at the American University of Beirut Medical Center (AUBMC) between 2000 and 2019. Methods We identified 29 HCL patients, with a median age of 50.5 (range: 30–71) years. Patients were divided into two cohorts based on treatment received: cohort A (N=14) received cladribine 5.6 mg/m2 intravenously (IV) for 7 days as a single agent, and cohort B (N=15) received the same dose of cladribine followed by rituximab 375 mg/m2 IV weekly for eight doses. Rituximab consolidation was given after a median time of 33 days (17–60 days) from cladribine completion. Complete remission rates were 64% and 100% in cohorts A and B, respectively. In cohort A, seven (50%) patients relapsed after a median duration of 48 months (range: 1–209 months), requiring second-line treatment with cladribine followed by rituximab. In cohort B, no relapses occurred. After a median follow up of 67 months (range: 1–227 months), the 5-year disease-free survival was significantly better in group B (100%) compared to group A (58%) (HR=0.16, 95% CI: 0.032–0.84, p=0.03). There was no significant difference in overall survival between the two groups. Grade 3/4 adverse events were observed in 92%% and 80% of patients in cohorts A and B, respectively, mainly neutropenia (78.5% vs 66.6%) and febrile neutropenia (71% vs. 40%). One patient in cohort B who received rituximab consolidation too early (day 17) died from febrile neutropenia and septic shock. Conclusion Consolidation rituximab after cladribine in frontline treatment of classical HCL showed high response rate of 100% and translated into a significant improvement in disease-free survival. Cladribine followed by rituximab consolidation may be considered as standard first-line therapy of HCL.

This retrospective single-center analysis studied the impact of the conditioning and the graft-versus-host disease (GVHD) prophylaxis on outcome in unselected patients allografted for chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML) secondary to documented prior CMML. A total of 44 patients (median age 61 years) allografted between 2002 and 2019 in our institution were analyzed. Fifteen patients had secondary AML. The conditioning regimen was fractionated 6–8 Gy total body irradiation (TBI) in combination with fludarabine in 33 (75%) patients. Eleven patients (25%) received alkylator-based conditioning therapy without TBI. For GVHD prophylaxis, a calcineurin inhibitor (CNI) backbone in combination with methotrexate (MTX) or mycophenolate mofetil (MMF) was applied in 21 and 23 patients, respectively. All patients allografted from an unrelated donor (UD) received antithymocyte globuline. In univariate analysis of the entire cohort, TBI-based conditioning and MMF-containing immunosuppression were associated with improved leukemia-free survival (LFS, HR 0.16, P

Elevated C-reactive protein is associated with shortened leukemia-free survival in patients with myelofibrosis

Several genes with relevant pathogenetic and prognostic value have been identified in patients with myelodysplastic syndromes. Overexpression of WT1 at diagnosis has been associated with increased progression to acute myeloid leukemia and reduced leukemia free survival. Conversely, few data are available on the prognostic value of BAALC gene overexpression in AML and MDS patients. We evaluated the prognostic value of the combined expression of WT1 and BAALC genes at diagnosis in 86 MDS patients who had been stratified according to IPSS and R-IPSS scoring systems. Our results suggest that in the whole group of patients, low levels of both WT1 and BAALC were associated with a favorable outcome (3-year LFS 74.5%, median not reached), whereas patients presenting high expression levels of both genes had the worst prognosis (3-year LFS 0%, median 12 months, p0.001). More specifically, molecular profiling was especially useful for intermediate 1 and intermediate-2/high risk groups. This study suggests that evaluating WT1 and BAALC gene expression at diagnosis may improve standard risk stratification and possibly refine the therapeutic approach for MDS patients.

Introduction: Immunotherapy is a promising modality of treatment of neoplastic diseases, including acute lymphoblastic leukemia (ALL). The CD19/CD3-bispecific T cell–engaging (BiTE®) monoclonal antibody blinatumomab can transiently bind cytotoxic T cells to CD19+ target B cells of ALL inducing their serial lysis.Areas covered: This review focuses on the efficacy and safety of blinatumomab used for the treatment of relapsed/refractory (R/R) ALL and minimal residual disease (MRD)-positive B-cell precursor (BCP) ALL in adults and children, as well as the future prospects of this drug in the treatment of ALL.Expert commentary: Blinatumomab has demonstrated encouraging response rates in MRD-positive and R/R in adults with Philadelphia chromosome-positive and -negative ALL, as well as in children with R/R ALL. Blinatumomab has a favorable safety profile, although reversible CNS events and cytokine release syndrome can occur. Ongoing trials in ALL incorporate blinatumomab in the first line therapy of BCP...

Introduction: Up to 40% of new acute myeloid leukemia (AML) patients fail to achieve complete remission (CR), and a significant number of patients achieving remission eventually relapse. Allogeneic hematopoietic cell transplantation (allo-HCT) remains the best curative option for these patients with a long-term leukemia free survival (LFS) of around 20-30% with the use of intensive myeloablative condition (MAC) transplants. Active disease AML patients otherwise deemed unfit for MAC regimens have limited treatment options. Although reduced intensity condition (RIC) has broadened transplant eligibility in the elderly AML patients particularly in CR, there is a paucity of data on the use RIC allo-HCT in AML patients with active disease. To answer this question, we retrospectively analyzed data from active disease AML patients who underwent RIC allo-HCT and compared their outcomes with contemporaneous patients who underwent MAC allo-HCT at our institution. Patients and methods: Our cohort included all patients with active disease AML (primary induction failure, relapsed refractory or cytogenetic persistence) at the time of transplantation, who underwent allo-HCT at Washington University Medical Center in St. Louis between January 2006 and June 2015. Patients were classified according to the intensity of conditioning regimens: MAC versus RIC. The primary study endpoints were leukemia free survival (LFS) and overall survival (OS). LFS was defined as the time from the achievement of CR after allo-HCT to the time of relapse, death in remission, or last follow-up. OS was defined as the time from transplantation to the time of death from any cause or last follow-up. The between-group differences in LFS and OS were described using Kaplan-Meier (KM) survival curves and compared by log-rank test. Univariate Cox regression analysis for LFS was performed. All analyses were two-sided, and significance was set at a p-value of 0.05, using SAS 9.4 (SAS Institutes, Cary, NC). Results: 138 patients were included. 30 patients (21.7%) underwent RIC allo-HCT and 108 (78.3%) underwent MAC allo-HCT. Their baseline characteristics are listed in Table 1. 21 patients (72.4%) in RIC and 77 (81.9%) in MAC achieved CR on day-28 bone marrow biopsy. Notably, there were 16 patients (1 RIC and 15 MAC) who died prematurely without post-transplant evaluation; subsequently they were excluded from LFS, relapse and NRM calculations. There was no difference in the LFS in these two groups; 1-year and 3-year LFS were 40.6% (95% CI 23-70) and 33.1% (95% CI 17-66) in the RIC patients while 40.7% (95% CI 31-54) and 33.2% (95% CI 23-47) in the MAC patients, respectively (p=0.99) (Figure 1A). Similarly the CI of relapse at 1 year and 3 year was not different in the two groups; 45.8% (95% CI 30-71) and 50.5% (95% CI 33-76) in RIC group vs. 51.9% (95% CI 43-63) and 56.8% (95% CI 48-67) in MAC group, respectively (p=0.61) (Figure 1B). The CI of NRM at 1-year and 3-year was 28.1% (95% CI 16-50) and 32.6% (95% CI 19-56) in RIC group compared to 17.9% (95% CI 11-28) and 21.0% (95% CI 14-31) in the MAC group (p = 0.21). However, OS in both groups remained poor with 1-year and 3-year OS of 25.1% (95% CI 14-44) and 13.2% (95% CI 6-31) in RIC vs. 35.5% (95% CI 28-46) and 22.0% (95% CI 15-32) in MAC, respectively (p = 0.21). On univariate analysis for LFS and relapse, only cGvHD was associated with higher LFS (p Conclusion: The use of RIC allo-HCT in active disease AML is associated with LFS and relapse comparable to MAC allo-HCT. However, high relapse rates and NRM, in both groups translated into poor long term OS. Careful selection of patients and early utilization of transplant without subjecting these patients to multiple salvage regimens might help lower NRM rates in future studies. Notably, our study might open a window for future prospective studies aimed at finding improved ways to harness the graft versus leukemia (GvL) effect associated with RIC transplantation in patients who are otherwise not able to tolerate more toxic intensive conditioning regimens. LFS LFS Figure 1 Relapse Figure 1. Relapse Figure 2 Figure 2. Disclosures DiPersio: Incyte Corporation: Research Funding. Vij:Karyopharm: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Novartis: Honoraria; Amgen: Honoraria, Research Funding; Celgene: Consultancy; Takeda: Honoraria, Research Funding.

Relapse is the major cause of treatment-failure in adults with B-cell acute lymphoblastic leukemia (ALL) achieving complete remission after induction chemotherapy. Greater precision identifying persons likely to relapse is important. We did bio-informatics analyses of transcriptomic data to identify mRNA transcripts aberrantly-expressed in B-cell ALL. We selected 9 candidate genes for validation 7 of which proved significantly-associated with B-cell ALL. We next focused on function and clinical correlations of the cysteine and glycine-rich protein 2 (CSRP2). Quantitative real-time polymerase chain reaction (RT-qPCR) was used to examine gene transcript levels in bone marrow samples from 236 adults with B-cell ALL compared with samples from normals. CSRP2 was over-expressed in 228 out of 236 adults (97%) with newly-diagnosed B-cell ALL. A prognostic value was assessed in 168 subjects. In subjects with normal cytogenetics those with high CSRP2 transcript levels had a higher 5-year cumulative incidence of relapse (CIR) and worse relapse-free survival (RFS) compared with subjects with low transcript levels (56% [95% confidence interval, 53, 59%] vs. 19% [18, 20%]; P = 0.011 and 41% [17, 65%] vs. 80% [66-95%]; P = 0.007). In multivariate analyses a high CSRP2 transcript level was independently-associated with CIR (HR = 5.32 [1.64-17.28]; P = 0.005) and RFS (HR = 5.56 [1.87, 16.53]; P = 0.002). Functional analyses indicated CSRP2 promoted cell proliferation, cell-cycle progression, in vitro colony formation and cell migration ability. Abnormal CSRP2 expression was associated with resistance to chemotherapy; sensitivity was restored by down-regulating CSRP2 expression.

Background In trials designed to evaluate new therapies for hematologic malignancies, end points such as leukemia-free survival are often used as surrogates for overall survival in acute leukemia. We aimed to assess whether leukemia-free survival is an acceptable statistical surrogate for overall survival when applied to remission maintenance therapy for acute myeloid leukemia. Design and Methods Data were analyzed from a randomized Phase III trial of remission maintenance immunotherapy with histamine dihydrochloride plus low-dose interleukin-2 versus no treatment in adults with acute myeloid leukemia. A two-stage surrogate validation model was applied in which correlations between Kaplan-Meier estimates of leukemia-free survival and overall survival, and between log hazard ratios reflecting treatment effects were analyzed. Country of patient enrollment was the unit of analysis. Results Kaplan-Meier estimates of overall survival at 36, 48, and 60 months and leukemia-free survival at 24 months were reasonably correlated (R(2) ranging from 0.44 to 0.84) both for the overall (n=320) and first complete remission (n=261) populations. The effects of histamine dihydrochloride/interleukin-2 on log hazard ratios for leukemia-free survival and overall survival were well correlated (R(2)=0.88-0.93). Conclusions The significant correlations between overall survival and the surrogate end point (leukemia-free survival) and between the effect of histamine dihydrochloride/interleukin-2 on leukemia-free survival and overall survival satisfy the two-stage surrogate validation model. (ClinicalTrials.gov Identifier: NCT00003991) funding to support these analyses and preparation of this paper was provided by EpiCept Corporation. EpiCept Corporation did not contribute to any of the analyses presented here, nor to their interpretation.

DNMT3A mutations are seen in ∼5% of patients with chronic myelomonocytic leukemia (CMML) and thus far, have had an indeterminate prognostic impact on survival. We carried out this study to assess the prognostic impact of DNMT3A mutations on a larger informative cohort of CMML patients (n = 261). DNMT3A mutations were seen in 6% (n = 16); 56% (n = 9) male, with a median age of 64 years. Eighty-one % of DNMT3A mutations were missense, with the Arg882 mutational hot spot accounting for 63% of all changes. Five (31%) patients had an abnormal karyotype whereas concurrent gene mutations (SF3B1/SRSF2/U2AF1-56%, TET2-50%, and ASXL1-25%) were seen in all patients. Apart from a higher frequency of SF3B1 (P = 0.0001) and PTPN11 (P = 0.005) mutations and a lower frequency of SRSF2 (P = 0.004) mutations, there were no significant differences between DNMT3A mutated patients and their wildtype counterparts. In univariate analysis, survival was shorter in DNMT3A mutated (median 8 months) versus wildtype (median 27 months) patients (P = 0.0007; HR 2.9, 95% CI 1.5-5.7); with other variables of significance including lower hemoglobin (P = 0.002), higher leukocyte count (P = 0.0009), higher monocyte count (P = 0.0012), circulating blast % (P = 0.001), circulating immature myeloid cells (P = 0.01), bone marrow blast % (P = 0.045), abnormal karyotype (P = 0.02), and ASXL1 (P = 0.01) mutations. In a multivariable model that included the aforementioned variables, when both DNMT3A and ASXL1 mutations were added, only DNMT3A (P

Background: Anthracylines are one of the major classes of drugs active against acute myeloid leukemia (AML). Increased doses of daunorubicin during induction therapy for AML have been shown to improve remission rates and survival. The ALLG used idarubicin in induction therapy at a dose of 9 mg/m2 x 3 days (total dose 27 mg/m2) in combination with high-dose cytarabine and etoposide (Blood 2005, 105:481), but showed that a total idarubicin dose of 36 mg/m2 was too toxic in this context (Leukemia 2001, 15:1331). In order to further improve outcomes in adult AML by anthracycline dose escalation, we conducted a phase 3 trial comparing standard to an increased idarubicin dose during consolidation therapy. Methods: Patients achieving complete remission after 1 or 2 cycles of intensive induction therapy (idarubicin 9 mg/m2 daily x3, cytarabine 3 g/m2 twice daily on days 1,3,5 and 7, and etoposide 75 mg/m2 daily x7; ICE protocol) were randomized to receive 2 cycles of consolidation therapy with cytarabine 100 mg/m2 per day for 5 days, etoposide 75 mg/m2 for 5 days, and idarubicin 9mg/m2 daily for either 2 or 3 days (standard and intensive arms respectively). No further protocol therapy was given. The primary endpoint was leukemia-free survival from randomization to consolidation therapy (LFS) with overall survival (OS) as secondary endpoint. Results: A total of 422 patients with AML (excluding cases with CBF rearrangements or APL) aged 16 to 60 years were enrolled between 2003-10, with 345 (82%) achieving complete remission, and 293 being randomized to standard (n=146) or intensive (n=147) consolidation arms. The median age was 45 years in both arms (range 16- 60), and both groups were balanced for intermediate versus unfavorable karyotypes and for frequency of mutations involving FLT3-ITD and NPM1 genes. Of the randomized patients, 120 in the standard arm (82%) and 95 in the intensive arm (65%) received the second consolidation cycle (p Conclusion: We conclude that in adult patients in complete remission after intensive induction chemotherapy an increased dose of idarubicin delivered during consolidation therapy results in improved LFS, without increased non-hematologic toxicity. Figure 1. Figure 1. Disclosures Szer: Ra Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alnylam: Honoraria, Membership on an entity's Board of Directors or advisory committees. Marlton:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wei:Novartis: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; CTI: Consultancy, Honoraria; Abbvie: Honoraria, Research Funding; Servier: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Cartwright:ROCHE: Consultancy, Membership on an entity's Board of Directors or advisory committees. Roberts:Servier: Research Funding; Janssen: Research Funding; Genentech: Research Funding; AbbVie: Research Funding. Mills:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Meeting attendance sponsorship. Gill:Janssen: Membership on an entity's Board of Directors or advisory committees. Seymour:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

e18501Background: HSCT has been reported to be a treatment option for elderly patients with AML. Here we analyze the outcome of CT compared to HSCT in elderly AML patients according to genetic risk...

Myelodysplastic syndromes (MDS) are myeloid neoplasms defined by peripheral cytopenia, dysplasia of myeloid cells and an increased risk to transform to secondary acute myeloid leukemia (AML). Although several laboratory and molecular risk factors and scoring systems have been established, little is known about genetic features contributing to disease evolution, AML development, and survival. Accumulating evidence suggests that iron metabolism and transfusion frequency are important prognostic determinants in MDS. It has also been described that patients with MDS frequently display HFE gene variants. However, little is known about the clinical impact of HFE variants. We examined the HFE status by restriction fragment length polymorphism (RFLP) analysis covering 2 common variants (H63D and C282Y) in 167 patients with MDS (observation-period: 1992-2019) and in 494 healthy Austrian controls. The median age of our MDS patients at diagnosis was 69 years (range 27-85 years) with a f:m ratio of 1:1.13. In the MDS cohort the international prognostic scoring systems, IPSS and IPSS-R, were applied, and in 94 patients a ´myeloid mutation´ screen was performed by next-generation sequencing (NGS). In all patients, serum ferritin levels were recorded at diagnosis and during follow up. Variant HFE species (H63D and/or C282Y) were detected in 63/167 patients with MDS (38.4%) and in 170/494 controls (34.4%). Median ferritin levels at diagnosis were slightly higher in HFE-mutated patients (409 mg/dL; range: 23-7415 mg/dL) compared to non-mutated patients (346.5 mg/dL; range: 10-5450 mg/dL) (p=0.62). During the first 2 years of transfusion therapy, HFE-mutated patients showed a slightly faster increase in serum ferritin levels compared to non-mutated patients. However, again, the difference was not significant, and patients with massive iron overload were found in both cohorts. When examining French-American-British (FAB) subgroups of MDS, the percentage of patients withHFE variants was higher in the group with refractory anemia, RA (22/53=41.5%) or RA with ring sideroblasts, RARS (17/39=43.9%) than in the group of RA with excess of blasts, RAEB (16/46=34.8%) or RAEB in transformation (5/17=29.4%). In CMML, 5/12 patients (41.7%) were found to carry a HFE variant. Clear differences were also observed between subgroups of MDS patients classified by World Health Organization (WHO) criteria. The prevalence of HFE mutations was 50.0% (13/26) in patients with ring sideroblasts (RS) and multilineage dysplasia (MDS-RS-MLD), 50.0% in MDS-MLD (6/12), 43% (7/18) in MDS with RS and single-lineage dysplasia (MDS-RS-SLD), 42.9% (12/28) in patients with excess of blasts-1 (MDS-EB1), 38.9% (7/18) in MDS-SLD, 21.4% (6/28) in MDS-EB2, and 20% (2/10) in MDS with isolated 5q-. When splitting patients according to the IPSS and IPSS-R, patients at highest risk were found to have a lower prevalence of HFE variants (IPSS high: 20%; IPSS-R very high: 15.4%) compared to other risk groups (IPSS low: 34.9%, int-1: 42.0%, int-2: 31.0%; and IPSS-R very low: 33.3%, low: 38.5%, int: 36.8%, high: 42.9%). Next, we examined correlations between HFE variants and somatic myeloid mutations in our MDS patients (n=94). No significant correlations were found when comparing expression of HFE variants with somatic mutations in ASXL1, ASXL1, SF3B1, SRSF2, TET2, DNMT3A, RUNX1, NRAS, TP53, IDH2 or EZH2 detected by NGS. Finally, we examined the HFE status in the context of clinical end points. In these studies, we found a clear difference in AML-free survival between HFE-mutated and non-mutated patients, although the difference did not reach statistical significance (p=0.089) (Figure 1A). No differences in overall survival (OS) were found when comparing patients with or without HFE variants (Figure 1B). In conclusion, the HFE variants H63D and C282Y are frequently detected in Austrian patients with MDS. These variants are more commonly detectable in low risk FAB patients and correlate roughly with higher ferritin levels at diagnosis and during transfusion therapy. In addition, HFE-mutated MDS patients have a slightly better AML-free survival. However, the correlation is weak. Therefore, we currently do not recommend screening for HFE gene variants at diagnosis in patients with MDS unless ferritin levels are excessively high or increase very rapidly during transfusion suggesting the possibility of a concomitant primary hemochromatosis. Disclosures Valent: Blueprint: Research Funding; Celgene: Honoraria; Deciphera: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Sperr:Novartis: Honoraria; Celgene: Consultancy, Honoraria.

Leukemia-free survival in myeloid leukemia, but not in lymphoid leukemia, is predicted by early CD4+ reconstitution following unrelated cord blood transplantation in children: a multicenter retrospective cohort analysis

Contains fulltext : 69575.pdf (Publisher’s version ) (Closed access) BACKGROUND: Alloreactive NK cells play a role in tumor eradication after allogeneic HLA mismatched stem cell transplantation (SCT). The effect of NK alloreactivity in HLA identical SCT is still under debate and in particular in transplantation for chronic myeloid leukemia (CML) the data are very limited and with conflicting outcome. The aim of our study was to evaluate the effect of KIR genes and KIR ligands on leukemia free survival (LFS) and relapse rate in a well-defined, homogeneous group of CML patients phase upon HLA identical sibling SCT. METHODOLOGY: We retrospectively analyzed the effect of KIRs and KIR ligands (C1 and C2) on LFS and relapse in 70 CML patients in 1st chronic phase, who had received an HLA identical sibling graft. For KIR typing we used a single PCR based KIR typing protocol that also included primers allowing for the identification of the KIR binding site on HLA-Cw (AA 77 and 80). PRINCIPAL FINDINGS: The data show clear differences in transplant outcome between patients having both ligands (C1 and C2) as compared to patients having only one ligand (C1 or C2). In the latter group, the stimulatory KIR2DS5 gene was associated with improved leukemia free survival (p=0.007; hazard ratio 4.3; 95% confidence interval 1.3-6.7) and lower relapse rates (p=0.028; HR 4.3, 95% CI 1.1-9.1). In contrast, in patients carrying both ligands, KIR2DS5 was associated with reduced LFS (p=0.0056; HR 0.3; 95% CI 0.1-0.7) and higher relapse rate (p=0.02; HR 0.35, 95% CI 0.1-0.8). CONCLUSIONS: Our data indicate a role for an NK mediated anti-CML response after HLA identical sibling SCT that is influenced by KIR ligands and, more importantly, by stimulatory KIRs present in the donor.

Background: Haploidentical (Haplo) stem cell transplantation (SCT) provide a curative option for nearly all Acute Myeloid Leukemia (AML) patients lacking an HLA matched donor. However, outcomes following Haplo-SCT vary and are dependent on a number of individual features. Integrative prognostic models for decision support towards a Haplo-SCT are lacking. We sought to develop a prediction model of Leukemia-Free Survival (LFS) for AML patients undergoing a Haplo-SCT. Methods: A total of 1,804 de-novo (80%) and secondary (20%) AML patients who received a non-T-cell depleted Haplo-SCT between the years 2005-2017 were included. All patients were reported to the registry of the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT). To account for non-linear associations, violation of the proportional hazard assumption, and to reduce bias associated with feature selection, a non-parsimonious non-parametric machine learning algorithm, Random Survival Forest (RSF), was used. RSF provides a continuous probabilistic estimation of LFS by fitting an ensemble of decision trees. Variables included in the model were reflective of patient, disease, and transplantation characteristics. Since RSF models are not readily interpretable (i.e., "black box" models) variable importance (VIMP) of covariates included in the model (Xv), were assessed by calculating the difference in prediction error before and after permuting Xv. The model's generalizability and accuracy were tested through repetitive bootstrapping (5000 iterations) and calculation of the C-index. Results: The median age of the patients was 53 years. The majority had an early disease status (complete remission [CR] 1[44%]) with intermediate cytogenetic risk (43%) and were undergoing allogeneic transplantation for the first time (93%). Reduced-intensity conditioning (RIC) was used in 57% of cases, and grafts were from peripheral blood in 54% of transplants. For graft-versus-host disease (GvHD) prophylaxis, 82% of the patients received post-transplant cyclophosphamide (PTCy) and 18% anti-thymocyte globulin (ATG). The median follow-up duration was 2.0 years. In the RSF prediction model, the top-ranking variables (Figure A) were disease status, GvHD prophylaxis, time from diagnosis to transplantation, and age. Bootstrapped C-index of the prediction model was 0.66. Prognostic discrimination was assessed by dividing the predicted LFS probabilities into quartiles that were then used to plot Kaplan-Meier curves, demonstrating LFS ranging from 24.8%-60.1% at 2-years (Figure B). Differing features of the four prognostic groups are listed in the Table. Conclusions: Our group has developed the first prediction model for LFS in AML patients treated with a Haplo-SCT. The model is based on a machine learning technique and provides an individualized estimation of LFS probability. It is conceivable that once this model is verified, it could serve as an important clinical tool when considering a patient to Haplo-SCT. Figure. Figure. Disclosures Angelucci: Vertex Pharmaceuticals Incorporated (MA) and CRISPR CAS9 Therapeutics AG (CH): Other: Chair DMC; Jazz Pharmaceuticals Italy: Other: Local ( national) advisory board; Celgene: Honoraria, Other: Chair DMC; Novartis: Honoraria, Other: Chair Steering Comiittee TELESTO Protocol; Roche Italy: Other: Local (national) advisory board. Tischer:Jazz Pharmaceuticals: Other: Jazz Advisory Board. Mohty:MaaT Pharma: Consultancy, Honoraria.

6523 Background: Complete remission rates similar to those of younger pts are obtained in elderly AML pts (OSHO AML 1997). However, OS and LFS remain dismal because of extremely high relapse rates....

6505 Background: Acquired mutations of the flt3 and npm1 genes have been shown to determine outcome in younger pts with AML. Here, the influence of flt3 and npm1 mutations on outcome of elderly pts (> 60 a) was analyzed in relation to either chemotherapy (CT) or SCT. Methods: Of the 498 pts entered into the curative arm of the #69 study for pts > 60 a, 357 are evaluable and 158 of these had flt3 and npm1 available as of Oct 2009. Complete remission was obtained in 191 of the 357 pts after induction chemotherapy. Flt3 and npm1 was available in 53 of 81 and 44 of 59 pts in CR1 receiving either a second consolidation or allogeneic SCT. Consolidation consisted of CT or, in pts with related or unrelated donors, of SCT after 200 cGy TBI. Results: Overall survival (OS) of the 158 pts with known npm1 and flt3(ITD) status was 33 ± 3% at 2a. Mutation status did not significantly influence OS, but did influence the EFS of pts in CR1 after induction (27 ± 11% vs. 51 ± 7% for flt3(ITD)+ vs. flt3(ITD)- p < 0.01; 69 ± 9...

A significant number of patients who relapse after allogeneic stem cell transplantation (SCT) for chronic myeloid leukemia (CML) will achieve sustained remissions after treatment with interferon-, second transplants, or donor lymphocyte infusions (DLI) from the original stem cell donor. Because leukemia-free survival (LFS) is at present defined as survival without evidence of relapse at any time posttransplant, patients who relapse but are then restored to complete remission are treated as failures when estimating LFS. We have established a new category of LFS, termed current LFS (CLFS), which we define as survival without evidence of leukemia at the time of most recent assessment. To gauge the contribution of treatment for relapse to the efficacy of allogeneic SCT in the management of CML in chronic phase, we compared conventional LFS and CLFS in 189 consecutive patients who underwent SCT over a 7-year period with a minimum follow-up of 3 years. Patients with sibling donors (n = 111) received cyclosporine and methotrexate as prophylaxis for graft versus host disease; patients with unrelated donors (n = 78) also received Campath-1G or 1H as intravenous T-cell depletion. The 5-year LFS defined conventionally was 36% (CI: 29% to 43%) versus a 5-year CLFS of 49% (CI: 36% to 62%). This new method of defining LFS confirms the view that appropriate “salvage” therapy, principally DLI, makes a major contribution to the capacity of allogeneic SCT to produce long-term LFS in patients who receive SCT for CML and emphasizes the importance of redefining LFS to take account of successful treatment of relapse.

7003 Background: Even after reaching initial CR, most AML patients > 60 years relapse within 2 years of diagnosis. Cytogenetic high risk AML (abn 3q26, abn 11q23, -5/5q-, -7/7q- and complex) has an even worse prognosis. Attempts to improve survival by intensifying consolidation chemotherapy have so far failed. We investigated the role of allogeneic HCT in comparison to chemotherapy among patients with high risk cytogenetics entered into the OSHO AML 97 protocol. Methods: Initial treatment consisted of a course of induction therapy (AraC 2 g/m2 iv on day 1,3,5,7 + mitoxantrone 10 mg/m2 iv day 1 –3, repeated once in case of PR) followed by one consolidation course (AraC 240 mg/m2 iv day 1 –5 + mitoxantrone 10 mg/m2 iv day 1 –2). Patients in CR1 after the consolidation I were either treated with an additional consolidation therapy or with an allogeneic HCT from related (n=2) or unrelated (n=10) donors. Transplant patients were conditioned with fludarabine and TBI 200 cGy and immunosuppressed with cyclosporine and mycofenolate mofetil. Results: A total of 347 patients are evaluable. Of 105 (33%) patients with high-risk cytogenetics, 53 (50%) went into remission after one or two cycles of induction chemotherapy. Of these 53 patients, 42 received consolidation I and 35 patients were available for either consolidation II (n=23) or HCT (n=12). Median age of the patients receiving chemotherapy was 64 (range 61–77) years and that of the transplant patients was 64 (range 61–68) years. LFS at 4 years was 42 ± 14% after HCT and 15 ± 8% after chemotherapy. Major differences in relapse incidences were seen between the two groups, with the lowest RI at 4 years after HCT (36 ± 15%) followed by chemotherapy (85±8%, p No significant financial relationships to disclose.

Between April 1982 and February 1997 39 patients (24 male, 15 female) with refractory acute leukemia and a median age of 31 years (19-51 years) received allogeneic marrow grafts from an HLA-identical sibling (n = 27), HLA-identical unrelated donor (MUD; n = 10) or 1-antigen mismatched unrelated donor (n = 2). Twenty-eight patients had acute myelogenous leukemia and 11 acute lymphoblastic leukemia. For conditioning most patients received total body irradiation combined with cyclophosphamide (n = 23) or etoposide (n = 7). For graft-versus-host disease prophylaxis patients received cyclosporin A (CsA) and methotrexate (MTX) (n = 20), MTX alone (n = 3), CsA and methylprednisone (n = 6), or CsA alone (n = 10), respectively. As of June 1997 probability of leukemia-free survival projected to 3 years after BMT was 14% for patients given sibling marrow grafts and 28% after MUD transplantation. Transplant-related mortality projected to 3 years was 32% after sibling and 37% after MUD marrow grafting. Although not significantly different, probability of relapse projected to 3 years after BMT was lower after MUD at 56% compared to 78% with sibling BMT. Thus, high-dose chemo/radiotherapy followed by allogeneic marrow infusion has a curative potential for patients with refractory leukemia and offers the chance of long-term disease-free survival for some patients.

Background The Dynamic International Prognostic Scoring System (DIPSS)-plus currently provides the most comprehensive prognostic model for primary myelofibrosis (PMF) (JCO 2011;29:392). DIPSS-pluse uses eight independent predictors of inferior survival: age >65 years, hemoglobin 25 x 109/L, circulating blasts ³1%, constitutional symptoms, unfavorable karyotype, red cell transfusion need and platelet count Methods Study patients fulfilled the 2016 WHO criteria for the diagnosis of PMF, including both pre-PMF and overt PMF (Blood. 2016;127:2391). Additional selection criteria included the availability of absolute monocyte count (AMC) and percentage at time of referral. Targeted next generation sequencing was used to screen for prognostically-relevant mutations (Blood 2015 126:354). Statistical analyses considered clinical and laboratory parameters obtained at time of initial referral to the Mayo Clinic. Results Patient characteristics: The study population included 454 patients (median age 64 years; 62% males); 293 (64%) patients harbored JAK2 mutations, 74 (16%) type 1/like CALR, 16 (3%) type 2/like CALR, 24 (5%) MPL and 47 (10%) were "triple-negative". DIPSS-plus risk distribution was 29% high, 38% intermediate-2, 17% intermediate-1 and 15% low; 27% displayed red cell transfusion-dependency, 29% constitutional symptoms, 70% palpable splenomegaly and 36% abnormal karyotype, including 13% with unfavorable karyotype. 301 patients were screened for ASXL1 mutations with 39% mutated, 297 for SRSF2 mutations with 15% mutated, 286 for U2AF1 with 18% mutated, 253 for SF3B1 with 6% mutated, 229 for EZH2 with 5% mutated and 110 for IDH1/2 with 7% mutated. Clinical, cytogenetic and molecular comparisons between PMF patients with and without monocytosis: Among all study patients, 376 (83%) displayed AMC 3 x 10(9)/L; n=13) monocytosis. Comparison of these three groups revealed that monocytosis was significantly associated with older age (p=0.0001), higher leukocyte count (p Survival analysis: After a median follow up of 3.2 years, 265 (58%) deaths and 38 (8%) leukemic transformations were documented. In univariate analysis, all 8 variables included in DIPSS-plus were significantly associated with shortened survival (p3 x 10(9)/L (p3 x 10(9)L) was independent of each one of the eight DIPSS-plus variables, DIPSS-plus, driver mutational status, ASXL1 and SRSF2 mutations (p Conclusion The current study identifies monocytosis as a powerful risk factor for both overall and leukemia-free survival in PMF and the effect was independent of currently established prognostic models and genetic risk factors. It was particularly noteworthy to document similar distribution of driver mutations among the three monocyte categories. Figure Figure. Disclosures No relevant conflicts of interest to declare.

Introduction: The prognosis of refractory/relapsed acute lymphoblastic leukemia (ALL) is poor with chemotherapy or even allogeneic hematopoietic stem cell transplantation (HSCT). Although our immunotherapy with autologous anti-CD19 chimeric antigen receptor T cells (CART) has resulted in 88.6% complete remission (CR) in refractory/relapsed B-cell ALL (B-ALL), many patients relapsed at around 2 months after CART therapy (unpublished data). Our current strategy is to perform HSCT for refractory/relapsed B-ALL in CR by CART therapy to attain continuous leukemia-free survival (LFS). However, majority of the patients with CART therapy developed cytokine release syndrome which may increase transplant-related mortality (TRM). Moreover, all patients with CART therapy have very tough diseases which could result in higher relapse rate after transplant. Objective: In current study, the safety and efficacy of HSCT for refractory/relapsed B-ALL after CART therapy were investigated. The patients with B-ALL who received HSCT during the same time period without CART therapy were as control. Patients and Methods: Between July 2015 and May 2016, consecutive 22 patients with refractory/relapsed CD19+ B-ALL in CR by CART therapy followed by allogeneic HSCT in our hospital were analyzed as CART group; and consecutive 89 patients with B-ALL in CR who received allogeneic HSCT in our hospital during the same time period but without previous CART therapy were as control group. Clinical characteristics between two groups was comparable except more CR1 (22.7% vs. 57.3%) in control group and more CD3+ cells infused (1.93x108/kg vs. 1.46 x108/kg, p=0.026) in CART group. The median age was 8 (2-44) years, 15 (2-52) years in CART and control groups (p=0.147). The median disease course was 19.1 (3.9-53.7) months, 10.6 (3.7-123.0) months in CART and control groups (p=0.385). The median time from CART therapy to HSCT was 86 (31-172) days. Disease status was 22.7% cases in CR1, 54.5% in CR2, 18.2% in CR3 and 4.5% in CR4 in CART group; and 57.3% cases in CR1, 36.0% in CR2 and 6.7% in CR3 in control group (p=0.08). Minimal residual disease pre-conditioning by flow cytometry was positive in 22.7%, 31.5% patients in CART and control groups (p=0.422). Donor source was identical sibling (IS) in 13.6%, unrelated (UR) in 31.8% and haploidentical (HI) in 54.5% in CART group; and IS in 14.6%, UR in 16.9% and HI in 68.5% in control group (p=0.313). Myeloablative conditioning regimens were administered with either total body irradiation (TBI) plus cyclophosphamide (Cy)/ fludarabine (Flu)-based in 90.9% cases or busulfan (Bu) plus Cy/ Flu-based in 9.1% cases in CART group; and TBICY/Flu-based in 85.4% cases or BuCy/Flu-based in 14.6% cases in control group (p=0.498). Antithymocyte globulin was used in UR and HI transplants. Cyclosporine, short-term methotrexate, and mycophenolate mofetil were employed for GVHD prophylaxis. Results: The median time to neutrophil engraftment was similar between two groups (14 days vs. 13 days, p=0.196), but platelet engraftment was slower in CART group (14 days vs. 12 days, p=0.031). Cumulative incidence of grade II-IV acute GVHD (aGVHD) was higher in CART group (57.6% vs. 33.1%, p=0.009), which may related to higher CD3+ cells infused in CART cohort; but the incidences of grade III-IV aGVHD were no statistical significance (25.1% vs. 15.7%, p=0.564) in two groups. No remarkable differences were seen in CMV reactivation (45% vs. 51.7%, p=0.601) and transplant-associated thrombotic microangiopathy (13.6% vs. 9.0%, p=0.514) in two groups. No significant difference was found in TRM between CART and control groups (7.1% vs. 15.2%, p=0.808). Relapse rates were similar in two groups (5.0% vs. 6.9%, p=0.888). With a median follow-up 9 (2-12) months, LFS was comparable in CART and control groups (84.8% vs. 80.9%, p=0.937). Conclusions: Our preliminary results have shown that the strategy with CART therapy followed by allogeneic HSCT in refractory/relapsed B-ALL is very safe and effective with similar outcomes in TRM, relapse rate and LFS compared with control group. CART therapy has resulted in very good CR in refractory/relapsed B-ALL and allowed the patients to achieve continuous LFS by subsequent allogeneic HSCT, which is revolutionary modality for those patients who have otherwise incurable diseases. Disclosures No relevant conflicts of interest to declare.

Survival in cytogenetically high-risk patients with acute myeloid leukemia or myelodysplastic syndromes is significantly worse in the presence of a monosomal karyotype (MK). The objective of the present study was to determine whether the same held true for primary myelofibrosis. Among 793 primary myelofibrosis patients seen at our institution, 62 displayed an unfavorable karyotype by way of complex karyotype (n = 41) or sole trisomy 8 (n = 21). Seventeen (41%) of the 41 patients with complex karyotype were classified as having an MK. Median survival was 6, 24, and 20 months in patients with MK, complex karyotype without monosomies, and sole trisomy 8, respectively (P < .0001). The corresponding 2-year leukemic transformation rates were 29.4%, 8.3%, and 0 (P < .0001); hazard ratios (95% confidence intervals) were 6.9 (1.3-37.3) and 14.8 (1.7-130.8). The prognostic relevance of MK was not accounted for by the Dynamic International Prognostic Scoring System. We conclude that MK in primary myelofibrosis is associated with extremely poor overall and leukemia-free survival.

Introduction In the treatment of acute myeloid leukemia, initial induction guidelines frequently include performing a day 14 bone marrow biopsy to assess response. A second induction is then recommended for patients with morphologic residual leukemia (≥5% blasts). Recent retrospective reviews have shown no difference in complete response (CR) rates amongst patients with residual leukemia based on day 14 marrow assessment who were and were not given a second induction. In our single center retrospective study, we compared patients with residual blast counts ≥5% to identify differences in leukemia free survival (LFS) and overall survival (OS) in those who did and did not receive a second induction. In addition we examined the cytogenetic profile of Day 14 and remission bone marrows. Methods: Consecutively treated patients with newly diagnosed primary and secondary AML over the age of 18 who received daunorubicin based induction with a curative intent from 2006 to 2014 were obtained via cancer center medical records. Outcome data was followed until May 1st 2015. We reviewed demographic (age, sex, ECOG PS, co-morbidities) as well as AML specific data (daunorubicin dose, use of etoposide, initial bone marrow blast count, initial white blood cell count, bone marrow blast count at day 14, cytogenetic stratification, CR rate, allogeneic stem cell transplant, LFS and OS). Patients included in survival analysis were required to have an initial and day 14 bone marrow biopsy with morphologic identification of residual leukemia on the day 14 marrow. Cytogenetic risk stratification was based on NCCN guidelines. Morphological CR was defined based on International Working Group criteria (Cheson, JCO, 2003). Positive (PPV) and negative predictive value (NPV) for CR were calculated by considering a BM of less than 5% at Day 14 a positive screening test for obtaining CR. Data was analyzed using Mann Whitney U test and chi square analysis as appropriate. LFS and OS were estimated using the Kaplan Meier method and compared using the log rank test. All calculations and graphs were obtained using STATA/SE 12.1. Results: Of the 91 patients initially identified, 67 had Day 14 marrows performed and 31 had residual blast counts ≥5%. For our overall cohort, we found a PPV of 76% and NPV of 65% for Day 14 marrows in determination of CR, which is in line with previous studies. No statistical differences were seen between the groups (Table 1), although patients who were reinduced trended toward higher initial white blood cell counts while those who were not reinduced trended towards improved CR rates. Comparing patients with residual disease at Day 14 who were or were not reinduced, we found no statistical difference for LFS and OS between the two groups (p 0.87 and 0.96 respectively). Interestingly, in comparing cytogenetics, two patients with unfavorable cytogenetics on initial BM converted to normal/intermediate cytogenetics after induction despite a residual blast count greater than 5%. Both obtained CR, one with and one without reinduction. Another patient with unfavorable cytogenetics at day 14 obtained CR with normal cytogenetics without reinduction. Conclusions: Although of limited size, our study suggests that reinduction based on Day 14 marrow is of limited use in predicting LFS and OS in AML. Better methods to determine residual leukemia following initial induction therapy are required in order to help guide treatment decisions. | | No Reinduction (n=17) | Reinduction (n=14) | p value | | ------------------------------------------------------- | ---------------------------- | ------------------------- | ------- | | Age (Median) | 63 | 57.5 | 0.46 | | Male:Female | 8:9 | 8:6 | 0.58 | | ECOG PS 0 1 | 11 6 | 10 4 | 0.69 | | Initial WBC (Median) | 5.2 | 11.7 | 0.06 | | Initial % Bone Marrow Blast (Median) | 0.53 | 0.48 | 0.56 | | DNR Dose 60mg/m2 90mg/m2 | 11 6 | 8 6 | 0.67 | | Etoposide Given | 5 | 4 | 0.96 | | Cytogenetic Risk Intermediate Unfavorable | 9 8 | 7 7 | 0.87 | | Complete Response | 10 | 4 | 0.09 | | Allo-SCT | 7 | 8 | 0.38 | Table 1. Demographics of patients with and without reinduction chemotherapy with residual disease on repeat bone marrow biopsy ![Figure 1.][1] Figure 1. Kaplan-Meier Curve for Overall Survival ![Figure 2.][1] Figure 2. Kaplan-Meier Curve for Leukemia Free Survival Disclosures No relevant conflicts of interest to declare. [1]: pending:yes

Among spliceosome component mutations, those involving SF3B1 are most frequent in myelodysplastic syndromes with ring sideroblasts (MDS-RS; ∼ 75% incidence) and SRSF2 in chronic myelomonocytic leukemia (∼ 28% incidence). We recently reported on the lack of prognostic significance for SF3B1 mutations in both MDS-RS and primary myelofibrosis (PMF). In the current study, we examined the prevalence and prognostic relevance of SRSF2 mutations in PMF. Among 187 patients screened, 32 (17%) harbored SRSF2 monoallelic mutations affecting residue P95. Significant associations were demonstrated between SRSF2 mutations and advanced age (P < .01), IDH mutations (P < .01), and higher DIPSS-plus risk category (P = .03). SRSF2 mutations were associated with shortened overall (P < .01) and leukemia-free (P < .01) survival; the adverse effect on survival was independent of DIPSS-plus (P = .01; HR = 1.9; 95% CI, 1.1-3.0) and IDH mutations (P < .01; HR = 2.3; 95% CI, 1.4-3.8). In conclusion, SRSF2 mutations are relatively common in PMF, cluster with IDH mutations, and are independently predictive of poor outcome.

Donor lymphocyte infusion (DLI) for patients who relapse following an allogeneic stem cell transplant has proved remarkably durable. Because of the potential for second remissions with DLI, the current leukemia free survival (CLFS), which is the probability that a patient has not failed the entire course of the treatment, is becoming of interest to clinical investigators. Based on either a multistate Markov model or a linear combination of Kaplan-Meier estimators, we explore regression models for the CLFS. We focus on the two sample problem and we develop confidence bands for the CLFS or for differences in CLFS as well as a Kolmogorov type hypothesis test using a re-sampling technique. We also examine the use of pseudo-values to make inference on the direct effects of covariates on the CLFS function and we develop a score test for the equality of two CLFS. We illustrate these inference methods on a bone marrow transplant dataset.

The clinical relevance of JAK2V617F allele burden in primary myelofibrosis (PMF) has not been previously studied. Bone marrow-derived DNA from 199 patients with PMF was subjected to qualitative (n=199) and quantitative (n=129) analysis for V617F. Mutational frequency was 58% and median mutant allele burden ratio in V617F-positive patients was 29% (range, 1-74%). Multivariable analysis identified older age, platelet countor =100 x 10(9) l(-1) and peripheral blood blast percentage3% as being associated with a positive mutational status. The mere presence of the mutation did not affect the incidence of thrombosis (P=0.78), overall survival (P=0.22) or leukemia-free survival (P=0.5). The 129 patients with allele burden information were divided into four groups: V617F-negative (n=53) and V617F-positive with mutant allele burden in the lower quartile (n=19), middle quartiles (n=38) or upper quartile (n=19) range. Kaplan-Meier plots revealed significantly shortened overall (P=0.0008) and leukemia-free (P=0.01) survival for the lower quartile, but not for upper quartile allele burden group; independent prognostic relevance was validated by multivariable analysis. We conclude that low V617F allele burden in PMF might indicate the presence of an overriding V617F-negative clone that confers a more aggressive disease phenotype.

Purpose Blinatumomab, a bispecific single-chain antibody targeting the CD19 antigen, is a member of a novel class of antibodies that redirect T cells for selective lysis of tumor cells. In acute lymphoblastic leukemia (ALL), persistence or relapse of minimal residual disease (MRD) after chemotherapy indicates resistance to chemotherapy and results in hematologic relapse. A phase II clinical study was conducted to determine the efficacy of blinatumomab in MRD-positive B-lineage ALL. Patients and Methods Patients with MRD persistence or relapse after induction and consolidation therapy were included. MRD was assessed by quantitative reverse transcriptase polymerase chain reaction for either rearrangements of immunoglobulin or T-cell receptor genes, or specific genetic aberrations. Blinatumomab was administered as a 4-week continuous intravenous infusion at a dose of 15 μg/m2/24 hours. Results Twenty-one patients were treated, of whom 16 patients became MRD negative. One patient was not evaluable due to a grade 3 adverse event leading to treatment discontinuation. Among the 16 responders, 12 patients had been molecularly refractory to previous chemotherapy. Probability for relapse-free survival is 78% at a median follow-up of 405 days. The most frequent grade 3 and 4 adverse event was lymphopenia, which was completely reversible like most other adverse events. Conclusion Blinatumomab is an efficacious and well-tolerated treatment in patients with MRD-positive B-lineage ALL after intensive chemotherapy. T cells engaged by blinatumomab seem capable of eradicating chemotherapy-resistant tumor cells that otherwise cause clinical relapse.

We have previously identified sole +9, 13q- or 20q-, as 'favorable' and sole +8 or complex karyotype as 'unfavorable' cytogenetic abnormalities in primary myelofibrosis (PMF). In this study of 433 PMF patients, we describe additional sole abnormalities with favorable (chromosome 1 translocations/duplications) or unfavorable (-7/7q-) prognosis and also show that other sole or two abnormalities that do not include i(17q), -5/5q-, 12p-, inv(3) or 11q23 rearrangement are prognostically aligned with normal karyotype, which is prognostically favorable. These findings were incorporated into a refined two-tired cytogenetic-risk stratification: unfavorable and favorable karyotype. The respective 5-year survival rates were 8 and 51% (hazard ratio (HR): 3.1, 95% confidence interval (CI): 2.2-4.3; P

Background: Umbilical cord blood transplantation (UCBT) is a potentially curative therapy acute leukemia (AL) patients. Transplantation benefit must be balanced against risks, such as transplant related mortality and relapse. The complex nature of hematopoietic stem cell transplantation data (HCT), rich in interactions and possibly nonlinear associations, has motivated us to apply machine learning (ML) for predictive modeling. ML is a field of artificial intelligence and is part of the data mining approach for data analysis. Our group has recently reported on a ML based prediction model for short term HCT outcomes (Shouval R et al; JCO 2015). Using a ML algorithm, the perspective of the current study was prediction of leukemia free survival (LFS) at 2 years after an UCBT, while exploring variables' importance and interactions. Patients & Methods: A cohort of 3,149 UCBT were analyzed. Inclusion criteria encompassed patients at all ages, undergoing an UCBT (single/double unit) in EBMT centers from the year 2004 to 2014, for AL, in all disease status. All conditioning and graft versus host disease prophylaxis regiments were included. A total of 24 variables were considered, including the number of total nucleated cell dose (TNC), donor and recipients HLA typing, as well as recipient, disease and transplant characteristics. The Random Survival Forest (RSF) ML algorithm was applied for model construction and data exploration. RSF is known to be adaptive to data, is able to automatically recover nonlinear effects and complex interactions among variables, and yields nonparametric prediction over test data. The analysis pipeline consisted of prediction model development, assessment of variable importance by their minimal depth from the tree trunk, and exploration of the top ranking variable with dependence plots. The latter promotes understanding of non-trivial associations between variables and outcomes. Results : The 2 years LFS was 49%, with a median follow up of 30 months. A RSF model of 1000 trees was developed, with each tree constructed on a bootstrap sample from the original cohort. A prediction error of 36.0% was calculated. The 10 most predictive variables (in ascending order) were disease status, age, TNC harvested and infused, recipient CMV serostatus, interval from diagnosis to UCBT, transplant year, previous autologous transplant, and use of anti-thymocyte globulin (ATG). Selected findings from exploration of variables-outcome relationship with dependence plots included a varying effect of TNCs in specific subpopulations. Increasing the number of infused TNCs had a positive effect on predicted LFS in patients receiving HLA mismatched (2 or more HLA mismatch) (figure) or single unit CB grafts, and patients in earlier disease status or older age. ATG administration was associated with worse LFS, whether unadjusted or adjusted to all other variables. However, there was an additional negative effect in advanced disease status patients, recipients of HLA mismatched or single CB units grafts, and older patients. Patients in 1st complete remission (CR) had higher predicted LFS as compared to those in 2nd CR. However, in patients receiving a HLA mismatched or a double CB graft, the difference in LFS between CR1 and CR2 was attenuated. Younger age had a favorable impact in early disease status, but lost its positive effect in advanced disease. Conclusions: A prediction model for LFS 2 years post UBCT was developed using the RSF ML algorithm. Variables were ranked according to their predictive contribution. Disease status, age, and TNC count were found to be the most important factors. Dependence plots revealed interactions and nonlinear associations between variables and the outcome, such as the effect of cell dose on HLA disparity. Apart from the study's clinical findings, it carries a methodological significance. A novel ML approach for prediction, variable selection and data exploration, accounting for long term time to event outcomes, has proved useful in the field of HCT. Figure 1. Variable marginal dependence coplot of predicted LFS at 2 years against TNC, conditional on HLA matching. Individual cases are marked with blue circles (alive or censored) and red `x's (event). Linear smooth (a linear extrapolation of the prediction function), with shaded 95% confidence band, indicates trends of variable dependence. Figure 1. Variable marginal dependence coplot of predicted LFS at 2 years against TNC, conditional on HLA matching. Individual cases are marked with blue circles (alive or censored) and red `x's (event). Linear smooth (a linear extrapolation of the prediction function), with shaded 95% confidence band, indicates trends of variable dependence. Disclosures Mohty: Janssen: Honoraria; Celgene: Honoraria. Sanz:JANSSEN CILAG: Honoraria, Research Funding, Speakers Bureau. Bader:Neovii: Other: Institutional grants; Medac: Other: Institutional grants; Riemser: Other: Institutional grants; Amgen: Consultancy; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy.

The primary objective of this phase 3 study was to determine whether postconsolidation immunotherapy with interleukin-2 (IL-2) and histamine dihydrochloride (HDC) improved the leukemia-free survival (LFS) of adult patients with acute myeloid leukemia (AML) in complete remission (CR). Three hundred twenty patients with AML (median age, 57 years; range, 18-84 years) were stratified by CR1 or subsequent CR (CR1) and randomly assigned to treatment with HDC/IL-2 or no treatment (control). Treatment comprised 10 21-day cycles with IL-2 (16 400 U/kg) plus HDC (0.5 mg); both compounds were administered by subcutaneous injection twice daily. Study arms were balanced for age, sex, previous treatment, leukemic karyotypes, time from CR to inclusion, and frequency of secondary leukemia. Three years after enrollment of the last patient, treatment with HDC/IL-2 was found to improve LFS over control in the study population (CR1 + CR1, n = 320; P.01, log-rank test). For patients in CR1 (n = 261), treatment significantly improved LFS (P = .01) with 3-year LFS estimates of 40% (HDC/IL-2) compared with 26% (control). Side effects were typically mild to moderate. These results indicate that HDC/IL-2 treatment offers an efficacious and tolerable treatment for patients with AML in remission.

Myelodysplastic syndromes (MDSs) pose an important diagnostic and treatment challenge because of the genetic heterogeneity and poorly understood biology of the disease. To investigate initiating genomic alterations and the potential prognostic significance of cryptic genomic changes in low-risk MDS, we performed whole genome tiling path array comparative genomic hybridization (aCGH) on CD34+ cells from 44 patients with an International Prognostic Scoring System score less than or equal to 1.0. Clonal copy number differences were detected in cells from 36 of 44 patients. In contrast, cells from only 16 of the 44 patients displayed karyotypic abnormalities. Although most patients had normal karyotype, aCGH identified 21 recurring copy number alterations. Examples of frequent cryptic alterations included gains at 11q24.2-qter, 17q11.2, and 17q12 and losses at 2q33.1-q33.2, 5q13.1-q13.2, and 10q21.3. Maintenance of genomic integrity defined as less than 3 Mb total disruption of the genome correlated with better overall survival (P = .002) and was less frequently associated with transformation to acute myeloid leukemia (P = .033). This study suggests a potential role for the use of aCGH in the clinical workup of MDS patients.

Secondary (or therapy-related) acute myelogenous leukemia (t-AML) and myelodysplastic syndrome (t-MDS) have been reported after chemotherapy with alkylating agents and/ or topoisomerase inhibitors for the treatment of Hodgkin disease, non-Hodgkin lymphoma, breast cancer, ovarian carcinoma or testicular carcinoma [1,2]. Th ese disorders usually have a very poor prognosis with conventional chemotherapy, with an estimated overall survival (OS) of less than 1 year, due to the association with several negative features, such as older age, poor risk karyotype and resistance to chemotherapy [1 – 3]. Recently, we reported a retrospective analysis of 50 patients with therapy-related myeloid neoplasms (t-MN) treated with azacitidine with an overall response rate of 42% and a median OS of 21 months. We found that OS was signifi cantly better in patients with fewer than 20% of blasts, normal karyotype and in patients treated frontline with azacitidine [4]. Quintas-Cardama and colleagues [5] recently proposed a new score for patients with t-MDS, which was created in a large series of 279 patients with a history of previous exposure to chemo- or radiotherapy for prior malignancies. Th e model was able to identify diff erent OS based on the negative prognostic weight of several features at baseline (each one with 1 point), such as age higher than 65 years, Eastern Cooperative Oncology Group (ECOG) performance score higher than 1, monosomy 7 or complex karyotype, refractory anemia with ringed sideroblasts (RARS) or refractory anemia with excess blasts types 1 and 2 (RAEB1 – 2) according to the World Health Organization (WHO) classifi cation, hemoglobin level less than 11 g/dL, platelet count less than 50 10 9 /L and transfusion requirement. Patients were divided into three prognostic groups and subdivided into good risk (0 – 2 points), with a median OS of 34 months, intermediate (3 – 4 points), with a median OS of 12 months, and poor risk (5 – 7 points), with a median OS of 5 months. Th e model was tested in 189 patients with t-MDS with a median OS of 26, 13 and 7 months, respectively. Not all patients received azacitidine, and the subset of patients treated with this drug were not specifi cally reported. We retrospectively applied this score to our series of patients uniformly treated with azacitidine with the aim of validating the new proposed t-MDS score in this setting. We applied the score in 34 patients with t-MDS (12 refractory cytopenia with multilineage dysplasia [RCMD], nine RAEB-1 and 13 RAEB-2), with an overall response rate to azacitidine of 50%. Six patients had a low score (17%), 15 patients had an intermediate score (43%) and 14 patients had a poor score (40%). Among the good risk group, one patient achieved a complete remission (CR), one patient a partial response (PR), two patients a hematological improvement (HI) and two patients stable disease. On the other hand, among the intermediate risk group of patients, six achieved a CR, three a HI and fi ve stable disease, and within poor risk patients, eight had stable disease, two patients achieved a HI and one patient a CR, whereas three patients experienced disease progression after a median of four cycles. Median OS estimated with the Kaplan – Meier method according to the score stratifi cation for low, intermediate and poor risk patients was 17, 11 and 8.6 months, respectively ( p 0.02). Similarly, leukemia-free survival (LFS) was also signifi cantly diff erent in patients with low, intermediate and poor risk score (83%, 73% and 57%, respectively, p 0.01). Two out of six low risk patients (33%) died during treatment, compared to four of 14 (28%) intermediate risk and nine of 14 (64%) poor risk patients ( p 0.02).

Allogeneic hematopoietic cell transplantation (HCT) from a matched sibling donor (MSD) may provide a cure for acute myeloid leukemia in first complete remission (AML/CR1), although the procedure is associated with a higher rate of treatment-related mortality (TRM) than autologous HCT, and it remains uncertain which modality is preferable as post-remission treatment. We therefore conducted a retrospective registry-based analysis to compare the outcomes of patients with AML/CR1 receiving autologous peripheral blood (PB) grafts (n=398, median age: 47, range: 17-80) and those receiving allogeneic MSD bone marrow (BM) grafts (n=633, median age: 38, range: 16-73) or allogeneic MSD PB grafts (n=475, median age: 42, range: 16-74) between 1995 and 2011. Consequently, the 5-year overall survival (OS) rates for the autologous PB, allogeneic BM and allogeneic PB recipients were 62% (95% confidence interval [CI], 57-67%), 61% (95% CI, 57-65%; P=0.90) and 54% (95% CI, 49-59%; P=0.07), respectively (Fig. 1-A), and the 5-year leukemia-free survival (LFS) rates were 57% (95% CI, 52-62%), 58% (95% CI, 54-63%; P=0.49) and 51% (95% CI, 46-56%; P=0.12), respectively(Fig. 1-B). Meanwhile, the 5-year cumulative incidence of TRM was 8% (95% CI, 5-11%), 16% (95% CI, 13-19%; P=0.009) and 19% (95% CI, 15-23%; P=0.0001), respectively, while that of relapse was 35% (95% CI, 30-40%), 26% (95% CI, 22-29%; P=0.003) and 30% (95% CI, 26-35%; P=0.08), respectively. A multivariate analysis performed with autologous PB HCT as the reference showed a hazard ratio (HR) for OS of 0.93 (95% CI, 0.73-1.18; P=0.53) for allogeneic BM HCT and 1.08 (95% CI, 0.83-1.39; P=0.57) for allogeneic PB HCT and an HR for LFS of 0.86 (95% CI, 0.69-1.09; P=0.21) and 0.98 (95% CI, 0.77-1.24; P=0.85), respectively. Stratifying the patients according to cytogenetics (favorable, intermediate and poor) and age ( Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Background While unfavorable karyotype at referral is associated with significantly inferior overall and leukemia-free survival in myelofibrosis (MF) patients (Blood. 2011 Oct 27;118(17):4595), the incidence of clonal evolution during JAK inhibitor (JAKi) treatment and its clinical significance are not currently known. We conducted a sponsor-independent, single-center retrospective analysis examining the phenotypic correlates and prognostic impact of clonal evolution during JAKi treatment. Methods Clinical, cytogenetic and molecular data were collected on MF patients treated with one or more JAKi on a clinical trial at the Mayo Clinic, Rochester, MN. Baseline data pertained to the onset of treatment with first JAKi. Karyotype risk categories were as previously defined (Blood. 2011 Oct 27;118(17):4595). Serial bone marrow biopsies were obtained at varying frequencies based on individual JAKi protocol requirements. Mutation screening was performed as previously described (Leukemia. 2013 Apr 26. doi: 10.1038/leu.2013.119). Information on survival and leukemic transformation was updated in July 2013. Results A total of 157 MF patients were studied (60% male; median age 65 years, range 34-89 years). The DIPSS-plus distribution was: Low/Int-1 20 (13%), Int-2 66 (42%), and High 71 (45%). The first JAKi was momelotinib (CYT387) in 79 patients (50%), ruxolitinib in 51 (33%) and fedratinib (SAR302503) in 27 (17%). Median follow up from first JAKi treatment was 30 months (range 1-67 months); during this period, 72 deaths (46%) and 14 (9%) leukemic transformations were documented. Eighty nine patients (57%) had a median total 3 (range 2-8) bone marrow biopsies with karyotype analysis during JAKi treatment. Of these, 21 patients (24%) showed clonal evolution (ie, acquisition or loss of one or more chromosome abnormalities when comparing last observed karyotype during JAKi treatment to baseline). Overall, 13 patients (15%) had upstaging of karyotype risk category (eg, normal to unfavorable), 9 (10%) had downstaging (eg, favorable to normal) and 67 (75%) had no change. Acquisition of worse-than-baseline karyotype was significantly higher in DIPSS-plus high-risk patients (26%) versus non-high risk patients (6%) (p=0.03). There was no association between acquisition of a worse karyotype category and baseline karyotype risk category or ASXL1 or SRSF2 mutation status. There was borderline association with RBC transfusion-dependence and constitutional symptoms at baseline (p=0.06). There was no relationship between clonal evolution and achievement of spleen or anemia response during JAKi treatment (p>0.05). The median overall survival of the entire cohort was 41 months. On univariate analysis, overall survival was significantly worse in patients who acquired a worse-than-baseline karyotype risk category during JAKi treatment (n=13, 77% deaths, median survival=31 months) versus those who did not (n=76, 43% deaths, median survival=52 months) (p=0.01) (Figure). On multivariate analysis, the prognostic significance of acquiring a worse karyotype risk category was maintained against all individual DIPSS-plus prognostic variables, including baseline karyotype risk category, except age >65 years. On univariate analysis, leukemia-free survival was significantly worse in patients who acquired a worse-than-baseline karyotype risk category during JAKi treatment (n=13, 31% leukemic transformation, median leukemia-free survival=32 months) versus those who did not (n=76, 8% leukemic transformation, median leukemia-free survival not reached) (p=0.0006) (Figure). On multivariate analysis against known predictors of leukemic risk in PMF patients (ie, baseline unfavorable karyotype, SRSF1 mutated status and platelet count Conclusions This is the first study to examine the incidence of clonal evolution during JAKi treatment in MF patients. Approximately 25% of patients exhibited clonal evolution; acquisition of a worse-than-baseline karyotype risk category had a strong and independent association with inferior leukemia-free survival. A similar association was also observed for inferior overall survival, albeit not independent of older age. In contrast, there was no association with spleen or anemia response during JAKi treatment. Disclosures: Pardanani: Bristol Myers Squibb: Clinical trial support Other; Sanofi: Clinical trial support. Publication support service., Clinical trial support. Publication support service. Other; PharmaMar: Clinical trial support, Clinical trial support Other; JW Pharmaceutical Corp.: Clinical trial support, Clinical trial support Other.

Treatment of elderly patients with AML remains challenging. While increasing doses of induction and consolidation chemotherapy have failed to improve outcome, efforts to decrease relapse rates using the graft-versus-leukemia effect have shown promising results in phase II studies. In the present analysis of the prospective OSHO 2004 study we evaluated the effect of post-induction hematopoietic cell transplantation (HCT) in comparison to conventional consolidation chemotherapy (CT) on outcome in elderly patients with AML. The OSHO 2004 study is part of the German intergroup study. Upon achieving complete remission (CR) after induction, patients were assigned to CT or HCT depending on the availability of a matched related or unrelated donor. Unrelated, single antigen mismatched donors were accepted in high risk situations. By April 2014 from 817 eligible patients, 505 entered CR (62%) after one or two induction therapies. From the 452 patients who received consolidation in CR 1, 31 patients (7%) relapsed and 10 (2%) died of complications during consolidation. No further therapy for medical reasons was given to 73 patients, 206 patients received second consolidation with cytarabine (0.5 g/m2 i.v. bid d1, 3, 5) plus mitoxantrone (10 mg/m² d1-2) and 132 patients underwent HCT. Most frequent conditioning regimens for HCT were low dose TBI (83%) and treosulfan/fludarabine (12%). Most of the patients received HCT from unrelated (80%) donors and the majority received grafts from HLA-identical (78%) donors. Our analysis was restricted to the 315 patients The median age was 67 (60-74) and 65 (60-74) years in the CT and the HCT groups (p Patients receiving related or unrelated matched/mismatched HCT had superior LFS than those receiving CT (32±5% vs. 13±4% at 8 years, respectively; p Subpopulation analyses identified no difference in LFS and OS between matched related versus unrelated HCT. The difference in LFS between HCT and CT was highest in patients with normal karyotype, high risk cytogenetics and patients with non-monosomal karyotyp. Prognostic factors for LFS, OS, RI and NRM were analyzed in a multivariate analysis. Significant prognostic factors for LFS were cytogenetic risk (p=0.04), HCT (p=0.01) and FLT3 mutation status (p=0.07). OS was determined by cytogenetics p Conclusions: HCT from related or unrelated donors improved LFS and OS in patients with AML over the age of 60 years and in particular in those with high risk cytogenetics or normal karyotype disease. The LFS of over 30% after 8 years achieved by HCT represents a marked improvement in the prognosis of patients with AML aged 60-75 years in CR1. Disclosures Al-Ali: Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Wolf:Bayer: Honoraria; Geo Pharma: Honoraria. Hochhaus:ARIAD Pharmaceuticals, Inc.: Research Funding. Maschmeyer:Celgene: Consultancy.

Abstract 4122 Background: We have previously identified sole +9, 13q- or 20q- as “favorable” and sole +8 or complex karyotype as “unfavorable” cytogenetic abnormalities in primary myelofibrosis (PMF) (Blood 2010; 115: 496). The purpose of the current study, which includes more than twice the number of patients included in previous studies, was to identify additional prognostically-relevant cytogenetic abnormalities in PMF and refine cytogenetic risk categorization for overall and leukemia-free survival. Methods: Clinical and laboratory data were collected from consecutive patients with PMF seen at our institution and in whom cytogenetic information at or within 1 year of diagnosis was available. Diagnosis of PMF and acute myeloid leukemia were according to the World Health organization (WHO) criteria. Results: A total of 433 patients with PMF were included in the current study. Median age at diagnosis was 65 years. IPSS risk distributions were low in 12% of patients, intermediate-1 in 25%, intermediate-2 in 24% and high in 39%. JAK2V617F mutational frequency was 60%. Cytogenetic findings were normal in 275 (64%) patients. Among the 158 (36%) patients with abnormal karyotype, 109 (69% of abnormal cases) represented sole abnormalities, 23 (15%) two abnormalities and 26 (17%) three or more (i.e. complex) abnormalities. In an effort to identify cytogenetic categories of similar prognosis, each one of 12 operational cytogenetic categories was separately compared with both normal and complex karyotype. Accordingly, we were able to devise a two-tired cytogenetic risk stratification with highly significant differences in overall and leukemia-free survival (Figures 1 and 2): unfavorable (complex karyotype or sole or two abnormalities that include +8, -7/7q-, i(17q), inv(3), -5/5q-, 12p- or 11q23 rearrangement) and favorable (all other cytogenetic findings including normal karyotype). Median survivals of patients with favorable and unfavorable karyotype were 5.2 and 2.0 years, respectively (p Conclusions: The current study provides the rationale and necessary details for incorporating cytogenetic findings and platelet count in future prognostic models for PMF. The study also revealed a highly significant association between sole 20q- and both leukopenia and thrombocytopenia, which suggests a 20q- haploinsufficient gene effect. Disclosures: No relevant conflicts of interest to declare.

PURPOSE. To assess the long-term outcome of AML patients (pts) in complete remission (CR) after a phase III study which compared the effect of post-consolidation immunotherapy with interleukin-2 (IL-2) and histamine dihydrochloride (HDC) on leukemia-free survival (LFS) and overall survival (OS). PATIENTS & METHODS. A multi-national, randomized, open-label, phase III study which recruited 261 AML pts in first remission (CR1) and 59 in subsequent remission (CR>1) was conducted between June 1998 and October 2000. Pts were enrolled after after termination of consolidation therapy, stratified by country and CR status, and randomized to either treatment or no treatment (standard of care, control). Forty-one % of pts were >60 yrs (median 57), and 54% were males. Study arms were balanced for known prognostic factors. Two patient populations were studied, i.e. all pts randomized (ITT population; n=320) and pts in CR1. The treatment was self-administered at home and included ten 3-week courses of low-dose IL-2 (aldesleukin, Chiron Corp) 18 000 U/kg sc bid, plus HDC (EpiCept) 0.5 mg sc bid. Cycles 1–3 comprised 3 wks of treatment and 3 wks of rest, whereas in cycles 4–10 the rest periods were 6 wks. As reported previously (Blood2006; 108:88), the trial met the primary endpoint of prolonged leukemia-free survival (LFS) for all pts randomized (p=0.008 in favor of the treatment arm) at a median of 46 months of follow-up. The present long-term assessment of efficacy was conducted in August 2006, 30 months after the lock of the original data base. RESULTS. Follow-up forms were retrieved from 86% (n=107; 59 HDC/IL-2 recipients, 48 no treatment,) of the 124 pts pts who were alive at original study cut-off. In the long-term analysis, median LFS in the ITT population was 11 and 8.8 months in HDC/IL-2 and no treatment groups, respectively. In the CR1 population, median LFS was 15 and 9.7 months in HDC/IL-2 and no treatment groups, respectively. The benefit of treatment both for the ITT population (p=0.017) and in CR1 pts (p=0.026) was demonstrated by log-rank testing. Kaplan-Meier (KM) estimates for LFS at 60 months revealed a trend in favor of the treatment group in the ITT population (29.6 vs 20.6%; p=0.065) and a significant difference in the CR1 population (34.4 vs 21.7%, p=0.024). The median OS of CR 1 pts were 44 months (HDC/IL-2) and 28 months (no treatment), but the difference did not attain statistical significance (log rank test: p=0.22; KM estimate at 60 months: p=0.07). CONCLUSION. Post-consolidation immunotherapy with HDC/IL-2 results in significant long-term improvement of LFS.

Background : Two previous studies have reported significant but inconsistent associations between the presence of JAK2V617F in primary myelofibrosis (PMF) and older age at diagnosis, risk of thrombosis, higher leukocyte count, and inferior survival (Tefferi, et al. BJH2005;131:320, Campbell, et al. Blood2006;107:2098). The clinical relevance of V617F allele burden in PMF has not been previously studied. Methods : Diagnosis of PMF was based on the World Health Organization criteria and study eligibility included the availability of bone marrow-derived DNA that was collected either at time of diagnosis or within one year of diagnosis. Quantitative allele specific PCR was utilized to meaure V617F allele burden. Results I. V617F-positive vs. V617F-negative comparisons: A total of 199 patients (60% males; median age 61 years) were suitable for analysis of comparisons between mutation-positive and mutation-negative disease. The Dupriez prognostic scoring system (PSS) risk distributions were 61% low-risk, 31% intermediate-risk, and 8% high-risk. Hypercatabolic symptoms were present in 27% of the patients and ≥1% peripheral blood (PB) blasts in 37%. At a median follow-up of 23 months (range 0–266), 57 patients (29%) had died, 17 (9%) developed leukemic transformation (LT) and 10 (5%) experienced major thrombosis. V617F mutational frequency was 58%. Univariate analysis identified older age (p=0.0007), platelet count ≥ 100 x 109/L (p=0.05), and PB blast percentage < 3% (p=0.001) as being associated with a positive mutational status; all three variables sustained their significance during multivariable analysis. The presence of the mutation did not affect the incidence of thrombosis (p=0.78), overall survival (p=0.22) or leukemia-free survival (p=0.5). Results II. Clinical correlates of V617F allele burden: Quantitative measurement of V617F allele burden was performed in 129 patients that were divided into four groups: V617F-negative (n=53) and V617F-positive with mutant allele burden in the lower quartile (n=19), middle quartiles (n=38), or upper quartile (n=19) range (median and range of V617F allele burden ratio was 29% and 1% to 74%). Kaplan-Meier plots revealed significantly shortened overall (Figure; p = 0.0008) and leukemia-free (p = 0.01) survival for the lower quartile allele burden group; survival significance was sustained in a multivariable analysis that included the Dupriez PSS. Lower quartile allele burden was also associated with lower leukocyte count (p = 0.003) and presence of hypercatabolic symptoms (p=0.05). Thrombosis incidence was not affected by allele burden. Conclusions: In PMF, patients with a low V617F allele burden, compared to those with either undetectable (i.e. wild-type) or higher allele burden, display significantly shorter overall and leukemia-free survival. In contrast, the presence or absence of the mutation, by itself, does not result in distinct groups that differ significantly in terms of survival, LT, or incidence of thrombosis. These data suggest that a low V617F allele burden in PMF is a surrogate for the development of dominant V617F-negative subclones that are more likely to undergo LT. Figure Figure

Abstract 2130 The use of granulocyte colony stimulating factor (G-CSF), either filgrastim or lenograstim, along with induction and consolidation of adults with acute lymphoblastic leukemia (ALL) was a subject of several trials documenting significant shortening of neutropenia, reduced rate of infections and better adherence to chemotherapy protocol. The above studies, however, were not powered to detect differences with regard to long-term outcome. We performed a joint analysis of follow-up data from five multicenter prospective, randomized trials performed in France, Poland, Sweden, Austria and Australia. Among 347 adults with ALL (median age 33 years), 185 were assigned to receive prophylactically G-CSF while 162 patients were treated without G-CSF support. G-CSF was administered either in parallel to chemotherapy or in a sequential mode. With the median follow-up of 3.2 years, the remission duration was significantly longer for patients receiving G-CSF compared to controls (33 vs. 17 months, p=0.007). The difference was particularly pronounced for T-ALL (median not reached vs. 13 m., p=0.01) and a trend was observed for B-ALL (22 vs. 17 m., p=0.11). The 5-years probability of leukemia-free survival (LFS) was 38% for patients assigned to the G-CSF arm and 23% for the remaining subjects (p=0.01). There was also a tendency to increased overall survival (OS) rate in favor of patients receiving G-CSF (45% vs. 39%, p=0.17), which reached statistical significance in a subgroup of T-ALL (54% vs. 33%, p=0.03). In a multivariate analysis adjusted to age, initial WBC and the presence of Ph chromosome the prophylactic use of G-CSF was associated with reduced risk of relapse (HR=0.65, p=0.01) and treatment failure (HR=0.7, p=0.02). The differences remained significant when the observations were censored at the time of alloHSCT. We conclude that the prophylactic use of G-CSF during induction and consolidation of adults with ALL is associated with reduced risk of relapse and improved LFS. The possible explanation could be better adherence to chemotherapy schedules, as demonstrated in previous studies. Patients with T-ALL appear to particularly benefit from the use of G-CSF. Disclosures: No relevant conflicts of interest to declare.

Abstract 2072 Poster Board II-49 Backgrounds Currently, there are many efforts to design risk-adapted strategies in newly diagnosed acute promyelocytic leukemia (APL) by modulating treatment intensity and those seem to be an efficient approach to minimize treatment-related morbidity and mortality (TRM) while maintain the potential in cure for each relapse-risk group. We had postulated that maintaining of Ara-C during induction therapy might have acceptable toxicities yet obtaining good CR in newly diagnosed APL, and idarubicin alone during consolidation periods might have excellent LFS and OS with low relapse rate. Patients and Methods Eighty six patients with newly diagnosed APL were enrolled in the “multicenter AML-2000 trial” after informed consents were obtained during the period of January 2000 to July 2007. For remission induction therapy, patients received oral ATRA (45mg/m2/d, maintained until CR) combined with idarubicin (12mg/m2/d, D1-D3) plus Ara-C (100mg/m2/d, D1-D7). After CR achievement, patients received 3 monthly consolidation courses consisting of idarubicin (12mg/m2/d, D1-D3) alone and maintenance therapy with ATRA (45mg/m2/d, D1-D15, every 2 month) alone had continued for 2 years. Total patients were divided into low-risk, intermediate-risk and high-risk groups according to a predictive model for relapse risk (Sanz score) based on pretreatment WBC and platelet count and the treatment outcomes were compared in the different risk groups. Results The median age of our cohort was 40 years old (range; 6-80) and median follow-up was 27 months (range; 1-90). The distribution of patients in the 3 risk groups was as follows ; 28 (32.6%) patients in low-risk, 40 (46.5%) in intermediate-risk and 18 (20.9%) in high-risk. Overall, CR was achieved in 78 (90.7%) of 86 patients. The CR rate according risk groups was 96.4% in low-risk, 87.5% in intermediate-risk, and 88.9% in high-risk group and there was no significant statistical difference among the different risk groups. During induction therapy, 48 (55.8%) patients experienced grade 3-4 treatment-related toxicity (TRT), mostly fever and infection (38.8% of all patients) and 6 (7.0%) patients died of treatment-related complications. During 3 consolidation courses, 25 (29.1%) of 78 patients experienced grade 3-4 TRT in 1st course, 27 (36.0%) of 75 patients in 2nd course, and 14 (28.0%) of 50 patients in 3rd course. Overall, 3 (3.5%) patients died of treatment-related complications in CR. The incidence of TRT and treatment-related mortality (TRM) during induction or consolidation therapy showed no significant statistical difference among the different risk groups. The relapse occurred in 6 (7.0%) patients; 2 cases in intermediate-risk and 4 cases in high-risk. However, none had relapsed in low risk group, 5 patients of relapsed patients relapsed during consolidation courses and only one patient, however, relapsed during maintenance therapy. The overall survival (OS) and leukemia-free survival (LFS) rate at 7 years in all of patients was 76.7% and 83.5%, respectively. The OS rate at 7 years was 92.9% in low-risk, 78.6% in intermediate-risk and 53.6% in high-risk group (P:0.04) and the LFS rate at 7 years was 96.4%, 83.4% and 62.2% respectively, showing the significant difference between 3 different risk groups (P:0.046). Conclusions This study indicates that our protocol composed of induction therapy with “3+7” chemotherapy plus ATRA followed by consolidations with three courses of idarubicin alone and maintenance therapy with ATRA alone yields a high CR rate and low relapse rate but minimal acceptable toxicities. Despite of adding Ara-C during induction therapy, we did not find much significant toxicities but having good CR rates, and despite of not adding any additional low/intermediate dose chemotherapies(ie, 6MP), we were able to observe significantly high relapse rate in low and intermediate risk group with excellent LFS and OS. Meanwhile, in high-risk group, the relapse rate was significantly higher than other risk groups and most of the relapses occurred in the middle of consolidation courses. This data suggests that our consolidation therapy composed of anthracycline alone may be not enough to minimize risk of relapse in high-risk group in contrast with the low and intermediate-risk groups. More intensive consolidation therapy combined with other effective, but get tolerable chemotherapies or hematopoietic stem cell transplantation in first CR or the combination of arsenic trioxide or others in front-line therapy should be considered in the patients with high-risk of relapse. Disclosures: No relevant conflicts of interest to declare.

Abstract 2197 Poster Board II-174 Background: Imatinib is very effective for patients with CML in chronic phase (CP). While some patients (pts) may fail therapy with imatinib (because of resistance or intolerance), effective salvage therapy is available with new generation TKI (dasatinib, nilotinib, bosutinib). Currently the efficacy of each therapy is judged by their individual impact on overall survival (OS) and event free survival (EFS). However calculations of EFS for a patient does not take into account the effect of successful salvage therapy with subsequent TKI. We therefore studied the current leukemia free survival (CLFS) to obtain a more accurate impression of the outcome of pts with CML treated with sequential TKI. Aim: To provide an accurate estimation of long-term outcome with TKI therapy among pts with CML treated with sequential TKI. Methods: All pts with CP CML who received imatinib after failure to interferon-alpha (IFN) therapy at MD Anderson Cancer Center (MDACC) were included n this analysis. Events were defined as failure to achieve a complete cytogenetic response (CCyR) by 12 months of therapy, loss of CCyR, or discontinuation of therapy because of toxicity or any other causes after 18 months without achieving CCyR. Pts who failed imatinib either went to a 2nd TKI or other class of therapy. EFS is defined as survival without evidence of relapse at anytime after imatinib while CLFS is defined as survival without evidence of leukemia relapse at the time of most recent assessment. Thus, a loss of response would count as an event, but a response to salvage therapy would “repair” that event. Pts receiving any therapy other than a TKI after imatinib or other TKI is counted as an irreparable failure. Results: Three hundred and five pts were treated at MDACC with imatinib after IFN failure. The median age was 54 years (range 23-81), 169 (55%) were males. Median time on IFN was 1.5 yrs (range 0.1-10 yrs). Best response to IFN was MCyR in 114 (37%), minor cytogenetic response in 35 (11%), and CHR in 86 (28%). Among the others, 15 were intolerant to IFN, 29 pts were resistant and 26 pts had an unknown response. Reasons for being off IFN included 141 (46%) cytogenetics .{/MAIN;137}resistance, 37 (12%) hematological resistance, 123 (40%) intolerance, and 4 (1%) unknown. On imatinib 201 (66%) pts achieved CCyR; 64 of them discontinued imatinib in CCyR because of toxicity or other reasons, none of 64 pts received a 3rd line TKI. 27 (9%) pts who failed imatinib were treated with another TKI and attained CCyR. Of them, 18 remained in CCyR, 7 eventually lost CCyR, and 2 lost CCyR but attained and maintained CCyR with a 3rd TKI. Seventy-seven (25%) pts failed imatinib and could not be salvaged either due to unavailability of a 2nd TKI or failure to achieve CCyR with a 2nd TKI. EFS for this patient population is 63% at 7 years, whereas the CLFS is 70%. Conclusion: CLFS can measure the actual benefit of TKI therapy by accounting for failures and subsequent responses. Despite the unavailability of 2nd generation TKI during the early part of the observation period, the CLFS of 71% at 7 years demonstrates the extraordinary benefit obtained with these agents alone or, when needed, in sequence. Disclosures: Kantarjian: BMS: Research Funding; Novartis: Research Funding. Cortes:Novartis: Research Funding; BMS: Research Funding.