BM Blasts Research Articles

Comparative Outcomes and Molecular Response Predictors of IDH1/2-Mutated Adult Acute Myeloid Leukemia (AML) Patients (Pts) after Frontline Treatment with Intensive Induction Chemotherapy (IC), Targeted Inhibitors, or Hypomethylating Agents (HMA) (Alliance)

Comparative Outcomes and Molecular Response Predictors of IDH1/2-Mutated Adult Acute Myeloid Leukemia (AML) Patients (Pts) after Frontline Treatment with Intensive Induction Chemotherapy (IC), Targeted Inhibitors, or Hypomethylating Agents (HMA) (Alliance)

Donor-Derived CAR T Cells Engineered with Sleeping Beauty in Pediatric and Adult Patients with Acute Lymphoblastic Leukemia Relapsed Post-HSCT

IntroductionAllogeneic Chimeric Antigen Receptor (CAR) T cells engineered with non-viral methods offer a modality to reduce costs and logistical complexity of the viral process and allow lymphodepleted patients to access CAR T cell treatment. We recently proposed the use of Sleeping Beauty (SB) transposon to engineer donor-derived T cells differentiated according to the cytokine-induced killer (CIK) cell protocol (Magnani CF et al. J Clin Invest. 2021). We report here outcomes on B-cell acute lymphoblastic leukemia (B-ALL) patients, relapsing after transplantation, treated with donor-derived anti-CD19 CAR T cells (CARCIK-CD19).MethodsWe conducted an academic, multi-center, phase I/II dose-escalation trial in patients relapsed after allogeneic hematopoietic stem cell transplantation (HSCT). The infusion product was manufactured in-house starting from 50 mL of peripheral blood from the HSCT donor by electroporation with GMP-grade plasmids. All patients underwent lymphodepletion with Fludarabine (30 mg/m 2/day x 4 days) and Cyclophosphamide (500 mg/m 2/day x 2 days), before proceeding to CARCIK-CD19 infusion. We used the Bayesian Optimal Interval (BOIN) design to define a four-dose escalation scheme. Primary objectives were to define the Maximum Tolerated Dose (MTD), safety, and feasibility. Secondary objectives included the assessment of complete hematologic response (CR), duration of response (DOR), progression-free (PFS), event-free (EFS), and overall survival (OS). This study was registered at ClinicalTrials.gov, NCT03389035.ResultsFrom January 2018 to June 2021, a total of 32 patients were screened, 26 enrolled (6 children and 20 adults) and 21 infused (4 children and 17 adults). Reasons for not receiving infusion included consent withdrawal (N=1), disease progression not controlled by bridging therapy (N=3), acquisition of myeloid phenotype (N=1). The median number of prior therapies was 4 (range, 1-7) with a median time interval from HSCT to relapse of 9 months. The median BM blasts was 60% (range, 5-100%) at enrollment and 7% (range, 0-96%) post lymphodepletion. Of the 21 patients infused, CARCIK-CD19 were obtained by HLA-identical sibling (n=6, 29%), matched unrelated (n= 7, 33%), and haploidentical donors (n=8, 38%). Three patients (14%) received the first dose level of 1x10 6 CARCIK-CD19 cells/Kg, three (14%) the second of 3x10 6, and three (14%) the third of 7.5x10 6 whereas 12 patients (57%) received the fourth and last planned dose level of 15x10 6 cells/Kg, as no dose limiting toxicity (DLT) was observed. CRS was observed in six patients (three grade I and three grade II) and immune effector cell-associated neurotoxicity in two patients at the highest dose. Although 9 out of 21 had experienced acute or chronic graft-versus-host disease (GvHD) after the previous HSCT, secondary GvHD was never induced by CARCIK-CD19. Complete response was achieved by 13 out of 21 patients (61.9%, 95%CI=38-82%) and by 11 out of 15 patients treated with the 2 highest doses (73.3%, 95%CI=45-92%). Eleven of these responders were MRD-negative. Notably, the type of donor did not influence the achievement of CR 28 days post-infusion. At a median follow up of 21.6 months (range, 1.0-38.4 months), 10 patients (47.6%) are alive in CR (9 in the 2 highest dose levels). Overall, the median OS and EFS were 9.7 and 3.2 months, respectively, with a median DOR of 4.0 months (range, 1.0-23.5 months). Patients in CR at 28-days had a 6-months relapse-free survival of 48.4% (SE=14.9). EFS at 6 months was 26.5% (SE=9.9) and OS was 67.6% (SE=11.1). Among the 13 patients who achieved CR, two children underwent consolidation with a second allo-HSCT in complete remission. Adult patients did not receive any additional anti-leukemic therapies unless a relapse occurred, and four of them remained in remission and alive (+24, +9, +6, and +4 months). Robust CARCIK-CD19 cell expansion was achieved in most patients and CARCIK-CD19 cells were measurable for up to 22 months.ConclusionsSB-engineered CAR T cells induce sustained responses in B-ALL patients relapsed after HSCT irrespective of the donor type and without severe toxicities. DisclosuresLussana: Incyte: Honoraria; Pfizer: Honoraria; Astellas Pharma: Honoraria; Amgen: Honoraria. Gritti: Takeda: Consultancy; Roche: Consultancy; Kite Gilead: Consultancy; IQvia: Consultancy; Italfarmaco: Consultancy; Clinigen: Consultancy. Biondi: Incyte: Consultancy, Other: Advisory Board; Bluebird: Other: Advisory Board; Novartis: Honoraria; Amgen: Honoraria; Colmmune: Honoraria.

Preliminary Results from the Flu/Cy/Alemtuzumab Arm of the Phase I BALLI-01 Trial of UCART22, an Anti-CD22 Allogeneic CAR-T Cell Product, in Adult Patients with Relapsed or Refractory (R/R) CD22+ B-Cell Acute Lymphoblastic Leukemia (B-ALL)

Preliminary Results from the Flu/Cy/Alemtuzumab Arm of the Phase I BALLI-01 Trial of UCART22, an Anti-CD22 Allogeneic CAR-T Cell Product, in Adult Patients with Relapsed or Refractory (R/R) CD22+ B-Cell Acute Lymphoblastic Leukemia (B-ALL)

T-MDS Is a Distinct Clinical and Pathological Entity Characterized By Better Survival Compared to t-AML

Introduction: Therapy-related myeloid neoplasm (t-MN) includes acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) that occur as a complication of DNA-damaging therapies. The World Health Organization recommends considering t-MN as a single entity. Whether t-MDS and t-AML have distinct characteristics and outcomes is not known. The aim of this study was to compare clinicopathological characteristics and outcomes of t-MDS and t-AML.Methods: All patients diagnosed with t-MN based on the World Health Organization criteria were identified. Bone marrow biopsies, cytogenetic, and next-generation sequencing (NGS) were obtained at the treating physician's discretion. Pathogenic/likely pathogenic variants (PV) were called based on the standard criteria. Overall survival (OS) was calculated from the time of t-MN diagnosis until the last follow up using Kaplan-Meier analysis using Wilcoxon test. For survival analysis comparing chemotherapy to best supportive care (BSC) only, patients were censored at the time of allogeneic stem cell transplant (SCT). Multivariate analysis was performed using Cox proportional hazard method and corrected using false discovery rate (FDR). Statistical analysis was performed using JMP (v14.1, SAS Institute) and significance was defined as P<0.05.Results: We identified 554 patients, of which 180 (32.4%), 365 (65.8%), and 9 (1.6%) presented as t-AML, t-MDS, and t-MDS/MPN respectively. t-MDS/MPN patients were excluded from further analysis due to a small number. Clinical and laboratory characteristics of the t-AML and t-MDS cohorts is shown in Table 1. t-AML patients were significantly more anemic and thrombocytopenic at presentation. As expected, t-AML had a higher peripheral blood and BM blast count. There was no difference in proportion of patients with chromosomal abnormalities, though a statistically significantly higher proportion of t-MDS patients had chromosome 5 abnormality, 5q deletion, monosomy 5, chromosome 7 abnormality, monosomy 7 compared to t-AML patients. On other hand, 11q23 (mixed lineage leukemia, MLL) rearrangement was more common in t-AML compared to t-MDS (9.3% vs. 2.8%, P=0.005).A higher proportion of t-MDS patients had PV detected by NGS compared to t-AML (92.9% vs. 85.6%, P=0.038). A higher proportion of t-MDS patients had PV in TP53 (37.6% vs. 21.4%, P=0.004) and ASXL1 (23% vs. 11.7%, P=0.016) genes; whereas a higher proportion of t-AML patients had PV in RAS (18.9% vs. 9.1%, P=0.013) and WT1 (8.1% vs. 2.9%, P=0.05) genes.One hundred twenty-eight (35%) of 365 t-MDS patients progressed to t-AML. The presence of any chromosomal abnormality at t-MDS diagnosis predicted a higher risk of transformation to t-AML (χ 2 3.9, P=0.03).t-AML patients had a significantly shorter OS compared to t-MDS (9.2 vs. 19.7 months, P<0.0001, Figure A). This difference persisted when stratified by no disease modifying therapies (BSC only) 2 vs. 17 months (P<0.0001, Figure B), as well as among those who received at least one line of chemotherapy (14 vs. 24.6 months, P<0.001). Finally, a higher proportion of patients with t-AML underwent SCT and there was a trend towards improved survival for t-AML patients (vs. t-MDS 52.9 vs. 20.7 months, P=0.07) from the time of transplant.Multivariate analysis for OS performed to control for all the variables that were different at presentation (except for blast count), showed that t-MDS (as opposed to t-AML) phenotype at diagnosis, and undergoing SCT were independent predictors of improved survival (Table 2).Conclusion: t-MDS and t-AML have distinct clinical, cytogenetic, and genetic features at presentation. In the absence of disease modifying therapies, t-AML is a more aggressive phenotype, consistently associated with a shorter survival. Even after controlling adverse risk features, t-AML phenotype had a shorter survival compared to t-MDS. [Display omitted] DisclosuresLitzow: AbbVie: Research Funding; Astellas: Research Funding; Amgen: Research Funding; Actinium: Research Funding; Pluristem: Research Funding; Jazz: Other: Advisory Board; Omeros: Other: Advisory Board; Biosight: Other: Data monitoring committee. Hiwase: Novartis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees.

ALL-440: Promising Safety and Efficacy Results from an Ongoing Phase 1/2 Study of Pembrolizumab in Combination with Blinatumomab in Patients (pts) with Relapsed or Refractory (R/R) Acute Lymphoblastic Leukemia (ALL)

<h3>Background:</h3> Blinatumomab, a bispecific anti-CD19/CD3 antibody, demonstrated single-agent efficacy with 42% CR/CRh in R/R B-ALL. Upregulation of immune inhibitory molecules has been shown to confer resistance to blinatumomab. Here, we set out to test the combination of pembrolizumab and blinatumomab in a phase 1/2 trial (NCT03512405). <h3>Methods:</h3> Pts [≥18 years old (yo); ECOG <1] with CD19+ R/R B-ALL received blinatumomab 9 mcg/day on days 1–7 and 28 mcg/day on days 8–28 in cycle 1 and on days 1–28 in subsequent cycles. Pembrolizumab was given on day 15 (schedule A) or day 22 (schedule B) in cycle 1 and on days 1 and 22 in subsequent cycles. Cycle length was 42 days, except 35 days for cycle 1 in schedule A. We completed the schedule A phase 1 portion with primary objectives of safety, tolerability, and recommended phase 2 dose (RP2D) using the "3+3" design. <h3>Results:</h3> As of February 1, 2021, 7 pts were enrolled to phase 1, with one unevaluable. Six treated and evaluable pts received a median of 2 (1–5) cycles of treatment. At baseline, the median age was 51 yo (29–74) with median 2 (2–4) prior lines of regimens and median 29% (0–83) BM blasts. Two pts had extramedullary disease. In cycle 1, all 6 pts experienced grade (gr) 1–2 cytokine release syndrome. Neurologic toxicities were all reversible with only 1 ≥ gr3 AE. All-non-hematologic gr3 toxicities, were reversible. No dose-limiting toxicity, ≥ gr4 non-hematologic toxicity, or treatment-related deaths were seen. Five of 6 evaluable pts (83%) achieved MRD-negative CR after a median of 1 (1–2) cycle. Three pts in CR received alloHCT, all engrafted. With a median follow-up of 2.8 (1.1–9.6) months, 4 CRs are ongoing (1 post-transplant), and 5 of 6 pts are still alive at the data cut-off. <h3>Conclusions:</h3> The combination of pembrolizumab and blinatumomab in phase 1 of this study in pts with B-ALL was deemed safe with a manageable side effect profile and encouraging anti-leukemic activity. The study is now open for phase 2 with the primary objective of overall response rate.

Clinical and molecular characterization of myeloid sarcoma without medullary leukemia

Myeloid sarcoma (MS) in the setting of concomitant medullary AML is relatively well described, while much less is known about patients presenting with MS with <20% bone marrow blasts. We conducted a retrospective analysis of 56 patients with MS with <20% marrow blasts seen at MD Anderson between 2005 and 2020. The prevalence of MS without medullary AML was 1.4% among all newly diagnosed AML patients. The majority (75%) of patients had a single known anatomic site involved, with the skin (34%) being the most frequent. The most common histologic subtype was monocytic, and 11% of patients had a known history of an antecedent hematologic disorder. The majority of patients (70%) received frontline intensive chemotherapy induction, with 75% of those evaluable attaining complete or partial responses. The median overall survival (OS) and event-free survival (EFS) were 3.41 and 3.07 years, respectively. Patients with bone marrow blasts of ≥5% or medullary relapse had inferior outcomes, while age (>60 years) was not associated with outcomes. There was a suggestion that patients with isolated leukemia cutis may have had better outcomes compared to patients with other organ involvement, but this did not reach statistical significance. Most patients who had cytogenetic analysis had a diploid karyotype within their MS and bone marrow. RAS pathway mutations were enriched in MS at diagnosis, and at time of medullary relapse. Our study provides a large dataset summarizing the clinical and molecular analysis of patients with MS with <20% BM blasts and suggests that monitoring for medullary leukemia is important for early detection of relapse.

Factors associated with treatment response to CD19 CAR-T therapy among a large cohort of B cell acute lymphoblastic leukemia.

CD19-targeted chimeric antigen receptor (CAR) T cell therapy has demonstrated striking responses among B cell acute lymphoblastic leukemia (B-ALL), but analyses of potential factors associated with poor response and relapse are lacking. Here, we summarize the long-term follow-up of 254 B-ALL treated with CD19 CAR-T cells from 5 clinical trials (NCT03173417, NCT02546739, and NCT03671460 retrospectively registered on May 23, 2017, March 1, 2018, and September 7, 2018, respectively, at www.clinicaltrials.gov ; ChiCTR-ONC-17012829, and ChiCTR1800016541 retrospectively registered on September 28, 2017, and June 7, 2018, at www.chictr.org.cn ). Our data showed that TP53 mutation, bone marrow blasts > 20%, prior CAR-T/blinatumomab treatment, and severe cytokine release syndrome (CRS) were associated with a lower complete remission (CR) rate while age, extramedullary disease, complex cytogenetics, history of prior transplant, prior courses of chemotherapy, CAR-T cell dose, and manufacturing source of the cellular product did not affect patients' CR rate. Risk factors related to leukemia-free survival (LFS) and overall survival (OS) were history of prior transplant, complex cytogenetics, TP53 mutation, severe CRS, neurotoxicity, and CAR-T therapy without consolidative allogeneic hematopoietic stem cell transplantation (allo-HSCT). Age and CAR-T cell dose did not influence LFS and OS. Patients with consolidative allo-HSCT after CAR-T therapy had a superior OS and LFS compared to those who did not. This benefit was also observed in both pediatric and adult patients as well as in patients either in high- or low-risk groups. This large study to identify risk factors of CR, LFS, and OS may help to maximize clinical outcomes of CAR-T therapy. Précis TP53 mutation and BM blasts > 20% are two independent factors associated with the CR rate. Patients with high tumor burden as well as those with bone marrow blasts < 5% can benefit from consolidative allo-HSCT post-CAR-T therapy.

Prognostic Impact of Concurrent DNMT3A, FLT3 and NPM1 Gene Mutations in Acute Myeloid Leukemia Patients

BackgroundAcute myeloid leukemia (AML) is one of the rapidly progressing malignancies which is characterized by unregulated proliferation of hematopoietic precursors. Technological improvements enhanced the availability of genetic AML biomarkers. The clinical relevance of these molecular markers for AML diagnosis, planning of therapy and risk stratification are increasing evidently. MethodsIn current study, one hundred newly diagnosed AML patients before receiving induction chemotherapy were included, they were subjected to clinical examination, cytochemical and morphological analysis of blood cells, flow cytometric, cytogenetic and molecular genetic analysis for detection of NPM1, FLT3-ITD and DNMT3A mutations. Direct sequencing analysis for detection of NPM1 and DNMT3A genes mutations were done. FLT3 /ITD gene mutation was detected by gel electrophoresis after PCR amplification. ResultsAccording to genetic markers, our AML patients are classified in to further 8groups. AML patients with three DNMT3A/FLT3/NPM1 gene mutations (AML DNMT3A /FLT3/NPM1) this group of patients presented with a heavy disease burden, had an elevated WBC in comparison to other groups (70 vs. 41 × 103/μL; P = .019), and BM blast counts (71% vs. 55.6%, P < .02). When comparing eight groups for death event there were significant difference among groups; P = .005, group 1 (AML DNMT3A /FLT3/NPM1) showed rapid decline of the cumulative overall survival. There was a significant difference among 8 groups as regards response to treatment after 14 days (P = .02), group 7 AML with (DNMT3A +NMP1) gene mutations showed better response to treatment (100%), groups 1 and 3 AML with (NPM1+DNMT3A +NMP1) gene mutations and AML with isolated FLT3-ITD showed no response to treatment after 14 days. And as regards response to treatment after 28 days, the eight groups showed no significant difference (P = .14). ConclusionOur study supports adverse prognostic effect of presence of DNMT3A gene mutation either alone or in the presence of FLT3 and/or NPM1 gene mutations.

2021 BSH guidelines for the management of adult myelodysplastic syndromes: a practical approach to a challenging disease.

Myelodysplastic syndromes (MDS) are a group of haematological malignancies with extremely variable biologic, genetic and clinical characteristics.1 The outcome of MDS patients is very heterogeneous, some having a near-normal life expectancy while others die within a few months of their diagnosis. The median age of patients at diagnosis is advanced, ranging between 70 and 75 years, thus further complicating the management of these complex syndromes, since non-haematological comorbidities frequently coexist in the elderly and tolerability of treatments is limited.2 Given the heterogeneity of the disease pathobiology and the highly variable disease course, prognostic risk stratification is of crucial importance in clinical decision-making.3 To drive appropriate counselling and individualisation of treatment decisions, several prognostic scoring systems based on clinical and haematological parameters have been developed. Principal scoring systems currently used in Europe are the International Prognostic Scoring System (IPSS), and the revised IPSS (R-IPSS), which are based on the evaluation of peripheral blood cytopenias, bone marrow blast count and cytogenetic features.4 In daily practice, reliability of these scores is limited by the variability of morphological evaluation and, less frequently, by non-informative cytogenetic findings in a proportion of patients. Moreover, other factors including the clonal mutational status have been reported to influence the prognosis of MDS patients, and to affect the clinical outcome.5, 6 In any case, diagnostic procedures and evaluation of prognosis are not covered by these guidelines as they will be published in a separate British Society for Haematology (BSH) document. Unlike the previous edition, the 2021 BSH guidelines also do not include recommendations for CMML, for which dedicated guidelines will follow. The 2021 updated BSH guidelines for the Management of Adult Myelodysplastic Syndromes provide clear, simple and practical recommendations to approach patients with such a challenging diagnosis.7 Given the heterogeneity of the disease, the importance of establishing an individual risk-adapted treatment strategy is crucial; nonetheless, transfusion requirements and infectious complications are common to almost all patients, sooner or later. The guidelines first exhaustively describe the supportive measures that should be adopted with most patients; in particular, recommendations are reported the for prevention of fungal infection, a common complication in neutropenic patients, and for transfusion thresholds and policies to be adopted to improve patient quality of life (QoL) on the one hand, saving blood products on the other. Then, individual planning of therapeutic options is described extensively, also by means of simplified algorithms. Although standard care for MDS is constantly changing, recommendations for the initial treatment choice are still based on IPSS and R-IPSS risk evaluation, and, importantly, on patient’s preference. Therapeutic measures for most lower risk patients aim to decrease the transfusion burden and improve QoL, whereas recommendations for higher risk patients aim to prolong their life. This distinction is clearly represented in these guidelines; for each group updated treatment strategies are reported, some reflecting the 2014 BSH document. Still relevant is the recommendation that the initial MDS diagnosis should be discussed by a multidisciplinary team, including a transplantation expert, as allogeneic transplantation remains the only potentially curative option. Worthy of note, in this setting recommendations for cytoreduction in advanced MDS with hypomethylating agents (HMA) or chemotherapy before transplant are still debated, although inferior survival outcomes for patients with excess BM blasts (> 5%) at the time of transplant have been reported. Moreover, it is important that clinicians review MDS cases regularly in multidisciplinary meetings to determine if a patient can become a possible transplant candidate and/or can possibly take part in a clinical trial. Patients’ details should also be made available to national and international dedicated registries, ‘to maximize information about the patient’s history and treatment of MDS in order to benefit future patients’. In general, the guidelines are proposed to improve the quality of care of patients as well as to help physicians in their daily practice. The BSH guidelines for the management of MDS represent a timely update and make a valid contribution for the diagnosis and treatment of this heterogeneous group of blood disorders.

Hypoplastic Myelodysplastic Syndrome: Clinical, Histopathological and Molecular Characterization

Introduction and AimsHypoplastic Myelodysplasic Syndrome (h-MDS) has distinct features compared to normo- or hypercellular MDS, with a higher response rate to immunosuppressive therapy and more favorable prognosis. However, to date, reproducible diagnostic criteria for h-MDS have not been clearly defined, making differential diagnosis from other bone marrow failure (BMF) syndromes challenging. Based on a large and well-annotated consecutive cohort of patients with BM hypocellularity from two tertiary centres, we aimed to delineate the clinical, histopathological and molecular features of h-MDS.MethodsOf 1262 consecutive adult patients analyzed at King's College Hospital, London, UK and IRCCS Policlinico San Matteo & University of Pavia, Italy: 533 patients had a hypocellular BM, including 205 MDS patients with BM cellularity ≤25%, 77 MDS with reduced age-adjusted BM cellularity, 139 with Aplastic Anemia (AA), 97 with a diagnosis of Idiopathic Cytopenia of Undetermined Significance (ICUS) and 15 with congenital BMF (c-BMF) and 729 with normo- or hypercellular MDS (n-MDS).ResultsComparison of clinical features and outcome of patients with h-MDS as defined by a BM cellularity ≤25% (n=205) and those with a reduced age-adjusted cellularity (n=77) did not detect any significant differences. Therefore, a reduced age-adjusted BM cellularity was adopted as a criterion to define h-MDS (n=282). Compared with patients with n-MDS, those with h-MDS were significantly younger, displayed higher levels of hemoglobin (p=.01), lower neutrophil and platelet counts and lower percentage of BM blasts, ring sideroblasts (RS) and CD34+cells as determined by immunohistochemistry (all p<.001). No significant difference was observed in the distribution of chromosomal abnormalities. A significantly higher prevalence of PNH clones was observed in h-MDS (24% vs 2%, p<.001). Those patients with h-MDS showed a significantly lower risk of leukemic evolution compared with n-MDS (4-year cumulative incidence 14% vs 26%, p=.003). Comparing h-MDS with AA, h-MDS showed a significantly higher percentage of RS (p=.004), BM blasts, dysmegakaryopoiesis and dysgranulopoiesis (p<.001), BM fibrosis (p=.002), clusters of CD34+ cells and chromosomal abnormalities (p<.001). H-MDS patients showed a significantly higher risk of leukemic evolution compared with AA (4-year cumulative incidence 14% vs 0%, p<.001).Targeted sequencing of 24 commonly mutated myeloid genes was performed on 358 patients (73 h-MDS, 45 AA and 240 n-MDS). Twenty-five patients with h-MDS (34%) showed one or more somatic mutation (median 1; range 1-4). Comparing h-MDS to n-MDS revealed a significantly lower number of mutations per subject and variant allele frequency (VAF) (p<.001). Moreover, a significantly lower number of mutations per patient and VAF were observed in AA compared to h-MDS (p=.031 and p=.003, respectively). Thirty-seven patients with a hypocellular BM had a peripheral blood telomere length (TL) ≤1st percentile and/or a germline mutation consistent with a diagnosis of c-BMF, leading to an estimated prevalence of unidentified c-BMF of 13% in cases without robust morphological evidence of MDS.Based on these findings, we defined a diagnostic score (h-score), including variables with the highest specificity for MDS: dysmegakaryopoiesis, dysgranulopoiesis, BM fibrosis, clusters of CD34+ cells, RS 2-14%, BM blasts 2-4% (score 1); RS≥15% and BM blasts ≥5% (score 2). By applying ROC analysis, a cut off value of 2 was associated with the highest specificity for MDS (0.98). Notably, 71% of patients with a hypoplastic BM and low h-score (0-1) had no evidence of clonal disease by cytogenetic or mutation analyses or had a mutation pattern consistent with age-related clonal hematopoiesis. These patients showed a significantly better OS and lower risk of leukemic evolution (P<.001).ConclusionsIntegration of cyto-histological and genetic features in patients with a hypocellular BM identifies two distinct groups, one with clinical and genetic features highly consistent with a clonal disease with high risk of leukemic evolution, and one with features more consistent with a non-malignant bone marrow failure. Furthermore, we identified relevant enrichment of patients with previously undiagnosed c-BMF. DisclosuresKulasekararaj:Akari Therapeutics Plc: Consultancy, Honoraria; Alexion Pharmaceuticals: Consultancy, Honoraria; Ra Pharmaceuticals: Consultancy, Honoraria; Achillion pharmaceuticals: Consultancy, Honoraria.

Omacetaxine Mepesuccinate for Patients with Higher-Risk MDS and CMML after Failure of Hypomethylating Agents: A Phase II Trial

Background: The outcome of patients (pts) with myelodysplastic syndromes (MDS) after hypomethylating agent (HMA) failure is poor with a median survival of 4-6 months. Omacetaxine mepesuccinate (OM) has been shown to be safe and effective in acute myeloid leukemia, including in pts who progressed from MDS. We designed a phase II trial to evaluate the safety and efficacy of OM in pts with MDS and chronic myelomonocytic leukemia (CMML) after HMA failure.Methods: Adult pts with MDS or CMML who had not responded to, progressed on, or relapsed after HMA therapy were eligible for this study. Pts were required to be intermediate-2- or high-risk by the International Prognostic Scoring System (IPSS) or be classified as RAEB-1 (5-9% BM blasts), RAEB-2 (10-19% BM blasts) or CMML (5-19% BM blasts). Pts received OM 1.25 mg/m2 SQ every 12 hours x 3 days on a 28-day cycle. The primary efficacy outcomes were overall survival (OS) and the overall response rate (ORR). Secondary outcomes included the remission duration, relapse-free survival (RFS), and the safety of the regimen.Results: Between 6/2015 and 6/2017, 35 pts have been treated. Baseline characteristics are shown in Table 1. The median age of the cohort was 73 years (range, 61-86 years). The median BM blasts was 10% (range, 2-19%) and 15 pts (43%) had poor-risk karyotype. IPSS risk group was intermediate-1 in 8 pts (23%), intermediate-2 in 13 (57%), and high in 7 (20%). 27 pts (77%) were either high risk (n=10) or very high risk (n=17) by IPSS-R. Among 33 pts who underwent comprehensive mutation profiling, 29 (88%) had at least one mutation identified. The most frequently identified mutations were RUNX1 in 10 pts (30%), TP53 in 10 (30%), ASXL1 in 6 (18%) and TET2 in 4 (12%).The median duration of follow-up was 17 months (range, 2-24 months), and the median number of cycles of OM received was 2 (range, 1-18). The ORR was 34%; 3 pts achieved CRp and 9 pts achieved CRi as best response. The median number of cycles to best response was 2 (range, 1-4 cycles). The response rates for pts with MDS and CMML were 41% and 0%, respectively (P=0.02). Responses were seen across cytogenetic risk groups: 5 responders were diploid, 4 had either complex cytogenetics or monosomy 7, and 3 had miscellaneous cytogenetic abnormalities. The response rate for pts with diploid and adverse-risk cytogenetics were 56% (5/9) and 27% (4/15), respectively (P=0.16).Of the 12 responders, 4 remain on study, 5 relapsed, 2 died while in response, and 1 was lost to follow-up. To date, 24 pts (69%) have died. The median OS was 7.6 months, and the 1-year OS rate was 22% (Figure 1). The median RFS was 2.9 months, and the 1-year RFS rate was 28%. Two pts have had ongoing response ≥12 months (15.6 and 19.8 months), both of whom had MDS with diploid cytogenetics.Treatment was overall well-tolerated. Among 26 pts who have received ≥2 cycles of OM, 2 (8%) required dose reduction during subsequent cycles. Most adverse events were grade 1-2; grade ≥3 adverse events occurred in 8 pts (23%). The most frequent non-hematologic adverse events were fatigue in 17 pts (49%), nausea in 12 (34%), mouth sores or mucositis in 6 (17%), infection in 5 (14%) and edema in 5 (14%). The 30-day and 60-day mortality rates were 11% and 14%, respectively.Conclusions: In pts with MDS and CMML who previously failed HMA therapy, OM was safe and resulted in an ORR of 34%. Responses were seen across cytogenetic risk groups but were restricted to patients with MDS. [Display omitted] DisclosuresTakahashi:Symbio Pharmaceuticals: Consultancy. DiNardo:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Agios: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Bose:Incyte Corporation: Honoraria. Cortes:BMS: Consultancy, Research Funding; Teva: Research Funding; Sun Pharma: Research Funding; ImmunoGen: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Kantarjian:Amgen: Research Funding; Delta-Fly Pharma: Research Funding; ARIAD: Research Funding; Bristol-Meyers Squibb: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. Jabbour:Bristol-Myers Squibb: Consultancy.

MVP Combined with FC As Lymphocyte-Depleting Chemotherapy before CAR-T Treatment Can Reduce the Incidence of Severe Cytokine Release Syndrome for Relapsed/Refractory ALL Patients with High Tumour Burden

Background: CAR-T immunotherapy have shown remarkable promising results for relapsed/ refractory (R/R) acute lymphoblastic leukemia(ALL). However, the most common toxicity associated with CD19 CAR-T treatment is Cytokine Release Syndrome(CRS) which can be a life threatening complication especially for high tumour burden ALL patients. How to reduce the incidence of severe CRS can be a great challenge for advanced high tumour patients.Objective: In order to evaluate the efficacy and safety of MVP+FC as lymphocyte-depleting chemotherapy to reduce tumour burden before CAR-T therapy. Method: If patients' blasts in bone marrow was more than 15%, the chemotherapy MVP(Mitoxantrone 10mg/w once(d1)+ Vindesine 4mg/w once(d1) + Dexamethasone 10mg/d×7d(d1-d7)followed by FC(Fludarabine 30mg/m2× 3d (d8- d10)+ cyclophosphamide 300mg/m2×3d(d8-d10))were performed. CD19 CAR-T were infused with dose escalation schedule: 10%–40%–60%(d13,d14,d15). Total dose of CD19 CAR-T was 5×106/kg.Results: Seven patients were enrolled in this study with median age of 22 (7-46) years old. Three patients were relapse post multiple chemotherapies. Another 4 patients were relapse post allo-HSCT including T315I and TP53 mutation patients. The median blasts in BM before and after MVP treatment were 43.5% (15-87%) and 24%(0-40%).Furthermore, the median blasts in BM after MVP+FC treatment were 4%(0-52%). Overall response of CAR-T were 86% with hematological remission 86% and molecular remission 71%.Only 1 patient experienced 3 grade CRS and other patients just had 1-2 grade of CRS. Only one presented sepsis.No one experienced neurotoxicity. The median duration of neutropenia was 5.5(2-18)days. Treatment related mortality was 0.With the median follow up of 8(1-17)months, both 6 and 12 months leukemia free survival were 47.62%. The accumulative relapse rate was 52%.Conclusion: MVP combined with FC was an effective and safety conditionning regimen before CAR-T treatment with low incidence of severe CRS especially for high tumour burden ALL patients. DisclosuresNo relevant conflicts of interest to declare.

Presence of Post Induction Minimal Residual Disease (MRD) Is an Independent Predictor for Relapse and Is Associated with Inferior Survival in Acute Myeloid Leukemia (AML)

Background:Acute myeloid leukemia (AML) is a highly heterogenous condition. Current risk stratification based on cytogenetics and molecular genetic markers at point of diagnosis is used to predict treatment response and relapse risk. The conventional way of defining complete remission (CR) is based on morphological identification of ≤5% blasts seen in bone marrow. However, this does not provide adequate insight to the quality of response as there is still a high proportion of patients that relapse despite being in CR.A significant proportion of AML patients have detectable MRD post induction. There is increasing evidence to support MRD as a significant prognostic factor for clinical outcome. Despite this, MRD status has yet to become an important factor in deciding on subsequent allogeneic stem cell transplant (allo-SCT). This study assessed the role MRD in predicting risk of relapse and survival rates and also looked into the role of allo-SCT in abrogating the adverse risk of MRD.Methods:All AML cases excluding acute promyelocytic leukemia who underwent curative chemotherapy from year 2001 until 2015 were retrospectively identified. Clinical data was gathered from computerized patient data system. Baseline patients and disease characteristic were correlated with post induction MRD status. MRD was assessed by flow cytometry analysis of bone marrow samples taken on day 26-30 days of post-induction. Samples from year 2001 to 2011 were analyzed using 4 color flow, and from 2011 onward, all samples were analyzed using 8 color flow. Leukemia-associated antigens were identified at baseline and followed up for MRD. Data collected were analyzed using SPSS Statistic Desktop V22.0.Results:235 patients underwent intensive chemotherapy. 61.7% achieved complete remission (CR) after induction chemotherapy. Among those who achieved CR after induction, 41.3% have detectable MRD. 42.8% eventually relapsed, after a median follow-up of 36.6 months. Median duration of CR was 49.5 months. The presenting WBC, LDH, time taken for neutrophil count or platelet count recovery after induction, cytogenetic risk group and FLT3-ITD and NPM1 molecular status did not correlate with MRD status.Post induction MRD positive status was associated with higher relapse rate, 42.6% vs 22.4% for MRD positive and negative respectively, p=0.015, (OR = 1.9) (95% CI: 1.14-3.19).In the multivariate analysis that include presenting WBC, LDH, BM blasts, risk group and post induction MRD status, risk group and MRD status remained an independent predictor for relapse. HR 1.95 (95% CI: 1.00-3.79), p=0.049 for positive MRD status, while adverse risk group gave a HR of 7.15 (95%CI: 2.01-25.49), p=0.002.The 3-year Leukemia free survival (LFS) was 38.3% and 59.6% for MRD+ and MRD- group respectively (p=0.043) (figure 1), while the overall survival (OS) was 55.5% and 69.5% for MRD+ and MRD- group respectively (p=0.388).55 patients underwent allo-SCT, 26 in MRD+ group and 29 in MRD- group. There was no statistical significance in terms of LFS among those who underwent allo-SCT according to MRD status (Median LFS were 13.1 months for MRD+, 29.2 months for MRD-, p=0.328). In the intermediate or adverse risk group who did not undergone allo-SCT, the median LFS in MRD+ group was only 2.5 months (95%CI: 0.0-21.2) compared to MRD- group, 39.9 months (p=0.041), (figure 2).Conclusions:Post induction MRD+ was associated with higher relapse rate and reduced LFS. Post induction MRD- status was associated with excellent LFS among AML with intermediate and adverse risk even without allo-SCT. Allo-SCT may be able to abrogate the adverse outcome of MRD+ AML. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Treatment of Relapse of MDS, AML and CMML after Allogeneic Blood Stem Cell Transplantation with Azacitidine, Lenalidomide and Donor Lymphocyte Infusions - Results from the First Interim Analysis of the Azalena-Trial (NCT02472691)

Background:Azacitidine (Aza) and donor lymphocyte infusions have become a standard treatment of myeloid malignancies relapsing after allo-SCT. Studies so far showed response rates ranging from 10% to 75% following treatment with Aza with or without donor lymphocyte infusions (DLI) and particularly patients (pts) with MDS and AML with low disease burden seem to benefit most. Lenalidomide (Len), due to its immunomodulatory and antileukemic properties, may act synergistically with Aza and DLI.Design/Methods:We initiated a prospective, multicenter, single-arm phase-II trial combining Aza, Len and DLI in patients with MDS, AML or CMML as first salvage treatment for relapse after allo-SCT. Pts were envisaged to receive up to 8 cycles Aza (75 mg/m2/d d1-7, every 28 days) and 3 DLI with increasing dosages (0.5×106 - 1.5×107 cells/kg) after cycles 4, 6 and 8. Concomitantly, eight cycles of Len were administered with a daily dose of 2.5 mg for the first 21 days of a 28 day-cycle each.To cope with the potential risk of GvHD induction by Len after allo-SCT the primary endpoint is safety and the study incorporates two interim analyses scheduled after the first 10 and 20 patients respectively. If no dose limiting toxicity (DLT) defined as steroid refractory acute GvHD grade III/IV, chronic GvHD NIH score severe or any unexpected hematologic and non-hematological toxicity grade ≥ III is observed in more than 3 patients in the first interim analysis, the dose of Len will be increased to 5 mg/day for the next 10 patients. Otherwise the study will be stopped.Results:Here we present the results of the first interim analysis (data lock February 20th 2017), which includes 10 patients (median age: 64 years, range 43 to 73) who experienced molecular (70%) or hematological (30%) relapse of MDS (70%), AML (20%) or CMML (10%) after median of 275 days (range: 91 to 937) following allo-SCT. So far, these 10 patients have received a total of 54 cycles of Len corresponding to median of 7 cycles per patient (range: 1 to 8). In addition, patients received a median of 7 courses of Aza (range 1-8) and 7 of 10 pts (70%) received at least one DLI (median: 1, range: 0-5).No DLT was observed. Two patients either developed acute GvHD (20%, overall grade I and III) and chronic GvHD (20%, NIH score mild and moderate). Treatment-associated neutropenia, thrombocytopenia or anemia CTC grade III/IV occurred in 75%, 50% and 0% of the patients, respectively. Common adverse events were gastrointestinal side effects, elevation of liver enzymes as well as infections. Nevertheless, during the treatment period only 2 patients needed to be hospitalized. Although efficacy was not the major scope of this first interim analysis, of 7 evaluable patients (early drop-out of 3 patients) 4 (57%) achieved complete remission and 1 patient (14%) achieved partial remission resulting in overall response rate of 71%.Conclusion:This interim-analysis shows that the combination of Aza, Len (21x2.5 mg/cycle) and DLI as first salvage therapy for relapse after allo-SCT is safe and feasible and not associated with excess GvHD. According to the protocol, the dose of Lena will now be increased to 21x5 mg/cycle for the next 10 patients. Furthermore, due to the label extension of Aza, the inclusion criteria will also be amended to AML patients with >30% BM blasts. DisclosuresSchroeder:Celgene: Consultancy, Honoraria, Other: travel support. Rautenberg:Celgene: Other: travel support. Scheid:BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Nachtkamp:Celgene: Other: Travel Support. Germing:Janssen: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Kröger:RIEMSER Pharma: Research Funding; Novartis AG: Research Funding; Amgen Inc.: Speakers Bureau; Janssen Global Services, LLC: Speakers Bureau; Neovii Pharmaceuticals AG: Speakers Bureau; Novartis AG: Speakers Bureau; Sanofi: Speakers Bureau. Kobbe:Celgene: Other: Advisory Board, Research Funding.

Characteristics and Survival of Patients with Chronic Phase Myelofibrosis and Elevated Blasts (5-9%), and the Effect of Therapy with JAK2 Inhibitor Ruxolitinib

Abstract Introduction: Patients with accelerated phase (AP) myelofibrosis (MF) (10-19% blasts in bone marrow [BM] or peripheral blood [PB]) have higher risk of leukemic transformation and shorter overall survival (OS) than those in the chronic phase ( Objective: We aimed to identify clinical characteristics, and survival, as well as evaluate effect of JAK2 inhibitor ruxolitinib (RUX) on outcome of patients with 5-9% PB / BM blasts seen at MD Anderson Cancer Center (MDACC). Methods: Medical charts of 1199 patients who presented to MDACC between years 1984 - 2015 with MF and available blast percentage in PB and BM, were retrospectively evaluated. All relevant clinical characteristics were collected at the time of referral. Chronic phase (CP) was defined as Results: Eighty five percent of patients (n=1020) were in CP; 10% (n=123) in CP-e, and 5% (n=56) in AP. Clinical characteristics and demographics are shown in Table 1. Patients with CP-e had similar clinical characteristics as patients in AP, and furthermore, both had higher white blood cell counts, lower hemoglobin and platelets, more frequent splenomegaly, systemic symptoms, and presence of abnormal and unfavorable karyotype (Caramazza, Leukemia 2011) than patients in CP. After median follow-up of 27 months (range, 1-251), 50% (n=594) of patients have died. Fourteen percent of patients (n=169) were untreated while being followed at MDACC. Among the remaining 1030 patients, 52% (n=533), 16% (n=162), and 12% (n=126) have received one, two, and ≥3 therapies. RUX was used in 30% of patients (n=328): in 289 (28%), 33 (27%) and 6 (11%) patients in CP, CP-e and AP, respectively. The median overall survival (OS) of the entire group was 48 months (range, 40-65). The median OS for patients in CP, CP-e and AP was 56, 34, and 23 months, respectively (p As the next step we analyzed the impact of RUX on OS in each of the groups. Patients who were exposed to RUX have superior overall survival within CP as well as CP-e groups, with respective OS of 61 vs 52 months in CP (with vs without RUX; p=0.002, HR 0.85, 95% CI 0.69-0.97), and 54 vs 27 months in CP-e (with vs without RUX; p=0.001, HR 0.50, 95% CI 0.29-0.85, Graph 1B, C). Furthermore, OS of patients in CP-e who were exposed to RUX has reached OS of patients in CP group, both with and without RUX, with respective OS of 54, 61, and 52 months (p>0.05, Graph 2B, C). RUX had no impact on OS among AP patients (with and without RUX, 23 vs 23.4 months, p>0.05, graph not shown). Progression to AML occurred in total of 139 (9%) patients, with overall incidence of 3.96 cases per 100 persons-years. Nine percent (n=93), 20% (n=25), and 39% (n=22) of patients have progressed to AML among CP, CP-e, and AP groups, respectively, (p Conclusions: RUX, the only FDA approved JAK2 inhibitor for patients with MF, has a potential to significantly improve an outcome of patients with 5-9% blast percentage whose clinical characteristics and outcome appear to be worse than patients with CP MF and Download : Download high-res image (181KB) Download : Download full-size image Table 1 . Disclosures Pemmaraju: abbvie: Research Funding; cellectis: Research Funding; novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria; stemline: Consultancy, Honoraria, Research Funding; roche diagnostics: Consultancy, Honoraria; affymetrix: Research Funding; Incyte Corporation: Consultancy, Honoraria. Daver: Sunesis Pharmaceuticals, Inc.: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Immunogen: Research Funding; Pfizer Inc.: Consultancy, Research Funding; Incyte Corporation: Honoraria, Research Funding; Bristol-Myers Squibb Company: Consultancy, Research Funding; Daiichi-Sankyo: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Otsuka America Pharmaceutical, Inc.: Consultancy; Kiromic: Research Funding; Jazz: Consultancy. Cortes: Sun Pharma: Research Funding; ImmunoGen: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding; BMS: Consultancy, Research Funding. Kantarjian: Amgen: Research Funding; Bristol-Meyers Squibb: Research Funding; ARIAD: Research Funding; Novartis: Research Funding; Delta-Fly Pharma: Research Funding; Pfizer: Research Funding. Verstovsek: Gilead: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; Lilly Oncology: Research Funding; Bristol Myers Squibb: Research Funding; Gilead: Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding; Incyte: Research Funding; Pfizer: Research Funding; Astrazeneca: Research Funding; Celgene: Research Funding; Blueprint Medicines Corp: Research Funding; Bristol Myers Squibb: Research Funding; Genentech: Research Funding; Promedior: Research Funding; Astrazeneca: Research Funding; Pfizer: Research Funding; Galena BioPharma: Research Funding; Genentech: Research Funding; Incyte: Research Funding; Galena BioPharma: Research Funding; CTI BioPharma Corp: Research Funding; NS Pharma: Research Funding; Roche: Research Funding; CTI BioPharma Corp: Research Funding; Seattle Genetics: Research Funding; Roche: Research Funding; Lilly Oncology: Research Funding; Blueprint Medicines Corp: Research Funding.

A Phase II Trial of Eltrombopag in Chronic Myelomonocytic Leukemia (CMML) with Thrombocytopenia

Context: Thrombocytopenia is a frequent complication in CMML associated with worse prognosis (Itzykson JCO 2013, Patnaik Leukemia 2013). Thrombopoietin (TPO) protects HSCs from DNA damage (de Laval Cell Stem Cell 2013). The TPO analog eltrombopag (ELT) has shown efficacy in MDS (Oliva Lancet Hematol 2017). The limited data on ELT in CMML is restricted to a small cohort (n=7) with high risk features, where 4 pts had disease progression during ELT (Ramadan Clin Lymphoma Myeloma Leuk 2016). We report interim results of a multicenter phase 2 trial investigating the efficacy, toxicity and biomarkers of ELT in 25 CMML with platelets (PLT) < 50 x109/L (NCT02323178).Methods: Key inclusion criteria were: WHO 2008 defined HMA-naive CMML, PLT < 50 x109/L, marrow blasts ≤ 5%, IPSS low/int-1 in MD-CMML, and in MP-CMML no or 1 severity criteria (Hb < 10 g/dL, ANC > 16 x109/L, abnormal karyotype, extramedullary disease) ,spleen size < 16 cm. ELT was started at 100 mg/d with escalating doses to 300 mg/d. Platelet Response (HI-P) was evaluated at 12 weeks, according to IWG 2006 criteria, and responders could continue treatment. Gene mutations were analyzed by NGS at inclusion. DNA repair was explored by counting gH2AX foci in CD34+ cells obtained at inclusion, evaluation and study exit.Results: We report on the first 19 evaluable pts (median age 79y, M/F 15/4), all CMML-1 by WHO 2008, including 14 MD-CMML and 5 MP-CMML, with a low/int-1/int-2 CPSS (Such Blood 2013) in 61%, 33% and 6% of pts respectively (resp). Median PLT count was 29 x109/L (IQR 19 - 43.5) and 10 (53%) pts had PLT transfusion dependency (PLT-TD). TET2, RUNX1, ASXL1, SRSF2, PHF6, and RAS pathway mutations were present in 17, 10, 6, 7, 4 and 7 of 18 pts sequenced, resp.The median maximal dose of ELT received was 200 mg/d (IQR: 150 - 300 mg/d). Clinical grade ≥3 toxicities, all cardiovascular or pulmonary, were noted in 5 pts in the first 12 weeks, and biological grade ≥3 toxicities in 6 pts, without grade ≥3 ALT/AST elevation. Six (32%) pts went off study before week 12 because of lack of efficacy (n=2), presence of in circulating blasts (n=1), progression to CMML-2 (n=1), pancreatic cancer (n=1) and patient decision (n=1). All were considered non-responders. At 12 weeks, 12 (63%, 95%CI: 38 - 84) pts had achieved HI-P, including 3/5 MP-CMML and 9/14 MD-CMML (p=1). Responses were obtained in 7/10 pts with baseline PLT-TD and 5/9 pts without PLT-TD (p=0.65). The mutational profile of responders was comparable to that of non-responders except that none of the 4 PHF6mut pts responded (p=0.01). Responders at 12 weeks were receiving a median of 125 mg/d of ELT, compared to 225 mg/d in non-responders.Responders received ELT for a median of 21 weeks (IQR 15 - 38). With a median follow-up of 18 months (95%CI: 16.8 - NR), 11 of the responders discontinued ELT because of loss of efficacy (n=2), patient decision (n=1), death from unrelated causes (n=2), liver toxicity (n=2), renal failure (n=1) and disease progression (n=3). Median response duration was 8 months (95%CI: 5 - NR), with one pt still on treatment with a response lasting more than 14 months. The 12-month cumulative incidence of AML was 19% (95%CI: 4 - 41%) and 12-month progression-free and overall survival (OS) were 41% (95%CI: 23 - 73) and 65% (95%CI: 45-92%). By comparison, in the 21 CMML pts with PLT < 50 x109/L and ≤5% BM blasts from our previous CMML cohort (Itzykson JCO 2013), none of whom received ELT, the 12-month estimates for cumulative incidence of AML and OS were 10% (95%CI 0 - 23%) and 71% (95%CI 47 - 86%), resp. An updated analysis including all 25 pts will be presented.At protocol screening, a higher number of gH2AX foci were seen in CMML bone marrow CD34+ cells (n=14) compared to age-matched controls (n=5, p<0.01), reflecting higher levels of baseline DNA damage. However, in the 5 pts for whom serial bone marrow samples were obtained during ELT, gH2AX foci were reduced in CD34+ cells from all 5 pts, suggesting that in vivo exposure to ELT protected CMML stem/progenitor cells from DNA damage.Conclusion: Our interim results suggest that ELT is manageable in CMML pts with no excess of marrow blasts and thrombocytopenia and results in a high response rate, with no obvious increase in disease progression, though prolonged responses seem infrequent. ELT could potentially protect CMML stem/progenitor cells from DNA damage. Larger pt numbers and longer follow-up are however required to determine precisely the role of ELT in thrombocytopenic CMML pts. DisclosuresItzykson:Janssen: Research Funding; Novartis: Research Funding. Fenaux:Astex: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding.

Final Analysis of the Phase I/II Study of CC-486 (Oral Azacitidine) Maintenance Therapy after Allogeneic Stem Cell Transplantation (Allo-SCT) in Patients with Acute Myeloid Leukemia (AML) or Myelodysplastic Syndromes (MDS)

Final Analysis of the Phase I/II Study of CC-486 (Oral Azacitidine) Maintenance Therapy after Allogeneic Stem Cell Transplantation (Allo-SCT) in Patients with Acute Myeloid Leukemia (AML) or Myelodysplastic Syndromes (MDS)

The Impact of the Administration Schedule and Mutational Profile on Outcomes of Patients with Relapsed and Refractory Acute Myeloid Leukemia Treated with Hypomethylating Agents: A Large, International, Multi-Center Analysis

The Impact of the Administration Schedule and Mutational Profile on Outcomes of Patients with Relapsed and Refractory Acute Myeloid Leukemia Treated with Hypomethylating Agents: A Large, International, Multi-Center Analysis

Results of the Full Pediatric, Minimal Residual Disease (MRD)-Oriented Trial LAL-RI/2008 for Adolescents and Young Adults (AYA) with Standard Risk (SR), Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia (ALL)

Background and objective. Full pediatric or pediatric-derived trials constitute the treatment of choice for AYA with SR-ALL. In the MRD era, patients (pts) with SR factors at baseline with poor MRD clearance should be considered as HR patients. The objectives of the full pediatric LAL-RI/2008 trial (NCT02036489) from the Spanish PETHEMA group were to assess the proportion of AYA with SR-ALL at baseline who have HR features based on poor early cytological response and/or poor MRD clearance, and to compare their prognosis with that from those pts who achieve good early cytological response and good MRD clearance.Patients and methods. SR ALL was defined in adolescents (age 15 to 18 years) and young adults (age 19 to 29 years) fulfilling all the following criteria: WBC count ≤30 × 109/L, and absence of t(9;22), t(1;19), t(4;11) or any other 11q23 rearrangements. Induction therapy included vincristine (VCR), prednisone (PDN), daunorubicin (DNR) and native E. coli asparaginase (ASP) for 4 weeks. Pts who achieved complete remission (CR) and MRD<0.1% proceeded to consolidation-1 (high-dose methotrexate [MTX], intermediate-dose ARA-C, etoposide and mercaptopurine [MP]), consolidation-2/reinduction (VCR, dexamethasone, DNR, cyclophosphamide and ASP), maintenance-1 (MP and MTX with monthly reinductions with VCR, PDN and ASP until the end of the 1st year) and maintenance-2 (MP and MTX without reinductions until the end of the 2nd year). CNS prophylaxis consisted of triple intrathecal therapy (MTX, ARA-C and hydrocortisone, 16 doses throughout the treatment). Pts with poor early cytological response (BM blast cells >10% on day 14 of induction), MRD level >0.1% (assessed by flow cytometry) at CR or MRD level >0.05% at any time after CR were considered as high risk (HR) pts and received the ALL-HR trial consisting of intensive chemotherapy followed by allogeneic hematopoietic stem cell transplantation (alloHSCT) (Ribera JM et al. J Clin Oncol 2014; 32:1595-604).Results. Between 2008 and 2017, 79 eligible pts were treated according to the ALL-RI-08 protocol. Median age (range) was 20 years (15-29), 34 (43%) were adolescents and 45 (57%) YA. The mean (SD) WBC count was 10 (9) x109/L, and 73 patients (94%) had B-cell precursor ALL. Two patients are on treatment and 74 out of the remaining 77 (96%) achieved the CR. From the 77 pts, 15 had poor early cytological response, 3 had MRD >0.1% at the time of CR and 1 pt showed reappearance of MRD level >0.05% during maintenance. In all, 19 patients were considered as HR. Of the 58 patients who remained SR and followed the LAL-RI/2008 protocol, 14 relapsed (7 during treatment and 7 off therapy), whereas in the HR group, 3 were resistant, 4 relapsed and 2 died by toxicity (transplant-related in 1 out of 4 pts submitted to alloHSCT). Table 1 shows the DFS, OS and cumulative incidence of relapse (CIR) at 5-yrs for the whole series, the patients remaining SR and those who turned HR. Of note, OS was lower in the HR pts (Figure 1). On comparison with the results of the ALL-RI-96 trial (same inclusion criteria, same treatment but no follow-up by MRD, Ribera JM et al. J Clin Oncol 2008; 26:1843-9), no differences were observed in DFS, OS and CIR (Table 1).ConclusionsTwenty-five percent of AYA pts with SR ALL at baseline are in fact HR based on slow early cytological response to therapy and/or poor MRD clearance. High-risk pts showed lower OS despite being moved to a HR protocol.Supported in part by grants RD12/0036/0029 (RTICC, FEDER), PI14/01971 FIS, Instituto Carlos III, and SGR225 (GRE), Spain. [Display omitted] DisclosuresRibera:Celgene: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Roche: Honoraria; ARIAD: Research Funding, Speakers Bureau; Incyte: Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Amgen Inc.: Research Funding, Speakers Bureau. Montesinos:Celgene Corporation: Honoraria, Research Funding.

Expression of SATB2 in Acute Myeloid Leukemia and Its Prognostic Significance

Background: Human special AT-rich sequence-binding protein-2 (SATB2) is a novel DNA binding protein, which is involved in regulating gene expression. Recent studies conducted to evaluate the clinical significance of SATB2 in multiple malignant carcinomas, and have yielded controversial results. The purpose of this study is to investigate the expression status of SATB2 and its prognostic significance in AML patients.Methods: Total RNA was extracted from bone marrow or plasma of 87 patients with AML and 21 health volunteers. The expression of SATB2 was examined by Realtime quantitative PCR. The relationship of SATB2 expression and other clinicopathological charactors and its prognosis significance were statistically analyzed.Results: The relative expression of SATB2 was significantly up-regulated in AML patients (median value 0.061, range: 0.007-0.328) in comparison to those of healthy volunteers (median value 0.033, range: 0.008-0.077; P < 0.001) , and SATB2 expression level was much lower in patients who had achieved CR (median value 0.005, range: 0.001-0.006;P < 0.001) compared with newly diagnosed AML patients(median value 0.010, range: 0.002-0.027;P < 0.001).Furthermore, the expression of SATB2 was markedly associated with gender(P =0.043), WBC count(P =0.001), platelet count (P =0.025), BM blast count (P = 0.007) and Complete Remission (P < 0.001). Patients with higher SATB2 expression had a relatively poor overall survival(OS) (P = 0.009) and short disease-free survival(DFS) (P < 0.001). Moreover, SATB2 expression was an independent prognostic factors for both OS (P = 0.001) and DFS (P = 0.006).Conclusions: SATB2 was significantly up-regulated in AML patients in comparison to healthy donors. Patients who had achieved CR usually had a lower level of SATB 2 expression compared with newly diagnosed AML patients. The over-expression of SATB2 is associated with poor prognosis in AML patients, and was an independent prognostic factor for both OS and DFS. DisclosuresNo relevant conflicts of interest to declare.