Risk Myelodysplastic Syndromes Research Articles

Efficacy and Safety of Decitabine Combined with CAG (Cytarabine, Aclarubicin, G-CSF) for Patients with Intermediate or High Risk Myelodysplastic Syndrome and Acute Myeloid Leukemia: a Meta-Analysis

To systematically evaluate the efficacy and safety of DCAG regimen for treating the intermediate or high risk MDS and AML. PubMed, EMbase, The Cochrane Library, WanFang Data and CNKI databases were searched to collect randomized controlled trials (RCTs) of decitabine combined with CAG regimen for intermediate or high risk MDS and AML from inception to March, 2018. The quality of each RCT was evaluated by the Cochrane collaboration´s tool for assessing the risk of bias.Then, the data were analyzed by using RevMan 5.3. Twenty-four RCTs were included in the meta-analysis, containing 1 557 patients with intermediate or high-risk MDS and AML, of whom 594 were AML patients and 590 were MDS patients. The patients treated with the DCAG regimen were enrolled in DCAG group, and the patients treated with single-agent decitabine or CAG regimen were enrolled in control group. The results of meta-analysis showed that compared with other therapies, the complete remission rate of DCAG regimen in patients with intermediate or high-risk MDS and AML was high (RR=1.63，95% CI=1.43-1.85，P＜0.000 01), and the overall response rate was also high (RR=1. 35，95% CI=1.24-1.46，P＜0.000 01); Subgroup analysis results showed that DCAG regimen was better than CAG regimen in the complete remission rate (RR=1.71，95% CI=1.49-1.97，P＜0.000 01), and slightly better than single-agent decitabine group (RR=1.43，95% CI=1.08-1.91，P=0.01). In terms of adverse reactions, there was no statistically significant difference in the rates of myelosuppression, pulmonary infection, gastrointestinal reactions, and bleeding events between the 2 groups (P＞0.05). DCAG regimen has significant efficacy in the treatment of intermediate or high-risk MDS and AML, and is superior to CAG regimen and single-agent dicitabine regimen. As compared with control group, there was no significant difference in adverse events. Due to limited quantity and quality of the included studies, more high quality studies are needed to verify above mentioned conclusion.

Decitabine improves overall survival in myelodysplastic syndromes-RAEB patients aged ≥60 years and has lower toxicities: Comparison with low-dose chemotherapy

Decitabine and low-dose chemotherapy are common treatments for intermediate and high risk myelodysplastic syndromes (MDS). In this study, we retrospectively assessed the efficacy and toxicity of the two regimens for MDS-refractory anemia with excess blasts (MDS-RAEB) patients. A total of 112 patients with a diagnosis of MDS-RAEB are included. The overall response (OR) and complete remission (CR) rate was comparable between the two groups (OR: 64.1% vs. 66.7%, p = 0.60; CR: 23.4% vs. 31.3%, p = 0.64). The OR rates of 20 mg/m2/day and 15 mg/m2/day decitabine regimen were comparable (69.0% vs. 60.0%, p = 0.46). Overall survival (OS) did not differ significantly between the groups (20.7 vs. 13.5 months, p = 0.17). In a subgroup analysis that included only patients at ≥60 years of age, survival benefit of decitabine was apparent (20.6 vs. 10.0 months, p = 0.03). In hematological toxicities, the lowest count of platelet in the decitabine group was higher significantly. And, the incidence of Grade 3–4 infection in the decitabine group was lower significantly. Our results demonstrate that both decitabine and low-dose chemotherapy are effective for MDS-RAEB, but decitabine was safer. Decitabine might be a better choice for patients at ≥60 years of age.

Lenalidomide-Induced High Grade Fever in a Patient with Multiple Myeloma: A Case Report

Lenalidomide is a second generation immunomodulatory agent and a potent analogue of thalidomide that is FDA approved mainly for the treatment of multiple myeloma (MM) and transfusion-dependent anemia due to low or intermediate-1- risk myelodysplastic syndromes (MDS) associated with 5q deletion among other indications. Through its action on the immune system, lenalidomide alters the production of different cytokines ultimately resulting in immune activation against tumors. This immune activation may lead to collateral immune toxicities like fever, angioedema, Stevens-Johnson syndrome, tumor flare and others. Here we report a case of lenalidomide-induced high grade fever in a patient with MM and we summarize the literature about the physiology of such reaction and how to mitigate this adverse event.

A Study of LB-100 in Patients With Low or Intermediate-1 Risk Myelodysplastic Syndromes (MDS)

A Study of LB-100 in Patients With Low or Intermediate-1 Risk Myelodysplastic Syndromes (MDS)

Efficacy of granulocyte colony stimulating factor in combination with erythropoiesis stimulating agents for treatment of anemia in patients with lower risk myelodysplastic syndromes: A systematic review.

Anemic patients with lower risk myelodysplastic syndromes are frequently treated with erythropoiesis stimulating agents (ESA), eventually in combination with granulocyte colony stimulating factor (G-CSF). However, the evidence for the efficacy of a combined treatment remains controversial. The goal of our analysis was to assess the available evidence for a combined treatment. We performed a systematic review and identified only nine eligible studies. In two randomized controlled trials (n = 98), erythroid response rates were 33% and 40% after low-/standard-doses of ESA alone (10,000-30,000 rHuEPO equivalents/week) versus 65% and 73% after combination treatment. In seven trials with sequential drug administration (n = 393), erythroid response rates ranged from 12% to 71% after full-doses of ESA alone (60,000-80,000 rHuEPO equivalents/week) and from 35% to 74% after combination therapy. Our analysis supports an additional efficacy of G-CSF added to low-/standard-dose ESA, but the available data remains controversial, if G-CSF is added to full-dose ESA.

Haploidentical BMT Using Fully Myeloablative Conditioning, T Cell Replete Bone Marrow Grafts, and Post-Transplant Cyclophosphamide (PT/Cy) Has Limited Toxicity and Promising Efficacy in the First Prospective Multicenter Trial for Pediatric, Adolescent, and Young Adult Patients with High Risk Acute Leukemias and Myelodysplastic Syndrome

Promising results have been reported for patients with high-risk hematologic malignancies undergoing T-cell-replete myeloablative bone marrow transplant (BMT) from HLA-haploidentical donors with post-transplantation cyclophosphamide (PT/Cy). Here, we report results from the first prospective multicenter pilot trial in the Pediatric Blood and Marrow Transplant Consortium (PBMTC) for pediatric, adolescent, and young adult patients with high risk acute leukemias and myelodysplastic syndrome (MDS) in the US and Canada. Nine centers transplanted 32 patients with acute leukemias or MDS in complete remission (CR) who received myeloablative conditioning consisting of IV Busulfan (pharmacokinetically adjusted) and Cyclophosphamide (Cy, 50 mg/kg/day) days –2 and –1 except for patients with acute lymphocytic leukemia who received Cy (50 mg/kg/day x 2) and total body irradiation (1200cGy). T-cell-replete bone marrow from haploidentical related donors was used for all patients. Postgrafting immunosuppression consisted of Cy (50 mg/kg/day) days 3 and 4, followed by mycophenolate mofetil for 30 days and tacrolimus for 90-180 days. Median age of patients was 12y (range, 1-23) and donors was 35y (range, 4-53). Diagnoses included AML (CR1 = 7, CR2 = 6), ALL (CR1 = 8, CR2 = 5), mixed lineage leukemia (1), and MDS (5). One patient had received a prior BMT. Donor engraftment occurred in 27/32 (84%). Primary graft failures included 3 patients with MDS and 2 with AML (CR1 = 1, CR2 = 1); three of these patients had received suboptimal bone marrow grafts (TNC/kg ≤2e8) and all successfully engrafted after second transplants. Median time to neutrophils >500/μL was 22 days and platelets >20,000/μL was 21 days. Transplant related mortality (TRM) at 180 days, our primary objective, was 0%. Cumulative incidence of acute GVHD grades II-IV at Day 100 was 13%. No patients developed severe acute GVHD grades III-IV. The cumulative incidence of mod-severe chronic GVHD at 1 year was 4%. The cumulative incidence of relapse at 1y was 32%. With a median follow-up of surviving patients of 477 days (range, 180-1127), actuarial overall survival is 77% at 1y. With a median follow-up of event-free patients of 451 days (180-1127), actuarial event-free survival is 68% at 1y. For this first reported multicenter pediatric myeloablative HLA-haploidentical HSCT for high-risk leukemias and MDS with T-cell replete bone marrow and PT/Cy, we have demonstrated a 0% TRM, low cumulative incidences of acute and chronic GVHD, and favorable rates of relapse and survival. Further investigation as to potential reasons for graft failure and consideration of any changes needed to ensure engraftment for certain disease groups are underway. A larger trial comparing haploidentical BMT with other alternative donor sources is in development.

Treatment of higher risk myelodysplastic syndromes

The two main treatment options for patients with higher risk of myelodysplastic syndromes (MDS) are allogeneic hematopoietic stem cell transplantation and azacitidine therapy. Of these, only allogeneic hematopoietic stem cell transplantation is curative, and azacitidine treatment is selected for patients not suitable for transplantation. Compared to conventional treatment with supportive treatment alone or with low dose cytarabine, azacitidine treatment improves survival in MDS patients, even in patients over the age of 75. Because azacitidine treatment takes 4-6 cycles until an initial response, several response-predicting scoring systems have been developed. Novel therapeutic agents and combination therapies of azacitidine with a variety of drugs are currently under study.

Clinical effectiveness and safety of erythropoietin-stimulating agents for the treatment of low- and intermediate-1-risk myelodysplastic syndrome: a systematic literature review.

Many patients with lower-risk myelodysplastic syndrome (MDS) experience anaemia, which has negative consequences. Erythropoiesis-stimulating agents (ESAs) and their biosimilars are used to treat anaemia in MDS and, currently, epoetin alfa and darbepoetin alfa are commonly used and recommended by clinical guidelines. To better understand the evidence available on the use of ESAs for anaemia in lower-risk MDS, we conducted a systematic literature review to identify randomized and nonrandomized prospective studies reporting on clinical efficacy/effectiveness, patient-reported quality of life (QoL), and safety. We extended our review to include retrospective studies for darbepoetin alfa specifically and to ascertain the feasibility of completing an indirect network meta-analysis comparing epoetin and darbepoetin alfa. Overall, 53 articles reporting on 35 studies were included. The studies indicated a clinical benefit of ESAs, with benefits observed across key clinical outcomes. ESAs showed consistent improvement in erythroid response rates (ESA-naïve, 45-73%; previous ESA exposure, 25-75%) and duration of response. Comparative studies demonstrated similar progression to acute myeloid leukaemia and several showed improved overall survival and QoL. Limited safety concerns were identified. This analysis confirmed ESA therapy should be the foremost first-line treatment of anaemia in most patients with lower-risk MDS who lack the 5q deletion.

Increasing therapy-related myeloid neoplasms in multiple myeloma.

Despite the longer survival achieved in multiple myeloma (MM) patients due to new therapy strategies, a concern is emerging regarding an increased risk of secondary primary malignancies (SPMs) and how to characterize those patients at risk. We performed a retrospective study covering a 28-year follow-up period (1991-2018) in a tertiary single institution. Data of 403 MM patients were recorded and compared with the epidemiologic register of the population area covered by our centre, calculating the standardize incidence ratio (SIR) for the different types of SPMs diagnosed in the MM cohort. Fine and Gray regression models were used to identify risk factors for SPMs. Out of the 403 MM patients, 23 (5.7%) developed SPMs: 13 therapy-related myeloid (TRM) malignancies (10 of them (77%) myelodysplastic syndrome (MDS), 1 acute lymphoid leukaemia and 9 solid neoplasms. In the MM cohort, the relative risk of MDS was significantly higher than in the general population. Survival of patients with TRM malignancies was poor with a median of 4 months from the diagnosis, and most of them showed complex karyotype. Within the MM subset, multivariable analysis showed a higher risk of TRM malignancies in patients that previously received prolonged treatment with lenalidomide (>18 months). Though the improvement in MM outcome during the last decades is an unprecedented achievement, it has been accompanied by the rise in TRM malignancies with complex cytogenetic profile and poor prognosis that are in the need of an improved biologic and therapeutic approach.

Effects of Abnormal Iron Metabolism on EPO-STAT5 Signaling Pathway in Anemia Patients

To study the effects of iron metabolism abnormality on EPO-STAT5 signaling pathway in anemia patients. According to diseases, the patients were divided into 3 groups: lower risk myelodysplastic syndrome (MDS) group (30 cases) including 14 cases of non-iron over load and 16 cases of iron over load, 12 cases of them were treated by iron chelation therapy; anemia of chronic disease (ACD) group (12 cases) and iron deficiency anemia (IDA) group (12 cases). In addition, the healthy control group was selected. The iron metaloslism index (SF, SI, TIBC), serum level of EPO, plasma level of P-STAT5 and STAT-5 mRNA expression in peripheral blood cells were detected and compared in different groups. Moreover, the effects of iron metabolism abnormality on the expression of EPO and STAT5 in anemia patients were analyzed. compared with non-iron over load group, the EPO level in iron over load group significantly increased (P<0.05), the expression of STAT5 mRNA and P-STAT5 significantly decreased (P<0.05). After iron chelation therapy, the EPO level in serum significantly decreased (P<0.05), the expression of STAT5 mRNA and P-STAT5 was up-regulated significantly (P<0.05). Compared with healthy control group, the expression of EPO in ACD group was down-regulated significantly, while the expression of STAT5 mRNA was not different, but the P-STAT5 expression was down-regulated significantly (P<0.05). Compared with the healtly control group, the EPO expression in IDA group was enhanced significantly (P<0.05), the expression of STAT5 mRNA and P-STAT5 were also significantly enhanced (P<0.05). The excessive iron load or chronic inflammation may inhibit the activation of EPO-STAT5 signaling pathway and aggravate the anemia.

Potential Barriers to Clinical Trials of New Therapeutics for Myelodysplastic Syndromes: Wide Variation in Risk Definitions and Trial Enrollment Criteria

Introduction: Myelodysplastic syndromes (MDS) are neoplasms characterized by cytopenias, high risk of leukemic progression, and poor overall survival. Chemotherapy for MDS is not curative, and no new drugs have been approved for the treatment of MDS in over a decade. Clinical trials should be considered at any time during the management of patients with MDS, but enrollment criteria may be barriers that limit accrual. In this study, we extracted MDS clinical trial data from clinicaltrials.gov, and compared study indications and characteristics, including inclusion and exclusion criteria.Methods: We identified MDS clinical trials via clinicaltrials.gov (accessed: April 16, 2018). Studies were included if they allowed “MDS,” “Myelodysplastic syndromes,” “Preleukemia,” and/or “Myelodysplasia,” based on the pre-defined ‘related terms’ criteria in the database. We included interventional studies open in the United States that were listed as recruiting or not yet recruiting, for adults (age 18-64) and older adults (age 65+). We excluded studies that were observational in nature, involved a transplant-based intervention, or did not use a pharmacological intervention. We coded inclusion and exclusion criteria based on those provided by study authors in the database.Results: 83 interventional clinical trials enrolling patients with MDS were identified. Studies started enrollment between 4/1/2013 and 3/27/2018, and anticipated reaching the primary objective between 5/1/2017 and 6/1/2025. The median planned study duration was 38 mo (range 10-95). In total, studies sought to enroll 8866 patients over 273 study-years; the median study enrollment estimate was 1.7 patients/month, or across all trials 247 patients/month. Clinical trials could be exclusive to MDS patients (n=28), include MDS patients and other myeloid malignancies e.g. AML (n=44), or include MDS patients and other cancers including solid tumors (n=11). For clinical trials exclusive to MDS, the total enrollment goal was 1966 patients over 96 study-years, with a median rate of 1.4 patients/month (range 0.3-13.2) or total of 63 patients/month across all studies.33 trials were phase 1 studies, 17 were phase 1/2, 26 were phase II, 1 trial was phase 2/3, and 6 were phase III studies. The primary endpoint was typically MTD (n=50) or ORR (n=22), while 5 studies had an OS endpoint.Most trials specified “higher risk” MDS (n=44); 8 specified “lower risk” MDS and 31 allowed all MDS risk or did not specify risk (Figure 1). Lower risk MDS studies were all exclusive to MDS patients. Inclusion criteria related to MDS risk varied significantly according to whether a study was MDS-specific or not (p=0.021): 82% of MDS-specific trials had risk exclusions, compared to 72% of myeloid trials, and only 36% of trials open across cancers. Of 52 trials specifying MDS risk, 20 included IPSS criteria, 24 included IPSS-R criteria, and 27 had blast count criteria.Lower risk MDS criteria was variably defined as IPSS low or INT-1 disease (n=3), IPSS-R very low or low risk (n=1), IPSS-R VL, L, or intermediate risk (n=4), or blast counts < 5% (n=1), < 10% (n=2), or <20% (n=2). There were variations in the criteria for transfusion dependence, including 2 transfusion units in 8 weeks (n=3), 4 in 8 weeks (n=2), 2 in 4 weeks (n=2), 1 in 6 weeks (n=1), and 2 in 16 weeks (n=1).For higher risk MDS, criteria included IPSS INT-1, INT-2, or High risk (n=7), IPSS INT-2 or High risk (n=12), IPSS-R intermediate, high, or very high risk (n=12), or IPSS-R high or very high (n=9); blast counts were set at >5% (n=12) or >10% blasts (n=12). Most studies specified exclusion of CNS disease, even though CNS involvement is exceptionally rare in MDS.43 trials excluded concurrent cardiovascular disease; most often (n=18) requiring 6mo since a cardiovascular event. 46 trials had language excluding concurrent cancers, including 4 that did not allow any prior cancer, and 17 required ³24mo disease free. Exclusions for prior cancers did not vary according to primary outcome (MTD or PK, vs ORR/OS, p=0.16). 20 of 56 studies with MTD or early outcomes (e.g. PK) required cancer-free intervals of ³1y, while 7 allowed concurrent cancers if not on active therapy.Discussion: Currently enrolling MDS clinical trials show significant variation in their inclusion and exclusion criteria. Heterogeneous definitions of basic entry criteria, such as the definition of higher- and lower-risk MDS, may cause barriers to enrollment. [Display omitted] DisclosuresBrunner:Takeda: Research Funding; Novartis: Research Funding; Celgene: Consultancy, Research Funding. Garcia:Celgene: Consultancy.

Safety and Efficacy, Including Event-Free Survival, of Deferasirox Versus Placebo in Iron-Overloaded Patients with Low- and Int-1-Risk Myelodysplastic Syndromes (MDS): Outcomes from the Randomized, Double-Blind Telesto Study

▪Background: MDS comprise a group of disorders characterized by bone marrow (BM) failure, cytogenetic and molecular alterations, and progression to acute myeloid leukemia (AML). Most lower-risk MDS patients (pts) eventually need chronic red blood cell (RBC) transfusions because of impaired hematopoiesis, resulting in iron overload (IO) that damages organ function and contributes to shortened survival. Though iron chelation therapy (ICT) has been consistently shown to improve outcomes in lower-risk MDS pts, most studies had limitations (eg retrospective analyses, registry studies, pts not stratified by performance status). As such, a prospective, controlled study of ICT and survival in Low/Intermediate (Int-1)-risk MDS pts was needed.Aims: TELESTO (NCT00940602) was a Phase II randomized, double-blind study that evaluated event-free survival (EFS) and safety of deferasirox (DFX) vs placebo (PBO) in Low/Int-1-risk MDS pts.Methods: Eligible pts were aged ≥18 yrs, had IPSS Low/Int-1-risk MDS (confirmed by BM examination within 6 months of study entry), serum ferritin (SF) >1000 ng/mL, transfusion history of 15-75 pRBC units, without cardiac, liver and renal abnormalities. Pts were randomized 2:1 to DFX (dispersible tablets; 10-40 mg/kg/day based on dosing guidelines) or PBO. Primary objective was to evaluate DFX and PBO for EFS, measured by a composite primary endpoint of time to first non-fatal event (related to cardiac and liver function and transformation to AML) or death, whichever occurred first; events were confirmed by an independent adjudication committee. With a planned sample size of 210 pts, no hypotheses were planned to be tested; statistical tests are exploratory, P values associated with treatment effect are nominal.Results: 225 pts were randomized to DFX (n=149) or PBO (n=76); 72.4% had Int-1 MDS, 60.9% were male, mean age was 61.0 yrs; baseline characteristics were balanced, but more pts in the DFX arm were aged ≥75 yrs (25.5% vs 17.1%). DFX and PBO pts received a mean of 20.28 and 20.27 international units of pRBC transfusions 6 months prior to randomization. Median time on treatment was longer with DFX vs PBO (587.5 vs 370.5 days); 43.9% and 25.0% of DFX and PBO pts received treatment for ≥2 yrs. Median EFS was prolonged by 349 days with DFX (1440 days; 95%CI 1167-1559) vs PBO (1091 days; 95%CI 820-1348): 36.4% risk reduction in EFS with DFX (P=0.015 [Figure 1]). Estimated EFS at 3 yrs was 61.5% (95%CI 52.2-69.6) with DFX and 47.3% (95%CI 31.8-61.3) with PBO. Events that occurred first with DFX (n=62; 41.6%) and PBO (n=37; 48.7%) included: worsening cardiac function (1.3 vs 2.6%); hospitalization for congestive heart failure (0.7 vs 3.9%); liver function impairment (0.7 vs 1.3%); progression to AML (6.7 vs 7.9%); death (32.2 vs 32.9%). Robustness of the positive treatment effect with DFX was confirmed by various sensitivity analyses, including censoring pts with premature treatment discontinuation and subsequent ICT.Median overall survival (OS) was 1907 days (95%CI: 1440-not estimable) with DFX and 1509 days (95%CI 1095-1804) with PBO; HR 0.832 (95%CI 0.54-1.28, P=0.200). ICT after study treatment discontinuation may have diluted any potential OS difference. SF declined over time with DFX and increased in the PBO arm (Figure 2).Most frequently reported AEs (≥20% in either arm) were diarrhea, pyrexia, upper respiratory tract infection, cough and increased blood creatinine. After adjustment for exposure, rates were: diarrhea (24.7 vs 23.9%), pyrexia (21.8 vs 18.7%), upper respiratory tract infection (16.7 vs 22.7%), cough (12.6 vs 11.3%) and increased blood creatinine (15.9 vs 0.9%) in the DFX and PBO arms, respectively. Most frequently reported severe AEs (≥5% in either arm) were anemia, pyrexia, thrombocytopenia and lung infection. When adjusted for the different exposure time, the rate of all severe AEs per 100 pt-yrs was overall comparable.Summary/conclusions: TELESTO is the first prospective, randomized study in Low/Int-1-risk MDS pts with IO to show ICT with DFX provides clinical benefit across multiple tissues, leading to longer EFS (including cardiac and liver events and transformation to AML) vs PBO. The safety profile was as expected, consistent with previous studies of DFX in adult MDS pts with IO. Considering the current treatment landscape, it is unlikely that a similar, randomized trial can be performed. These results support the use of DFX in Low/Int-1-risk MDS pts with IO. [Display omitted] DisclosuresAngelucci:Celgene: Honoraria, Other: Chair DMC; Vertex Pharmaceuticals Incorporated (MA) and CRISPR CAS9 Therapeutics AG (CH): Other: Chair DMC; Jazz Pharmaceuticals Italy: Other: Local ( national) advisory board; Roche Italy: Other: Local (national) advisory board; Novartis: Honoraria, Other: Chair Steering Comiittee TELESTO Protocol. Rodriguez:Novartis: Speakers Bureau. Dong:Novartis: Employment. Ghosh:Novartis: Employment. Bornstein:Novartis: Employment.

What Is the Optimal Time to Initiate Hypomethylating Agents (HMA) in Higher Risk Myelodysplastic Syndromes (MDS)?

What Is the Optimal Time to Initiate Hypomethylating Agents (HMA) in Higher Risk Myelodysplastic Syndromes (MDS)?

BRCA1 & BRCA2 Germline Variants Are Enriched in MDS/AML and Portend Higher Average Mutational Burden

The homologous DNA repair pathway genes BRCA1 and BRCA2 are classically associated with increased susceptibility to hereditary breast and ovarian cancer due to increased vulnerability to double stranded DNA breaks (mutator phenotype). In addition to their role in breast/ovarian cancer, defects in these genes may predispose to myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). For example, in large populations of breast cancer patients, those with inherited defects in homologous repair (HR) showed a propensity to therapy-related MDS and AML; however, a relationship between BRCA gene variants and spontaneous myeloid neoplasms has yet to be elucidated. Moreover, analyses are complicated by the large number of clinically uncharacterized single nucleotide variants (SNV) in BRCA gene loci.We thus evaluated the relationship between germline BRCA variants (GLVs) and the risk of adult MDS or AML. We applied next generation sequencing to a large cohort of patients (N =463) presenting with MDS (402) and AML (61). In these analyses, all mutations with a variant allele frequency of less than 30% were considered somatic. We then identified alterations known to be linked with breast/ovarian cancer development by linkage analyses. These mutations (n=2), along with missense mutations with an allele frequency <.001% and previously unknown mutations with a CADD score >10, were considered Tier-1 mutations (n=37). Tier 2 mutations were defined as missense mutations with a population frequency >.01% or mutations in patients with incomplete clinical or sequencing data. After excluding Tier-2 variants, 39 of 88 GLVs were further analyzed.BRCA Tier-1 GLV were significantly over-represented in the MDS/AML cohort compared to the general population, estimated via publically available exome aggregation databases (ExAC, 8% vs 0.1% p<.001). No biallelic mutations were detected. We compared the pattern of somatic mutation and cytogenetic alteration in patients with Tier-1 GLVs to those without these mutations. Patients carrying Tier-1 GLVs exhibited a significantly higher average mutational burden compared to those without GLVs, measured by an NGS panel including 186 genes (1.2 vs. 0.4, p<.005). The most common co-occurring mutations in BRCA GLV carriers affected DNMT3A(4), ASXL1(3), SF3B1(3), TET2(3), and TP53(3). Among these mutations, TP53 alterations were significantly enriched in BRCA GLV carriers (OR = 6.8, p = 0.003, Figure 1). There was no difference in complex karyotype, del5q, and del7 alterations in BRCA GLV carriers when compared to other MDS/AML patients. BRCA GLV carriers had a higher burden of familial cancer (41% vs. 19%, p<.001). There was no difference in gender, age-at-diagnosis of MDS/AML, or 10-year survival in carriers of BRCA 1/2 GLVs in comparison to the broader cohort (Figure 2).BRCA GLVs (Tier-1) are over-represented in MDS/AML patients as compared to the general population, and linked with a higher rate of somatic point mutations but not common MDS/AML-associated cytogenetic abnormalities. This suggests the possibility that defects in HDR may facilitate the evolution of apparently spontaneous MDS/AML that is actually germline predisposed. As with breast and ovarian cancers, another possibility is that such variants could have implications in treatment selection, especially in the context of the evolution of PARP inhibition as a therapeutic modality in MDS/AML. [Display omitted] DisclosuresSaunthararajah:Novo Nordisk, A/S: Patents & Royalties; EpiDestiny, LLC: Patents & Royalties. Carraway:Jazz: Speakers Bureau; FibroGen: Consultancy; Balaxa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Agios: Consultancy, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees. Nazha:MEI: Consultancy. Sekeres:Opsona: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis Pharmaceuticals: Consultancy; Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ra Pharmaceuticals, Inc: Consultancy.

Prognostic Impact of Circulating Tumor DNA Status Post-Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemia and Myelodysplastic Syndrome

Background: Allogeneic hematopoietic stem cell transplantation (alloSCT) is the only curative option for patients with high risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Whereas, relapse is the main event in therapeutic failure for these patients. We previously reported the utility of residual circulating tumor DNA (ctDNA) status for identifying patients with AML and MDS at high risk for relapse post myeloablative alloSCT (Nakamura et al, ASH. 2017). However, it remains to be elucidated whether persistent mutation status in serum and bone marrow (BM) have comparable ability to identify patients at high risk for relapse. Additionally, recent reports indicated mutation persistence (MP) in BM based on three genes regarding clonal hematopoiesis, DNMT3A, TET2, and ASXL1 (DTA), was not informative for relapse prediction of patients with AML in the setting of chemotherapy (Jongen-Lavrencic et al, N Engl J Med. 2018). Therefore, the prognostic impact of residual ctDNA status based on DTA genes should also be tested.Methods: To address these questions, we retrospectively collected tumor and matched serum samples at diagnosis and 1 and 3 months post-alloSCT from 53 patients with AML and MDS. Cell-free DNA was extracted from serum samples. We subjected tumor DNA, extracted from BM or peripheral blood, and buccal swab DNA, to next-generation sequencing (NGS), identifying candidate driver mutations. After identifying driver mutations, we designed droplet digital PCR (ddPCR) assay. The primary endpoint was the cumulative incidence of relapse (CIR) rate, and the secondary endpoint was the overall survival (OS) rate. We used DeLong's test to compare the performance between two assays based on the area under the curve (AUC) of receiver operating characteristics (ROC) curves.Results: Driver mutations were identified in 51 of 53 patients by NGS, and our cohort consisted of 37 patients with AML and 14 patients with MDS. The median age of the patients was 53 years. The conventional cytogenetic risk category was an adverse or high risk in 39.2% of patients, and 49.0% were in relapse or refractory disease status at alloSCT, and all patients received myeloablative conditioning; in most cases, the stem cell source was cord blood. The most frequent mutations found involved epigenetic regulators (DNMT3A/TET2/ASXL1, mutated in 32.1%), followed by signal transduction proteins (NRAS/FLT3, 31.4%). We could design at least one representative ddPCR assay for 51 patients. There was a clear correlation of variant allele frequency measurement between diagnostic ctDNA and matched tumor DNA (r2 = 0.67; P < 0.0001). Sixteen patients relapsed after a median of 7 months post-alloSCT. Both MP in BM at 1 and 3 months post-alloSCT and corresponding ctDNA persistence (CP) in serum (MP1 and MP3; CP1 and CP3, respectively) were comparably associated with higher 3-year CIR rates and inferior OS rates [3-year CIR (3-year OS): MP1 vs. non-MP1: 72.9 (50.0)% vs. 13.8 (88.0)%; P = 0.0012 (.0304) (Figure 1A); CP1 vs. non-CP1: 65.6 (45.8)% vs. 9.0 (91.7)%; P = 0.0002 (.0014) (Figure 1B); MP3 vs. non-MP3; 80.0 (30.0)% vs. 11.6 (94.1)%; P = 0.0002 (.0007); CP3 vs. non-CP3: 71.4 (53.4)% vs. 8.4 (92.5)%; P < 0.0001 (.0021)]. We next tested whether CP based on DTA could also be helpful in relapse prediction, we performed a subset analysis of patients with DTA based ddPCR assays (n=12). As a result, CP based on DTA genes also had the prognostic impact on CIR (Figure 1C). Finally, we compared the discriminatory ability of CP with those of MP. There was no significant difference between either CP and MP (Figure 1D). Additionally, when CP1 was compared with CP3, CP3 was found to be a better indicator of CIR and OS.Conclusions: In summary, we, for the first time, demonstrated that non-invasive serum ctDNA-testing, regardless of DTA genes, had comparable utility to molecular MRD testing of BM with regard to identifying patients at high risk for relapse in AML and MDS undergoing myeloablative alloSCT. Although prospective large-scale analyses are needed to confirm our findings, such non-invasive ctDNA-testing might allow for rapid clinical decision-making and, ultimately, subsequent risk-adapted therapeutic interventions post-alloSCT in AML and MDS.Figure 1. CIR based on the 1 month (A) MP and (B) CP status. (C) CIR based on the 1month CP status according to DTA subset. (D) Comparison of ROC curves for relapse prediction between 1 month CP and MP. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Eltrombopag Improves Hematopoiesis in Patients with Low to Intermediate-2 Risk Myelodysplastic Syndrome (MDS)

Eltrombopag (EPAG), a thrombopoietin receptor agonist, has been shown to improve hematopoiesis in patients with aplastic anemia (AA), but in MDS patients the effect of thrombopoietin mimetics in bone marrow function is still unclear. In this phase-2 dose escalation study, we investigated the safety and effectiveness of EPAG treatment in low to intermediate-2 risk MDS patients (NCT 00961064).Thirty patients were enrolled from March 2011 to July 2017. Preceding enrollment the majority of patients were either diagnosed with AA (n=13) or hypoplastic MDS (n=5). EPAG was started at 50 mg/day, up to a maximal dose of 150 mg/day, increasing the dose by 25mg every 2 weeks. The primary endpoint was hematologic response at 16 or 20 weeks, defined as either: (1) an increase in platelet counts ≥20.000/uL or transfusion independence for a minimum of 8 weeks; (2) hemoglobin (Hb) increase of ≥1.5g/dL from baseline, or a reduction in red blood cells (RBC) transfusion of at least 50%; or (3) an increase in absolute neutrophil counts (ANC) of ≥0.5x109/L or by at least 100% in patients with a baseline ANC <0.5x109/L. Responding patients could continue EPAG treatment on an extension arm.The primary endpoint of hematological response was met in 14/30 patients (47%). All responders continued EPAG on the extension arm. In 3 patients, peripheral blood cell counts declined on EPAG after the initial response. One patient withdrew from the study. Ten of the 14 responding patients achieved a robust response (RR) after a median treatment duration of 15 months (range 7-27 months). Robust response was defined as stable hematopoiesis with at least a hemoglobin >10g/dl, and thrombocytes >50.000/L, and ANC>1000/L. However, peripheral blood cell counts significantly declined in 5/10 RR and EPAG was restarted per protocol. In 4 of these patients peripheral blood cell counts recovered. One patient did not achieve a second response.Based on International Prognostic Score System (IPSS), 4/30 (13%) patients progressed on study, including 3 non-responders and 1 responder, at a median follow-up of 4 months (3-35 months). The responding patient was diagnosed with increased bone marrow myeloblast 7 months after discontinuation of EPAG for robust response and 35 months after enrolling in the study. New cytogenetic abnormalities determined progression in non-responding patients (Figure).Novel dose limiting toxicities were not observed. Three patients developed CTCAE grade III hepatic toxicities. One of them discontinued EPAG at 3 months. Elevated transaminases returned to baseline after EPAG discontinuation in 2 patients. In both cases EPAG was resumed either at the same (150mg/day) or reduced dose (50mg/day) level. There were no treatment-related death cases. One patient died on study before the primary endpoint from acute respiratory distress syndrome.Sequential acquisition of genomic aberrations has been associated with malignant transformation. Targeting next-generation sequencing for somatic variants in genes previously associated with myeloid malignancies (Myeloid cancer genes, MCG) was performed in 29/30 patients with sufficient material (bone marrow mononuclear cells) available from baseline, primary endpoint, and at time of progression. At baseline, 22/29 (76%) patients were found with at least one mutation:TET2 (14.5%), ASXL1 (12.5%), SF3B1 (8.3%), SETBP1 (8.3%), ATM (8.3%), and ZRSR2 (8.3%). After EPAG, additional somatic variants in different genes were detected in 4/14 responders and 7/16 non-responders. Variants present at baseline were no longer detected in post EPAG samples from 4 responding and 6 non-responding patients. The VAF of variants detected at both time points were similar, indicating no selective expansion of clones with EPAG in neither responder, non-responder nor patients with progression based on IPSS.In conclusion, our results suggest that EPAG is well-tolerated and effective in restoring hematopoiesis in patients with low to intermediate-2 risk MDS, particular with a prior history of hypoplastic bone marrow failure syndromes. EPAG was discontinued for robust response in the majority of responders but declining blood cell counts were observed in about 50% of them. Variants in MCG were more common at study entry compared to patients with aplastic anemia (Yoshizato, NEJM, 2015). However, EPAG appears not to selectively promote expansion of clones harboring MCGs in this patient population. [Display omitted] DisclosuresTownsley:National Institute of Health: Research Funding. Scheinberg:Pfizer: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Janssen: Honoraria, Research Funding. Dunbar:National Institute of Health: Research Funding. Young:GlaxoSmithKline: Research Funding; CRADA with Novartis: Research Funding; National Institute of Health: Research Funding. Winkler:National Institute of Health: Research Funding.

Addition of the SMO Inhibitor Sonidegib to Azacitidine in Patients with Higher Risk Myelodysplastic Syndrome (MDS) Who Failed to Respond or Lost Response to AZA Alone: Results of a Phase 1-2 Add-on Study By the GFM

Background: although azacitidine (AZA) is an established frontline therapy for HR-MDS, approximately 40% of the patients fail to respond and virtually all of the responders will ultimately relapse. We previously reported the poor outcome of patients who failed AZA treatment for whom a median survival of 6 months is expected (Prebet, J Clin Oncol. 2011;29(24):3322). Overexpression of SMO a member of the hedgehog pathways has been observed in HR-MDS. Preclinical data have shown the activity of hedgehog pathway inhibitors and suggested synergism with Hypomethylating agents (HMA) (Zou, PLoSONE 2015; 10(8):e0136843). To harness potential synergism, we designed an add-on trial in which sonidegib (LDE-225), an oral inhibitor, was added to AZA in patients who failed AZA monotherapy.Patients and methods:Eligible patients should have IPSS Int-2 or HR-MDS or AML, (to have 10% to 30% marrow blasts), have received a minimum of 6 cycles of AZA monotherapy and to have failed to achieve a response to AZA (defined as CR, CRi, PR or HI as per IWG criteria) in the absence of marrow progression or have relapsed after achieving a response. Patients were scheduled to receive sonidegib daily from day 1 to 28 of 28-day cycles while continuing on AZA at the maximum previously tolerated dose (ie 50 to 75 mg/m²/d for 5-7 days). Two sonidegib dose levels were evaluated in the phase 1 part of the trial (400 and 800 mg/d) according to a classical 3+3 scheme.Results:23 patients, median age 76, were included in the study. One withdrew consent before starting the study treatment and is not included in the analysis. Characteristics of the remaining 22 patients are summarized in the Table. At the 800 mg/d dose level, 3 pts experienced DLT (grade 4 ASAT elevation (1 pt); grade 4 CPK elevation (2 pts)). The recommended dose for the expansion phase was 400 mg/d and no DLT was observed. 19 patients received 400 mg/d. Pts received a median of 3.5 cycles [IQR 2 ; 5], and 5 pts (23 %) received ≥ 6 cycles. All of them were withdrawn from study: 5 (26%) for disease progression (including 1 pt who progressed before starting cycle 1 and did not received treatment), 5 (26%) for death (all due to infection in the context of active disease) and 9 for miscellaneous reasons. 25 SAEs were reported including 23 infections, 1 intra cranial hemorrhage and 1 urinary retention. The most frequent non-hematologic toxicity was infection that occurred in 16/22 (73%) pts. In addition, 243 non hematologic toxicities of any grade were recorded in 20 pts for a total of 83 cycles, all but 3 of grade 1-2, including GI, cutaneous and musculo-skeletal toxicities and fatigue. Hospitalization was required in 45% of the pts. Only 3 responses were observed (1 CR, 1 marrow CR and 1 PR). Response durations were 1, 9 and 15 months .With a median follow-up of 23 months, 13 pts have died and the median overall survival is 6.8 months.ConclusionSonidegib at the dose of 400 mg/d can be given in combination with azacitidine with an acceptable toxicity. With a response rate of only 13%, our results indicate that the addition of sonidegib failed to reverse resistance to azacitidine in pts with higher risk MDS. This contrasts with the positive effect of the combination of glasdegib, another hedgehog pathway inhibitor with cytarabine in pts with AML and MDS (Cortes, Blood 2016 128:99). Besides potential differences in drug potency, our results may highlight the difficulty to identify active agents in the difficult-to-treat patient population selected after HMA therapy failure. The recommended dose-schedule of AZA-sonidegib established here could be used for further investigation in previously untreated patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Clonal Suppression of TP53 Mutant MDS and Oligoblastic AML with Hypomethylating Agent Therapy Improves Overall Survival

Background Hypomethylating agent (HMA) therapy represents the standard of care for patients with higher risk myelodysplastic syndromes (MDS) although only 50% of patients respond to treatment. Recent evidence from molecular profiling through next-generation sequencing (NGS) in myeloid diseases has been conflicting as to the value of somatic mutations as a biomarker for response to HMA. In particular, there have been conflicting data on response rates and outcomes in TP53 mutant (MT) MDS and acute myeloid leukemia (AML) based on azacitidine versus decitabine (Welch et al., NEJM 2016; Garcia-Manero et al., NEJM 2017). However, the TP53 mutant cohorts in these studies were small (median 23 patients, range 13-39) and heterogeneous based on treatment status (treatment naïve versus relapse/refractory). Therefore, our goal was to characterize outcomes of TP53 mutant MDS patients who received frontline HMA therapy.Patients and MethodsTP53 MT MDS and oligoblastic AML (20-30% blasts) cases were retrospectively identified from the Moffitt Cancer Center MDS database. All patients had NGS of TP53 and up to 53 additional genes performed prior to the initiation of HMA. The lower limit of VAF detection was set at 5% and the minimum depth of coverage at each position was 500X. Clinical variables and outcomes of MDS patients were characterized at the time of sample procurement. Fisher's exact tests were used for comparative analyses. Kaplan-Meier curves were used to estimate overall survival (OS) and analyzed from the date of HMA initiation. Response rates and outcomes of TP53 MT patients were compared to a cohort of wildtype (WT) patients (n=63).Results From May 2013 to May 2018, a total of 71 patients with TP53 mutant MDS were identified with a median age of 68 years (39-82) and male predominance (66%). Fourteen patients (20%) had multiple mutations in TP53. Of the cohort, 82% of patients (n=58) were treated with azacitidine (88% (n=51) with AZA monotherapy; 12% (n=7) with AZA in combination (2 pts with lenalidomide and 5 pts with investigational agents)) with 18% (n=13) receiving decitabine. The median # of HMA cycles was 4 (range 1-33). Thirteen pts (18%) proceeded to allogeneic hematopoietic stem cell transplant (HSCT). Of the cohort, 18% (n=13) obtained complete remission (CR) with 39% (n=28) overall response rate (ORR). There was no difference in CR or ORR in pts treated with AZA vs DAC (P=0.24 and P=0.2, respectively). At a median follow up 20 months, the median OS of the entire cohort was 9.7 months. There was no difference in median OS between AZA vs AZA combo vs DAC (7.6 vs 15.2 vs 12.5 months; P = 0.44; Figure 1A). TP53 variant allele frequency (VAF > 20% vs ≤ 20%) was not predictive of outcomes to HMA (7.8 vs 10.4 months, P = 0.36).However, TP53 MT patients who had clonal response to HMA (i.e. VAF < 5%; n=19 (27%)) had improved OS (14.5 vs 7.5 months; HR 0.33, 95% CI 0.18 to 0.59; P = 0.001; Figure 1B). In multivariable analysis incorporating age, revised international prognostic scoring system (IPSS-R) category, HSCT status, or type of HMA, TP53 clonal clearance remained an independent covariate for improved OS (HR 0.34, 95% CI 0.16 to 0.72; P = 0.005). Pts who underwent HSCT (n=13) had a trend for improved OS (14.5 months vs 7.9 months; P = 0.09). Notably in transplanted pts who had serial TP53 NGS (n=7), pts who achieved a VAF < 5% had significant improved OS (16.3 months vs 8.9 months; P=0.03). Compared to higher risk MDS/AML TP53 WT patients treated with HMA, there was no difference in CR (18% vs 14% (P = 0.64) or ORR rates (39% vs 40%). In contrast, TP53 MT patients had significantly inferior OS with HMA therapy (9.7 vs 15.4 months; HR 2.14, 95% CI 1.32. to 3.27; P = 0.001; Figure 1C).Conclusion In this large cohort of higher risk MDS and oligoblastic AML pts who received frontline HMA therapy, TP53 MT patients have significantly inferior OS with no significant differences in response rates or outcomes by HMA. TP53 MT patients who achieve maximum clonal suppression with HMA treatment (i.e. VAF < 5%) have improved OS as well as improved outcome with HSCT. Novel therapy targeting TP53 mutation is needed to improve outcomes. [Display omitted] DisclosuresSallman:Celgene: Research Funding, Speakers Bureau. Sweet:Agios: Consultancy; Jazz: Speakers Bureau; Astellas: Consultancy; Phizer: Consultancy; Phizer: Consultancy; Astellas: Consultancy; Jazz: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Agios: Consultancy; BMS: Honoraria; Celgene: Honoraria, Speakers Bureau; BMS: Honoraria. List:Celgene: Research Funding. Komrokji:Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau.

A Pilot Prospective Single-Arm Clinical Study on Decitabine Plus CAG or IA Followed with HLA-Mismatched Nonmyeloablative Transplantation (micro transplantation) on De Novo Elderly Acute Myeloid Leukemia and Int-2/High Risk Myelodysplastic Syndrome Patients

Objective: To observe the efficacy and safety of Decitabine plus CAG or IA followed with HLA-mismatched nonmyeloablative transplantation (micro transplantation) on de novo elderly Acute Myeloid Leukemia and Int-2/high risk Myelodysplastic Syndrome patientsMethods: Till submission of this article, 10 patients were enrolled in this prospective clinical study. Patients were admitted from January 2017 to June 2018 to our centre. 6 of whom were elderly AML (≥60 years) and 4 were Int-2/high risk MDS according to IPSS-R scoring system. Induction chemotherapy were decitabine (15 mg/m2) for 5 days followed with CAG (cytarabine 10 mg/m2 q12h; aclarubicin 10 mg/day and G-CSF at 300 μg/day x 6 days for AML and 4 days for MDS), then followed with a transfusion of HLA-mismatched (≤7/10 matched HLA loci) related donor peripheral stem cells (micro transplantation) 24 hours after chemotherapy. Consolidation therapy was another 3 courses of chemotherapies which were decitabine (15 mg/m2) for 5 days with IA (3+7) for AML or CAG (6 days) for MDS, followed by micro transplantation 24 hours after each course. Till now, the total observable treatment courses were 21.Results: The average age of the patients was 63.5 years (range from 55 to 71 years). The average number of transfusion mononuclear cells (MNC) at per course was 3.26 (1.87-5.25) x 108/kg, the average CD34+ cells was 1.12 (0.34-3.16) x 106/kg, and the average of CD3+ T cells was 3.93 (1.87-7.17) x 107/kg. Among them, 5 cases (50%) obtained CR (CR+CRi), 3 cases obtained PR (30%). The ORR was 83.3% for elderly AML patients, 75% for MDS patients and 80% for all patients. The median recovery time of neutrophil (from the end of chemo to neutrophil ≥0.5 x 109) was 9 days and was 8.5 days for platelets (from the end of chemo to platelets ≥20 x 109). 1 patient developed severe aGVHD and died, 1 patient died of heart failure, no other serious adverse events were observed in rest patients. 7 of 10 cases developed peripheral T cell increase after stem cell transfusion, including the total CD3+ T cells, CD4+ and CD8+ T cells, with an average peak at day7. The increased T cells were verified as host origin by short tandem repeat (STR) detection performed on 1 patient. 8 of 10 cases occurred cytokine related fever (CRF) after stem cell transfusion. The fever was usually happened within 24 hours after stem cell transfusion, with an average duration of 5 days and a mean peak temperature at 39.7 ℃. With CRF there was an increase of cytokines with different patterns in different patients but majorly on IL-6, IL-2, IFN-r and TNF-a. Also there was an increase of C-Reactive Protein (CRP) which reached an average peak level as 116.9 mg/L. Patients with CRF had a CR+CRi rate at 62.5%.Conclusion: Our preliminary results of this study indicate that Decitabine plus CAG or IA followed with micro transplantation have an ORR at 80% in de novo elderly Acute Myeloid Leukemia and Int-2/high risk Myelodysplastic Syndrome patients with controllable recover time of neutrophils and platelets. Although the incidence of acute graft versus host disease (aGVHD) in micro transplantation was as low as 1-2% according to reports, it is still possible. How to predict and avoid severe aGVHD is still under investigate. The presence of cytokine related fever may associate with the increase of hosts' T cells, which may relate to the improvement of therapeutic response. Larger cohorts and more investigates need to be done to clarify above findings. DisclosuresNo relevant conflicts of interest to declare.

P53 and CD34 Immunohistochemical Expression on Bone Marrow Biopsy As Predictive Marker of Response to Erythropoietin in Low Risk Myelodysplastic Syndrome

Introduction: Erythropoietin stimulating agents (ESAs) are first-line therapy for International Prognostic Scoring System (IPSS)-low risk myelodysplastic syndrome (MDS) when symptomatic anaemia (Hb <10 g/dl) is associated with serum erythropoietin (EPO) <500 mU/mL. Treatment response rate, according to international working group (IWG) response criteria (1- 5), ranges from 40 to 60%.Attempts have been made to build prognostic scores (integrating transfusion need, erythropoietin level, R-IPSS and ferritin) able to predict response to ESAs (6-7). No data concerning the predictive value of morphological and immunohistochemical analysis on bone marrow biopsy in low risk MDS patients are emerged till now.Methods: We retrospectively examined 96 IPSS low/int-1 MDS patients treated with ESAs in order to evaluate the morphological and immunohistochemical features of the bone marrow biopsies performed at baseline.All the patients had hemoglobin (Hb) ≤10 g/dL and serum EPO <500 mU/mL and received EPO alfa or β 40 000-80 000 IU/week for at least 12 weeks. Response to ESAs treatment was evaluated according to IWG 2006 criteria.A detailed analysis of the morphological features (including quantitative and qualitative changes in the erythroid, myeloid and megakariopoyetic lineages) was performed, together with an immunohistochemical evaluation of p53 expression and CD34-positive blasts percentage.Results: Sixty-eight percent of the patients were classified as responder while 32% as non-responder. The morphologic profiles of the responder and non-responder did not differ significantly.A significant correlation was found between the response to the therapy and a percentage of CD34-positive blasts > 3% (univariate analysis: p= .0211).Moreover p53 expression in less than 1% of the nucleated cells correlated with the treatment response (univariate analysis: p = .0086). These results were also confirmed on multivariate analysis (p= .002).Fifty-eight percent of patients maintained response to ESAs for the entire duration of the follow up while 42% lost the response (median follow up: 35 months). More than 3% CD34-positive blasts was associated with a higher probability to lose the response to ESAs (p = .00003).Kaplan-Meier method was than applied to estimate the response duration. Patients with more than 3% CD34-positive blasts showed earlier loss of response in comparison with those with a lower percentage of blasts (p value= .0003; HR=3.9, IC 95% 1.8154-8.6238).Finally, the expression of p53 in more than ≥ 1% of the nucleated cells correlated with the loss of response before 24 mounts (p value= 0.029).Conclusions: Our study identifies 2 well-known parameters that could be useful to better predict outcome of ESAs therapy in low risk MDS patients. Therefore role of bone marrow biopsy together with its diagnostic contribution in the clinical evaluation of MDS patients (cellularity, morphologic dysplasia, percentage of CD34-positive blasts, grading of bone marrow fibrosis) could be helpful as a predictive tool in ESAs candidate patients. Further studies based on larger series of patients are needed to confirm these preliminary results. DisclosuresReda:Gilead: Consultancy; ABBVIE: Consultancy; Janssen and Cilag: Consultancy; Celgene: Consultancy. Riva:Jannsen and Cilag: Consultancy; Novartis: Consultancy; Celgene: Consultancy. Molteni:Janssen and Cilag: Consultancy; Novartis: Consultancy; Italfarmaco: Consultancy; Celgene: Consultancy; AMGEN: Consultancy. Cortelezzi:abbvie: Consultancy; novartis: Consultancy; roche: Consultancy; janssen: Consultancy.