European LeukemiaNet-defined primary refractory acute myeloid leukemia: the value of allogeneic hematopoietic stem cell transplant and overall response.

We sought to appraise the value of overall response and salvage chemotherapy, inclusive of allogeneic hematopoietic stem cell transplant (AHSCT), in primary refractory acute myeloid leukemia (prAML). For establishing consistency in clinical practice, the 2017 European LeukemiaNet (ELN) defines prAML as failure to attain CR after at least 2 courses of intensive induction chemotherapy. Among 60 consecutive patients (median age 63 years) correspondent with ELN-criteria for prAML, salvage was documented in 48 cases, 30/48 (63%) being administered intensive chemotherapy regimens and 2/48 consolidated with AHSCT as first line salvage. 13/48 (27%) attained response: CR, 7/13 (54%), CRi, 2/13 (15%), MLFS, 4/13 (31%). The CR/CRi rate was 9/48 (19%), with CR rate of 7/48 (15%). On univariate analysis, intermediate-risk karyotype was the only predictor of response (44% vs 17% in unfavorable karyotype; P = 0.04). Administration of any higher-dose (>1 g/m2) cytarabine intensive induction (P = 0.50), intensive salvage chemotherapy (P = 0.72), targeted salvage (FLT3 or IDH inhibitors) (P = 0.42), greater than 1 salvage regimen (P = 0.89), age < 60 years (P = 0.30), and de novo AML (P = 0.10) did not enhance response achievement, nor a survival advantage. AHSCT was performed in 12 patients with (n = 8) or without (n = 4) CR/CRi/MLFS. 1/2/5-year overall survival (OS) rates were 63%/38%/33% in patients who received AHSCT (n = 12) vs 27%/0%/0% in those who achieved CR/CRi/MLFS but were not transplanted (n = 5), vs 14%/0%/0% who were neither transplanted nor achieved CR/CRi/MLFS (n = 43; P < 0.001); the median OS was 18.6, 12.6 and 5.6 months, respectively. Although CR/CRi/MLFS bridged to AHSCT (n = 8), appeared to manifest a longer median OS (20 months), vs (13.4 months) for those with no response consolidated with AHSCT (n = 4), the difference was not significant P = 0.47. We conclude AHSCT as indispensable for securing long-term survival in prAML (p = 0.03 on multivariate analysis), irrespective of response achievement.

A vicious loop of fatty acid-binding protein 4 and DNA methyltransferase 1 promotes acute myeloid leukemia and acts as a therapeutic target.

Aberrant DNA methylation mediated by deregulation of DNA methyltransferases (DNMT) is a key hallmark of acute myeloid leukemia (AML), yet efforts to target DNMT deregulation for drug development have lagged. We previously demonstrated that upregulation of fatty acid-binding protein 4 (FABP4) promotes AML aggressiveness through enhanced DNMT1-dependent DNA methylation. Here, we demonstrate that FABP4 upregulation in AML cells occurs through vascular endothelial growth factor (VEGF) signaling, thus elucidating a crucial FABP4-DNMT1 regulatory feedback loop in AML biology. We show that FABP4 dysfunction by its selective inhibitor BMS309403 leads to downregulation of DNMT1, decrease of global DNA methylation and re-expression of p15INK4B tumor suppressor gene by promoter DNA hypomethylation in vitro, ex vivo and in vivo. Functionally, BMS309403 suppresses cell colony formation, induces cell differentiation, and, importantly, impairs leukemic disease progression in mouse models of leukemia. Our findings highlight AML-promoting properties of the FABP4-DNMT1 vicious loop, and identify an attractive class of therapeutic agents with a high potential for clinical use in AML patients. The results will also assist in establishing the FABP4-DNMT1 loop as a target for therapeutic discovery to enhance the index of current epigenetic therapies.

Prognostic relevance of lymphocytopenia, monocytopenia and lymphocyte-to-monocyte ratio in primary myelodysplastic syndromes: a single center experience in 889 patients.

Current prognostic models for myelodysplastic syndromes (MDS), including the Revised International Prognostic Scoring System (IPSS-R), do not account for host immunity. We retrospectively examined the prognostic relevance of monocytopenia, lymphocytopenia and lymphocyte-to-monocyte ratio (LMR) in a cohort of 889 patients with primary MDS. After a median follow-up of 27 months, 712 (80%) deaths and 116 (13%) leukemic transformation were documented. In univariate analysis, subnormal absolute lymphocyte count (ALC) <0.9 × 109/l; P=0.001), ALC<1.2 × 109/l (P=0.0002), subnormal absolute monocyte count (AMC) <0.3 × 109/l (P=0.0003), LMR (P⩽0.0001) and LMR⩾5 (P=0.03) were all associated with inferior overall survival. In multivariable analysis that included other risk factors, significance was retained for LMR (P=0.02) and became borderline for ALC <1.2 × 109/l (P=0.06). Analysis in the context of IPSS-R resulted in P-values of 0.06 for ALC<1.2 × 109/l, 0.7 for monocytopenia and 0.2 for LMR. Leukemia-free survival was not affected by ALC, AMC or LMR. The observations from the current study suggest a possible detrimental role for altered host immunity in primary MDS, which might partly explain the therapeutic benefit of immune-directed therapy, including the use of immune modulators; however, IPSS-R-independent prognostic value for either ALC or AMC was limited.

Fatty acid-binding protein FABP4 mechanistically links obesity with aggressive AML by enhancing aberrant DNA methylation in AML cells.

Obesity is becoming more prevalent worldwide and is a major risk factor for cancer development. Acute myeloid leukemia (AML), the most common acute leukemia in adults, remains a frequently fatal disease. Here we investigated the molecular mechanisms by which obesity favors AML growth and uncovered the fatty acid-binding protein 4 (FABP4) and DNA methyltransferase 1 (DNMT1) regulatory axis that mediates aggressive AML in obesity. We showed that leukemia burden was much higher in high-fat diet-induced obese mice, which had higher levels of FABP4 and interleukin (IL)-6 in the sera. Upregulation of environmental and cellular FABP4 accelerated AML cell growth in both a cell-autonomous and cell-non-autonomous manner. Genetic disruption of FABP4 in AML cells or in mice blocked cell proliferation in vitro and induced leukemia regression in vivo. Mechanistic investigations showed that FABP4 upregulation increased IL-6 expression and signal transducer and activator of transcription factor 3 phosphorylation leading to DNMT1 overexpression and further silencing of the p15INK4B tumor-suppressor gene in AML cells. Conversely, FABP4 ablation reduced DNMT1-dependent DNA methylation and restored p15INK4B expression, thus conferring substantial protection against AML growth. Our findings reveal the FABP4/DNMT1 axis in the control of AML cell fate in obesity and suggest that interference with the FABP4/DNMT1 axis might be a new strategy to treat leukemia.

Mayo prognostic model for WHO-defined chronic myelomonocytic leukemia: ASXL1 and spliceosome component mutations and outcomes.

We evaluated the prognostic relevance of several clinical and laboratory parameters in 226 Mayo Clinic patients with chronic myelomonocytic leukemia (CMML): 152 (67%) males and median age 71 years. At a median follow-up of 15 months, 166 (73%) deaths and 33 (14.5%) leukemic transformations were documented. In univariate analysis, significant risk factors for survival included anemia, thrombocytopenia, increased levels of white blood cells, absolute neutrophils, absolute monocyte count (AMC), absolute lymphocytes, peripheral blood and bone marrow blasts, and presence of circulating immature myeloid cells (IMCs). Spliceosome component (P=0.4) and ASXL1 mutations (P=0.37) had no impact survival. On multivariable analysis, increased AMC (>10 × 10(9)/l, relative risk (RR) 2.5, 95% confidence interval (CI) 1.7-3.8), presence of circulating IMC (RR 2.0, 95% CI 1.4-2.7), decreased hemoglobin (<10 g/dl, RR 1.6, 99% CI 1.2-2.2) and decreased platelet count (<100 × 10(9)/l, RR 1.4, 99% CI 1.0-1.9) remained significant. Using these four risk factors, a new prognostic model for overall (high risk, RR 4.4, 95% CI 2.9-6.7; intermediate risk, RR 2.0, 95% CI 1.4-2.9) and leukemia-free survival (high risk, RR 4.9, 95% CI 1.9-12.8; intermediate risk, RR 2.6, 95% CI 1.1-5.9) performed better than other conventional risk models and was validated in an independent cohort of 268 CMML patients.

Safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor, in myelofibrosis.

JAK-STAT is a rational drug target in myelofibrosis (MF) given its association with JAK2/MPL mutations and aberrant inflammatory cytokine expression. We conducted a Phase 1/2 trial of CYT387, a potent JAK1/2 inhibitor, in patients with high- or intermediate-risk primary or post-polycythemia vera/essential thrombocythemia MF. Pre-planned safety and efficacy analysis has been completed for the initial 60 patients. In the dose-escalation phase (n=21), the maximum-tolerated dose was 300 mg/day based on reversible grade 3 headache and asymptomatic hyperlipasemia. Twenty-one and 18 additional patients were accrued at two biologically effective doses, 300 mg/day and 150 mg/day, respectively. Anemia and spleen responses, per International Working Group criteria, were 59% and 48%, respectively. Among 33 patients who were red cell-transfused in the month prior to study entry, 70% achieved a minimum 12-week period without transfusions (range 4.7->18.3 months). Most patients experienced constitutional symptoms improvement. Grade 3/4 adverse reactions included thrombocytopenia (32%), hyperlipasemia (5%), elevated liver transaminases (3%) and headache (3%). New-onset treatment-related peripheral neuropathy was observed in 22% of patients (sensory symptoms, grade 1). CYT387 is well tolerated and produces significant anemia, spleen and symptom responses in MF patients. Plasma cytokine and gene expression studies suggested a broad anticytokine drug effect.

IPSS-independent prognostic value of plasma CXCL10, IL-7 and IL-6 levels in myelodysplastic syndromes.

Recent studies suggest a powerful prognostic value for plasma cytokine levels in primary myelofibrosis (interleukin (IL)-2R, IL-8, IL-12, IL-15 and C-X-C motif chemokine 10 (CXCL10)) and large-cell lymphoma (IL-2R, IL-8, IL-10, IL-12, CXCL9 and CXCL10). To examine the possibility of a similar phenomenon in myelodysplastic syndromes (MDS), we used multiplex enzyme-linked immunosorbent assay to measure 30 plasma cytokines in 78 patients with primary MDS. Compared with normal controls (n = 35), the levels of 19 cytokines were significantly altered. Multivariable analysis identified increased levels of CXCL10 (P<0.01), IL-7 (P = 0.02) and IL-6 (P = 0.07) as predictors of shortened survival; the survival association remained significant when the Cox model was adjusted for the International Prognostic Scoring System, age, transfusion-need or thrombocytopenia. MDS patients with normal plasma levels of CXCL10, IL-7 and IL-6 lived significantly longer (median survival 76 months) than those with elevated levels of at least one of the three cytokines (median survival 25 months) (P<0.01). Increased levels of IL-6 were associated with inferior leukemia-free survival, independent of other prognostic factors (P = 0.01). Comparison of plasma cytokines between MDS (n = 78) and primary myelofibrosis (n = 127) revealed a significantly different pattern of abnormalities. These observations reinforce the concept of distinct and prognostically relevant plasma cytokine signatures in hematological malignancies.

Tumor lysis syndrome after starting treatment with Gleevec in a patient with chronic myelogenous leukemia.

Chronic myelogenous leukemia (CML) is one of the myeloproliferative disorders. It accounts for 15-20% of all leukemias in adults. The mainstay of diagnosis is the detection of Philadelphia chromosome or one of its products. Tyrosine kinase inhibitors changed the paradigm of treating such disease with the good responses. However, they do have side effects. In our case we will report tumor lysis syndrome happening after starting Imatinib myselate. We did a literature review and looked all the cases that documented this complication.