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Application of next generation sequencing (NGS) has shed light on the molecular heterogeneity of hematological malignancies. NGS panels targeting recurrent mutations have become common in many large centers and commercial laboratories. However, its impact in clinical practice is unclear. We sought to characterize the use of NGS at a tertiary care center in an observational study of 343 patients with suspected hematological malignancies. We found that NGS changed or refined the clinical and pathologic diagnosis in 9% of patients and affected management decisions in 65% (including clinical trial eligibility, targeted therapy selection, and consideration for stem cell transplantation). This study emphasizes early incorporation of NGS in clinical practice while also highlighting the present limitations. As our understanding of these disorders increases and more clinically relevant genetic targets emerge, it will be important to refine the molecular testing strategy to deliver personalized medicine given the high cost associated with this technology. [ABSTRACT FROM AUTHOR]

FF-10501-01 potently inhibits inosine-5-monophosphate dehydrogenase (IMPDH), inducing anti-proliferative and pro-apoptotic effects in acute myeloid leukemia (AML) human cell lines resistant to hypomethylating agents. In this Phase 1/2a study, Phase 1 enrolled 38 patients with relapsed/refractory AML (n = 28) or myelodysplastic syndromes (MDS/CMML, n = 10) to receive FF-10501 oral doses 50–500 mg/m2 BID for 14 or 21 days out of each 28-day cycle. Fifteen additional patients with HMA-resistant MDS/CMML (Phase 2a) were treated at 400 mg/m2 BID for 21 days. Most Phase 1 adverse events were disease-related and low-grade. 3 of 19 (16%) evaluable AML patients achieved partial remission (31, 7, and 5 months). 2 of 20 (10%) evaluable MDS/CMML patients (Phase 1 and 2a) attained marrow complete remission, one continuing treatment for 17 months. While FF-10501-01 demonstrated clinical activity and target inhibition in heavily pretreated patients with AML and MDS/CMML, increased mucositis events led to Phase 2a closure (ClinTrials.gov#NCT02193958). [ABSTRACT FROM AUTHOR]

Acquired aplastic anemia (AA) is a bone marrow failure disorder caused by immune mediated destruction of hematopoietic progenitor cells. Equally important is the presence of paroxysmal nocturnal hemoglobinuria (PNH), a rare clonal hematopoietic stem cell disorder that arises from the I PIGA i gene mutation, which can occur with acquired AA and is associated with complement-mediated hemolysis and thrombosis [[8]]. Notably, there was a shift in her clonal dynamic, with her PNH clone dramatically declining in size (type II erythrocyte of 47% declining to 3.31%, type III erythrocyte of 2% declining to 0.1% and granulocyte clone down to 0.27% from 48%) in the absence of active PNH treatment. N-RAS gene mutation in patients with aplastic anemia and aplastic anemia/paroxysmal nocturnal hemoglobinuria during evolution to clonal disease. [Extracted from the article]

Outcomes of relapsed adult acute lymphoblastic leukemia (ALL) have improved over time with the introduction of new therapies as well as better supportive care. However, there is still a need for easy-to-use and accurate prognostic tools for patients in first relapse. Whether complete response (CR) with incomplete count recovery (CRh) can be grouped with CR in relapsed ALL trials has not been formally studied. We analyzed 106 ALL patients at first relapse who were treated at three academic centers and achieved CR/CRh. White blood cell count at initial diagnosis and receiving hematopoietic cell transplant (HCT) were independent predictors of overall survival after relapse, while minimal residual disease (MRD) positivity and performance of HCT were predictors of relapse free survival (RFS). Patients who achieved MRD negativity and underwent HCT had the best outcomes. Our results suggest that MRD is a more powerful predictor of outcome than CRh. [ABSTRACT FROM AUTHOR]

The article discusses findings of a study on effects of combined azacitidine and entinostat on the induction of fetal hemoglobin in patients with acute myeloid leukemias and myelodysplastic syndromes. It states that dose of 5-azacytidine (AZA) was positively correlated with fold increase in F-cells, and mentions slight inverse correlation between Entinostat (MS-275) and hemoglobin F (HbF) production. It infers role of AZA as an inducer of HbF and its utility in sickle cell disease treatment.

Older patients with Burkitt lymphoma/leukemia (BL) have inferior outcomes. Because cyclophosphamide is highly active in BL and can be dose-escalated without stem-cell rescue, we designed a short, cyclophosphamide-intensive regimen without anthracyclines for patients aged ≥ 30 with untreated, non-HIV-associated BL/atypical BL. Two cycles involving cyclophosphamide 1500 mg/m2, vincristine, rituximab, prednisone, methotrexate 3 g/m2, and intrathecal cytarabine were delivered 2 weeks apart, followed by intensification with high-dose cyclophosphamide (50 mg/kg/day for 4 days) and rituximab. Of 21 patients, median age 53 (range, 34-75), 71% had stage IV, 95% were high-risk and 29% had performance status 3-4. Response occurred in all evaluable patients post-cycle 2 and in 76% post-intensification. Five non-relapse deaths occurred (four before intensification). The estimated 1-year and 3-year event-free survival was 52%; 1-year and 3-year overall survival was 57%. Seventeen (81%) received intensification (median 30 days to intensification). Brief, anthracycline-sparing, intensive cyclophosphamide (BASIC) therapy yields durable remissions in poorer-risk BL/atypical BL. [ABSTRACT FROM AUTHOR]

Nuclear localization of non-phosphorylated, active β-catenin is a measure of Wnt pathway activation and is associated with adverse outcome in patients with acute myeloid leukemia (AML). While genetic alterations of the Wnt pathway are infrequent in AML, inhibitors of this pathway are silenced by promoter methylation in other malignanices. Leukemia cell lines were examined for Wnt pathway inhibitor methylation and total β-catenin levels, and had frequent methylation of Wnt inhibitors and upregulated β-catenin by Western blot and immunofluorescence. One hundred sixty-nine AML samples were examined for methylation of Wnt inhibitor genes. Diagnostic samples from 72 patients with normal cytogenetics who received standard high-dose induction chemotherapy were evaluated for associations between methylation and event-free or overall survival. Extensive methylation of Wnt pathway inhibitor genes was observed in cell lines, and 89% of primary AML samples had at least one methylated gene: DKK1 (16%), DKK3 (8%), RUNX3 (27%), sFRP1 (34%), sFRP2 (66%), sFRP4 (9%), sFRP5 (54%), SOX17 (29%), and WIF1 (32%). In contrast to epithelial tumors, methylation of APC (2%) and RASSF1A (0%) was rare. In patients with AML with normal cytogenetics, sFRP2 and sFRP5 methylation at the time of diagnosis was associated with an increased risk of relapse, and sFRP2 methylation was associated with an increased risk for death. In patients with AML: (a) there is a high frequency of Wnt pathway inhibitor methylation; (b) Wnt pathway inhibitor methylation is distinct from that observed in epithelial malignancies; and (c) methylation of sFRP2 and sFRP5 may predict adverse clinical outcome in patients with normal karyotype AML. [ABSTRACT FROM AUTHOR]