WT1 Expression in Peripheral Blood at Diagnosis and During the Course of Early Consolidation Treatment Correlates With Survival in Patients With Intermediate and Poor-Risk Acute Myeloid Leukemia

BackgroundUp to 55% of non-APL acute myeloid leukemias (AML) lack a molecular target suitable for standardized disease monitoring. We aimed to evaluate the prognostic significance of WT1 gene expression at early stages of intensive treatment.Patients and MethodsA total of 106 consecutive patients with intermediate and high-risk AML who had WT1 expression at diagnosis >500 copies/10⁴ ABL and who achieved remission after 1 to 2 cycles of induction treatment were analyzed. WT1 expression was measured in peripheral blood using a standardized European LeukemiaNet method. Overexpression was defined as >50 copies/10⁴ ABL. The median follow-up was 30 months.ResultsPatients with normal versus high WT1 expression after 2 cycles of chemotherapy had overall survival (OS) at 3 years of 66% versus 41% (P = .01); event-free survival (EFS) 45% versus 22% (P = .01). Prognostic significance of WT1 expression after 2 cycles of treatment was maintained in the group of patients treated with chemotherapy alone without hematopoietic stem cell transplantation in first line treatment (OS 70% vs. 36%, P = .02; EFS 35% vs. 0%, P = .03). Significant prognostic factors for EFS on multivariate analysis were the achievement of molecular remission (<50 copies of WT1) at any time during treatment (hazard ratio [HR] 0.47, P = .04) and increased WT1 expression after 2 cycles of chemotherapy (HR 2.0, P = .03).ConclusionIncreased WT1 expression after 2 cycles of chemotherapy is a negative prognostic factor for survival. WT1 remains a valuable molecular marker in AML without any leukemia-specific mutation, especially if next generation sequencing and/or digital polymerase chain reaction are not routinely available.     

DARTS,Bites and ADCs for the Treatment of AML and for Conditioning for Allogeneic Stem Cell Transplantation

There are over 50 bispecific antibodies that are currently being tested for the treatment of patients with acute leukemias and other hematologic malignancies. In addition to bispecific therapies both chimeric antigen receptor T (CART) cells and antibody drug conjugates (ADC) are being tested for both the treatment of acute leukemias and for conditioning for allogeneic stem cell transplantation. These are being developed to replace chemotherapy and radiation therapy in conditioning regimens to     

A Phase II Study of Midostaurin and 5-Azacitidine for Untreated Elderly and Unfit Patients With FLT3 Wild-type Acute Myelogenous Leukemia

BackgroundMidostaurin, a multikinase inhibitor, is approved for treatment of FLT3-mutant acute myeloid leukemia (AML). A phase I study established that midostaurin 75 mg orally twice daily for 14 days with standard dose azacitidine was safe and tolerable in elderly patients with AML. Herein, we report the phase II expansion cohort of previously untreated elderly or unfit patients with AML.Patients and MethodsPrimary objectives were to further describe the toxicity profile and determine the response rate in untreated patients with AML. Patients received midostaurin 75 mg orally twice daily on days 8 to 21 in combination with intravenous azacitidine at 75 mg/m² on days 1 to 7. Plasma inhibitory activity assay for FLT3 was performed pretreatment and on day 8 and day 15 of each cycle.ResultsTwenty-six patients (median age, 74 years; range, 59-85 years) with FLT3 wild-type AML were accrued. Patients received a median of 2 cycles of therapy (range, 1-10 cycles). Seven (29%) of 24 evaluable patients achieved a clinical response (4 complete response; 1 complete response with incomplete count recovery; and 2 partial response). The median overall survival was 244 days (95% confidence interval, 203-467 days). Hematologic, infectious, and gastrointestinal toxicities were comparable to similar studies. Peripheral blood FLT3 wild-type phosphorylation declined to 8% to 55% of pretreatment by day 15 of cycle 1 (7 patients) and declined with subsequent cycles (< 10% baseline) in 2 patients who were analyzed after cycle 3.ConclusionMultiple cycles of azacitidine and midostaurin were not well-tolerated, but persistent inhibition of FLT3 wild-type phosphorylation suggest intermittent dosing of midostaurin should be considered in future low-intensity regimens for FLT3-mutant AML.     

Absence of FGFR3–TACC3 rearrangement in hematological malignancies with numerical chromosomal alteration

FGFR–TACC, found in different tumor types, is characterized by the fusion of a member of fibroblast grown factor receptor (FGFR) tyrosine kinase (TK) family to a member of the transforming acidic coiled-coil (TACC) proteins. Because chromosome numerical alterations, hallmarks of FGFR–TACC fusions are present in many hematological disorders and there are no data on the prevalence, we studied a series of patients with acute myeloid leukemia and myelodysplastic syndrome who presented numerical alterations using cytogenetic traditional analysis. None of the analyzed samples showed FGFR3–TACC3 gene fusion, so screening for this mutation at diagnosis is not recommended.     

Venetoclax and decitabine for treatment of relapsed T-cell acute lymphoblastic leukemia: A case report and review of literature

Despite improvements in first‐line treatment of T‐cell acute lymphoblastic leukemia (T‐ALL), the outcome of relapsed T-ALL remains dismal with less than 7% achieving a long-term survival. Thus, there is an unmet need for new treatment strategies to improve outcomes in this setting. Suppression of apoptosis is one of the hallmarks of anticancer drug resistance. Hence, over the past few years, antiapoptotic proteins have become an attractive target for therapeutic intervention in several hematologic malignancies. Venetoclax (ABT-199) is a novel, orally bioavailable small-molecule inhibitor of B-cell lymphoma 2 (BCL-2), a key regulator of the intrinsic apoptotic pathway. Recent preclinical studies have suggested that inhibition of BCL-2 may be a novel therapeutic strategy for patients with T-ALL. Herein, we report a case of clinical response to venetoclax in combination with a hypomethylating agent in a patient with relapsed T-ALL after allogeneic stem cell transplant and review the existing literature.     

MDMX acts as a pervasive preleukemic-to-acute myeloid leukemia transition mechanism

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