Classification Of Acute Myelogenous Leukemia (AML) Based On Functionally Related Proteins Groups

Overexpression of Cyclin E in Acute Myelogenous Leukemia

<div>Abstract<p><b>Purpose:</b> Recent studies suggested that AKT activation might confer poor prognosis in acute myelogenous leukemia (AML), providing the rationale for therapeutic targeting of this signaling pathway. We, therefore, explored the preclinical and clinical anti-AML activity of an oral AKT inhibitor, MK-2206.</p><p><b>Experimental Methods:</b> We first studied the effects of MK-2206 in human AML cell lines and primary AML specimens <i>in vitro</i>. Subsequently, we conducted a phase II trial of MK-2206 (200 mg weekly) in adults requiring second salvage therapy for relapsed/refractory AML, and assessed target inhibition via reverse phase protein array (RPPA).</p><p><b>Results:</b> In preclinical studies, MK-2206 dose-dependently inhibited growth and induced apoptosis in AML cell lines and primary AML blasts. We then treated 19 patients with MK-2206 but, among 18 evaluable participants, observed only 1 (95% confidence interval, 0%–17%) response (complete remission with incomplete platelet count recovery), leading to early study termination. The most common grade 3/4 drug-related toxicity was a pruritic rash in 6 of 18 patients. Nevertheless, despite the use of MK-2206 at maximum tolerated doses, RPPA analyses indicated only modest decreases in Ser473 AKT (median 28%; range, 12%–45%) and limited inhibition of downstream targets.</p><p><b>Conclusions:</b> Although preclinical activity of MK-2206 can be demonstrated, this inhibitor has insufficient clinical antileukemia activity when given alone at tolerated doses, and alternative approaches to block AKT signaling should be explored. <i>Clin Cancer Res; 20(8); 2226–35. ©2014 AACR</i>.</p></div>

To compare the receipt of clofarabine plus cytarabine (Clo+Ara-C arm) with cytarabine (Ara-C arm) in patients ≥ 55 years old with refractory or relapsed acute myelogenous leukemia (AML). Patients were randomly assigned to receive either clofarabine (Clo) 40 mg/m(2) or a placebo followed by Ara-C 1 g/m(2) for five consecutive days. The primary end point was overall survival (OS). Secondary end points included event-free survival (EFS), 4-month EFS, overall remission rate (ORR; complete remission [CR] plus CR with incomplete peripheral blood count recovery), disease-free survival (DFS), duration of remission (DOR), and safety. Among 320 patients with confirmed AML (median age, 67 years), the median OS was 6.6 months in the Clo+Ara-C arm and 6.3 months in the Ara-C arm (hazard ratio [HR], 1.00; 95% CI, 0.78 to 1.28; P = 1.00). The ORR was 46.9% in the Clo+Ara-C arm (35.2% CR) versus 22.9% in the Ara-C arm (17.8% CR; P < .01). EFS (HR: 0.63; 95% CI, 0.49 to 0.80; P < .01) and 4-month EFS (37.7% v 16.6%; P < .01) favored the Clo+Ara-C arm compared with Ara-C arm, respectively. DFS and DOR were similar in both arms. Overall 30-day mortality was 16% and 5% for CLO+Ara-C and Ara-C arms, respectively. In the Clo+Ara-C and Ara-C arms, the most common grade 3 to 4 toxicities were febrile neutropenia (47% v 35%, respectively), hypokalemia (18% v 11%, respectively), thrombocytopenia (16% v 17%, respectively), pneumonia (14% v 10%, respectively), anemia (13% v 0%, respectively), neutropenia (11% v 9%, respectively), increased AST (11% v 2%, respectively), and increased ALT (10% v 3%, respectively). Although the primary end point of OS did not differ between arms, Clo+Ara-C significantly improved response rates and EFS. Study follow-up continues, and the role of clofarabine in the treatment of adult patients with AML continues to be investigated.

OCT-2 Expression and OCT-2/BOB.1 Co-Expression Predict Prognosis in Patients with Newly Diagnosed Acute Myelogenous Leukemia.

PCT3, a Combination of Active Steroidal Saponins from the Paris Forrestii (Takht.) H. Li, Displays Potent Activity Against Acute Myeloid Leukemia By Suppressing the PBX1/RNF6/AKT/mTOR Signaling Pathway

Low-Dose Hypomethylating Agents (HMAs) Are Effective in Patients (Pts) with Low- or Intermediate-1-Risk Myelodysplastic Syndrome (MDS): A Report on Behalf of the MDS Clinical Research Consortium

Prognostic Significance of Somatic Mutations in Treatment of AML in Salvage Setting: A Retrospective Analysis

Once-daily intravenous busulfan and fludarabine: clinical and pharmacokinetic results of a myeloablative, reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS

FLT3 Mutations Determine the Clinical Outcome in Children with De Novo Acute Myelogenous Leukemia (AML) and Normal Karyotype: Pediatric Oncology Group (POG) Study # 9421.

Impact of Conditioning Regimen in Allogeneic Hematopoetic Stem Cell Transplantation for Children with Acute Myelogenous Leukemia beyond First Complete Remission: A Pediatric Blood and Marrow Transplant Consortium (PBMTC) Study

Outpatient Treatment with Clofarabine in a Phase II Study of Older Adult Patients with Previously Untreated Acute Myelogenous Leukemia (AML).

Evolutionary Action Score of Missense TP53 Mutations Can Predict Outcome in Patients with Myelodysplastic Syndrome and Acute Myeloid Leukemia

Long-Term Outcomes of Patients with Systemic Light Chain Amyloidosis (AL) Treated At Diagnosis with Risk-Adapted Stem Cell Transplant and Consolidation with Novel Agents.

RAS Mutations Are Independently Associated with Decreased Overall Survival and Event-Free Survival in Patients with AML Receiving Induction Chemotherapy

Sirolimus as Primary Treatment of Acute Graft-versus-Host Disease following Allogeneic Hematopoietic Cell Transplantation