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The primary objective of this trial was to assess the feasibility, toxicity profile, and antitumor activity of gemtuzumab ozogamicin (GO) combined with a chemotherapy remission-induction regimen in adults with untreated high-risk myelodysplastic syndrome (HR-MDS) or secondary acute myeloid leukemia (sAML). In this phase II trial, 30 patients with median age of 58 years received 1 day of GO as a 1-h infusion at the dose level of 5 mg/m(2) on day 7 of the remission-induction course further consisting of a continuous infusion of cytarabine 100 mg/m(2)/day for 10 days and idarubicin 12 mg/m(2)/day on days 1, 3, and 5. A consolidation course, consisting of intermediate-dose cytarabine (A) and idarubicin (I) followed by hematopoietic stem cell transplantation (HSCT) was planned for patients in complete remission (CR). The primary endpoints were response rate (CR/CRi) and severe toxicity rate. The secondary endpoint(s) were survival and progression-free survival (PFS) from start of treatment. Thirteen patients (43 %) achieved CR (eight patients) or CR with incomplete hematopoietic recovery (CRi) (five patients). In patients who achieved CR or CRi, the median time to recovery of neutrophils to 0.5 × 10(9)/l and of platelets to >50 × 10(9)/l was 29 and 30 days, respectively. Grade 3 to 4 severe toxicities occurred in nine patients. The most prominent was liver toxicity, as shown by elevated bilirubin levels in 16 patients and one case of nonfatal veno-occlusive disease (VOD). All 13 patients with CR/CRi received consolidation therapy, which was followed by allogeneic HSCT in five patients and autologous HSCT in three patients. According to the statistical design of the study, the idarubicin and cytarabine in combination with gemtuzumab ozogamicin (IAGO) regimen did not show sufficient activity to warrant further exploration of this regimen in adult patients with HR-MDS or sAML. [ABSTRACT FROM AUTHOR]

We assessed the prognostic impact of TET2 mutations and mRNA expression in a prospective cohort of 357 adult AML patients < 60 years of age enrolled in the European Organization For Research and Treatment of Cancer (EORTC)/Gruppo Italiano Malattie Ematologiche dell' Adulto (GIMEMA) AML-12 06991 clinical trial. In addition the co-occurrence with other genetic defects and the functional consequences of TET2 mutations were investigated. TET2 mutations occurred in 7.6 % of the patients and were an independent marker of poor prognosis ( p = 0.024). TET2 and IDH1/ 2 mutations strongly associated with aberrations in the DNA methyltransferase DNMT3A. Functional studies confirmed previous work that neither nonsense truncations, nor missense TET2 mutations, induced 5-hydroxymethylcytosine formation. In addition, we now show that mutant TET2 forms did not act in a dominant negative manner when co-expressed with the wild-type protein. Finally, as loss-of-function TET2 mutations predicted poor outcome, we questioned whether low TET2 mRNA expression in cases of AML without TET2 mutations would affect overall survival. Notably, also AML patients with low TET2 mRNA expression levels showed inferior overall survival. [ABSTRACT FROM AUTHOR]

Twenty years of published literature was reviewed for chemotherapy regimens used to treat patients with acute myeloid leukemia (AML) in first relapse. Thirty-one trials containing at least 20 patients in first relapse and information on patient age, duration of first complete remission (CRI), and rate of second complete remission (CR2) were analyzed. These trials included 10 retrospective studies with CR2 rates ranging from 30 to 64%, two phase II single-agent studies with CR2 rates of 8 and 25%, 15 phase II combination-agent studies with CR2 rates ranging from 14 to 87%, and four phase III randomized studies with CR2 rates ranging from 40 to 89%. When reported, median duration of CR2 was ≤ 14 months and overall median survival was ≤ 12 months. The probability of 3-year survival ranged from 8 to 29%. Combination therapies resulted in higher CR2 rates but were associated with longer duration of myelosuppression and greater incidence of mucositis. None of the reviewed regimens provided durable remissions for the majority of AML patients in first relapse. The CR2 rates were closely associated with age and duration of CR1. Therefore, considering the poor clinical outcomes of patients with AML in first relapse, improved therapies need to be developed. [ABSTRACT FROM AUTHOR]

Abstract: Resistance to cytarabine (AraC) is a major problem in treatment of patients with acute myeloid leukemia (AML). In contrast to in vitro AraC resistance, deoxycytidine kinase (dCK) mutations are rarely found in patients with refractory or relapsed AML. Previously we have demonstrated alternatively spliced dCK mRNA predominantly expressed in leukemic blasts from patients with resistant AML. In this study we investigated wild-type (wt) dCK expression and activity to elucidate the possible role of decreased dCK expression or activity in unresponsiveness to AraC in patients with AML. No alterations in dCK mRNA and protein expression or in dCK activity were detected between patients with clinically resistant vs. sensitive AML. In addition, wt dCK expression and activity were not reduced in leukemic blasts expressing alternatively spliced dCK forms as compared to blasts with only wt dCK. Also, no major differences in wt dCK expression and activity were observed between samples obtained from patients with AML and bone marrow or peripheral blood samples from healthy donors. These data implicate that in our patient group of refractory or relapsed AML cases, alterations in dCK expression and/or activity cannot explain unresponsiveness to chemotherapy including AraC. [ABSTRACT FROM AUTHOR]

Intensive chemotherapy regimens with or without stem cell transplantation are the current standard treatment in patients with acute myeloid leukemia (AML). The identification of new mutations in AML may provide the basis for a more targeted therapeutic approach. In one or several genetic subsets, some new drugs, as single drug or in combination with standard antileukemic drugs, demonstrated promising results. Typical examples are tyrosine kinase inhibitors, such as dasatinib for f c-Kit mutated core binding factor positive AML or FLT-3 inhibitors, such as midostaurin or sorafenib, in cases with FLT-3 mutations. Clofarabine is a second generation hybrid purine nucleoside analogue: standard induction regimens containing clofarabine provided a high remission rates in patients with intermediate and high risk AML. In patients unfit for intensive chemotherapy, treatment with hypomethilating agents is widely used. Gemtuzumab ozogamicin, anti-CD33 monoclonal antibody conjugated to calicheamicin, has shown significant antileukemic activity in older patients with relapsed AML. [ABSTRACT FROM AUTHOR]