Bob Löwenberg

Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet

In 2003, an international working group last reported on recommendations for diagnosis, response assessment, and treatment outcomes in acute myeloid leukemia (AML). Since that time, considerable progress has been made in elucidating the molecular pathogenesis of the disease that has resulted in the identification of new diagnostic and prognostic markers. Furthermore, therapies are now being developed that target disease-associated molecular defects. Recent developments prompted an international expert panel to provide updated evidence- and expert opinion-based recommendations for the diagnosis and management of AML, that contain both minimal requirements for general practice as well as standards for clinical trials. A new standardized reporting system for correlation of cytogenetic and molecular genetic data with clinical data is proposed.

Revised Recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia

An International Working Group met to revise the diagnostic and response criteria for acute myelogenous leukemia originally published in 1990, as well as to provide definitions of outcomes and reporting standards to improve interpretability of data and comparisons among trials. Since the original publication, there have been major advances in our understanding of the biology and molecular genetics of acute leukemia that are clinically relevant and warrant incorporation into response definitions. Differences from the 1990 recommendations included a category of leukemia-free state, new criteria for complete remission, including cytogenetic and molecular remissions and remission duration. Storage of viable blasts for correlative studies is important for future progress in the therapy of these disorders.

Leukemic IDH1 and IDH2 Mutations Result in a Hypermethylation Phenotype, Disrupt TET2 Function, and Impair Hematopoietic Differentiation

Cancer-associated IDH mutations are characterized by neomorphic enzyme activity and resultant 2-hydroxyglutarate (2HG) production. Mutational and epigenetic profiling of a large acute myeloid leukemia (AML) patient cohort revealed that IDH1/2-mutant AMLs display global DNA hypermethylation and a specific hypermethylation signature. Furthermore, expression of 2HG-producing IDH alleles in cells induced global DNA hypermethylation. In the AML cohort, IDH1/2 mutations were mutually exclusive with mutations in the α-ketoglutarate-dependent enzyme TET2, and TET2 loss-of-function mutations were associated with similar epigenetic defects as IDH1/2 mutants. Consistent with these genetic and epigenetic data, expression of IDH mutants impaired TET2 catalytic function in cells. Finally, either expression of mutant IDH1/2 or Tet2 depletion impaired hematopoietic differentiation and increased stem/progenitor cell marker expression, suggesting a shared proleukemogenic effect.

Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet

The introduction of all-trans retinoic acid (ATRA) and, more recently, arsenic trioxide (ATO) into the therapy of acute promyelocytic leukemia (APL) has revolutionized the management and outcome of this disease. Several treatment strategies using these agents, usually in combination with chemotherapy, but also without or with minimal use of cytotoxic agents, have provided excellent therapeutic results. Cure of APL patients, however, is also dependent on peculiar aspects related to the management and supportive measures that are crucial to counteract life-threatening complications associated with the disease biology and molecularly targeted treatment. The European LeukemiaNet recently appointed an international panel of experts to develop evidence- and expert opinion-based guidelines on the diagnosis and management of APL. Together with providing current indications on genetic diagnosis, modern risk-adapted front-line therapy and salvage treatment, the review contains specific recommendations for the identification and management of most important complications such as the bleeding disorder, APL differentiation syndrome, QT prolongation and other ATRA- and ATO-related toxicities, as well as for molecular assessment of response to treatment. Finally, the approach to special situations is also discussed, including management of APL in children, elderly patients, and pregnant women.

DNA Methylation Signatures Identify Biologically Distinct Subtypes in Acute Myeloid Leukemia

We hypothesized that DNA methylation distributes into specific patterns in cancer cells, which reflect critical biological differences. We therefore examined the methylation profiles of 344 patients with acute myeloid leukemia (AML). Clustering of these patients by methylation data segregated patients into 16 groups. Five of these groups defined new AML subtypes that shared no other known feature. In addition, DNA methylation profiles segregated patients with CEBPA aberrations from other subtypes of leukemia, defined four epigenetically distinct forms of AML with NPM1 mutations, and showed that established AML1-ETO, CBFb-MYH11, and PML-RARA leukemia entities are associated with specific methylation profiles. We report a 15 gene methylation classifier predictive of overall survival in an independent patient cohort (p < 0.001, adjusted for known covariates).

High-dose daunorubicin in older patients with acute myeloid leukemia

BACKGROUND A complete remission is essential for prolonging survival in patients with acute myeloid leukemia (AML). Daunorubicin is a cornerstone of the induction regimen, but the optimal dose is unknown. In older patients, it is usual to give daunorubicin at a dose of 45 to 50 mg per square meter of body-surface area. METHODS Patients in whom AML or high-risk refractory anemia had been newly diagnosed and who were 60 to 83 years of age (median, 67) were randomly assigned to receive cytarabine, at a dose of 200 mg per square meter by continuous infusion for 7 days, plus daunorubicin for 3 days, either at the conventional dose of 45 mg per square meter (411 patients) or at an escalated dose of 90 mg per square meter (402 patients); this treatment was followed by a second cycle of cytarabine at a dose of 1000 mg per square meter every 12 hours [DOSAGE ERROR CORRECTED] for 6 days. The primary end point was event-free survival. RESULTS The complete remission rates were 64% in the group that received the escalated dose of daunorubicin and 54% in the group that received the conventional dose (P=0.002); the rates of remission after the first cycle of induction treatment were 52% and 35%, respectively (P<0.001). There was no significant difference between the two groups in the incidence of hematologic toxic effects, 30-day mortality (11% and 12% in the two groups, respectively), or the incidence of moderate, severe, or life-threatening adverse events (P=0.08). Survival end points in the two groups did not differ significantly overall, but patients in the escalated-treatment group who were 60 to 65 years of age, as compared with the patients in the same age group who received the conventional dose, had higher rates of complete remission (73% vs. 51%), event-free survival (29% vs. 14%), and overall survival (38% vs. 23%). CONCLUSIONS In patients with AML who are older than 60 years of age, escalation of the dose of daunorubicin to twice the conventional dose, with the entire dose administered in the first induction cycle, effects a more rapid response and a higher response rate than does the conventional dose, without additional toxic effects. (Current Controlled Trials number, ISRCTN77039377; and Netherlands National Trial Register number, NTR212.)

Guidelines on the management of acute promyelocytic leukemia: Recommendations from an expert panel on behalf of the European LeukemiaNet

The introduction of all-trans retinoic acid (ATRA) and, more recently, arsenic trioxide (ATO) into the therapy of acute promyelocytic leukemia (APL) has revolutionized the management and outcome of this disease. Several treatment strategies using these agents, usually in combination with chemotherapy, but also without or with minimal use of cytotoxic agents, have provided excellent therapeutic results. Cure of APL patients, however, is also dependent on peculiar aspects related to the management and supportive measures that are crucial to counteract life-threatening complications associated with the disease biology and molecularly targeted treatment. The European LeukemiaNet recently appointed an international panel of experts to develop evidence- and expert opinion-based guidelines on the diagnosis and management of APL. Together with providing current indications on genetic diagnosis, modern risk-adapted front-line therapy and salvage treatment, the review contains specific recommendations for the identification and management of most important complications such as the bleeding disorder, APL differentiation syndrome, QT prolongation and other ATRA- and ATO-related toxicities, as well as for molecular assessment of response to treatment. Finally, the approach to special situations is also discussed, including management of APL in children, elderly patients, and pregnant women.

Monosomal Karyotype in Acute Myeloid Leukemia: A Better Indicator of Poor Prognosis Than a Complex Karyotype

PURPOSE To investigate the prognostic value of various cytogenetic components of a complex karyotype in acute myeloid leukemia (AML). PATIENTS AND METHODS Cytogenetics and overall survival (OS) were analyzed in 1,975 AML patients age 15 to 60 years. RESULTS Besides AML with normal cytogenetics (CN) and core binding factor (CBF) abnormalities, we distinguished 733 patients with cytogenetic abnormalities. Among the latter subgroup, loss of a single chromosome (n = 109) conferred negative prognostic impact (4-year OS, 12%; poor outcome). Loss of chromosome 7 was most common, but outcome of AML patients with single monosomy -7 (n = 63; 4-year OS, 13%) and other single autosomal monosomies (n = 46; 4-year OS, 12%) did not differ. Structural chromosomal abnormalities influenced prognosis only in association with a single autosomal monosomy (4-year OS, 4% for very poor v 24% for poor). We derived a monosomal karyotype (MK) as a predictor for very poor prognosis of AML that refers to two or more distinct autosomal chromosome monosomies (n = 116; 4-year OS, 3%) or one single autosomal monosomy in the presence of structural abnormalities (n = 68; 4-year OS, 4%). In direct comparisons, MK provides significantly better prognostic prediction than the traditionally defined complex karyotype, which considers any three or more or five or more clonal cytogenetic abnormalities, and also than various individual specific cytogenetic abnormalities (eg, del[5q], inv[3]/t[3;3]) associated with very poor outcome. CONCLUSION MK enables (in addition to CN and CBF) the prognostic classification of two new aggregates of cytogenetically abnormal AML, the unfavorable risk MK-negative category (4-year OS, 26% +/- 2%) and the highly unfavorable risk MK-positive category (4-year OS, 4% +/- 1%).

Mutations in the Gene for the Granulocyte Colony-Stimulating–Factor Receptor in Patients with Acute Myeloid Leukemia Preceded by Severe Congenital Neutropenia

BACKGROUND In severe congenital neutropenia the maturation of myeloid progenitor cells is arrested. The myelodysplastic syndrome and acute myeloid leukemia develop in some patients with severe congenital neutropenia. Abnormalities in the signal-transduction pathways for granulocyte colony-stimulating factor (G-CSF) may play a part in the progression to acute myeloid leukemia. METHODS We isolated genomic DNA and RNA from hematopoietic cells obtained from two patients with acute myeloid leukemia and histories of severe congenital neutropenia. The nucleotide sequences encoding the cytoplasmic domain of the G-CSF receptor were amplified by means of the polymerase chain reaction and sequenced. Murine myeloid 32D.C10 cells were transfected with complementary DNA encoding the wild-type or mutant G-CSF receptors and tested for their responses to G-CSF. RESULTS Point mutations in the gene for the G-CSF receptor were identified in both patients. The mutations, a substitution of thymine for cytosine at the codon for glutamine at position 718 (Gln718) in one patient and at the codon for glutamine at position 731(Gln731) in the other, caused a truncation of the C-terminal cytoplasmic region of the receptor. Both mutant and wild-type genes for the G-CSF receptor were present in leukemic cells from the two patients. In one patient, the mutation was also found in the neutropenic stage, before the progression to acute myeloid leukemia. The 32D.C10 cells expressing mutant receptors had abnormally high proliferative responses but failed to mature when cultured in G-CSF. The mutant G-CSF receptors also interfered with terminal maturation mediated by the wild-type G-CSF receptor in the 32D.C10 cells that coexpressed the wild-type and mutant receptors. CONCLUSIONS Mutations in the gene for the G-CSF receptor that interrupt signals required for the maturation of myeloid cells are involved in the pathogenesis of severe congenital neutropenia and associated with the progression to acute myeloid leukemia.

Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel

The first edition of the European LeukemiaNet (ELN) recommendations for diagnosis and management of acute myeloid leukemia (AML) in adults, published in 2010, has found broad acceptance by physicians and investigators caring for patients with AML. Recent advances, for example, in the discovery of the genomic landscape of the disease, in the development of assays for genetic testing and for detecting minimal residual disease (MRD), as well as in the development of novel antileukemic agents, prompted an international panel to provide updated evidence- and expert opinion-based recommendations. The recommendations include a revised version of the ELN genetic categories, a proposal for a response category based on MRD status, and criteria for progressive disease.