Molecular, clinical and therapeutic determinants of outcome in NPM1 mutated AML.

Although NPM1-mutated acute myeloid leukemia (AML) carries a generally favorable prognosis, many patients still relapse and die. Previous studies identified several molecular and clinical features associated with poor outcome, however only FLT3-ITD mutation and adverse karyotype are currently used for risk stratification due to inconsistent results and uncertainty around how other factors should influence treatment, particularly given the strong prognostic impact of post-induction measurable residual disease (MRD). Here we analyzed a large group of patients with NPM1mut AML enrolled in prospective trials (NCRI AML17 and AML19, n=1357) to delineate the impact of baseline molecular and clinical features, post induction MRD status and treatment intensity on outcome. FLT3-ITD (HR 1.28, 95%CI 1.01-1.63), DNMT3A (HR 1.65, 95%CI 1.32-2.05), WT1 (HR 1.74, 95%CI 1272-2.38) and non-ABD NPM1 mutations (HR 1.64, 95%CI 1.22-2.21) were independently associated with poorer overall survival (OS). These factors were also strongly associated with MRD positivity. For patients achieving MRD negativity, these mutations (except FLT3-ITD) were associated with an increased cumulative incidence of relapse (CIR) and poorer OS. However, apart from the few patients with adverse cytogenetics, we could not identify any group of MRD negative patients with a CIR >40% or with benefit from allograft in first remission. Intensified chemotherapy with the FLAG-Ida regimen was associated with improved outcomes in all subgroups, with greater benefits observed in the highest risk molecular subgroups.

Size matters: the prognostic implications of large and small deletions of the derivative 9 chromosome in chronic myeloid leukemia.

Deletions of the derivative 9 chromosome (der(9)) are associated with poor prognosis in chronic myeloid leukemia (CML). Several models have been proposed to account for this association. To distinguish between the various models we mapped the deletion in 69 Philadelphia-positive CML patients carrying a der(9) deletion and compared the size of the deletion with the patients' outcome. Our results demonstrate that patients with large deletions had a significantly worse survival than those with small deletions whereas the outcome for patients with small deletions was similar to that of patients lacking a deletion. These results support the tumor suppressor gene model for the pathogenesis of der(9) deletions, argue against alternative models and provide insight into candidate gene location.

A Polycythemia Vera Updated: Diagnosis, Pathobiology, and Treatment.

This review focuses on polycythemia vera (PV)-its diagnosis, cellular and genetic pathology, and management. In Section I, Dr. Pearson, with Drs. Messinezy and Westwood, reviews the diagnostic challenge of the investigation of patients with a raised hematocrit. The suggested approach divides patients on their red cell mass (RCM) results into those with absolute (raised RCM) and apparent (normal RCM) erythrocytosis. A standardized series of investigations is proposed for those with an absolute erythrocytosis to confirm the presence of a primary (PV) or secondary erythrocytosis, with abnormal and normal erythropoietic compartments respectively, leaving a heterogenous group, idiopathic erythrocytosis, where the cause cannot be established. Since there is no single diagnostic test for PV, its presence is confirmed following the use of updated diagnostic criteria and confirmatory marrow histology. In Section II, Dr. Green with Drs. Bench, Huntly, and Nacheva reviews the evidence from studies of X chromosome inactivation patterns that support the concept that PV results from clonal expansion of a transformed hemopoietic stem cell. Analyses of the pattern of erythroid and myeloid colony growth have demonstrated abnormal responses to several cytokines, raising the possibility of a defect in a signal transduction pathway shared by several growth factors. A number of cytogenetic and molecular approaches are now focused on defining the molecular lesion(s). In the last section, Dr. Barbui with Dr. Finazzi addresses the complications of PV, notably thrombosis, myelofibrosis and acute leukemia. Following an evaluation of published data, a management approach is proposed. All patients should undergo phlebotomy to keep the hematocrit (Hct) below 0.45, which may be all that is required in those at low thrombotic risk and with stable disease. In those at high thrombotic risk or with progressive thrombocytosis or splenomegaly, a myelosuppressive agent should be used. Hydroxyurea has a role at all ages, but (32)P or busulfan may be used in the elderly. In younger patients, interferon-alpha or anagrelide should be considered. Low-dose aspirin should be used in those with thrombotic or ischemic complications.