Acute myeloid leukemia: 2013 update on risk‐stratification and management

Abstract

Disease overviewAcute myeloid leukemia (AML) results from accumulation of abnormal blasts in the marrow. These cells interfere with normal hematopoiesis, can escape into the peripheral blood, and infiltrate CSF and lung. It is likely that many different mutations, epigenetic aberrations, or abnormalities in micro RNA expression can produce the same morphologic disease with these differences responsible for the very variable response to therapy, which is AMLs principal feature.DiagnosisThis rests on demonstration that the marrow or blood has > 20% blasts of myeloid lineage. Blast lineage is assessed by multiparameter flow cytometry, with CD33 and CD13 being surface markers typically expressed by myeloid blasts. It should be realized that clinical/prognostic considerations, not the blast % per se, should be the main factor determining how a patient is treated.Risk StratificationTwo features determine risk: the probability of treatment‐related mortality (TRM) and, more important, even in patients aged >75 with Zubrod performance status 1, the probability of resistance to standard therapy despite not incurring TRM. The chief predictor of resistance is cytogenetics, with a monosomal karyotype (MK) denoting the disease is essentially incurable with standard therapy even if followed by a standard allogeneic transplant (HCT). The most common cytogentic finding is a normal karyotype(NK) and those of such patients with an NPM1 mutation but no FLT3 internal tandem duplication (ITD), or with a CEBPA mutation, have a prognosis similar to that of patients with the most favorable cytogenetics (inv 16 or t[8;21]) (60–70% cure rate). In contrast, NK patients with a FLT3 ITD have only a 30–40% chance of cure even after HCT. Accordingly analyses of NPM1, FLT3, and CEBPA should be part of routine evaluation, much as is cytogenetics. Risk is best assessed considering several variables simultaneously rather than, for example, only age. Increasing evidence indicates that other mutations and abnormalities in microRNA (miRNA) expression also affect resistance as do post treatment factors, in particular the presence of minimal residual disease. These newer mutations and MRD are discussed in this update.Risk‐adapted therapyPatients with inv (16) or t(8;21) or who are NPM1+/FLT3ITD—can receive standard therapy (daunorubicin + cytarabine) and should not receive HCT in first CR. It seems likely that use of a daily daunorubicin dose of 90 mg/m2 will further improve outcome in these patients. There appears no reason to use doses of cytarabine > 1 g/m2 (for example bid X 6 days), as opposed to the more commonly used 3 g/m2. Patients with an unfavorable karyotype (particularly MK) are unlikely to benefit from standard therapy (even with dose escalation) and are thus prime candidates for clinical trials of new drugs or new approaches to HCT; the latter should be done in first CR. Patients with intermediate prognoses (for example NK and NPM and FLT3ITD negative) should also receive HCT in first CR and can plausibly receive either investigational or standard induction therapy, with the same prognostic information about standard therapy leading one patient to choose the standard and another an investigational option. This update discusses results with newer agents: quizartinib and crenolanib, gemtuzumab ozogamicin, clofarabine and cladribine, azacitidine and decitabine, volasertib, and means to prevent relapse after allogeneic transplant.The diagnosis of AML essentially is made as it was in 2012. Thus this review will emphasize new developments in risk stratification and treatment using as references many papers published in 2012. Am. J. Hematol. 88:318–327, 2013. © 2013 Wiley Periodicals, Inc.

Molecular response assessment by quantitative real-time polymerase chain reaction after induction therapy in NPM1-mutated patients identifies those at high risk of relapse

“…At present, therapy decisions are guided by pre-therapeutic risk assessments. 1 Nevertheless, there are still patients who suffer from relapse despite belonging to the favorable risk group 2,3 and more individualized therapy regimens are needed to prevent relapses.…”

EGFR inhibitors exacerbate differentiation and cell cycle arrest induced by retinoic acid and vitamin D3in acute myeloid leukemia cells

“…11 Although AML is a relatively rare disease, accounting for slightly over 1% of cancer-related deaths in the western world, its incidence is expected to augment as the population ages. 12 AML develops along a complex, multistep course characterized by the progressive accumulation of a variety of genetic defects that either confer a proliferative/survival advantage to myeloid progenitors (e.g., FLT3 or KIT mutations) or contribute to the failure of these cells to differentiate into mature granulocytes or monocytes (e.g., CEBPA or NPM1 mutations).…”

Multi-color flow cytometric immunophenotyping for detection of minimal residual disease in AML: past, present and future

“…2 Currently, pre-treatment factors such as age, cytogenetic risk score and mutational profile are used for risk stratification and clinical decision making. 1,5,6 However, the individual patient's response to therapy is also an important prognostic factor that should ideally be integrated into the risk stratification to help identify candidates who may benefit from alternative therapeutic agents or hematopoietic SCT. CR is the obvious desired response to induction therapy for all patients; however, current response criteria remain defined by clinical and microscopic data (Table 1).…”

“…Numerous methods have been described in the literature; however, MRD monitoring is still regarded as an investigational technique and has not been completely incorporated into current models of AML risk stratification. 1,5,6 The most commonly used methods fall into two general categories: (1) detection of cell surface immunophenotypic aberrations by MFC, (2) identification of MRD through molecular genetic techniques such as reverse transcriptase polymerase chain reaction (RT-PCR). Such techniques provide an extremely sensitive and specific method for detection of MRD by several means (Table 2).…”

“…1 Current treatment regimens achieve CR in the majority of adult patients; however, approximately 65% of patients develop relapsed disease. 2,3 Thus, there is a need to effectively identify which patients are at most risk for impending relapse.…”