Acute Leukemias VIII: Prognostic Factors and Treatment Strategies


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Molecular mutations resulting in chromosomal rearrangements

Additional chapters report new trends in leukemia cell biology,the monitoring of minimal residual disease, and secondary leukemias, as well as new antileukemic drugs, antimicrobial strategies, and the use of cytokines. The combined efforts against acute leukemias described in this book explain the recent improvements in the outcome of patients suffering from acute leukemias. Significant Differences in the Pharmacokinetics of two l-Asparaginase Preparations from Escherichia coli. Results of the German-Austrian Study Group.

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Treatment of Acute Lymphoblastic Leukemia (ALL)

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General Information About Adult Acute Myeloid Leukemia (AML)

FAQ Policy. About this book For 10 years the book series Ac ute Leukemias has been providing updates on the rapid progress being made internationally concerning this group of diseases. Show all. Pages Schoch, C. Moreover, midostaurin provided an increase in EFS 8. Many other trials aimed to test the activity of midostaurin in prevent relapse after standard chemotherapy or SCT, or in elderly patients in combination with hypomethylating agents are ongoing Quizartinib demonstrated, in vitro , a fold lower activity on other receptor TKs and a very high potency against FLT3 and, in vivo, a good tolerability profile Various trials evaluating crenolanib activity in combination with conventional chemotherapy or hypomethylating agents or as maintenance therapy after SCT are currently active Moreover, for its activity against AXL kinase, it appears a molecule potentially able to escape resistance To counteract the rapid emergence of resistance remains the major challenge in the use of FLT3 inhibitors.

Despite the low prognostic significance of TKD mutations at diagnosis, the acquisition of additional point mutation under inhibitor pressure can induce resistance to many compounds of the same class. However, it is becoming evident that a major role in resistance is played by the activation of alternative intracellular pathways, so new strategies preventing the development of resistance or sensitizing leukemic cells to inhibitors are needed.

Gene mutations

CCAAT enhancer binding protein alpha is a transcription factor coded on an intronless gene on chromosome 9q Moreover, recent data demonstrated its role in proliferation control and self-renewal capacity of hematopoietic stem cells In CEPBA deficient mice models, neutrophil maturation reaches only the myeloblast stage, resembling the clinical feature of leukemia patients. Compared to other subtypes, CEPBA-mutated AML tends to have lower platelets counts, higher hemoglobin levels, higher peripheral blast percentages and rarer extra medullary involvement.

In acute leukemia two major CEPBA mutations have been described: at the N-terminal region, resulting in a nonfunctional truncated protein due to a premature termination of the synthesis, or at the C-terminal region, in which in-frame deletions or insertions impair its DNA binding and dimerization ability. About two-thirds of AML patients display two mutations biallelic or double mutations , while the remaining third carry single allele mutation Only biallelic mutation is associated with favorable prognosis, retained despite the presence of associated multilineage dysplasia - Patients with a single mutation show contradicting outcome Furthermore, the positive effect of CEPBA double mutation on survival is confirmed also in patients who acquired mutation at relapse Data emerging from gene expression profiling confirmed the distinct gene expression signature associated with biallelic CEPBA mutations, so this AML subgroup has been recognized as a distinct diagnostic entity by the WHO classification of myeloid neoplasms 7.

In mouse models CEPBA-induced leukemogenesis demonstrated that N-terminal and C-terminal mutations have different impact on stem cell homeostasis.

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Prognosis and survival for acute myelogenous leukemia

The maximum leukemogenic effect was obtained when a C-terminal mutation present in premalignant stem cells was combined with an N-terminal mutation. The first induced the expansion of stem cell compartment, the second maintained the myeloid lineage commitment, as observed in double mutated patients RUNX1 gene located on chromosome 21q The homozygous lack of RUNX1 is lethal, with mid-gestation death of embryos due to hemorrhagic necrosis of central nervous system and block of definitive hematopoiesis The disruption of RUNX1 in adult models results in an increase of hematopoietic progenitors, defective megakaryocytic maturation and defective lymphocytic development.

However, the functional changes induced by RUNX1 loss result in overt leukemia only after acquisition of additional mutations Besides the involvement of RUNX1 in many recurrent chromosomal translocations, in AML also intragenic recurrent mutations in the functional domain and in the DNA binding domain of the protein have been found Patients with RUNX1 -mutated AML are mostly older male, with secondary disease arising from an antecedent myelodysplastic syndrome, minimally differentiated M0 cytology.

Moreover, CD is expressed also on megakaryocytes.

Introduction

Most of them are point mutations in exon 17 such as DV or in exon 8, with a gain of function leading to increased receptor activation upon SCF binding However, other mutation on codon or in different exons, insertion and deletion in exon 8, or internal tandem duplication of the juxtamembrane domain exon 11 , have been less commonly reported. The prognostic impact of KIT mutation is controversial. Many authors reported an increased relapse risk and reduced survival - , while others did not find significant differences , The engagement of receptors by growth factors determine a conformational change of RAS, followed by GTP hydrolysis and consequent activation of many downstream effectors involved in cell-cycle progression and proliferation, block of apoptosis and survival advantage, increased cell motility vesicles budding and transport NRAS mutations are more frequent in cases with t 3 ; 5 and KRAS mutations in patients with inv 16 and younger than 60 years, but their prognostic impact remain still controversial.

Despite small-size studies have hypothesized an adverse impact on outcome - , the evaluation in larger number of patients did not confirm their negative effect , Since RAS activity depends on post-translational farnesylation, from the early s many studies tried to target the RAS pathway with farnesyl-transferase inhibitor tipifarnib, with disappointing results - In response to cellular stress it promotes cell cycle arrest, apoptosis and DNA repair Moreover, in those patients TP53 mutations correlate with the total number of chromosomal abnormalities and with monosomal karyotype The negative prognostic significance of TP53 mutations appears independent from age, cytogenetics and all other co-occurring molecular alterations - WT1 is a gene of 10 exomes located at chromosome 11p13, encoding for a transcription factor involved in cell growth and metabolism by modulating the expression of membrane receptors and growth factors, components of extracellular matrix, and genes affecting cell survival In normal hematopoiesis WT1 expression is confined to the CD34 positive population, and acts as a suppressor gene regulating progenitor cell growth and maturation , In AML WT1 is overexpressed in most patients, and increased expression is associated with resistance to chemotherapy, high relapse rate and poor survival However, the role of WT1 overexpression in leukemogenesis is not completely understood.

Studies in murine models suggest that its pathogenic role may be context-specific and may depend from the temporal acquisition of co-occurring mutational events. These include deletions, insertion or base substitutions in exons 1, 7 and 9, resulting in the expression of a protein lacking the zinc-finger domain.

As for gene overexpression, little is known about the leukemogenic role of mutated WT1. It has been recently hypothesized a role as epigenetic modifier, even if the pattern of genes deregulated by mutations remains under investigation The suggested perturbation of epigenome by WT1 mutations may open new therapeutic options employing epigenetic-targeted therapies.

Adult Acute Myeloid Leukemia Treatment (PDQ®)

The PHF6 gene consists of 11 exons coded on chromosome X, acting as a suppressor gene involved in neurogenesis and hematopoiesis. Van Vlierberghe and colleagues reported a higher frequency in males and in less mature subtypes FAB M0-M2 and frequent association with other cooperative mutations The DNA methyltransferase family catalyze the formation of 5-methylcitosine by adding a methyl group to cytosine in CpG dinucleotides. The increased methylation of CpG islands results in transcriptional silencing of downstream genes They result in the production of a truncated protein, with reduced methyltransferase activity through a missense mutation causing in most of cases an arginine to histidine substitution at codon R Even if the precise mechanism by which they contribute to leukemogenesis is not completely understood, it is well known that DNAMT3 mutations are an early event in leukemic transformation, may be present in pre-leukemic stem cells and can persist also after CR achievement , Regarding their clinical role, two recent meta-analysis including more than 10, patients confirmed a poor prognostic impact on OS and RFS in de novo adult patients , Nonetheless, improved outcome has been reported in intermediate cytogenetics patients receiving induction chemotherapy with high dose anthracyclines , suggesting their potential role as therapeutic marker.

On the other hand, patients harboring DNAMT3A mutation show high response rates and superior OS by employing the DNA methyltransferase inhibitor decitabine , suggesting their usefulness in the therapeutic decision-making. Clinical trials evaluating the efficacy of DNA methyltranferase inhibitors decitabine and guadecitabine are ongoing - IDH mutations detected at diagnosis tend to be stable during disease progression and, in general, patients do not acquire mutations during follow up However, differences in detection limits or expansion of the mutant clone could uncover, at relapse, only apparently new mutations, complicating their use as a marker of minimal residual disease.

Besides, hematopoietic cells harboring IDH mutations show a dramatic decrease of ataxia-telangiectasia mutated ATM protein, that represent the first trigger to recruit repair factors in response to DNA damage. The impaired DNA repair promotes the acquisition of additional mutations and clonal expansion of IDH mutated stem cells and favors the evasion of pmediated tumor suppression upon oncogenic stress. From a clinical point of view, patients carrying IDH mutations tend to be older and to have higher blast cell count and platelets count at diagnosis A meta-analysis including patients concluded that those with mIDH1 have inferior OS, and in the subgroup with normal cytogenetics mIDH1 seemed to confer resistance to induction therapy resulting in a lower CR rate Likewise, studies on prognostic significance of mIDH2 are inconsistent regarding all outcome variables.

The different results among studies may depend from study methodology i. Many selective mIDH inhibitors are in in preclinical development and many other in various stages of clinical investigation Six percent of patients developed an IDH-associated differentiation syndrome resembling that observed in acute promyelocytic leukemia during treatment with retinoic acid.

Prognostic factors and treatment of pediatric acute lymphoblastic leukemia

Clinical efficacy was good with an overall response rate of CR was achieved in of Amatangelo and colleagues, analyzing samples from patients included in that trial demonstrated that, in responsive patients enasidenib reduced intracellular RHG and restored differentiation generating fully functional neutrophils A phase 3 trial evaluating enasidenib vs.

The recently reported results of phase I trial on the mIDH1 inhibitor ivosidenib AG , demonstrated similar efficacy and safety profile. Overall response rate was If appropriately managed, ivosidenib-associated adverse events i. Trails assessing safety, efficacy and tolerability of ivosidenib in combination with standard chemotherapy or with azacytidine in untreated patients harboring IDH1 mutation are currently recruiting However, TET2 mutations are mutually exclusive with IDH mutations, supporting the hypothesis of a distinct leukemogenic mechanism In humans TET2 inactivation is present in pre-leukemic stem cells and is associated with clonal expansion Experimental models have demonstrated that the TET2 mutations-induced hypermethylation especially affects enhancer regions regulating tumor suppressor genes so facilitating leukemogenesis The prognostic impact of TET2 mutations is still under debate.

Some studies failed to find an association between TET2 mutation and outcome , , while others demonstrated an inferior EFS in presence of TET2 mutations, either considering the whole population or in specific subgroups such as CN-AML, age less than 65 years and ELN favorable risk , - Liu and colleagues performed a meta-analysis including AML patients with TET2 mutations concluding that it could be considered an adverse prognostic factor in patients with normal karyotype

Acute Leukemias VIII: Prognostic Factors and Treatment Strategies Acute Leukemias VIII: Prognostic Factors and Treatment Strategies
Acute Leukemias VIII: Prognostic Factors and Treatment Strategies Acute Leukemias VIII: Prognostic Factors and Treatment Strategies
Acute Leukemias VIII: Prognostic Factors and Treatment Strategies Acute Leukemias VIII: Prognostic Factors and Treatment Strategies
Acute Leukemias VIII: Prognostic Factors and Treatment Strategies Acute Leukemias VIII: Prognostic Factors and Treatment Strategies
Acute Leukemias VIII: Prognostic Factors and Treatment Strategies Acute Leukemias VIII: Prognostic Factors and Treatment Strategies
Acute Leukemias VIII: Prognostic Factors and Treatment Strategies Acute Leukemias VIII: Prognostic Factors and Treatment Strategies
Acute Leukemias VIII: Prognostic Factors and Treatment Strategies Acute Leukemias VIII: Prognostic Factors and Treatment Strategies
Acute Leukemias VIII: Prognostic Factors and Treatment Strategies Acute Leukemias VIII: Prognostic Factors and Treatment Strategies
Acute Leukemias VIII: Prognostic Factors and Treatment Strategies

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