Biologic and Therapeutic Implications of Genomic Alterations in Acute Lymphoblastic Leukemia

Iacobucci, Ilaria; Kimura, Shunsuke; Mullighan, Charles G.

doi:10.3390/jcm10173792

Cited by 57 publications

(50 citation statements)

References 195 publications

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“…The genetic landscape of ALL is heterogeneous and varies with age. Philadelphia-chromosome is the most common cytogenetic abnormality among adult ALL patients, accounting for 25% of cases with incidence increasing to more than 40% in the elderly [ 1 , 2 ]. Philadelphia-chromosome positive (Ph+) ALL is characterized by the presence of reciprocal translocation t(9;22)(q34;q11), leading to BCR-ABL fusion gene encoding BCR-ABL oncoprotein, that has constitutive tyrosine kinase activity and plays a central role in ALL development [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

Treatment of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia in Adults

Saleh

Fernández

Pasquier

2022

Cancers

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Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL) is the most common subtype of B-ALL in adults and its incidence increases with age. It is characterized by the presence of BCR-ABL oncoprotein that plays a central role in the leukemogenesis of Ph+ ALL. Ph+ ALL patients traditionally had dismal prognosis and long-term survivors were only observed among patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1). However, feasibility of allo-HSCT is limited in this elderly population. Fortunately, development of increasingly powerful tyrosine kinase inhibitors (TKIs) from the beginning of the 2000′s dramatically improved the prognosis of Ph+ ALL patients with complete response rates above 90%, deep molecular responses and prolonged survival, altogether with good tolerance. TKIs became the keystone of Ph+ ALL management and their great efficacy led to develop reduced-intensity chemotherapy backbones. Subsequent introduction of blinatumomab allowed going further with development of chemo free strategies. This review will focus on these amazing recent advances as well as novel therapeutic strategies in adult Ph+ ALL.

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Section: Introductionmentioning

confidence: 99%

Treatment of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia in Adults

Saleh

Fernández

Pasquier

2022

Cancers

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“…These hematological parameters may be associated with genetic abnormalities in ALL ( 10 ). Various chromosomal alterations in ALL are important in driving chromosomal gains and losses that may be associated with the target therapy, survival and relapse of the disease ( 5 , 11 , 12 ). Chromosomal abnormalities such as t (4;11) (q21;q23) are associated with poor prognosis ( 13 , 14 ), whereas patients with t(12;21)(p13;q22) translocation have a better survival rate ( 15 , 16 ).…”

Section: Introductionmentioning

confidence: 99%

“…The clinical significance of the mutated genes is still controversial. However, patients with mutated IKZF1 and PAX5 had poor survivals ( 11 ).…”

Section: Introductionmentioning

confidence: 99%

An easy-to-use nomogram predicting overall survival of adult acute lymphoblastic leukemia

et al. 2022

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Adult acute lymphoblastic leukemia (ALL) is heterogeneous both biologically and clinically. The outcomes of ALL have been improved with the application of children-like regimens and novel agents including immune therapy in young adults. The refractory to therapy and relapse of ALL have occurred in most adult cases. Factors affecting the prognosis of ALL include age and white blood cell (WBC) count at diagnosis. The clinical implications of genetic biomarkers, including chromosome translocation and gene mutation, have been explored in ALL. The interactions of these factors on the prediction of prognosis have not been evaluated in adult ALL. A prognostic model based on clinical and genetic abnormalities is necessary for clinical practice in the management of adult ALL. The newly diagnosed adult ALL patients were divided into the training and the validation cohort at 7:3 ratio. Factors associated with overall survival (OS) were assessed by univariate/multivariate Cox regression analyses and a signature score was assigned to each independent factor. A nomogram based on the signature score was developed and validated. The receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA) were used to assess the performance of the nomogram model. This study included a total of 229 newly diagnosed ALL patients. Five independent variables including age, WBC, bone marrow (BM) blasts, MLL rearrangement, and ICT gene mutations (carried any positive mutation of IKZF1, CREBBP and TP53) were identified as independent adverse factors for OS evaluated by the univariate, Kaplan-Meier survival and multivariate Cox regression analyses. A prognostic nomogram was built based on these factors. The areas under the ROC curve and calibration curve showed good accuracy between the predicted and observed values. The DCA curve showed that the performance of our model was superior to current risk factors. A nomogram was developed and validated based on the clinical and laboratory factors in newly diagnosed ALL patients. This model is effective to predict the overall survival of adult ALL. It is a simple and easy-to-use model that could efficiently predict the prognosis of adult ALL and is useful for decision making of treatment.

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“…In addition, some cell lines have been reported to be resistant to anticancer molecules 6 , which has further reduced their applicability for drug testing. More recently, the growing clinical interest in genomic profiling of primary leukemia cases has greatly helped to understand the lesions that occur in cancer, especially for pediatric ALL, with implications on treatment identification 7,8 . This improved understanding has led to several functional approaches to develop precision and personalized medicine tools by sequencing and testing primary leukemia cells at single-cell resolution to identify drug response profiles of patients [9][10][11][12][13] .…”

Section: Introductionmentioning

confidence: 99%

Microphysiological Drug-Testing Platform for Identifying Responses to Prodrug Treatment in Primary Leukemia

Gökçe

Kaestli

Lohasz

et al. 2022

Preprint

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Despite increasing survival rates of pediatric leukemia patients over the past decades, the outcome of some leukemia subtypes has remained dismal. Drug sensitivity and resistance testing on patient-derived leukemia samples provides important information to tailor treatments for high-risk patients. However, currently used well-based drug screening platforms are severely limited in predicting the effects of prodrugs, a class of therapeutics that require metabolic activation to become effective. To address this limitation, we developed a microphysiological drug-testing platform that enables co-culturing of patient-derived leukemia cells, human bone marrow mesenchymal stromal cells, and human liver microtissues within the same microfluidic platform that, at the same time, regulates the physical interaction between the diverse cell types. Our model recapitulates hepatic prodrug activation of ifosfamide, which cannot be assessed in traditional well-based assays. By testing the susceptibility of primary patient-derived leukemia samples to the prodrug ifosfamide, we identified sample-specific sensitivities to ifosfamide in primary leukemia samples. Our microfluidic platform enables the recapitulation of physiologically relevant conditions and the testing of prodrugs, particularly with short-lived and unstable metabolites, which provides a basis for clinical translation and precision chemotherapy selection.

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Biologic and Therapeutic Implications of Genomic Alterations in Acute Lymphoblastic Leukemia

Cited by 57 publications

References 195 publications

Treatment of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia in Adults

Treatment of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia in Adults

An easy-to-use nomogram predicting overall survival of adult acute lymphoblastic leukemia

Microphysiological Drug-Testing Platform for Identifying Responses to Prodrug Treatment in Primary Leukemia

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