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Genetic and Genomic Landscape of Secondary and Therapy-Related Acute Myeloid Leukemia

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Genetic and Genomic Landscape of Secondary and Therapy-Related Acute Myeloid Leukemia G C A T T A C G G C A T genes Review Genetic and Genomic Landscape of Secondary and Therapy-Related Acute Myeloid Leukemia Alexandra Higgins and Mithun Vinod Shah * Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA; [email protected] * Correspondence: [email protected] Received: 21 May 2020; Accepted: 2 July 2020; Published: 6 July 2020 Abstract: A subset of acute myeloid leukemia (AML) arises either from an antecedent myeloid malignancy (secondary AML, sAML) or as a complication of DNA-damaging therapy for other cancers (therapy-related myeloid neoplasm, t-MN). These secondary leukemias have unique biological and clinical features that distinguish them from de novo AML. Over the last decade, molecular techniques have unraveled the complex subclonal architecture of sAML and t-MN. In this review, we compare and contrast biological and clinical features of de novo AML with sAML and t-MN. We discuss the role of genetic mutations, including those involved in RNA splicing, epigenetic modification, tumor suppression, transcription regulation, and cell signaling, in the pathogenesis of secondary leukemia. We also discuss clonal hematopoiesis in otherwise healthy individuals, as well as in the context of another malignancy, and how it challenges the conventional notion of sAML/t-MN. We conclude by summarizing the current and emerging treatment strategies, including allogenic transplant, in these complex scenarios. Keywords: acute myeloid leukemia; myelodysplastic syndrome; myeloproliferative neoplasm; next-generation sequencing; molecular markers; clonal hematopoiesis; allogeneic transplant 1. Introduction Acute myeloid leukemia (AML) can arise de novo or as a complication of a prior malignancy. Secondary leukemia can be classified into one of two broad entities: AML arising from an antecedent myeloid malignancy—myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), or MDS/MPN overlap syndrome, where progression to AML is considered a part of the natural history of the disease (secondary AML (sAML))—as well as therapy-related myeloid neoplasm (t-MN), which arises as a complication of prior cytotoxic therapy (Figure1). When combined, these entities account for 25–35% of all AML cases [1,2]. The incidence of sAML and t-MN is rising, and is likely related to the increasing survivorship of prior solid and hematological malignancies [3], increasing use of chemotherapy and other treatment modalities in the adjuvant setting [4], and improved reporting of myeloid malignancies [3,5]. Secondary AML and t-MN are characterized by unique cytogenetic and molecular abnormalities that confer distinct clinical and biological features. These are consistently associated with poor prognosis [2,6–10], with age and adverse cytogenetic features predicting a poor response to treatment [10,11]. Determining the secondary status of AML has significant therapeutic implications as well. Recently, CPX-351 (liposomal formulation of cytarabine and daunorubicin) was approved for use in high-risk AML including AML with myelodysplasia-related changes (AML-MRC) and t-AML. After remission is achieved, patients with sAML or t-MN are recommended to undergo allogeneic stem cell transplant, though there is a significant debate in the field regarding whether transplant improves outcomes in many of these patients. Genes 2020, 11, 749; doi:10.3390/genes11070749 www.mdpi.com/journal/genes Genes 2020, 11, 749 2 of 25 Genes 2020, 11, x FOR PEER REVIEW 2 of 27 Figure 1. Definition of key terms. Figure 1. Definition of key terms. Traditionally, sAML/t-MN have been either lumped with de novo AML or excluded from trials, precludingTraditionally, an analysissAML/t-MN of secondary have been leukemia either lumped as a unique with de entity. novo With AML unprecedented or excluded from advances trials, in precludingmolecular an genetics,analysis theof secondary clonal hierarchy leukemia of secondary as a unique leukemia entity. isWith being unprecedented elucidated. A advances deeper insight in molecularinto the genetics, biology the has clonal opened hierarchy doors toof individualizedsecondary leukemia prognostication is being elucidated. as well A as deeper the development insight into of the therapeuticbiology has approaches opened doors in the to hope individualized of achieving durableprognostication remissions as andwell improving as the development survival. The of aim therapeuticof this review approaches is to comparein the hope and of contrastachieving the durable clinical remissions and biological and improving features ofsurvival. de novo The AML aim withof thissAML review arising is to compare from MDS, and MDS contrast/MPN the overlap clinical syndromes, and biological or MPN features in blast of de phase novo (MPN-BP) AML with and sAML t-MN. arisingFinally, from we MDS, discuss MDS/MPN the emerging overlap field syndromes, of clonal hematopoiesisor MPN in blast (CH) phase that (MPN-BP) precedes and a majority t-MN. ofFinally, cases of we AMLdiscuss by the years emerging or even field decades, of clonal and thus,hematopoiesis poses an interesting(CH) that precedes dilemma a as majority to how of AML cases is classified.of AML by We yearsconclude or even thatdecades, further and understanding thus, poses an of interestin the genomicg dilemma landscape as to of how sAML AML and is t-MNclassified. is essential We conclude to better thatunderstand further understanding the prognostic of impact the genomic of the molecular landscape characteristics of sAML ofand the t-MN disease is on essential progression to better to acute understandleukemia the and prognostic how these impact differences of the might molecular be important characteristics for determining of the disease most on eff progressionective management to acute of leukemiathese complexand how diseases.these differences might be important for determining most effective management of these complex diseases. 2. Secondary AML Arising from Myelodysplastic Syndrome (MDS) and MPN in Blast Phase 2. Secondary(MPN-BP) AML Arising from Myelodysplastic Syndrome (MDS) and MPN in Blast Phase (MPN-BP) TheThe 2016 2016 World World Health Health Organization Organization (WHO) (WHO) cla classificationssification of ofmyeloid myeloid neoplasms neoplasms and and acute acute leukemialeukemia includes includes two two categories categories for forsecondary secondary leukemias: leukemias: AML-MRC AML-MRC (Table (Table 1) 1and) and t-MN. t-MN. The The median median timetime to development to development of sAML of sAML from from MDS MDS or orchroni chronicc myelomonocytic myelomonocytic leukemia leukemia (CMML) (CMML) is around is around 18 18 monthsmonths while while the themedian median time time is 43 is months 43 months from from an anantecedent antecedent MPN. MPN. AML AML aris arisinging from from an anantecedent antecedent MPNMPN or CMML or CMML has hasbeen been demonstrated demonstrated to have to have a poor a poorerer response response to chemotherapy to chemotherapy and and a worse a worse overall overall survivalsurvival (OS) (OS) than than AML AML from from antecedent antecedent MDS, MDS, while while all entities all entities have havea poor a poorprognosis prognosis compared compared to de to novode AML, novo independent AML, independent of cytogenetics of cytogenetics and age and [1]. age [1]. MDSMDS is a is clonal a clonal disease disease of ofthe the hematopoietic hematopoietic stem stem cells cells (HSCs) (HSCs) characterized characterized by byineffective ineffective hematopoiesis and increased apoptosis, which results in cytopenia [12–15]. Leukemic progression from hematopoiesis and increased apoptosis, which results in cytopenia [12–15]. Leukemic progression from MDS occurs in about 20% of patients with a range from 2% in refractory cytopenia with unilineage MDS occurs in about 20% of patients with a range from 2% in refractory cytopenia with unilineage dysplasia to 40% in MDS with excess blasts [16]. Approximately 11% of cases of AML are thought to dysplasia to 40% in MDS with excess blasts [16]. Approximately 11% of cases of AML are thought to have progressed from an antecedent MDS [1]. A combination of clinical and cytogenetic variables, have progressed from an antecedent MDS [1]. A combination of clinical and cytogenetic variables, known as the revised international prognostic scoring system (R-IPSS), is the most commonly used known as the revised international prognostic scoring system (R-IPSS), is the most commonly used clinical tool to estimate the risk of progression to sAML [17]. Poor prognosis is associated with −7, clinical tool to estimate the risk of progression to sAML [17]. Poor prognosis is associated with inv(3)/t(3q)/del(3q), double clone including −7/del(7q), or complex karyotype (CK) with ≥3 7, inv(3)/t(3q)/del(3q), double clone including 7/del(7q), or complex karyotype (CK) with 3 abnormalities,− which substantially increases the risk of− leukemic progression [17,18]. For instance, the≥ abnormalities, which substantially increases the risk of leukemic progression [17,18]. For instance, presence of CK increases the risk of leukemic transformation by approximately fivefold. Since then, multiplethe presence attempts of to CK refine increases the tool the incorporating risk of leukemic molecular transformation abnormalities by approximately have been proposed fivefold. [19,20]. Since then, multiple attempts to refine the tool incorporating molecular abnormalities have been proposed [19,20]. Genes 2020, 11, 749 3 of 25 Table 1. Per WHO classification, cytogenetic abnormalities sufficient to diagnose acute myeloid leukemia (AML) with myelodysplasia-related changes when 20% peripheral blood or bone marrow ≥ blasts are present and prior therapy has been excluded [21]. Complex Karyotype (CK) Unbalanced Abnormalities Balanced Abnormalities 3 or more abnormalities 7/del(7q) t(11;16)(q23.3;p13.3) − del(5q)/t(5q) t(3;21)(q26.2;q22.1) i(17q)/t(17p) t(1;3)(p36.3;q21.2) -13/del(13q) t(2;11)(p21;q23.3) del(11q) t(5;12)(q32;p13.2) del(12p)/t(12p) t(5;7)(q32;q11.2) idic(X)(q13) t(5;17)(q32;p13.2) t(5;10)(q32;q21.2) t(3;5)(q25.3;q35.1) Classical MPNs (BCR-ABL-negative MPNs) include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) [21].
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