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‘Acute myeloid leukemia: a comprehensive review and 2016 update’

‘Acute myeloid leukemia: a comprehensive review and 2016 update’ OPEN Citation: Blood Cancer Journal (2016) 6, e441; doi:10.1038/bcj.2016.50 www.nature.com/bcj REVIEW ‘Acute myeloid leukemia: a comprehensive review and 2016 update’ 1 1,2 I De Kouchkovsky and M Abdul-Hay Acute myeloid leukemia (AML) is the most common acute leukemia in adults, with an incidence of over 20 000 cases per year in the United States alone. Large chromosomal translocations as well as mutations in the genes involved in hematopoietic proliferation and differentiation result in the accumulation of poorly differentiated myeloid cells. AML is a highly heterogeneous disease; although cases can be stratified into favorable, intermediate and adverse-risk groups based on their cytogenetic profile, prognosis within these categories varies widely. The identification of recurrent genetic mutations, such as FLT3-ITD, NMP1 and CEBPA, has helped refine individual prognosis and guide management. Despite advances in supportive care, the backbone of therapy remains a combination of cytarabine- and anthracycline-based regimens with allogeneic stem cell transplantation for eligible candidates. Elderly patients are often unable to tolerate such regimens, and carry a particularly poor prognosis. Here, we review the major recent advances in the treatment of AML. Blood Cancer Journal (2016) 6, e441; doi:10.1038/bcj.2016.50; published online 1 July 2016 INTRODUCTION absence of any large chromosomal abnormality. Studies of animal models at the turn of the century led to the development of Acute myeloid leukemia (AML) is the most common acute leukemia a two-hit model of leukemogenesis, which offers a conceptual in adults, accounting for ~ 80 percent of cases in this group. Within framework for classifying the various mutations associated with the United States, the incidence of AML ranges from three to five AML. According to this model, class I mutations which result in the cases per 100 000 population. In 2015 alone, an estimated 20 830 activation of pro-proliferative pathways must occur in conjunction new cases were diagnosed, and over 10 000 patients died from this disease. The incidence of AML increases with age, from ~ 1.3 per with class II mutations which impair normal hematopoietic 9,10 100 000 population in patients less than 65 years old, to 12.2 cases differentiation in order for leukemia to develop. Common class I mutations, such as FLT3 (internal tandem duplications, ITD, and per 100 000 population in those over 65 years. Although advances in the treatment of AML have led to significant improvements in tyrosine kinase domain mutations, TKD), K/NRAS, TP53 and c-KIT are outcomes for younger patients, prognosis in the elderly who found in ~ 28, 12, 8 and 4% of cases, respectively. Studies of solid account for the majority of new cases remains poor. Even with and hematological malignancies have also highlighted the role current treatments, as much as 70% of patients 65 years or older will of signal transducer and activator of transcription 3 (STAT3) in the 11–13 die of their disease within 1 year of diagnosis. stimulation of cellular proliferation and survival. Enhanced tyrosine phosphorylation of STAT3 whether due to increased secretion of cytokines, such as IL-6(ref. 14) or mutations in receptor PATHOPHYSIOLOGY tyrosine kinases (for example, FLT3 duplications or less frequently JAK2) is seen in up to 50% of AML cases and signifies a worse AML can arise in patients with an underlying hematological prognosis. Notable class II mutations include NPM1 and CEBPA, disorder, or as a consequence of prior therapy (for example, which are found in ~ 27% and 6% of cases, respectively, and confer exposure to topoisomerases II, alkylating agents or radiation). a better prognosis. Alterations in genes involved in epigenetic However in majority of cases, it appears as a de novo malignancy regulation have recently emerged as a third class of mutations, with in previously healthy individuals. Regardless of its etiology, downstream effects on both cellular differentiation and prolifera- the pathogenesis of AML involves the abnormal proliferation tion. These include mutations in the DNA-methylation related genes and differentiation of a clonal population of myeloid stem cells. 6,7 DNMT3A, TET2, and IDH-1 and IDH-2, which are found in more Well-characterized chromosomal translocations, such as t(8:21) in core-binding factor AML (CBF-AML) or t(15:17) in acute promye- than 40% of AML cases. Despite significant advances, much remains to be discovered locytic leukemia (APL) result in the formation of chimeric proteins on the exact contribution of these individual mutations (RUNX1-RUNX1T1 and PML-RARA, respectively), which alter the normal maturation process of myeloid precursor cells. In addition to the development of AML. As suggested by the ‘two-hit model,’ to large chromosomal rearrangements, molecular changes have the pathogenesis and behavior of AML depends heavily on the interactions between different somatic alterations and also been implicated in the development of AML. In fact, genetic mutations are identified in more than 97% of cases, often in the chromosomal rearrangements. Thus, the c-KIT mutation has been 1 2 Department of Medicine, New York University School of Medicine, New York, NY, USA and Department of Hematology/Oncology, New York University Perlmutter Cancer Center, New York, NY, USA. Correspondence: Dr M Abdul-Hay, Department of Hematology/Oncology, NYU School of Medicine, New York Perimutter Cancer Center, 240 East 38th Street, 19 Floor, New York, NY 10016, USA. E-mail: Maher.Abdulhay@nyumc.org Received 13 April 2016; revised 3 May 2016; accepted 19 May 2016 AML: a comprehensive review and 2016 update I De Kouchkovsky and M Abdul-Hay associated with t(8;21) or inv(16), and its presence carries significant morphology, immunophenotype and clinical presentation to implications regarding prognosis. Similarly, NMP1 (a class II mutation) define six major disease entities: AML with recurrent genetic frequently occurs in conjunction with the class I mutation FLT3-ITD, abnormalities; AML with myelodysplasia-related features; therapy- or mutations in the epigenetic genes DNMT3A and IDH-1 or IDH-2. related AML; AML not otherwise specified; myeloid sarcoma; and Most of the clinical manifestations of AML reflect the accumulation myeloid proliferation related to Down syndrome (Table 1). of malignant, poorly differentiated myeloid cells within the bone Among cases of AML with recurrent genetic abnormalities, 11 marrow, peripheral blood and infrequently in other organs. The subtypes are further delineated according to distinct chromoso- majority of patients presents with a combination of leuko- mal translocations. In addition, the provisional entities AML with cytosis and signs of bone marrow failure such as anemia and mutated NPM1 and AML with mutated CEBPA were introduced thrombocytopenia. Fatigue, anorexia and weight loss are common as part of the 2008 revision, while AML with BCR-ABL1 and complaints; lymphadenopathy and organomegaly are not typically AML with mutated RUNX1 were introduced as part of the 2016 seen. If left untreated, death usually ensues within months revision. Genetic abnormalities also inform the diagnosis of AML of diagnosis secondary to infection or bleeding. The diagnosis with myelodysplasia-related changes: along with a history of MDS of acute leukemia is established by the presence of 20% or more or morphological evidence of dysplasia in two or more myeloid blasts in the bone marrow or peripheral blood. AML is further cell lineages, the presence of myelodysplasia-related cytogenetic diagnosed by demonstrating the myeloid origin of these cells abnormalities such as monosomy 5 or 7, and deletion 5q or 7q through testing for myeloperoxidase activity, immunophenotyp- identify cases of AML with myelodysplasia-related features. ing or documenting the presence of Auer rods. The latter finding consists of azurophilic, often needle-shaped cytoplasmic inclusion PROGNOSTIC FACTORS bodies that are commonly seen in APL, acute myelomonocytic leukemia and the majority of AML with t(8;21). The diagnosis of Accurate assessment of prognosis is central to the management AML can also be established in the presence of an extramedullary of AML. By stratifying patients according to their risk of treatment tissue infiltrate, or a documented t(8;21), inv(16) or t(15;17) in the resistance or treatment-related mortality (TRM), prognostic factors appropriate clinical setting, regardless of the blast percentage. help guide the physician in deciding between standard or increased treatment intensity, consolidation chemotherapy or allogenic hematopoietic stem cell transplant, or more fundamen- CLASSIFICATION tally in choosing between established or investigational therapies. The French–American–British classification system represents Among clinical factors, increased age and poor performance the first attempt to distinguish between different types of AML. status are both associated with lower rates of complete remission 3,20 Established in 1976, it defines eight subtypes (M0 through M7) (CR) and decreased overall survival (OS). Age and performance based on the morphological and cyto-chemical characteristics status at diagnosis similarly help to predict the risk of TRM, of the leukemic cells. In 2001, as part of an effort to integrate although multivariate model analyses suggest that other variables advances made in the diagnosis and management of AML, the such as platelet count, serum creatinine or albumin rather than World Health Organization (WHO) introduced a new classification age itself account for most of the increased risk of TRM seen system followed by a revised version in 2008. Later in 2016 Therapy-related AML and AML associated with in older patients. a new revised version was released, the WHO classification of AML a prior hematological malignancy also carry a significantly poorer distinguishes itself by incorporating genetic information with prognosis. Although clinical factors have an important role in Table 1. WHO classification of AML and related neoplasms Types Genetic abnormalites AML with recurrent genetic abnormalities AML with t(8:21)(q22;q22); RUNX1-RUNX1T1 AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 APL with PML-RARA AML with t(9;11)(p21.3;q23.3); MLLT3-KMT2A ML with t(6;9)(p23;q34.1); DEK-NUP214 AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM AML (megakaryoblastic) with t(1;22)(p13.3;q13.3); RBM15-MKL1 AML with BCR-ABL1 (provisional entity) AML with mutated NPM1 AML with biallelic mutations of CEBPA AML with mutated RUNX1 (provisional entity) AML with myelodysplasia-related changes Therapy-related myeloid neoplasms AML with minimal differentiation AML without maturation AML with maturation Acute myelomonocytic leukemia Acute monoblastic/monocytic leukemia Acute erythroid leukemia Pure erythroid leukemia Acute megakaryoblastic leukemia Acute basophilic leukemia Acute panmyelosis with myelofibrosis Myeloid sarcoma Myeloid proliferations related to Down syndrome Transient abnormal myelopoiesis ML associated with Down syndrome Abbreviations: AML, acute myeloid leukemia; APL, acute promyelocytic leukemia; ML, myeloid leukemia; WHO, World Health Organization. Blood Cancer Journal AML: a comprehensive review and 2016 update I De Kouchkovsky and M Abdul-Hay guiding therapy, cytogenetic changes constitute the single stron- cytogenetic and a complex karyotype. However regardless gest prognostic factor for CR and OS in AML. Accordingly, cases of the cytogenetic profile, TP53 mutations are associated with of AML can be stratified into favorable, intermediate or adverse a very poor prognosis and may in fact represent the single worst prognostic risk groups based on their cytogenetic profile alone. genetic prognostic factor. Mutations in DNA-related genes The chromosomal rearrangements t(8;21), t(15;17) or inv(16) all also carry important implications for the prognosis and treatment 17,23 confer a favorable prognosis, with a 3 year OS of 66% and 33% of AML. The presence of a mutated DNA methyl transferase in patients younger and older than 60 years, respectively. In gene DNMT3A has been associated with a worsened prognosis contrast, cytogenetic changes such as a complex karyotype (that is, in CN-AML and adverse-risk AML. Partial tandem duplica- three or more chromosomal abnormalities in the absence of tions of KMT2A (previously known as MLL), which encodes a any of the recurrent genetic abnormalities identified in the WHO histone methyltransferase, have also been associated with a worse 6,10,36 2008 classification), monosomy 5 or 7, t(6;9), inv(3) or 11q changes prognosis in CN-AML. The prognostic impact of IDH-1/IDH-2 other than t(9;11) have all been associated with a significantly mutations is less well established and is likely modified by higher risk of treatment failure and death (Table 2). AML cases co-occurring mutations. Among cases of FLT3-ITD-negative and with an intermediate prognostic risk mainly constitute of patients NPM1-mutated CN-AML, IDH-1/IDH-2 mutations have been 17,24 6 with normal cytogenetics (CN-AML). shown to improve OS. However a recent study of 826 patients Gene mutations have helped further refine risk stratification with known IDH-1 and IDH-2 status found no prognostic impact based on cytogenetic changes alone. Among patients with t(8;21), on treatment response or OS. Further analysis is required the presence of a c-KIT mutation significantly increases the risk to delineate the role of DNA-related genes in OS and treatment of relapse, and decreases OS to levels comparable to those of response. In addition to genetic profiling at the time of diagnosis, 6,23,25 patient with intermediate-risk AML. Although there is some information gained after treatment initiation plays a growing evidence that the presence of c-KIT mutations similarly lowers role in refining patient prognosis: As could be expected, prognosis in patients with inv(16), recent studies have failed individuals who achieve CR (defined morphologically as a blast 6,27,28 to show any prognostic impact in this subset of cases. count of o5% of total nonerythroid cells in the bone marrow) after Molecular changes have a particularly important role in refining induction therapy have a significantly increased survival compared 39,40 the prognosis of patients with CN-AML, which includes nearly with patients with treatment resistant AML. Survival among half of de novo AML cases. Thus CN-AML with a mutated CEBPA patients achieving CR is further influenced by the correction or or a mutated NPM1 in the absence of FLT3-ITD has been identified persistence of thrombocytopenia, with a shorter duration of survival as having a prognostic risk similar to that of AML with favorable observed in the latter group. More recently, techniques such 17,29 cytogenetic changes. The favorable prognostic impact as real-time PCR and flow cytometry have been used to measure of CEBPA mutations has been further refined to biallelic mutations the presence of minimal residual disease among patients in CR. 30 29,31 only. On the other hand, multiple studies including a Persistently elevated levels of RUNX1-RUNX1T1 transcripts after meta-analysis of relapse-free survival (RFS) and OS in patients with induction therapy in patients with t(8;21) AML are thus associated 41,42 CN-AML o60 years of age have consistently shown the presence with an increased incidence of relapse. Similarly among patients 6,32 of FLT3-ITD to be associated with a worsened prognosis. This with intermediate-risk disease, detection of minimal residual disease has led to the classification of CN-AML with FLT3-ITD into by flow cytometry is an independent predictor of relapse and 23,33 43,44 45 the adverse prognostic-risk group. As with CEBPA mutations, survival and carries important implications for management. the prognostic impact of FLT3-ITD may depend on the presence of biallelic mutations. Several studies have shown a significantly ESTABLISHED TREATMENTS worse prognosis in patients with higher mutant to wild-type 34,35 allelic ratios. TP53 mutations, which are found in only 2– 8% Eligible patients first undergo induction therapy to achieve CR. 6,7 of cases, occur more frequently in cases with unfavorable Unfortunately, minimal residual disease often persists in CR, and Table 2. Prognostic-risk group based on cytogenetic and molecular profile Prognostic-risk group Cytogenetic profile alone Cytogenetic profile and molecular abnormalities Favorable t(8:21)(q22;q22) t(8:21)(q22;q22) with no c-KIT mutation inv(16)(p13;1q22) inv(16)(p13;1q22) t(15;17)(q22;q12) t(15;17)(q22;q12) Mutated NPM1 without FLT3-ITD (CN-AML) Mutated biallelic CEBPA (CN-AML) Intermediate CN-AML t(8:21)(q22;q22) with mutated c-KIT t(9;11)(p22;q23) CN-AML other than those included in the favorable or adverse prognostic group Cytogenetic abnormalities not included in the t(9;11)(p22;q23) favorable or adverse prognostic risk groups Cytogenetic abnormalities not included in the favorable or adverse prognostic risk groups Adverse inv(3)(q21q26.2) TP53 mutation, regardless of cytogenetic profile t(6;9)(p23;q34) CN with FLT3-ITD 11q abnormalities other than t(9;11) CN with DNMT3A − 5 or del(5q) CN with KMT2A-PTD − 7 inv(3)(q21q26.2) Complex karyotype t(6;9)(p23;q34) 11q abnormalities other than t(9;11) − 5 or del(5q) − 7 Complex karyotype Abbreviations: AML, acute myeloid leukemia; ITD, internal tandem duplications. Blood Cancer Journal AML: a comprehensive review and 2016 update I De Kouchkovsky and M Abdul-Hay relapse will inevitably occur if treatment is discontinued. There- and prevent relapse. Available options for consolidation include fore, a favorable response to induction therapy should be followed chemotherapy and allogeneic hematopoietic stem cell transplant by consolidation therapy in order to eradicate any residual (allo-HSCT). When choosing between these different options, the disease and achieve lasting remission. The mainstay of induction risk of TRM should be weighted against the risk of treatment therapy consists of the ‘7+3’ regimen, which combines 7 days failure or relapse. Intention-to-treat analyses (allocating patients of continuous infusion cytarabine with 3 days of anthracycline. to allo-HSCT or chemotherapy based on the availability of a related- It is generally offered to patients with an intermediate to favorable donor) have found no benefit to allo-HSCT when compared with prognosis and a low risk of TRM (for example, younger patients chemotherapy in patients with cytogenetically favorable AML in first 61,62 with good performance status, normal creatinine, albumin and CR. Thus chemotherapy is a reasonable first-line consolidation platelet count). Studies of induction regimens using either choice for patients with a favorable prognosis. Regimens generally 2 2 daunorubicin at 60 or 90 mg/m , or idarubicin at 12 mg/m consist of intermediate-dose cytarabine (two to four cycles each 23,46,47 have shown similar rates of CR and survival. A subset of consisting of six doses at 1.5–3g/m ), which has been shown to be as 48,50,63 50 patients with DNMT3A and KMT2A mutations, which represents effective as high-dose cytarabine or multi-agent regimens. a poor prognostic marker, may however benefit from higher The optimal choice of consolidation therapy for patients with doses of daunorubicin. Standard dosing of cytarabine consists an intermediate-risk cytogenetic profile but favorable genetic of 100–200 mg/m daily administered as a continuous infusion mutations is more controversial: several studies have found over 7 days. Although studies have shown greater efficacy at no benefit to transplantation in patients with NPM1-mutated, 64,65 higher doses, this added benefit is small and accrued at the cost FLT3-ITD-negative CN-AML. However in a recent intention-to- 23,48,49 of increased toxicity; induction therapy with high-dose treat analysis, allo-HSCT was shown to improve RFS in this cytarabine is generally reserved for refractory disease. The subset of patients. While these conflicting results may reflect combination of fludarabine, cytarabine, G-CSF and idarubicin differences in study design, the difference in observed outcomes (FLAG-IDA), which was traditionally used for the treatment may also reflect the modulating effect of co-occurring mutations, of relapse, has also been shown to be a reasonable alternative such as IDH-1/-2. On the other hand allo-HSCT significantly to standard induction regimens and results in similar CR rates and prolongs RFS and OS in some patients with intermediate-risk and OS overall but higher rates of CR after a single course. in most with adverse-risk AML, and should be offered as a first-line 62,67–69 An optimal approach to elderly patients with AML has not consolidation therapy in eligible patients. In addition, allo- been established. Individuals over the age of 65 are more likely HSCT has been shown to prolong RFS and improve OS in patients to present with an adverse cytogenetic-risk profile, are less likely 70 with CN-AML and a high FLT3-ITD allelic ratio. to respond to chemotherapy and are often more susceptible to treatment-related toxicities. However despite a significantly worse prognosis, induction therapy improves survival in patients over NOVEL AGENTS the age of 65 when compared with supportive care and palliative FLT3-ITD inhibitors chemotherapy, and should be pursued whenever possible. Inhibition of tyrosine kinase (TK) receptors has been used Hypomethylating agents, traditionally used for the treatment successfully in various solid and hematological malignancies, of myelodysplastic syndrome (MDS), have also shown efficacy including Philadelphia-chromosome positive leukemias. Given the in elderly patients with AML. Evidence of a therapeutic benefit was prognostic impact and the high rate of FLT3 mutations, inhibition first demonstrated in post hoc analyses of patients with MDS who of this TK has long been recognized as a potential therapeutic were retrospectively found to meet diagnostic criteria for AML target in AML. Tested agents include the first-generation inhibitors under the WHO classification. A 2012 randomized trial of the sorafenib and midostaurin, as well as newer second-generation hypomethylating agent decitabine versus supportive care or low- agents such as quizartinib and crenolanib. dose cytarabine in patients 65 years or older showed a significant improvement in OS with hypomethylating therapy (although Sorafenib. Sorafenib is a tyrosine kinase inhibitors (TKI) of RAF this survival advantage failed to meet statistical significance in kinase, c-KIT, VGFR, PGFR and FLT3-ITD, which was first used the primary analysis). A more recent trial comparing the for the treatment of hepatocellular and renal cell carcinoma. As early hypomethylating agent azacitidine to supportive care, low-dose as 2008, phase I trials of sorafenib administered as a single agent cytarabine or standard induction therapy in patients 65 years or n patients with FLT3-ITD-positive relapsed or refractory (r/r) AML older did not show any significant improvement in median OS. demonstrated significant reductions in the number of leukemic cells However among patients pre-selected to receive supportive both in the peripheral blood and bone marrow, achieving CR in care, a subgroup analysis suggested a benefit to azacitidine 71–74 several patients. In a phase II trial of 13 patients with r/r FLT3- therapy. A similar benefit was seen among patients with adverse ITD-positive AML, single-agent sorafenib at doses of 200–400 mg cytogenetic-risk profile or MDR-AML. These results suggest twice daily established CR (including CR with insufficient hemato- a promising role for the use of hypomethylating agents in older logic recovery) in over 90% of cases. The agent was well-tolerated, individuals, including as a bridge for induction chemotherapy with with grades 3 to 4 adverse events consisting of hyperbilirubinemia the goal of achieving CR. (in 4/13 patients), elevated transaminases (5/13), diarrhea (4/13), Response to induction therapy should be evaluated 14 days rash (2/13), pancreatitis (1/13), colitis (1/13), pericarditis (1/13), after initiation of treatment with a bone marrow aspirate and core hand and foot syndrome (2/13) and elevated creatinine (1/13). biopsy. Up to 25–50% of patients show persistent cytological Yet despite a strong initial response, the majority of patients evidence of disease after one cycle of standard induction therapy relapsed within 72 days of remission. Treatment failure was and require reinduction. Treatment options for such patients associated with the emergence of D835Y and D835H mutations (as well as patients with a disease relapse) include a second cycle within the FLT3 TKD. The addition of sorafenib to standard induction of standard dose cytarabine combined with an anthracycline, regimens has yielded similarly mixed results: although initial phases I high-dose cytarabine alone or FLAG-IDA, with roughly similar CR 23,56,57 and II trials of combination therapy were able to achieve longer rates of up to 50%. In addition, mitoxantrone-based regimens periods of disease-free survival, relapse invariably ensued within (in combination with etoposide and/or cytarabine) have been shown 75–77 several months of treatment. In one such study, the combina- to achieve CR up to 40–60% of patients with recurrent or refractory 58,59 AML. Ultimately, around 60–80% of patients with de novo AML tion of sorafenib with cytarabine and idarubicin as induction and will achieve CR with induction therapy. Patients in remission consolidation therapy was able to achieve CR (or CR with an should be offered consolidation therapy to eradicate residual disease incomplete platelet recovery) in 18 out of 18 patients with previously Blood Cancer Journal AML: a comprehensive review and 2016 update I De Kouchkovsky and M Abdul-Hay untreated FLT3-ITD-positive AML. However after a median follow-up Midostaurin. Midostaurin is another first-generation FLT3 TKI of 9 months, more than half of these patients had relapsed. with significant but transient single-agent activity in patients 86,87 Interestingly, no new mutation was observed in the FLT3 TKD of with AML. As with sorafenib, its effects are limited by the the relapsed samples available for genetic sequencing. Alternative rapid emergence of resistance. Combinations of midostaurin mechanisms of resistance, such as the increased levels of FLT3 and existing chemotherapy regimens are currently under inves- tigation: results of a phase I and combined phase I/II trial of receptor ligand seen in patients receiving standard chemotherapy, midostaurin and azacitidine have recently been published, have been postulated to contribute to treatment failure. Combina- demonstrating the tolerability and efficacy of this combination in tions of sorafenib and hypomethylating agents, which have not been patients with AML. In their cohort of 17 patients with a median age associated with an increase in FLT3 receptor ligand levels, are currently of 73, Cooper et al. established a MTD level of 75 mg PO twice being investigated. An encouraging phase II trial of sorafenib and daily with no observed dose-limiting toxicities. In another phase I/II azacitidine in 43 patients with relapsed/refractory AML reported a trial of the combination of midostaurin and azacitidine was tested response rate of 46%, including 16% CR and 27% CR with incomplete in patients with AML (primary or secondary) and MDS, Strati et al. count recovery. reported a lower MTD of 50 mg PO twice daily. The combination The role of sorafenib as a first-line therapy in AML was further achieved an overall response rate of 26%, with median remission delineated in two recent randomized trials: In 2013, Serve et al. duration of 20 weeks. Although no DLT were observed in this published the results of study, in which 201 patients 60 years or study, neutropenia, thrombocytopenia and anemia developed older with newly diagnosed AML were randomized to receive in 96, 94 and 61% of patients, as well as infections and a decreased sorafenib or placebo in addition to standard chemotherapy. left ventricular ejection fraction in 56 and 11% of patients, Even within the subset of patients with FLT3-ITD-positive disease, respectively. In a recent randomized, double-blind trial of 717 the addition of sorafenib did not result in an improved EFS or OS, patients with previously untreated FLT3 (ITD and TKD) positive AML, and was instead associated with an increased incidence of adverse 80 81 Stone et al. explored the role of midostaurin in combination with events. Most recently, Rollig et al. investigated the combina- a standard ‘7+3’ induction regimen and high-dose cytarabine tion of sorafenib with standard chemotherapy in a multicenter consolidation therapy. Patients randomized to the midostaurin randomized controlled phase II trial of 267 patients age 60 treatment arm also received midostaurin as maintenance therapy or younger with newly diagnosed AML. In this study, patients for one year. Although no difference in the rate of CR was observed were randomly assigned to receive two cycles of standard ‘7+3’ between the midostaurin and placebo arms, patients receiving induction therapy followed by three cycles of high-dose cytarabine midostaurin had a significantly higher OS and EFS (with a hazard as consolidation therapy in combination with either sorafenib ratio of 0.77 and 0.80, respectively). (400 mg twice daily) or placebo. Patients assigned to the sorafenib group also received 12 months of sorafenib maintenance therapy Quizartinib. Second-generation inhibitors such as quizartinib after their last consolidation cycle. After 3 years the primary end have been designed to specifically target the FLT3 kinase, in order point, event-free survival, was achieved in 40% of patients in the to reduce toxicity from off-target effects. In addition to this sorafenib group, versus 20% in the placebo group (with an increased selectivity, quizartinib also possesses a good bioavail- unadjusted hazard ratio of 0.64). The occurrence of grades 3–5 ability and a half-life of more than 24 h, which allows for a more diarrhea, rash, fever and bleeding were significantly increased continuous FLT3 inhibition. A phase I study of oral quizartinib in among patients receiving sorafenib (occurring in 11, 7, 54 and 7%, 76 patients with relapsed/refractory AML was able to achieve respectively). Importantly, only 17% of the individuals enrolled a hematological response in 30% of patients, and a CR in 13% in this study were positive for the FLT3-ITD mutation. The observed regardless of FLT3 mutational status. Among patients with FLT3-ITD, benefit in FLT3-ITD-negative AML may in part be explained by off- the rate of hematologic response increased to 53%, with ~ 23% target inhibition of other tyrosine kinases, such as c-KIT, PGFR and of patients achieving CR. Patients were able to tolerate doses of RAF kinase. Alternatively as suggested by the observed increased up to 200 mg/day, with grade 3 QT interval prolongation as the in FLT3 receptor ligands level activation of wild-type FLT3 TK may only DLT. In one phase 2 trial, 137 patients with relapsed/ become a driver of leukemogenesis in patients receiving standard refractory AML were given quizartinib monotherapy. The agent was chemotherapy. By targeting FLT3 TK in the period immediately administered in 28-day cycles at doses of 90 mg/day in females after cytarabine or daunorubicin therapy, sorafenib may exert and 135 mg/day in males; the most common treatment toxicities significant anti-leukemic activity even in FLT3-ITD-negative cells. were nausea and vomiting in 38 and 26% of patients, anemia in In an interesting parallel to the use of TKI in Philadelphia- 29%, QT interval prolongation in 26%, febrile neutropenia in 25%, chromosome-positive leukemias, inhibition of FLT3 TK has also diarrhea in 20% and fatigue in 20%. The rate of composite CR shown a promising role in the post-allo-HSCT setting, either as (that is, CR, CR with incomplete platelet recovery and CR with maintenance therapy or treatment of relapse. This was explored incomplete hematological recovery) and the median OS were 34% recently by Chen et al. in a phase I trial of 22 patients with and 25.6 months in FLT3-ITD-negative cases, and 44% and FLT3-ITD-positive disease who received sorafenib as maintenance 23.1 months in FLT3-ITD positive cases. The observed benefitin therapy following allo-HSCT. In addition to establishing safety FLT3-ITD-negative disease may be explained by off-target effects, and feasibility, the authors of this study reported rates of PFS and or by the upregulation of the FLT3 TK pathway as suggested by the OS which compared favorably to historical controls, particularly rise in FLT3 receptor ligand levels in patients receiving standard in the subset of patients in CR1 or CR2 at the time of transplant. chemotherapy. Once again however, the response to FLT3 TKI is In a retrospective analysis of six patients status post allo-HSCT, limited by the rapid emergence of resistance: the median duration sorafenib as maintenance therapy (n = 5) or treatment of relapse of remission was only 5 weeks in patients with FLT3-ITD-positive (n = 1) resulted in a median PFS of 16 months, with all patients AML. Interim analysis of a phase I/II trial of quizartinib in remaining in molecular remission (that is, FLT3-ITD-negative combination with azacitidine or cytarabine (NCT01892371) reported by PCR). Interestingly, skin graft-versus-host-disease occurred an overall response rate of 82% in FLT3-ITD-positive AML, MDS or shortly after initiation of therapy in five out of these six patients. chronic myelomonocytic leukemia. A phase III trial comparing In addition to its action as a TKI, sorafenib may therefore possess quizartinib monotherapy to salvage chemotherapy in relapsed and an immunomodulatory role, which synergizes with the graft- refractory AML (NCT02039726) is similarly underway. versus-leukemia effect. Two phase I trials of sorafenib use in the peri-transplant setting are currently underway (NCT01398501 and Crenolanib. Crenolanib besylate is an orally available second- NCT01578109). generation FLT3 TKI, with activity against FLT3-ITD and FLT3-TKD Blood Cancer Journal AML: a comprehensive review and 2016 update I De Kouchkovsky and M Abdul-Hay mutants. Unlike other FLT3 TKIs, which are subject to the it was reported a CR rate of 63% using the combination of emergence of resistance conferring kinase domain mutations clofarabine with low-dose cytarabine, compared with 31% with (such as D835Y), crenolanib appears to possess extensive ‘pan- clofarabine alone. In a study of 320 patients over the age of 55 kinase’ inhibition of secondary TKD mutations. Using concentra- with relapsed/refractory AML, the combination of clofarabine and tions far below the clinically achievable plasma levels, Smith et al. cytarabine achieved significantly higher rates of CR, CR with were unable to identify any single TKD mutation able to confer incomplete platelet count and DFS when compared with cytarabine resistance to crenolanib. In a phase II study of 38 patients with alone. Although neither of these studies was able to show FLT3-mutated AML (including relapsed and refractory patients), an improved OS, these results suggest a synergistic action between crenolanib administered at doses of 200 mg/m per day three clofarabine and cytarabine, and have spurred interest in the times a day in 28 days cycle achieved a median EFS and OS of combination of these two agents. Recently a study was published 8 and 19 weeks, respectively. Crenolanib is currently being showing the results of a phase 2 trial of clofarabine and low-dose studied in multiple clinical trials in AML patients, both with and cytarabine in older patients with newly diagnosed AML. In this without FLT3-mutated AMLs. study, 118 patients age 60 or older (median age of 68 years) received induction therapy with clofarabine at 20 mg/m on day 1 STAT inhibitors through 5 and low-dose cytarabine at 20 mg subcutaneously STAT3 tyrosine phosphorylation is upregulated in up to 50% of AML twice daily on day 1 through 10. In an attempt to improve survival, cases and confers a worse prognosis. Activation of the STAT3 this was followed by consolidation and maintenance therapy with signaling pathway is also stimulated by the FLT3 receptor ligand, up to 18 cycles of clofarabine and low-dose cytarabine alternating and may represent a key step in the development of FLT3 TKI with decitabine. CR was achieved in 60% of cases, with a median resistance. Several small molecules of STAT3 inhibitors have been OS of 11.1 months, and a median RFS of 14.1 months. The regimen developed and are currently being investigated for the treatment was well-tolerated, with a 4-week mortality rate of 3%. The most of AML: in 2011, Redell et al. showed decreased STAT3 phosphory- common non-hematological toxicities reported in this study lation and induction of apoptosis in AML cell lines treated with the included nausea in 81% of cases, elevated liver transaminases STAT3 inhibitor C188-9. More recently, the optimized compound and bilirubin in 64 and 47% of cases, as well as rash in 56% of MM-206 demonstrated a dose-dependent induction of apoptosis cases. Clofarabine may thus represent a well-tolerated addition to in AML cell lines cultured in the presence of bone marrow stromal low-dose cytarabine in elderly patients unable to receive standard cells. The anti-tumor activity of MM-206 was confirmed in vivo chemotherapy or allo-HSCT for consolidation therapy. Clofarabine by reducing blast count and improving survival in AML-engrafted 99 has shown similarly promising results in younger patients when mice. OPB-31121 is a small molecule inhibitor of STAT3 and STAT5 combined with the standard ‘7+3’ induction regimen. In a study of phosphorylation, which has demonstrated activity in advanced 57 newly diagnosed patients under the age of 60, the combination solid tumors. Treatment of various leukemic cell lines with this of clofarabine (at 22.5 mg/m IV daily for 5 days) with idarubicin compound resulted in significant growth inhibition, including and cytarabine used as a frontline induction and consolidation FLT3-ITD-positive AML cells. Importantly, OPB-31121 was able therapy achieved CR rates of 74% and a median EFS of 13.5 months to overcome FLT3 receptor ligand-induced STAT3 phosphoryla- (the median OS and RFS had not been reached by a median follow- tion, and may help to prevent the emergence of resistance in up of 10.9 months). A phase I/II study of frontline clofarabine, patients receiving FLT3-ITD TKI. Other STAT3 inhibitors that work cytarabine and idarubicin in patients with intermediate and poor as antisense oligonucleotide (ASO) for STAT3 are in clinical trials in risk AML is currently underway (NCT00838240). The potential role hematological malignancies including AML and will have to wait of clofarabine in the peri-transplant setting is also currently under to see their efficacies in near future. investigation. In a multicenter two-stage phase II trial, 84 patients with relapsed and refractory AML received clofarabine (at 30 mg/m IDH1/IDH2 small molecule inhibitors for 5 days) in combination with cytarabine as salvage therapy, Gain of function mutations in IDH-1 and IDH-2 enzymes are found 7 followed by 4 days of clofarabine and one dose of melphalan in approximately 20% of cases. Recent attempts have been in chemo-responsive patients with HLA-compatible donors. Out of made to target these mutant enzymes as a potential treatment the 56 patients who underwent allo-HSCT, CR was achieved in 50 for AML. In 2013, Wang et al. published the results of AGI-6780, (including 11 CR with incomplete platelet recovery and 10 CR by a small molecule inhibitor of the R140Q mutant IDH-2 enzyme. In an chimerism). The 2-year OS of 43% compared favorably with historical ex vivo model of primary human AML cells, treatment with AGI-6780 controls. Although randomized controlled trials are needed to was able to overcome the differentiation block of leukemic cells. clearly delineate the role of clofarabine in AML these studies present Recently, the IDH-2 inhibitor AG-221 was found to confer a dose- promising results in support of this agent, particularly in combina- dependent survival benefits in a primary human IDH-2 mutant tion with cytarabine in the elderly. AML xenograft model. At a cellular level, AG-221 treatment was In addition to its activity as an intravenous agent, clofarabine associated with an initial phase of CD45+ blast cells proliferation, followed by cellular differentiation. A phase I trial of AG-221 has also captured interest as an oral agent for the treatment of AML. in IDH-2 mutant leukemia is currently underway (NCT01915498). Unlike previous purine nucleoside analogs, clofarabine is able to IDH-1 mutant enzymes are also the targets of new therapeutic resist acidic pH as well as phosphorolytic cleavage by gastro- inhibitors: Preliminary results of a phase I trial of the small molecule intestinal Escherichia coli. As a result it possesses a bioavailability of inhibitor AG-120 (NCT02074839) demonstrated hematological roughly 50%. In a phase I/II study of 35 patients 60 years or older response in 7 out of 14 IDH-1 positive patients, including 4 CR. with relapsed/refractory AML or high-risk MDS the feasibility and efficacy of oral clofarabine combined with low-dose cytarabine was Clofarabine investigated as a first-line therapy. At a MTD of oral clofarabine of 20 mg per day for 5 days, CR was achieved in 42% of patients Clofarabine is a second-generation purine nucleoside analog (including CR with incomplete count recovery in 4%). Most approved for the treatment of relapsed or refractory pediatric importantly, more than 50% of cycles administered at the MTD acute lymphocytic leukemia. In AML, it has shown activity and tolerability as a single-agent, administered intravenously at doses of were given in the outpatient setting. In a population at an increased 2 105,106 20–30 mg/m for 5 days, with overall response rates of ~ 40%. risk of TRM, oral clofarabine may thus offer a valuable addition to In a 2008 randomized study of 70 patients aged 60 years and older, reduced intensity chemotherapy. Blood Cancer Journal AML: a comprehensive review and 2016 update I De Kouchkovsky and M Abdul-Hay Monoclonal antibodies depletion of the normal cells of myeloid lineage is associated with unacceptable neutropenia, and attempts to apply CART cell Monoclonal antibodies exert their anti-tumor activity through therapy to the treatment of AML have had to focus on identifying direct antibody-dependent cytotoxicity or through the conjuga- tion of cytotoxic agents, which allows for the targeted delivery an appropriate antigen to target malignant cells while sparing of potent chemotherapy to neoplastic cells. Gemtuzumab non-malignant myeloid cells. Kenderian et al. recently developed ozogamicin (GO) is a humanized recombinant antibody directed a CD33-specific CAR based on the single-chain variable fragment at CD33, a transmembrane protein expressed on cells of myeloid of gemtuzumab ozogamicin. They have reported potent in vitro lineage. The antibody is conjugated to the DNA-cleaving cytotoxic activity of such CD33-specific CART cells against AML cell lines. agent calicheamicin, and is internalized by CD33-positive cells. GO CD33-specific CART therapy also prolonged survival in AML received FDA approval in 2000 for the treatment of CD33-positive xenografts. However CD33 is expressed on normal cells of myeloid AML in patients 60 years or older at first relapse. However in 2009, lineage and the reported anti-tumor effects were associated interim analysis of a randomized clinical trial of 637 patients with profound cytopenias. Using electroporation of CD33-specific with newly diagnosed AML revealed increased fatal toxicity with CAR mRNA into human T cells, the authors are able to induce the no improvement in CR, disease-free survival or OS in patients transient expression of anti-CD33 CAR, which may confer receiving GO in combination with standard chemotherapy. The clinically significant anti-tumor activity while avoiding long-term trial was prematurely terminated and FDA approval was rescinded. myelosuppression. In an attempt to selectively target leukemic Despite its removal from the market, a 2014 meta-analysis of five myeloid cells, others have focused instead on the β member of the randomized clinical trials demonstrated a decrease in relapse folate receptor family (FRβ). This receptor subtype is primarily and improved survival in patients receiving GO in addition to expressed on myeloid-lineage hematopoietic cells, and is upregu- standard chemotherapy. A subset analysis further revealed lated in the setting of malignancy. FRβ is expressed in 70% of that this survival benefit was limited to patients with a favorable or cases of primary AML, and its expression can be further upregulated intermediate cytogenetic-risk profile. Most recently, a randomized trial of 237 patients 60 years of age or older ineligible for intensive following treatment with all-trans retinoic acid. In a recent chemotherapy showed an improved OS (hazard ratio of 0.69) in publication the effect of FRβ-specificCARTcells therapy in vitro as those assigned to GO induction and consolidation compared well as in AML xenograft was reported. The study demonstrated lytic with best supportive care. This survival benefit was again activity against FRβ positive AML cell lines both in vitro and in vivo. most pronounced in patients with an intermediate to favorable Importantly, no evidence of toxic activity against healthy human cytogenetic-risk profile. Although further studies are required CD34-positive stem cells was observed in vitro. Although still in its to fully delineate the effects of gemtuzumab in the treatment early stages, CART cell therapy may thus provide an alternative of AML, these data suggest a benefit among elderly patients mechanism of treatment for patients with relapsed/refractory AML. with favorable or intermediate cytogenetic-risk profile. CD37 is a transmembrane protein that is expressed in high levels on maturing B cells. Although its exact function has not yet been elucidated, it is upregulated in non-Hogkin lymphoma and chronic CONCLUSION lymphocytic leukemia. Initially conceived as a therapy for B-cell AML is a biologically and clinically heterogeneous disease. Although malignancies, AGS67E is a fully human anti-CD37 IgG antibody advances in supportive care and prognostic risk stratification that is conjugated with monomethyl auristatin E (MMAE), a potent have optimized established therapies, overall long-term survival microtubule-disrupting agent. AGS67E allows for the selective remains poor. Elderly patients who account for the majority of delivery of MMAE to CD37-positive malignant cells and results newly diagnosed cases are more likely to present with an adverse in apoptosis. Although CD37 is minimally expressed on normal cytogenetic profile. At the same time the increased risk of TRM often myeloid stem cells it was recently demonstrated to have differential + − precludes this population of patients from receiving optimal expression of CD37 on the surface of CD34 /CD38 AML stem cells. chemotherapy or stem cell transplantation. Novel targeted therapies In vitro treatment of leukemic cells with nanomolar concentrations offer the promise of effective anti-leukemic activity with reduced of AGS67E resulted in cytotoxicity, altered cell growth and apoptosis toxicity from off-target effects. However given the molecular in seven out of 16 AML cell lines. The administration of AGS67E was diversity of AML, it is unlikely that targeted therapies such as FLT3 further found to significantly decreased tumor engraftment in tyrosine kinase inhibitors will provide a single ‘magic bullet’ against a murine xenograft model of AML, resulting in undetectable this disease. Rather the development of new treatments, in concert leukemic cell levels in three out of four AML samples. CD37 may thus represent a novel therapeutic target for the selective inhibition with improved genetic profiling and risk stratification, can be of leukemic cell growth. Although still at an early stage of its clinical expected to result in incremental gains in remission and survival. development, AGS67E is a promising new therapy. More impor- Furthermore in addition to mutated enzymes and upregulated tantly, the identification of unique molecular markers expressed on pathways, the identification of unique cell surface markers can the surface of leukemic cells is an emerging avenue for the provide a therapeutic target for recombinant monoclonal antibodies discovery of novel targeted therapies against AML. or chimeric antigen receptors. Here, the challenge lays in selectively targeting leukemic myeloid cells while sparing non-malignant CART therapy myeloid precursors. Lastly, the development of well-tolerated oral therapies, such as clofarabine, will increasingly broaden the range of Chimeric antigen receptors are synthetic T-cell receptors with antibody-like specificity. They combine a single-chain variable available treatment for elderly patients at a higher risk of mortality fragment from a monoclonal antibody with the transmembrane from standard chemotherapy regimens. We are looking to a new era and intracellular domains of a T-cell receptor. This allows for the in the treatment of AML to begin with novel agents so we can creation of a host-derived population of chimeric antigen receptor-T achieve better responses with prolong OS particularly for patients (CART) cells, which can be directed at a pre-determined antigen. with relapsed or refractory diseases and poor cytogenetic features. CD19-directed CART cell therapy has shown exciting efficacy in the treatment of acute lymphoblastic leukemia and B-cell lymphoma. Although this treatment does not distinguish between malignant CONFLICT OF INTEREST and healthy CD19 cells, patients tolerate the depletion of CD19 lymphocytes with relatively little morbidity. In contrast to this, The authors declare no conflict of interest. Blood Cancer Journal AML: a comprehensive review and 2016 update I De Kouchkovsky and M Abdul-Hay REFERENCES leukemia: a comprehensive large-scale study from a single Chinese center. 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Clinical otherwise in the credit line; if the material is not included under the Creative Commons safety and activity in a phase I trial of AG-120, a first in class, selective, potent license, users will need to obtain permission from the license holder to reproduce the inhibitor of the IDH1-mutant protein, in patients with IDH1 mutant positive material. To view a copy of this license, visit http://creativecommons.org/licenses/ advanced hematologic malignancies. Eur J Cancer 2014; 50: 195. by/4.0/ 105 Burnett AK, Russell NH, Hunter AE, Milligan D, Knapper S, Wheatley K et al. Clofarabine doubles the response rate in older patients with acute myeloid © The Author(s) 2016 leukemia but does not improve survival. Blood 2013; 122: 1384–1394. Blood Cancer Journal http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Blood Cancer Journal Springer Journals

‘Acute myeloid leukemia: a comprehensive review and 2016 update’

Blood Cancer Journal , Volume 6 (7) – Jul 1, 2016

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Abstract

OPEN Citation: Blood Cancer Journal (2016) 6, e441; doi:10.1038/bcj.2016.50 www.nature.com/bcj REVIEW ‘Acute myeloid leukemia: a comprehensive review and 2016 update’ 1 1,2 I De Kouchkovsky and M Abdul-Hay Acute myeloid leukemia (AML) is the most common acute leukemia in adults, with an incidence of over 20 000 cases per year in the United States alone. Large chromosomal translocations as well as mutations in the genes involved in hematopoietic proliferation and differentiation result in the accumulation of poorly differentiated myeloid cells. AML is a highly heterogeneous disease; although cases can be stratified into favorable, intermediate and adverse-risk groups based on their cytogenetic profile, prognosis within these categories varies widely. The identification of recurrent genetic mutations, such as FLT3-ITD, NMP1 and CEBPA, has helped refine individual prognosis and guide management. Despite advances in supportive care, the backbone of therapy remains a combination of cytarabine- and anthracycline-based regimens with allogeneic stem cell transplantation for eligible candidates. Elderly patients are often unable to tolerate such regimens, and carry a particularly poor prognosis. Here, we review the major recent advances in the treatment of AML. Blood Cancer Journal (2016) 6, e441; doi:10.1038/bcj.2016.50; published online 1 July 2016 INTRODUCTION absence of any large chromosomal abnormality. Studies of animal models at the turn of the century led to the development of Acute myeloid leukemia (AML) is the most common acute leukemia a two-hit model of leukemogenesis, which offers a conceptual in adults, accounting for ~ 80 percent of cases in this group. Within framework for classifying the various mutations associated with the United States, the incidence of AML ranges from three to five AML. According to this model, class I mutations which result in the cases per 100 000 population. In 2015 alone, an estimated 20 830 activation of pro-proliferative pathways must occur in conjunction new cases were diagnosed, and over 10 000 patients died from this disease. The incidence of AML increases with age, from ~ 1.3 per with class II mutations which impair normal hematopoietic 9,10 100 000 population in patients less than 65 years old, to 12.2 cases differentiation in order for leukemia to develop. Common class I mutations, such as FLT3 (internal tandem duplications, ITD, and per 100 000 population in those over 65 years. Although advances in the treatment of AML have led to significant improvements in tyrosine kinase domain mutations, TKD), K/NRAS, TP53 and c-KIT are outcomes for younger patients, prognosis in the elderly who found in ~ 28, 12, 8 and 4% of cases, respectively. Studies of solid account for the majority of new cases remains poor. Even with and hematological malignancies have also highlighted the role current treatments, as much as 70% of patients 65 years or older will of signal transducer and activator of transcription 3 (STAT3) in the 11–13 die of their disease within 1 year of diagnosis. stimulation of cellular proliferation and survival. Enhanced tyrosine phosphorylation of STAT3 whether due to increased secretion of cytokines, such as IL-6(ref. 14) or mutations in receptor PATHOPHYSIOLOGY tyrosine kinases (for example, FLT3 duplications or less frequently JAK2) is seen in up to 50% of AML cases and signifies a worse AML can arise in patients with an underlying hematological prognosis. Notable class II mutations include NPM1 and CEBPA, disorder, or as a consequence of prior therapy (for example, which are found in ~ 27% and 6% of cases, respectively, and confer exposure to topoisomerases II, alkylating agents or radiation). a better prognosis. Alterations in genes involved in epigenetic However in majority of cases, it appears as a de novo malignancy regulation have recently emerged as a third class of mutations, with in previously healthy individuals. Regardless of its etiology, downstream effects on both cellular differentiation and prolifera- the pathogenesis of AML involves the abnormal proliferation tion. These include mutations in the DNA-methylation related genes and differentiation of a clonal population of myeloid stem cells. 6,7 DNMT3A, TET2, and IDH-1 and IDH-2, which are found in more Well-characterized chromosomal translocations, such as t(8:21) in core-binding factor AML (CBF-AML) or t(15:17) in acute promye- than 40% of AML cases. Despite significant advances, much remains to be discovered locytic leukemia (APL) result in the formation of chimeric proteins on the exact contribution of these individual mutations (RUNX1-RUNX1T1 and PML-RARA, respectively), which alter the normal maturation process of myeloid precursor cells. In addition to the development of AML. As suggested by the ‘two-hit model,’ to large chromosomal rearrangements, molecular changes have the pathogenesis and behavior of AML depends heavily on the interactions between different somatic alterations and also been implicated in the development of AML. In fact, genetic mutations are identified in more than 97% of cases, often in the chromosomal rearrangements. Thus, the c-KIT mutation has been 1 2 Department of Medicine, New York University School of Medicine, New York, NY, USA and Department of Hematology/Oncology, New York University Perlmutter Cancer Center, New York, NY, USA. Correspondence: Dr M Abdul-Hay, Department of Hematology/Oncology, NYU School of Medicine, New York Perimutter Cancer Center, 240 East 38th Street, 19 Floor, New York, NY 10016, USA. E-mail: Maher.Abdulhay@nyumc.org Received 13 April 2016; revised 3 May 2016; accepted 19 May 2016 AML: a comprehensive review and 2016 update I De Kouchkovsky and M Abdul-Hay associated with t(8;21) or inv(16), and its presence carries significant morphology, immunophenotype and clinical presentation to implications regarding prognosis. Similarly, NMP1 (a class II mutation) define six major disease entities: AML with recurrent genetic frequently occurs in conjunction with the class I mutation FLT3-ITD, abnormalities; AML with myelodysplasia-related features; therapy- or mutations in the epigenetic genes DNMT3A and IDH-1 or IDH-2. related AML; AML not otherwise specified; myeloid sarcoma; and Most of the clinical manifestations of AML reflect the accumulation myeloid proliferation related to Down syndrome (Table 1). of malignant, poorly differentiated myeloid cells within the bone Among cases of AML with recurrent genetic abnormalities, 11 marrow, peripheral blood and infrequently in other organs. The subtypes are further delineated according to distinct chromoso- majority of patients presents with a combination of leuko- mal translocations. In addition, the provisional entities AML with cytosis and signs of bone marrow failure such as anemia and mutated NPM1 and AML with mutated CEBPA were introduced thrombocytopenia. Fatigue, anorexia and weight loss are common as part of the 2008 revision, while AML with BCR-ABL1 and complaints; lymphadenopathy and organomegaly are not typically AML with mutated RUNX1 were introduced as part of the 2016 seen. If left untreated, death usually ensues within months revision. Genetic abnormalities also inform the diagnosis of AML of diagnosis secondary to infection or bleeding. The diagnosis with myelodysplasia-related changes: along with a history of MDS of acute leukemia is established by the presence of 20% or more or morphological evidence of dysplasia in two or more myeloid blasts in the bone marrow or peripheral blood. AML is further cell lineages, the presence of myelodysplasia-related cytogenetic diagnosed by demonstrating the myeloid origin of these cells abnormalities such as monosomy 5 or 7, and deletion 5q or 7q through testing for myeloperoxidase activity, immunophenotyp- identify cases of AML with myelodysplasia-related features. ing or documenting the presence of Auer rods. The latter finding consists of azurophilic, often needle-shaped cytoplasmic inclusion PROGNOSTIC FACTORS bodies that are commonly seen in APL, acute myelomonocytic leukemia and the majority of AML with t(8;21). The diagnosis of Accurate assessment of prognosis is central to the management AML can also be established in the presence of an extramedullary of AML. By stratifying patients according to their risk of treatment tissue infiltrate, or a documented t(8;21), inv(16) or t(15;17) in the resistance or treatment-related mortality (TRM), prognostic factors appropriate clinical setting, regardless of the blast percentage. help guide the physician in deciding between standard or increased treatment intensity, consolidation chemotherapy or allogenic hematopoietic stem cell transplant, or more fundamen- CLASSIFICATION tally in choosing between established or investigational therapies. The French–American–British classification system represents Among clinical factors, increased age and poor performance the first attempt to distinguish between different types of AML. status are both associated with lower rates of complete remission 3,20 Established in 1976, it defines eight subtypes (M0 through M7) (CR) and decreased overall survival (OS). Age and performance based on the morphological and cyto-chemical characteristics status at diagnosis similarly help to predict the risk of TRM, of the leukemic cells. In 2001, as part of an effort to integrate although multivariate model analyses suggest that other variables advances made in the diagnosis and management of AML, the such as platelet count, serum creatinine or albumin rather than World Health Organization (WHO) introduced a new classification age itself account for most of the increased risk of TRM seen system followed by a revised version in 2008. Later in 2016 Therapy-related AML and AML associated with in older patients. a new revised version was released, the WHO classification of AML a prior hematological malignancy also carry a significantly poorer distinguishes itself by incorporating genetic information with prognosis. Although clinical factors have an important role in Table 1. WHO classification of AML and related neoplasms Types Genetic abnormalites AML with recurrent genetic abnormalities AML with t(8:21)(q22;q22); RUNX1-RUNX1T1 AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 APL with PML-RARA AML with t(9;11)(p21.3;q23.3); MLLT3-KMT2A ML with t(6;9)(p23;q34.1); DEK-NUP214 AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM AML (megakaryoblastic) with t(1;22)(p13.3;q13.3); RBM15-MKL1 AML with BCR-ABL1 (provisional entity) AML with mutated NPM1 AML with biallelic mutations of CEBPA AML with mutated RUNX1 (provisional entity) AML with myelodysplasia-related changes Therapy-related myeloid neoplasms AML with minimal differentiation AML without maturation AML with maturation Acute myelomonocytic leukemia Acute monoblastic/monocytic leukemia Acute erythroid leukemia Pure erythroid leukemia Acute megakaryoblastic leukemia Acute basophilic leukemia Acute panmyelosis with myelofibrosis Myeloid sarcoma Myeloid proliferations related to Down syndrome Transient abnormal myelopoiesis ML associated with Down syndrome Abbreviations: AML, acute myeloid leukemia; APL, acute promyelocytic leukemia; ML, myeloid leukemia; WHO, World Health Organization. Blood Cancer Journal AML: a comprehensive review and 2016 update I De Kouchkovsky and M Abdul-Hay guiding therapy, cytogenetic changes constitute the single stron- cytogenetic and a complex karyotype. However regardless gest prognostic factor for CR and OS in AML. Accordingly, cases of the cytogenetic profile, TP53 mutations are associated with of AML can be stratified into favorable, intermediate or adverse a very poor prognosis and may in fact represent the single worst prognostic risk groups based on their cytogenetic profile alone. genetic prognostic factor. Mutations in DNA-related genes The chromosomal rearrangements t(8;21), t(15;17) or inv(16) all also carry important implications for the prognosis and treatment 17,23 confer a favorable prognosis, with a 3 year OS of 66% and 33% of AML. The presence of a mutated DNA methyl transferase in patients younger and older than 60 years, respectively. In gene DNMT3A has been associated with a worsened prognosis contrast, cytogenetic changes such as a complex karyotype (that is, in CN-AML and adverse-risk AML. Partial tandem duplica- three or more chromosomal abnormalities in the absence of tions of KMT2A (previously known as MLL), which encodes a any of the recurrent genetic abnormalities identified in the WHO histone methyltransferase, have also been associated with a worse 6,10,36 2008 classification), monosomy 5 or 7, t(6;9), inv(3) or 11q changes prognosis in CN-AML. The prognostic impact of IDH-1/IDH-2 other than t(9;11) have all been associated with a significantly mutations is less well established and is likely modified by higher risk of treatment failure and death (Table 2). AML cases co-occurring mutations. Among cases of FLT3-ITD-negative and with an intermediate prognostic risk mainly constitute of patients NPM1-mutated CN-AML, IDH-1/IDH-2 mutations have been 17,24 6 with normal cytogenetics (CN-AML). shown to improve OS. However a recent study of 826 patients Gene mutations have helped further refine risk stratification with known IDH-1 and IDH-2 status found no prognostic impact based on cytogenetic changes alone. Among patients with t(8;21), on treatment response or OS. Further analysis is required the presence of a c-KIT mutation significantly increases the risk to delineate the role of DNA-related genes in OS and treatment of relapse, and decreases OS to levels comparable to those of response. In addition to genetic profiling at the time of diagnosis, 6,23,25 patient with intermediate-risk AML. Although there is some information gained after treatment initiation plays a growing evidence that the presence of c-KIT mutations similarly lowers role in refining patient prognosis: As could be expected, prognosis in patients with inv(16), recent studies have failed individuals who achieve CR (defined morphologically as a blast 6,27,28 to show any prognostic impact in this subset of cases. count of o5% of total nonerythroid cells in the bone marrow) after Molecular changes have a particularly important role in refining induction therapy have a significantly increased survival compared 39,40 the prognosis of patients with CN-AML, which includes nearly with patients with treatment resistant AML. Survival among half of de novo AML cases. Thus CN-AML with a mutated CEBPA patients achieving CR is further influenced by the correction or or a mutated NPM1 in the absence of FLT3-ITD has been identified persistence of thrombocytopenia, with a shorter duration of survival as having a prognostic risk similar to that of AML with favorable observed in the latter group. More recently, techniques such 17,29 cytogenetic changes. The favorable prognostic impact as real-time PCR and flow cytometry have been used to measure of CEBPA mutations has been further refined to biallelic mutations the presence of minimal residual disease among patients in CR. 30 29,31 only. On the other hand, multiple studies including a Persistently elevated levels of RUNX1-RUNX1T1 transcripts after meta-analysis of relapse-free survival (RFS) and OS in patients with induction therapy in patients with t(8;21) AML are thus associated 41,42 CN-AML o60 years of age have consistently shown the presence with an increased incidence of relapse. Similarly among patients 6,32 of FLT3-ITD to be associated with a worsened prognosis. This with intermediate-risk disease, detection of minimal residual disease has led to the classification of CN-AML with FLT3-ITD into by flow cytometry is an independent predictor of relapse and 23,33 43,44 45 the adverse prognostic-risk group. As with CEBPA mutations, survival and carries important implications for management. the prognostic impact of FLT3-ITD may depend on the presence of biallelic mutations. Several studies have shown a significantly ESTABLISHED TREATMENTS worse prognosis in patients with higher mutant to wild-type 34,35 allelic ratios. TP53 mutations, which are found in only 2– 8% Eligible patients first undergo induction therapy to achieve CR. 6,7 of cases, occur more frequently in cases with unfavorable Unfortunately, minimal residual disease often persists in CR, and Table 2. Prognostic-risk group based on cytogenetic and molecular profile Prognostic-risk group Cytogenetic profile alone Cytogenetic profile and molecular abnormalities Favorable t(8:21)(q22;q22) t(8:21)(q22;q22) with no c-KIT mutation inv(16)(p13;1q22) inv(16)(p13;1q22) t(15;17)(q22;q12) t(15;17)(q22;q12) Mutated NPM1 without FLT3-ITD (CN-AML) Mutated biallelic CEBPA (CN-AML) Intermediate CN-AML t(8:21)(q22;q22) with mutated c-KIT t(9;11)(p22;q23) CN-AML other than those included in the favorable or adverse prognostic group Cytogenetic abnormalities not included in the t(9;11)(p22;q23) favorable or adverse prognostic risk groups Cytogenetic abnormalities not included in the favorable or adverse prognostic risk groups Adverse inv(3)(q21q26.2) TP53 mutation, regardless of cytogenetic profile t(6;9)(p23;q34) CN with FLT3-ITD 11q abnormalities other than t(9;11) CN with DNMT3A − 5 or del(5q) CN with KMT2A-PTD − 7 inv(3)(q21q26.2) Complex karyotype t(6;9)(p23;q34) 11q abnormalities other than t(9;11) − 5 or del(5q) − 7 Complex karyotype Abbreviations: AML, acute myeloid leukemia; ITD, internal tandem duplications. Blood Cancer Journal AML: a comprehensive review and 2016 update I De Kouchkovsky and M Abdul-Hay relapse will inevitably occur if treatment is discontinued. There- and prevent relapse. Available options for consolidation include fore, a favorable response to induction therapy should be followed chemotherapy and allogeneic hematopoietic stem cell transplant by consolidation therapy in order to eradicate any residual (allo-HSCT). When choosing between these different options, the disease and achieve lasting remission. The mainstay of induction risk of TRM should be weighted against the risk of treatment therapy consists of the ‘7+3’ regimen, which combines 7 days failure or relapse. Intention-to-treat analyses (allocating patients of continuous infusion cytarabine with 3 days of anthracycline. to allo-HSCT or chemotherapy based on the availability of a related- It is generally offered to patients with an intermediate to favorable donor) have found no benefit to allo-HSCT when compared with prognosis and a low risk of TRM (for example, younger patients chemotherapy in patients with cytogenetically favorable AML in first 61,62 with good performance status, normal creatinine, albumin and CR. Thus chemotherapy is a reasonable first-line consolidation platelet count). Studies of induction regimens using either choice for patients with a favorable prognosis. Regimens generally 2 2 daunorubicin at 60 or 90 mg/m , or idarubicin at 12 mg/m consist of intermediate-dose cytarabine (two to four cycles each 23,46,47 have shown similar rates of CR and survival. A subset of consisting of six doses at 1.5–3g/m ), which has been shown to be as 48,50,63 50 patients with DNMT3A and KMT2A mutations, which represents effective as high-dose cytarabine or multi-agent regimens. a poor prognostic marker, may however benefit from higher The optimal choice of consolidation therapy for patients with doses of daunorubicin. Standard dosing of cytarabine consists an intermediate-risk cytogenetic profile but favorable genetic of 100–200 mg/m daily administered as a continuous infusion mutations is more controversial: several studies have found over 7 days. Although studies have shown greater efficacy at no benefit to transplantation in patients with NPM1-mutated, 64,65 higher doses, this added benefit is small and accrued at the cost FLT3-ITD-negative CN-AML. However in a recent intention-to- 23,48,49 of increased toxicity; induction therapy with high-dose treat analysis, allo-HSCT was shown to improve RFS in this cytarabine is generally reserved for refractory disease. The subset of patients. While these conflicting results may reflect combination of fludarabine, cytarabine, G-CSF and idarubicin differences in study design, the difference in observed outcomes (FLAG-IDA), which was traditionally used for the treatment may also reflect the modulating effect of co-occurring mutations, of relapse, has also been shown to be a reasonable alternative such as IDH-1/-2. On the other hand allo-HSCT significantly to standard induction regimens and results in similar CR rates and prolongs RFS and OS in some patients with intermediate-risk and OS overall but higher rates of CR after a single course. in most with adverse-risk AML, and should be offered as a first-line 62,67–69 An optimal approach to elderly patients with AML has not consolidation therapy in eligible patients. In addition, allo- been established. Individuals over the age of 65 are more likely HSCT has been shown to prolong RFS and improve OS in patients to present with an adverse cytogenetic-risk profile, are less likely 70 with CN-AML and a high FLT3-ITD allelic ratio. to respond to chemotherapy and are often more susceptible to treatment-related toxicities. However despite a significantly worse prognosis, induction therapy improves survival in patients over NOVEL AGENTS the age of 65 when compared with supportive care and palliative FLT3-ITD inhibitors chemotherapy, and should be pursued whenever possible. Inhibition of tyrosine kinase (TK) receptors has been used Hypomethylating agents, traditionally used for the treatment successfully in various solid and hematological malignancies, of myelodysplastic syndrome (MDS), have also shown efficacy including Philadelphia-chromosome positive leukemias. Given the in elderly patients with AML. Evidence of a therapeutic benefit was prognostic impact and the high rate of FLT3 mutations, inhibition first demonstrated in post hoc analyses of patients with MDS who of this TK has long been recognized as a potential therapeutic were retrospectively found to meet diagnostic criteria for AML target in AML. Tested agents include the first-generation inhibitors under the WHO classification. A 2012 randomized trial of the sorafenib and midostaurin, as well as newer second-generation hypomethylating agent decitabine versus supportive care or low- agents such as quizartinib and crenolanib. dose cytarabine in patients 65 years or older showed a significant improvement in OS with hypomethylating therapy (although Sorafenib. Sorafenib is a tyrosine kinase inhibitors (TKI) of RAF this survival advantage failed to meet statistical significance in kinase, c-KIT, VGFR, PGFR and FLT3-ITD, which was first used the primary analysis). A more recent trial comparing the for the treatment of hepatocellular and renal cell carcinoma. As early hypomethylating agent azacitidine to supportive care, low-dose as 2008, phase I trials of sorafenib administered as a single agent cytarabine or standard induction therapy in patients 65 years or n patients with FLT3-ITD-positive relapsed or refractory (r/r) AML older did not show any significant improvement in median OS. demonstrated significant reductions in the number of leukemic cells However among patients pre-selected to receive supportive both in the peripheral blood and bone marrow, achieving CR in care, a subgroup analysis suggested a benefit to azacitidine 71–74 several patients. In a phase II trial of 13 patients with r/r FLT3- therapy. A similar benefit was seen among patients with adverse ITD-positive AML, single-agent sorafenib at doses of 200–400 mg cytogenetic-risk profile or MDR-AML. These results suggest twice daily established CR (including CR with insufficient hemato- a promising role for the use of hypomethylating agents in older logic recovery) in over 90% of cases. The agent was well-tolerated, individuals, including as a bridge for induction chemotherapy with with grades 3 to 4 adverse events consisting of hyperbilirubinemia the goal of achieving CR. (in 4/13 patients), elevated transaminases (5/13), diarrhea (4/13), Response to induction therapy should be evaluated 14 days rash (2/13), pancreatitis (1/13), colitis (1/13), pericarditis (1/13), after initiation of treatment with a bone marrow aspirate and core hand and foot syndrome (2/13) and elevated creatinine (1/13). biopsy. Up to 25–50% of patients show persistent cytological Yet despite a strong initial response, the majority of patients evidence of disease after one cycle of standard induction therapy relapsed within 72 days of remission. Treatment failure was and require reinduction. Treatment options for such patients associated with the emergence of D835Y and D835H mutations (as well as patients with a disease relapse) include a second cycle within the FLT3 TKD. The addition of sorafenib to standard induction of standard dose cytarabine combined with an anthracycline, regimens has yielded similarly mixed results: although initial phases I high-dose cytarabine alone or FLAG-IDA, with roughly similar CR 23,56,57 and II trials of combination therapy were able to achieve longer rates of up to 50%. In addition, mitoxantrone-based regimens periods of disease-free survival, relapse invariably ensued within (in combination with etoposide and/or cytarabine) have been shown 75–77 several months of treatment. In one such study, the combina- to achieve CR up to 40–60% of patients with recurrent or refractory 58,59 AML. Ultimately, around 60–80% of patients with de novo AML tion of sorafenib with cytarabine and idarubicin as induction and will achieve CR with induction therapy. Patients in remission consolidation therapy was able to achieve CR (or CR with an should be offered consolidation therapy to eradicate residual disease incomplete platelet recovery) in 18 out of 18 patients with previously Blood Cancer Journal AML: a comprehensive review and 2016 update I De Kouchkovsky and M Abdul-Hay untreated FLT3-ITD-positive AML. However after a median follow-up Midostaurin. Midostaurin is another first-generation FLT3 TKI of 9 months, more than half of these patients had relapsed. with significant but transient single-agent activity in patients 86,87 Interestingly, no new mutation was observed in the FLT3 TKD of with AML. As with sorafenib, its effects are limited by the the relapsed samples available for genetic sequencing. Alternative rapid emergence of resistance. Combinations of midostaurin mechanisms of resistance, such as the increased levels of FLT3 and existing chemotherapy regimens are currently under inves- tigation: results of a phase I and combined phase I/II trial of receptor ligand seen in patients receiving standard chemotherapy, midostaurin and azacitidine have recently been published, have been postulated to contribute to treatment failure. Combina- demonstrating the tolerability and efficacy of this combination in tions of sorafenib and hypomethylating agents, which have not been patients with AML. In their cohort of 17 patients with a median age associated with an increase in FLT3 receptor ligand levels, are currently of 73, Cooper et al. established a MTD level of 75 mg PO twice being investigated. An encouraging phase II trial of sorafenib and daily with no observed dose-limiting toxicities. In another phase I/II azacitidine in 43 patients with relapsed/refractory AML reported a trial of the combination of midostaurin and azacitidine was tested response rate of 46%, including 16% CR and 27% CR with incomplete in patients with AML (primary or secondary) and MDS, Strati et al. count recovery. reported a lower MTD of 50 mg PO twice daily. The combination The role of sorafenib as a first-line therapy in AML was further achieved an overall response rate of 26%, with median remission delineated in two recent randomized trials: In 2013, Serve et al. duration of 20 weeks. Although no DLT were observed in this published the results of study, in which 201 patients 60 years or study, neutropenia, thrombocytopenia and anemia developed older with newly diagnosed AML were randomized to receive in 96, 94 and 61% of patients, as well as infections and a decreased sorafenib or placebo in addition to standard chemotherapy. left ventricular ejection fraction in 56 and 11% of patients, Even within the subset of patients with FLT3-ITD-positive disease, respectively. In a recent randomized, double-blind trial of 717 the addition of sorafenib did not result in an improved EFS or OS, patients with previously untreated FLT3 (ITD and TKD) positive AML, and was instead associated with an increased incidence of adverse 80 81 Stone et al. explored the role of midostaurin in combination with events. Most recently, Rollig et al. investigated the combina- a standard ‘7+3’ induction regimen and high-dose cytarabine tion of sorafenib with standard chemotherapy in a multicenter consolidation therapy. Patients randomized to the midostaurin randomized controlled phase II trial of 267 patients age 60 treatment arm also received midostaurin as maintenance therapy or younger with newly diagnosed AML. In this study, patients for one year. Although no difference in the rate of CR was observed were randomly assigned to receive two cycles of standard ‘7+3’ between the midostaurin and placebo arms, patients receiving induction therapy followed by three cycles of high-dose cytarabine midostaurin had a significantly higher OS and EFS (with a hazard as consolidation therapy in combination with either sorafenib ratio of 0.77 and 0.80, respectively). (400 mg twice daily) or placebo. Patients assigned to the sorafenib group also received 12 months of sorafenib maintenance therapy Quizartinib. Second-generation inhibitors such as quizartinib after their last consolidation cycle. After 3 years the primary end have been designed to specifically target the FLT3 kinase, in order point, event-free survival, was achieved in 40% of patients in the to reduce toxicity from off-target effects. In addition to this sorafenib group, versus 20% in the placebo group (with an increased selectivity, quizartinib also possesses a good bioavail- unadjusted hazard ratio of 0.64). The occurrence of grades 3–5 ability and a half-life of more than 24 h, which allows for a more diarrhea, rash, fever and bleeding were significantly increased continuous FLT3 inhibition. A phase I study of oral quizartinib in among patients receiving sorafenib (occurring in 11, 7, 54 and 7%, 76 patients with relapsed/refractory AML was able to achieve respectively). Importantly, only 17% of the individuals enrolled a hematological response in 30% of patients, and a CR in 13% in this study were positive for the FLT3-ITD mutation. The observed regardless of FLT3 mutational status. Among patients with FLT3-ITD, benefit in FLT3-ITD-negative AML may in part be explained by off- the rate of hematologic response increased to 53%, with ~ 23% target inhibition of other tyrosine kinases, such as c-KIT, PGFR and of patients achieving CR. Patients were able to tolerate doses of RAF kinase. Alternatively as suggested by the observed increased up to 200 mg/day, with grade 3 QT interval prolongation as the in FLT3 receptor ligands level activation of wild-type FLT3 TK may only DLT. In one phase 2 trial, 137 patients with relapsed/ become a driver of leukemogenesis in patients receiving standard refractory AML were given quizartinib monotherapy. The agent was chemotherapy. By targeting FLT3 TK in the period immediately administered in 28-day cycles at doses of 90 mg/day in females after cytarabine or daunorubicin therapy, sorafenib may exert and 135 mg/day in males; the most common treatment toxicities significant anti-leukemic activity even in FLT3-ITD-negative cells. were nausea and vomiting in 38 and 26% of patients, anemia in In an interesting parallel to the use of TKI in Philadelphia- 29%, QT interval prolongation in 26%, febrile neutropenia in 25%, chromosome-positive leukemias, inhibition of FLT3 TK has also diarrhea in 20% and fatigue in 20%. The rate of composite CR shown a promising role in the post-allo-HSCT setting, either as (that is, CR, CR with incomplete platelet recovery and CR with maintenance therapy or treatment of relapse. This was explored incomplete hematological recovery) and the median OS were 34% recently by Chen et al. in a phase I trial of 22 patients with and 25.6 months in FLT3-ITD-negative cases, and 44% and FLT3-ITD-positive disease who received sorafenib as maintenance 23.1 months in FLT3-ITD positive cases. The observed benefitin therapy following allo-HSCT. In addition to establishing safety FLT3-ITD-negative disease may be explained by off-target effects, and feasibility, the authors of this study reported rates of PFS and or by the upregulation of the FLT3 TK pathway as suggested by the OS which compared favorably to historical controls, particularly rise in FLT3 receptor ligand levels in patients receiving standard in the subset of patients in CR1 or CR2 at the time of transplant. chemotherapy. Once again however, the response to FLT3 TKI is In a retrospective analysis of six patients status post allo-HSCT, limited by the rapid emergence of resistance: the median duration sorafenib as maintenance therapy (n = 5) or treatment of relapse of remission was only 5 weeks in patients with FLT3-ITD-positive (n = 1) resulted in a median PFS of 16 months, with all patients AML. Interim analysis of a phase I/II trial of quizartinib in remaining in molecular remission (that is, FLT3-ITD-negative combination with azacitidine or cytarabine (NCT01892371) reported by PCR). Interestingly, skin graft-versus-host-disease occurred an overall response rate of 82% in FLT3-ITD-positive AML, MDS or shortly after initiation of therapy in five out of these six patients. chronic myelomonocytic leukemia. A phase III trial comparing In addition to its action as a TKI, sorafenib may therefore possess quizartinib monotherapy to salvage chemotherapy in relapsed and an immunomodulatory role, which synergizes with the graft- refractory AML (NCT02039726) is similarly underway. versus-leukemia effect. Two phase I trials of sorafenib use in the peri-transplant setting are currently underway (NCT01398501 and Crenolanib. Crenolanib besylate is an orally available second- NCT01578109). generation FLT3 TKI, with activity against FLT3-ITD and FLT3-TKD Blood Cancer Journal AML: a comprehensive review and 2016 update I De Kouchkovsky and M Abdul-Hay mutants. Unlike other FLT3 TKIs, which are subject to the it was reported a CR rate of 63% using the combination of emergence of resistance conferring kinase domain mutations clofarabine with low-dose cytarabine, compared with 31% with (such as D835Y), crenolanib appears to possess extensive ‘pan- clofarabine alone. In a study of 320 patients over the age of 55 kinase’ inhibition of secondary TKD mutations. Using concentra- with relapsed/refractory AML, the combination of clofarabine and tions far below the clinically achievable plasma levels, Smith et al. cytarabine achieved significantly higher rates of CR, CR with were unable to identify any single TKD mutation able to confer incomplete platelet count and DFS when compared with cytarabine resistance to crenolanib. In a phase II study of 38 patients with alone. Although neither of these studies was able to show FLT3-mutated AML (including relapsed and refractory patients), an improved OS, these results suggest a synergistic action between crenolanib administered at doses of 200 mg/m per day three clofarabine and cytarabine, and have spurred interest in the times a day in 28 days cycle achieved a median EFS and OS of combination of these two agents. Recently a study was published 8 and 19 weeks, respectively. Crenolanib is currently being showing the results of a phase 2 trial of clofarabine and low-dose studied in multiple clinical trials in AML patients, both with and cytarabine in older patients with newly diagnosed AML. In this without FLT3-mutated AMLs. study, 118 patients age 60 or older (median age of 68 years) received induction therapy with clofarabine at 20 mg/m on day 1 STAT inhibitors through 5 and low-dose cytarabine at 20 mg subcutaneously STAT3 tyrosine phosphorylation is upregulated in up to 50% of AML twice daily on day 1 through 10. In an attempt to improve survival, cases and confers a worse prognosis. Activation of the STAT3 this was followed by consolidation and maintenance therapy with signaling pathway is also stimulated by the FLT3 receptor ligand, up to 18 cycles of clofarabine and low-dose cytarabine alternating and may represent a key step in the development of FLT3 TKI with decitabine. CR was achieved in 60% of cases, with a median resistance. Several small molecules of STAT3 inhibitors have been OS of 11.1 months, and a median RFS of 14.1 months. The regimen developed and are currently being investigated for the treatment was well-tolerated, with a 4-week mortality rate of 3%. The most of AML: in 2011, Redell et al. showed decreased STAT3 phosphory- common non-hematological toxicities reported in this study lation and induction of apoptosis in AML cell lines treated with the included nausea in 81% of cases, elevated liver transaminases STAT3 inhibitor C188-9. More recently, the optimized compound and bilirubin in 64 and 47% of cases, as well as rash in 56% of MM-206 demonstrated a dose-dependent induction of apoptosis cases. Clofarabine may thus represent a well-tolerated addition to in AML cell lines cultured in the presence of bone marrow stromal low-dose cytarabine in elderly patients unable to receive standard cells. The anti-tumor activity of MM-206 was confirmed in vivo chemotherapy or allo-HSCT for consolidation therapy. Clofarabine by reducing blast count and improving survival in AML-engrafted 99 has shown similarly promising results in younger patients when mice. OPB-31121 is a small molecule inhibitor of STAT3 and STAT5 combined with the standard ‘7+3’ induction regimen. In a study of phosphorylation, which has demonstrated activity in advanced 57 newly diagnosed patients under the age of 60, the combination solid tumors. Treatment of various leukemic cell lines with this of clofarabine (at 22.5 mg/m IV daily for 5 days) with idarubicin compound resulted in significant growth inhibition, including and cytarabine used as a frontline induction and consolidation FLT3-ITD-positive AML cells. Importantly, OPB-31121 was able therapy achieved CR rates of 74% and a median EFS of 13.5 months to overcome FLT3 receptor ligand-induced STAT3 phosphoryla- (the median OS and RFS had not been reached by a median follow- tion, and may help to prevent the emergence of resistance in up of 10.9 months). A phase I/II study of frontline clofarabine, patients receiving FLT3-ITD TKI. Other STAT3 inhibitors that work cytarabine and idarubicin in patients with intermediate and poor as antisense oligonucleotide (ASO) for STAT3 are in clinical trials in risk AML is currently underway (NCT00838240). The potential role hematological malignancies including AML and will have to wait of clofarabine in the peri-transplant setting is also currently under to see their efficacies in near future. investigation. In a multicenter two-stage phase II trial, 84 patients with relapsed and refractory AML received clofarabine (at 30 mg/m IDH1/IDH2 small molecule inhibitors for 5 days) in combination with cytarabine as salvage therapy, Gain of function mutations in IDH-1 and IDH-2 enzymes are found 7 followed by 4 days of clofarabine and one dose of melphalan in approximately 20% of cases. Recent attempts have been in chemo-responsive patients with HLA-compatible donors. Out of made to target these mutant enzymes as a potential treatment the 56 patients who underwent allo-HSCT, CR was achieved in 50 for AML. In 2013, Wang et al. published the results of AGI-6780, (including 11 CR with incomplete platelet recovery and 10 CR by a small molecule inhibitor of the R140Q mutant IDH-2 enzyme. In an chimerism). The 2-year OS of 43% compared favorably with historical ex vivo model of primary human AML cells, treatment with AGI-6780 controls. Although randomized controlled trials are needed to was able to overcome the differentiation block of leukemic cells. clearly delineate the role of clofarabine in AML these studies present Recently, the IDH-2 inhibitor AG-221 was found to confer a dose- promising results in support of this agent, particularly in combina- dependent survival benefits in a primary human IDH-2 mutant tion with cytarabine in the elderly. AML xenograft model. At a cellular level, AG-221 treatment was In addition to its activity as an intravenous agent, clofarabine associated with an initial phase of CD45+ blast cells proliferation, followed by cellular differentiation. A phase I trial of AG-221 has also captured interest as an oral agent for the treatment of AML. in IDH-2 mutant leukemia is currently underway (NCT01915498). Unlike previous purine nucleoside analogs, clofarabine is able to IDH-1 mutant enzymes are also the targets of new therapeutic resist acidic pH as well as phosphorolytic cleavage by gastro- inhibitors: Preliminary results of a phase I trial of the small molecule intestinal Escherichia coli. As a result it possesses a bioavailability of inhibitor AG-120 (NCT02074839) demonstrated hematological roughly 50%. In a phase I/II study of 35 patients 60 years or older response in 7 out of 14 IDH-1 positive patients, including 4 CR. with relapsed/refractory AML or high-risk MDS the feasibility and efficacy of oral clofarabine combined with low-dose cytarabine was Clofarabine investigated as a first-line therapy. At a MTD of oral clofarabine of 20 mg per day for 5 days, CR was achieved in 42% of patients Clofarabine is a second-generation purine nucleoside analog (including CR with incomplete count recovery in 4%). Most approved for the treatment of relapsed or refractory pediatric importantly, more than 50% of cycles administered at the MTD acute lymphocytic leukemia. In AML, it has shown activity and tolerability as a single-agent, administered intravenously at doses of were given in the outpatient setting. In a population at an increased 2 105,106 20–30 mg/m for 5 days, with overall response rates of ~ 40%. risk of TRM, oral clofarabine may thus offer a valuable addition to In a 2008 randomized study of 70 patients aged 60 years and older, reduced intensity chemotherapy. Blood Cancer Journal AML: a comprehensive review and 2016 update I De Kouchkovsky and M Abdul-Hay Monoclonal antibodies depletion of the normal cells of myeloid lineage is associated with unacceptable neutropenia, and attempts to apply CART cell Monoclonal antibodies exert their anti-tumor activity through therapy to the treatment of AML have had to focus on identifying direct antibody-dependent cytotoxicity or through the conjuga- tion of cytotoxic agents, which allows for the targeted delivery an appropriate antigen to target malignant cells while sparing of potent chemotherapy to neoplastic cells. Gemtuzumab non-malignant myeloid cells. Kenderian et al. recently developed ozogamicin (GO) is a humanized recombinant antibody directed a CD33-specific CAR based on the single-chain variable fragment at CD33, a transmembrane protein expressed on cells of myeloid of gemtuzumab ozogamicin. They have reported potent in vitro lineage. The antibody is conjugated to the DNA-cleaving cytotoxic activity of such CD33-specific CART cells against AML cell lines. agent calicheamicin, and is internalized by CD33-positive cells. GO CD33-specific CART therapy also prolonged survival in AML received FDA approval in 2000 for the treatment of CD33-positive xenografts. However CD33 is expressed on normal cells of myeloid AML in patients 60 years or older at first relapse. However in 2009, lineage and the reported anti-tumor effects were associated interim analysis of a randomized clinical trial of 637 patients with profound cytopenias. Using electroporation of CD33-specific with newly diagnosed AML revealed increased fatal toxicity with CAR mRNA into human T cells, the authors are able to induce the no improvement in CR, disease-free survival or OS in patients transient expression of anti-CD33 CAR, which may confer receiving GO in combination with standard chemotherapy. The clinically significant anti-tumor activity while avoiding long-term trial was prematurely terminated and FDA approval was rescinded. myelosuppression. In an attempt to selectively target leukemic Despite its removal from the market, a 2014 meta-analysis of five myeloid cells, others have focused instead on the β member of the randomized clinical trials demonstrated a decrease in relapse folate receptor family (FRβ). This receptor subtype is primarily and improved survival in patients receiving GO in addition to expressed on myeloid-lineage hematopoietic cells, and is upregu- standard chemotherapy. A subset analysis further revealed lated in the setting of malignancy. FRβ is expressed in 70% of that this survival benefit was limited to patients with a favorable or cases of primary AML, and its expression can be further upregulated intermediate cytogenetic-risk profile. Most recently, a randomized trial of 237 patients 60 years of age or older ineligible for intensive following treatment with all-trans retinoic acid. In a recent chemotherapy showed an improved OS (hazard ratio of 0.69) in publication the effect of FRβ-specificCARTcells therapy in vitro as those assigned to GO induction and consolidation compared well as in AML xenograft was reported. The study demonstrated lytic with best supportive care. This survival benefit was again activity against FRβ positive AML cell lines both in vitro and in vivo. most pronounced in patients with an intermediate to favorable Importantly, no evidence of toxic activity against healthy human cytogenetic-risk profile. Although further studies are required CD34-positive stem cells was observed in vitro. Although still in its to fully delineate the effects of gemtuzumab in the treatment early stages, CART cell therapy may thus provide an alternative of AML, these data suggest a benefit among elderly patients mechanism of treatment for patients with relapsed/refractory AML. with favorable or intermediate cytogenetic-risk profile. CD37 is a transmembrane protein that is expressed in high levels on maturing B cells. Although its exact function has not yet been elucidated, it is upregulated in non-Hogkin lymphoma and chronic CONCLUSION lymphocytic leukemia. Initially conceived as a therapy for B-cell AML is a biologically and clinically heterogeneous disease. Although malignancies, AGS67E is a fully human anti-CD37 IgG antibody advances in supportive care and prognostic risk stratification that is conjugated with monomethyl auristatin E (MMAE), a potent have optimized established therapies, overall long-term survival microtubule-disrupting agent. AGS67E allows for the selective remains poor. Elderly patients who account for the majority of delivery of MMAE to CD37-positive malignant cells and results newly diagnosed cases are more likely to present with an adverse in apoptosis. Although CD37 is minimally expressed on normal cytogenetic profile. At the same time the increased risk of TRM often myeloid stem cells it was recently demonstrated to have differential + − precludes this population of patients from receiving optimal expression of CD37 on the surface of CD34 /CD38 AML stem cells. chemotherapy or stem cell transplantation. Novel targeted therapies In vitro treatment of leukemic cells with nanomolar concentrations offer the promise of effective anti-leukemic activity with reduced of AGS67E resulted in cytotoxicity, altered cell growth and apoptosis toxicity from off-target effects. However given the molecular in seven out of 16 AML cell lines. The administration of AGS67E was diversity of AML, it is unlikely that targeted therapies such as FLT3 further found to significantly decreased tumor engraftment in tyrosine kinase inhibitors will provide a single ‘magic bullet’ against a murine xenograft model of AML, resulting in undetectable this disease. Rather the development of new treatments, in concert leukemic cell levels in three out of four AML samples. CD37 may thus represent a novel therapeutic target for the selective inhibition with improved genetic profiling and risk stratification, can be of leukemic cell growth. Although still at an early stage of its clinical expected to result in incremental gains in remission and survival. development, AGS67E is a promising new therapy. More impor- Furthermore in addition to mutated enzymes and upregulated tantly, the identification of unique molecular markers expressed on pathways, the identification of unique cell surface markers can the surface of leukemic cells is an emerging avenue for the provide a therapeutic target for recombinant monoclonal antibodies discovery of novel targeted therapies against AML. or chimeric antigen receptors. Here, the challenge lays in selectively targeting leukemic myeloid cells while sparing non-malignant CART therapy myeloid precursors. Lastly, the development of well-tolerated oral therapies, such as clofarabine, will increasingly broaden the range of Chimeric antigen receptors are synthetic T-cell receptors with antibody-like specificity. They combine a single-chain variable available treatment for elderly patients at a higher risk of mortality fragment from a monoclonal antibody with the transmembrane from standard chemotherapy regimens. We are looking to a new era and intracellular domains of a T-cell receptor. This allows for the in the treatment of AML to begin with novel agents so we can creation of a host-derived population of chimeric antigen receptor-T achieve better responses with prolong OS particularly for patients (CART) cells, which can be directed at a pre-determined antigen. with relapsed or refractory diseases and poor cytogenetic features. CD19-directed CART cell therapy has shown exciting efficacy in the treatment of acute lymphoblastic leukemia and B-cell lymphoma. Although this treatment does not distinguish between malignant CONFLICT OF INTEREST and healthy CD19 cells, patients tolerate the depletion of CD19 lymphocytes with relatively little morbidity. In contrast to this, The authors declare no conflict of interest. Blood Cancer Journal AML: a comprehensive review and 2016 update I De Kouchkovsky and M Abdul-Hay REFERENCES leukemia: a comprehensive large-scale study from a single Chinese center. 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Published: Jul 1, 2016

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