A User’s Guide to Novel Therapies for Acute Myeloid Leukemia

Few diseases have been marked by a 40-year period of stagnation with regard to therapeutic advances and United States Food and Drug Administration (FDA) approvals, as has been the case for acute myeloid leukemia (AML). Cytarabine and anthracyclines were introduced for the treatment of AML in the 1970s, and in the ensuing 4 decades, the pharmacologic pipeline has experienced a standstill. The absence of FDA approvals in AML is not a reflection of the lack of understanding of the disease biology. The field has seen major advances from the standpoint of stem cell biology and clonal evolution, and the field has also seen some therapeutic advances, but these therapeutic advances have arisen from optimization of the same traditional cytotoxic chemotherapeutics rather than the development of novel therapies. The year 2017 marked a turning point with regard to FDA approvals. This review summarizes the salient clinical trials that led to the approval of 8 novel agents in AML in the past 2 years. For these agents, the clinical activity is often defined by specific molecular aberrations or metabolic features of AML cells. We also emphasize the principles of management of AML in the current era of genomic medicine, with a focus on considerations for targeting mutation-specific vulnerabilities in select patients. This review also highlights unique challenges to the use of novel agents in 2020, including considerations of curative potential with regards to bridging to allogeneic stem cell transplant, tolerability, financial toxicities, and microenvironmental hurdles. Finally, we discuss prospects on future immunotherapeutic investigational agents in the pharmacologic pipeline.     

Targeted therapies for high-risk acute myeloid leukemia.

Approximately half of children with acute myeloid leukemia (AML) can be cured with contemporary chemotherapy regimens; however, various forms of drug resistance pose considerable obstacles for curing the remaining patients. Recent advances in immunology, cytogenetics, and cellular and molecular biology have provided new insights into fundamental biological differences between leukemic myeloid blasts and their normal counterparts. This article focuses on new technologies involving: (1) antibody- or growth factor-mediated targeting of antigens or growth factor receptors found on AML blasts and restricted sub-groups of normal cells, (2) pharmacologic targeting of the pathologic t(15;17) translocation of acute promyelocytic leukemia with all-trans retinoic acid, (3) pharmacologic and immunologic targeting of mutant RAS oncogenes and related aberrant signaling in AML blasts, and (4) targeting of pathological signaling of the Bcr-Abl oncoprotein and c-kit tyrosine kinase in myeloid leukemias. These advances herald an exciting new era of AML-specific therapies.     

Genetic variations of DNA repair genes and their prognostic significance in patients with acute myeloid leukemia

Common genetic variations in genes involved in DNA repair or response to genotoxic stress may influence both cancer susceptibility and treatment response individually or interactively. However, in acute myeloid leukemia (AML), the relevance of these genetic variations remains to be fully established. In this study, we analyzed 42 genetic variations among 15 candidate genes in 307 AML patients and 560 age‐sex matched controls. Their associations with chemotherapy response were further evaluated in combination with other well‐established prognostic factors. An increased risk of AML was found in individuals heterozygous for XPD 2251A>C (rs13181) with an odds ratio (OR) of 1.637 (95% confidence interval [CI]: 1.118–2.395), and the increased risk could be attributed to C allele (OR = 1.505, 95% CI: 1.061–2.134). Postchemotherapy response analysis revealed that AML patients heterozygous for ATM 4138C>T (rs3092856) or GG homozygous for TP53 215C>G (rs1042522) were independently linked to inferior treatment outcomes. These results uncover novel prognostic factors for AML patients treated with chemotherapy and may also indicate an etiological role of XPD in this disease.     

Top advances of the year: Leukemia

In the year 2021, there were three new Food and Drug Administration approvals for all leukemia types: asciminib (Scemblix) for chronic myeloid leukemia, brexucabtagene autoleucel (Tecartus) for relapsed/refractory B-cell acute lymphocytic leukemia, and asparaginase erwinia chrysanthemi (recombinant)-rywn (Rylaze) for acute lymphocytic leukemia. This is down from 2017–2018 when eight new therapies were approved for acute myeloid leukemia alone. However, this decrease from prior years does not imply that little progress was made in our understanding or treatment of leukemias in 2021. Asciminib and brexucabtagene autoleucel, in particular, are representative of major developing trends. Asciminib, a targeted therapy, is only one of many drugs in development that are products of a bedside-to-bench approach fueled by new sequencing and other genetic technologies that have greatly increased our understanding of the biology behind hematologic diseases. Brexucabtagene autoleucel, an adoptive cell therapy, is the newest of several similar treatments for B cell–associated neoplasms, and it is representative of a massive push to develop novel immunotherapies for a broad range of hematologic malignancies. This commentary reviews the development of asciminib and brexucabtagene autoleucel and describes other major advances in the associated fields of targeted therapy and immunotherapy for leukemias.     

Genetic alteration patterns and clinical outcomes of elderly and secondary acute myeloid leukemia

To illustrate the clinical and genetic features of elderly and secondary acute myeloid leukemia (AML) patients, we compared 145 elderly AML (e‐AML) and 55 secondary AML (s‐AML) patients with 451 young de novo AML patients. Both e‐AML and s‐AML patients showed lower white blood cell (WBC) and bone marrow (BM) blasts at diagnosis. NPM1, DNMT3A, and IDH2 mutations were more common while biallelic CEBPA and IDH1 mutations were less seen in e‐AML patients. s‐AML patients carried a higher frequency of KMT2A‐AF9. In treatment response and survival, e/s‐AML conferred a lower complete remission (CR) rate and shorter duration of event‐free survival (EFS) and overall survival (OS) compared with young patients. In multivariate analysis, s‐AML was an independent risk factor for OS but not EFS in the whole cohort. Importantly, intensive therapy tended to improve the survival of e/s‐AML patients without increasing the risk of early death, and hematopoietic stem cell transplantation (HSCT) could rescue the prognosis of s‐AML, which should be recommended for the treatment of fit patients.     

Is Targeted Therapy Feasible in Acute Myelogenous Leukemia?

The prognosis for patients with acute myeloid leukemia (AML) is determined to a large degree by the biology of the leukemic cell. In recent years, the identification and characterization of genetic aberrations has vastly improved our understanding of the pathogenesis of AML. In contrast, however, there has been a lack of clinically meaningful therapeutic advances. The same chemotherapeutic strategies have been applied to AML for several decades now, and while these regimens are effective in inducing remission, most patients relapse within months after initial treatment. Hence, there is an urgent need for novel therapies. We review herein a number of lines of laboratory and clinical trial data supporting the clinical value of targeted treatment approaches that will likely result in improved outcomes for patients with AML.     

Development of a scoring system for predicting primary resistance to venetoclax plus hypomethylating agents (HMAs) in acute myeloid leukemia patients

In recent years, one of the most promising advances in the treatment of acute myeloid leukemia (AML) is the combination of a hypomethylating agent (HMA) with the BCL2 inhibitor venetoclax (VEN). To better understand the key factors associated with the response of VEN plus HMA, 212 consecutive AML patients were retrospectively recruited to establish and validate a scoring system for predicting the primary resistance to VEN-based induced therapy. All AML patients were divided randomly into a training set (n = 155) and a validation set (n = 57). Factors were selected using a multivariate logistic regression model, including FAB-M5, myelodysplastic syndrome-secondary acute myeloid leukemia (MDS-sAML), RUNX1-RUNX1T1 and FLT3-ITD mutation (FLT3-ITDm). A nomogram was then constructed including all these four predictors. The nomogram both presented a good performance of discrimination and calibration, with a C-index of 0.770 and 0.733 in the training and validation set. Decision curve analysis also indicated that the nomogram was feasible to make beneficial decisions. Eventually a total scoring system of 8 points was developed, which was divided into three risk groups: low-risk (score 0–2), medium-risk (score 3–4), and high-risk (score 5–8). There was a significant difference in the nonremission (NR) rate of these three risk groups (22.8% vs. 60.0% vs. 77.8%, p < 0.001). After adjustment of the other variables, patients in medium- or high-risk groups also presented a worse event-free survival (EFS) than that in the low-risk group (hazard ratio [HR] = 1.62, p = 0.03). In conclusion, we highlighted the response determinants of AML patients receiving a combination therapy of VEN plus HMAs. The scoring system can be used to predict the resistance of VEN, providing better guidance for clinical treatment.     

The clinical relevance of Wilms Tumour 1 (WT1) gene mutations in acute leukaemia

Recurrent genetic aberrations are important predictors of outcome in acute myeloid leukaemia (AML). Numerous novel molecular abnormalities have been identified and investigated in recent years adding to the risk stratification and prognostication of conventional karyotyping. Mutations in the Wilms Tumour 1 (WT1) gene were first described more than a decade ago but their clinical significance has only recently been evaluated. WT1 mutations occur in approximately 10% of adult AML patients at diagnosis and are most frequent in the cytogenetically normal (CN) AML subgroup. These mutations appear to confer a negative prognostic outcome by increasing the risk of relapse and death. Mutation frequency is higher in pediatric patients and also appears to confer a negative impact on relapse and survival. Herein, we discuss the importance of WT1 mutations in AML. Copyright © 2009 John Wiley & Sons, Ltd.     

Feasibility of the AML profiler (Skyline™ Array) for patient risk stratification in a multicentre trial: a preliminary comparison with the conventional approach

Deoxyribonucleic acid microarrays allow researchers to measure mRNA levels of thousands of genes in a single experiment and could be useful for diagnostic purposes in patients with acute myeloid leukaemia (AML). We assessed the feasibility of the AML profiler (Skyline? Array) in genetic stratification of patients with de novo AML and compared the results with those obtained using the standard cytogenetic and molecular approach. Diagnostic bone marrow from 31 consecutive de novo AML cases was used to test MLL‐PTD , FLT3‐ITD and TKD , NPM1 and CEBPAdm mutations. Purified RNA was used to assess RUNX1‐RUNX1T1 , PML‐RARα and CBFβ‐MYH11 rearrangements. RNA remnants underwent gene expression profiling analysis using the AML profiler, which detects chromosomal aberrations: t(8;21), t(15;17), inv(16), mutations (CEBPAdm , ABD‐NPM1 ) and BAALC and EVI1 expression. Thirty cases were successfully analysed with both methods. Five cases had FLT3‐ITD. In one case, a t(8;21) was correctly detected by both methods. Four cases had inv(16); in one, the RNA quality was unsatisfactory and it was not hybridized, and in the other three, the AML profiler detected the genetic lesion — this being a rare type I translocation in one case. Two cases with acute promyelocytic leukaemia were diagnosed by both methods. Results for NPM1 mutations were concordant in all but two cases (2/11, non‐ABD mutations). Analysis of costs and turnaround times showed that the AML profiler was no more expensive than the conventional molecular approach. These results suggest that the AML profiler could be useful in multicentre trials to rapidly identify patients with AML with a good prognosis. Copyright © 2016 John Wiley & Sons, Ltd.     

Genetics of myeloid malignancies: pathogenetic and clinical implications.

Myeloid malignancies are clonal disorders that are characterized by acquired somatic mutation in hematopoietic progenitors. Recent advances in our understanding of the genetic basis of myeloid malignancies have provided important insights into the pathogenesis of acute myeloid leukemia (AML) and myeloproliferative diseases (MPD) and have led to the development of novel therapeutic approaches. In this review, we describe our current state of understanding of the genetic basis of AML and MPD, with a specific focus on pathogenetic and therapeutic significance. Specific examples discussed include RAS mutations, KIT mutations, FLT3 mutations, and core binding factor rearrangements in AML, and JAK2 mutations in polycythemia vera, essential thrombocytosis, and chronic idiopathic myelofibrosis.     

Impact of residual normal metaphases in core binding factor acute myeloid leukemia

BACKGROUND:

Karyotype allows for stratification of outcomes in acute myeloid leukemia (AML) patients. Previous data suggested that the presence of residual normal cells improved the prognosis in patients with monosomy 7. The Southwest Oncology Group (SWOG) reported the impact of residual normal metaphases in AML patients with monosomal karyotype (MK) and found a similar relationship. We determined the influence of residual normal metaphases in patients with core binding factor (CBF) AML.

METHODS:

The presence and total number of normal and abnormal metaphases were tallied for patients with CBF AML treated in 10 consecutive SWOG trials and used as a variable to determine the effect on complete remission, refractory disease, and overall survival (OS) rates.

RESULTS:

Among 113 CBF AML patients, median age of diagnosis was 45 years (range, 18‐77 years), and median OS was 4 years (CI—2 years—not reached). Patients with inv(16) and no normal metaphases had improved OS compared with those with 1+ normal metaphases (P = .00005), whereas no difference was noted for patients with t(8;21). Multivariate analysis demonstrated that having cells with a normal karyotype had a negative impact on survival (HR, 2.11; 95% CI, 1.09‐4.08; P = .026). This shorter survival was a consequence of a higher rate of refractory disease in older patients (OR, 1.03; 95% CI, 0.9998‐1.06; P = .05) and in those with normal metaphases (HR, 1.26 95% CI, 1.04‐1.51; P = .02).

CONCLUSIONS:

In patients with CBF AML, the presence of cells with normal metaphases and increasing age negatively affect the prognosis, especially in patients with inv(16). Cancer 2012;. © 2011 American Cancer Society.     

Treatment outcome in older patients with childhood acute myeloid leukemia

BACKGROUND.

Older age has historically been an adverse prognostic factor in pediatric acute myeloid leukemia (AML). To the authors' knowledge, the impact of age relative to that of other prognostic factors on the outcome of patients treated in recent trials is unknown.

METHODS.

Clinical outcome and causes of treatment failure of 351 patients enrolled on 3 consecutive protocols for childhood AML between 1991 and 2008 were analyzed according to age and protocol.

RESULTS.

The more recent protocol (AML02) produced improved outcomes for patients aged 10 years to 21 years compared with 2 earlier studies (AML91 and AML97), with 3‐year rates of event‐free survival (EFS), overall survival (OS), and cumulative incidence of refractory leukemia or recurrence (CIR) for this group being similar to those of patients aged birth to 9 years: EFS: 58.3% ± 5.4% versus 66.6% ± 4.9% (P = .20); OS: 68.9% ± 5.1% versus 75.1% ± 4.5% (P = .36); and CIR: 21.9% ± 4.4% versus 25.3% ± 4.2% (P = .59). The EFS and OS estimates for patients aged 10 to 15 years overlapped those for patients aged 16 to 21 years. However, the cumulative incidence of toxic death was significantly higher for patients aged 10 to 21 years compared with younger patients (13.2% ± 3.6% vs 4.5% ± 2.0%; P = .028).

CONCLUSIONS.

The survival rate for older children with AML has improved on the results of a recent trial and is now similar to that of younger patients. However, deaths from toxicity remain a significant problem for patients in the older age group. Future trials should focus on improving supportive care while striving to develop more effective antileukemic therapy. Cancer 2012. © 2012 American Cancer Society.     

Myeloid neoplasms with isolated isochromosome 17q represent a clinicopathologic entity associated with myelodysplastic/myeloproliferative features, a high risk of leukemic transformation, and wild-type TP53

BACKGROUND:

Isolated isochromosome (17q) is a rare cytogenetic abnormality in Philadelphia chromosome‐negative myeloid neoplasms, usually myelodysplastic and/or myeloproliferative neoplasms (MDS/MPN). De novo acute myeloid leukemia (AML) with isochromosome 17q has rarely been reported. The frequency of genetic mutations is unknown.

METHODS:

The authors assessed clinicopathologic, immunophenotypic, and molecular genetic features of 22 myeloid neoplasms with isolated isochromosome 17q.

RESULTS:

Fourteen patients presented as MDS/MPN; 8 as de novo AML. Most presented with leukocytosis, anemia, thrombocytopenia, and splenomegaly. Morphologically, all showed myelodysplastic and myeloproliferative features, including pseudo‐Pelger‐Huet‐like neutrophils, micromegakaryocytic hyperplasia, hypercellularity, fibrosis, and osteosclerosis. Blasts were increased (median, 40% in de novo AML; 9% in MDS/MPN). Immunohistochemical assessment of proliferation and apoptosis rates in AML were similar to a matched group without isochromosome 17q. In most patients, isochromosome 17q occurred at time of blast transformation or disease progression. DNA sequencing revealed no mutation in the uninvolved TP53 allele. Mutational analyses showed rare mutations in NRAS (3 of 10), FLT3 (2 of 16), and JAK2 (1 of 18), and no mutations in NPM1 (0 of 15), KIT (0 of 4), and CEBPA (0 of 4). The median overall survival was 14.5 months for de novo AML, and 11.0 months for MDS/MPN. With a median follow‐up of 8.5 months (range, 1.5‐107 months), 15 died of disease, 6 had persistent disease, and 1 was in remission after bone marrow transplantation.

CONCLUSIONS:

The authors conclude that myeloid neoplasms with isolated isochromosome 17q represent a distinct clinicopathologic entity with myelodysplastic and myeloproliferative features, high risk of leukemic transformation, and wild‐type TP53. Cancer 2011;. © 2011 American Cancer Society.     

Risk of MDM2 SNP309 alone or in combination with the p53 codon 72 polymorphism in acute myeloid leukemia

A single nucleotide polymorphism (SNP) in the promoter of MDM2 gene, SNP309 T > G (a T–G exchange at nucleotide 309 in the first intron), can increase the expression level of MDM2, thereby causing an impairment of p53 tumor suppressor activity. A G–C exchange at p53 codon 72 polymorphism results in a substitution of proline (Pro) for arginine (Arg) in the transactivation domain, which was shown to alter the primary structure of the p53 protein. Both polymorphisms have been implicated in cancer. To investigate whether that MDM2 SNP309 and p53 codon 72 polymorphism should be at least partially responsible for genetic susceptibility to acute myeloid leukemia (AML), both polymorphisms were determined in a case–control study consisting of 231 AML patients and 128 normal individuals. The MDM2 SNP309G allele was associated with increased risk of AML. Furthermore, the p53 codon 72 and MDM2 SNP309 polymorphisms did not associate with age of onset and any other clinical parameters studied. When the p53 and MDM2 polymorphisms were combined, no multiplicative joint effect between the MDM2 GG and p53 Pro/Pro genotypes exists in the risk of developing AML. These results suggest that the MDM2 SNP309 homozygous GG genotype may be a genetic susceptibility factor in the pathogenesis of AML.     

The glutathione S-transferase inhibitor 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol overcomes the MDR1-P-glycoprotein and MRP1-mediated multidrug resistance in acute myeloid leukemia cells

Purpose  There has been an ever growing interest in the search for new anti-tumor compounds that do not interact with MDR1-Pgp and MRP1 drug transporters and so circumvent the effect of these proteins conferring multidrug resistance (MDR) and poor prognosis in AML patients. We have investigated the cytotoxic activity of the strong glutathione S-transferase (GST) inhibitor 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) on AML (HL60) cell lines. Methods  Functional drug efflux studies and cell proliferation assays were performed on both sensitive and MDR AML (HL60) cells after incubation with NBDHEX. Moreover, the mode of cell death (apoptosis vs. necrosis) as well as the correlation between NBDHEX susceptibility and GST activity or Bcl-2 expression was investigated. Results  NBDHEX is not a substrate of either MDR1-Pgp or MRP1 efflux pumps; in fact, it is not only cytotoxic toward the parental HL60 cell line, but also overcomes the MDR phenotype of its HL60/DNR and HL60/ADR variants. Conclusions  The data herein reported show that NBDHEX mediates efficient killing of both MDR1-Pgp and MRP1 over-expressing AML cells. Therefore, this drug can potentially be used as an effective agent for treating MDR in AML patients.     

Stratification of pediatric acute myeloid leukemia through cancer cell gene-expression profiling

Evaluation of: Balgobind BV, Marry M, van den Heuvel-Eibrink MM et al. Evaluation of gene expression signatures predictive for cytogenetic and molecular subtypes of pediatric acute myeloid leukemia. Haematologica 96(2), 221–230 (2010).

Treatment of children^’s acute lymphoblastic leukemia has been at the forefront of conventional chemotherapy development. Despite outstanding results in long-term survival of acute lymphoblastic leukemia, development of therapies for acute myeloid leukemia (AML) have lagged behind. AML in children demonstrate similar long-term survival compared with adults 18–65 years of age: 40–50% overall long-term survival. AML is a heterogeneous disease in both adults and children, but the presence of recurrent chromosome translocations and mutations in children are lower than in adult AML. In particular, patients without chromosome aberrancies have been examined for stratification through examination of gene expression. The paper from Baglobind and coauthors proposes a useful prognostication by gene-expression analysis of 75 gene pairs in 40% of patient cases, accurately discriminating mixed lineage leukemia (MLL) gene rearrangement, t(8;21)(q22;q22), inv(16)(p13q22), t(15;17)(q21;q22) and t(7;12)(q36;p13)-positive AML. Gene-expression analysis of AML has provided an important research tool for uncovering information about AML biology that can be used for the development of novel therapies.     

Hematopoietic stem cell transplantation rates and long-term survival in acute myeloid and lymphoblastic leukemia: real-world population-based data from the Swedish Acute Leukemia Registry 1997-2006

BACKGROUND:

Allogeneic stem cell transplantation (alloSCT) reduces relapse rates in acute leukemia, but outcome is hampered by toxicity. Population‐based data avoid patient selection and may therefore substitute for lack of randomized trials.

METHODS:

We evaluated alloSCT rates within the Swedish Acute Leukemia Registry, including 3899 adult patients diagnosed from 1997 through 2006 with a coverage of 98% and a median follow‐up of 6.2 years.

RESULTS:

AlloSCT rates and survival decreased rapidly with age >55 years. The 8‐year overall survival (OS) was 65% in patients <30 years and 38% in patients <60 years and was similar for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Among 1073 patients <60 years, alloSCT was performed in 42% and 49% of patients with AML and ALL, respectively. Two‐thirds of the alloSCTs were performed in first complete remission, and half used unrelated donors, the same in AML and ALL. Regional differences in management and outcome were found: 60% of AML patients <40 years received alloSCT in all parts of Sweden, but two‐thirds of AML patients 40‐59 years had alloSCT in one region compared with one‐third in other regions (P<.001), with improved 8‐year OS among all AML patients in this age cohort (51% vs 30%; P = .005).

CONCLUSIONS:

More Swedish AML patients received alloSCT, and long‐term survival was better than in recently published large international studies, despite our lack of selection bias. There was no correlation between alloSCT rate and survival in ALL. In adult AML patients <60 years of age, a high alloSCT rate was associated with better long‐term survival, but there was no such correlation in ALL. Cancer 2011;. © 2011 American Cancer Society.     

Treatment of acute myelogenous leukemia in children

Progress in the treatment of childhood AML has not equalled the advances obtained in the management of ALL. Two recent chemotherapy studies (i.e. VAPA and BFM 78), however, reported marked increase in the proportion of long-term remissions. The initial therapy of the cooperative study BFM 78 consisted of two 4-week phases of intensive induction/consolidation with 7 different drugs and cranial irradiation followed by maintenance with thioguanine and cytosine arabinoside for 2 years and additional adriamycin during the first year. A total of 151 children with AML were enrolled in the study from 30 centers. Of these 119 (79%) patients achieved complete remission. After a median observation time of 34 (14-57) months, there have been 46 relapses. CNS was involved in 6 of these relapses. Life table analyses revealed the following probabilities after 4 1/2 years: survival: 46%; disease-free survival: 41% (total group), 52% (remission group); disease-free interval 56% (remission group). The risk of relapse appears to decrease considerably after 2 1/2 years. No risk factors for the occurrence of relapse have been identified.     

New agents in acute myeloid leukemia and other myeloid disorders

Over the past several decades, improvements in chemotherapeutic agents and supportive care have resulted in significant progress in treating patients with acute myeloid leukemia (AML). More recently, advances in understanding the biology of AML have resulted in the identification of new therapeutic targets. The success of all-trans-retinoic acid in acute promyelocytic leukemia and of imatinib mesylate in chronic myeloid leukemia have demonstrated that targeted therapy may be more effective and less toxic when well defined targets are available. At the same time, understanding mechanisms of drug resistance and means to overcome them has led to modification of some of the existing cytotoxic agents. Rational design and conduct of clinical trials is necessary to ensure that the full potential of these new agents is realized.