Recent years have seen tremendous advances in treating acute myeloid leukemia (AML), largely because of progress in understanding the genetic basis of the disease. The US Food and Drug Administration ...approved 7 agents for AML in the last 2 years: the first new drugs in decades. In this review, the authors discuss these new approvals in the backdrop of an overall strategy for treating AML today. Treating AML in the modern era requires: 1) access to and use of upfront genetic and cytogenetic testing, not only to describe prognosis but also to help identify the best available therapy; 2) effectively working new therapies into a conventional backbone of treatment, including transplantation; and 3) continued commitment to clinical trials designed to capitalize on advances in genetics and immunology to foster the next wave of drug approvals.
Novel drugs for acute myeloid leukemia (AML) improve outcomes for patients and should be carefully incorporated into an overall treatment plan. Critical to the development of successful future treatments for AML will be an increased understanding of the clonal architecture and biology of the disease, the development of additional molecularly targeted agents, and advances in immunology, cell therapy, and transplantation.
Patients with blastic plasmacytoid dendritic-cell neoplasm, an aggressive hematologic cancer, were treated with the cytotoxin tagraxofusp in a dose-escalation case series. Previously untreated ...patients had a 72% complete response rate, and 45% underwent stem-cell transplantation. Toxic effects included hepatic dysfunction, thrombocytopenia, and capillary leak syndrome.
Chromosome maintenance protein 1 (CRM1) is a nuclear export receptor involved in the active transport of tumor suppressors (eg, p53 and nucleophosmin) whose function is altered in cancer because of ...increased expression and overactive transport. Blocking CRM1-mediated nuclear export of such proteins is a novel therapeutic strategy to restore tumor suppressor function. Orally bioavailable selective inhibitors of nuclear export (SINE) that irreversibly bind to CRM1 and block the function of this protein have been recently developed. Here we investigated the antileukemic activity of KPT-SINE (KPT-185 and KPT-276) in vitro and in vivo in acute myeloid leukemia (AML). KPT-185 displayed potent antiproliferative properties at submicromolar concentrations (IC50 values; 100-500nM), induced apoptosis (average 5-fold increase), cell-cycle arrest, and myeloid differentiation in AML cell lines and patient blasts. A strong down-regulation of the oncogene FLT3 after KPT treatment in both FLT3-ITD and wild-type cell lines was observed. Finally, using the FLT3-ITD–positive MV4-11 xenograft murine model, we show that treatment of mice with oral KPT-276 (analog of KPT-185 for in vivo studies) significantly prolongs survival of leukemic mice (P < .01). In summary, KPT-SINE are highly potent in vitro and in vivo in AML. The preclinical results reported here support clinical trials of KPT-SINE in AML.
Long noncoding RNAs (lncRNAs) are transcripts longer than 200 nucleotides, located within the intergenic stretches or overlapping antisense transcripts of protein coding genes. LncRNAs are involved ...in numerous biological roles including imprinting, epigenetic regulation, apoptosis, and cell cycle. To determine whether lncRNAs are associated with clinical features and recurrent mutations in older patients (aged ≥60 y) with cytogenetically normal (CN) acute myeloid leukemia (AML), we evaluated lncRNA expression in 148 untreated older CN-AML cases using a custom microarray platform. An independent set of 71 untreated older patients with CN-AML was used to validate the outcome scores using RNA sequencing. Distinctive lncRNA profiles were found associated with selected mutations, such as internal tandem duplications in the FLT3 gene ( FLT3 -ITD) and mutations in the NPM1 , CEBPA , IDH2 , ASXL1 , and RUNX1 genes. Using the lncRNAs most associated with event-free survival in a training cohort of 148 older patients with CN-AML, we derived a lncRNA score composed of 48 lncRNAs. Patients with an unfavorable compared with favorable lncRNA score had a lower complete response (CR) rate P < 0.001, odds ratio = 0.14, 54% vs. 89%, shorter disease-free survival (DFS) P < 0.001, hazard ratio (HR) = 2.88 and overall survival (OS) ( P < 0.001, HR = 2.95). The validation set analyses confirmed these results (CR, P = 0.03; DFS, P = 0.009; OS, P = 0.009). Multivariable analyses for CR, DFS, and OS identified the lncRNA score as an independent marker for outcome. In conclusion, lncRNA expression in AML is closely associated with recurrent mutations. A small subset of lncRNAs is correlated strongly with treatment response and survival.
Significance Long noncoding RNAs (lncRNAs) are involved in numerous biological roles including epigenetic regulation, apoptosis, and cell cycle. Whereas lncRNAs contribute to epigenetic gene regulation, metastasis, and prognosis in solid tumors, their role in acute myeloid leukemia (AML) has not been hitherto reported. Here, we show that lncRNA expression profiles are associated with recurrent mutations, clinical features, and outcome in AML. A fraction of these lncRNAs may have a functional role in leukemogenesis. Furthermore, lncRNAs could be used as biomarkers for outcome in AML. The identification of patients likely to achieve complete remission with standard therapy alone, based on lncRNA expression, is a significant advance potentially sparing such patients from other toxicities and focusing investigational approaches on postremission studies.
Abstract The question posed above assumes that we are going nowhere in therapies for myelodysplastic syndromes (MDS) and asks, why? Yet, in recent years novel and effective therapies for MDS indeed ...have begun to emerge, particularly in patients with lower-risk disease. Beyond this, however, most of the progress has been limited to advances in allogeneic transplantation for higher-risk patients. This discussion will focus first on areas where we have moved beyond “stagnation,” including these advances in supportive care for lower-risk patients and in emerging transplant gains. Further, in areas that have not seen the same encouraging advances, suggestions are made on how to move the field forward. The promise for the future lies in finding more creative ways to partner molecular genetics, novel drugs, and novel clinical trial designs.
Spleen tyrosine kinase (SYK) signaling is a proposed target in acute myeloid leukemia (AML). Sensitivity to SYK inhibition has been linked to
and
overexpression in preclinical studies. This trial ...evaluated the safety and efficacy of entospletinib, a selective inhibitor of SYK, in combination with chemotherapy in untreated AML.
This was an international multicenter phase Ib/II study, entospletinib dose escalation (standard 3+3 design between 200 and 400 mg twice daily) + 7+3 (cytarabine + daunorubicin) in phase Ib and entospletinib dose expansion (400 mg twice daily) + 7+3 in phase II.
Fifty-three patients (
= 12, phase Ib and
= 41, phase II) with previously untreated
(
= 39) or secondary (
= 14) AML were enrolled (58% male; median age, 60 years) in this study. The composite complete response with entospletinib + 7+3 was 70%. Patients with baseline
and
expression higher than the median had improved overall survival compared with patients with below median
and
expression. Common adverse events were cytopenias, febrile neutropenia, and infection. There were no dose-limiting toxicities. Entospletinib-related skin rash and hyperbilirubinemia were also observed.
Entospletinib with intensive chemotherapy was well-tolerated in patients with AML. Improved survival was observed in patients with
overexpression, contrasting published data demonstrating poor survival in such patients. A randomized study will be necessary to determine whether entospletinib was a mediator this observation.
Allogeneic stem cell transplantation is the standard approach to Philadelphia chromosome positive acute lymphoblastic leukemia. We hypothesized that imatinib plus sequential chemotherapy will result ...in significant leukemia cell cytoreduction in patients with Philadelphia chromosome positive acute lymphoblastic leukemia, allowing collection of normal hematopoietic stem cells uncontaminated by residual BCR/ABL1(+) lymphoblasts and thus reduce the likelihood of relapse after autologous stem cell transplantation for patients under 60 years of age without sibling donors. We enrolled 58 patients; 19 underwent autologous and 15 underwent allogeneic stem cell transplantation on study. Imatinib plus sequential chemotherapy resulted in reverse-transcriptase polymerase chain reaction-negative stem cells in 9 patients and remained minimally positive in 4 (6 were not evaluable). Overall survival (median 6.0 years vs. not reached) and disease-free survival (median 3.5 vs. 4.1 years) were similar between those who underwent autologous and those who underwent allogeneic stem cell transplantation. We conclude that autologous stem cell transplantation represents a safe and effective alternative for allogeneic stem cell transplantation in Philadelphia chromosome positive acute lymphoblastic leukemia patients without sibling donors (clinicaltrials.gov identifier:00039377).
Advances in the treatment of myelodysplastic syndromes (MDSs) over the last decade have given patients and their hematologists a multitude of treatment options. Therapeutic options now exist that ...reduce disease-related symptoms, improve quality of life, and alter the natural history of the disease. Three drugs are now specifically Food and Drug Administration-approved for treatment of MDS: (1) azacitidine, (2) decitabine, and (3) lenalidomide. Clinical results with each of these agents, plus results with immunosuppressive therapy, are reviewed to guide clinical decision making. Although each therapy has made a substantial impact in improving the care of patients with MDS, unfortunately MDS treatment in 2010 ultimately fails in most patients, but these therapies provide a foundation on which we can build to further improve outcomes.
Aberrant DNA hypermethylation contributes to myeloid leukemogenesis by silencing structurally normal genes involved in hematopoiesis. MicroRNAs (miRNAs) are noncoding RNAs that regulate gene ...expression by targeting protein-coding mRNAs. Recently, miRNAs have been shown to play a role as both targets and effectors in gene hypermethylation and silencing in malignant cells. In the current study, we showed that enforced expression of miR-29b in acute myeloid leukemia cells resulted in marked reduction of the expression of DNA methyltransferases DNMT1, DNMT3A, and DNMT3B at both RNA and protein levels. This in turn led to decrease in global DNA methylation and reexpression of p15INK4b and ESR1 via promoter DNA hypomethylation. Although down-regulation of DNMT3A and DNMT3B was the result of a direct interaction of miR-29b with the 3′ untranslated regions of these genes, no predicted miR-29b interaction sites were found in the DNMT1 3′ untranslated regions. Further experiments revealed that miR-29b down-regulates DNMT1 indirectly by targeting Sp1, a transactivator of the DNMT1 gene. Altogether, these data provide novel functional links between miRNAs and aberrant DNA hypermethylation in acute myeloid leukemia and suggest a potentially therapeutic use of synthetic miR-29b oligonucleotides as effective hypomethylating compounds.
Recently, the European LeukemiaNet (ELN) revised its genetic-risk classification of acute myeloid leukemia (AML). We categorized 1637 adults with AML treated with cytarabine/anthracycline regimens ...according to the 2022 and 2017 ELN classifications. Compared with the 2017 ELN classification, 2022 favorable group decreased from 40% to 35% and adverse group increased from 37% to 41% of patients. The 2022 genetic-risk groups seemed to accurately reflect treatment outcomes in all patients and patients aged <60 years, but in patients aged ≥60 years, relapse rates, disease-free (DFS) and overall (OS) survival were not significantly different between intermediate and adverse groups. In younger African-American patients, DFS and OS did not differ between intermediate-risk and adverse-risk patients nor did DFS between favorable and intermediate groups. In Hispanic patients, DFS and OS did not differ between favorable and intermediate groups. Outcome prediction abilities of 2022 and 2017 ELN classifications were similar. Among favorable-risk patients, myelodysplasia-related mutations did not affect patients with CEBPA
mutations or core-binding factor AML, but changed risk assignment of NPM1-mutated/FLT3-ITD-negative patients to intermediate. NPM1-mutated patients with adverse-risk cytogenetic abnormalities were closer prognostically to the intermediate than adverse group. Our analyses both confirm and challenge prognostic significance of some of the newly added markers.
PDF
