Acute myeloid leukemia (AML) is a genetically heterogeneous malignancy comprised of various cytogenetic and molecular abnormalities that has notoriously been difficult to treat with an overall poor ...prognosis. For decades, treatment options were limited to either intensive chemotherapy with anthracycline and cytarabine-based regimens (7 + 3) or lower intensity regimens including hypomethylating agents or low dose cytarabine, followed by either allogeneic stem cell transplant or consolidation chemotherapy. Fortunately, with the influx of rapidly evolving molecular technologies and new genetic understanding, the treatment landscape for AML has dramatically changed. Advances in the formulation and delivery of 7 + 3 with liposomal cytarabine and daunorubicin (Vyxeos) have improved overall survival in secondary AML. Increased understanding of the genetic underpinnings of AML has led to targeting actionable mutations such as FLT3, IDH1/2 and TP53, and BCL2 or hedgehog pathways in more frail populations. Antibody drug conjugates have resurfaced in the AML landscape and there have been numerous advances utilizing immunotherapies including immune checkpoint inhibitors, antibody-drug conjugates, bispecific T cell engager antibodies, chimeric antigen receptor (CAR)-T therapy and the development of AML vaccines. While there are dozens of ongoing studies and new drugs in the pipeline, this paper serves as a review of the advances achieved in the treatment of AML in the last several years and the most promising future avenues of advancement
Cytarabine is the backbone of AML therapy, but the dose used during induction has remained controversial. Using an intermediate dose of cytarabine, compared with conventional dose, was shown to ...improve disease-free and overall survival in adult patients in China up to age 55, particularly in patients with intermediate cytogenetic risk.
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Ivosidenib (AG-120) is an oral, targeted agent that suppresses production of the oncometabolite 2-hydroxyglutarate via inhibition of the mutant isocitrate dehydrogenase 1 (IDH1; mIDH1) enzyme. From a ...phase 1 study of 258 patients with IDH1-mutant hematologic malignancies, we report results for 34 patients with newly diagnosed acute myeloid leukemia (AML) ineligible for standard therapy who received 500 mg ivosidenib daily. Median age was 76.5 years, 26 patients (76%) had secondary AML, and 16 (47%) had received ≥1 hypomethylating agent for an antecedent hematologic disorder. The most common all-grade adverse events were diarrhea (n = 18; 53%), fatigue (n = 16; 47%), nausea (n = 13; 38%), and decreased appetite (n = 12; 35%). Differentiation syndrome was reported in 6 patients (18%) (grade ≥3 in 3 9%) and did not require treatment discontinuation. Complete remission (CR) plus CR with partial hematologic recovery (CRh) rate was 42.4% (95% confidence interval CI, 25.5% to 60.8%); CR 30.3% (95% CI, 15.6% to 48.7%). Median durations of CR+CRh and CR were not reached, with 95% CI lower bounds of 4.6 and 4.2 months, respectively; 61.5% and 77.8% of patients remained in remission at 1 year. With median follow-up of 23.5 months (range, 0.6-40.9 months), median overall survival was 12.6 months (95% CI, 4.5-25.7). Of 21 transfusion-dependent patients (63.6%) at baseline, 9 (42.9%) became transfusion independent. IDH1 mutation clearance was seen in 9/14 patients achieving CR+CRh (5/10 CR; 4/4 CRh). Ivosidenib monotherapy was well-tolerated and induced durable remissions and transfusion independence in patients with newly diagnosed AML. This trial was registered at www.clinicaltrials.gov as #NCT02074839.
•In patients with newly diagnosed mIDH1 AML (median age, 76 years), ivosidenib monotherapy achieved median overall survival of 12.6 months.•The CR/CRh rate was 42.4%; mutation clearance in 64% patients with CR/CRh suggests that ivosidenib alters the biology of mIDH1 AML.
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Abstract Acute promyelocytic leukemia (APL) is one of the most exciting stories of modern medicine. Once a disease that was highly lethal, the majority of patients are now cured with the advent of ...molecularly targeted therapy with all- trans retinoic acid (ATRA) and arsenic trioxide (ATO). In many patients, chemotherapy can be omitted completely, particularly in patients with low- or intermediate-risk disease (white blood cell count ≤ 10,000/μl). Recent data show overall survival exceeding 90% with ATRA and ATO-based induction and consolidation strategies. In the uncommon patient in whom relapse does occur, most can still be cured with ATO and autologous hematopoietic cell transplantation. Remaining challenges in APL management include the rapid identification and treatment of newly diagnosed patients to decrease the early death rate, optimizing treatment strategies in high-risk patients (white blood cell count > 10,000/μl), and the role of maintenance therapy in lower risk patients.
Myelofibrosis is characterized by bone marrow fibrosis, atypical megakaryocytes, splenomegaly, constitutional symptoms, thrombotic and hemorrhagic complications, and a risk of evolution to acute ...leukemia. The JAK kinase inhibitor ruxolitinib provides therapeutic benefit, but the effects are limited. The purpose of this study was to determine whether targeting AURKA, which has been shown to increase maturation of atypical megakaryocytes, has potential benefit for patients with myelofibrosis.
Twenty-four patients with myelofibrosis were enrolled in a phase I study at three centers. The objective of the study was to evaluate the safety and preliminary efficacy of alisertib. Correlative studies involved assessment of the effect of alisertib on the megakaryocyte lineage, allele burden, and fibrosis.
In addition to being well tolerated, alisertib reduced splenomegaly and symptom burden in 29% and 32% of patients, respectively, despite not consistently reducing the degree of inflammatory cytokines. Moreover, alisertib normalized megakaryocytes and reduced fibrosis in 5 of 7 patients for whom sequential marrows were available. Alisertib also decreased the mutant allele burden in a subset of patients.
Given the limitations of ruxolitinib, novel therapies are needed for myelofibrosis. In this study, alisertib provided clinical benefit and exhibited the expected on-target effect on the megakaryocyte lineage, resulting in normalization of these cells and reduced fibrosis in the majority of patients for which sequential marrows were available. Thus, AURKA inhibition should be further developed as a therapeutic option in myelofibrosis.
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In preclinical studies, the lysine-specific histone demethylase 1A (LSD1) inhibitor tranylcypromine (TCP) combined with all-trans retinoic acid (ATRA) induces differentiation and impairs survival of ...myeloid blasts in non-acute promyelocytic leukemia acute myeloid leukemia (AML). We conducted a phase I clinical trial (NCT02273102) to evaluate the safety and activity of ATRA plus TCP in patients with relapsed/refractory AML and myelodysplasia (MDS).
Seventeen patients were treated with ATRA and TCP (three dose levels: 10 mg twice daily, 20 mg twice daily, and 30 mg twice daily).
ATRA-TCP had an acceptable safety profile. The MTD of TCP was 20 mg twice daily. Best responses included one morphologic leukemia-free state, one marrow complete remission with hematologic improvement, two stable disease with hematologic improvement, and two stable disease. By intention to treat, the overall response rate was 23.5% and clinical benefit rate was 35.3%. Gene expression profiling of patient blasts showed that responding patients had a more quiescent CD34
cell phenotype at baseline, including decreased
and
expression, compared with nonresponders that exhibited a more proliferative CD34
phenotype, with gene expression enrichment for cell growth signaling. Upon ATRA-TCP treatment, we observed significant induction of retinoic acid-target genes in responders but not nonresponders. We corroborated this in AML cell lines, showing that ATRA-TCP synergistically increased differentiation capacity and cell death by regulating the expression of key gene sets that segregate patients by their clinical response.
These data indicate that LSD1 inhibition sensitizes AML cells to ATRA and may restore ATRA responsiveness in subsets of patients with MDS and AML.
Isocitrate dehydrogenase (IDH) 1 and 2 mutations result in overproduction of D-2-hydroxyglutarate (2-HG) and impaired cellular differentiation. Ivosidenib, a targeted mutant IDH1 (mIDH1) enzyme ...inhibitor, can restore normal differentiation and results in clinical responses in a subset of patients with mIDH1 relapsed/refractory (R/R) acute myeloid leukemia (AML). We explored mechanisms of ivosidenib resistance in 174 patients with confirmed mIDH1 R/R AML from a phase 1 trial. Receptor tyrosine kinase (RTK) pathway mutations were associated with primary resistance to ivosidenib. Multiple mechanisms contributed to acquired resistance, particularly outgrowth of RTK pathway mutations and 2-HG–restoring mutations (second-site IDH1 mutations, IDH2 mutations). Observation of multiple concurrent mechanisms in individual patients underscores the complex biology of resistance and has important implications for rational combination therapy design. This trial was registered at www.clinicaltrials.gov as #NCT02074839
•Baseline mutations are associated with response (JAK2) or resistance (NRAS, PTPN11) to ivosidenib monotherapy in mIDH1 R/R AML.•2-HG restoration via novel IDH1 second-site and IDH2 mutations, and non-IDH–related pathways, are identified at relapse.
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Rearrangements involving the neurotrophic receptor kinase genes (NTRK1, NTRK2, and NTRK3; hereafter referred to as TRK) produce oncogenic fusions in a wide variety of cancers in adults and children. ...Although TRK fusions occur in fewer than 1% of all solid tumors, inhibition of TRK results in profound therapeutic responses, resulting in Breakthrough Therapy FDA approval of the TRK inhibitor larotrectinib for adult and pediatric patients with solid tumors, regardless of histology. In contrast to solid tumors, the frequency of TRK fusions and the clinical effects of targeting TRK in hematologic malignancies are unknown. Here, through an evaluation for TRK fusions across more than 7,000 patients with hematologic malignancies, we identified TRK fusions in acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), histiocytosis, multiple myeloma, and dendritic cell neoplasms. Although TRK fusions occurred in only 0.1% of patients (8 of 7,311 patients), they conferred responsiveness to TRK inhibition in vitro and in vivo in a patient-derived xenograft and a corresponding AML patient with ETV6-NTRK2 fusion. These data identify that despite their individual rarity, collectively, TRK fusions are present in a wide variety of hematologic malignancies and predict clinically significant therapeutic responses to TRK inhibition.
Process‐based models are becoming increasingly used tools for understanding how species are likely to respond to environmental changes and to potential management options. RangeShifter is one such ...modelling platform, which has been used to address a range of questions including identifying effective reintroduction strategies, understanding patterns of range expansion and assessing population viability of species across complex landscapes. Here we introduce a new version, RangeShifter 2.0, which incorporates important new functionality. It is now possible to simulate dynamics over user‐specified, temporally changing landscapes. Additionally, we integrated a new genetic module, notably introducing an explicit genetic modelling architecture, which allows for simulation of neutral and adaptive genetic processes. Furthermore, emigration, transfer and settlement traits can now all evolve, allowing for sophisticated simulation of the evolution of dispersal. We illustrate the potential application of RangeShifter 2.0's new functionality by two examples. The first illustrates the range expansion of a virtual species across a dynamically changing UK landscape. The second demonstrates how the software can be used to explore the concept of evolving connectivity in response to land‐use modification, by examining how movement rules come under selection over landscapes of different structure and composition. RangeShifter 2.0 is built using object‐oriented C++ providing computationally efficient simulation of complex individual‐based, eco‐evolutionary models. The code has been redeveloped to enable use across operating systems, including on high performance computing clusters, and the Windows graphical user interface has been enhanced. RangeShifter 2.0 will facilitate the development of in‐silico assessments of how species will respond to environmental changes and to potential management options for conserving or controlling them. By making the code available open source, we hope to inspire further collaborations and extensions by the ecological community.
Highlights • KB004 is a novel anti-ephrin novel monoclonal antibody targeting EphA3. • KB004 was safe and relatively well-tolerated in patients with myeloid neoplasms. • Manageable infusion reactions ...were dose limiting. • There was clinical activity in patients with fibrotic MDS and myelofibrosis.
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