Evolution of Therapy for Older Patients With Acute Myeloid Leukemia: How Should We Use Currently Available Agents?
Most patients with newly diagnosed acute myeloid leukemia (AML) are 65 years or older. The treatment of AML in older patients has been characterized by distinct patient- and disease-related challenges that have impeded the meaningful progress that has been observed in younger patients with AML. Higher rates of comorbidities and frailty contribute to higher rates of treatment-related complications, whereas adverse disease features such as poor-risk genomics and secondary AML are associated with therapeutic resistance and shortened survival. Intensive chemotherapy and allogeneic stem cell transplant, although still considere...
Source: The Cancer Journal - January 1, 2022 Category: Cancer & Oncology Tags: Review Articles Source Type: research
Menin Inhibitors in Acute Myeloid Leukemia—What Does the Future Hold?
Menin inhibitors constitute a novel class of agents targeting the underlying biology of nucleophosmin (NPM1) mutant and KMT2A (formerly known as MLL1) rearranged (KMT2Ar) acute leukemias. KMT2Ar acute leukemias constitute 5% to 10% of acute leukemias, and NPM1 mutations are identified in 30% of newly diagnosed acute myeloid leukemias (AMLs). In preclinical AML models, small molecule inhibitors of the menin-KMT2A protein-protein interaction induce differentiation, downregulate critical gene expression programs, and confer a survival advantage in patient-derived xenograft models of NPM1 mutant and KMT2Ar AML. Multiple clinic...
Source: The Cancer Journal - January 1, 2022 Category: Cancer & Oncology Tags: Review Articles Source Type: research
What Are the Prospects for Treating TP53 Mutated Myelodysplastic Syndromes and Acute Myeloid Leukemia?
TP53 is a key tumor suppressor gene involved in fundamental biological processes of genomic stability and is recurrently mutated in a subgroup of myelodysplastic syndromes and acute myeloid leukemia. These patients have unique clinical and molecular features resulting in dismal outcomes despite standard cytotoxic chemotherapy, and long-term survival is seldom achieved with allogeneic stem cell transplant. Upfront use of hypomethylating agents with or without venetoclax has resulted in a favorable initial response over intensive cytotoxic chemotherapy, albeit responses are nondurable, and the median overall survival is typi...
Source: The Cancer Journal - January 1, 2022 Category: Cancer & Oncology Tags: Review Articles Source Type: research
Checkpoint Inhibitors and Other Immune-Based Therapies in Acute Myeloid Leukemia
Immune checkpoint inhibitors have been investigated in acute myeloid leukemia (AML) with an intent to harness the immune microenvironment components to generate an immune response against leukemia. Anti–cytotoxic T-lymphocyte–associated antigen 4 and anti–programmed cell death 1/programmed cell death ligand 1 antibodies have been evaluated in combination with low-intensity therapy and cytotoxic chemotherapy, both in the pretransplant and posttransplant settings. Although the objective response rates with programmed cell death 1– and programmed cell death ligand 1–based therapies have been relatively low, durable ...
Source: The Cancer Journal - January 1, 2022 Category: Cancer & Oncology Tags: Review Articles Source Type: research
Monoclonal Antibodies in Acute Myeloid Leukemia—Are We There Yet?
This article provides an overview of the progress made in targeted immunotherapy in AML, particularly focusing on unconjugated and conjugated mAbs. (Source: The Cancer Journal)
Source: The Cancer Journal - January 1, 2022 Category: Cancer & Oncology Tags: Review Articles Source Type: research
The Evolution of Research and Therapy With Hypomethylating Agents in Acute Myeloid Leukemia and Myelodysplastic Syndrome: New Directions for Old Drugs
Azacitidine and decitabine are cytosine analogs that function as DNA methyltransferase inhibitors. These agents, commonly referred to as “hypomethylating agents,” are widely used for the treatment of myelodysplastic syndrome and acute myeloid leukemia (AML). In this review, we discuss the clinical development of these drugs, including the early studies that led to the optimization of their doses and schedules, and the pivotal studies that led to their regulatory approval, both as monotherapy and in combination with venetoclax for older adults with AML who are unfit for intensive chemotherapy. We also review the more re...
Source: The Cancer Journal - January 1, 2022 Category: Cancer & Oncology Tags: Review Articles Source Type: research
Combining Isocitrate Dehydrogenase Inhibitors With Existing Regimens in Acute Myeloid Leukemia: An Evolving Treatment Landscape
Identification of recurrent mutations in isocitrate dehydrogenase genes (IDH1 and IDH2) in patients with acute myeloid leukemia (AML) coupled with an understanding of the pathologic role these mutant IDH isoforms impart in leukemogenesis resulted in the development of IDH1 and IDH2 inhibitors comprising a novel, molecularly defined class of targeted therapies for the treatment of AML. This review herein describes the unique cellular pathophysiology and vulnerabilities in IDH-mutated AML; the clinical development, efficacy, and known resistance mechanisms to first-generation IDH inhibitors; summarizes the literature surroun...
Source: The Cancer Journal - January 1, 2022 Category: Cancer & Oncology Tags: Review Articles Source Type: research
Incorporation of FLT3 Inhibitors Into the Treatment Regimens for FLT3 Mutated Acute Myeloid Leukemia: The Case for Total Therapy
Therapeutic outcomes for acute myeloid leukemia patients with Fms-like tyrosine kinase 3 (FLT3) mutations have improved substantially since the discovery of small molecule tyrosine kinase inhibitors. Today, use of FLT3 inhibitors is standard in frontline intensive chemotherapy as well as patients with relapsed or refractory acute myeloid leukemia and FLT3 mutations and increasingly used as for prolonged remission maintenance posttransplant and/or postconsolidation. Yet, FLT3 inhibitors alone are not curative, and best outcomes are seen when the drugs are used as part of combination regimens. Optimizing therapy for patients...
Source: The Cancer Journal - January 1, 2022 Category: Cancer & Oncology Tags: Review Articles Source Type: research
How We Incorporate Venetoclax in Treatment Regimens for Acute Myeloid Leukemia
Venetoclax has transformed the therapeutic landscape of acute myeloid leukemia (AML). Hypomethylating agents with venetoclax (HMA-VEN) have significantly improved outcomes and have become the standard therapy for older/unfit patients with newly diagnosed AML and are comparable to intensive chemotherapy in salvage setting. Venetoclax with intensive chemotherapy have shown high response rates in both frontline and salvage setting in younger patients, and triplet combinations with HMA-VEN and FLT3 inhibitors have shown encouraging results in FLT3mut AML. While patients with NPM1mut, IDH1/2mut experience favorable outcomes, th...
Source: The Cancer Journal - January 1, 2022 Category: Cancer & Oncology Tags: Review Articles Source Type: research
Are We Witnessing a Paradigm Shift in the Treatment of Acute Myeloid Leukemia?
No abstract available (Source: The Cancer Journal)
Source: The Cancer Journal - January 1, 2022 Category: Cancer & Oncology Tags: Introduction From the Guest Editor Source Type: research
Development of Next-Generation Poly(ADP-Ribose) Polymerase 1–Selective Inhibitors
Poly(ADP-ribose) polymerase (PARP) inhibitors have transformed the therapeutic landscape for advanced ovarian cancer and expanded treatment options for other tumor types, including breast, pancreas, and prostate cancer. Yet, despite the success of PARP inhibitors in our current therapeutic armamentarium, not all patients benefit because of primary resistance, whereas different acquired resistance mechanisms can lead to disease progression on therapy. In addition, the toxicity profile of PARP inhibitors, primarily myelosuppression, has led to adverse events in a proportion of patients as monotherapy, and has limited the use...
Source: The Cancer Journal - November 1, 2021 Category: Cancer & Oncology Tags: Review Articles Source Type: research
With Our Powers Combined: Exploring PARP Inhibitors and Immunotherapy
The use of poly(ADP-ribose) polymerase inhibitors and immune checkpoint inhibitor therapies has seen substantial clinical success in oncology therapeutic development. Although multiple agents within these classes have achieved regulatory approval globally—in several malignancies in early and advanced stages—drug resistance remains an issue. Building on preclinical evidence, several early trials and late-phase studies are underway. This review explores the therapeutic potential of combination poly(ADP-ribose) polymerase inhibitors and immune checkpoint inhibitor therapy in solid tumors, including the scientific and ther...
Source: The Cancer Journal - November 1, 2021 Category: Cancer & Oncology Tags: Review Articles Source Type: research
Poly(ADP-Ribose) Polymerase Inhibitor Combination Therapy
The introduction of poly(ADP-ribose) polymerase (PARP) inhibitors has led to significant improvements in outcome for several cancer types, most notably high-grade serous ovarian cancer. However, in general, benefit is restricted to tumors characterized by either BRCA1/2 mutation or homologous recombination deficiency. Combination therapy offers the potential to overcome innate and acquired PARP inhibitor resistance by either working synergistically with PARP inhibitors or by targeting the homologous recombination repair pathway through an alternate strategy, to restore homologous recombination deficiency. Several biologica...
Source: The Cancer Journal - November 1, 2021 Category: Cancer & Oncology Tags: Review Articles Source Type: research
DNA Damage Repair Inhibitors—Combination Therapies
DNA damage response and repair (DDR) is responsible for ensuring genomic integrity. It is composed of intricate, complex pathways that detect various DNA insults and then activate pathways to restore DNA fidelity. Mutations in this network are implicated in many malignancies but can also be exploited for cancer therapies. The advent of inhibitors of poly(ADP-ribose) polymerase has led to the investigation of other DDR inhibitors and combinations to address high unmet needs in cancer therapeutics. Specifically, regimens, often in combination with chemotherapy, radiation, or other DDR inhibitors, are being investigated. This...
Source: The Cancer Journal - November 1, 2021 Category: Cancer & Oncology Tags: Review Articles Source Type: research
The Clinical Challenges, Trials, and Errors of Combatting Poly(ADP-Ribose) Polymerase Inhibitors Resistance
The use of poly(ADP-ribose) polymerase inhibitor (PARPi) exploits synthetic lethality in solid tumors with homologous recombination repair (HRR) defects. Significant clinical benefit has been established in breast and ovarian cancers harboring BRCA1/2 mutations, as well as tumors harboring characteristics of “BRCAness.” However, the durability of treatment responses is limited, and emerging data have demonstrated the clinical challenge of PARPi resistance. With the expanding use of PARPi, the significance of PARP therapy in patients pretreated with PARPi remains in need of significant further investigation. Molecular m...
Source: The Cancer Journal - November 1, 2021 Category: Cancer & Oncology Tags: Review Articles Source Type: research
