Progress in the understanding of the biology and therapy of acute myeloid leukemia (AML) is occurring rapidly. Since 2017, nine agents have been approved for various indications in AML. These ...included several targeted therapies like venetoclax, FLT3 inhibitors, IDH inhibitors, and others. The management of AML is complicated, highlighting the need for expertise in order to deliver optimal therapy and achieve optimal outcomes. The multiple subentities in AML require very different therapies. In this review, we summarize the important pathophysiologies driving AML, review current therapies in standard practice, and address present and future research directions.
Background
Several important treatment and supportive care strategies have been implemented over the past 4 decades in the management of acute myeloid leukemia (AML).
Methods
The authors identified ...29,107 patients who were diagnosed with de novo AML between 1980 and 2017 in the National Cancer Institute's Surveillance, Epidemiology, and End Results database. Patients were categorized into 5 age groups (ages birth to 14, 15‐39, 40‐59, 60‐69, and ≥70 years) and 4 calendar periods (1980‐1989, 1990‐1999, 2000‐2009, and 2010‐2017). The outcomes of patients who had AML within these categories were analyzed.
Results
The overall 5‐year survival rates in patients with AML were 9%, 15%, 22%, and 28% in the decades 1980 to 1989, 1990 to 1999, 2000 to 2009, and 2010 to 2017, respectively. Among patients aged 15 to 39 years, the 5‐year survival rates were 24%, 41%, 52%, and 63%, respectively; among those aged ≥70 years, the 5‐year survival rates were 1%, 2%, 3%, and 5%, respectively. Four‐week mortality was surprising high among adults and older patients (range, 20%‐45%), even in modern times. Overall, survival continued to improve over the calendar periods and was best in the period from 2010 to 2017. Survival improvement was noticeable across all age groups except patients aged ≥70 years, in whom the estimated 5‐year survival rate remained 5% even during the period from 2010 to 2017.
Conclusions
The outcomes of patients with AML showed incremental improvement over time in a population‐based study of the Surveillance, Epidemiology, and End Results data. The introduction since 2017 of targeted therapies among older patients and optimizations in supportive care hopefully will continue to improve outcomes in AML, particularly among older patients.
The outcome of patients with acute myeloid leukemia demonstrates incremental improvement over time in a population‐based study of the National Cancer Institute's Surveillance, Epidemiology, and End Results data. For older patients with acute myeloid leukemia, the introduction since 2017 of targeted therapies and optimizations in supportive care hopefully will continue to improve outcomes.
The last decade has seen a steadfast progression in drug development in acute myeloid leukemia (AML) which have moved progressively towards genomics-based therapy. With these advancements, outcomes ...in AML have improved but remains far from satisfactory. An approach towards preventing relapse in AML is the use of a maintenance therapy in patients, after attaining remission. Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective post-remission therapy that has been proven to reduce the risk of relapse. However, in patients who are ineligible for HSCT or have a high risk of relapse, other effective measures to prevent relapse are needed. There also exists a need for post HSCT maintenance to reduce relapse in high-risk subsets. Over the last 3 decades maintenance therapy in AML has evolved from the use of chemotherapeutic agents to more targeted therapies and better modulation of the immune system. Unfortunately, improvement in survival outcomes from these agents have not been consistently demonstrated in clinical trials. To derive the optimum benefit from maintenance therapy the time points of therapy initiation need to be defined and therapy selection must be precise with respect to the AML genetics and risk stratification, prior treatment exposure, transplant eligibility, expected toxicity and patient's clinical profile and desires. The far-reaching goal is to facilitate patients with AML in remission to achieve a normal quality of life while improving remission duration and overall survival. The QUAZAR trial was a welcome step towards a safe maintenance drug with ease of administration and showed survival benefit but leaves many open issues for discussion. In this review we will discuss these issues, highlighting the development of AML maintenance therapies over the last 3 decades.
The unraveling of the pathophysiology of acute myeloid leukemia (AML) has resulted in rapid translation of the information into clinical practice. After more than 40 years of slow progress in AML ...research, the US Food and Drug Administration has approved nine agents for different AML treatment indications since 2017. In this review, we detail the progress that has been made in the research and treatment of AML, citing key publications related to AML research and therapy in the English literature since 2000. The notable subsets of AML include acute promyelocytic leukemia (APL), core‐binding factor AML (CBF‐AML), AML in younger patients fit for intensive chemotherapy, and AML in older/unfit patients (usually at the age cutoff of 60‐70 years). We also consider within each subset whether the AML is primary or secondary (therapy‐related, evolving from untreated or treated myelodysplastic syndrome or myeloproliferative neoplasm). In APL, therapy with all‐trans retinoic acid and arsenic trioxide results in estimated 10‐year survival rates of ≥80%. Treatment of CBF‐AML with fludarabine, high‐dose cytarabine, and gemtuzumab ozogamicin (GO) results in estimated 10‐year survival rates of ≥75%. In younger/fit patients, the “3+7” regimen (3 days of daunorubicin + 7 days of cytarabine) produces less favorable results (estimated 5‐year survival rates of 35%; worse in real‐world experience); regimens that incorporate high‐dose cytarabine, adenosine nucleoside analogs, and GO are producing better results. Adding venetoclax, FLT3, and IDH inhibitors into these regimens has resulted in encouraging preliminary data. In older/unfit patients, low‐intensity therapy with hypomethylating agents (HMAs) and venetoclax is now the new standard of care. Better low‐intensity regimens incorporating cladribine, low‐dose cytarabine, and other targeted therapies (FLT3 and IDH inhibitors) are emerging. Maintenance therapy now has a definite role in the treatment of AML, and oral HMAs with potential treatment benefits are also available. In conclusion, AML therapy is evolving rapidly and treatment results are improving in all AML subsets as novel agents and strategies are incorporated into traditional AML chemotherapy.
LAY SUMMARY
Ongoing research in acute myeloid leukemia (AML) is progressing rapidly.
Since 2017, the US Food and Drug Administration has approved 10 drugs for different AML indications.
This review updates the research and treatment pathways for AML.
Progress in our understanding of acute myeloid leukemia is occurring rapidly. This review updates the research and treatment pathways for this disease.
Curative treatment in acute myeloid leukemia (AML) depends on successful induction therapy to achieve a complete remission (CR), and subsequent post‐remission therapy to prevent relapse. High relapse ...rates after consolidation therapy and after allogeneic stem cell transplant contribute to suboptimal outcomes in AML patients, and continue to represent a difficult challenge. Effective maintenance therapy could play an important role in prolonging the remission interval in the post‐consolidation setting, especially in high risk AML patients. Maintenance treatment approaches based on conventional chemotherapy, immunotherapy, hypomethylating agents, and targeted small molecules have been explored in this setting, but no data so far have been convincing enough to establish this approach as the standard of care. However, ongoing and future studies including novel targeted therapies may demonstrate promising efficacy that could facilitate incorporation of maintenance therapy into clinical practice. In this review we summarize previous and ongoing approaches of maintenance therapy in AML and discuss the most promising strategies.
Background
TP53 mutation (TP53mut) confers an adverse prognosis in acute myeloid leukemia (AML). Venetoclax with hypomethylating agents is a current standard for older patients; however, recent ...reports suggest that TP53mut confers resistance to venetoclax. The authors investigated the outcomes of patients with TP53mut AML who were treated with a 10‐day decitabine and venetoclax (DEC10‐VEN) (ClinicalTrials.gov identifier NCT03404193).
Methods
Patients with newly diagnosed AML received decitabine 20 mg/m2 for 10 days every 4 to 6 weeks for induction, followed by decitabine for 5 days after response. The venetoclax dose was 400 mg daily. TP53mut was identified in bone marrow samples using next‐generation sequencing, with sensitivity of 5%. Outcomes were analyzed according to European LeukemiaNet 2017 guidelines.
Results
Among 118 patients (median age, 72 years; age range, 49‐89 years), 63 (53%) had secondary AML, 39 (33%) had AML with complex karyotype, and 35 (30%) had TP53mut AML. The median TP53 variant allele frequency was 32% (interquartile range, 16%‐65%), 8 patients (23%) had only a single TP53 mutation, 15 (43%) had multiple mutations, and 12 (34%) had mutation and deletion. Outcomes were significantly worse in patients who had TP53mut AML compared with those who had wild‐type TP53 AML, with an overall response rate of 66% vs 89% (P = .002), a complete response/complete response with incomplete hematologic recovery rate of 57% vs 77% (P = .029), and a 60‐day mortality of 26% vs 4% (P < .001), respectively. Patients with TP53mut versus wild‐type TP53 had shorter overall survival at 5.2 versus 19.4 months, respectively (hazard ratio, 4.67; 95% CI, 2.44‐8.93; P < .0001), and shorter relapse‐free survival at 3.4 versus 18.9 months (hazard ratio, 4.80; 95% CI, 1.97‐11.69; P < .0001), respectively. Outcomes with DEC10‐VEN in patients with TP53mut AML were comparable to historical results with 10‐day decitabine alone.
Conclusions
Patients with TP53mut AML have lower response rates and shorter survival with DEC10‐VEN.
Acute myeloid leukemia(AML) with TP53 mutations continues to be a therapeutic challenge and has been implicated as a resistance mechanism to venetoclax. Post‐hoc analysis of a prospective clinical trial of decitabine and venetoclax shows significantly lower response rate, overall survival, and relapse‐free survival in patients with TP53‐mutated compared with wild‐type AML.
TP53-mutated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) form a distinct group of myeloid disorders with dismal outcomes. TP53-mutated MDS and AML have lower response rates to ...either induction chemotherapy, hypomethylating agent-based regimens, or venetoclax-based therapies compared with non-TP53-mutated counterparts and a poor median overall survival of 5 to 10 months. Recent advances have identified novel pathogenic mechanisms in TP53-mutated myeloid malignancies, which have the potential to improve treatment strategies in this distinct clinical subgroup. In this review, we discuss recent insights into the biology of TP53-mutated MDS/AML, current treatments, and emerging therapies, including immunotherapeutic and nonimmune-based approaches for this entity.
Emerging data on the impact of cytogenetic aberrations, TP53 allelic burden, immunobiology, and tumor microenvironment of TP53-mutated MDS and AML are further unraveling the complexity of this disease. An improved understanding of the functional consequences of TP53 mutations and immune dysregulation in TP53-mutated AML/MDS coupled with dismal outcomes has resulted in a shift from the use of cytotoxic and hypomethylating agent-based therapies to novel immune and nonimmune strategies for the treatment of this entity. It is hoped that these novel, rationally designed combinations will improve outcomes in this area of significant unmet need.
Ibrutinib and Venetoclax for First-Line Treatment of CLL Jain, Nitin; Keating, Michael; Thompson, Philip ...
New England journal of medicine/The New England journal of medicine,
05/2019, Volume:
380, Issue:
22
Journal Article
Peer reviewed
Open access
Ibrutinib, an inhibitor of Bruton's tyrosine kinase, and venetoclax, an inhibitor of B-cell lymphoma 2 protein, have been approved for patients with chronic lymphocytic leukemia (CLL). Preclinical ...investigations have indicated potential synergistic interaction of their combination.
We conducted an investigator-initiated phase 2 study of combined ibrutinib and venetoclax involving previously untreated high-risk and older patients with CLL. All patients had at least one of the following features: chromosome 17p deletion, mutated
, chromosome 11q deletion, unmutated
, or an age of 65 years or older. Patients received ibrutinib monotherapy (420 mg once daily) for 3 cycles, followed by the addition of venetoclax (weekly dose escalation to 400 mg once daily). Combined therapy was administered for 24 cycles. Response assessments were performed according to International Workshop on Chronic Lymphocytic Leukemia 2008 criteria. Minimal residual disease was assessed by means of multicolor flow cytometry in bone marrow (sensitivity, 10
).
A total of 80 patients were treated. The median age was 65 years (range, 26 to 83). A total of 30% of the patients were 70 years of age or older. Overall, 92% of the patients had unmutated
,
aberration, or chromosome 11q deletion. With combined treatment, the proportions of patients who had complete remission (with or without normal blood count recovery) and remission with undetectable minimal residual disease increased over time. After 12 cycles of combined treatment, 88% of the patients had complete remission or complete remission with incomplete count recovery, and 61% had remission with undetectable minimal residual disease. Responses were noted in older adults and across all high-risk subgroups. Three patients had laboratory evidence of tumor lysis syndrome. The adverse-event profile was similar to what has been reported with ibrutinib and venetoclax.
In this study, combined venetoclax and ibrutinib was an effective oral regimen for high-risk and older patients with CLL. (Funded by AbbVie and others; ClinicalTrials.gov number, NCT02756897.).
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