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.
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.).
Maintenance Therapy in AML Reville, Patrick K; Kadia, Tapan M
Frontiers in oncology,
02/2021, Letnik:
10
Journal Article
Recenzirano
Odprti dostop
Recent advances in therapeutics coupled with steady improvements in supportive care for patients with acute myeloid leukemia (AML) have led to improved outcomes. Despite these advances, even in ...patients that achieve a complete remission with initial therapy high rates of relapse remain a clinical dilemma. For decades, investigators have attempted strategies of maintenance therapy to prolong both remission duration and overall survival in patients with AML. These approaches have included cytotoxic chemotherapy, immunotherapy, hypomethylating agents, and targeted small molecule therapy. Overall, the evidence in favor of maintenance therapy is limited. Recent strategies, especially with hypomethylating agents have begun to show promise as maintenance therapy in improving clinical outcomes. Ongoing and future studies will continue to elucidate the true role for maintenance therapy options in patients with AML. In this review we summarize prior and ongoing maintenance therapy approaches in AML and highlight some of the most promising strategies.
Background
The revised 2017 European LeukemiaNet (ELN) classification (ELN‐2017) of acute myeloid leukemia (AML) divides patients into 3 prognostic risk categories, with additional factors such as ...the fms‐like tyrosine kinase 3 (FLT3)–internal tandem duplication (ITD) allele ratio (AR) considered for risk stratification. To the best of the authors' knowledge, the prognostic usefulness of ELN‐2017 in comparison with ELN‐2010 in younger patients with AML has not been validated to date.
Methods
The authors performed a retrospective study on patients aged <60 years who received idarubicin plus cytarabine (IA)–based induction chemotherapy for newly diagnosed AML.
Results
According to ELN‐2017 criteria, the number of patients in the favorable (Fav), intermediate (Int), and adverse (Adv) risk categories was 192 patients (27%), 331 patients (46%), and 192 patients (27%), respectively. Overall survival probabilities at 5 years in the Fav, Int, and Adv groups were 57%, 37%, and 18%, respectively. In comparison, the 5‐year overall survival probabilities in the Fav (169 patients), intermediate (IR)‐1 (80 patients), IR‐2 (306 patients), and Adv (160 patients) ELN‐2010 categories were 59%, 32%, 40%, and 14%, respectively. Although ELN‐2010 historically distinguishes prognosis into IR‐1 and IR‐2 categories in younger patients, this difference was nullified in the current study cohort. When comparing patients with a low FLT3‐ITD AR with those with a high FLT3‐ITD AR, no significant differences in survival were noted among patients with nucleophosmin 1 (NPM1)‐mutated AML (P = .28) or wild‐type NPM1 (P = .35), and in those treated with IA alone (P = .79) or those treated with IA and a FLT3 inhibitor (P = .10).
Conclusions
The ELN‐2017 more accurately distinguishes prognosis in patients with newly diagnosed AML. The lack of prognostic significance for the FLT3‐ITD AR needs further evaluation in different treatment settings.
The 2017 European LeukemiaNet (ELN‐2017) classification system more accurately distinguishes prognosis compared with the ELN‐2010 in patients with de novo acute myeloid leukemia. The prognostic significance of the fms‐like tyrosine kinase 3 (FLT3)–internal tandem duplication allele ratio is controversial and needs further evaluation in different treatment settings.
PDF
