Mechanisms for resistance in AML insights into molecular pathways mediating resistance to venetoclax

Resistance to therapy continues to pose hurdles in the therapeutic management of acute myeloid leukemia (AML). Although the approval and development of therapies such as venetoclax, was expected to overcome this issue, resistance remains a common occurrence in AML treatment. This review has summarized evidence that will provide insights into acquired mutations that influence response to venetoclax therapy and the utility of novel combination approaches in improving outcomes.     

Current status and new treatment approaches in TP53 mutated AML

Mutations in the essential tumor suppressor gene, TP53, are observed in only 5–10% of acute myeloid leukemia (AML) cases, but are highly associated with therapy-related AML and cases with complex karyotype. The mutational status of TP53 is a critical prognostic indicator, with dismal outcomes consistently observed across studies. Response rates to traditional cytotoxic chemotherapy are poor and long-term survival after allogeneic hematopoietic stem cell transplant is rare. Therapy with hypomethylating agents has resulted in a modest improvement in outcomes over intensive chemotherapy, but durable responses are seldom observed. In view of the intrinsic resistance to standard chemotherapies conferred by mutations in TP53, novel treatment approaches are required. In this review, we examine the current treatment landscape in TP53 mutated AML and discuss emerging therapeutic approaches currently under clinical investigation.     

Can venetoclax-based therapy replace 7+3 induction in fit older adults with AML?

Older patients with acute myeloid leukemia (AML) face a dismal prognosis. Although venetoclax-based therapy has led to improved outcomes among unfit older patients with AML, it is not curative and its efficacy and long-term outcomes among fit older patients is unclear. This review provides insights into factors that influence treatment choices among older patients with AML and what we would need to know for venetoclax-based therapy to replace standard intensive 7 + 3 induction therapy.     

Improving clinical trials in higher-risk myelodysplastic syndromes

Patients with higher-risk myelodysplastic syndromes (HR-MDS) have poor survival and are in need of more effective therapy options. Hypomethylating agents (HMAs) are the current standard of care and are being studied in combination with a number of novel therapies. Recent evidence, however, has delivered sub-optimal results, prompting the need to revisit patient selection criteria, treatment schedules, and clinical endpoints to better inform future studies and steer endpoints towards those that are clinically meaningful to patients.     

Progress and predictions: AML in 2018

The FLT3 inhibitor midostaurin, the antibody-drug conjugate gemtuzumab ozogamicin, CPX-351 (liposomal daunorubicin and cytarabine), and the IDH2 inhibitor enasidenib are among the novel agents approved for use in the clinic this past year. This year, 2018, already has seen the regulatory approval of the BCL2 inhibitor venetoclax in the form of breakthrough designation and the IDH1 inhibitor ivosidenib received full FDA approval. Much remains to be learned about how best to use these drugs to improve patient outcomes and how best to employ and interpret next-generation sequencing to determine measurable residual disease (MRD) levels that can more accurately predict risk of relapse.     

Why isn't there a one-size-fits-all approach for relapsed/refractory acute myeloid leukemia? Insights into different variables for decision-making

Relapsed refractory acute myeloid leukemia (R/R AML) has a poor prognosis. While the heterogeneity and diversity of R/R AML pose hurdles towards defining a standard of care, there have been various advances over the years. These, however, have added to the complexity of decision-making for R/R AML. This review has summarized evidence that will provide insights into factors that influence treatment choices in R/R AML and determine whether ongoing clinical trials can aid in identifying a standard approach for different sub-groups of patients.     

Age is an independent adverse prognostic factor for overall survival in acute myeloid leukemia in Japan

AIM: To elucidate risk factors for survival of elderly acute myeloid leukemia (AML) patients in a real-world practice by observational study. METHODS: We conducted a population-based study in 213 adult and elderly AML patients (127 males and 86 females) in Kagawa Prefecture, Japan. To construct this cohort, we gathered all data for patients diagnosed with AML at 7 hospitals in Kagawa between 2006 and 2010. The primary end point was overall survival (OS) after AML diagnosis. Unadjusted Kaplan-Meier survival plots were used to determine OS in the overall cohort. Multivariate analysis was used to determine the independent adverse prognostic factors for OS, with the covariates of interest including age, gender, race/ethnicity, CCI, education, median income, metropolitan statistical area size and history of myelodysplastic syndrome. RESULTS: The average population of Kagawa during the study period was 992489, and the incidence of AML was 4.26 per 100000 person-years. A total of 197 patients with non-acute promyelocytic leukemia (non-APL) (119 males and 78 females) were also included. The median age of non-APL patients was 70 years (average 67, range 24-95). The 5-year OS rate was 21.1%. Subsequent analysis by age group showed that the survival rate declined with age; the 5-year OS rates of non-APL patients younger than 64 years, 65-74 years, and older than 75 years were 41.5%, 14.1%, and 8.9%, respectively. Multivariate analysis revealed that unfavorable risk karyotype, older age, poor performance status (PS) (3-4), lack of induction chemotherapy, and antecedent haematological disease were independent prognostic predictors. In the subgroup analysis, we also found that older patients with non-APL had lower complete remission rates and higher early death rates than younger patients, irrespective of PS. However, intensive chemotherapy was a significant predictor for longer survival not only in the patients < 75 years of age, but also in those over 75 with PS 0-2. CONCLUSION: Age would contribute considerable life expectancy to indicate induction chemotherapy with eligible dose of cytotoxic drugs for a favorable case even in advanced elderly.     

APR-246 exhibits anti-leukemic activity and synergism with conventional chemotherapeutic drugs in acute myeloid leukemia cells

Background: APR‐246 belongs to a new generation of the compounds that restore normal p53 function in cells with mutated or wild type p53. The purpose of this study was to examine the effects of APR‐246 alone and in combination with other drugs in acute myeloid leukemia (AML) cells. Methods: Primary leukemic cells from patients with AML and AML cell lines were studied with respect to cytotoxic and apoptotic effects and mechanism of action of APR‐246, alone and in combination with Ara‐C, daunorubicin and fludarabine. Results: APR‐246 showed dose‐dependent cytotoxic and apoptotic effects in AML cell lines as well as in primary AML patient cells. Cells from patients with TP53 mutation and complex karyotype were more resistant to conventional drugs while these factors did not significantly affect the sensitivity to APR‐246. APR‐246 increased active caspase‐3, upregulated p53 protein levels, and increased the bax/bcl‐2 ratio independently of TP53 mutational status in patient cells sensitive to APR‐246. AML cells with high p14^ARF expression were significantly more sensitive to APR‐246. APR‐246 induced significant synergistic effects in combination with conventional chemotherapeutic agents. Pre‐incubation with APR‐246 induced more synergistic effects compared to other schedules. In patient cells, pronounced synergism was found when combining APR‐246 with danuorubicin. Conclusion: We conclude that APR‐246 is effective in AML cells irrespectively of TP53 mutational status and that it has promising properties for combination studies in AML.     

维奈克拉联合阿扎胞苷与地西他滨联合预激方案治疗老年复发急性髓系白血病的疗效及安全性比较的初步观察

目的比较维奈克拉(venetoclax, VEN)联合阿扎胞苷(azacitidine, AZA)方案与地西他滨(decitabine/dacogen, DAC)联合预激方案治疗老年复发急性髓系白血病(acute myeloid leukemia, AML)的疗效及安全性。方法回顾性分析2018年1月至 2020年8月苏州大学附属第一医院血液科收治的45例老年复发AML患者的临床资料, 男性31例、女性14例, 年龄60～80岁, 中位年龄66岁, 其中18例采用VEN+AZA方案治疗, 27例采用DAC+预激方案治疗。比较两组患者的完全缓解率(complete remission, CR)、部分缓解率(partial remission, PR)、总有效率(overall response rate, ORR), 不良反应发生率以及总体生存(overall survival, OS)。结果 VEN+AZA组ORR为 14/18, 其中CR 11例、PR 3例;DAC+预激组ORR为37.0%(10/27), 其中CR 8例、PR 2例, 两组患者疗效差异有统计学意义(P=0.007)...     

High expression of costimulatory molecules correlates with low relapse-free survival probability in acute myeloid leukemia (AML)

Costimulatory molecules such as lymphocyte function-associated antigen (LFA)-1 (CD11a), LFA-3 (CD58), intercellular adhesion molecule (ICAM)-1 (CD54), neuronal cell adhesion molecule (NCAM) (CD56), B7-1 (CD80), or B7-2 (CD86) are important regulatory elements in healthy immunological cascades, but their role in acute myeloid leukemia (AML) has only been rarely investigated. We studied their expression on mononuclear bone marrow (BM) cells from 105 patients with AML at initial diagnosis and evaluated their prognostic significance. Fluorescence-activated cell sorter (FACS) analyses were performed using antibodies directly conjugated with fluorescein. A BM sample was considered positive if more than 20% of the cells in the blast containing gate expressed the respective marker. The surface expression of CD11a (27 of 29 cases positive with an average of 71% positive blasts; 27⁺/29, 71%), CD54 (23⁺/33, 37%), CD56 (24⁺/93, 20%), CD58 (29⁺/29, 95%), CD80 (13⁺/28, 30%), and CD86 (19⁺/29, 39%) was measured. The expression of these markers in different French-American-British (FAB) classification types (M0–M5) was heterogeneous, except for CD56, which showed a higher proportion of positive cells in monocytic subtypes of AML. In addition, cases with a poor risk karyotype as well as patients succumbing to early death after double induction therapy according to the AML Cooperative Group (CG) protocol were characterized by a high expression of CD56. Relapse-free survival analyses demonstrated that patients with more than 8% CD56⁺ cells in the BM relapsed significantly sooner. CD54 was preferentially expressed in AML M4_eo and in addition in favorable cytogenetic risk groups and in cases that had responded to AML-CG therapy. Only very high proportions (>60%) of CD54⁺ cells were associated with a lower probability for relapse-free survival. CD80 and CD86 expressions were similar in all FAB types. Patients who had responded to AML-CG therapy showed higher CD80 proportions and lower CD86 proportions compared to the nonresponder group. Whereas cases with more than 15% CD80⁺ cells had a significantly lower probability for relapse-free survival, only cases with more than 65% CD86⁺ were characterized by a significantly lower probability for relapse-free survival. Expression profiles of CD11a and CD58 were not associated with specific FAB types or prognostically relevant groups. We can conclude: (1) Expression of costimulatory molecules in AML is very variable. This reflects the great diversity of immunophenotypes in AML. (2) CD56 is mainly expressed in monocytic subtypes of AML. CD56⁺ subtypes of AML seem to be a separate entity with a worse prognosis independent of the karyotype. (3) High expression of some costimulatory molecules correlates with a worse prognosis concerning relapse-free survival times.     

Clinical features and outcomes of hypocellular acute myeloid leukemia in adults: A Korean AML registry data

The hypocellular variant of acute myeloid leukemia (AML) is defined as bone marrow cellularity of <20% in a biopsy specimen at presentation. We performed a retrospective analysis of the clinical features and survival outcomes of hypocellular AML in a Korean population. We reviewed the medical records of all patients diagnosed with AML at nine hospitals participating in the Korean AML registry from 2006 to 2012. Overall survival (OS) and event-free survival (EFS) rates were calculated from the time of diagnosis until death or an event, respectively. In total, 2110 patients were enrolled and 102 (4.8%) were identified as having hypocellular AML. Patients with hypocellular AML were older than those with non-hypocellular AML (median age: 59 vs 49 years; P < .001) and presented with leukopenia more frequently (mean white blood cell count: 5810/μL vs 40549/μL; P < .001). There was no difference between patients with and without hypocellular AML in terms of the presence of antecedent hematologic disorders (5.9% vs 5.3%; P = .809). FLT3-ITD and NPM1 mutations were less common in hypocellular than non-hypocellular AML (FLT3-ITD mutations: 1.2% vs 14.3%, P < .001; NPM1 mutations: 0% vs 9.5%, P = .019). No differences were seen between the hypocellular and non-hypocellular AML groups in the complete remission rate (53.9% vs 61.3%, P = .139) or early death rate (defined as any death before 8 weeks; 14.7% vs 13.0%, P = .629). The OS and EFS did not differ between the hypocellular and non-hypocellular AML groups (median OS: 16 vs 23 months, P = .169; median EFS: 6 vs 9 months, P = .215). Hypocellular AML is more frequently observed in older-aged patients and have fewer FLT3-ITD and NPM1 mutation, but the clinical outcomes of hypocellular AML do not differ from those of non-hypocellular AML.     

Can molecular insights guide treatment of AML evolved from MPNs?

Leukemic transformation of myeloproliferative neoplasms (MPNs) is associated with dismal outcomes. The genetic complexity of leukemic transformation of MPNs is being deciphered and will likely result in targeted therapy approaches. Ongoing trials are investigating the efficacy of emerging treatments for this high-risk patient population. This review has outlined recent progress in the understanding and treatment of leukemia arising from MPNs.     

Patterns of mutations in TP53 mutated AML

TP53 mutated acute myeloid leukemia (AML) responds poorly to chemotherapy and has a short overall survival rate with a median of 5–9 months. Poor outcomes in TP53 mutated AML following chemotherapy have been observed and treatment options remain limited, although the presence of TP53 mutations alone should not be a barrier to therapy. Decitabine is emerging as an alternative treatment option for patients with TP53 mutated AML, although the agent has not been associated with deep molecular remissions and requires additional consolidation. The clinical and genomic characteristics of TP53 mutated AML are reviewed in this paper.     

Daunorubicin-cytarabine liposome (CPX-351) in the management of newly diagnosed secondary AML: A new twist on an old cocktail

Initial therapy for acute myeloid leukemia (AML) remained stagnant for approximately four decades despite advances in improved understanding of pathogenesis and prognostication of the disease.      Treatment has typically consisted of an anthracycline combined with continuous infusion of cytarabine for 7 days, the “7 + 3” regimen. Attempts have been made to improve on this regimen with modest improvements in response rates but no change in overalll survival, until the recent introduction of mutation-specific agents. However, the re-vamping of the delivery of both daunorubicin and cytarabine in a liposomal encapsulation, known as CPX-351, did show improvements of overall survival compared to traditional 7 + 3 in newly diagnosed secondary and therapy-related AML in patients aged 60–75. This led to the Food and Drug Administration (FDA) approval of the agent for both of these subtypes of AML in August of 2017. Herein we will review the rationale and preclinical development of CPX-351 and discuss the pivotal studies that led to its FDA approval.     

Population‐based assessment of chronic myeloid leukemia in Sweden: striking increase in survival and prevalence

The clinical outcome for patients with chronic myeloid leukemia (CML) has improved dramatically following the introduction of tyrosine kinase inhibitors. An improved survival, combined with a constant incidence, is expected to increase the prevalence of CML. However, data on the prevalence of CML remain scarce. We examined the overall and relative (age and gender matched) survival and assessed the past, present, and projected future prevalence of CML in Sweden. Data on all patients diagnosed with CML between 1970 and 2012 were retrieved from the Swedish Cancer Register and the Swedish Cause of Death Register. The 5‐year overall survival increased from 0.18 to 0.82, during the observed time period. Between 2006 and 2012, the 5‐year relative survival was close to normal for 40‐year‐old, but considerably lower for 80‐year‐old CML patients. The observed prevalence tripled from 1985 to 2012, from 3.9 to 11.9 per 100 000 inhabitants. Assuming no further improvements in relative survival, the prevalence is projected to further increase by 2060 to 22.0 per 100 000 inhabitants (2587 persons in Sweden). The projected dramatic increase in CML prevalence has major medical and health economic implications and needs to be considered in planning how to organize future care of CML patients.     

Which novel agents hold the greatest promise in AML?

The therapeutic landscape for acute myeloid leukemia (AML) has changed dramatically with the approval of targeted agents, including venetoclax, midostaurin, gilteritinib, ivosidenib, and enasidenib, among others. However, older patients with AML continue to experience poorer outcomes and are in ongoing need of more effective and less toxic regimens. This review examines the efficacy of novel therapeutics and promising combination approaches to further improve outcomes in the treatment of patients with AML.     

Recent progress in acute leukemia and myelodysplasia

The advances and progress in the understanding and management of acute leukemia and myelodysplasia continue to occur at an exponential rate. While this has led to more therapy options, clinicians and researchers are now facing more challenges in terms of clinical decision-making and more unanswered questions. This paper has outlined some conundrums in acute leukemia and myelodysplasia, and the efforts that are underway to address these.     

The phenotype of L-CFU and its correlation with the immunological characteristics of the blast cell population in AML

Summary The membrane phenotype of AML clonogenic cells (L-CFU) was analyzed in 19 AML patients using an in vitro culture technique after a complement-mediated lysis assay employing a panel of six monoclonal antibodies (McAb) -HLA-DR, FMC56 (CD9), FMC27 (CD9), CD14, CD15, CD41a-. Our results show that L-CFU has a heterogeneous but immature phenotype lacking on the expression of differentiation antigens (CD14, CD15, CD41a). In addition, we observed that the L-CFU phenotype is different from that of the whole blast cell population. Interestingly, L-CFU showed a higher expression of HLA-DR antigens with respect to their progeny. Upon analyzing whether the L-CFU phenotype was related to both the morphological and immunological features of AML blast cells, it was observed that, while there is no correlation with the FAB classification, there was a partial relationship between the immunological phenotype of AML blast cells and that of L-CFU. Accordingly, the more immature AML cases showed a more differentiated L-CFU phenotype (HLA-DR⁺, CD9⁺, FMC27⁺) when compared with cases with a more mature blast cell phenotype. These results suggest that those AML cases with a relatively immature myeloblastic phenotype may arise from a progenitor cell that has undergone partial differentiation and that is unable to acquire myeloid differentiation antigens, while those AML cases with mature blast cells might emerge from a very early L-CFU that has the capacity to undergo a greater degree of differentiation.