Changing trends in the therapy of acute myeloid leukemia

There has been remarkable progress in the treatment of acute myeloid leukemia (AML) which has spanned 5 decades. The changing trends have led to new approaches and significant improvement in outcomes. This review has summarized the historical insights that have shaped the current treatment paradigms of AML.     

A new era of immuno-oncology in acute myeloid leukemia - antibody-based therapies and immune checkpoint inhibition

Acute myeloid leukemia (AML) remains a therapeutically challenging malignancy with high rate of relapse and poor outcomes. There has been increased understanding of the molecular characteristics of AML and the various roles of the immune system in its pathogenesis, the result of which has led to the study and development of multiple immune-based approaches for this disease. In this review, we aim to provide an overview of the recent advancements made in antibody-based approaches to the treatment of AML including monoclonal antibodies, antibody-drug conjugates, and immune checkpoint inhibition. In addition, we provide insight and discuss the promise of these agents, some of which may soon enter the therapeutic armamentarium we currently employ against this lethal disease.     

Venetoclax-based therapies for acute myeloid leukemia

The prognosis of adult acute myeloid leukemia (AML) remains poor, with the long-term survival rate less than 50%. However, the current paradigms of treatment are changing through a better understanding of the disease genetics and pathophysiology. Since 2017, eight new drugs have been approved by the U.S. Food and Drug Administration for the treatment of AML, including the FLT3 inhibitors midostaurin and gilteritinib, the IDH inhibitors ivosidenib and enasidenib, the anti-CD33 monoclonal antibody gemtuzumab ozogamicin, liposomal daunorubicin and cytarabine, the hedgehog pathway inhibitor glasdegib and the BCL-2 inhibitor venetoclax. Preclinical data demonstrated the anti-leukemic efficacy of venetoclax in AML and its synergy when combined with hypomethylating agents or chemotherapy agents. Clinical trials have demonstrated the clinical benefit of venetoclax-based therapies in newly diagnosed AML, leading to the recent FDA approval of venetoclax in combination with hypomethylating agents or low-dose cytarabine for older adults with newly diagnosed AML. Herein, we focus on the role of single-agent BCL-2 inhibition in AML and review the clinical studies of venetoclax-based combination regimens and the evolving mechanisms of resistance.     

Annular promyelocytes in acute myeloid leukemia

Summary Granulocytes with ring-shaped nuclei (annular granulocytes; ring granulocytes) are normal bone marrow constituents in rodents. Studies in man have shown a small number of these cells in cases of myeloproliferative disease. Myelocytes and metamyelocytes have also been described. Similar to rodents and some other animal species, the annular promyelocyte also exists in humans. The significance of these very rare cells in human haemopoesis becomes an interesting question.     

The role of Clofarabine in the treatment of adults with acute myeloid leukemia

The therapeutic scenario available for adult patients with acute myeloid leukemia (AML) has shown only partial progresses over the last few years. This is especially true for refractory and relapsed AML whose outcome is still extremely disappointing. In this context Clofarabine has offered new promising perspectives within first and second line protocols. This review will firstly describe the initial development in monotherapy, considering then the different potential combination strategies which include both polichemotherapeutic regimens and less conventional approaches with new generation drugs. The potential use of Clofarabine as induction treatment for patients candidate to stem cell transplantation and within conditioning regimens will be finally evaluated.     

Prognostic implications of NPM1 mutations and FLT3 internal tandem duplications in Egyptian patients with cytogenetically normal acute myeloid leukemia

Nucleophosmin (NPM1) and fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) gene mutations represent the most frequent molecular aberrations in patients with cytogenetically normal-acute myeloid leukemia (CN-AML). We analyzed the prognostic impact of these mutations and their interactions in adults with CN-AML. NPM1 mutation (NPM1mut) and FLT3-ITD mutation (FLT3-ITD+) were analyzed by polymerase chain reaction and GeneScan assays of bone marrow samples obtained from newly diagnosed 104 CN-AML patients. FLT3-ITD+ and NPM1mut were detected in 36 (34.6%) and 30 (28.8%) out of 104 subjects, respectively, 16 cases (15.4%) had double NPM1mut/FLT3-ITD+. The incidence of FLT3-ITD+ was significantly higher in the NPM1mut group than in the NPM1 wild (NPM1wt) group (P = 0.018). Statistical analysis revealed that isolated NPM1mut group had a better clinical outcomes in terms of higher complete response (CR) rate (P = 0.01) and a trend towards favorable overall survival (OS) and disease-free survival (DFS) (P = 0.28, 0.40, respectively). In contrast, the isolated FLT3-ITD+ group had an unfavorable outcome in terms of lower CR rate (P = 0.12), shorter OS, and DFS (P < 0.0001 for both). The NPM1mut/FLT3-ITD-group had the best OS and DFS, while the NPM1wt/FLT3-ITD+ group had the worst OS and DFS than other groups (NPM1mut/FLT3-ITD+ or NPM1wt/FLT3-ITD?) (P < 0.0001 for both). Multivariate Cox regression analysis showed that age and FLT3/ITD+ were independent poor prognostic factors for OS (P = 0.006, <0.0001, respectively), while FLT3/ITD+ was independent predictor for DFS (P = 0.04). However, NPM1mut did not have a significant impact on OS and DFS. In conclusion, adult patients with CN-AML carrying isolated NPM1mut and isolated FLT3-ITD+ exhibit different clinical outcomes than those with NPM1mut/FLT3-ITD+ or NPM1wt/FLT3-ITD?. Patients with NPM1mut/FLT3-ITD? had the best prognosis in terms of higher CR, OS, and DFS, while those with NPM1mut/FLT3-ITD+ had the worst CR rate, and NPM1wt/FLT3-ITD+ had the lowest OS and DFS.     

The promise of macrophage directed checkpoint inhibitors in myeloid malignancies

To date, many of the most successful checkpoint inhibitor-based therapies in cancer have targeted T-cells and adaptive immunity. However, there is an ongoing search for novel checkpoints with targeting innate immunity via activation of macrophage phagocytosis representing an exciting therapeutic strategy. CD47 is the dominant negative macrophage immune checkpoint expressed on cancer cells which acts as a “don't eat me signal”, preventing phagocytosis via its interaction with SIRP-α on macrophages. CD47 has been shown to be upregulated in many cancer types including myeloid malignancies with increased expression associated with inferior OS. Magrolimab, an anti-CD47 antibody, has shown proof-of-principle of efficacy in this therapeutic class with promising early results in both higher risk myelodysplastic syndromes (MDS) and TP53 mutant acute myeloid leukemia (AML). The toxicity profile to date has been shown safe and manageable with on-target anemia related to CD47 being present on aged red blood cells and without evidence of immune related toxicities. Investigation of novel agents targeting this pathway and novel combinations are ongoing. New strategies targeting macrophage checkpoints are encouraging and likely will lead a paradigm shift in the current treatment of myeloid malignancies.     

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)...     

Timed sequential chemotherapy for advanced acute myeloid leukemia

Timed sequential chemotherapy (TSC) combining mitoxantrone on days 1–3, etoposide on days 8–10 and cytarabine on days 1–3 and 8–10, was administered to 240 patients with advanced acute myelogenous leukemia (AML). Sixty one percent of patients, with a 95% confidence interval (CI) ranging from 54 to 67%, achieved complete remission (CR), including 47% (CI: 38–55%) of refractory patients and 78% (CI: 70–86%) of late first relapse patients (p < 0.0001). Thirty percent of patients did not respond to therapy and 9% died from toxicity. Median duration of neutropenia was 32 days and of thrombocytopenia 29 days. Severe non hematologic toxicity included sepsis in 45% of patients and mucositis in 27%. Post-remission therapy varied but included maintenance chemotherapy in most patients, a second course of TSC in 27, autologous stem cell transplantation in 17 and allogeneic transplantation in 20. Median survival of patients who were not transplanted was 7 months with 13% (CI: 7–19%) survival at 5 years. Median disease-free survival (DFS) was 9 months with 13% (CI: 6–20%) DFS at 5 years. Previous refractoriness was the main factor associated with poor prognosis for achieving CR, DFS and survival in a multivariate analysis. There was no difference in DFS between patients receiving the different modalities of intensive post-remission therapy. These results confirm initial reports on TSC and show that some patients with first relapse off therapy can enjoy prolonged DFS using chemotherapy only.     

Novel monoclonal antibody-based therapies for acute myeloid leukemia

There has been long-standing interest in using monoclonal antibodies to improve outcomes of people with acute myeloid leukemia (AML). While several candidate therapeutics have failed at various stages of clinical testing, improved survival of some patients receiving the CD33 antibody-drug conjugate gemtuzumab ozogamicin has provided first evidence that monoclonal antibodies have a role in the armamentarium against AML. Over the last several years, work to improve the success of monoclonal antibody-based therapies in AML has focused on the identification and exploration of new antigen targets as much as on the development of novel treatment formats such as use of unconjugated engineered monoclonal antibodies and conjugated antibodies, delivering highly potent small molecule drugs or radionuclides to AML cells. Here, we will provide a brief overview of current efforts with such investigational monoclonal antibody-based therapeutics.     

Allogeneic hematopoietic cell transplantation in acute myeloid leukemia

Allogeneic hematopoietic cell transplantation (HCT) is a curative treatment modality for select patients with acute myeloid leukemia (AML), functioning as a restorative agent following intensified chemo- and/or radiotherapy and also engendering the disease-directed immunologic threat of graft-versus-leukemia effect. Advancements in conditioning regimen intensity, donor availability, and supportive care have broadened the eligibility for allogeneic HCT, reduced rates of transplant related mortality, and improved outcomes over time. There are still obstacles to transplant in AML, offering opportunities for ongoing discovery, including poor recipient fitness, insufficient donor availability for certain populations, and limited access to care. Relapse remains the most common cause of treatment failure and a high priority area of investigative efforts. Post-transplant maintenance and novel applications of cellular therapeutics are expected to usher in a new era of promise for successful HCT in AML and will aim to overcome the remaining barriers impeding favorable outcomes for these patients.     

Atypical presentation of acute myeloid leukemia: cardiac myeloid sarcoma

We present the case of a 52-year-old man with a 2-month history of dyspnea, bilateral pleural effusion and cardiomegaly of rapid onset. A cardiac ultrasound showed pericardial effusion with infiltration of the infero-lateral cardiac wall, right auricle and aortic arch by a mass of unknown origin. Despite 1% blast cells in the peripheral blood, 2 bone marrow biopsies were negative for malignancy. Flow cytometry analysis of the blood and immunohistochemistry study of the pleural liquid showed a blast population of CD34+, CD33+, CD13+ and HLA-DR+ cells; a percutaneous cardiac biopsy showed CD34+ cells in the pericardium which led to the diagnosis of extramedullary acute myeloid leukemia (AML). The patient was treated with induction chemotherapy allowing remission, but unfortunately died of septic shock of fungal origin. This case illustrates a rare presentation of cardiac extramedullary AML.     

Familial CEBPA-mutated acute myeloid leukemia

Familial CEBPA-mutated acute myeloid leukemia (AML) represents a recognized leukemia predisposition syndrome, with several families described in the literature since the initial report in 2004. The pathological features and long-term survival of individuals with familial CEBPA-mutated AML are reminiscent of sporadic CEBPAdm AML.  Germline mutations predominantly localize to the N-terminal and are associated with near complete penetrance, with age of AML onset from 2–50 years, frequently accompanied by the acquisition of a second CEBPA mutation in C-terminal domain.  Patients appear to have a significant risk of late AML recurrence and these typically represent independent leukemic episodes, characterized by a unique molecular profile that is distinct from that of the preceding tumor.  While these patients respond well to salvage therapies, allogeneic hematopoietic stem cell transplantation (HSCT) should be considered for patients with high-risk features at presentation or recurrent disease, with the aim of eradicating the germline mutation and improving long-term survival. In contrast, inherited C-terminal CEBPA mutations occur less frequently and appear to demonstrate reduced penetrance, impeding clinical detection and surveillance.     

老年人急性髓细胞白血病P-糖蛋白表达的临床意义

目的探讨Ｐ－糖蛋白（Ｐ－ｇｌｙｃｏｐｒｏｔｅｉｎ，Ｐ－ｇｐ）在初治老年人急性髓细胞白血病（ＡＭＬ）中的表达特点及其预后意义。方法采用流式细胞术（ｆｌｏｗｃｙｔｏｍｅｔｒｙ，ＦＣＭ）及抗Ｐ－ｇｐ细胞膜外区域单克隆抗体ＵＩＣ２检测了３７例初治老年人ＡＭＬ白血病细胞Ｐ－ｇｐ表达。结果１６例（４３％）患者Ｐ－ｇｐ阳性（Ｐ－ｇｐ＋），Ｐ－ｇｐ与干细胞或祖细胞抗原ＣＤ３４表达显著相关，与其它免疫表型无关。在可评估疗效的３２例中，Ｐ－ｇｐ＋１５例中的４例（２７％）获得完全缓解（ＣＲ），缓解率显著低于Ｐ－ｇｐ阴性（Ｐ－ｇｐ－）１７例中的１１例（６５％）（Ｐ＜０．０５）。ＣＤ３４阳性（ＣＤ３４＋）１４例中ＣＲ３例（２１％），也显著低于ＣＤ３４阴性（ＣＤ３４－）者１８例中１２例（６７％）（Ｐ＜０．０５）。Ｐ－ｇｐ－及ＣＤ３４－１３例中１１例（８５％）获得ＣＲ。结论Ｐ－ｇｐ阳性及ＣＤ３４阳性是老年人ＡＭＬ预后差的重要指标     

Immunotherapeutic strategies for relapse control in acute myeloid leukemia

Despite that the initial phases of chemotherapy induce disappearance of leukemic cells in many patients with acute myeloid leukemia (AML), the prevention of life-threatening relapses in the post-remission phase remains a significant clinical challenge. Allogeneic bone marrow transplantation, which is available for a minority of patients, efficiently prevents recurrences of leukemia by inducing immune-mediated elimination of leukemic cells, and over the past decades, numerous immunotherapeutic protocols have been developed aiming to mimic the graft-versus-leukemia reaction for the prevention of relapse. Here we review past and present strategies for relapse control with focus on overcoming leukemia-related immunosuppression in AML. We envisage future treatment protocols, in which systemic immune activators, such as vaccines, dendritic cell-based therapies, engineered variants of IL-2, or IL-15, are combined with agents that counter immunosuppression mediated by, e.g., the PD/PDL interaction, CTLA-4, CD200, reactive oxygen species, IDO expression, CXCR4, or the KIR/class I interaction, based on characteristics of the prevailing malignant clone. This combinatorial approach may pave the way for individualized immunotherapy in AML.     

Bulky lymphadenopathy in acute myeloid leukemia

 Two cases of acute myeloid leukemia (AML) presenting with bulky adenopathy are reported. Both patients were febrile at admission and showed massive and diffuse lymph node involvement, hepatomegaly, and splenomegaly. Erythematopapular leukemic skin lesions were present in one case at the onset and developed in the other at the time of relapse. Anemia, thrombocytopenia, and moderate leukocytosis were present in both. The presence of immature cells in peripheral blood and bone marrow allowed a rapid diagnosis of AML, FAB M1, in one patient. In the other case, owing to the paucity of immature cells in peripheral blood and bone marrow, lymph node biopsy with histology, imprint cytology, and immunocytochemistry were essential for the diagnosis (AML, FAB M2, with trilineage dysplasia and basophilic involvement). Both patients achieved complete remission (CR), followed by an early relapse 3 months later. They underwent allogeneic bone marrow transplantation (BMT) from HLA identical siblings. One patient is actually alive and in CR at 6 months after BMT; the other patient showed a leukemic regrowth after transplantation and died 4 months later. Received: December 8, 1997 / Accepted: April 29, 1998     

When the good go bad: Mutant NPM1 in acute myeloid leukemia

Nucleophosmin 1 (NPM1) is a nucleolar phosphoprotein that performs diverse biological functions including molecular chaperoning, ribosome biogenesis, DNA repair, and genome stability. Acute myeloid leukemia (AML) is a heterogeneous disease, more than half of the AML cases exhibit normal karyotype (NK). Approximately 50–60 percent of patients with NK-AML carry NPM1 mutations which are characterized by cytoplasmic dislocation of the NPM1 protein. In AML, mutant NPM1 (NPM1c+) acts in a dominant negative fashion and also blocks the differentiation of myeloid cells through gain-of-function for the AML phenotype. Currently, there is limited knowledge on the gain-of-function mechanism of mutant NPM1. Here, we review the known mechanisms of mutant NPM1 in the pathogenesis of AML. We describe genetic abnormalities, the clinical significance of exon-12 mutations in the NPM1 gene, and chromosomal translocations including the recently discovered NPM1-TYK2, and NPM1-HAUS1. Also, we outline the possible therapeutic interventions for the treatment of AML by targeting NPM1. Overall, the review will summarize present knowledge on mutant NPM1 origin, pathogenesis, and therapy in AML.