FA方案用于急性髓系白血病不同治疗阶段疗效分析

Objective  To evaluate the therapeutic effect of the fludarabine and cytarabine (FA) regimen on acute myeloid leukemia (AML) at different phases during treatment. Methods  A total of 185 patients with AML were divided into 4 groups based on the outcome of previous treatments. Patients in Group 1 had no remission after the first course of induction chemotherapy (n = 55). Patients in Group 2 had no remission after no less than two courses of induction chemotherapy (n = 41). Patients in Group 3 had early relapse (n = 40). Patients in Group 4 had late relapse (n = 49). Patients in groups 2, 3 and 4 had refractory AML or AML with relapse. We assessed the efficacy and toxicity of FA combination chemotherapy in each of these 4 groups. Results  The complete remission (CR) rates of Groups 1, 2, 3 and 4 were 74.5% (41/55), 45.9% (19/41), 17.5% (7/40) and 38.8% (19/49), respectively. The CR rate was higher in Group 1 than in the other 3 groups (34.6%, 45/130) (P = 0.000). A significant correlation was found between CR rate and the number of chemotherapeutic courses (P = 0.023). The main adverse reactions included bone marrow suppression and secondary infection. Conclusion  FA regimen is a good choice for patients with AML, especially those who have failed to achieve CR after the first course of induction chemotherapy. Supported by a grant from the Planned Science and Technology Project of Guangzhou (No. 2006Z3-E0401).     

Hyperglycemia in patients with acute myeloid leukemia is associated with increased hospital mortality

BACKGROUND: Hyperglycemia is often observed in medically ill patients. Previous studies have shown that patients with hyperglycemia during induction therapy for acute lymphoblastic leukemia develop more infections and have shorter disease-free survival. The authors hypothesized that hyperglycemia may be associated with adverse outcomes in patients with acute myeloid leukemia (AML) and sought to determine whether this association exists in this population. METHODS: The authors performed a retrospective cohort study to examine the relation between hyperglycemia and hospital mortality in patients with the diagnosis of AML. Two hundred eighty-three adult patients were treated over a 3-year period. All hospitalizations were reviewed during the study period, and glucose exposure and outcomes were quantified. RESULTS: Hyperglycemia during a patient's hospitalization was associated with increased hospital mortality (OR, 1.38; 95% CI, 1.23-1.55; P < .001) after adjusting for covariates, including disease state, treatment type, and response. The rise in mortality was evident at even mild levels (110-150 mg/dL) of glucose elevation. Although the odds of developing severe sepsis (OR, 1.24; 95% CI, 1.13.-1.38; P < .001) or severe sepsis with respiratory failure (OR, 2.04; 95% CI, 1.44-2.91; P < .001) were increased with hyperglycemia, sepsis did not appear to be the main factor responsible for the negative impact of hyperglycemia on hospital mortality. CONCLUSIONS: This study demonstrated an association between hospital mortality and even modest levels of hyperglycemia in AML patients. Prospective studies are needed to confirm this association and to discern causal pathways that mediate this effect.     

The incidence,risk factors,and survival of acute myeloid leukemia secondary to myelodysplastic syndrome: A population‐based study

To determine the incidence, risk factors, and relative survival of acute myeloid leukemia (AML) secondary to myelodysplastic syndrome (MDS) in the Surveillance, Epidemiology, and End Results (SEER) database. Retrospective analysis of all patients with new MDS onset in the SEER‐18 database from 2001 to 2013. We identified 36 558 patients with primary MDS. The rate of secondary AML (sAML) was 3.7% among patients 40 years or younger and 2.5% among those older than 40 (P = .039). The median transformation interval was significantly shorter for the younger group (4.04 vs 13.1 mo; P < .001). For both age groups, median overall and cancer‐specific survival were significantly longer for patients who did not develop sAML. Although the younger patients survived longer than the older patients, sAML development had a more negative effect on the survival of younger patients. Female sex, age, and World Health Organization (WHO) type MDS with single lineage dysplasia (MDS‐SLD) were associated with a decreased risk of sAML for older but not younger patients. Among older patients with MDS, a married status, Black race, female sex, shorter time to sAML, and WHO type MDS‐SLD or MDS with ringed sideroblasts were favorable prognostic factors for survival. In the SEER database, the rate of sAML among patients with MDS is lower than that in previous reports, but these patients still have worse survival. Risk assessment should include clinical and demographic factors.     

吉妥珠单抗在CD33阳性急性髓系白血病中的研究进展

急性髓系白血病（acute myeloid leukemia,AML）是一种异质性髓系恶性肿瘤,目前化疗联合造血干细胞移植是主要治疗方法,但是总体预后较差。吉妥珠单抗（gemtuzumab ozogamicin,GO）是一种人源化抗CD33单抗与卡奇霉素结合的抗体偶联药物,主要用于治疗CD33阳性AML。虽然研究发现GO可以改善CD33阳性AML患者的预后,但是仍有部分AML患者并未获益。GO治疗AML的疗效主要与CD33表达及单核苷酸多态性（single nucleotide polymorphism,SNP）、ATP 结合盒亚家族B成员1（ATP-binding cassette subfamily B member 1,ABCB1）基因及SNP、特异的分子生物学和细胞遗传学等因素有关。本文就GO对AML疗效影响因素的研究进展进行综述。     

Gemtuzumab ozogamicin in the treatment of acute myeloid leukemia

Gemtuzumab ozogamicin (GO) is a chemotherapeutic agent that consists of a humanized anti-CD33 antibody (hP67.6) linked to N-acetyl-calicheamicin 1,2-dimethyl hydrazine dichloride, a potent enediyne antitumor antibiotic. GO was approved conditionally by the Federal Drug Administration in May 2000 as single-agent therapy for first recurrence of acute myeloid leukemia (AML) in patients over the age of 60 years who are unfit for conventional cytotoxic therapy. In this setting, it produces a complete response (CR) rate of 13%, with another 13% achieving CR with inadequate platelet recovery (CRp). The most common adverse effects associated with GO are infusion-related reactions and myelosuppression. GO monotherapy at the dose of 9 mg/m(2) is complicated with hepatic veno-occlusive disease in approximately 5% of cases, particularly prior to or following stem cell transplantation. Attenuated doses of GO or fractionated doses appear to be equally effective and better tolerated. GO has shown remarkable activity in acute promyelocytic leukemia, particularly for the elimination of minimal residual disease. Combinations of GO with chemotherapy as induction or post-remission therapy are promising, and phase III trials are ongoing.     

Clinical potential of introducing next-generation sequencing in patients at relapse of acute myeloid leukemia

Relapse of acute myeloid leukemia (AML) remains a major determinant of outcome. A number of molecularly directed treatment options have recently emerged making comprehensive diagnostics an important pillar of clinical decision making at relapse. Acknowledging the high degree of individual genetic variability at AML relapse, next-generation sequencing (NGS) has opened the opportunity for assessing the unique clonal hierarchy of individual AML patients. Knowledge on the genetic makeup of AML is reflected in patient customized treatment strategies thereby providing improved outcomes. For example, the emergence of druggable mutations at relapse enable the use of novel targeted therapies, including FLT3 inhibitors or the recently approved IDH1/2 inhibitors ivosidenib and enasidenib, respectively. Consequently, some patients may undergo novel bridging approaches for reinduction before allogeneic stem cell transplantation, or the identification of an adverse prognostic marker may initiate early donor search. In this review, we summarize the current knowledge of NGS in identifying clonal stability, clonal evolution, and clonal devolution in the context of AML relapse. In light of recent improvements in AML treatment options, NGS-based molecular diagnostics emerges as the basis for molecularly directed treatment decisions in patients at relapse.     

Current treatment strategies for measurable residual disease in patients with acute myeloid leukemia

Patients with acute myeloid leukemia (AML) who achieve a morphologic complete remission still can have measurable residual disease (MRD) detected by multiparametric flow cytometry, molecular methods, or cytogenetics. Such patients with MRD have a high risk of disease recurrence over a short timeframe, but optimal treatment strategies are unknown. Outcomes with conventional treatment, including allogeneic hematopoietic cell transplantation, are worse than those for patients without MRD. Herein, the authors review current strategies, including novel clinical trials, targeted toward patients with MRD.     

Clinical and proteomic characterization of acute myeloid leukemia with mutated RAS

BACKGROUND:

Activating mutations in RAS are frequently present in patients with acute myeloid leukemia (AML), but their overall prognostic impact is not clear.

METHODS:

A retrospective analysis was performed to establish the clinical characteristics of patients with RAS‐mutated (RAS^mut) AML, to analyze their outcome by therapy, and to describe the proteomic profile of RAS^mut compared with wild‐type RAS (RAS^WT) AML.

RESULTS:

Of 609 patients with newly diagnosed AML, 11% had RAS^mut. Compared with RAS^WT, patients with RAS^mut AML were younger (median age, 54 years vs 63 years; P = .001), had a higher white blood cell count (16K mm^?3 vs 4K mm^?3 ; P < 0.001) and bone marrow blast percentage (56% vs 42%; P = .01) at diagnosis, and were less likely to have an antecedent hematologic disorder (36% vs 50%; P = .03). The inv(16) karyotype was overrepresented in patients with RAS^mut and the ?5 and/or ?7 karyotype was underrepresented. RAS mutations were found to have no prognostic impact on overall survival or disease‐free survival overall or within cytogenetic subgroups. There was a suggestion that patients with RAS^mut benefited from cytarabine (AraC)‐based therapy. Proteomic analysis revealed simultaneous upregulation of the RAS‐Raf‐MAP kinase and phosphoinositide 3‐kinase (PI3K) signaling pathways in patients with RAS^mut.

CONCLUSIONS:

RAS mutations in AML may delineate a subset of patients who benefit from AraC‐based therapy and who may be amenable to treatment with inhibitors of RAS and PI3K signaling pathways. Cancer 2012. © 2012 American Cancer Society.     

The clinical significance of soluble CD86 levels in patients with acute myeloid leukemia and myelodysplastic syndrome

BACKGROUND: Levels of the soluble form of CD86 (sCD86) are elevated in a proportion of patients with leukemia. Although it is a potential modulator of antitumor responses, the significance of sCD86 in patients with hematologic malignancies is unknown. METHODS: The authors evaluated sCD86 levels by enzyme-linked immunosorbent assay in patients with acute myeloid leukemia (AML) (n = 57 patients) and patients with myelodysplastic syndrome (MDS) (n = 40 patients) and analyzed the relation between sCD86 levels and various clinical parameters. RESULTS: Levels of sCD86 were elevated (> 2.32 ng/mL) relative to normal donors (0.22-2.32 ng/mL; n = 51 patients) in 25% of patients with AML and in 27% of patients with MDS. Patients with AML who had elevated sCD86 levels had significantly lower complete remission (CR) rates compared with patients with AML who had normal sCD86 levels. In multivariate analysis using sCD86 as a continuous variable and including the interaction of age and sCD86 as a variable, sCD86 was a significant prognostic factor (P = 0.014) independent of cytogenetics. Further analysis demonstrated that, in patients with AML age 60 years and younger, but not in patients older than 60 years, elevated sCD86 levels were associated with significantly shorter survival (P = 0.04). There was no correlation between sCD86 levels and CR rates or survival in patients with MDS. CONCLUSIONS: The presence in patients with AML of elevated levels of circulating sCD86 were associated with lower CR rates and poor survival. The prognostic significance of sCD86 was independent of cytogenetics but was modulated by age, in that it was independently significant only in younger patients. The results suggest that sCD86 may play a role in modulating immune responses associated with the progression of AML.