Outcome of hyperleukocytic adult acute myeloid leukaemia: a single-center retrospective study and review of literature

Hyperleukocytic acute myeloid leukaemia is considered to have a poor prognosis due to high early death rate secondary to leukostasis. Supportive treatments do not seem to have reduced early exitus in this subset of patients. Prognostic impact of hyperleukocytosis on outcome has been the object of few studies. Clinical characteristics and outcome of 45 consecutive adult patients with newly diagnosed acute myeloid leukaemia presenting to our institution with a white cell count (WBC) above 100 × 10⁹ L⁻¹ were reviewed. The outcome of this subset of patients was compared with 200 patients with a leukocyte count lower than 100 × 10⁹ L⁻¹ similarly treated in the same period. Eight hyperleukocytic patients (17%) died of intracranial haemorrhage or pulmonary failure due to leukostasis within the first 7 days of treatment. A significant association was found between complete response (CR) and absence of hyperleukocytosis, but if early deaths were removed from analysis the difference was no longer significant. Hyperleukocytosis also significantly reduces the overall survival (OS) but does not significantly influence the disease-free survival (DFS). We reviewed in literature studies in which the outcome of series of at least 10 patients with hyperleukocytosis were compared with that of patients with a leukocyte count lower than 100 × 10⁹ L⁻¹. Our data were consistent with those of the literature regarding the rate of early mortality and causes of death. In most of the reviewed series hyperleukocytosis does not seem to influence the outcome of patients. Avoiding early death seems to be an important step in this subset of patients. New data about pathophysiology of leukostasis are needed.     

多发性骨髓瘤化疗后发生急性髓系白血病一例并文献复习

多发性骨髓瘤(MM)患者比普通人有更大的几率发生第二肿瘤,且大部分为AML/MDS。男性及诊断多发性骨髓瘤年龄小于60岁的年轻患者比女性及诊断多发性骨髓瘤年龄大于60的患者发生血液学恶性肿瘤的可能性大。MM治疗后继发急性白血病的报道越来越多,但MM患者继发白血病以及其他第二肿瘤的机制及治疗目前尚不清楚。MM患者继发白血病后病情进展迅速,死亡率高,化疗后达完全缓解率低。     

Failure of lithium to reduce period of neutropenia during induction therapy of acute myeloid leukemia

Fifty-four patients treated with daunorubicin, cytosine arabinoside and thioquanine for acute myeloid leukemia were randomly assigned to receive oral lithium carbonate 1200 mg daily or no lithium. The duration of neutropenia (less than 0.5 x 10(9)/L) was similar between controls (median 22.5 days) and patients treated with lithium (median 24 days). The number of remissions, relapse-free survival and survival were similar for the lithium treated and control groups of patients. There was no apparent clinical efficacy in the use of lithium to reduce the period of neutropenia in patients undergoing remission induction therapy for acute myeloid leukemia.     

大剂量阿糖胞苷强化疗对急性髓性白血病长期生存的影响

目的探讨应用大剂量阿糖胞苷治疗缓解后急性髓细胞白血病（AML）的疗效及安全性。方法采用回顾性分析方法,对初次治疗完全缓解的AML患者给予4个大剂量阿糖胞苷强化化疗,治疗后对长期存活者进行随访观察。结果24例患者中存活2年以上者15例（62．5％）,其中8例（33．3％）已无病生存5年以上。结论大剂量阿糖胞苷强化疗安全有效,是AML患者获得长期无病生存的重要治疗方法,其治疗效果值得更大规模临床应用。     

Treatment of acute myeloid leukemia in the elderly: a clinical dilemma

Fifty-four patients representing all the cases of acute myeloid leukemia in patients aged over 60 years, presenting to three adjacent hospitals, were studied. Only 26 of the 54 patients were considered suitable for remission induction with intensive combination chemotherapy which produced seven complete remissions (CR) (26 per cent). Eighteen of the 54 patients survived longer than three months--11 of these had received remission induction chemotherapy (five CRs), two low dose cytarabine, one vincristine and vitamin A and four supportive treatment alone. By six months all the patients who had received supportive treatment had died. Patients who received intensive chemotherapy spent 77 per cent of the first 90 days in hospital and half died in hospital. Patients receiving differentiating agents or supportive care spent more time at home (37 per cent, 34 per cent of the first 90 days, respectively) but had shorter overall survival. Assessment of clinical characteristics in an attempt to predict response to treatment and survival indicated that poor performance status and the presence of infection were the most important factors. Analysis was limited by the statistically small number in the group. At present there is no reliable method of predicting which patients will respond well to treatment with intensive chemotherapy. The clinical dilemma is whether to treat more intensively to benefit a minority, or to use supportive treatment to allow more time to be spent at home albeit with a shorter overall survival.     

老年急性髓系白血病治疗进展

 由于老年患者本身的特点及疾病的生物学特征,老年急性髓系白血病（AML）患者的疗效及预后均较差。近年老年AML患者的治疗取得许多进展诸如标准化疗方案的改良、新化疗药物的应用、免疫治疗、表观遗传学治疗药物及靶向治疗药物的研发等,临床试验结果提示部分患者疗效改善。     

Relative and absolute deficiency of bone marrow endogenous colony stimulating activity in acute myeloid leukemia: Relation to response to chemotherapy

The purpose of this study was to determine possible mechanisms for the recently observed association between insensitivity of acute myeloid leukemia (AML) clonogenic cells to colony stimulating activity (CSA) and poor response to induction chemotherapy. The bone marrow endogenous CSA was determined using semi-solid agar cultures by measuring the response of the AML patients' own clonogenic cells to endogenous CSA. The results show that whereas 31% ($\text{5}\text{16}$) of patients at presentation have deficient bone marrow endogenous CSA production over 50% ($\text{11}\text{21}$) have relative deficiency of endogenous CSA, due to insensitivity of the patients' clonogenic cells to CSA.Although there is an association between relative deficiency of endogenous CSA and a poor response to therapy the relationship is not close enough to explain the previously observed highly significant correlation between insensitivity to CSA and poor response to therapy. The results suggest that two independent mechanisms are operative in the association between the CSA-insensitive phenotype and poor response to therapy, one via the tendency to relative endogenous CSA deficiency in the CSA-insensitive group and another via some additional feature of these poor response AML phenotypes which is independent of the presence or absence of endogenous CSA deficiency.     

Dynamics of procalcitonin and bacteremia in neutropenic adults with acute myeloid leukemia

Sensitive markers of infection are rare or of limited validity in neutropenic patients. Procalcitonin (PCT), a precursor protein of calcitonin, is a specific and sensitive marker of severe bacterial infections during short-term neutropenia. Because the value of PCT measurements among patients undergoing long periods of neutropenia remains uncertain and because several mechanisms, such as bacterial or fungal infections, reactions to drugs or blood products or tumor-associated events, can cause fever, we described the dynamics of PCT in 29 acute myeloid leukemia (AML) patients with 39 instances of chemotherapy-induced neutropenia. Plasma levels of PCT were determined prospectively by an immunoluminometric assay every four days starting at the onset of chemotherapy and continuing until the resolution of fever. We found that bacteremia did increase PCT levels above 0.5 ng/mL and these levels predicted bacteremia at day 15 of chemotherapy. This finding may be relevant in the decision to alter antibiotic regimens to decrease toxicity and cost when patients remain febrile at day 15.     

KIAA1524: A novel MLL translocation partner in acute myeloid leukemia

The Mixed Lineage Leukemia gene on chromosome 11q23 is a frequent site of recurrent translocations in acute leukemias. Its promiscuous character is reflected by the more than 60 different translocation partners described in literature. Prompted by karyotype and atypical FISH results, we identified a new translocation partner in infant acute myeloid leukemia, KIAA1524 on 3q13.13, also known as ‘Cancerous Inhibitor of Protein phosphatase 2A (CIP2A)’. This gene was recently identified as a proto-oncogene stabilizing MYC protein in gastric carcinoma. KIAA1524 has never been related to hematologic malignancies before, and the current AML case is the first case in which an MLL-KIAA1524 fusion was described.     

Hedgehog pathway inhibition as a therapeutic target in acute myeloid leukemia

Introduction: The Hedgehog (HH) pathway constitutes a collection of signaling molecules which critically influence embryogenesis. In adults, however, the HH pathway remains integral to the proliferation, maintenance, and apoptosis of adult stem cells including hematopoietic stem cells.

Areas covered: We discuss the current understanding of the HH pathway as it relates to normal hematopoiesis, the pathology of acute myeloid leukemia (AML), the rationale for and data from combination therapies including HH pathway inhibitors, and ultimately the prospects that might offer promise in targeting this pathway in AML.

Expert opinion: Efforts to target the HH pathway have been focused on impeding this disposition and restoring chemosensitivity to conventional myeloid neoplasm therapies. The year 2018 saw the first approval of a HH pathway inhibitor (glasdegib) for AML, though for an older population and in combination with an uncommonly-used therapy. Several other clinical trials with agents targeting modulators of HH signaling in AML and MDS are underway. Further study and understanding of the interplay between the numerous aspects of HH signaling and how it relates to the augmented survival of AML will provide a more reliable substrate for therapeutic strategies in patients with this poor-risk disease.     

Clinical and biologic features and treatment outcome of children with newly diagnosed acute myeloid leukemia and hyperleukocytosis

BACKGROUND: Acute myeloid leukemia (AML) with hyperleukocytosis often is associated with early complications. To the authors' knowledge, no recently published study has evaluated the management and clinical course in this regard, especially in relation to pediatric patients. METHODS: The authors reviewed 579 patients with newly diagnosed pediatric AML who were treated at St. Jude Children's Research Hospital from 1968 to 2002 and carefully examined 106 patients with initial leukocyte counts > or = 100 x 10(9)/L and French-American-British (FAB) AML subtypes other than M3. These patients with hyperleukocytosis were divided into 2 groups-'before' (early period; 70 patients) and 'after' (late period; 36 patients) the initiation of the AML-83 protocol-to address potential differences in supportive measures (including leukoreduction). RESULTS: Forty-five patients (42.5%) had early complications that were associated strongly with M4 and M5 FAB subtypes and had higher initial leukocyte counts than the patients without complications. Early deaths were less common in the late period (2.8%) than in the early period (22.9%; P = .01), although the incidence of early complications was similar. The late period was associated with a shorter time for referral (P = .0018), a longer time from admission to chemotherapy initiation (P < .0001), and lower white blood cell counts at chemotherapy initiation (P < .0001). In the late period, patients with or without hyperleukocytosis had similar complete remission rates. However, those with hyperleukocytosis had a lower postremission 10-year event-free survival rate (21.2% vs 41.7%; P = .0228). CONCLUSIONS: With improved management, including supportive care, early mortality in patients with AML and hyperleukocytosis decreased remarkably in the more recent period. However, better postremission treatment is required to improve long-term survival.     

HLA-G expression is irrelevant to prognosis in patients with acute myeloid leukemia

Human leukocyte antigen (HLA)-G could contribute to escape of cancer cells from host anti-tumor responses, and its potential clinical relevance in various malignancies was also addressed. However, the prognostic value of HLA-G in acute myeloid leukemia (AML) remains debated. In this study, HLA-G expression in malignant blasts was analyzed from 77 de novo AML patients (AML-M2, n = 26; AML-M3, n = 24; AML-M4, n = 10; AML-M5, n = 17) with flow cytometry. The proportion of HLA-G expressing blasts varied from 0% to 93.96% (median: 0.42%; 95% CI: 0–89.0%). Blasts with 0.5% or fewer HLA-G expressing were defined as negative according to its expression in normal CD34⁺CD45⁺ cells (n = 20, range: 0–0.5%; median: 0.13%; 95% CI: 0–0.42%). HLA-G expression status on leukemic blasts was not associated with the clinical parameters such as patient age at diagnosis, sex, sub-type of AML, percentage of blasts at diagnosis. Survival analysis revealed that HLA-G expression status on leukemic blasts is unrelated to the prognosis (p = 0.884). The mean overall survival time for the HLA-G negative and positive patients was 20.7 months (95% CI: 16.1–25.3) and 20.1 months (95% CI: 14.3–25.8), respectively. Taken together, our findings indicated that HLA-G expression is of no significance for the prognosis of patients with AML.     

Consolidation therapy for adult acute myeloid leukemia: a systematic analysis according to evidence based medicine

Post-remission therapy in acute myeloid leukemia (AML) remains problematic. It has been demonstrated that younger patients can maintain longer complete remissions (CR) with aggressive post-remission therapies after induction treatment: allogeneic (allo), autologous (auto) stem cell transplantation (SCT), or intensive chemotherapy (ICC). The purpose of our study was to identify the most important randomized and controlled studies comparing these three therapeutic options, in order to draw conclusions and possible suggestions for post-remission therapy of AML, according to the evidence based medicine (EBM) rules. We performed an exhaustive analysis of the literature, searching either in electronic databases or among the references of the identified articles (hand searching). We searched the MEDLINE computer database for reports from 1985 through January 2005 and selected for analysis the clinical trials conducted over adults affected by newly diagnosed AML aged less than 65 years. The study design had to satisfy strict methodological criteria and must consider global mortality and/or disease free survival as primary outcomes. Overall we found 7750 papers; by using the limits "clinical trial" as publication type, "all adults 19+ years", we were able to select 344 papers. Among these, a further selection was made, based on two main clinical queries: 1) is auto-SCT superior to ICC/no other therapy in improving DFS and/or OS in adult AML patients in first CR? 2) is allo-SCT superior to auto-SCT/other therapeutic options in improving DFS and/or OS in adult AML patients in first CR? Concerning the first query, a possible advantage of auto-SCT over ICC was not clearly supported by data from clinical trials; there is no evidence that auto-SCT is superior in terms of OS to chemotherapy. Nevertheless, the reported TRM has been significantly reduced within the past years. Thus, the percentage of patients suitable for auto-SCT in CR has increased. Moreover, the scarce data concerning the comparison between auto-SCT and chemotherapy in different subsets of patients are unable to suggest a differentiated approach in patients with high-risk, standard-risk or low-risk AML. Data from the literature show that patients with unfavorable risk disease are more often addressed to allo-SCT and patients with low-risk disease receive more often intensive consolidation chemotherapy. Concerning the second query, interpretation of data from the main prospective studies about the role of allo-SCT in previously untreated AML is not easy. The first problem is the lack of real randomized clinical trials; in fact, according to the reported studies, AML patients generally receive allo-SCT on the basis of donor availability (the so called "genetic randomization"). The second problem is the frequent absence of intention to treat analysis. Despite methodological limitations, it was possible to compare allo-SCT with auto-SCT on a donor versus no-donor analysis and within risk groups. No overall benefit of allo-grafting on survival was demonstrated by any trial. In conclusion, the EBM approach highlighted the limitations observed in the published studies concerning consolidation therapy in AML; some suggestions, emerging from non-randomized, as well as randomized studies, are adequate, but not conclusive. This point, coupled with the intrinsic complexity to study AML biological heterogeneity, is probably a major obstacle to draw conclusive evidences for consolidation therapy in AML. These observations should plan to address new randomized studies on AML therapy; however, due to the emergence of genetic subgroups and new drugs targeting specific abnormalities, these trials should probably be designed directly focusing on the single entities. In this way, the cure of AML could eventually become the cure of each specific AML subset with its peculiar biological, molecular and prognostic features.     

Different Outcome of Myeloid Sarcoma with Spinal Cord Compression Preceding Acute Myeloid Leukemia： Report of Two Cases and Review of Literatures

Myeloid sarcomas (MS) preceding acute myeloid leukemia (AML) are rare, which presenting as acute spinal cord compression is even rare. Here we report two new cases of myeloid sarcoma patients, whose outcomes were different. Twenty-seven patients with spinal MS preceding AML have been reported to date, including the two cases presented in this article. Surgical decompression was performed in 25 of the 27 patients, and 23 of these additional anti-AML therapy. Considering our patients and the published cases in the literature we suggest that immunohistochemical study plays an essential role in arriving at a correct diagnosis of MS, and that emergency surgery to resect spinal MS is an available treatment to make neural function recovery, and that the disease must be treated with intensive chemotherapy similar to that used to treat AML as soon as possible after resection or irradiation of the tumor.     

Arsenic trioxide and low-dose cytarabine in older patients with untreated acute myeloid leukemia, excluding acute promyelocytic leukemia

BACKGROUND: Acute myeloid leukemia (AML) carries a dismal prognosis in older patients. In this study, the authors evaluated the safety and efficacy of arsenic trioxide combined with low-dose cytarabine in untreated patients aged >or=60 years with AML. METHODS: In a phase 1/2 design, arsenic trioxide was administered intravenously at a dose of 0.25 mg/kg on Days 1 through 5 and on Days 8 through 12, and low-dose cytarabine was given subcutaneously twice daily on Days 1 through 14 in escalating doses to a target of 10 mg/m(2) per dose. Of 64 patients who had pathologically confirmed AML, excluding patients with acute promyelocytic leukemia and using World Health Organization criteria, the median age was 71 years, 10 patients (16%) had treatment-related AML, 40 patients (63%) had an antecedent myelodysplastic syndrome or myeloproliferative disorder, and 35 patients (55%) had unfavorable cytogenetics. Thirty-four patients (53%) had an Eastern Cooperative Oncology Group performance status of 2 or 3. RESULTS: Complete remission was achieved in 21 of 61 patients (34%), including 15 of 50 patients (30%) who had secondary or treatment-related AML, 10 of 33 patients (30%) who had unfavorable cytogenetics, and 6 of 34 patients (18%) who had a poor baseline performance status. The mortality rate within the first 4 weeks was 8%. Neutropenic fever was observed in >80% of patients, and 41% of patients had bacteremia. Nonhematologic toxicity generally was mild and reversible and included fatigue, nausea, diarrhea, rash, peripheral edema, and elevated transaminases. There were no clinically significant cardiac arrhythmias. CONCLUSIONS: The addition of arsenic trioxide to low-dose cytarabine appeared to improve responses in elderly patients who had AML compared with either agent alone, and a randomized trial of the combination versus single-agent low-dose cytarabine is ongoing.     

Fludarabine and cytarabine in patients with acute myeloid leukemia refractory to two different courses of front-line chemotherapy

The most effective regimen for acute myeloid leukemia (AML) patients who do not achieve complete remission (CR) after two different courses of front-line chemotherapy has not been established. We therefore evaluated the efficacy, toxicity, and prognostic factors for achieving CR following treatment with fludarabine and cytarabine in 25 newly diagnosed AML patients who did not respond to initial therapy with idarubicin and cytarabine followed by mitoxantrone and etoposide. CR was achieved in 32% of patients; in 55% of patients with intermediate-risk karyotype and in 14% with unfavorable-risk. Eight percent died of infectious complications. Median duration of overall survival was 6.6 months (95% CI 3.4 months to ∞); 3.4 months (95% CI 0.8-8.6 months) for patients with an unfavorable-risk karyotype and 18.1 months (95% CI 5.0 months to ∞) with an intermediate-risk karyotype (p = 0.02). Our data suggest that poor-risk karyotype patients are unlikely to benefit from third course treatment with fludarabine-cytarabine, and that this regimen merits further investigation in AML patients with good or intermediate-risk karyotype that have persistent leukemia after two courses of front-line chemotherapy.     

Intakes of selected food groups and beverages and adult acute myeloid leukemia

Few studies have explored the association between diet and adult acute myeloid leukemia (AML). In a hospital-based case–control study among 111 cases and 439 controls, AML risk was negatively associated with milk intake among women (OR 0.25, 95% CI 0.08–0.73) and tea (OR 0.50, 95% CI 0.23–1.09), and positively associated among women with beer (OR 2.48, 95% CI 1.05–5.85), wine (OR 2.32, 95% CI 1.05–5.09), and beef (OR 4.78, 95% CI 1.35–16.94). Our findings support a role of diet in adult AML; however, further research is needed to explore gender differences in risk.     

急性髓系白血病16号染色体倒位的研究进展

 inv(16)是急性髓系白血病（AML）M4Eo的特征性的异常核型,是预后较好的一个标志。inv(16)的结果是16q22上的CBFb基因和 16p13上的MYH11基因重排,产生CBFb-MYH11融合基因,可能在白血病的发病机制中起重要作用。本文就inv(16) AML的临床、血液学特点及分子生物学特征等方面的研究进展作一综述。