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.     

Cognitive impairment, fatigue, and cytokine levels in patients with acute myelogenous leukemia or myelodysplastic syndrome

BACKGROUND: The objective of the current study was to assess the correlations between cognitive function, fatigue, quality of life, and circulating cytokine levels in patients with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). METHODS: Fifty-four patients with AML/MDS were seen for pretreatment evaluation of their cognitive function and symptoms. Fifty percent of the sample was reevaluated 1 month later, when response to protocol chemotherapy was assessed. RESULTS: A significant proportion of patients had impaired cognitive function prior to the institution of chemotherapy. Sixty-five percent of patients also experienced significant fatigue. Levels of the circulating cytokines interleukin 1 (IL-1), IL-1 receptor antagonist (IL-1RA), IL-6, IL-8, and tumor necrosis factor-alpha (TNF-alpha) were elevated highly compared with normal controls. Higher IL-6 levels were associated with poorer executive function, whereas higher IL-8 levels were associated with better memory performance. IL-6, IL-1RA, and TNF-alpha levels were related to ratings of fatigue. Fatigue and cognitive dysfunction were unrelated. Hemoglobin levels were not associated significantly with either cognitive dysfunction or fatigue. Patients who obtained a complete response tended to have better fine motor control at baseline and lower circulating IL-1 levels. Treatment did not have a significant impact on cognition, although fatigue levels tended to increase. CONCLUSIONS: Patients with AML/MDS are highly symptomatic and experience cognitive impairment and fatigue before the initiation of their treatment. The current results indicated a correlation between these symptoms and levels of circulating cytokines, providing some support to the hypothesis that cancer-related symptoms are related at least in part to cytokine-immunologic activation. Elucidation of immunologic correlates of symptoms will allow for targeted interventions.     

t(1;7) in acute myeloblastic leukemia following myelodysplastic syndrome (RAEB-T)

A case is described of myelodysplastic syndrome (MDS) refractory anemia type with an excess of blasts in transformation with early leukemic evolution (AML-M1). All bone marrow cells examined showed an unbalanced translocation t(1;7). The karyotype was 45, xy, -21, -7, + der dic t(1;7) (q12;q21). There are reports in the literature of the translocation t(1;7) (p11;p11), which leads to trisomy of the long arms of chromosome #1 and monosomy of the long arms of chromosome #7. In the case here described the breakpoints of the chromosomes involved in the translocation differ from the classic ones: in this case there is trisomy of the region 1q12----1qter and monosomy of the region 7q21----7qter. Some clinical and cytogenetic considerations are suggested.     

Circulating levels of inflammatory cytokines and risk of colorectal adenomas

The association between obesity and colorectal neoplasia may be mediated by inflammation. Circulating levels of C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) are elevated in the obese. Adipose tissue can produce and release the inflammatory cytokines that are potentially procarcinogenic. We examined circulating levels of CRP, IL-6, and TNF-alpha in relation to risk factors and the prevalence of colorectal adenomas. Plasma levels of CRP, IL-6, and TNF-alpha were quantified in 873 participants (242 colorectal adenoma cases and 631 controls) in a colonoscopy-based cross-sectional study conducted between 1998 and 2002. Multivariable logistic regression was used to estimate associations between known risk factors for colorectal neoplasia and circulating levels of inflammatory cytokines and associations between inflammatory cytokines and colorectal adenomas. Several known risk factors for colorectal neoplasia were associated with higher levels of inflammatory cytokines, including older age, current smoking, and increasing adiposity. The prevalence of colorectal adenomas was associated with higher concentrations of IL-6 and TNF-alpha and, to a lesser degree, with CRP. For IL-6, adjusted odds ratios (OR) for colorectal adenomas were 1.79 [95% confidence interval (CI), 1.19-2.69] for the second highest plasma level and 1.85 (95% CI, 1.24-2.75) for the highest level compared with the reference level. A similar association was found with TNF-alpha, with adjusted ORs of 1.56 (95% CI, 1.03-2.36) and 1.66 (95% CI, 1.10-2.52), respectively. Our findings indicate that systemic inflammation might be involved in the early development of colorectal neoplasia.     

Therapy-related acute myelogenous leukemia and myelodysplastic syndrome

Therapy-related acute myelogenous leukemia and myelodysplastic syndrome (t-AML/MDS) are increasing in prevalence with aging of the population and improved survival of patients treated with chemotherapy or radiotherapy for other malignancies. Research focused on the pathogenesis of t-AML/MDS will provide insight into the pathogenesis of de novo AML/MDS. Participation in clinical trials should be encouraged for this patient population because results with available treatment options are clearly suboptimal.     

骨髓增生异常综合征转化的急性髓系白血病52例临床观察

目的 探讨骨髓增生异常综合征(MDS)转化的急性髓系白血病(AML)的临床特征、疗效及影响因素.方法 回顾性分析52例MDS转化的AML患者转化时间、临床特点、MDS转化的AML亚型、疗效及其影响因素等临床资料.结果 52例患者转化为AML的中位时间为6.75个月.单因素分析显示,按中位年龄分层,≥46岁组转化为AML时间短于＜46岁组;男性短于女性;修订国际预后积分系统(IPSS-R)核型预后差组短于预后好组.多因素分析显示,年龄≥46岁、IPSS-R核型预后差为MDS较早转化为AML的独立危险因素.MDS转化的AML亚型为M2 35例(67.31％),M56例(11.54％),M4、M6各5例(9.62％),M1 1例(1.92％).髓外浸润发生率为32.69％(17/52),主要部位为肝、脾、淋巴结、牙龈、消化道及扁桃体.转化为AML后白细胞计数、中性粒细胞计数较初诊MDS时明显增高(P＜0.05).MDS转化的AML治疗完全缓解(CR)率为33.3％(8/24).结论 年龄大、IPSS-R核型预后差为MDS向AML转化的危险因素.MDS转化的AML临床亚型主要为M2,髓外浸润表现不少见,其治疗缓解率低,治疗相关死亡率高,预后差.     

Phase I-II study of bendamustine in patients with acute leukemia and high risk myelodysplastic syndrome

BackgroundAlkylating agents have shown activity in leukemia. Bendamustine, an active alkylating agent in lymphoma and chronic lymphocytic leukemia, was given in a fractionated twice daily schedule for 4 days to patients with acute leukemia and myelodysplastic syndrome (MDS) to define the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD).Patients and MethodsAdults with refractory acute leukemia or high-risk MDS were treated with bendamustine at a starting dose of 50 mg/m² IV over 1-2 hours twice daily for 4 days. Dose escalations were by 25 mg/m² in the 1st 3 levels. The study used the 3 + 3 design.ResultsA total of 25 patients were treated. Their median age was 57 years; the median salvage number was 3. Grade 2 creatinine elevations were observed in 1 of 6 patients at the 50 mg/m² dose, in 2 of 13 patients at the 75 mg/m² dose, and in 3 of 6 patients at the 100 mg/m² dose. This was considered significant, even though DLT was not reached. One patient achieved marrow complete remission. Significant reductions of marrow blasts (50% or more) were observed in 6 of 25 patients (24%).ConclusionBendamustine fractionated dose level of 100 mg/m² IV twice daily for 4 days (800 mg/m² per course) was associated with Grade 2 renal toxicity. The proposed phase II schedule is 75 mg/m² IV twice daily for 4 days. Future studies should evaluate this schedule in less heavily treated patients.     

CAG预激方案治疗急性髓系白血病及骨髓增生异常综合征

 目的　探讨小剂量阿糖胞苷（Ara-C）、阿克拉霉素（Acla）联合粒细胞集落刺激因子（G-CSF）（CAG方案）治疗急性髓系白血病（AML）及骨髓增生异常综合征（MDS）的临床疗效及患者不良反应。方法　选择初治或复发难治的AML与MDS患者54例,采用CAG方案化疗;获得完全缓解（CR）后选择不同方案交替巩固化疗。结果　CAG预激化疗治疗AML及MDS总有效39例（72.2 %）,CR 26例（48.1 %）,部分缓解（PR）13例（24.1 %）;化疗相关不良反应：粒细胞及血小板减少发生率40.7 %（22／54）,重症感染发生率24.1 %（13／54）。1例并发肝功能损害死亡。36例年龄＜60岁的患者总有效28例（77.8 %）,18例年龄≥60岁的患者总有效11例（61.1 %）,差异有统计学意义（P＜0.05）。结论　CAG方案治疗AML与MDS-原始细胞过多难治性贫血（RAEB）的疗效肯定,不良反应小,无病生存期长,是高效低毒的新型化疗方案。     

CAG预激方案治疗急性髓系白血病及骨髓增生异常综合征

Objective To explore the efficacy and side effect of CAG (G-CSF, aclarubicin and cytarabine) priming chemotherapy for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Methods 54 patients with AML at diagnosis and relapse or MDS were'enrolled for the initial treatment with CAG regimen. Patients who have achieved complete remission (CR) were treated with various regimens. Results The total effective rate was 72.2 %, complete remission rate was 48.1% and partial remission rate was 24.1%. The incidence of granulocyte deficiency was 40.7 %(22/54). The severe infection rate was 24.1%(13/54). One case died of function damage in liver. The study includes 36 patients below 60 years, 18 patients above 60 years, and overall effective cases are 28 (77.8 %), 11 (61.1%),respectively. There was significant difference (P ＜0.05). Conclusion CAG regimen is effective and well tolerated in remission for AML and MDS-RAEB.     

Outcomes after induction chemotherapy in patients with acute myeloid leukemia arising from myelodysplastic syndrome

BACKGROUND:

Secondary acute myeloid leukemia (AML) from an antecedent myelodysplastic syndrome (MDS)/myeloproliferative neoplasm is associated with a poor prognosis. The authors evaluated predictive factors in patients with secondary AML treated with anthracycline‐based induction therapy.

METHODS:

This was a retrospective review of secondary AML patients treated with induction therapy. Age, International Prognostic Scoring System, Eastern Cooperative Oncology Group performance status, cytogenetics, duration of MDS/myeloproliferative neoplasm, and prior MDS/myeloproliferative neoplasm treatment were evaluated for their impact on complete response (CR), CR with low platelets, and overall survival (OS).

RESULTS:

The authors evaluated 61 secondary AML patients who received induction chemotherapy; 59% (36 patients) achieved CR/CR with low platelets (95% confidence interval [CI], 46%‐71%), and median OS was 6.5 (95% CI, 3.9‐8.1) months. Three factors were associated with lower CR/CR with low platelets and OS: poor risk cytogenetics, prior treatment with hypomethylating agents or lenalidomide, and longer time to transformation to AML. Of those treated with hypomethylating agents or lenalidomide, 32% achieved CR/CR with low platelets versus 78% in the group not treated with a hypomethylating agent or lenalidomide (odds ratio [OR], 0.13; 95% CI, 0.04‐0.42). Median OS for those treated with a hypomethylating agent or lenalidomide was 3.7 versus 10.5 months for those not treated with a hypomethylating agent or lenalidomide (P < .0001). The CR/CR with low platelets rate for those with intermediate risk cytogenetics was 70% versus 35% for those with poor risk (OR, 4.33; 95% CI, 1.38‐13.6). Those with poor risk cytogenetics had a median OS of 2.8 versus 7.5 months for those with intermediate risk (P = .01).

CONCLUSIONS:

Prior treatment with hypomethylating agents or lenalidomide, poor risk cytogenetics, and longer time to transformation to AML are independent negative predictive factors for response and OS in patients with secondary AML after induction therapy. Cancer 2011. © 2010 American Cancer Society.     

Triapine and cytarabine is an active combination in patients with acute leukemia or myelodysplastic syndrome

Triapine, an iron chelator and a potent inhibitor of ribonucleotide reductase, has significant anti-leukemia activity. A phase I study of Triapine in combination with ara-C was conducted in 32 patients with refractory acute leukemia and high-risk MDS. Triapine (105 mg/m2/day 6-h infusion) was followed immediately by ara-C [100 (n=4), 200 (n=6), 400 (n=7), or 800 (n=8)mg/m2/day] as an 18-h infusion for 5 consecutive days. Dose-limiting toxicities (DLTs) were observed at the 800 mg/m2 ara-C dose level (one patient each with grade 4 mucositis; grade 4 neutropenic colitis, sepsis; grade 4 neuropathy; and grade 4 hyperbilirubinemia). Therefore, the study was amended to include an ara-C dose level of 600 mg/m2/day, no DLTs occurred in seven patients treated at this dose level. Mean Triapine C(max) and AUC were 1.13 microg/mL and 251.5 minmicrog/mL. Of 31 evaluable patients, 4 (13%) (3 AML, 1 Ph+ALL) achieved a CR (1 at a dose of 800 mg/m2; 2 at 600 mg/m2; 1 at 200mg/m2). The recommended phase II regimen is Triapine 105 mg/m2/day followed by ara-C 600 mg/m2/day for 5 consecutive days every 3-6 weeks.     

The clinical effect of low-dose Ara-C in patients with refractory acute nonlymphocytic leukemia and myelodysplastic syndrome

Twenty-one patients with refractory acute nonlymphocytic leukemia (ANLL) and myelodysplastic syndrome were treated with low-dose cytosine arabinoside (LDARC). LDARC was administered by subcutaneous injection every 12 hours at a dose of 10 mg/m2 (regimen A) or at a dose of 20 mg/m2 by continuous intravenous infusion (CIV) or continuous subcutaneous injection (CSC) (regimen B). Among 22 courses, two elderly patients with ANLL (M4 and M5) and one M4 patient with myelofibrosis obtained complete remission (CR) and three elderly patients with ANLL (one M1 and two M2) and one patient with ANLL developed from RAEB in transformation obtained partial remission (PR). The overall remission rate (CR + PR) was 31.8%. The CR durations were 2.5, 5 and 2 months, respectively. The plasma concentration of Ara-C determined in regimen B was 8.26 +/- 4.12 ng/ml. There was no difference in the plasma concentration of Ara-C between CIV and CSC. We consider that the major mode of action of LDARC lies in its cytotoxic effect, since all patients who obtained remission exhibited pancytopenia and bone marrow hypoplasia. However, in several patients, we observed transient monocytosis and granulocytosis which were considered to be suggestive evidence of differentiation of leukemia cells.     

Lack of nucleophosmin mutation in patients with myelodysplastic syndrome and acute myeloid leukemia with chromosome 5 abnormalities

Nucleophosmin (NPM1) gene exon 12 mutations are frequently present in patients with acute myeloid leukemia (AML) with normal karyotype. The NPM1 gene is located on chromosome 5q35, which is often affected in myeloid malignancies including myelodysplastic syndrome (MDS). This suggests that the NPM1 gene is a one of the target genes affected by chromosome 5 abnormalities and play a role in the development of MDS. It has not been clarified whether MPM1 mutations are present in patients with MDS and AML with chromosome 5 abnormalities. Therefore, we carried out a mutational analysis on the NPM1 gene exon 12. NPM1 mutations were not detected in the 28 patients with MDS and AML with chromosome 5 abnormalities.     

Cytogenetic analogy between myelodysplastic syndrome and acute myeloid leukemia of elderly patients.

The biological and clinical importance of cytogenetic analysis in myelodysplastic syndrome (MDS) and in acute myeloid leukemia (AML) is being increasingly recognized. Recently, cytogenetic similarities were noted between elderly de novo AML and secondary AML, suggesting common etiopathogenetic mechanisms. In the present study we analyzed the cytogenetic similarities between patients with AML of different age and patients with MDS consecutively diagnosed during a 5-year period at a single, primary referral, hematologic center. Of 246 patients aged <86 years, 195 (80%) had a cytogenetic study at diagnosis. Informative metaphases were obtained in 182 cases (93%), including 17 (9.3%) with secondary MDS/AML. Patients were classified according to FAB criteria and were subdivided into four groups: (1) 'early MDS': 42 patients with MDS of FAB subtypes other than refractory anemia with excess of blasts (RAEB) or RAEB in transformation (RAEB-T); (2) 'late MDS': 35 patients with RAEB and RAEB-T; (3) 'old AML': 48 patients with AML aged 65 to 85 years; (4) 'young AML': 57 patients with AML aged <65 years. Results showed that 'late MDS' and 'old AML' had striking cytogenetic similarities both in the frequency of normal karyotypes (31% and 27%), single abnormalities (14% and 13%), double abnormalities (17% and 14%), complex karyotypes (37% and 46%), and numerical abnormalities (89% and 93%), as well as in the frequency of rearrangements involving chromosome 5 (20% and 31%) and 7 (27% and 27%). The only difference between the two groups was found in the median number of chromosomes involved in complex karyotypes (5 vs 8; P=0.03). 'Early MDS' had significantly less complex karyotypes (21%; P<0.05), but its cytogenetic features resembled otherwise those of 'late MDS' and 'old AML', and any significant difference disappeared when patients with chronic myelomonocytic leukemia (CMML) were excluded. CMML markedly differed from other MDS subtypes in the frequency of normal (57%) and of complex karyotypes (6%). Secondary MDS/AML and AML with trilineage dysplasia shared the same cytogenetic features of 'late MDS' and 'old AML'. 'Young AML' strikingly differed from all other groups, particularly in the higher frequency of balanced translocations (29%; P<0.001) and single karyotype abnormalities (32%; P<0.02), and in the lower frequency of complex karyotypes (19%; P<0.01) and of chromosome 5 (2%; P<0.001) and 7 (9%; P<0.01) involvement. We conclude that in a population-based series of patients, the cytogenetic profile of MDS, particularly of RAEB/RAEB-T, was nearly identical to that of elderly patients with AML both in the frequency and in the type of chromosomal abnormalities. These results support the possibility that MDS and AML of elderly patients may represent the same disease seen at different stages of evolution.     

Chronic neutrophilic leukemia with acute myeloblastic transformation

We report a rare case of chronic neutrophilic leukemia (CNL) which terminated in acute myeloblastic transformation 3 years after the onset of the disease. The increased leukocytes were mainly neutrophils at various maturational stages until 1 month before transformation without dysplastic hematopoietic cells or other myeloproliferative disorders. Repeated analyses for the Philadelphia chromosome (Ph1), rearrangement of the BCR gene or chimeric BCR/ABL mRNA, major, minor and mu, were negative. Genomic analysis of granulocyte colony-stimulating factor (G-CSF) receptor did not reveal any abnormality. The clinical manifestations were characterized by hyperleukocyte syndrome with respiratory distress and ischemic legs with gangrene.     

Use of thrombopoietic growth factors in acute leukemia.

Several hematopoietic growth factors have been shown to affect megakaryocyte development, and two, interleukin (IL)-11 and thrombopoietin (TPO) are presently being evaluated for use in patients with thrombocytopenia. In two studies patients who required one or more platelet transfusions during their first course of chemotherapy were found to require fewer platelet transfusions if their second cycle was augmented with IL-11. The drug was generally safe, with cardiovascular compromise the only significant complication occurring in a minority of patients. Although these reports included patients with various malignancies, studies of IL-11 in patients with myeloproliferative disorders have not been presented. In several clinical trials in cancer patients treatment with TPO was safe, and when administered early following a moderately aggressive cytotoxic insult was effective in accelerating platelet recovery. In addition, in both pre-clinical and clinical trials, TPO given to stem cell donors during mobilization lead to accelerated hematopoietic recovery. Finally, TPO appears safe when administered to patients with acute myelogenous leukemia (AML), both with respect to acute toxicity and long-term outcome of the leukemia. However, when used following a 7-day course of standard chemotherapy, the agent does not appear to accelerate platelet recovery. As such, additional clinical trials to test different growth factor regimens are ongoing. A number of studies have suggested that megakaryocytic growth factors may play a role in the biology of myeloproliferative disorders. Given the potential for adversely affecting patients with these disorders, the affects of IL-11 or TPO in patients with AML must continue to be carefully studied.