Phase II trial of clofarabine and daunorubicin as induction therapy for acute myeloid leukemia patients greater than or equal to 60 years of age

We designed a phase II study evaluating the upfront combination of clofarabine and daunorubicin in acute myeloid leukemia (AML) patients ≥ 60 years old. The median age of the 21 patients was 69 (range 60–85) years. Fourteen patients (67%) had unfavorable risk features. The principal toxicities were grade ≥3 infections and prolonged myelosuppression. Three (14%) deaths occurred from infectious complications. Six (28.6%) patients achieved complete remission including three (21.4%) of 14 patients with unfavorable AML. The median disease-free survival was 6.8 months and the median overall survival was 11.2 months.     

AML1/ETO阳性急性髓系白血病的生物学特征及预后分析

目的 分析AML1/ETO阳性急性髓系白血病（AML）患者的分子生物学特征及多因素对其预后的影响.方法 回顾分析63例AML1/ETO阳性AML患者的细胞形态学、免疫分型、细胞遗传学、分子生物学特征、临床疗效、预后等资料,以同期收治的56例AML1/ETO阴性的AML患者作为对照.结果 63例AML1/ETO阳性的AML患者中,M2a占57.12％（36例）,M2b占33.33％（21例）.初诊时骨髓原始细胞比例为0.46±0.16.CD34、CD13、CD33、CD19、CD7、CD56阳性率分别为67.21％、52.46％ 、40.98％、63.93％、4.92％、50.82％.伴t（8;21）占82.54％,附加染色体占4.76％.3例伴EV11融合基因表达,1例伴MLL/AT9融合基因表达.总缓解率、复发率、3年及5年预计总体生存（OS）率分别为71.43％、51.11％、（43.01 ±5.31）％、（32.79±3.81）％,与对照组比较差异均无统计学意义（均P＞ 0.05）.髓外浸润、是否表达CD56、有无附加染色体对OS率有影响（P＜0.05）.结论 AML1/ETO阳性的AML有其独特的特点,疗效和预后受多因素影响,不能单独依靠AML1/ETO融合基因来评估其疗效及预后.     

Prognostic relevance of circulating matrix metalloproteinase-2 in acute myeloid leukaemia patients

Matrix metalloproteinases (MMPs) were postulated to have important implication in progression and invasiveness of many malignant disorders. On the other hand the biological role of MMP-2 in acute myeloid leukaemia (AML) is not fully clear. Serum samples from 37 adult patients with AML had been taken before chemotherapy was administered. In addition 20 out of the 37 patients were analysed again after achieving complete remission (CR). Ten samples from healthy volunteers were evaluated as the control. Total MMP-2 levels were measured using ELISA Kit obtained from R&D system. MMP-2 serum levels were significantly lower in pretreatment AML patients than that in the normal controls (p = 0.000) and in CR (p = 0.007). No significant correlations were detected between pretreatment sMMP-2 levels and FAB subtypes, peripheral blood blast cell counts, peripheral blood WBCs, bone marrow blast cell counts or blast cell distribution ratio. The prognostic value of MMP-2 was evaluated by dividing AML patients into high and low MMP-2 groups using the pretreatment median MMP-2 level of the AML group as the cut-off. The authors found that patients in the high group survived for a significantly shorter time than those patients in the lower MMP-2 group. High pretreatment levels of sMMP-2 among AML patients were associated with poor survival. Prospective studies are recommended to establish the clinical value of longitudinal sMMP-2 measurement.     

Outcome for children with relapsed acute myeloid leukaemia following initial therapy in the Medical Research Council (MRC) AML 10 trial. MRC Childhood Leukaemia Working Party.

Between May 1988 and March 1995, 359 children with acute myeloid leukaemia (AML) were treated in the MRC AML 10 trial. Three risk groups were identified based on cytogenetics and response to treatment. One hundred and twenty-five children relapsed--103 in the bone marrow only, 12 in the bone marrow combined with other sites, and six had isolated extramedullary relapses (site was not known in four cases). Eighty-seven children received further combination chemotherapy, one all-trans retinoic acid for acute promyelocytic leukaemia, and one a matched unrelated donor allograft in relapse, and 61 achieved a second remission. One patient with no details on reinduction therapy also achieved second remission. Treatment in second remission varied--44 children received a BMT (22 autografts, 12 matched unrelated donor allografts, 10 family donor allografts), and 17 were treated with chemotherapy alone. The overall survival rate for all children (treated and untreated) was 24% at 3 years, with a disease-free survival of 44% for those achieving a second remission. Length of first remission was the most important factor affecting response rates--children with a first remission of less than 1 year fared poorly (second remission rate 36%, 3 year survival 11%), whereas those with longer first remissions had a higher response rate (second remission rate 75%, 3 year survival 49%, P < 0.0001).     

IA联合CAG方案序贯诱导缓解治疗原发性初治急性髓系白血病

 目的 观察IA[去甲氧柔红霉素（IDA）+阿糖胞苷（Ara-C）]联合CAG方案[粒细胞集落刺激因子（G-CSF）+Ara-C+阿克拉霉素（ACLA）]序贯诱导缓解治疗原发初治急性髓系白血病（AML）的疗效和安全性。方法 患者选用IA联合CAG方案序贯诱导缓解治疗。治疗过程中,随访患者临床表现、血常规、血生化和骨髓细胞学检查指标。结果 14例患者接受本方案治疗,其中男性9例,女性5例,中位年龄37岁（15 ~ 64岁）。CR 10例,PR 2例,NR 2例。CR率71.4 %,总反应率（CR+PR）85.7 %。达到CR中位时间为距CAG方案治疗结束第15（14 ~ 29）天。最常见的毒副反应为骨髓抑制,其次为感染,以肺部感染最常见（发生率42.8 %）。结论 IA联合CAG方案序贯诱导缓解治疗原发性初治AML有效且安全。     

Circumvention of ara-C resistance by aphidicolin in blast cells from patients with AML

Treatment failure in AML is often attributed to P-glycoprotein-associated multidrug resistance. However, the importance of increased DNA repair in resistant cells is becoming more apparent. In order to investigate the ability of the DNA repair inhibitor aphidicolin to modulate drug resistance, we continually exposed blasts cells, isolated from 22 patients with AML, to a variety of agents +/- 15 microM aphidicolin for 48 hours. Cell survival was measured using the MTT assay. Overall, there was no significant effect of aphidicolin on sensitivity to daunorubicin, doxorubicin, etoposide or fludarabine. However, there was a marked increase in sensitivity to ara-C with a median 4.75-fold increase overall (range 0.8-80-fold;P< 0.005). The effect of aphidicolin was significantly greater in blast cells found resistant in vitro to ara-C (8.9-fold compared to 2.12-fold, P< 0.01). This observation was further validated by the correlation between ara-C LC(50)and extent of modulation effect (P< 0.05). Cells isolated from 10 cord blood samples were also tested in order to establish the haematological toxicity of combining ara-C and aphidicolin. The therapeutic index (LC(50)normal cells/tumour cells) for ara-C + aphidicolin was higher than that for ara-C alone suggesting no increased myelotoxicity for the combination. Increased cytotoxicity without increased haematotoxicity makes the combination of ara-C plus aphidicolin ideal for inclusion in future clinical trials.     

The role of MDR-related proteins in the prognosis of adult acute myeloid leukaemia (AML) with normal karyotype

Cytogenetic abnormalities are among the most important factors affecting the outcome of patients with acute myeloid leukaemia (AML), but approximately 40-50% of AML cases display a normal karyotype at diagnosis. Multidrug resistance (MDR) proteins overexpression is associated with worse prognosis in acute leukaemias, but its role in normal karyotype AML is less defined. We analysed the expression of P-glycoprotein (PGP), MDR-related protein (MRP) and lung resistance protein (LRP) in 135 adult patients with normal karyotype AML and its correlation with other biological features of the disease, to evaluate the impact of MDR proteins on response to therapy and on survival. Increased PGP expression was associated with lower rate of complete remission (CR; p = 0.006), similarly to advanced age. Cases overexpressing PGP displayed also a shorter event-free survival (EFS; 4 vs. 10 months, p = 0.035) and the increased expression of at least one MDR protein was associated with a reduced overall survival (OS; p = 0.038). Also age was predictive of worse prognosis. Our data confirm the prognostic role of MDR proteins, in particular of PGP, also in AML patients with normal karyotype at diagnosis. This finding could be used to stratify patients with different prognosis and to design risk-adapted therapeutic strategies.     

Treatment and long-term results in children with acute myeloid leukaemia treated according to the AIEOP AML protocols.

Since 1982, four consecutive studies on childhood acute myeloid leukaemia (AML) (namely LAM-82, -87, -87M and -92) have been conducted in Italy by the Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP) group. The induction therapy of the first three studies consisted of daunorubicin and cytarabine structured in a 3+7 backbone. In the most recent protocol (LAM92), patients received two induction courses including idarubicin, cytarabine and etoposide. Patients with acute promyelocytic leukaemia (20% of diagnoses) were included in LAM-87 and 87M studies. Postremissional therapy significantly changed over time, with an ever-increasing role given to stem cell transplantation (SCT). The long-term outcome of patients enrolled in the LAM-82, 87 and 87M studies was comparable, whereas that of children treated according to LAM-92 study was significantly better (P<0.005). Either allogeneic or autologous SCT was employed as consolidation therapy in more than 75% of cases enrolled in this latter study. Patients enrolled in the LAM-92 study were stratified in standard and high-risk groups with different outcome (67 vs 47%, respectively, P=0.04). Altogether, the results obtained in these four studies have permitted a progressive refinement of treatment, contributing to the structure of the ongoing LAM-2002 protocol that stratifies patients according to the presence of definite genetic anomalies and response to induction therapy.     

Efficacy of CLARA in recurrent/refractory acute myeloid leukaemia patients unresponsive to FLAG chemotherapy

We hereby report our multicentre, retrospective experience with CLARA in patients with fludarabine/cytarabine/G-CSF (FLAG) refractory AML. The study included all consecutive R/R AML patients, who received CLARA salvage during October 2010–October 2015 period. All patients were unresponsive to FLAG salvage chemotherapy regimen and did not undergo previous allo-HCT. A total of 40 patients were included. Following CLARA 5 (12.5%) patients experienced induction mortality and 10 (25%) patients achieved CR. 25 (62.5%) patients were unresponsive to CLARA. 7 (17.5%) out of 10 patients in CR received allo-HCT. Median overall survival of patients who achieved CR after CLARA was 24.5 months (8.5–54.5) and 3 months (2.5–5), in patients who underwent and didn’t allo-HCT, respectively. Our results indicate that CLARA may be good alternative even in FLAG refractory AML patients and can be used as a bridge to allo-HCT, who have a suitable donor and able to tolerate the procedure.     

Characterisation of the GRAF gene promoter and its methylation in patients with acute myeloid leukaemia and myelodysplastic syndrome

We report the isolation of the 5' flanking region of GRAF (GTPase regulator associated with the focal adhesion kinase), previously described as a putative tumour suppressor gene of acute myelogenous leukaemia and myelodysplastic syndrome, and demonstrate its promoter activity in reporter gene assays. Two putative protein-binding sites are identified of which one was sensitive to CpG methylation. The suppressed GRAF expression could be restored in leukaemia cell lines by treatment with a demethylating agent and an inhibitor of histone deacetylases. In contrast to normal tissues, which tested negative for GRAF promoter methylation, 11 of 29 (38%) bone marrow samples from patients with acute myeloid leukaemia or myelodysplastic syndrome were positive.     

Phase I dose escalation study of bortezomib in combination with lenalidomide in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML)

We conducted a phase I dose escalation study to determine the maximal tolerated dose of bortezomib that could be combined with standard dose lenalidomide in patients with MDS or AML. Treatment consisted of bortezomib (IV) on Days 1, 4, 8, and 11 and lenalidomide 10 mg daily (PO) days 1–21 in 28 day cycles for up to 9 cycles. 23 patients (14 MDS/CMML, 9 AML) were enrolled. The maximally tested dose of bortezomib, 1.3 mg/m², was tolerable in this regimen. Responses were seen in patients with MDS and AML. Further testing of this regimen is planned.     

Cost of de novo acute myeloid leukemia induction therapy in adults: analysis of EORTC-GIMEMA AML10 and FLANG regimens

Since the social and financial impact of AML therapy is becoming more and more relevant we analyzed the cost of induction therapy of two different regimens. The first one is part of the widely employed EORTC-GIMEMA AML-10 and consists often days of therapy. The second (FLANG) is a short (three day), Fludarabine, Ara-C, mitoxantrone and G-CSF containing regimen. We first retrospectively analyzed the outcome of 77 consecutive AML patients with comparable clinical and haematological features receiving FLANG (25) or AML-10 (52), between June 1993 and October 1999, and observed equivalent CR rate, as well as DFS and overall survival duration. We then selected 9 non pretreated patients per group who reached CR after one course of therapy. Patients treated with FLANG had a statistically significant earlier platelet recovery compared to those treated with AML-10, fewer days of intravenous antibiotic therapy (14/22, respectively, p < 0.05), and a shorter hospitalization period (22/33 days, p < 0.01). FLANG was significantly more expensive than AML 10 as far as the cost of antiblastic drugs (p < 0.01) and G-CSF support (p < 0.05) are concerned. On the contrary, the expense for antiemetic drugs (p < 0.01) and the cost of personnel and other services ($5,906/$3,970, p < 0.05) were higher for AML-10 than for FLANG. Overall, the average costs of FLANG and AML10 were $9,269 and $12,424 respectively (p < 0.05; difference = -25%). Our study seems to indicate that, compared to AML-10, FLANG induction is as effective, less expensive and it allows for a decrease in the length of hospitalization and thus for better exploitation of the financial resources of Hematology-Oncology departments.     

AML1-ETO融合基因转阴对急性髓细胞白血病预后的影响

目的:探讨AML1-ETO融合基因阳性表达的急性髓细胞白血病（acute myelocytic leukemia,AML）患者治疗后融合基因转阴及转阴时间长短对AML患者预后的影响。方法:对2012年1月1日至2016年12月31日在中国医科大学附属盛京医院住院治疗的35例初诊AML1-ETO融合基因阳性AML患者的临床资料进行回顾性分析,总结其形态学、免疫学和分子生物学特征,用 Kaplan-Meier 曲线评估患者生存情况。结果:35例患者男女比例 1.33∶1,中位年龄为34岁(15~71岁)。中位随访时间为16(4~61)个月,诱导缓解率为82.9%,3个疗程或以上缓解占14.3%(n=5),始终未缓解占2.9%(n=1),复发率35.3％(n=12),复发中位时间 12（6~20）个月。其中11例治疗后融合基因转阴,包括3个月内转阴占63.6%（n=7）,大于3个月转阴占36.4%（n=4）。单因素分析表明AML1-ETO融合基因转阴患者OS和PFS高,预后较好,AML1-ETO融合基因转阴时间长短对患者长期生存的影响无统计学意义（P=0.707）。结论:AML1-ETO融合基因转阴的AML患者预后较好,AML1-ETO融合基因转阴时间长短对患者的长期生存无明显影响。