A phase I/II study of oral etoposide and idarubicin in elderly patients with high-risk acute myeloid leukemia unable to undergo intensive chemotherapy

Acute myeloid leukemia (AML) is a disease of mostly elderly patients who are often unable to undergo intensive intravenous chemotherapy. In an attempt to provide an all-oral regimen suitable for palliative treatment, we assessed the antileukemic efficacy of combination therapy of idarubicin 20 mg/m² (days 1, 3, and 5) and etoposide (EI) in increasing doses (75–125 mg/m²) on days 1–5. Eleven patients were included (median age 69 years, range: 56–77) with prognostically unfavorable characteristics (myelodysplastic syndrome, relapse, or unfavorable karyotypes). No complete remission and five partial remissions were observed whereas four patients had persistent leukemia. There were two patients who succumbed to early death. Median overall survival was 100 days (range: 8–493 days). Nonhematological toxicities were acceptable with nausea/vomiting being the predominant side effect. Hematological toxicity with grade III/IV aplasia was seen in all patients. In this study EI did not show convincing antileukemic efficacy and was unable to induce clinically useful complete remissions, with a substantial risk profile. In contrast to the situation of elderly patients with standard-risk AML in which similar oral treatment has shown promising activity, EI cannot be recommended for elderly patients with high-risk AML.     

标准剂量去甲氧柔红霉素联合阿糖胞苷治疗急性髓细胞白血病

目的:探讨标准剂量的去甲氧柔红霉素(IDA)联合阿糖胞苷(Ara-C)治疗急性髓细胞白血病(AML)的疗效和不良反应。方法:14例AML患者,年龄13～70岁(中位年龄36岁),男8例,女6例。初治AML10例,难治、复发AML4例。所有患者均在治疗前进行染色体核型分析,4例染色体异常。诱导方案为IDA 12 mg·m-2·d-1,第1～3天,Ara-C 100 mg·m-2·d-1,持续静脉点滴,第1～7天。结果:1个疗程结束后总有效率92．9％(13／14),完全缓解率85．7％(12／14),其中初治AML的CR率为90．0％(9／10),复发、难治AML的CR率为75．0％(3／4),3例染色体异常患者达细胞遗传学缓解,未发生早期死亡。化疗的不良反应主要为骨髓抑制和粒细胞缺乏所致感染,未见严重的非造血系统不良反应。结论:标准剂量的IDA联合Ara-C 24 h持续静脉点滴,为初治、复发难治AML的高效、安全的方案。     

去甲氧柔红霉素联合HA方案治疗急性髓细胞白血病初治患者的临床观察

目的:探讨去甲氧柔红霉素(IDA)联合HA方案[(高三尖杉酯碱(HH)加阿糖胞苷(Ara-C)]治疗初发急性髓细胞白血病(AML)的疗效和不良反应。方法:14例AML患者,年龄17～62岁(中位年龄40岁),男8例,女6例,均为初治AML病例。诱导方案为IDA10mg/d,第1～3天,HH3mg/d第1～7天,Ara-C100mg.m-2.d-1第1～7天,静脉滴注。结果:总有效率92.9(13/14),完全缓解率78.6(11/14),治疗过程中未发生早期死亡。化疗的不良反应主要为骨髓抑制和粒细胞缺乏所致感染,未见严重的非造血系统不良反应。结论:IDA联合HA方案为初治AML的高效、安全的方案。     

Maintenance with low-dose cytarabine for acute myeloid leukemia in complete remission

Summary Thirty-four patients with acute myeloid leukemia (AML) in complete remission (CR), 30 of them aged over 60, received maintenance therapy scheduling four courses of low-dose cytarabine (LDA) 20 mg/m²/day in two subcutaneous injections for 3 weeks every 6 weeks. Each course was stopped when hematologic toxicity occurred, and doses of LDA were subsequently reduced by 50% for the following courses. During the first course of LDA, 15 patients needed blood and four patients platelet transfusions. Overall, 28 patients received four courses of LDA: 11 did not require any dose reduction, while 14 required one dose reduction and three neeeded two successive dose reductions. Two patients were hospitalized during maintenance. Median disease-free survival (DFS) is 308 days, with 16% of patients surviving at 5 years. Seven patients relapsed during the 168 days of maintenance, while ten of the 27 patients remaining at risk on day 169 relapsed during the 168 days following maintenance. We conclude that in AML in CR, the maximal dose of LDA tolerated by ambulatory patients is 10 mg/m²/day for 3 weeks. LDA seemed to delay relapse; however, precise assessment of the efficacy of this approach would require a randomized trial.     

Intensive chemotherapy with idarubicin, ara-C, etoposide, and m-AMSA followed by immunotherapy with interleukin-2 for myelodysplastic syndromes and high-risk Acute Myeloid Leukemia (AML)

 Intensive chemotherapy followed by treatment with interleukin-2 (IL-2) was evaluated in a prospective, randomized, multicenter trial including 18 patients with refractory anemia with excess of blasts in transformation (RAEB-T), 86 patients with acute myeloid leukemia (AML) evolving from myelodysplastic syndromes, and six patients with secondary AML after previous chemotherapy. Median age was 58 years (range: 18–76 years). Forty-nine patients (45%) achieved a complete remission (CR) after two induction cycles with idarubicin, ara-C, and etoposide, 52% of them aged ≤60 years and 35% aged >60 years (p=0.06). After two consolidation courses, patients were randomized to four cycles of either high- or low-dose IL-2. Patients aged up to 55 years with an HLA-identical sibling donor were eligible for allogeneic bone marrow transplantation. The median relapse-free survival was 12.5 months, with a probability of ongoing CR at 6.5 years of 19%. Overall survival of all patients was 8 months, and 21 months for the CR patients. Median survival was significantly longer among patients aged ≤60 years than among the older patients (16 vs 6 months, p<0.001). Median duration of survival and relapse-free survival were not statistically different in the two IL-2 treatment arms. Received: March 23, 1999 / Accepted: June 23, 1999     

Results of conventional-dose cytosine arabinoside and idarubicin in elderly patients with acute myeloid leukemia

Summary Conventional-dose Ara-C (200 mg/m² d 1–5) combined with idarubicin (12 mg/m² d 1–3) was employed as remission induction and consolidation therapy in 23 elderly AML patients with a median age of 66 years (range, 60–75) with AML according to the FAB criteria (M1n=3, M2n=10, M4n=6, M5n=2, M6n=2), eligible for the study. In seven patients earlier MDS had been documented by previous bone marrow aspirates. The CR rate after one induction course was 65% (15/23). Toxicity was acceptable, with four patients dying during the chemotherapy-induced hypoplasia (4/23). Although 80% of the CR patients received two additional cycles of Ara-C and idarubicin as consolidation therapy, only two patients are still in continuous complete remission more than 12 months after achieving CR. The median disease-free survival of the CR patients was 11.5 months and the median survival of the entire group was 10 months. We conclude that conventional dose Ara-C/idarubicin is an effective protocol for inducing complete remission in elderly patients with AML, but that consolidation therapy consisting of two courses of the same regimen does not produce a relevant rate of long-term disease-free survival.     

大剂量阿糖胞苷巩固治疗核心结合因子相关急性髓系白血病的疗效及安全性分析

目的:探讨大剂量阿糖胞苷(HDAraC)巩固治疗核心结合因子相关急性髓系白血病(CBF-AML)的疗效和安全性。方法:回顾分析本院血液科骨髓移植病区2007年至2012年收治的CBF-AML患者应用HDAraC巩固化学治疗(化疗)的临床资料。评估患者总生存(OS)率、无病生存(DFS)率及复发率,并评价其治疗安全性,包括血液学不良反应及胃肠道、中枢神经系统等非血液学不良反应。结果:入选14例患者(男9例、女5例),中位年龄36.5(15~58)岁;AML-M2b 7例,AML-M4Eo 7例。共进行38个疗程HDAraC治疗。中位随访32.3个月,预期5年OS率为67.4%±14.0%,5年DFS率为44.6%±14.4%,5年复发率56.3%±14.4%。截止末次随访,10例患者存活,1例死于血小板减少所致颅内出血,3例死于疾病复发。7例患者复发,其中1例为复杂染色体异常,2例AML-M2b伴c-kit基因突变。29个疗程可评价不良反应:所有患者均出现Ⅳ度粒细胞减少和Ⅳ度血小板降低以及粒细胞缺乏性发热,经治疗无严重感染致死病例,1例因血小板减少致颅内出血死亡。患者均有Ⅰ~Ⅱ度胃肠道不良反应。未见中枢神经系统、皮肤等不良反应。结论:HDAraC应用于CBF-AML缓解后巩固化疗的效果和安全性令人满意,值得临床推广应用。     

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.     

Therapy-related patterns of cytogenetic abnormalities in acute myeloid leukemia and myelodysplastic syndrome post polycythemia vera

A minor fraction of patients with polycythemia vera (PV) develop a terminal acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Analysis of the cytogenetic abnormalities during AML or MDS may help in understanding if this development is part of the natural course of the disease or induced by myelosuppressive therapy. Thirty-six cases with AML or MDS post PV, collected in a single Swedish institution during a 33-year period, are described with special regard to time to development of AML or MDS, therapy given during active PV, and cytogenetic findings during AML or MDS. A further 118 cases of AML or MDS post PV, in whom type of therapy during active PV and cytogenetic findings during AML or MDS were reported, were collected from the literature. AML or MDS developed in our own series after 1–30 years with a fairly constant rate (two cases per year). The most frequent cytogenetic abnormalities were +1q, −5, 5q−, −7, 7q−, +8, +9, 11q−, 13q−, and 20q−. When patients in the total material (n = 154) were divided with regard to treatment during active PV, marked differences were observed. The highest frequency of abnormalities was found in patients given multiple lines of therapy (n = 61), dominating features being −5/5q− in 28 patients (46%), −7/7q− in 19 patients (31%), numerous translocations in 24 patients (39%), and unidentified markers in 22 patients (36%). Half of the patients treated with hydroxyurea alone showed a −5 or 5q− abnormality. In patients treated with phlebotomy alone, +8 and +9 were the most frequent findings. The type of therapy given during active PV influences the type of chromosome abnormalities present during terminal AML or MDS and can also be instrumental in the development of leukemia.     

Arsenic disulfide-triggered apoptosis and erythroid differentiation in myelodysplastic syndrome and acute myeloid leukemia cell lines

Objectives

Effects of arsenic disulfide (As₂S₂) were investigated by focusing on growth inhibition, apoptosis induction, and erythroid differentiation in MDS-L, F-36p and HL-60 cells, derived from myelodysplastic syndrome (MDS), MDS/acute myeloid leukemia (AML), and de novo AML, respectively.

Methods

Cell viability was determined by MTT assay. Apoptosis induction was analyzed using Annexin V/propidium iodide staining. Erythroid differentiation was assessed by the expression level of CD235a, a marker for detection of the erythroid cell lineage. The activation of p38 MAPK and the expression profile of apoptosis-related proteins Bcl-2 and Bid were analyzed using western blot.

Results

As₂S₂ inhibited cell growth of these cell lines. Of note, the IC₅₀ value of As₂S₂ in MDS-L cells was comparable to that in F-36p cells, and was half of that in HL-60 cells. A dose-dependent decrease in cell viability and concomitant increase in the percentage of apoptotic cells were observed in F-36p cells treated with 8 and 16 µM As₂S₂ for 72 hours. However, similar phenomena were only observed in HL-60 cells when treated with as high as 16 µM As₂S₂. Furthermore, As₂S₂ exerted more potent erythroid differentiation-inducing activity on F-36p cells than HL-60 cells. Interestingly, negative correlation between p38 MAPK signaling pathway and As₂S₂-induced erythroid differentiation was observed in HL-60 cells. Treatment with relatively high concentration of As₂S₂ resulted in the downregulation of Bcl-2 and Bid proteins in HL-60 cells.

Discussion

These results suggest that compared to AML cell line, MDS and MDS/AML cell lines are more sensitive to not only the erythroid differentiation-inducing activity of As₂S₂, but also its cytotoxicity associated with apoptosis induction. These findings further provide novel insight into As₂S₂ action toward its use for clinical application in patients with hematological disorders.     

Reversible posterior leukoencephalopathy syndrome after repeat intermediate-dose cytarabine chemotherapy in a patient with acute myeloid leukemia

A 56-year-old man was admitted to our hospital with leukocytosis, anemia, and thrombocytopenia. Acute monoblastic leukemia was diagnosed. Two subsequent courses of consolidation chemotherapy consisted of conventional doses of cytarabine and intermediate-dose cytarabine. Intermediate-dose cytarabine was infused intravenously every 12 hr for 6 days. On day 15 after the final infusion of cytarabine, the patient suffered headache, and on day 21, he experienced a decrease in sensation on the sole of his left foot. Magnetic resonance imaging (MRI) of the brain revealed widespread areas of white matter edema. Cerebrospinal fluid (CSF) examination revealed an increase in the number of cells to 31 mm(-3); the majority were lymphocytes. No infiltration of leukemia cells was seen. After 2 months, brain MRI findings were normal. The clinicoradiologic features of the case were consistent with reversible posterior leukoencephalopathy syndrome (RPLS). RPLS in the present case was unlikely to have been caused by direct neurotoxicity because (1) the doses of cytarabine (500 mg/m(2); total dose 9.2 g) were much smaller than those in reported cases and were repeatedly infused until RPLS developed; (2) the RPLS developed 21 days after the final infusion of cytarabine, a much longer period than previously reported; (3) the slight leukocytosis in the CSF observed on day 33 might also have been related to the cellular immune responses evoked by the infused cytarabine. These details suggest not only that direct cerebral neurotoxicity of cytarabine but also that some type of allergic response may have been involved in the development of RPLS.     

粒细胞集落刺激因子预激下小剂量Ara-C和ACR治疗复发难治急性髓细胞性白血病及骨髓增生异常综合征

目的:观察并评价在粒细胞集落刺激因子(GCSF)预激下小剂量阿糖胞苷(AraC)联合阿克拉霉素(ACR)方案(以下称AGA方案)治疗复发和(或)难治急性髓细胞性白血病(AML)和骨髓增生异常综合征(MDS)患者有效性和不良反应,从细胞凋亡方面探讨治疗方案的可能机制。方法:对复发难治的18例AML及4例MDS患者行AGA方案治疗。化疗方案:AraC10mg/m2,第1～14天,1次/12h,皮下注射;ACR8mg·m-2·d-1,第1～8天,静脉滴注;GCSF200μg·m-2·d-1,第1～14天,皮下注射,每次先于皮下注射AraC前1h开始。结果:9/18(50%)例AML接受1个AGA治疗即获完全缓解(CR),中位数缓解期4个月,其中6/10(60%)例M2获CR,22例治疗病例均无治疗相关死亡。20例接受传统标准剂量化疗对照组7例获得CR,4例死于化疗相关毒性。体外研究证实AGA方案明显提高新鲜白血病细胞凋亡率。结论:AGA方案对正常造血抑制较轻,非血液学不良反应小,外周血白细胞和血小板恢复较常规化疗组明显缩短。适于不能耐受常规治疗的、骨髓呈低增生的复发难治或老年AML患者,该药物协同诱导凋亡可能是该方案的治疗机制之一。     

The value of oral cytarabine ocfosfate and etoposide in the treatment of refractory and elderly AML patients

Twenty-one acute myeloid leukemia (AML) patients were enrolled and received oral induction therapy with cytarabine ocfosfate (SPAC) and etoposide (EP). The median age was 69 years (range: 33–86). There were 11 patients with de novo AML and 10 AML cases that had evolved from myelodysplastic syndromes. Seventeen patients had abnormal karyotypes including eight complex abnormalities, various complications, and 7 of 21 had a poor performance status (PS) with Eastern Cooperative Oncology Group (ECOG) scores of 3–4. All patients completed induction therapy without severe adverse events. Seven achieved complete remission (CR), and two achieved partial remission (PR). Uni- and multivariate analyses demonstrated a positive and significant correlation between the results of therapy (CR ± PR) and overall survival. The plasma concentrations of cytosine arabinoside (ara-C) in some cases were higher than those previously reported, indicating the accumulation of ara-C with increasing numbers of days of SPAC administration. We conclude that this therapy is well tolerated and useful for refractory and elderly AML patients.     

Long-term survival after induction therapy with idarubicin and cytosine arabinoside for de novo acute myeloid leukemia

 We treated 153 patients with de novo acute myeloid leukemia (AML) with two induction courses of conventional-dose cytosine arabinoside (ara-C) and idarubicin (AIDA) followed by either a third course of AIDA, high-dose ara-C or bone-marrow transplantation. The complete remission (CR) rate for all patients was 63.4%, with a higher CR rate for patients with a normal (versus unfavorable) karyotype (73.2% vs 52.5%;P=0.038). The probability of overall survival (OS) was 30.7% after 5 years (26.3% after 7 years). Improved OS at 5 years could be observed for patients up to 50 years old versus patients older than 50 years of age (37.6% vs 19.9%;P=0.001) and patients with a normal (versus unfavorable) karyotype (42.9% vs 14.1%;P=0.0016). Disease-free survival (DFS) after 5 years was 33.2% for all 97 CR patients and was significantly better for patients with a normal (versus unfavorable) karyotype (44.3% vs 12.3%;P=0.003). Multivariate analysis revealed that the age for OS (P<0.02) and the karyotype for both OS (P<0.03) and DFS (P<0.05) were independent prognostic factors. In conclusion, AIDA is an effective and well-tolerated induction regimen (even in elderly patients) with a 5-year survival of more than 30% when combined with ara-C-containing postremission therapy. The karyotype is the most powerful prognostic factor for predicting the outcome of patients treated with this protocol. Received: 10 December 1999 / Accepted: 25 February 2000     

Controversies in the recent (2016) World Health Organization classification of acute myeloid leukemia

The current World Health Organization (WHO) Classification of acute myeloid leukemia (AML), developed in 2016 and published in 2017, codifies the defining features of AML and recognizes several subtypes based on clinical, morphologic, and genetic features. This classification is widely used for the purposes of assigning patients to specific therapeutic approaches and entry into clinical trials. Although the WHO Classification ultimately has its origins in the original 1976 French-American-British Classification, it has been periodically updated by the incorporation of a large body of evidence and input from both diagnosticians and clinicians who study and treat AML. Nevertheless, the recent accumulation of genetic data on the molecular underpinnings of myeloid neoplasms as well as numerous recently approved novel therapies have highlighted areas of controversy in how we currently define and classify AML; the 2016 WHO Classification will continually be revised and updated in future versions based on these advances. The purpose of this review is to explore areas of potential refinement in the current WHO Classification of AML, both in terms of its criteria defining the disease as well as the specific disease subtypes.     

Pure red cell aplasia evolving through the hyperfibrotic myelodysplastic syndrome to the acute myeloid leukemia: some pathogenetic aspects

The authors report a 58-year-old female who originally presented with acquired pure red cell aplasia (PRCA). At diagnosis, the karyotype was normal, the serum erythropoietin level was highly elevated and no T-cell mediated inhibition of erythropoiesis was demonstrated in coculture studies. Conventional immunossupressive therapy proved ineffective. A year later a diagnosis of hyperfibrotic myelodysplastic syndrome was assessed. The sequential bone marrow examinations in the course of the three years showed a progressive increase in bone marrow fibrosis, erythroid hyperplasia and dysmegakaryocytopoiesis, terminating in the acute myeloid leukemia. This sequence of the events included the appearance of del(5)(q13q33), four years after setting a diagnosis of PRCA. The authors suggest that the absence of both cytogenetic abnormality and the signs of dyshematopoiesis at the diagnosis of PRCA does not exclude ultimately a clonal category of the disease. Thus, repeated hematological and cytogenetical reevaluations are recommended.The work was carried out in the Cytogenetics Laboratory and Cell Culture Laboratory of the Institute of Hematology     

Clinical effect of increasing doses of lenalidomide in high-risk myelodysplastic syndrome and acute myeloid leukemia with chromosome 5 abnormalities

Background

Patients with chromosome 5 abnormalities and high-risk myelodysplastic syndromes or acute myeloid leukemia have a poor outcome. We hypothesized that increasing doses of lenalidomide may benefit this group of patients by inhibiting the tumor clone, as assessed by fluorescence in situ hybridization for del(5q31).

Design and Methods

Twenty-eight patients at diagnosis or with relapsed disease and not eligible for standard therapy (16 with acute myeloid leukemia, 12 with intermediate-risk 2 or high-risk myelodysplastic syndrome) were enrolled in this prospective phase II multicenter trial and treated with lenalidomide up to 30 mg daily for 16 weeks. Three patients had isolated del(5q), six had del(5q) plus one additional aberration, 14 had del(5q) and a complex karyotype, four had monosomy 5, and one had del(5q) identified by fluorescence in situ hybridization only.

Results

Major and minor cytogenetic responses, assessed by fluorescence in situ hybridization, were achieved in 5/26 (19%) and 2/26 (8%) patients, respectively, who received one or more dose of lenalidomide, while two patients achieved only a bone marrow response. Nine of all 26 patients (35%) and nine of the ten who completed the 16 weeks of trial responded to treatment. Using the International Working Group criteria for acute myeloid leukemia and myelodysplastic syndrome the overall response rate in treated patients with acute myeloid leukemia was 20% (3/15), while that for patients with myelodysplastic syndrome was 36% (4/11). Seven patients stopped therapy due to progressive disease and nine because of complications, most of which were disease-related. Response rates were similar in patients with isolated del(5q) and in those with additional aberrations. Interestingly, patients with TP53 mutations responded less well than those without mutations (2/13 versus 5/9, respectively; P=0.047). No responses were observed among 11 cases with deleterious TP53 mutations.

Conclusions

Our data support a role for higher doses of lenalidomide in poor prognosis patients with myelodysplastic syndrome and acute myeloid leukemia with deletion 5q. (Clinicaltrials.gov identifier {"type":"clinical-trial","attrs":{"text":"NCT00761449","term_id":"NCT00761449"}}NCT00761449).     

Recent-onset myelodysplastic syndrome mimicking acute leukemia during infection

A previously healthy 74-year-old patient without a prior history of hematological disease presented with an acute respiratory infection. Peripheral pancytopenia led us to perform a bone marrow biopsy, and the diagnosis of undifferentiated acute myelogenous leukemia (AML, 61% blasts) was made. Following antibiotic treatment and resolution of the infection, the blast count in the bone marrow fell to 2%, leaving a clinicopathologic picture consistent with myelodysplastic syndrome (MDS, French-American-British type refractory anemia), and the patient survived for a total of 16.5 months following the initial presentation with cytokine support. A preterminal blast proliferation occurred during a bacterial ear infection and rapidly responded to a withdrawal of cytokine support, antibiotic therapy, and hydroxyurea. The patient succumbed ultimately to an apparent myocardial infarct. Clinicians should consider transient acceleration of MDS in their differential diagnosis when confronted with apparent AML and acute infection.