Clinical trial of low dose cytosine arabinoside in the treatment of acute promyelocytic leukemia.

The purpose of this study is to determine the efficacy of low dose cytosine arabinoside (LD Ara-C) as an alternative treatment to conventional cytotoxic induction chemotherapy in childhood acute promyelocytic leukemia (APL). Four children with APL in poor medical condition prior to chemotherapy were treated with LD Ara-C (10 mg/m2/12 h) for 3 weeks. In three patients, the second course was administered after a resting period of two weeks. Subsequent conventional cytotoxic induction chemotherapy was applied in patients who did not enter complete remission (CR). After induction of CR, maintenance chemotherapy with a conventional monthly multi-drug regimen was applied. CR in one patient and partial remission (PR) in two patients were obtained after two courses of LD Ara-C. Patients who did not enter CR after LD Ara-C entered on subsequent conventional chemotherapy. There were no major complications such as intracranial hemorrhage and sepsis; myelosuppression was not as severe as in conventional chemotherapy; there was clinical and laboratory improvement in coagulopathy. We concluded that LD Ara-C may be an alternative treatment to the conventional chemotherapy in children with APL, especially in whom conventional cytotoxic induction chemotherapy is thought to increase the risk of serious complications and early fatality during induction chemotherapy.     

Detection of residual disease in acute myeloid leukemia using light density gradients and culture assay

For monitoring the effect of chemotherapy in acute myeloid leukemia (AML), we attempt to detect minimal numbers of AML clonogenic cells (CFU-L) during remission using light density gradients combined with PHA-LCM methyl cellulose assay. Fifteen patients in complete remission (CR) of AML were studied: 8 patients with Auer Rods (AR+), and 7 without Auer Rods (AR-). The cluster/colonies ratio and the granulocytic maturation of cells from pooled colonies were not significantly different whatever the density cut used (1077, 1062 or 1059). In all the AR+ patients, few AR+ cells (.06% +/- .03) were observed in bone marrow cultures during remission, without differences between density gradients, but not before plating. These AR+ cells were not found in culture of AR- patient bone marrows nor in normal marrows. The serial studies performed in 6 patients (4 AR+, 2 AR-) were not contributive for relapse prediction. In 2 cases, the second examination failed to detect AR+ cells: one was performed after an autologous bone marrow transplantation and the other in a patient with prolonged CR (54+ months). A quantitative analysis of residual CFU-L with our technique requires a cytological examination of each colony, that is very time consuming and limits its routine use.     

Acute promyelocytic leukemia is a distinct subset of acute myelocytic leukemia with unique clinicopathologic characteristics including longer duration of relapse free survival: experience in 13 cases.

Acute promyelocytic leukemia(APL) is a subtype of acute myelocytic leukemia(AML) associated with unique features such as the presence of atypical promyelocytes and bleeding tendency due to disseminated intravascular coagulation(DIC). In a retrospective study, we analyzed 96 cases of AML seen at our hospital between June, 1989 and December 1993. Thirteen cases of APL(14%) were identified and their clinicopathologic characteristics were analyzed. The 86 cases of other types of AML served as controls. The distinct clinicopathologic features of APL as contrasted to other types of AML included younger age of patients, shorter duration of symptom before diagnosis, higher level of albumin at presentation, and a higher proportion of patients having coagulation abnormalities (75 vs. 25%). Bone marrow cellularity was higher in APL when compared to other types of AML (100 vs. 90%, P = 0.013). Of 13 patients with APL, 4 died of bleeding/sepsis between days 2 to 4 after admission. Seven of 9 patients who received induction therapy achieved complete remission(CR). CR rate in APL was similar to other types of AML (78 vs. 64%, P = 0.743). Five of seven patients who achieved CR remain in continuous CR at 9+ to 42+ months. CR duration is significantly longer in APL when compared to other types of AML (P = 0.029). In conclusion, this study showed that APL is a distinct entity among subtypes of AML with clinically significant bleeding tendency and rapidly fatal course if untreated. With appropriate antileukemic therapy, CR can be achieved in the majority of patients and the patients show a longer duration of CR when compared to other types of AML.     

High expression of FCHSD2 is associated with chemoresistance in adult acute myeloid leukemia

Acute myeloid leukemia (AML) is a clonal disease, characterized by the growth and accumulation of immature cells in the bone marrow, which in turn affects production of normal blood cells. Increasing need for biomarkers that can predict the outcome of treatment are becoming of potential value because of the heterogenous response to induction chemotherapy. FCHSD2 was identified as a potential chemoprotector. In the present study, we used qRT-PCR to assess FCHSD2 expression levels in peripheral blood or bone marrow blasts of 50 de novo AML patients before remission induction chemotherapy. There was higher expression levels of mRNA in AML patients than control group median (1.36, 0.70), respectively. Patients were subgrouped into responders(R) and nonresponders (NR) after remission induction therapy. The mean expression level of FCHSD2 mRNA in responders (32/50) was 1.7?±?2.8, while it was 7.9?±?6.6 in NR (18/50). Our results demonstrated that the patients with lower FCHSD2 expression prior to the treatment had an increased chance of attaining remission compared to patients with high-level FCHSD2. In conclusion, our data suggests that FCHSD2 can serve as a new biomarker for the prediction of treatment outcome in AML patients. The quantitation of FCHSD2 expression at the time of diagnosis could help to identify the responses to chemotherapy.     

Intensive retreatment of childhood acute lymphoblastic leukemia in first bone marrow relapse. A Pediatric Oncology Group Study

We devised a plan of intensive chemotherapy to address the problem of inadequate results of treatment in children with acute lymphoblastic leukemia in first bone marrow relapse. Immediately after remission was induced with four conventional drugs, a two-week intensification course of teniposide and cytarabine was given to eradicate subclinical leukemia. Patients in remission were then treated for two years with rapid rotation of pairs of drugs that were not cross-resistant and periodic courses of the same agents used to induce remission. A second complete remission was induced in 31 of the 39 patients in whom response to chemotherapy could be assessed. The probability of maintaining bone marrow remission in these patients for one year was 0.38 +/- 0.19 (95 percent confidence interval); the two-year probability was 0.29 +/- 0.17. Seven patients completed the treatment program, five of whom have been in continuous second complete remission 17 to 20 months after the cessation of therapy. Children whose initial bone marrow remission lasted less than 18 months had significantly poorer responses to retreatment than did those with a longer first remission (P = 0.004). Intensive chemotherapy, as described here, may save half of the children with acute lymphoblastic leukemia in whom bone marrow relapse occurs after a relatively long initial remission.     

New strategies for the treatment of acute myelogenous leukemia: differentiation induction--present use and future possibilities

A differentiation block and an accumulation of immature myeloid cells characterize acute myelogenous leukemia (AML). However, native AML cells usually show some morphological signs of differentiation that allow a classification into different subsets, and further differentiation may be induced by exposure to various soluble mediators, for example, all-trans retinoic acid (ATRA) and several cytokines. Combination therapy with ATRA and chemotherapy should now be regarded as the standard treatment of the acute promyelocytic leukemia (APL) variant of AML. Although several agents can also induce leukemic cell differentiation for other AML subgroups, in vitro studies as well as clinical data have demonstrated that these agents often have heterogeneous effects on the leukemic progenitors. This makes the clinical impact of differentiation induction therapy for individual patients difficult to predict. However, differentiation induction should be regarded as a promising therapeutic approach, especially as a part of immunotherapy or in combination with intensive chemotherapy to increase the susceptibility of AML blasts to drug-induced apoptosis. Although the morphology-based French-American-British classification was used to identify APL as an AML subset that required a special treatment, it seems unlikely that this classification alone can be used to identify new subsets of AML patients with special therapeutic requirements. Future studies on differentiation induction in AML should therefore focus on A) the identification of therapeutic agents with more predictable effects; B) the use of clinical and laboratory parameters to define new subsets of AML patients in which differentiation induction has a predictable and beneficial effect, and C) the characterization of how AML blast sensitivity to drug-induced apoptosis is altered by differentiation induction.     

High risk of streptococcal septicemia after high dose cytosine arabinoside treatment for acute myelogenous leukemia

Summary Twenty-nine adult patients with acute myelogenous leukemia AML who received 40 treatment courses with high dose cytosine arabinoside (HD-A), alone or combined with other cytotoxic drugs, for remission induction (RI) or postremission intensive consolidation (IC) were retrospectively analysed for types and severity of infectious complications. In this paper, we report the unusually high rate of streptococcal septicemia in our patients. Of 13 bacteremic infections in a total of 45 infectious episodes, 10 were caused by streptococci (9 viridans streptococci, 1 group B hemolytic streptococcus). Three of them were lethal. After reviewing all documented cases of streptococcal septicemia in the same study period, four additional cases among adult patients with AML were identified. Three of them have had antileukemic chemotherapy without HD-A, while one have had HD-A as a conditioning regimen for bone marrow transplantation. Only three cases were documented to occur in adult patients with AML. Patients treated with HD-A for RI or IC had a significantly lower risk of streptococcal septicemia during previous chemotherapy-associated febrile neutropenic episodes (1/55 vs 10/45;P=0.01). Neither prophylactic regimens including trimethoprim-sulfamethoxazole nor those without it were effective in preventing streptococcal septicemia. Further studies are needed to confirm these data before the value of additional or alternative prophylactic antibiotics is proven necessary.Abbreviations AML Acute myelogenous leukemia - HD-A High dose cytosine arabinoside - IC Postremission intensive consolidation - RI Remission induction     

去甲柔红霉素联合中剂量阿糖胞苷强化治疗急性髓细胞白血病（附53例报告）

目的探讨去甲柔红霉素联合中剂量阿糖胞苷(IDAra-C)治疗急性髓细胞白血病(AML)治疗效果。方法用去甲柔红霉素联合IDAra-C,对53例AML患者进行化疗,其中用于原发性治疗30例,用于难治性复发性AML诱导缓解治疗23例。结果原发性治疗组中,中位完全缓解期17个月,治疗相关死亡2例;难治性复发性AML组12例取得完全缓解。结论去甲柔红霉素联合IDAra-C,用于原发性AML的缓解治疗,可减少复发率,延长缓解期,提高无病生存率,用于难治性复发性AML的治疗也疗效明显,绝大多数病人可耐受治疗。     

Treatment of acute myeloid leukemia by directly targeting both leukemia stem cells and oncogenic molecule with specific scFv-immunolipoplexes as a deliverer

Acute myeloid leukemia (AML) is characterized by the accumulation of immature myeloid cells in the bone marrow and the suppression of normal hematopoiesis, chemotherapy is currently the most used method to treat AML. The standard chemotherapy results in a more than 50% complete remission rate in AML patients. However, treatment with drugs such as anthracyclines is associated with severe side effects and a high incidence of relapse, the long-term survival of AML is poor. The success of the treatment of acute promyelocytic leukemia with all trans retinoic acid and chronic myeloid leukemia with imatinib mesylate (Gleevec) has led to increased efforts to look for agents for AML targeted therapy. But, most of presented targeted therapy agents do only direct some oncogenic molecules involved in the leukemogenesis of AML, their anti-leukemic efficacy is unsatisfied. Thus, novel therapeutic approaches are required. In recent years, a leukemia stem cells (LSCs) origin for AML has been demonstrated, and some unique immunophenotype and specific molecular features of LSCs have also been identified. With the technique development of Immunoliposomes (antibody-coupled liposomes) and the recombination of the variable regions of heavy and light chains and their integration into a single polypeptide that offer the possibility of using single-chain antibody variable region fragments (scFv) for targeting purposes, here we put the hypothesis that treatment of AML by targeting both LSCs and oncogenic molecule participated in AML pathogenesis, with LSCs-specific scFv-immunolipoplexes as a deliverer, might be possible. If successfully using this approach in practice, LSCs might be selectively eradicated and AML might be cured.     

自体造血干细胞移植联合异体细胞因子诱导的杀伤细胞及白细胞介素2治疗高危急性髓系白血病2例*

背景：自体造血干细胞移植治疗高危急性髓系白血病的复发率极高,如何降低移植后复发率至今仍是难点。 目的：观察自体造血干细胞移植联合异体细胞因子活化杀伤(CIK)细胞及白细胞介素2治疗高危急性髓系白血病的临床效果。 方法：2例高危急性髓系白血病患者,经诱导化疗及巩固强化治疗后,在第1次缓解期行自体造血干细胞移植, 移植后1个月给予三四疗程异体CIK细胞输注,每隔半年1个疗程,每疗程分5次输注异体CIK细胞,每隔1日输注1次。每次输注CIK细胞前半小时内给予皮下注射白细胞介素2,第1次输注后隔日皮下注射白细胞介素2,半年后减为隔2日1次,1年后减为隔3日1次,1年半后减为1次/周,维持半年后结束,预防白血病复发。 结果与结论：2例患者自体造血干细胞移植后输注异体CIK细胞及皮下注射白细胞介素2无发热、寒战、皮疹等不良反应,无骨髓抑制及移植物抗宿主反应,治疗安全。2例患者持续缓解时间分别为20个月及2年,目前仍无复发。首次得出对于无合适供者的高危急性髓系白血病患者,在缓解后可行自体造血干细胞移植联合异体CIK细胞及白细胞介素2治疗,有机会获得长期无病生存。       

Recent progress in the treatment of adult acute leukemia

In 3 studies for adult acute myelogenous leukemia (AML) treated with BHAC-DMP, BHAC-DMP(II) and M-85 from 1979 to 1987, intensive induction resulted in a higher cure rate, since reduction of the blasts in bone marrow at 2 weeks after the initiation of therapy to less than 20% was the most significant prognostic factor to predict the long complete remission (CR), followed by initial WBC counts (less than 60,000/cmm) and achievement of CR within 50 days or by one course of induction therapy. However, it seemed impractical to give very intensive chemotherapy during the induction because of the high frequency of complications due to prolonged myelosuppression. Consolidation should be as intensive as possible. Non-cross resistant drugs will theoretically produce better results. In M-85 protocol, 71% of 41 adult AML achieved CR. The predicted 3.5-year survival and CR length of CR cases are 74 and 56%; respectively. The preliminary results of JALSG-AML87 and -ALL87 were also reviewed.     

Therapy-related myelodysplastic syndrome/acute myeloid leukemia with del(7)(q22) in a patient with de novo AML

A 55-year-old Korean woman was initially diagnosed with acute myelomonocytic leukemia (AML). After induction chemotherapy was performed using cytarabine, idarubicin, and G-CSF, complete remission (CR) was subsequently achieved following reinduction chemotherapy using the same chemotherapeutic agents. Thirty-six months after the initial CR, an increase in immature cells (up to 12.0%) was observed in the patient's bone marrow. Because chromosome analysis revealed a karyotype of 46,XX,del(7)(q22) in all of the analyzed cells, the patient was diagnosed with therapy-related myelodysplastic syndrome (t-MDS). Although the patient subsequently received chemotherapy and G-CSF for neutropenia, t-MDS rapidly progressed after 3 months to therapy-related acute myeloid leukemia (t-AML). Although very rare, de novo AML can progress to a secondary MDS/AML with del(7q) after chemotherapy with cytarabine, idarubicin, and G-CSF. Further investigation into the role of genes located in 7q22 may provide more information about the mechanisms of leukemogenesis.     

New trends in the treatment of leukemia]

More than 50% cure can be obtained with allogeneic bone marrow transplantation (BMT) when patients are transplanted in first remission of AML and ALL or chronic phase of CML. On the other hand, considerable progress has been made recently in treating acute leukemia with chemotherapy. Recent studies of intensive chemotherapy in adults with AML report approximately 40-50% 3-year disease-free survival (DFS). Accordingly, several prospective randomized clinical trials have been conducted on the use of BMT versus intensive chemotherapy in the treatment of AML. Significant differences in DFS were found only in a few studies though the results of BMT appear to be comparable or superior to chemotherapy. Therefore, the overall advantage of BMT in first remission AML is smaller than expected. We should know not whether to transplant or to perform chemotherapy, but rather whether to transplant in first remission or to perform chemotherapy first and reserve transplantation as salvage therapy. Recently acute promyelocytic leukemia has been successfully treated with differentiation therapy using all-trans retinoic acid. Low-dose aclarubicin has also been reported to be effective as differentiation therapy in some patients with myelodysplastic syndrome and atypical AML. With the advance of molecular biology of cytokines, several of them are now available for clinical use. G-CSF, GM-CSF and M-CSF are potent stimulators for the granulocyte-macrophage production; they are very effective for accelerating hematologic recovery after chemotherapy-induced myelosuppression or BMT. Interferon-alpha (IFN-alpha) has been used in the several studies. Furthermore, Ph chromosome positivity can be reduced with long-term administration of IFN-alpha; Ph-positive clone can be undetectable in some patients. Thus, IFN-alpha will be the choice of treatment for CML even if BMT is planned.     

Długotrwała odpowiedź na leczenie azacytydyną pacjentki z ostrą białaczką szpikową z niekorzystnym profilem cytogenetycznym – prezentacja przypadku

Acute myeloid leukemia (AML) is the most common type of leukaemia found in adults and the number of disease cases increases with age. Despite the advances in the AML treatment, the results in patients over the age of 60 remain unsatisfactory.In this study we present the case of a 73-year-old female patient with an unfavourable cytogenetic profile, in whom we observe long-term response to azacitidine, after previous failures of classic polychemotherapy.In February 2010, a 70-year-old patient was admitted to the Department of Haematology USK in Bialystok on suspicion of AML. The patient was qualified for intensive chemotherapy regimen of daunorubicin (DNR) and cytarabine (Ara-C).Cytogenetic examination revealed the presence of double minutes – acentric fragments of extrachromosomal DNA, which is associated with resistance to standard chemotherapy. Induction chemotherapy was complicated by febrile neutropenia, pneumonia and episodes of atrial fibrillation. Due to the lack of remission and severe after-induction period, a brief reinduction chemotherapy with DNR and Ara-C was applied to obtain complete remission with incomplete regeneration (CRi).Due to the recurrence in October 2010, reinduction chemotherapy was given followed by two cycles of maintenance chemotherapy. After another relapse in February 2011 (23,6% blasts in the bone marrow), a chemotherapy regimen designed for refractory and relapsed leukaemia was given, without any effect. In April 2011, the patient began azacitidine treatment. By the end of March 2013, the patient received twenty-one treatment cycles. The twelfth cycle of chemotherapy was complicated by pulmonary embolism which was treated successfully. The complete blood count remains at normal values.Recent reports indicate a clear relationship processes such as epigenetic regulation of DNA methylation with leukaemogenesis. The use of hypomethylating drugs in AML is yielding promising results.     

肝移植后的继发急性髓系白血病

背景：肝移植后急性髓系白血病是一种极少见但病死率极高的并发症。 目的：分析肝移植后急性髓系白血病的临床特征。 方法：报告1例肝移植后发生急性早幼粒细胞性白血病病例,并辅以文献复习。 结果与结论：患者接受原位肝移植后85个月,拔牙后出血不止,进一步查凝血功能异常、血常规、骨髓细胞学、白血病免疫分型检查提示为急性早幼粒细胞白血病、PML/RARa融合基因阳性,明确诊断急性早幼粒细胞性白血病,合并弥散性血管内凝血,给予输注新鲜冰冻血浆纠正凝血异常,经维甲酸、亚砷酸、柔红霉素联合诱导化疗,骨髓完全缓解。予柔红霉素和阿糖胞苷,米托蒽醌和阿糖胞苷巩固化疗2个疗程,之后定期予亚砷酸化疗,骨髓持续缓解。化疗同时,调整免疫抑制剂剂量和类型,患者肝功能稳定,未发生严重感染等并发症。结果说明,肝移植后可并发急性髓系白血病,以急性早幼粒细胞白血病常见,肝移植患者出现血象、凝血异常,要考虑急性早幼粒细胞白血病可能。应早期诊断及治疗,以减少死亡率。     

Prognostic factors of acute myelocytic leukemia: an analysis of 132 patients in a single institution.

Patients with acute myelocytic leukemia (AML) have varied outlooks for survival after the diagnosis. To identify pretreatment prognostic indicators in AML, we analyzed 132 cases of AML seen at our hospital between June, 1989 and December, 1994. The median age of the patients was 40 years (range, 15-81). There were 63 male and 69 female patients. One hundred eight patients (82%) received induction chemotherapy which was based on cytarabine plus anthracyclines. Sixty six patients achieved complete remission (CR) and the CR rate among the patients given induction chemotherapy was 61%. The median duration of CR was 11.2 months. After median follow up of 6.6 months (range 0.5-51.4), 26 patients (39%) remain in continuous CR. The median duration of overall survival of the patients was 6.7 months. After median follow up of 10.6 months (range, 0.1-52.7), 41 patients (31%) are alive. Variables affecting duration of CR included the age of the patients, performance status of the patients, percentage of blast in the peripheral blood, hemoglobin level, percentage of blast in the bone marrow, FAB subtype, and CD7 marker positivity. Variables affecting survival duration included age of the patients, performance status of the patients, absolute blast count (ABC) in the peripheral blood, bone marrow cellularity, the percentage of blast in the bone marrow, and CD5 marker positivity. Multivariate analysis showed that the age of the patients and percentage of blast in the bone marrow were significant independent indicators for overall survival of the patients. Further studies utilizing cytogenetics and molecular characteristics of leukemic cell are warranted to better define the prognostic factors of patients with AML.     

Secondary acute myeloid leukemia in children treated for acute lymphoid leukemia

We studied the risk of the development of acute myeloid leukemia (AML) during initial remission in 733 consecutive children with acute lymphoid leukemia (ALL) who were treated with intensive chemotherapy. This complication was identified according to standard morphologic and cytochemical criteria in 13 patients 1.2 to 6 years (median, 3.0) after the diagnosis of ALL. At three years of follow-up, the cumulative risk of secondary AML during the first bone marrow remission was 1.6 percent (95 percent confidence limits, 0.7 and 3.5 percent); at six years, it was 4.7 percent (2 and 10 percent). The development of secondary AML was much more likely among patients with a T-cell than a non-T-cell immunophenotype (cumulative risk, 19.1 percent [6 and 47 percent] at six years). Sequential cytogenetic studies in 10 patients revealed entirely different karyotypes in 9, suggesting the induction of a second neoplasm. In eight of these patients, the blast cells had abnormalities of the 11q23 chromosomal region, which has been associated with malignant transformation of a pluripotential stem cell. There was no evidence of loss of DNA from chromosome 5 or 7, a karyotypic change commonly observed in cases of AML secondary to treatment with alkylating agents, irradiation, or both. We conclude that there is a substantial risk of AML in patients who receive intensive treatment for ALL, especially in those with a T-cell immunophenotype, and that 11q23 chromosomal abnormalities may be important in the pathogenesis of this complication.     

Growth rate and sister chromatid exchange (SCE) incidence of bone marrow cells in Acute Myeloblastic Leukemia (AML)

The sister chromatid exchange (SCE) incidence and growth kinetics have been studied by means of an in vitro bromodeoxyuridine (BrdU) chromosome labeling method in the bone marrow cells of 17 acute myeloblastic leukemia (AML) patients with only diploid cells at diagnosis, remission, and relapse of the disease. At diagnosis, the cells tended to exhibit a low SCE frequency as compared to that during remission. An increased SCE frequency was observed after chemotherapy during remission or relapse. At diagnosis and relapse, when leukemic blast cells predominated in the marrow, they were characterized by the predominance of cells that had undergone only one cell cycle after BrdU exposure. In contrast, the marrow cells during remission tended to resemble the control pattern of growth kinetics, with a predominance of cells undergoing second and third cell cycles in the presence of BrdU. These results suggest that the growth rate of leukemic and nonleukemic cells is different, and that chemotherapy can cause an increased SCE frequency in the marrow cells of AML patients irrespective of the state of the disease.