Effect of Dose Ratio on Mitoxantrone and Daunorubicin in Acute Myeloid Leukemia: A Systematic Review and Meta-analysis of Randomized Controlled Trials

PurposeTo investigate the effects of mitoxantrone and daunorubicin in induced chemotherapy on complete remission (CR), death during induction therapy, overall survival (OS), disease-free survival (DFS), and relapse in patients of all ages with acute myeloid leukemia (AML).MethodsWe searched published reports at the Medline, Embase, and Cochrane Databases as well as other databases from inception through July 2019. There was no restriction on date of publication or language (PROSPERO registration CRD42018095843).ResultsWe enrolled 12 randomized controlled trials that included data of 4583 AML patients whose disease was untreated or relapsed/refractory, and compared the CR, death during induction therapy, DFS, and OS between mitoxantrone and daunorubicin. Mitoxantrone significantly increased the CR rate (relative risk = 1.07; 95% confidence interval [CI], 1.01, 1.14; P = .03) and DFS (hazard ratio = 0.87; 95% CI, 0.79, 0.96; P = .005) compared to daunorubicin. However, there was no significant difference in death during induction therapy (relative risk = 1.00; 95% CI, 0.81, 1.24; P = .99) and OS (hazard ratio = 0.94; 95% CI, 0.87, 1.01; P = .077) between the two drugs.ConclusionAlthough more studies are needed to compare mitoxantrone with higher-dose daunorubicin, the results showed that compared to daunorubicin, mitoxantrone can significantly improve CR and DFS in patients of all ages. These findings suggest that mitoxantrone may be a better choice than daunorubicin as an induction chemotherapy agent for AML patients, especially in developing countries.     

吡喃阿霉素米托蒽醌治疗非霍奇金淋巴瘤

目的 观察以吡喃阿霉素为主的CTOP方案治疗非霍奇金淋巴瘤的疗效，并与以米托蒽醌为主的CMOP方案进行比较。方法 THP方案组治疗NHL26例，21d一个周期；MIT方案组治疗NHL25例，21d一个周期。结果 初发患者以THP为主方案治疗后有效率为81．81％，复发或难治患者的有效率为53．33％；MIT方案组治疗初发患者的有效率为75．00％，复发或难治患者的有效率为33．33％。THP及MIT治疗非霍奇金淋巴瘤的疗效无差异（P〉0．05）。结论 THP是治疗非霍奇金淋巴瘤的高效低毒的化疗药物。     

肝动脉栓塞米托蒽醌乙基纤维素微球的制剂学研究

利用正交实验设计法优选适用于肝动脉栓塞的米托蒽醌乙基纤维素微球制备条件和工艺，采用动态透析法模拟体内情况研究了该微球的体外释药规律；根据混悬液的稳定性理论，优选并制备了适于临床肝动脉介导栓塞使用的米托蒽醌乙基纤维素微球混悬注射液。结果表明：在优化工艺条件下制得的米托蒽醌乙基纤维素微球外观圆整，球径在４０～１５０μｍ范围内的占总数的８６．５％，平均球径为１１０．２４±３８．１９μｍ；包封率为５５．６％；载药量为１２．５％，体外释药符合单指数模型，释药方程为ｌｏｇ（Ｙ∞－Ｙ）＝－０．１１６ｔ－１．１９８×１０（－３）（ｒ＝０．９９９２，ｔ（５０）＝２．６ｈ）；其混悬注射液理化性质稳定，可适于临床应用。     

Fludarabine, cyclophosphamide and mitoxantrone for untreated follicular lymphoma: a report from the non-Hodgkin's lymphoma co-operative study group

The aim of the study was to determine the safety and efficacy of the combination of fludarabine (FLU), cyclophosphamide (CY) and mitoxantrone (FLU/CY/MITO) in untreated follicular lymphomas (FL). Sixty patients with newly diagnosed stage II bulky to IV FL, median age 59 years (range 36 - 70), received FLU/CY/MITO regimen (FLU 25 mg/m² days 1 - 3, CY 300 mg/m² days 1 - 3, Mito 10 mg/m² day 1). Patients received antibiotic oral prophylaxis during all treatments, and growth factors (G-CSF) when grade III granulocytopenia (WHO) occurred. The overall response rate was 87%: 46 patients achieved complete response (CR) (77%), 6 a partial response (10%) and 8 were non-responders. Fifty patients are surviving with a median observation time of 31 months. The 4-year estimated probability of overall survival and failure-free survival were 78.2% and 45% respectively. Thirty-five patients (58%) are still in CR. Sixty percent of patients experienced grade III-IV granulocytopenia. Two patients suffered grade III pulmonary infection and one grade III liver toxicity. In a subset of 46 patients, bcl-2 translocation was positive in bone marrow (BM) and/or peripheral blood (PB) of 36 patients. At the end of treatment, 25 of these patients had CR and 19 (76%) converted to polymerase chain reaction (PCR) negativity. FLU/CY/MITO regimen showed a high level of activity in follicular lymphoma. Toxicity, mainly hematological, was acceptable and the treatment was made feasible by the use of antibiotic prophylaxis and G-CSF. Significant non-hematological toxicities were seen, but no patients died. The conversion of bcl-2 from positive to negative by PCR in BM and/or PB suggests a possible role for this treatment in clearing minimal residual disease and improving patients' outcome.     

Therapy-related acute leukemia in two patients with multiple sclerosis treated with Mitoxantrone

Two cases of therapy-related acute leukemia (TRAL) after the use of Mitoxantrone for the treatment of secondary progressive multiple sclerosis (MS) are reported. They were extracted from the group of 42 consecutive patients with TRAL diagnosed and treated in single centre between 2000–2010. They were the only two with MS and the only two treated with Mitoxantrone. The first patient was a 43-year-old male with a previous history of MS of 15-year-duration, who developed acute promyelocytic leukemia 9 months following Mitoxantrone therapy (cumulative dose 120 mg). The second patient was a 55-year-old female suffering from MS for 16 years, who developed acute mixed-phenotype leukemia, T/myeloid type, with 46,XX,del(7)(p13)[12]/47,XX,idem,+3/[6]/46,XX[2], 15 months after completion of Mitoxantrone therapy (cumulative dose 100 mg). Acute mixed-phenotype leukemia, T/myeloid type is for the first time described in the context of prior Mitoxantrone therapy. Although the incidence of TRAL in relation to Mitoxantrone pretreatment is rare, we should be vigilant for the prompt identification of this adverse event.     

Stability of cognitive functions under mitoxantrone therapy in patients with progressive multiple sclerosis: a pilot analysis

Objective

Mitoxantrone (MX) is a potent immunosuppressant that is licensed as escalation therapy for the treatment of active multiple sclerosis (MS).

Methods

In an open-label, retrospective analysis, we investigated effects of MX therapy on parameters of cognitive functions in patients with progressive MS and significant disability. Twenty patients received a total of 42 mg/m² MX in 4 cycles. Six patients who fulfilled the criteria for MX therapy, yet did not receive this treatment, served as controls. Before initiation of therapy and after a mean observation period of 24 months, neurological examination and a neuropsychological test battery were performed. Neuropsychological analyses comprised tests for cognitive flexibility as a part of executive functioning, and verbal as well as non-verbal tests for memory and attention. Additionally, intelligence and symptoms of depression were investigated.

Results

While there was stability of EDSS over time, there were no differences in cognitive functions before and after MX treatment. In contrast, patients not receiving MX showed a worsening of verbal short term memory and cognitive flexibility over the same time period.

Conclusion

In conclusion, this preliminary observational study points at stability of cognitive functions under MX therapy in patients with progressive multiple sclerosis.     

米托蒽醌增加肿瘤组织对微波热疗敏感性的研究

目的 改善米托蒽醌的抗肿瘤活性.方法以增敏效果细胞实验,将米托蒽醌加入到细胞培养液中,在微波0.18～0.2 mW·cm-2功率密度下辐射2.5 min,在显微镜下观察细胞的生长情况,评价米托蒽醌的增敏效果.结果米托蒽醌组的细胞死亡率与对照组有显著差别.结论米托蒽醌可作为微波热疗增敏剂,以增大肿瘤组织与正常组织吸收微波的差异,提高微波热疗效果和改善米托蒽醌治疗肿瘤的效果.     

The effect of mitoxantrone as an anticancer drug on hepatocytes nuclei and chromatin: Selective release of histone proteins

Objectives:

Mitoxantrone is an anticancer drug widely used in the treatment of various cancers. In the present study the effect of mitoxantrone on chromatin proteins of intact hepatocytes nuclei was investigated and compared with soluble chromatin.

Materials and Methods:

UV/Vis spectroscopy, SDS polyacrylamide gel electrophoresis, and western bolting were used.

Results:

The results show that exposure of intact nuclei to various concentrations of mitoxantrone resulted in the release of histone H1 family proteins, H1 and H1°, in a dose-dependent manner but not core histones and high mobility group proteins. Western blot analysis using antiserum against histones H1 and H1° revealed cross-reactivity and confirmed the result. Spectroscopy results showed that mitoxantrone binds to nuclear components and reduces the absorbances at 608 and 400 nm. The binding isotherms revealed cooperative binding with one binding site.

Conclusion:

From the results it is suggested that mitoxantrone binds to intact nuclei and chromatin with different affinities and linker DNA can be considered as a main binding site for mitoxantrone at the nuclei level.     

盐酸米托蒽醌膀胱灌注预防尿路上皮移行细胞癌复发

目的：评价盐酸米托蒽醌膀胱灌注预防尿路移行上皮细胞癌膀胱内复发的有效性、患者耐受性及其毒副作用。方法：对21例手术后经病理检查证实为尿路上皮移行细胞癌而且保留膀胱的患者,以盐酸米托蒽醌作膀胱灌注,记录膀胱灌注过程中的相关情况。结果：随访1～12个月,4例复发,1例恶化,复发率为19．0％(4／21),1年未复发率76．2％(16／21),平均无瘤间期10．3个月。9例发生局部并发症,复查血常规及肝、肾功能灌注前后差异无统计学意义。结论：初步随访证实,盐酸米托蒽醌降低尿路上皮移行细胞癌术后复发,大部分患者耐受良好,无明显全身毒副作用。