Multidrug resistance modulation in vivo: The effect of cyclosporin A alone or with dexverapamil on idarubicin pharmacokinetics in acute leukemia

Objective: To determine the effect of the coadministration of the multidrug resistance (MDR) modulators cyclosporin A (CyA) alone or plus dexverapamil (D-Ver) on idarubicin (IDA) pharmacokinetics in patients with acute leukemia. Methods: Pharmacokinetic studies were performed in 27 patients with a diagnosis of acute myelogenous leukemia (AML), who were being treated with a combination chemotherapy regimen including idarubicin and cytarabine for the induction of a first remission (n = 14), or of a second remission (n = 7), or for remission consolidation (n = 6). Of these 27 patients, nine were coadministered CyA and seven were coadministered CyA plus D-Ver as MDR modulators. Blood was sampled at appropriate intervals after each of the three IDA daily administrations. IDA and idarubicinol (IDAOL) were assayed by HPLC. Pharmacokinetic evaluations were performed by means of a two-compartment open model with zero-order absorption and first-order elimination using the WinNonlin pharmacokinetic software package. Results: CyA markedly increased the area under the concentration time-curve (AUC) of both IDA [558.26 (197.25) μg · h · l⁻¹ vs 315.44 (158.28) μg · h · l⁻¹; P < 0.01] and IDAOL [2896.60 (736.38) μg · h · l⁻¹ vs 1028.49 (603.95) μg · h · l⁻¹; P < 0.001] when coadministered as a single modulator, due to a lower total body clearance (CL) [83.51 (52.44) l · h⁻¹ · m⁻² vs 139.65 (69.45) l · h⁻¹ · m⁻²; NS]. When patients received two MDR modulators simultaneously (D-Ver plus CyA), IDA exposure was essentially the same as in those of the no inhibitor group [331.29 (95.49) μg · h · l⁻¹ vs 315.44 (158.28) μg · h · l⁻¹; NS], whereas the IDAOL total body exposure was greater than in the no inhibitor group [2030.32 (401.11) μg · h · l⁻¹ vs 1028.49 (603.95) μg · h · l⁻¹; P < 0.01], even if less than in patients receiving CyA as a single MDR modulator (IDA + CyA group) [AUC 2030.32 (401.11) μg · h · l⁻¹ vs 2896.60 (736.38) μg · h · l⁻¹; P < 0.05], suggesting an antagonistic effect against those of CyA on IDA and IDAOL elimination and/or an unpredictable redistribution. The main pharmacokinetic parameters of IDA, such as CL and volume of distribution at steady state (Vd_ss), were remarkably affected by the coadministration of CyA or CyA plus D-Ver, but no statistically significant difference was noted because of IDA pharmacokinetic interpatient variation. Conclusion: The results show that CyA alone at a dose of 10 mg · kg⁻¹ daily significantly increased systemic body exposure to both IDA and IDAOL in acute leukemia, and suggest that these pharmacokinetic effects were at least partially decreased when D-Ver was coadministered with CyA. Our findings raise important questions concerning the need for a dosage adjustment of IDA when MDR modulators are coadministered. Received: 2 June 1998 / Accepted in revised form: 3 December 1998     

多药耐药逆转剂增加去甲柔红霉素对正常造血干细胞的毒性

目的 探讨多药耐药逆转剂是否增加化疗药物对正常造血干细胞的毒性。方法 采用甲基纤维素半固体增减方法,培养正常人粒细胞－巨噬细胞克隆形成单位（ＣＦＵ－ＧＭ）。测定去甲柔红霉素对ＣＦＵ－ＧＭ的抑制率。将多药耐药逆转剂ＭＳ－２０９及去甲红霉素与骨髓红细胞共同短期作用后,了解去甲柔红霉素对ＣＦＵ－ＧＭ抑制率的变化。结果 去甲柔红霉素对ＣＦＵ－ＧＭ的平均抑制率为２９．６％,在ＭＳ－２０９作用下,其抑制纺增加     

标准剂量IA方案治疗≥55岁初诊急性髓系白血病患者效果观察

目的 探讨标准剂量IA方案治疗≥55岁初诊急性髓系白血病(AML)患者的疗效及不良反应.方法 回顾性分析江苏省人民医院血液科收治的32例≥55岁初诊AML患者应用标准剂量IA方案诱导治疗后的缓解情况、生存情况和治疗相关不良反应.结果 32例患者经IA方案诱导治疗后完全缓解(CR)率为71.9%(23/32),部分缓解(PR)率为9.4%(3/32),总有效(OR)率为81.3%(26/32).按细胞遗传学或分子生物学指标分组:预后良好组7例,CR 6例,PR 1例,OR率100.0%(7/7);预后中等组19例,CR 14例,PR 2例,OR率84.2%(16/19);预后不良组6例,CR 3例,PR 0例,OR率50.0%(3/6);三组CR率和OR率比较差异均无统计学意义(χ2=5.571,P=0.067;χ2=2.114,P=0.359).预后良好、中等和不良组的中位总生存(OS)时间分别为28.07个月(6.57~46.33个月)、16.93个月(0.40~87.57个月)和3.03个月(2.00~6.00个月),差异有统计学意义(Z=9.630,P=0.008);2年OS率分别为83.33%、46.80%和0,差异亦有统计学意义(χ2=12.206,P<0.001).化疗后主要不良反应为骨髓抑制及感染,未发生严重非血液系统不良反应.结论 ≥55岁初诊AML患者可选择标准剂量IA方案作为诱导方案.预后良好组和预后中等组患者诱导治疗后OR率、CR率高,OS时间长,而预后不良组患者未能从治疗中获益.     

Is there an optimal adjunct therapy to traditional cytotoxic induction?

The traditional cytotoxic induction regimen for acute myeloid leukemia (AML) is seven days of standard-dose cytarabine and three days of an anthracycline antibiotic (such as daunorubicin or idarubicin), commonly known as “7 + 3.” Many studies have been conducted to find an additional agent that might improve efficacy. Data from select studies has shown, in certain populations, benefit to adding cladribine, clofarabine and lomustine to a traditional backbone. For mutation-based chemotherapy regimens, midostaurin with 7 + 3 is the current standard of care for FLT3-mutant, younger AML patients. As we learn more about the synergism of molecular agents and traditional anti-cancer treatments, we can hopefully develop novel regimens without abandoning some of the benefits of these mutation agnostic historical therapies.     

Improvement of Induction Remission Rate by Modifying the Dose of Idarubicin for Relapsed Childhood Acute Lymphoblastic Leukemia

Relapse is the major cause of treatment failure in acute lymphoblastic leukemia (ALL), yet there is no established treatment for relapsed ALL. To improve the induction remission rate, we modified the dose of idarubicin in the original Children''s Cancer Group (CCG)-1884 protocol, and retrospectively compared the results. Twenty-eight patients diagnosed with relapsed ALL received induction chemotherapy according to the CCG-1884 protocol. Complete remission (CR) rate in all patients after induction chemotherapy was 57%. The idarubicin 10 mg/m²/week group showed CR rate of 74%, compared with the 22% CR rate of the idarubicin 12.5 mg/m²/week group (p=0.010). Remission failure due to treatment-related mortality (TRM) was 44% and 5.2% in the idarubicin 12.5 mg/m²/week and 10 mg/m²/week groups, respectively (p=0.011). Overall survival (OS) and 4-yr event-free survival (EFS) were 12.8% and 10.3%, respectively. OS and 4-yr EFS were higher in the idarubicin 10 mg/m²/week group (19.3% and 15.6%) than in the 12.5 mg/m²/week group (0% and 0%). In conclusion, a modified dose of idarubicin from 12.5 mg/m²/week to 10 mg/m²/week resulted in an improved CR rate in the treatment of relapsed ALL, which was due to lower TRM. However, despite improved CR rate with modified dose of idarubicin, survival rates were unsatisfactory.     

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.     

Intensive chemotherapy with idarubicin, cytarabine, etoposide, and G-CSF priming in patients with advanced myelodysplastic syndrome and high-risk acute myeloid leukemia

In an attempt to improve the complete remission (CR) rates and to prolong the remission duration especially in elderly patients >50 years of age, we have used a combination chemotherapy of idarubicin (10 mg/m² IV×3 days), cytarabine (AraC, 100 mg/m² CIVI×7d), and etoposide (100 mg/m²×5 days) in combination with granulocyte colony-stimulating factor (G-CSF) priming [5 mg/kg SQ day 1 until absolute neutrophil count (ANC) recovery] for remission induction. Responding patients received two consolidation courses of idarubicin, AraC, and etoposide, followed by a late consolidation course of intermediate-dose AraC (600 mg/m² IV every 12 h×5 days) and amsacrine (60 mg/m² IV×5 days). A total of 112 patients (57 male/55 female) with a median age of 58 years (range: 22–75) have been entered and are evaluable for response: 19 refractory anemia with excess of blast cells in transformation (RAEB-T), 84 acute myeloid leukemia (AML) evolving from myelodysplastic syndrome (MDS), and 9 secondary AML after chemotherapy/radiotherapy. The overall CR rate was 62%, partial remission (PR) rate 10%, treatment failure 16%, and early death rate 12%. The CR rate was higher in patients 60 years (68 vs 55%), mainly due to a lower early death rate (5 vs 21%, p<0.001). After a median follow-up of 58 months, the median overall survival is 14.5% and median duration of relapse-free survival 8 months. After 60 months, the probability of CR patients to still be in CR and alive is 16% (20% in patients 60 years and 13% in patients >60 years), while the probability of overall survival is 12% (15% in patients 60 years and 9% in patients >60 years). Compared to our previous trial (AML-MDS Study 01-92) which was done with identical chemotherapy but no G-CSF priming in 110 patients with RAEB-T, AML after MDS, or secondary AML (identical median age, age range, and distribution of subtypes), the CR rate in all patients, as well as CR rate, overall survival, and relapse-free survival in patients >60 years have significantly been improved. Thus, intensive chemotherapy with G-CSF priming is both well tolerated and highly effective for remission induction in these high-risk patients.     

地西他滨联合IAG/DAG治疗急性髓系白血病的临床疗效

目的 探讨地西他滨（DAC）联合IAG/DAG治疗急性髓系白血病（AML）的临床疗效与安全性。方法 选取2017年6月至2019年12月安徽医科大学第一附属医院血液科收治的23例初治或复发AML患者,采用DAC联合IAG/DAG诱导治疗,统计分析临床疗效及安全性。结果 23例患者均予以DAC联合IAG/DAG诱导化疗,其中完全缓解13例,部分缓解2例,总有效率为65.22%。23例患者均出现Ⅲ～Ⅳ级的粒细胞和血小板减少,1例患者因严重脑出血死亡。结论 DAC联合IAG/DAG治疗AML临床疗效较好,且不良反应可耐受,安全性高,值得临床推广应用。     

Comparison of idarubicin and daunorubicin and their main metabolites regarding intracellular uptake and effect on sensitive and multidrug-resistant HL60 cells

 To study the effect of the main metabolites on the cytotoxic effect of daunorubicin and idarubicin in human HL-60 cells, drug-sensitive and multidrug-resistant HL60 cells were incubated with idarubicin and daunorubicin and their metabolites idarubicinol and daunorubicinol over a wide range of concentrations. The intracellular uptake of the drugs was determined by photofluorometry, and the cytotoxic effect in vitro was determined by a bioluminescence assay of intracellular adenosine triphosphate (ATP) after 4 days of culture in liquid medium. The effect of intracellular drugs was calculated from the incubation-concentration versus intracellular-uptake and cytotoxic-effect curves. The intracellular uptake of idarubicin was 6 times that of daunorubicin in drug-sensitive cells and 25 times higher in resistant cells. For idarubicinol as compared with daunorubicinol the corresponding factors were 25 and 7, respectively. As compared with the parent substances, the uptake of idarubicinol and daunorubicinol was 16% and 4%, respectively, in sensitive cells and 40% and >100%, respectively, in resistant cells. An intracellular concentration of 0.5 nmol/mg protein of both parent substances caused a 50% growth inhibition in drug-sensitive cells as compared with 10 nmol/mg protein for drug-resistant cells. For the metabolites an intracellular concentration of 0.4 nmol/mg protein of idarubicinol and 2.0 nmol/mg protein of daunorubicinol was required to inhibit cells’ growth by 50% in drug-sensitive HL60 cells. In the resistant HL60 cells the corresponding values were 30 nmol/mg protein for idarubicinol and 40 nmol/mg protein for daunorubicinol. These results confirm that idarubicinol may significantly contribute to the clinical effect of idarubicin. However, in combination with previous results that have shown low intracellular concentrations of the metabolites in vivo, it appears that the pharmacokinetic properties of the mother substances provide the major explanation for the clinical effect of idarubicin. Received: 26 July 1996/Accepted: 17 January 1996     

Comparative resistance of idarubicin,doxorubicin and their C-13 alcohol metabolites in human MDR1 transfected NIH-3T3 cells

The anthracycline analog idarubicin (ID) is useful in the treatment of leukemias, and is of further interest because of the unique activity of its major circulating metabolite idarubicinol (IDOL). In vitro studies have shown that ID retains activity against tumor cells made resistant by prolonged exposure to substrates of the p-glycoprotein energy-dependent efflux pump. To selectively investigate multidrug resistance to ID in tumor cells, ID, IDOL, doxorubicin (DX) and doxorubicinol (DXOL) were evaluated for growth inhibitory activity when incubated with NIH-MDR1-G185 (MDR) cells or with the parent NIH-3T3 (3T3) cells. The MDR cells are transfected with the human multidrug genemdr ₁, and express a functional p-glycoprotein. ID growth inhibitory activity was much less affected by p-glycoprotein-mediated efflux than was DX. ID IC₅₀ values were only 1.8-fold greater in the MDR cell line than in the parental 3T3 cell line, while the IC₅₀ value for DX was 12.3-fold greater in the transfected cell line. Verapamil (VRP) fully restored drug sensitivity of the MDR cell line to ID and DX. In studies with the alcohol metabolites, IDOL and DXOL IC₅₀ values were 7.8- and 18.9-fold greater, respectively, for the MDR cell line than for the parental cell line. Intracellular concentrations of DX and DXOL, but not ID and IDOL, were substantially increased in the MDR cells when VRP was present in the incubation mixtures. ID and IDOL retain substantial growth inhibitory activity inmdr ₁-transfected cells, and ID may be of value in clinical settings where multidrug resistance mediated by p-glycoprotein is a potential limitation of therapy.Work partially supported by funds from Pharmacia Int. and by Mayo Comprehensive Cancer Center Grant CA 15083.