维甲酸治疗急性早幼粒细胞白血病诱发维甲酸综合征的临床研究

目的：探讨全反式维甲酸治疗急性早幼粒细胞白血病过程中维甲酸综合征的临床特点及其治疗。方法：对于初治的154例APL患者，ATRA治疗后，白细胞小于20×109／L者单用A-TRA治疗，白细胞大于20×109／L者加用化疗，治疗前白细胞大于20×109／L者ATRA与化疗同时应用。结果：14例APL患者发生RAS。临床症状出现的中位时间为7天，主要症状为发热，呼吸困难，低氧血病，肺部浸润等。14例RAS患者至少有以上3种症状。13例囡白细胞增高化疗，5例ATRA减量，7例停用ATRA，患者均加用大剂量糖皮质激素，12例RAS患者CR，2例死亡。未发生RAS患者CR率为89％。获得缓解后的RAS患者继续用ATRA维持治疗无RAS再发生。结论：APL初诊时白细胞高，应用ATRA后白细胞升高过快、过高者易发生RAS，应立即加用化疗和糖皮质激素治疗。     

全反式维甲酸相关综合征临床研究(结合文献复习报告38例)

目的：研究全反式维甲酸（ATRA）治疗急性早幼粒细胞白血病（APL）常见及少见毒副反应。方法：回顾分析38例APL在ATRA治疗期间出现的毒副反应。结果：APL在ATRA治疗过程中常见毒副反应有不同程度的口干、皮肤干燥、脱屑、皲裂（100％），19例出现胃肠道症状伴谷丙转氨酶增高（50％），18例高白细胞综合征（47.5%)，16例出现头痛、头晕（42.4%)，8例有肌肉、关节疼痛（21.2%)。少见毒副反应包括高颅压综合征4／38，血糖升高2／38，高组胺综合征1／38等。结论：ATRA治疗APL过程中常出现口干、皮肤干燥、脱屑、皲裂、胃肠道症状及高白细胞综合征等毒副反应。使用小剂量ATRA（20－30mg/日），可减少毒副反应的发生而对疗效无明显影响。     

全反式维甲酸联合化疗治疗小儿急性早幼粒细胞白血病

目的观察全反式维甲酸（ATRA）联合化疗治疗小儿急性早幼粒细胞白血病（APL）的疗效。方法22例初治患儿用ATRA诱导治疗;当患儿获完全缓解（CR）后,给予DA方案或IDA方案或HA方案或AA方案巩固治疗3个疗程;以后再用ATRA、化疗交替巩固治疗36个月。结果2例在诱导治疗前死于弥散性血管内凝血（DIC）、颅内出血;22例获CR,CR率100％（20／20）。1、3、5年无病生存（DFS）率分别为100％（20／20）、93．3％（14／15）、84．7％（11／13）。ATRA常见毒副作用依次为皮肤和口唇干燥、头痛、恶心、呕吐、肝功能损害及维甲酸综合征。结论ATRA联合化疗治疗小儿APLCR率高、远期疗效好;在诱导治疗前,DIC、颅内出血仍是APL患儿死亡的主要原因;ATRA毒副作用可耐受。     

维甲酸联合三氧化二砷及化疗治疗急性早幼粒细胞白血病21例

 目的 观察全反式维甲酸（ATRA）联合三氧化二砷（As2O3）及小剂量DA方案化疗治疗急性早幼粒细胞白血病（APL）的疗效和患者不良反应。方法 采用ATRA联合As2O3及小剂量DA方案化疗对21例APL患者进行治疗观察,其中初治APL 15例,经ATRA治疗未缓解2例,ATRA治疗完全缓解（CR）后复发4例,ATRA 25 mg·m-2·d-1,分2～3次口服;As2O3 0.1％注射液10 ml加入5 ％葡萄糖溶液500 ml静脉滴注,持续4～5 h;治疗2周左右时加用DA方案化疗（D：柔红霉素30～40 mg·m-2·d-1×3 d,A：阿糖胞苷50～100 mg m-2·d-1×7 d）,观察CR率、获得CR所需时间、患者不良反应。结果 19例患者获得CR,CR率90.5 ％,获得缓解的时间（28.4±3.6）d,未发现明显的不良反应。结论 ATRA联合As2O3及小剂量化疗治疗APL患者疗效好,能缩短CR的时间,改善高白细胞综合征。     

雄黄治疗维甲酸耐药急性早幼粒细胞白血病临床研究

目的：观察诱导凋亡剂雄黄治疗维甲酸（ATRA）的急性早幼粒细胞白血病（APL）的治疗效果及毒副作用。方法：对比应用雄黄治疗APL20例前后结果。结果：完全缓解（CR）17例，部分缓解（PR）1例，总有效率（CR＋PR）90％，结论：雄黄对ATRA耐药的APL仍有较高的缓解率，二无交叉耐药，毒性小，适用于临床推广应用。     

三氧化二砷联合维甲酸治疗骨髓增生异常综合征

目的：探讨三氧化二砷联合维甲酸(ATRA)治疗MDS的疗效。方法：31例MDS患者均采用三氧化二砷联合维甲酸等治疗。结果：RA RAS组有效率87．1％,RAEB RAEB-T组有效率42．9％。结论：三氧化二砷是一种治疗MDS的有效药物,尤其是在RA的治疗中有显著效果。     

减量HA方案和ATRA治疗高危骨髓增生异常综合征20例

目的：观察减量的三尖杉酯碱（H），阿糖胞苷（A）和全反式维甲酸（ATRA）诱导治疗高危骨髓增生异常综合征的疗效。方法：对20例高危骨髓增生异常综合征患者，应用三尖杉酯碱2－3mg／天，静脉滴注，连用5天，阿糖胞苷100mg/天，静脉滴注，连用5天，ATRA30－60mg/天，分次口服，结果：完全缓解（CR）6例（30％），部分缓解3例（15％），无效11例（55％），7例（35％）在治疗中转化为急性白血病，化疗相关性死亡3例（15％），结论：减量HA方案和全反式维甲酸治疗高危MDS有明显疗效，但老年患者治疗相关性死亡率较高，需注意个体化治疗。     

全反式维甲酸联合三氧化二砷治疗儿童急性早幼粒细胞白血病疗效观察

 目的　观察全反式维甲酸（ ATRA ）联合三氧化二砷（ As2O3）治疗儿童初发急性早幼粒细胞白血病（ APL）的疗效和不良反应。方法　ATRA 联合As2O3治疗初发 APL患儿16例。治疗方案：ATRA 25 mg·m-2·d-1，分2～3次口服，As2O3 0.16 mg·kg-1·d-1，加入生理盐水或50 g／L葡萄糖溶液静脉滴注，持续 4～6 h，1次／d。结果　14 例患者获得完全缓解（CR），CR率87.5 ％，CR时间短，没有明显不良反应。结论　ATRA联合As2O3治疗儿童APL能获得很好疗效。     

全反式维甲酸联合三氧化二砷治疗急性早幼粒细胞白血病29例观察

目的　观察全反式维甲酸 (ATRA)联合三氧化二砷 (As2 O3 )治疗急性早幼粒细胞白血病 (APL)的临床疗效、作用特点及毒副作用。方法　As2 O3 注射液 0 .16mg/ (kg·d) ,ATRA 2 5mg/ (m2 ·d)联合治疗初治APL 2 9例 ,根据外周血白细胞计数、维甲酸综合征以及肝功能变化调整ATRA和As2 O3 的剂量。治疗过程中每周检查血象、骨髓像 ,随机检查凝血纤溶指标和肝、肾功能、心电图。结果　治疗初治APL 2 9例 ,1例因并发颅内出血而早期死亡 ,其余 2 8例均达到CR ,完全缓解率 96.6% ,平均缓解时间 ( 2 6.3± 4.1)天。结论　As2 O3 联合ATRA治疗APL的CR率高 ,达CR时间缩短 ,不良反应少。     

全反式维甲酸加DNA方案治疗急性早幼粒细胞白血病临床观察

对12例根据病史、经周围血象、骨髓象检查确诊的急性早幼粒细胞白血病的初治患者应用全反式维甲酸（ATRA）40－60mg/d，分3－4次口服，连续应用直到完全缓解（CR）。同时加用柔红霉素（DNR），40－60mg/d，加入生理盐水40ml，静推，连用3天；阿糖胞苷100－200mg/d，加入5％葡萄糖500ml，静滴，连用5天，休息10－14天，必要时可以重复应用。结果12例中CR11例，完全缓解率91．6％，达CR的时间30－37天。其安全缓解率高于及达完全缓解时间短于国内报告的单用ATRA治疗组。且无高白细胞现象及临床危急性象出现，其原因可能是在ATRA诱导细胞分化的基础上，DNR、Ara-c抑制其增殖所致。     

Retinoic acid syndrome induced by arsenic trioxide in treating recurrent all-trans retinoic acid resistant acute promyelocytic leukemia

Arsenic Trioxide (As2O3) is an effective agent for treating acute promyelocytic leukemia achieving a complete remission rate of about 60% to 90%. It is similar to all-trans retinoic acid (ATRA) when treating acute promyelocytic leukemia (APL), because both agents have limited side effects compared to conventional chemotherapy, although the treatment period is more prolonged. During treatment, both agents may induce leukocytosis, and in patients taking ATRA, leukocytosis appears to be related to the development of retinoic acid syndrome (RAS). We report here a case of APL treated with ATRA in combination with chemotherapy 3 years earlier. During treatment, an episode of RAS with fever, edema, pericardiac effusion etc. was encountered. Recently, she had a relapse of leukemia, and As2O3 therapy was used. Leukocytosis developed again, and symptoms of fever, skin rash, edema resembling a RAS also developed, which was quickly relieved by steroid administration in a manner resembling response to RAS.     

丙戊酸钠联合全反式维甲酸治疗骨髓增生异常综合征22例

 目的　探讨丙戊酸钠联合全反式维甲酸治疗骨髓增生异常综合征（MDS）的有效性和安全性。方法　入组患者22例,其中：难治性贫血（RA） 4例,环形铁粒幼细胞性难治性贫血（RARS）1例,RA并多系发育异常（RCMD）10例,难治性血细胞减少症伴有多系发育异常和环状铁粒幼细胞（RCMD-RS）1例,RA伴原始细胞增多-1（RAEB-1）3例,RA伴原始细胞增多-2（RAEB-2）3例。患者入组后给予丙戊酸钠0.2 g／次,3次／d起,1周后加量至0.4 g／次,3次／d;丙戊酸钠使用1周后开始联用全反式维甲酸,10 mg／次,3次／d,每2周连用1周。治疗持续至少3个月,出现严重的不良反应或疾病明显进展时停用,治疗后每4周复查一次骨髓,评价疗效。结果　22例患者治疗有效6例,有效率27.3 %,平均8周开始显效,其中无完全缓解病例,2例患者部分缓解,4例血液学改善,9例治疗期间病情稳定,7例治疗失败。部分患者有轻微的药物不良反应。结论　丙戊酸钠联合全反式维甲酸治疗MDS治疗有效,不良反应轻微,可以耐受。     

Clinical trial of valproic acid and all-trans retinoic acid in patients with poor-risk acute myeloid leukemia

BACKGROUND: Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, induced in vitro differentiation of primary acute myeloid leukemia (AML) blasts, an effect enhanced by all-trans retinoic acid (ATRA). Clinical responses to VPA were recently observed in patients with myelodysplastic syndrome (MDS). Herein, the authors have described results of a clinical trial with VPA plus ATRA in 26 patients with poor-risk AML. METHODS: VPA (5-10 mg/kg starting dose) and ATRA (45 mg/m(2)) were administered orally. Low-dose AraC or hydroxyurea were permitted to control leukocytosis. Biologic activity of VPA was confirmed by serial analysis of HDAC2 protein levels in peripheral blood (PB) mononuclear cells. RESULTS: Nineteen of 26 patients completed at least 4 weeks of VPA/ATRA treatment; 7 patients were withdrawn prematurely because of rapidly progressive disease (n = 3) or unacceptable neurologic and cardiovascular toxicity (n = 4). Additional cytoreductive treatment was required in 58% of patients enrolled. Median treatment duration was 3 months. No patient achieved complete remission, one with de novo AML had a minor response, and two patients with secondary AML arising from myeloproliferative disorder (MPD) achieved a partial remission and clearance of PB blasts, respectively. The latter responses were accompanied by profound granulocytosis and erythrocytosis in both patients, reminiscent of the response pattern known from ATRA treatment of acute promyelocytic leukemia. However, cytogenetic analysis of isolated CD34(+) cells and granulocytes did not reveal terminal differentiation of leukemic blasts. CONCLUSIONS: Treatment with VPA/ATRA results in transient disease control in a subset of patients with AML that has evolved from a myeloproliferative disorder but not in patients with a primary or MDS-related AML.     

Thrombosis in patients with acute promyelocytic leukemia treated with and without all-trans retinoic acid

Laboratory evidence of disseminated intravascular coagulation (DIC) and/or fibrinolysis is present in the majority of patients with acute promyelocytic leukemia (APL). Historically, early hemorrhagic death (EHD) occured in 10% to 30% of patients treated with chemotherapy. All-trans retinoic acid (ATRA), a differentiating agent, has a CR rate above 80% in patients, with ATRA-associated leukocytosis. We studied thrombotic events in this population and compared it to patients treated with chemotherapy alone. The results of studies using ATRA in patients with APL were reviewed. Patients received ATRA 45-50 mg/m² orally in two divided doses daily until complete remission. In newly diagnosed patients, Idarubicin 12 mg/m²/day was given intravenously for 4 to 5 days beginning on the fifth day of ATRA therapy or when the white blood cell count (WBC) was over 10×10³/μl. Thrombotic complications were noted in 3 of 31 patients during induction. Two died from thrombotic events during therapy with multiple thromboses documented at autopsy. ATRA syndrome was suspected in 2 of the patients with thromboses and only 1 of the patients without thrombosis. In previous studies, 1 of 25 APL patients treated with chemotherapy alone had thrombotic events during therapy. In conclusion, treatment of APL with ATRA may decrease the incidence of hemorrhagic complications, but does not eliminate thrombosis. While thrombotic events were not significantly increased in patients treated with ATRA, they were more common in patients suspected of having ATRA syndrome.     

Retinoic acid syndrome in NOD/scid mice induced by injecting an acute promyelocytic leukemia cell line.

All-trans retinoic acid (ATRA) induces complete remission in patients with acute promyelocytic leukemia (APL). However, ATRA sometimes causes retinoic acid syndrome (RAS) characterized by respiratory distress, pleural effusions, fever and weight gain. To investigate the pathophysiology of RAS, we generated an animal model by injecting an APL cell line, NB4, into immunodeficient mice. When NOD/scid mice were injected intravenously with fully differentiated NB4 cells (1 x 10(7)) and then given a daily administration of ATRA, three of 12 mice died of pulmonary edema within 14 days. Pathologically, dilated lung capillary vessels and alveolar effusions were observed. After the injection, NB4 cells were detected in the lung within 2 days and in the pleural effusion later on. The gene expression levels of CXC chemokines (MIP-2 and KC) and ICAM-1 were increased in the lung and heart by the ATRA administration. In immunohistochemical analyses, MIP-2 was clearly detected in alveolar macrophages of the lung in mice with RAS. Dexamethasone treatment prevented the development of RAS and decreased the CXC chemokine mRNA expression in the lung. These findings suggested that the activation of adhesion molecules for leukocytes and expression of CXC chemokines in the lung are closely involved in triggering RAS.     

Increasing the intracellular availability of all-trans retinoic acid in neuroblastoma cells

Recent data indicate that isomerisation to all-trans retinoic acid (ATRA) is the key mechanism underlying the favourable clinical properties of 13-cis retinoic acid (13cisRA) in the treatment of neuroblastoma. Retinoic acid (RA) metabolism is thought to contribute to resistance, and strategies to modulate this may increase the clinical efficacy of 13cisRA. The aim of this study was to test the hypothesis that retinoids, such as acitretin, which bind preferentially to cellular retinoic acid binding proteins (CRABPs), or specific inhibitors of the RA hydroxylase CYP26, such as R116010, can increase the intracellular availability of ATRA. Incubation of SH-SY5Y cells with acitretin (50 microM) or R116010 (1 or 10 microM) in combination with either 10 microM ATRA or 13cisRA induced a selective increase in intracellular levels of ATRA, while 13cisRA levels were unaffected. CRABP was induced in SH-SY5Y cells in response to RA. In contrast, acitretin had no significant effect on intracellular retinoid concentrations in those neuroblastoma cell lines that showed little or no induction of CRABP after RA treatment. Both ATRA and 13cisRA dramatically induced the expression of CYP26A1 in SH-SY5Y cells, and treatment with R116010, but not acitretin, potentiated the RA-induced expression of a reporter gene and CYP26A1. The response of neuroblastoma cells to R116010 was consistent with inhibition of CYP26, indicating that inhibition of RA metabolism may further optimise retinoid treatment in neuroblastoma.     

All-trans retinoic acid in relapsing malignant gliomas: clinical and radiological stabilization associated with the appearance of intratumoral calcifications

(1) Purpose: To evaluate the therapeutic effect ofall-trans retinoic acid (ATRA) with and without cytosinearabinoside in relapsing malignant gliomas.(2) Patients and methods: 9 patients (8 male,1 female, age 53.9 ± 11.2) with relapsingmalignant gliomas (grade IV:6; grade III:3) were treatedby ATRA 1 to 21 months after theend of their initial treatment. ATRA was givenunceasingly during 2 to 17 months at 90mg/d. In 6 patients it was associated tocytosine arabinoside (4 g/course, 1 to 9 coursesevery 4 weeks).(3) Results: 4 non-responder patients died 2.5 to4 months after starting therapy. One patient whohad been reoperated before receiving ATRA and cytosinearabinoside (5 courses) had no sign of tumorrecurrence after 17 months of treatment. In 4responder patients (2 glioblastoma and 2 anaplastic astrocytoma)a clinical and radiological stabilization (time to progression)during 9 ± 2.5 months was observed. Thisstabilization was associated in 3 of them withthe appearance of intra tumoral calcifications visualized onrepeated CT scans and confirmed in one patientby post-mortem examination. All of them had receivedcytosine arabinoside (1 to 9 courses) with ATRA;however small calcifications were also observed in onenon-responder patient who did not receive aracytine.(4) Conclusion: These results suggest: a) a therapeuticeffect of ATRA in combination with cytosine arabinosidein patients with relapsing malignant gliomas b) thatintratumoral calcifications are related to the effects ofATRA on differentiation and/or on endothelial t-PA productionand that these effects explain the tumor progressionarrest in responder patients. The transient efficiency isprobably related to the pharmacokinetics of ATRA orto changes of cellular mechanisms that modulate thecell response to the drug and is acritical issue for this therapy.     

The histone deacetylase (HDAC) inhibitor valproic acid as monotherapy or in combination with all-trans retinoic acid in patients with acute myeloid leukemia

BACKGROUND: Valproic acid (VPA) inhibits histone deacetylase activity and, synergizing with all-trans retinoic acid (ATRA), achieves differentiation induction of myeloid blast cells in vitro. METHODS: We used VPA in 58 patients with acute myeloid leukemia (AML) who were too old and/or medically unfit to receive intensive chemotherapy (32 AML secondary to myelodysplastic syndrome [MDS], 22 de novo AML, 4 AML secondary to myeloproliferative syndrome). VPA serum concentrations were 50-100 mug/mL. Thirty-one patients received VPA monotherapy. ATRA was added later in 13 patients who did not respond or who relapsed. Another 27 patients received VPA plus ATRA from the start. Median treatment duration was 93 days for VPA and 88 days for ATRA. RESULTS: The response rate was only 5% according to International Working Group (IWG) criteria for AML but was 16% when IWG response criteria for MDS were used, which capture hematologic improvement and stabilization of the disease. These endpoints, which are not necessarily correlated with diminishing blast counts, are relevant for the patients' quality of life. Among 23 patients with a peripheral blast count > 5%, 6 (26%) showed a diminishing blast count, and 5 of these had a complete peripheral blast clearance. CONCLUSIONS: Future trials should combine VPA with chemotherapy or demethylating agents.     

Phase 2 clinical trial of 5-azacitidine, valproic acid, and all-trans retinoic acid in patients with high-risk acute myeloid leukemia or myelodysplastic syndrome

In this Phase 2 study, we evaluated the efficacy of combination of 5-azacitidine (AZA), valproic acid (VPA), and all-trans retinoic acid (ATRA) in patients with high-risk acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Treatment consisted of six cycles of AZA and VPA for 7 days, followed by ATRA for 21 days. Sixty-five patients were enrolled (median age, 72 years; 55 AML including 13 relapsed/refractory patients, 10 MDS; 30 unfavorable karyotypes). Best responses included 14 CR and 3 PR (26%), 75% of the responders and 36% of the non-responders achieving an erythroid response. Median overall survival (OS) was 12.4 months. Untreated patients had a longer OS than relapsed/refractory patients. In patients who fulfilled the 6 planned cycles, OS did not appear to depend on CR/PR achievement, suggesting that stable disease while on-treatment would be a surrogate for survival with this approach. During therapy, early platelet response and demethylation of the FZD9, ALOX12, HPN, and CALCA genes were associated with clinical response. Finally, there was no evidence for the restoration of an ATRA-induced differentiation during therapy. Epigenetic modulation deserves prospective comparisons to conventional care in patients with high-risk AML, at least in those presenting previously untreated disease and low blast count.     

Extramedullary relapse after all-trans retinoic acid treatment in acute promyelocytic leukemia--the occurrence of retinoic acid syndrome is a risk factor.

All-trans retinoic acid (ATRA) is now a standard agent for remission induction of acute promyelocytic leukemia (APL). Recently, extramedullary relapse, which was a rare condition in APL patients after chemotherapy alone, was reported with an increased frequency after ATRA treatment. However, it is not yet clear whether ATRA truly increases the risk of extramedullary recurrence and what are the risk factors. In this study, three of 13 patients with recurrent APL after prior treatment of ATRA were found to have extramedullary involvement, compared with none in 11 recurrent patients previously treated with chemotherapy alone (estimated relative risk 2.100, 95% confidence interval 1.341-3.289). Furthermore, in the former group of patients, the development of retinoic acid (RA) syndrome during prior induction treatment was significantly associated with extramedullary involvement at relapse (three in five patients with RA syndrome vs none in eight without the syndrome, estimated relative risk 5.000, 95% confidence interval 1.448-17.271). In conclusion, ATRA may predispose APL patients to extramedullary involvement at relapse and the occurrence of RA syndrome is a risk factor for it. Further studies are needed to confirm these findings. It also remains to be clarified whether treatment modification is necessary in patients who develop RA syndrome during ATRA treatment.