砷剂为主治疗急性早幼粒细胞白血病疗效分析与辨证分型探讨
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摘要
近几十年来,白血病发病率呈逐渐上升趋势,给人民生命和健康带来极大危害。因此,白血病治疗倍受关注。祖国医学深入研究和现代医学发展相结合为白血病治疗开辟了新的治疗途径。
全反式维甲酸(ATRA)治疗开创了靶向治疗急性早幼粒细胞白血病(APL)的先河,而中药砷剂的应用又进一步提高了APL临床治愈率。APL是第一个应用诱导分化和针对肿瘤特异性分子标志进行治疗并取得显著疗效的恶性肿瘤,成为一种可以“治愈”的恶性血液病。本文在文献综述急性早幼粒细胞研究进展的基础上,回顾整理我院APL患者资料,分析不同方案及中医辨证分型对APL疗效的影响,为临床方案的优化提供客观依据。
一不同方案治疗急性早幼粒细胞白血病临床疗效分析
目的：分析比较不同方案对APL临床疗效。寻找出APL治疗最佳组合方案,为拟定更有效治疗组合方案提供依据。
方法：以我院1993年9月-2007年9月15年间收治的初发APL患者74例为研究对象,可进行疗效评价者72例。诱导治疗以单用ATRA、单用三氧化二砷(As2O3)、ATRA+化疗、As2O3+化疗为主,所有患者诱导治疗均加用凉血解毒为主汤剂,比较四组诱导方案的缓解率、达缓解时间(TC)和复发率、无复发生存率(RFS)和总体生存率(0S)。TC以30天为界,将达完全缓解(CR)71例患者分为两组,比较两组RFS和0S。缓解后治疗以单用砷剂和砷剂与化疗交替两组,比较两组RFS和0S。
结果：四组诱导治疗患者都达CR, CR率均为100%；单用As203组TC 28.31±4.5天,明显短于其他各组(其中单用ATRA组TC：39.75±4.68天,ATRA联合化疗组TC 35.95±6.11天,ATRA联合As20。组TC 42.0±10.94天),具有显著性差异(P<0.05)。各诱导方案2年内复发率分别为：11.8%、0%、14.3%、14.3%；5年预计RFS和0S分别为：82.4%和88.2%、81.3%和81.3%、78.6%和85.7%、71.4%和71.4%。各组RFS和0S无显著性差异。TC>30天组RFS和OS明显低于TC≤30天组[100%vs(76.9±14.1)%,100%vs(85.0±12.2)%,P<0.05]。两组缓解后治疗,5年预计RFS和0S分别为：85.7%和85.7%、90.0%和90.0%,两组RFS和0S无明显差异。
结论：(1)四种方案诱导治疗APL的CR率无显著性差异。(2)单用As2O3诱导治疗,达CR时间最短。(3)联合用药并没有减低2年复发率和增加5年生存率(4)达CR时间<30天,可能有利于患者长生存。(5)缓解后治疗,选择单用砷剂或砷剂与化疗交替,5年生存率无明显差别。
二急性早幼粒细胞白血病辨证分型与临床疗效关系探讨
目的：分析APL患者初发病时不同证型缓解率、复发率和生存率,探讨疾病初发时中医证型与预后关系。
方法：以我院1993年-2007年15年间收治确诊为APL,初发病时有详细症状记载可以进行中医辨证的85例患者病例资料为研究对象,根据已制定的调查表辨证分型,用Fisher确切概率法检验各组患者缓解率；以患者确诊时间为随访开始至2010年1月结束,失访10例,对所得资料采用乘积极限法进行RFS和0S分析。
结果：发病时APL证型分为气虚、气血两虚、气阴两虚和热盛气虚及其他。各组患者缓解率分别为：100%、91.7%、88.9%、89.5%、100%,各组CR率差异无显著性。各组RFS分别为气虚组：0.70±0.19(x±1.96s)；气血两虚组：0.83±0.21；气阴两虚组：0.78±0.27；热盛气虚组：0.57±0.23：其他组：0.66±0.27。各组无复发生存曲线在5年后趋于平坦,整体比较各组RFS,差异无统计学意义(P>0.05)。各组0S分别为气虚组：0.91±0.12(x±1.96s),发病3年后生存曲线趋于平坦；气血两虚组：0.92±0.16,发病1年后生存曲线趋于平坦；气阴两虚组：0.78±0.27,发病2年后生存曲线趋于平坦；热盛气虚组：0.57±0.23,发病9年后生存曲线趋于平坦；其他组：0.66±0.27,发病5年后生存曲线趋于平坦。。各组患者生存曲线在得病第一年内变化较大,死亡事件发生率高。整体比较各组生存情况,P<0.05,有显著性差异。经组间成对比较,热盛气虚组的生存情况明显低于其他各组,P<0.05,差别有显著性差异。
结论：(1)各证型组患者CR率和RFS无显著性差异。(2)初发病时表现为单纯气虚证型的患者其生存时间较长,预后相对较好,而表现为热盛气虚的患者OS相对较短,预后偏差。(3)对于发病时辨证非热盛气虚患者维持治疗一般在2-3年为宜,而热盛气虚患者应延长维持治疗时间,减少复发死亡事件发生。
In recent decades, the incidence of leukemia has been increasing gradually, and the number of leukemia patients are increasing year by year. It brings great harm to people's health. The treatment of leukemia has been great concern. The combination of Traditional Chinese Medicine (TCM) in-depth study with the development of modern medicine has opened up a new gateway for leukemia treatment.
Application of all-trans retinoic acid (ATRA) has opened the door targeted to acute promyelocytic leukemia (APL) and good outcomes have been observed. Application of arsenic preparations has increased the clinical cure rate of APL. APL has been a first disease in clinical application of inducing differentiation and targeting to tumor-specific markers and a significant effect on malignant tumors has been obtained. It has been a hematologic malignancy which could be cured. This paper relatively analysis the clinical outcome of different treatment and differentiation of symptoms in APL patients based on literature review, and the objective evidence of better clinical treatment could be provided.
Part one The comparative analysis on clinical outcome of different treatment in patients with acute promyelocytic leukemia
Objective:To analysis the clinical efficacy of different treatment on patients with APL, then the best combinated plan of treatment in APL could be found out, and the evidence of more effective therapy could be provided.
Methods:The 74 cases of APL were the hospital patients from September 1993 to September 2007, and the clinical efficacy.of 72 out of 74 cases was evaluated Inductive treatments included:ATRA alone, arsenic trioxide (As2O3) alone, ATRA combined with chemotherapy, and As2O3 combined chemotherapy. All patients took cooling blood detoxification-based medicinal broth during in inductive therapy. The remission rate (CR), the time to get complete remission(TC), the rate of relapse, relapse-free survival (RFS) and overall survival (OS) were compared in the four groups.71 patients who had achieved CR were divided into two groups when 30 days was as a boundary. Their RFS and OS were compared. The post-remission treatments included arsenic alone and arsenic combined with chemotherapy, and the 5-year RFS and OS estimated between two groups were compared.
Results:All of patients with APL in four inductive therapy groups reached CR, the CR rate in each group was 100%. The TC was 28.31±4.5 days in As2O3 alone group. It was significantly shorter than that in other groups(P<0.05). The recurrence rate in four groups at 2 years were 11.8%,0%,14.3% and 14.3%, respectively; the 5-year RFS and OS were 82.4% and 88.2%,81.3% and 81.3%,78.6% and 85.7%, 71.4% and 71.4%, respectively. The RFS in four groups was not significantly different, so was the OS. The RFS and OS were significantly shorter in group of TC more than 30 days than that in group of TC less than 30 days(P<0.05). The 5-year RFS and OS of patients with the post-remission treatment were estimated of 85.7% and 85.7%,90.0% and 90.0%, respectively. The RFS between two groups was not significantly different, so was the OS.
Conclusions:(1) The CR rate was not significantly different in patients with APL treated with four programs. (2) The TC was shorter in patients used by As2O3 alone than that by other programs. (3)Combinative medication didn't decrease the 2-year relapse rate and didn't increase the 5-year survival rate. (4) Patients with APL might have a longer survival as the TC less than 30 days. (5) The 5-year RFS and OS were not significantly different in patients with a post-remission treatment of As2O3 alone or As2O3 and chemotherapy in turn.
Part two The comparative study on clinical outcomes of differentiation of symptoms and signs in patients with acute promyelocytic leukemia
Objective:To analysis the CR rate, relapse rate, and survival rate in APL patients based on differentiation of symptoms and signs, and to investigate the prognosis of APL patients with different pattern of syndrome.
Methods:The 85 cases of APL were the hospital patients from September 1993 to September 2007. The detailed symptoms were recorded in these cases at initial diagnosis. The differentiation of symptoms and signs for classification of syndrome was used by virtue of questionnaire form comprised of symptoms and signs. The CR rate and relapse rate were analyzed by Fisher exact test, and the survival was analyzed by product limit method with a follow-up from the time of diagnoses to January 2010, and 10 patients were lossed to follow up.
Results:The types of syndrome in APL patients were classified as deficiency of QI, deficiency of both QI and blood, deficiency of QI and yin, excessive heat and deficiency of QI, and other. The CR rate was 100%,91.7%,88.9%, and 89.5%, respectively, the CR rate were not significantly diferent in four groups. The RFS of patients with QI deficiency, QI and blood deficiency, QI and yin deficiency and predominant heat deficiency of QI and other were 0.70±0.19 (x±1.96s),0.83±0.21,0.78±0.27,0.57±0.23,0.66±0.27, respectively, the RFS curve become flattened after 5 years, and the RFS were not significantly diferent in four groups. The OS of patients with QI deficiency was 0.91±0.12 (x±1.96s), and the OS curve became flattened after 3 years; The survival rate of patients with QI and blood deficiency was 0.92±0.16, and the OS curve became flattened after 1 year; The OS rate of patients with QI and yin deficiency was 0.78±0.27, and the OS curve becomes flattened after 2 years; The OS of patients with excessive heat and QI dificiency was 0.57±0.23, and the survival curve becomes flattened after 9 years; The OS of patients with other was 0.66±0.27, and the OS curve becomes flattened after 5 years;. The OS curves changed dramatically during 1 year after diagnosis, and the incidence of death was high. The OS rate of patients with excessive heat and QI dificiency was significantly lower than that of those with other types (P<0.05).
Conclusions:(1) The CR rate and RFS of APL patients were similar in four groups, so was the relapse rate. (2) The APL patients with deficiency of QI had a long life and a good prognoses, while the patients with excessive heat and QI deficiency had a short survival and a poor prognoses. (3)It might be appropriate to keep the maintenane therapy time for 2-3 years in patients without excessive heat..Contrarily, it might be necessary to prolong the treatment time in patients with excessive heat to reduce the incedence of relapse and death.
全反式维甲酸(ATRA)治疗开创了靶向治疗急性早幼粒细胞白血病(APL)的先河,而中药砷剂的应用又进一步提高了APL临床治愈率。APL是第一个应用诱导分化和针对肿瘤特异性分子标志进行治疗并取得显著疗效的恶性肿瘤,成为一种可以“治愈”的恶性血液病。本文在文献综述急性早幼粒细胞研究进展的基础上,回顾整理我院APL患者资料,分析不同方案及中医辨证分型对APL疗效的影响,为临床方案的优化提供客观依据。
一不同方案治疗急性早幼粒细胞白血病临床疗效分析
目的：分析比较不同方案对APL临床疗效。寻找出APL治疗最佳组合方案,为拟定更有效治疗组合方案提供依据。
方法：以我院1993年9月-2007年9月15年间收治的初发APL患者74例为研究对象,可进行疗效评价者72例。诱导治疗以单用ATRA、单用三氧化二砷(As2O3)、ATRA+化疗、As2O3+化疗为主,所有患者诱导治疗均加用凉血解毒为主汤剂,比较四组诱导方案的缓解率、达缓解时间(TC)和复发率、无复发生存率(RFS)和总体生存率(0S)。TC以30天为界,将达完全缓解(CR)71例患者分为两组,比较两组RFS和0S。缓解后治疗以单用砷剂和砷剂与化疗交替两组,比较两组RFS和0S。
结果：四组诱导治疗患者都达CR, CR率均为100%；单用As203组TC 28.31±4.5天,明显短于其他各组(其中单用ATRA组TC：39.75±4.68天,ATRA联合化疗组TC 35.95±6.11天,ATRA联合As20。组TC 42.0±10.94天),具有显著性差异(P<0.05)。各诱导方案2年内复发率分别为：11.8%、0%、14.3%、14.3%；5年预计RFS和0S分别为：82.4%和88.2%、81.3%和81.3%、78.6%和85.7%、71.4%和71.4%。各组RFS和0S无显著性差异。TC>30天组RFS和OS明显低于TC≤30天组[100%vs(76.9±14.1)%,100%vs(85.0±12.2)%,P<0.05]。两组缓解后治疗,5年预计RFS和0S分别为：85.7%和85.7%、90.0%和90.0%,两组RFS和0S无明显差异。
结论：(1)四种方案诱导治疗APL的CR率无显著性差异。(2)单用As2O3诱导治疗,达CR时间最短。(3)联合用药并没有减低2年复发率和增加5年生存率(4)达CR时间<30天,可能有利于患者长生存。(5)缓解后治疗,选择单用砷剂或砷剂与化疗交替,5年生存率无明显差别。
二急性早幼粒细胞白血病辨证分型与临床疗效关系探讨
目的：分析APL患者初发病时不同证型缓解率、复发率和生存率,探讨疾病初发时中医证型与预后关系。
方法：以我院1993年-2007年15年间收治确诊为APL,初发病时有详细症状记载可以进行中医辨证的85例患者病例资料为研究对象,根据已制定的调查表辨证分型,用Fisher确切概率法检验各组患者缓解率；以患者确诊时间为随访开始至2010年1月结束,失访10例,对所得资料采用乘积极限法进行RFS和0S分析。
结果：发病时APL证型分为气虚、气血两虚、气阴两虚和热盛气虚及其他。各组患者缓解率分别为：100%、91.7%、88.9%、89.5%、100%,各组CR率差异无显著性。各组RFS分别为气虚组：0.70±0.19(x±1.96s)；气血两虚组：0.83±0.21；气阴两虚组：0.78±0.27；热盛气虚组：0.57±0.23：其他组：0.66±0.27。各组无复发生存曲线在5年后趋于平坦,整体比较各组RFS,差异无统计学意义(P>0.05)。各组0S分别为气虚组：0.91±0.12(x±1.96s),发病3年后生存曲线趋于平坦；气血两虚组：0.92±0.16,发病1年后生存曲线趋于平坦；气阴两虚组：0.78±0.27,发病2年后生存曲线趋于平坦；热盛气虚组：0.57±0.23,发病9年后生存曲线趋于平坦；其他组：0.66±0.27,发病5年后生存曲线趋于平坦。。各组患者生存曲线在得病第一年内变化较大,死亡事件发生率高。整体比较各组生存情况,P<0.05,有显著性差异。经组间成对比较,热盛气虚组的生存情况明显低于其他各组,P<0.05,差别有显著性差异。
结论：(1)各证型组患者CR率和RFS无显著性差异。(2)初发病时表现为单纯气虚证型的患者其生存时间较长,预后相对较好,而表现为热盛气虚的患者OS相对较短,预后偏差。(3)对于发病时辨证非热盛气虚患者维持治疗一般在2-3年为宜,而热盛气虚患者应延长维持治疗时间,减少复发死亡事件发生。
In recent decades, the incidence of leukemia has been increasing gradually, and the number of leukemia patients are increasing year by year. It brings great harm to people's health. The treatment of leukemia has been great concern. The combination of Traditional Chinese Medicine (TCM) in-depth study with the development of modern medicine has opened up a new gateway for leukemia treatment.
Application of all-trans retinoic acid (ATRA) has opened the door targeted to acute promyelocytic leukemia (APL) and good outcomes have been observed. Application of arsenic preparations has increased the clinical cure rate of APL. APL has been a first disease in clinical application of inducing differentiation and targeting to tumor-specific markers and a significant effect on malignant tumors has been obtained. It has been a hematologic malignancy which could be cured. This paper relatively analysis the clinical outcome of different treatment and differentiation of symptoms in APL patients based on literature review, and the objective evidence of better clinical treatment could be provided.
Part one The comparative analysis on clinical outcome of different treatment in patients with acute promyelocytic leukemia
Objective:To analysis the clinical efficacy of different treatment on patients with APL, then the best combinated plan of treatment in APL could be found out, and the evidence of more effective therapy could be provided.
Methods:The 74 cases of APL were the hospital patients from September 1993 to September 2007, and the clinical efficacy.of 72 out of 74 cases was evaluated Inductive treatments included:ATRA alone, arsenic trioxide (As2O3) alone, ATRA combined with chemotherapy, and As2O3 combined chemotherapy. All patients took cooling blood detoxification-based medicinal broth during in inductive therapy. The remission rate (CR), the time to get complete remission(TC), the rate of relapse, relapse-free survival (RFS) and overall survival (OS) were compared in the four groups.71 patients who had achieved CR were divided into two groups when 30 days was as a boundary. Their RFS and OS were compared. The post-remission treatments included arsenic alone and arsenic combined with chemotherapy, and the 5-year RFS and OS estimated between two groups were compared.
Results:All of patients with APL in four inductive therapy groups reached CR, the CR rate in each group was 100%. The TC was 28.31±4.5 days in As2O3 alone group. It was significantly shorter than that in other groups(P<0.05). The recurrence rate in four groups at 2 years were 11.8%,0%,14.3% and 14.3%, respectively; the 5-year RFS and OS were 82.4% and 88.2%,81.3% and 81.3%,78.6% and 85.7%, 71.4% and 71.4%, respectively. The RFS in four groups was not significantly different, so was the OS. The RFS and OS were significantly shorter in group of TC more than 30 days than that in group of TC less than 30 days(P<0.05). The 5-year RFS and OS of patients with the post-remission treatment were estimated of 85.7% and 85.7%,90.0% and 90.0%, respectively. The RFS between two groups was not significantly different, so was the OS.
Conclusions:(1) The CR rate was not significantly different in patients with APL treated with four programs. (2) The TC was shorter in patients used by As2O3 alone than that by other programs. (3)Combinative medication didn't decrease the 2-year relapse rate and didn't increase the 5-year survival rate. (4) Patients with APL might have a longer survival as the TC less than 30 days. (5) The 5-year RFS and OS were not significantly different in patients with a post-remission treatment of As2O3 alone or As2O3 and chemotherapy in turn.
Part two The comparative study on clinical outcomes of differentiation of symptoms and signs in patients with acute promyelocytic leukemia
Objective:To analysis the CR rate, relapse rate, and survival rate in APL patients based on differentiation of symptoms and signs, and to investigate the prognosis of APL patients with different pattern of syndrome.
Methods:The 85 cases of APL were the hospital patients from September 1993 to September 2007. The detailed symptoms were recorded in these cases at initial diagnosis. The differentiation of symptoms and signs for classification of syndrome was used by virtue of questionnaire form comprised of symptoms and signs. The CR rate and relapse rate were analyzed by Fisher exact test, and the survival was analyzed by product limit method with a follow-up from the time of diagnoses to January 2010, and 10 patients were lossed to follow up.
Results:The types of syndrome in APL patients were classified as deficiency of QI, deficiency of both QI and blood, deficiency of QI and yin, excessive heat and deficiency of QI, and other. The CR rate was 100%,91.7%,88.9%, and 89.5%, respectively, the CR rate were not significantly diferent in four groups. The RFS of patients with QI deficiency, QI and blood deficiency, QI and yin deficiency and predominant heat deficiency of QI and other were 0.70±0.19 (x±1.96s),0.83±0.21,0.78±0.27,0.57±0.23,0.66±0.27, respectively, the RFS curve become flattened after 5 years, and the RFS were not significantly diferent in four groups. The OS of patients with QI deficiency was 0.91±0.12 (x±1.96s), and the OS curve became flattened after 3 years; The survival rate of patients with QI and blood deficiency was 0.92±0.16, and the OS curve became flattened after 1 year; The OS rate of patients with QI and yin deficiency was 0.78±0.27, and the OS curve becomes flattened after 2 years; The OS of patients with excessive heat and QI dificiency was 0.57±0.23, and the survival curve becomes flattened after 9 years; The OS of patients with other was 0.66±0.27, and the OS curve becomes flattened after 5 years;. The OS curves changed dramatically during 1 year after diagnosis, and the incidence of death was high. The OS rate of patients with excessive heat and QI dificiency was significantly lower than that of those with other types (P<0.05).
Conclusions:(1) The CR rate and RFS of APL patients were similar in four groups, so was the relapse rate. (2) The APL patients with deficiency of QI had a long life and a good prognoses, while the patients with excessive heat and QI deficiency had a short survival and a poor prognoses. (3)It might be appropriate to keep the maintenane therapy time for 2-3 years in patients without excessive heat..Contrarily, it might be necessary to prolong the treatment time in patients with excessive heat to reduce the incedence of relapse and death.
引文
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