大剂量甲氨蝶呤治疗儿童急性白血病的现状和进展

<正>自上世纪70年代,由于采用了联合化疗,小儿急性淋巴细胞白血病(ALL)的生存期明显延长。但研究发现,约65%的ALL患儿在缓解期出现髓外白血病复发,主要是中枢神经系统(CNS)复发。随后开始采用CNS白血病(CNSL)预防治疗,包括头颅放疗(CRT)、鞘内注射甲氨蝶呤(IT-MTX)或三联药物鞘内注射治疗(TIT)及可透过血脑屏障的中剂量甲氨蝶呤(IDMTX,0.5～1 g/m2)或大剂量甲氨蝶呤     

中枢神经系统微小残留白血病检测的临床意义

急性白血病是儿童时期最常见的恶性肿瘤。由于血脑屏障的存在,使化疗药物浓度不易达到中枢神经系统(CNS)的治疗水平而成为白血病细胞残留的最佳庇护所。中枢神经系统白血病(CNSL)是导致白血病复发的主要原因之一;初诊时是否合并CNSL是评判儿童急性淋巴细胞白血病(ALL)危险度的独立因素之一,对制订适宜的治疗方案、判断预后具有重要意义。因此CNSL的早期诊断和有效防治已成为儿童急性白血病患儿获得长期生存的关键之一。本研究采用单克隆抗体双重直接免疫荧光素标记法,对急性白血病患儿脑脊液(CSF)微小残留病(MRD)的检出和临床意义进行探讨。     

中枢神经系统白血病的诊治现状

采用现代治疗方案已使70%~80%小儿急性淋巴细胞白血病(ALL)达到长期无病生存即治愈。中枢神经系统白血病(CNSL)的预防治疗是小儿ALL治疗的组成部分。如果不进行系统的针对CNSL的预防治疗,整个疾病过程中CNSL发生率达70%。采取防治措施后CNSL发生率可降至5%以下。本文就CNSL若干     

“三联药”鞘注加静滴HD-MTX防治小儿中枢神经系统白血病363例疗效观察

尽管化学治疗迅速发展,但许多化疗药物不易透过血脑屏障,使中枢神经系统(CNS)成为白血病细胞的第一庇护所,中枢神经系统白血病(CNSL)成为急性淋巴细胞白血病(ALL)患儿复发的最重要原因。我们对1986～1996年收治的363例ALL患儿随访观察2年,结果表明:鞘注MTX、Ara-C、Dx加静滴HD-MTX可明显降低CNSL的发生率,对提高ALL患儿的持续完全缓解率(CCR)有着十分重要的意义;而且副作用少、安全可靠,适用于基层医疗单位开展。     

儿童中枢神经系统白血病治疗进展

白血病是全身性疾病 ,各重要脏器均有浸润。血脑脊液屏障使多数药物未能在脑脊液 (CSF)中达到有效浓度 ,从而使中枢神经系统 (CNS)常成为疾病复发的根源。 70年代急性淋巴细胞性白血病 (ALL)的中枢神经系统白血病 (CNSL)发生率约 2 6%～ 3 0 % ,急性非淋巴细胞性白血病 (ANLL)的CNSL发生率约 5 %～ 18%。近年来采用放疗、化疗鞘注等方法使发生率降至 5 %～ 10 %。CNSL可发生在白血病的不同时期 ,约 5 0 %发生在缓解期 (CR) ,3 %发病时有CNSL者[1] 。ALL在CR 2个月内很少发生CNSL ,2个月后发病率开始上升 ,2～ 40个月为发病…     

ALL-2005方案对儿童急性淋巴细胞白血病髓外白血病防治效果分析

目的总结ALL-2005方案对急性淋巴细胞白血病(ALL)患儿髓外白血病,包括中枢神经系统白血病(CNSL)及睾丸白血病(TL)的防治效果。方法 2005年5月—2008年5月共218例ALL患儿,采用ALL-2005方案进行治疗,总结其临床及治疗情况。结果 218例ALL患儿中,5例初诊时伴CNSL,1例于诱导治疗期间发生CNSL,4例于维持治疗期间发生CNSL;1例初诊时伴TL发生,4例维持治疗期间发生TL。经治疗,2例CNSL患儿骨髓复发,其余8例均缓解至今;TL患儿1例骨髓复发,1例放弃治疗,3例缓解至今。结论 ALL-2005方案疗效良好,有利于提高患儿长期生存质量。[临床儿科杂志,2012,30(5):412-414]     

儿童中枢神经系统白血病22例临床分析

目的分析22例急性白血病合并中枢神经系统白血病(CNSL)患儿的住院资料,为CNSL诊治提供参考。方法分析22例儿童CNSL的临床特征、实验室检查及预后。结果在303例儿童急性白血病中发生CNSL 22例,发生率7.3%,其中急性淋巴细胞白血病(ALL)18例,急性混合型白血病(MPAL)1例,急性髓细胞白血病(AML)3例;在18例ALL中,B-ALL 11例,T-ALL 7例,T-ALL合并CNSL发生率(22.6%)高于B-ALL(5.6%);CNSL常见临床表现有头痛、呕吐、惊厥及瘫痪等;CNSL预后差,死亡率高。结论 CNSL是急性白血病复发的主要原因之一,根据危险度来预防和治疗CNSL是关键。     

中枢神经系统白血病的发生特点及防治措施

随着白血病化疗方法的不断改进和支持治疗的完善，小儿急性白血病尤其是急性淋巴细胞白血病(ALL)的治疗效果得到非常显著的提高，但诱导缓解后约有20％～30％的病例因复发而影响疗效，而中枢神经系统白血病(CNSL)是造成复发的重要原因之一。因此，加强CNSL的防治，对进一步提高急性白血病的治疗效果具有重要意义。     

中枢神经系统白血病的发生特点及防治措施

随着白血病化疗方法的不断改进和支持治疗的完善 ,小儿急性白血病尤其是急性淋巴细胞白血病 (ALL)的治疗效果得到非常显著的提高 ,但诱导缓解后约有 2 0 %～ 30 %的病例因复发而影响疗效 ,而中枢神经系统白血病 (CNSL)是造成复发的重要原因之一。因此 ,加强CNSL的防治 ,对进一步提高急性白血病的治疗效果具有重要意义。1　CNSL的发病特点1 1　高危因素　CNSL的发生与白血病的种类有关 ,ALL的发生率较高 ,而急性髓细胞性白血病(AML)相对较少。在进行预防性CNSL治疗之前 ,ALL的CNSL发生率达 5 0 %～ 70 % ,近年已下降至 5 %～…     

大剂量甲氨喋呤预防标危型儿童急性淋巴细胞白血病中枢神经系统浸润

中枢神经系统白血病(CNSL)是影响小儿急性淋巴细胞白血病(ALL)无病长期生存的重要因素。甲氨喋呤预防CNSL的作用已得到认可，但每次剂量多少、疗程多长，尚无明确定论。我院对标危ALL患儿获得诱导完全缓解(CR)后，连续3次用大剂量甲氨喋呤(HDMTX)，早期强化后，每间隔3个     

Remission maintenance of adult acute lymphoblastic leukemia

This report describes the results of a study of central nervous system (CNS) prophylaxis and combination chemotherapy for the maintenance of remission in adult acute lymphoblastic leukemia. Adults with acute lymphoblastic leukemia who achieved complete remission were treated with 2,400 rads cranial irradiation and intrathecal methotrexate for CNS prophylaxis followed by continuation systemic chemotherapy with oral methotrexate, 6-mercaptopurine and cyclophosphamide. There were no CNS relapses following treatment. One-half of the patients relapsed within 11 months, with 5 patients remaining in remission for 27+ to 31+ months. The toxicity was acceptable with no treatment-related deaths. This regimen is capable of producing long remissions in a significant proportion of adults with acute lymphoblastic leukemia and appears to be effective in reducing the incidence of CNS relapse. It has the additional advantage of ease of administration and can be largely administered in the community.     

Long-term survivors of acute lymphoblastic leukemia — risk of relapse after cessation of therapy

The results of cessation of therapy (COT) in 64 long-term survivors (disease-free survival of five years or more) of acute lymphoblastic leukemia (ALL) were analyzed to determine the incidence of relapse off therapy. Thirty-seven of the patients had intermittent central nervous system (CNS) prophylaxis. Total follow-up from diagnosis varied from 5.75 to 27.75 years. The median time off therapy was three years (range, 8 months to 26 years). Eighty-six percent (55/64) of the patients continue in their initial remission. Eight patients had relapse, and one patient had a morphologically different leukemia at recurrence. All the relapses occurred between five to eight years from diagnosis and the cumulative rate of relapse for this period was 0.14. There was no significant difference in the rate of relapse for those receiving CNS prophylaxis (0.08) versus those not receiving CNS prophylaxis (0.19). The difference in the relapse rates for boys (0.24) versus girls (0.04) was statistically significant (P=0.04). Isolated testicular relapse (ITR) was not seen in any of the 34 boys. The present study confirms the earlier observations by others that relapse is uncommon in ALL patients remaining in remission longer than seven to eight years. ALL patients treated with intermittent CNS prophylaxis administered throughout the period of maintenance chemotherapy appear to be at no greater risk for relapse off therapy than those treated with high-dose initial cranial irradiation and intrathecal methotrexate. The longer duration of therapy and the use of a repetitive reinduction regimen for maintainance seem to be associated with a decreased risk of ITR after discontinuation of therapy for boys and men. There appears to be a small but definite risk of “second” leukemia in the long-term survivors of leukemia.     

Neuropsychological status of children with acute lymphoblastic leukemia treated for central nervous system relapse

Approximately 10% of children treated with contemporary therapy for acute lymphoblastic leukemia (ALL) will experience an isolated relapse in the central nervous system (CNS). From 5 to 25% of this group will become long-term survivors, but only after additional, more aggressive therapy. A review of the limited number of studies of children surviving treatment for CNS relapse disclosed a strikingly higher incidence of intellectual impairment than was found in similarly treated patients who remain in complete remission. Specific risk factors for this complication included the number of courses of cranial irradiation, a young age at treatment, increasing time since treatment, neuropathological changes apparent on abnormal computed tomography scans of the brain, and seizures. The methodological problems inherent in neurobehavioral research in childhood acute lymphoblastic leukemia are critically reviewed and suggestions for future studies are offered. Children with a CNS relapse should be serially evaluated for psychoeducational performance to facilitate early intervention in cases of learning difficulties.     

The Prognosis and Survival of Childhood Acute Lymphoblastic Leukemia with Central Nervous System Relapse

Central nervous system (CNS) relapse in childhood acute lymphoblastic leukemia (ALL) has been overcome by sensitive therapatic approachs. This study was planned to present the development of CNS relapse and survival in newly diagnosed 190 ALL patients whose cases were followed in the authors' unit between March 1991 and May 2002. St. Jude Study XI protocol was given to the patients who applied between March 1991 and March 1997 (group A) (n = 122), and St. Jude Study XIII protocol was given to the patients who applied between March 1997 and May 2002 (group B) (n = 68). The patients having isolated CNS relapse in group A received craniospinal irradiation (CSI) median 3.5 months after CNS relapse (range 2–6 months), a short time after reinduction, and 2 cures of consolidation. In group B, patients having isolated CNS relapse received IT once a month and a high-dose methotrexate treatment once every 8 weeks and 3 or 4, cures later therapy CSI median 7 months after CNS relapse (range 6–8 months) was given. When the overall survival rates of the 2 groups are compared, a statistically significant higher survival rate at 5 years was determined in group B than in group A (respectively, 82.3%, 58.4%) (p < .05). When subgroups of the patients (that is, those with no relapse, isolated CNS or BM relapse, or CNS + BM relapse) were compared in both groups, it was found that survival was much higher for the ones with no relapse and with isolated CNS relapse (respectively, 87.9%, 72.7%) compared to isolated BM or CNS + BM relapse groups (respectively, 10%, 13.3%) (p < .05). In a conclusion, for children with acute lymphoblastic leukemia and an isolated CNS relapse, with delayed definitive craniospinal irradiation allowing more intensive systemic and intrathecal chemotherapy results in better overall survival than has been previously reported.     

The influence of traumatic lumbar puncture and timing of intrathecal therapy on outcome of pediatric acute lymphoblastic leukemia

The CNS is a frequent site of relapse of childhood acute lymphoblastic leukemia (ALL). Traumatic lumbar puncture (TLP) is thought to increase the risk of CNS relapse. The authors examined whether TLP at the time of diagnosis affected outcome and whether this effect was influenced by the timing of intrathecal therapy (IT) in 77 patients with newly diagnosed ALL. IT was instilled at the time of either the diagnostic LP (early) or a second LP 24-48 h later (delayed). Of the 19 patients who had a TLP at diagnosis and received late IT therapy, 6 had isolated CNS relapse and 2 had combined CNS and bone marrow (BM) relapse. Of the 9 patients who had TLP and received early IT therapy, 1 had a CNS relapse (p = .20). In an analysis stratified according to risk of relapse, the odds ratio (OR) for relapse was 0.8 among patients at low and standard risk who had delayed IT therapy after TLP (p = .99) vs. 0.17 for those who had early IT (p = .47). Importantly, among patients with high-risk ALL, the OR for relapse was 21.0 for delayed IT therapy (p = .09) and only 1.5 for early IT therapy after TLP (p = .99). The results indicate that TLP at diagnosis appears to increase the risk of CNS relapse markedly in patients with high-risk ALL, and the use of early IT therapy appears to reduce this risk. These findings need to be confirmed by prospective, randomized studies.     

The prognosis and survival of childhood acute lymphoblastic leukemia with central nervous system relapse

Central nervous system (CNS) relapse in childhood acute lymphoblastic leukemia (ALL) has been overcome by sensitive therapeutic approachs. This study was planned to present the development of CNS relapse and survival in newly diagnosed 190 ALL patients whose cases were followed in the authors' unit between March 1991 and May 2002. St. Jude Study XI protocol was given to the patients who applied between March 1991 and March 1997 (group A) (n = 122), and St. Jude Study XIII protocol was given to the patients who applied between March 1997 and May 2002 (group B) (n = 68). The patients having isolated CNS relapse in group A received craniospinal irradiation (CSI) median 3.5 months after CNS relapse (range 2-6 months), a short time after reinduction, and 2 cures of consolidation. In group B, patients having isolated CNS relapse received IT once a month and a high-dose methotrexate treatment once every 8 weeks and 3 or 4, cures later therapy CSI median 7 months after CNS relapse (range 6-8 months) was given. When the overall survival rates of the 2 groups are compared, a statistically significant higher survival rate at 5 years was determined in group B than in group A (respectively, 82.3%, 58.4%) (p < .05). When subgroups of the patients (that is, those with no relapse, isolated CNS or BM relapse, or CNS + BM relapse) were compared in both groups, it was found that survival was much higher for the ones with no relapse and with isolated CNS relapse (respectively, 87.9%, 72.7%) compared to isolated BM or CNS + BM relapse groups (respectively, 10%, 13.3%) (p < .05). In a conclusion, for children with acute lymphoblastic leukemia and an isolated CNS relapse, with delayed definitive craniospinal irradiation allowing more intensive systemic and intrathecal chemotherapy results in better overall survival than has been previously reported.     

Remission maintenance of adult acute lymphoblastic leukemia.

This report describes the results of a study of central nervous system (CNS) prophylaxis and combination chemotherapy for the maintenance of remission in adult acute lymphoblastic leukemia. Adults with acute lymphoblastic leukemia who achieved complete remission were treated with 2,400 rads cranial irradiation and intrathecal methotrexate for CNS prophylaxis followed by continuation systemic chemotherapy with oral methotrexate, 6-mercaptopurine and cyclophosphamide. There were no CNS relapses following treatment. One-half of the patients relapsed within 11 months, with 5 patients remaining in remission for 27+ to 31+ months. The toxicity was acceptable with no treatment-related deaths. This regimen is capable of producing long remissions in a significant proportion of adults with acute lymphoblastic leukemia and appears to be effective in reducing the incidence of CNS relapse. It has the additional advantage of ease of administration and can be largely administered in the community.     

儿童急性淋巴细胞白血病复发与基因突变相关性

急性淋巴细胞白血病是儿童恶性肿瘤中最常见的类型,急性淋巴细胞白血病复发仍然是治疗的难题.随着近几年关于儿童急性淋巴细胞白血病复发机制的研究逐渐深入,越来越多的基因异常已经被证实与儿童急性淋巴细胞白血病复发相关,包括IKZF1缺失、PRED1缺失、JAK突变、CREBBP突变、CEBPE突变、ARID5B突变等.该文重点综述以上基因突变对儿童急性淋巴细胞白血病复发的影响.     

Biology and pathogenesis of CNS leukemia

Despite routine preventive central-nervous-system (CNS) therapy, 5-10% of children with acute lymphoblastic leukemia continue to suffer CNS relapse. In a majority of these patients, bone marrow relapse ensues and is usually fatal. A better understanding of the biology and pathogenesis of CNS leukemia is needed to develop more effective methods of prevention and treatment of this adverse complication of acute leukemia. Concepts of the origin and proliferation of leukemic cells in the CNS are reviewed, as well postulated mechanisms of their ingress into and egress out of the CNS.     

The results of high risk children's acute lyrnphoblastic leukemia total therapy. A report from the Polish children's leukemia/lymphoma study group

The study evaluates the efficacy of seven drug systemic therapy and three drug intrathecal treatment in children with acute lymphoblastic leukemia (ALL). Three hundred and thirty-five children with ALL treated at six hematological centers in Poland were divided into two groups: standard group and high risk group according to the BFM score method. Ninety-two children estimated as high risk patients diagnosed between 1978 and 1981 were treated according to the Polish Children's Leukemia/Lymphoma Study Group (PCLSG) program adopted from LSA₂L₂ regimen. The patients received prednisone, vincristine, adriamycin and cyclophosphamide as remission induction treatment, followed by cytarabin and 6-thioguanine given as consolidation therapy. The central nervous system prophylaxis consisted of cranial irradiation and intrathecal methotrexate, cytarabin and hydrocortisone. In maintenance phase, three different drug combinations were given as intermittent therapy. The total duration of therapy was 2.5 years. The life table analysis showed a 38% disease free survival and 50% complete continuous remission (CCR) for the total group of patients. A relatively high incidence of CNS relapse was observed. These results indicated that the regimen applied was not satisfactorily effective for the increased risk of ALL. Three of seven evaluated prognostic indices—age, mediastinal mass and cytochemical features—were significantly associated with probability of survival of the patients with protocol applied. Some other therapy proposals are discussed.