急性淋巴细胞白血病糖皮质激素耐药的分子机制及其相关问题

糖皮质激素(GC)能特异性地诱导淋巴细胞周期停滞和凋亡,因此几十年来一直是治疗淋巴系统肿瘤,尤其是急性淋巴细胞白血病(ALL)的主要组成药物。然而对GC产生耐药性是临床ALL治疗中常见的难题,也是导致治疗失败的主要原因。GC耐药的确切的分子机制尚未阐明,与不同的疾病类型、治疗方案,尤其是患者的遗传背景有关。最近发现mTOR激酶介导的信号通路的活化能够诱导淋巴细胞对GC耐药,以及mTOR激酶抑制剂雷帕霉素能够有效地逆转ALL细胞对GC耐药作用提示联合应用mTOR激酶抑制剂和GC有望成为治疗ALL的有效措施。GC敏感试验是儿童ALL的一项主要预后判断指标,然而本身还有很多局限性,因此有必要寻找精确的特异性高的体外GC敏感试验。     

Treatment and biology of pediatric acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. In the past ALL was intractable but now the survival probability is as high as 80–90%. Improved supportive care, treatment stratification based on relapse risk, biological features of leukemic cells, and optimization of treatment regimens by nationwide and international collaboration have contributed to this dramatic improvement. While including traditional risk factors (e.g. age and leukocyte count at diagnosis), the treatment has been modified based on biological characteristics (aneuploidy and translocation) and treatment response (assessed by minimal residual disease). Treatment for pediatric ALL typically consists of induction therapy with steroids, vincristine, and asparaginase with or without anthracycline, followed by multi‐agent consolidation including high‐dose methotrexate and re‐induction therapy. After consolidation, less intensive maintenance therapy is required for 1–2 years to maintain event‐free survival. Recently, using advanced genomic analysis technology, novel sentinel genomic alterations that may provide more precise stratification or therapeutic targets, were identified. Moreover, in the last decade germline variations have been recognized as similarly important contributors to understanding the etiology and sensitivity of ALL to treatment. A more individualized approach based on genomic features (somatic and germline) and treatment response, the introduction of newly developed agents such as molecular targeted drugs or immunotherapy, and social support including long‐term follow up are required for further improvement.     

儿童急性淋巴细胞性白血病ALL-2005方案治疗失败病例分析

目的分析ALL-2005方案治疗儿童急性淋巴细胞性白血病(ALL)失败的原因。方法将初治ALL失败病例分为诱导治疗失败、复发和依从失败以及治疗相关死亡三类,回顾性分析失败的原因。结果 2005年5月1日至2009年4月30日,共388例初治ALL患儿,随访时间中位数48个月(24～72个月)。101例患儿治疗失败,总失败率为26.0%;其中诱导治疗失败6例,复发69例,依从失败17例,治疗相关死亡9例。骨髓复发率为13.2%,单纯中枢神经系统复发率为2.4%,男性患儿睾丸复发率为3.9%。388例ALL患儿中,300例B系ALL患儿在诱导治疗第35天监测微小残留病(MRD),MRD≤0.01%患儿的复发率为15.4%,而MRD>0.01%患儿为28.8%,两者间差异有统计学意义(χ2=5.818,P=0.016)。结论复发是导致ALL-2005方案治疗ALL失败的主要原因,诱导治疗第35天MRD水平可以预测患儿的预后。     

Overt testicular disease (OTD) at diagnosis is not associated with a poor prognosis in childhood acute lymphoblastic leukemia: results of the EORTC CLG Study 58881

To assess the prognosis of overt testicular disease (OTD) at diagnosis of acute lymphoblastic leukemia (ALL), we analyzed the outcome of 1,165 boys enrolled in EORTC trial 58881. Thirteen (1.1%) boys had OTD associated with bad prognostic features. Patients with and without OTD did not differ in event-free survival (EFS) (P=0.30) or overall survival (OS) (P=0.54), even after adjustment for the three most important independent factors (NCI risk group, presence of very high risk features, type of asparaginase used). OTD was not an independent prognostic factor. These results may be due to the use of risk-adjusted intensive chemotherapy comprising high-dose methotrexate.     

Immunocompetence and prognosis in children with acute lymphoblastic leukemia: Combination of two different maintenance therapies

Intensive chemotherapy in patients with leukemia produces immunosuppression. The level of immunocompetence correlates with prognosis. The immunological function of 29 children with acute lymphoblastic leukemia (ALL) in complete remission and on 2 different maintenance therapies was evaluated and compared with 16 normal children (Group A). Sixteen children (Group B) with ALL received 6 mercaptopurine (6MP) daily and methotrexate (MTX) twice a week, and 13 children (Group C) received 6MP and MTX weekly for maintenance. There was depression of both cellular immunity, measured by the number of T cells and skin tests, and humoral immunity, measured by number of B cells, primary antibody production to typhoid vaccine, and levels of immunoglobulins. However, continuous maintenance therapy (Group B) produced significantly more severe immunosuppression of cellular immunity than the intermittent therapy (Group C). Humoral immunity was equally depressed in both groups of leukemia patients, but was less altered than cellular immunity. Concomitantly, patients with intermittent maintenance chemotherapy had less hematologic depression, fewer episodes of infection, and fewer died in complete remission. Patients of both groups with higher levels of immunocompetence had better prognosis with longer duration of complete remission than patients with severe immunosuppression. Out of 6 patients with “favorable immunocompetence” only 1 relapsed at 7 months and the other 5 remain in complete remission from 8 to 31 months. Among 23 leukemic patients with “unfavorable immunocompetence,” 15 relapsed and 8 remain in complete remission from 9 to 26 months.     

Osteonecrosis is unrelated to hip anatomy in children with acute lymphoblastic leukemia

Osteonecrosis is a debilitating toxicity associated with acute lymphoblastic leukemia (ALL) treatment. A recent report associated interindividual differences in hip anatomy with the development of idiopathic osteonecrosis in adults. To evaluate the impact of hip anatomy on the development of therapy‐related osteonecrosis, we retrospectively evaluated the femoral neck‐shaft angle, femoral neck offset, and lateral center‐edge angle using x‐rays of 18 osteonecrosis cases and 46 control children treated for newly diagnosed ALL on a single protocol. Despite adequate statistical power, we found no association between hip anatomy and osteonecrosis. Investigation of other factors contributing to ALL‐associated osteonecrosis is warranted.     

��ͯ����T�ܰ�ϸ����Ѫ���ٴ���Ч��Ԥ���������73������

??Objective??To analyze the clinical characteristics and prognosis of pediatric acute T lymphoblastic leukemia. Methods??Clinical characteristics of 73 children with acute T lymphoblastic leukemia and T-cell lymphoblastic lymphoma involving the bone marrow treated in Peking University People’s Hospital from March 2003 to March 2014 were retrospectively analysed?? and the prognosis factors were analyzed. Results??Of the 73 patients?? 25 children relapsed and 3 died from complications during chemotherapy or transplantation. Their 5-year CRF was ??37.89±6.02??% and 5-year EFS was ??58.74±6.01??%. The 5-year EFS decreased significantly when the initial onset age was more than 13. The 5-year CRF increased significantly when the initial onset size of spleen was bigger than 9 cm under the costal margin or the IgH rearrangement was positive. The 5-year CRF decreased significantly and 5-year EFS increased significantly when average peak methotrexate ??MTX?? blood concentration was more than 40 μmol/L during high-dose MTX chemotherapy. Conclusion??The treatment result of children with T-ALL is unsatisfactory. Initial onset age ≥13 and huge spleen indicate poor prognosis. Positive IgH rearrangement may be associated with high risk of recurrence. T-ALL patients can benefit from high-dose MTX therapy.     

Desensitization to pegaspargase in children with acute lymphoblastic leukemia and lymphoblastic lymphoma

Hypersensitivity to pegaspargase is associated with inferior survival in pediatric patients with acute lymphoblastic leukemia and lymphoblastic lymphoma. In the past year, drug‐supply shortages have led to the lack of an available alternative to pegaspargase. Rather than omit asparaginase from the treatment of acute lymphoblastic leukemia or lymphoblastic lymphoma patients with hypersensitivity to pegaspargase, we continued pegaspargase treatments for nine pediatric patients, utilizing a rapid desensitization protocol. There were no adverse events related to the pegaspargase during desensitization, and all patients who were checked had asparaginase serum levels above the threshold of 0.1 IU/mL at 7 to 14 days after pegaspargase therapy.     

Hemophagocytic lymphohistiocytosis associated with precursor B acute lymphoblastic leukemia

We report a case of a child with precursor-B acute lymphoblastic leukemia (ALL) who experienced refractory thrombocytopenia and massive splenomegaly during standard induction chemotherapy. He was diagnosed with hemophatocytic lymphohistiocytosis (HLH) during induction. Clinical and laboratory evaluation showed no evidence of infectious cause to HLH. Pancytopenia and HLH persisted after consolidation therapy even with remission from leukemia. After failure to control HLH with ALL-directed therapy and HLH-directed therapy, the patient underwent unrelated donor hematopoietic stem cell transplantation 8 months after diagnosis. He is 34 months post-transplant and in remission from leukemia and HLH.     

A medication diary‐book for pediatric patients with acute lymphoblastic leukemia in Indonesia

Background

Event‐free survival of pediatric patients with acute lymphoblastic leukemia (ALL) in Yogyakarta, Indonesia was low (20%). The aim of the study was to evaluate the effectiveness of using a medication diary‐book on the treatment outcome of childhood ALL.

Procedure

A randomized study was conducted with 109 pediatric patients with ALL in a pediatric oncology center in Yogyakarta, Indonesia. Both intervention and control groups received a structured parental education program and donated chemotherapy. The intervention group received a medication diary‐book to remind parents and families to take oral chemotherapy and present for scheduled appointments or admissions. Event‐free survival estimate (EFS) at 3 years was assessed.

Results

Among pediatric patients with ALL with highly educated mothers (senior high school or higher), the EFS‐estimate at 3 years of the intervention group was significantly higher than the EFS‐estimate at 3 years of the control group (62% vs. 29%, P = 0.04). Among pediatric patients with ALL with low‐educated mothers, no significant difference was found in the EFS‐estimates at 3 years between the intervention and control group (26% vs. 18%, P = 0.86).

Conclusions

We conclude that a medication diary‐book might be useful to improve the survival of pediatric patients with ALL in resource‐limited settings, particularly in patients with highly educated mothers. Pediatr Blood Cancer 2013;60:1593–1597. © 2013 Wiley Periodicals, Inc.     

Blinatumomab activity in a patient with Down syndrome B‐precursor acute lymphoblastic leukemia

Persistent minimal residual disease (MRD) after consolidation may indicate chemotherapy insensitivity in B‐precursor acute lymphoblastic leukemia (BP‐ALL). Given the strong association of MRD and outcome in non‐Down syndrome (non‐DS) BP‐ALL, it is likely that MRD levels are also of prognostic significance in DS BP‐ALL. We report here the successful use of blinatumomab, a bispecific T‐cell engager antibody construct, in a patient with DS BP‐ALL and persistent MRD at the end of consolidation. Blinatumomab has been shown to have excellent results in patients with relapsed/refractory BP‐ALL. This patient had no significant toxicity and achieved MRD negativity after only one cycle of blinatumomab.