Treatment of T-lineage acute lymphoblastic leukemia

T-cell acute lymphoblastic leukemia is an aggressive disease that responds poorly to "standard" therapy designed for the more common B-lineage ALLs in childhood. The principles of this "standard" therapy were derived from empiric clinical trials. Thus, it is not surprising that the therapy that had the greatest impact on survival in the group as a whole would be found to be most successful for the most common subset of patients. T-cell malignant lymphoblasts share many biologic features that set them apart from the more common B-lineage lymphoblasts. Some of these biologic features suggest therapeutic approaches that should be particularly successful in treating patients with T-cell leukemia. The use of aggressive, multiple-agent "pulse" chemotherapy has been shown through empiric trials to have relative efficacy in T-cell lymphoblastic leukemia, presumably because of the rapid generation time and high growth fraction. Future studies will (1) determine the optimal dose and schedule of cytosine arabinoside needed to exploit the increased Ara-CTP accumulation in T-cell blasts, (2) determine the efficacy of a new agent, deoxycoformycin, an inhibitor of adenosine deaminase, to exploit the biochemical phenotype of T-cell blasts, and (3) assess the ability of conjugated anti-T monoclonal antibodies to deliver a cytotoxic agent, thus exploiting unique antigenic determinants at the cell surface. As more is learned about the biology of T-cell malignancies, further treatment strategies may be suggested to exploit the new features that are discovered. Similarly, it is hoped that the unique features of the B-lineage leukemias will suggest treatment strategies that will improve survival in those patients as well. Certainly, improved survival has already been achieved in the case of the B-cell leukemias and Burkitt's lymphomas, and improvement may also be possible for the pre-B and early pre-B phenotypes of lymphoblastic leukemia.     

Immunophenotype predicts radiation resistance in T-lineage acute lymphoblastic leukemia and T-lineage non-Hodgkin's lymphoma.

In the preclinical arm of our study, the radiobiologic features of primary malignant cells from newly diagnosed and relapsed T-lineage acute lymphoblastic leukemia/non-Hodgkin's lymphoma patients were analyzed using clonogenic assays. A marked heterogeneity existed relative to the intrinsic radiation sensitivity of clonogenic T-lineage ALL/NHL cells from 42 patients. The mean SF2 (surviving fraction at 200 cGy) and alpha values (initial slope of the survival curve) were 0.36 +/- 0.04, and 0.558 +/- 0.079 Gy-1. Fourteen cases had SF2 values of > or = 0.50 and alpha values of < or = 0.2 Gy-1, consistent with a marked intrinsic radiation resistance at the level of clonogenic leukemia/lymphoma cells. Of these 14 radiation resistant cases, 12 were CD3+. Furthermore, the SF2 and D0 values of the 28 CD3+ cases were significantly higher than the SF2 and D0 values of the 14 CD3- cases (SF2: 0.441 +/- 0.048 versus 0.189 +/- 0.045, p = 0.002; D0: 189.6 +/- 26.3 cGy versus 108.7 +/- 18.2 cGy, p = 0.047) and CD3+ cases had smaller alpha values than CD3- cases (0.454 +/- 0.087 versus 0.765 +/- 0.152, p = 0.06). Thus, clonogenic cells from CD3+ T-lineage ALL/NHL patients were more resistant to radiation than clonogenic cells from CD3- T-lineage ALL/NHL patients. In the clinical arm of our study, 33 T-lineage ALL/NHL patients received autologous bone marrow transplants during remission. Pretransplant conditioning consisted of total body irradiation combined with high dose chemotherapy. The expression of CD3 antigen predicted the outcome of relapsed T-lineage ALL/NHL patients undergoing autologous bone marrow transplantation following total body irradiation plus high dose chemotherapy. Overall, the Kaplan-Meier estimate and standard error of the probability of remaining in remission at 3.5 years was 11 +/- 9% with a median relapse-free interval of 102 days. The disease-free survival at 3.5 years was 8 +/- 7% with a median disease-free survival time of 96 days. Notably, the expression of CD3 antigen on T-lineage ALL/NHL cells correlated with the probability of relapse after bone marrow transplantation. While 16 of 19 CD3+ patients relapsed after bone marrow transplantation, only 3 of 8 CD3- patients relapsed. The Kaplan-Meier estimates and standard errors of the probability of remaining in remission at 1 year after bone marrow transplantation were 7 +/- 6% (median relapse-free interval = 74 days) for CD3+ patients (n = 19) and 63 +/- 17% for CD3- patients (n = 8) (p = 0.006).(ABSTRACT TRUNCATED AT 400 WORDS)     

Managing Philadelphia chromosome-positive acute lymphoblastic leukemia: role of tyrosine kinase inhibitors

Before the introduction of tyrosine kinase inhibitors, the prognosis for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia was poor. The treatment of choice, stem cell transplantation, is a potentially curative option, but it is available only for a minority of patients and is associated with significant risk of morbidity and mortality. Although imatinib is largely effective, a substantial proportion of patients become resistant or intolerant to it. The activity of imatinib may be enhanced by coadministration with chemotherapy; such treatment is effective in many patients. Dasatinib is established as a second-line treatment in patients with resistance to or intolerance of imatinib. Recent data suggest that dasatinib, either alone or in combination with chemotherapy, has utility as first-line therapy. Dasatinib is more potent than imatinib, is less susceptible to drug-resistance mechanisms, and has been shown to penetrate the blood-brain barrier, making it potentially effective for treating central nervous system disease. Patients who relapse during treatment with dasatinib frequently carry the T315I mutation of BCR-ABL. Future regimens combining dasatinib with an agent able to inhibit this mutation may further improve outcome.     

酪氨酸激酶抑制剂在费城染色体阳性急性淋巴细胞白血病诱导治疗中的作用

目的 探讨低剂量化疗联合酪氨酸激酶抑制剂(TKI)作为初诊费城染色体阳性急性淋巴细胞白血病(Ph+ ALL)一线诱导治疗方案的可行性.方法 回顾性分析61例初诊Ph+ ALL患者接受不同诱导治疗方案的疗效与不良反应.结果 全部患者初次诱导治疗的完全缓解(CR)率为73.8％(45/61),再次诱导CR率为86.7％(13/15),两程诱导治疗总的CR率为95.1％(58/61),治疗相关死亡1例(1.6％).无论是否联用TKI,常规剂量组与低剂量组有效率差异无统计学意义[未联用组:65.5 ％(19/29)比60.0％(3/5),P=0.812;联用组:90.5％(19/21)比100.0％(6/6),P=0.432];低剂量化疗联合TKI的有效率与单用常规剂量化疗比较,差异亦无统计学意义(P=0.089).无论化疗强度如何,联合TKI均能提高初次诱导治疗有效率(常规剂量组:P=0.041;低剂量组:P=0.087);联用TKI方案总有效率显著高于未联用TKI方案[92.6％(25/27)比64.7％(22/34),P=0.010].对于未获CR患者,初次诱导时未联用TKI者再次诱导治疗联用TKI的有效率明显高于初次诱导曾联用TKI者[100.0％(8/8)比33.3％(1/3),P=0.011].不同遗传学亚组间初次诱导治疗的有效率差异无统计学意义(均P＞0.05),联用TKI可在一定程度上提高有效率,但差异均无统计学意义(均P＞0.05).全部患者初次诱导治疗的感染率为50.8％(31/61),出血发生率为4.9％(3/61).常规剂量组总感染率[56.0％(28/50)]高于低剂量组[27.3％(3/11)],但差异无统计学意义(P=0.084),两组总出血发生率差异亦无统计学意义[6.0％(3/50)比0(0/11),P=0.405].低剂量化疗联合TKI组的感染率低于常规剂量化疗联合TKI组[0(0/6)比71.4％(15/21),P=0.002],也低于单用常规剂量化疗组[0(0/6)比44.8％(13/29),P=0.039],组间出血发生率差异均无统计学意义(均P＞ 0.05).结论 低剂量化疗联合TKI作为Ph+ ALL一线诱导治疗方案值得进一步探索.     

Detection of minimal residual disease: methods and relationship to outcome in T-lineage acute lymphoblastic leukemia

The molecular basis of acute lymphoblastic leukemia (ALL) of both B-cell and T-cell lineages seems better understood using polymerase chain reaction (PCR) methods. The analysis of clone-specific junctional regions of rearranged genes for both Immunoglobulin (Ig H) and T-cell receptor (TcR) is the most sensitive tool for detection of minimal residual disease (MRD) in ALL. Because of the heterogeneity of all ALL patients examined in several studies, the detection of MRD at different times of treatment has not as yet been correlated with disease outcome. In contrast, T-ALL is a homogeneous disease characterized by expansion of a single clone showing a specific Rearranged junctional region of TcR delta and/or gamma genes. The use of a clone-specific probe allows detection of residual leukemia throughout treatment. However, 60 % of patients with T-ALL relapse during treatment or towards the end of therapy, with resurgence of the original leukemic clone. It is possible that the detection of MRD at a specific time-point after diagnosis, as well as at the beginning of maintenance, may help to identify a group of T-ALL patients at high risk of relapse. The correlation between detection of MRD and treatment phase may be used in the future to evaluate whether treatment regimens can be improved allowing for stratification, based on PCR-mediated detection of MRD.     

Effects of interleukins 1–7 on the proliferation of T-lineage acute lymphoblastic leukemia cells

We investigated the proliferative effects of interleukins 1–7 (IL-1 to -7) on leukemic cells from 10 patients with T-lineage acute lymphoblastic leukemia (T-ALL). Five patients had CD7⁺4⁻8⁻ acute leukemia, one had CD5⁺ acute leukemia, and four had CD1⁺ acute leukemia. To examine the proliferative effect of each interleukin, ³H-TdR incorporation method was used. In the presence of IL-1, no increase in ³H-TdR incorporation was observed for any of the T-ALL cells. With IL−2, ³H-TdR incorporation increased in cells from 5 out of 10 T-ALL patients, including those with CD7⁺4⁻8⁻, CD5⁺, and CD1⁺ acute leukemia. In the presence of IL−3 or IL−6, ³H-TdR incorporation increased in cells from 2 out of 5 patients with CD7⁺4⁻8⁻ acute leukemia. However, CD5⁺ or CD1⁺ acute leukemia cells were not stimulated by IL−3 or IL−6. With IL−4, ³H-TdR incorporation was increased in the cells from 2 out of 5 patients with CD7⁺4⁻8⁻ acute leukemia and in the cells of 2 of those with CD1⁺ acute leukemia. IL-5 increased the ³H-TdR incorporation by cells from 2 out of 5 patients with CD7⁺4⁻8⁻ acute leukemia and 1 patient with CD1⁺ acute leukemia. IL-7 increased ³H-TdR incorporation in cells from all five CD7⁺4⁻8⁻ acute leukemia and 2 of those with CD5⁺ or CD1⁺ leukemia. No synergistic effect was found when IL-7 and other cytokines were added to cells from the 3 patients with CD7⁺4⁻8⁻ acute leukemia who were tested.     

Treatment of therapy-refractory B-lineage acute lymphoblastic leukemia with an apoptosis-inducing CD19-directed tyrosine kinase inhibitor.

Seven children and eight adults with CD19+ B-lineage acute lymphoblastic leukemia, as well as one adult with chronic lymphocytic leukemia, were treated with the CD19 receptor-directed tyrosine kinase inhibitor B43-Genistein. All patients had failed previous chemotherapy regimens, and six patients had relapsed after bone marrow transplantation. B43-Genistein was administered as a 1-hour i.v. infusion at 0.1-0.32 mg/kg/day dose levels for 10 consecutive days or 3 consecutive days weekly for a total of nine doses. B43-Genistein was well tolerated by all patients with no life-threatening side effects. There were six episodes of grade 2-3 fever, two of which were clearly drug related, one episode each of grade 3 myalgia, grade 2 sinus tachycardia, and grade 2 vascular leak syndrome. There was one durable complete remission and two transient responses. Pharmacokinetic analyses in 12 patients revealed a plasma half-life of 20 +/- 5 h, mean residence time of 24 +/- 5 h, and a systemic clearance rate of 20 +/- 3 ml/h/kg. Moderate levels of human antimouse antibody (HAMA) ranging from 20-87 ng/ml were detected in the day 28 blood samples from three of nine cases examined. Treatment of these three HAMA-positive patients with a second course of B43-Genistein did not yield measurable immunoconjugate levels in the plasma, indicating that the administered B43-Genistein molecules were rapidly cleared from circulation due to the HAMA. On the basis of its acceptable toxicity profile and its ability to elicit objective responses at nontoxic dose levels, B43-Genistein may provide the basis for an effective treatment strategy for B-lineage acute lymphoblastic leukemia patients who have failed standard therapy.     

Hypermethylation of CpG island in the promoter region of CALCA in acute lymphoblastic leukemia with central nervous system (CNS) infiltration correlates with poorer prognosis

Promoter hypermethylation occurs early in leukemogenesis and seems to be associated with poor prognosis in acute lymphoblastic leukemia (ALL). The methylation status of the promoter region of six genes was analyzed in 71 children with ALL using methylation specific PCR (MSP). Calcitonin (CALCA) and E-cadherin (CDH1) were the most frequently methylated genes in this group of patients. Considering the patients with central nervous system (CNS) infiltration, the estimated 2-year overall survival (OS) was 20% for those with methylation in CALCA promoter and 85% for those without (p=0.001). Our results suggest that the hypermethylation of CALCA promoter is a promising prognostic marker and may predict a higher risk for ALL patients with CNS infiltration.     

Aurora B kinase as a therapeutic target in acute lymphoblastic leukemia

Cancer Chemotherapy and Pharmacology - Acute lymphoblastic leukemia (ALL) is curable with standardized chemotherapy. However, the development of novel therapies is still required, especially for...     

死亡相关蛋白激酶基因启动子区过甲基化与喉癌的关系

目的　探讨死亡相关蛋白激酶 (DAPK)基因启动子区过甲基化与喉癌的关系。方法采用MSP和RT PCR法分析喉部正常黏膜、喉癌及相应癌旁组织中DAPK基因启动子区过甲基化及其mRNA表达状况。结果　 5 8例喉癌组织中 ,有 39(6 7.2 % )例DAPK基因启动子区过甲基化 ,其在各病理分级和T分级之间差异无显著性 (P >0 .0 5 ) ,而在N分级 (N0和N1)之间差异有显著性 (P <0 .0 0 1)。 5 8例癌旁组织中 ,有 6例甲基化 ,且均为喉癌组织中有甲基化的病例。RT PCR结果显示 ,所有甲基化的喉癌组织中均无DAPKmRNA表达 ,而喉部正常组织、非甲基化的喉癌组织和癌旁组织中均有其表达。结论　喉癌中DAPK基因启动子区过甲基化与其mRNA失表达有关 ,可能是喉癌发生、发展的原因之一 ,可作为喉癌诊断和预后分析的检测指标     

Hypermethylation of two CpG sites upstream of CASP8AP2 promoter influences gene expression and treatment outcome in childhood acute lymphoblastic leukemia

DNA hypermethylation of Caspase 8 associated protein 2 (CASP8AP2) and its role in childhood acute lymphoblastic leukemia (ALL) is unclear. We analyzed methylation status of CpG sites upstream of CASP8AP2 gene in 86 children with ALL by bisulfite sequencing and quantitative PCR. Methylation percentage of two CpG sites at positions of −1189 and −1176 was inversely correlated with mRNA expression (Spearman correlation: −0.333, P = 0.002). High methylation was associated with the existence of minimal residual disease (MRD) at day 78 (P = 0.035), The patients in high methylation group had a poor treatment outcome. The combination of methylation level and MRD at day 33 might improve current risk stratification.     

Adult acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL), a clonal expansion of hematopoietic blasts, is a highly heterogeneous disease comprising many entities for which distinct treatment strategies are pursued. Although ALL is a success story in pediatric oncology, results in adults lag behind those in children. An expansion of new drugs, more reliable immunologic and molecular techniques for the assessment of minimal residual disease, and efforts at more precise risk stratification are generating new aspects of adult ALL therapy. For this review, the authors summarized pertinent and recent literature on ALL biology and therapy, and they discuss current strategies and potential implications of novel approaches to the management of adult ALL. Cancer 2010. © 2010 American Cancer Society.