Immunophenotyping of childhood acute lymphoblastic leukemia in Saudi Arabia: Second look

Geographical variations in the incidence of disease are of considerable theoretical and practical importance. It has been claimed that the distribution of acute lymphoblastic leukemia (ALL) phenotypes in Saudi Arabia is different from that recorded in the Western literature. One hundred and twelve (112) patients under 15 years of age, diagnosed as ALL between January 1992 and May 1994 had immunophenotypes performed on their blast cells. Common ALL (cALL) together with pre-B-ALL, formed 86.5% of the total; B-cell 3%, T-cell 6% and null cell 4.5%. These figures are not significantly different from the Western literature. A previous claim from this institution in 1990, that both null and B-cell ALL were significantly increased compared with elsewhere, is not supported by the present figures. Age and sex distribution, and FAB classification, L1 77%, L2 20% and L3 3%, were also of the same order as described elsewhere and, in particular, there was no increase in the frequency of L3 subtype.     

Rhinocerebral zygomycosis in a patient with acute lymphoblastic leukemia

We report a case of a 28-year-old man with acute lymphoblastic leukemia whodeveloped rhinocerebral zygomycosis during induction chemotherapy. Thislife-threatening fungal infection is an infrequent cause of neutropenic fever,and is occasionally found in patients with leukemia and lymphoma, or patientswith severely compromised defence mechanisms due to other diseases. Itis caused by moulds belonging to theMucoraceaefamily, and ischaracterized by local destruction of the affected organ. In our patient, theinfection spread from the paranasal sinuses to the right orbit, destroyedintraorbital structures and resulted in blindness within days. Biopsy from theright maxillary sinus was performed and mucormycosis was suspected throughmicroscopic examination. Culture of the resected specimen identifiedRhizopus arrhizusas the causing agent.Treatment of zygomycosis should consist of radical surgical debridement ofthe infected tissue, together with intensive broad-spectrum antimycotictherapy with amphotericin B. What could be learned from this case is, thataggressive approaches to identify the cause of infection is necessary, andthat aggressive treatment strategies are inevitable to overcome the infection.Furthermore, treatment of the underlying disease should be continued as soonas possible.     

Skeletal changes in childhood acute lymphoblastic leukemia: Correlation with the presence of the cALL antigen

We studied the occurrence of the radiolucent metaphyseal bands in pretreatment skeletal X-rays and the phenotype of leukemic cell in 66 children with non-T, non-B ALL. A striking correlation was found between the expression of the CALLA on the leukemic cell and the occurrence of the early metaphyseal bands. We speculate that the bands might reflect an ongoing anti-leukemic reaction which may have been in progress before the disease became clinically manifest and which is associated with relatively favorable prognosis after even a modest chemotherapy.     

Detection of circulating ‘terminal transferase-positive’ cells does not predict relapse in acute lymphoblastic leukemia

Serial samples of peripheral blood were obtained from 35 children with ALL over a period of 18 months. The mononuclear cells were examined for TdT by indirect immunofluorescence using an unpurified anti-calf thymus TdT as the primary antibody. This analysis failed to distinguish those children who were destined to relapse (n = 9) from those who remained in continuous complete remission. Rather, the exhibition of fluorescence was linked to the co-existence of infection, with a negative predictive value of 0.91. Putative ‘TdT-positive’ cells were concentrated in the T-lymphocyte fraction and the very process of E-rosette formation seemed to contribute to this phenomenon. It appears as if the anti-TdT reagent recognizes not only TdT but also a variety of antigens which are expressed on or in immature and activated lymphocytes.     

Immunological typing of acute lymphoblastic leukemia: Concurrent analysis by flow cytofluorometry and immunocytology

For 60 cases of acute lymphoblastic leukemia (ALL) immunological typing was done concurrently by the avidin-biotin-peroxidase method using cytocentrifuged smears and by flow cytofluorometry for the study of surface antigens. The use of a large panel of antibodies detecting differentiation antigens allowed us to sub-classify 57/60 cases as 43 B-lineage ALLs and 14 B-Lineage ALLs. The two types of ALL can be accurately distinguished by the expression of the antigens recognized by the antibodies of the clusters of differentiation CD19 (B4) and CD7 (Leu 9). Almost perfect agreement was obtained between the results of the two methods for antigens DR, CD10 (cALLA; J5) and CD7. A number of discordances were observed with other antigens [CD19 (B4), CD20 (B1), CD22 (To15), CDl (T6), CD2 (Tll), CD4 (T4). CD8 (T8), CD3 (T3), T9, T10]. In spite of these discordances, the avidin-biotin-peroxidase method can predict the lineage involved in most ALLs with a high degree of reliability. Nevertheless, for weakly expressed surface antigens (such as 134 and 131) the immunocytological method is less sensitive than flow cytofluorometry and can only approximately determine the stage of differentiation of neoplastic cells. Furthermore, the existence of cases which are at the same time negative with flow cytofluorometry and positive with immunocytology is consistent with the intracytoplasmic expression of certain differentiation antigens. Thus in the course of lymphoid differentiation, intra-cytoplasmic expression of T3, To15 and possibly J5 precedes their expression at the cell surface.     

Response of recurrent acute lymphoblastic leukemia to glucocorticoids: Serial studies of receptor content, in vivo cytokinetic changes and clinical responses

The sensitivity of relapsed acute lymphoblastic leukemia (ALL) to treatment with steroids was assessed by measuring bone marrow blast, whole-cell glucocorticoid receptor (GR) levels and serial cytokinetic and clinical responses to steroids, both as single agents and in combination reinduction chemotherapy. GR levels ranged widely, from 1800 to 47,800 sites/cell (median 16,000), and did not differ significantly from levels measured in newly diagnosed patients (p = 0.50). Nineteen of the 48 children studied had GR levels measured both at diagnosis and relapse, and in 14 the values at relapse were either decreased or increased by more than 25%. For nine children, the sensitivity to a three-day oral course of dexamethasone alone (6 mg/m² per day) was estimated from daily leukocyte counts and serial bone marrow cytokinetic studies. A clinical oncolytic effect of dexamethasone was associated with a reduction in the marrow cell proliferating compartment, as judged from labeling indices, mitotic indices and percent S + G₂ + M in five patients. We found, however, that GR levels either alone or combined with clinical or cytokinetic responses to dexamethasone as a single agent did not reliably identify patients who were likely to respond favorably to reinduction with steroid-containing combination chemotherapy. The 35 children who successfully attained subsequent remissions had GR levels similar to those who failed (p = 0.35). While not statistically significant, two observations suggest an association between lower receptor content and drug resistance. Receptor levels from patients with ALL who relapsed while on chemotherapy were appreciably lower (median 15,700, n = 31) than GR levels from patients who relapsed off therapy (median 20,300, n = 17) (p = 0.08). Moreover, three of seven patients with serial studies, whose GR levels at relapse were lower than at diagnosis, failed reinduction — compared to only one of twelve whose levels were either increased or remained unchanged (p = 0.11). Although not having any obvious clinical utility, studies of GR at diagnosis and at relapse may aid in clarifying mechanisms of drug resistance in leukemic blasts.     

Detection of aneuploid cells in acute lymphoblastic leukemia with flow cytometry before and after therapy

We have evaluated the proliferative activity and DNA content of immunophenotyped hematopoietic cells applying flow cytometry. After indirect immunofluorescence the cell membrane was permeabilized for propidium iodide staining of DNA. Compared with single parameter detection of DNA content this method has more certainty in the determination of aneuploidies in lymphatic leukemia cells. Immunophenotyped residual normal hematopoietic cells were used as an internal standard. If this method was tested for evaluation of therapeutic effects after chemotherapy greater sensitivity in detection of minimal residual disease was observed than when using microscopic evaluation or single parameter DNA analysis in cases of aneuploid lymphoblastic leukemias.     

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.     

Is Mycoplasma Pneumonia associated with childhood acute lymphoblastic leukemia?

Acute lymphoblastic leukemia (ALL) in the childhood peak may be arare response to delayed first exposure to one or more common infectiousagent(s). Mycoplasma Pneumonia has the appropriate socioeconomic correlatesand clinical symptoms and the hypothesis that delayed first exposure to itmay contribute to ALL is considered. Counts of positive reports of MPneumonia from disease surveillance data for England and Wales (UnitedKingdom) for 1975-92 have been taken as proxies for community burden ofinfection. Variation by months of birth (cohort) and diagnosis (period) ofincidence of ALL in children born and diagnosed 1975-92 are compared withpredictions. When periods were classified by mean M Pneumonia count rate inthe nine preceding months, standardized morbidity ratios (SMR) for thehighest and lowest 20 percent were 108 and 89 (rate ratio [RR] = 1.2, 95percent confidence interval [CI] = 1.1-1.4). SMRs for cohorts with highestand lowest predicted risk (i.e., lowest and hi ghest M Pneumonia count ratearound birth and during infancy) were 110 and 97 (RR = 1.1, CI = 1.0-1.3).The trend for period was most marked in the cohorts with low opportunity forexposure when young. This ecologic analysis provides preliminary support forthe hypothesis.     

Improved treatment outcome in adult acute lymphoblastic leukemia using the intensive German protocol,a preliminary report

Thirty-nine consecutive patients with acute lymphoblastic leukemia were treated with an intensive chemotherapy protocol. There were 23 males and 16 females with a median age of 37 years (range: 15–65). Eighteen patients had common ALL, seven had pre-B ALL, three earlyprecursor B ALL, seven T-ALL and four had aberrant expression of myeloid antigens (c-ALL in three and pre-B ALL in one). The median initial leukocyte count was 11.8×10⁹/l (range: 0.65–295). Cytogenetic result of the marrow was available in 16 of 39 patients (41 per cent) and showed Philadelphia positivity in six, a normal result in six and one each of t(4,11), t(1,19), hyperdiploidy and del 12p. Hepatosplenomegaly was present in about 20 per cent of the patients. l-Asparaginase-related hepatic toxicity was the commonest toxicity (48.7 per cent) during phase I of induction. Prolonged pancytopenia and hypoplastic death were common during phase II. With the use of growth factors during the neutropenic period of phase II induction, the rate of hypoplastic death was reduced from 40 per cent to 3 per cent. Common causes of treatment failure included early hypoplastic death (27.8 per cent) and leukemia relapses (50 per cent) while primary refractory leukemia, hepatic failure and perforated peptic ulcer contributed to 11.1, 5.5 and 5.5 per cent of the other deaths. A high complete remission (CR) rate (87·4 per cent) was achieved after phase I induction. The median event-free survival (EFS) was 8 months and the 3-year event-free survival was 43 per cent. This result compared favourably to the other regimens previously employed in our institution. In conclusion, satisfactory survival can be achieved with this intensive regimen. Good supportive care was however, essential to minimize toxicities. © 1997 John Wiley & Sons, Ltd.     

青少年急性淋巴细胞白血病治疗后多发性骨坏死(附1例)

目的:报告1例急性淋巴细胞白血病(ALL)青少年治疗后并发多发性骨坏死及其治疗,并复习相关文献。方法:1例15岁的青少年ALL接受了BFM方案化疗,皮质激素(泼尼松和地塞米松,并将地塞米松换算为泼尼松的等效剂量)的累积剂量为7876mg/m2。结果:治疗结束后6个患者出现肩关节和髋关节骨坏死。ALL诊断和骨坏死诊断的相隔时间为41个月。病人有长期疼痛和活动受限。已建议行手术治疗。结论:接受强烈ALL化疗的青少年是发生ON的高危人群,未来的研究应在保证疾病控制的前提下,尽量减少治疗相关ON的发生。     

New insights into the pathophysiology and therapy of adult acute lymphoblastic leukemia

Significant advances have been made in the last decade toward a better understanding of the disease pathogenesis and the development of novel therapies that target specific subsets of adult acute lymphoblastic leukemia (ALL). Risk‐adapted strategies are transforming the disease treatment and prognosis. With current treatment regimens, long‐term survival is achieved by approximately 50% of patients with B‐cell ALL, 50% to 60% of patients with Philadelphia chromosome–positive ALL, and approximately 80% of patients with Burkitt's leukemia. Genomic profiling in ALL has identified new prognostic markers, new therapeutic targets, and novel ALL subtypes. These may be amenable to future targeted therapies that can further improve outcomes. The early recognition of early precursor T‐cell ALL, a distinct pathobiological entity with a poor prognosis, is essential for the development of an effective clinical management strategy. The role of monoclonal antibodies and cytotoxic T‐cell therapies continues to be defined. Many of the approaches are currently being evaluated for ALL salvage. Their incorporation into frontline adult ALL therapy, in concomitant or sequential strategies, may increase the cure rates to levels achieved in pediatric ALL and may reduce the need for prolonged intensive and maintenance chemotherapy. Cancer 2015;121:2517–2528 . © 2015 American Cancer Society.     

青少年急性淋巴细胞白血病治疗后多发性骨坏死（附1例）

目的：报告1例急性淋巴细胞白血病（ALL）青少年治疗后并发多发性骨坏死及其治疗,并复习相关文献。方法：1例15岁的青少年ALL接受了BFM方案化疗,皮质激素（泼尼松和地塞米松,并将地塞米松换算为泼尼松的等效剂量）的累积剂量为7876mg/m2。结果：治疗结束后6个患者出现肩关节和髋关节骨坏死。ALL诊断和骨坏死诊断的相隔时间为41个月。病人有长期疼痛和活动受限。已建议行手术治疗。结论：接受强烈ALL化疗的青少年是发生ON的高危人群,未来的研究应在保证疾病控制的前提下,尽量减少治疗相关ON的发生。     

Prophylaxis and treatment of neoplastic meningeosis in childhood acute lymphoblastic leukemia

The introduction of cranial radiotherapy (CRT) has provided efficient control of overt or subclinical meningeosis in acute leukemia. Especially due to the long-term toxicity of CRT, reduction or elimination of radiotherapy appeared mandatory after cure rates of more than 70% had been achieved in acute lymphoblastic leukemia (ALL). Several large clinical trials of the Berlin-Frankfurt-Münster (BFM) Study Group with more than 3500 patients since 1981 have demonstrated that intensive systemic and intrathecal chemotherapy without or with limited CRT can efficiently prevent central nervous system (CNS) relapses in a large percentage of patients. However, only in low-risk patients prophylactic radiotherapy can be completely and safely replaced by conventional doses of methotrexate. In addition, reduction of chemotherapy in low-risk ALL increased the rate of relapses with CNS involvement. Thus, only a combination of multidrug induction, high-dose methotrexate (HD-MTX) consolidation, and reintensification allowed safe elimination of CRT in low-risk ALL. This approach combined with CRT with 12Gy and 18 Gy in medium and high risk ALL, respectively, reduced the incidence of relapses with CNS involvement to less than 5% (trial ALL-BFM 86). Patients with inadequate response to therapy, or with T-cell ALL, or with overt CNS disease are at particularly high risk for relapse with CNS involvement, and require more systemic and intrathecal chemotherapy combined with cranial irradiation. In B-cell ALL, short intensive chemotherapy pulses including HD-MTX could completely replace radiotherapy. In AML, post-consolidation CRT appears to be advantageous with regard to control of extramedullary as well as systemic relapses.     

Complete remission with romidepsin in a patient with T‐cell acute lymphoblastic leukemia refractory to induction hyper‐CVAD

T‐cell acute lymphoblastic leukemia (T‐ALL) and T‐cell lymphoblastic lymphoma (T‐LBL) are neoplasms that originate from T‐cell precursors. Outcomes in adult patients with T‐ALL/LBL remain unsatisfactory; early relapse following intensive induction chemotherapy is a concern, and patients with relapsed or refractory disease have a poor prognosis. Romidepsin is a potent, class 1 selective histone deacetylase inhibitor approved for the treatment of patients with peripheral T‐cell lymphoma who have had ≥1 prior therapy and patients with cutaneous T‐cell lymphoma who have had ≥1 prior systemic therapy. Here, we report the case of an adult patient with T‐ALL refractory to induction hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper‐CVAD). Treatment with romidepsin was initiated, and romidepsin in combination with hyper‐CVAD resulted in complete remission, with mild tumor lysis syndrome as the only detectable additional toxicity. The patient eventually underwent allogeneic stem cell transplant while in first complete remission. Prior studies have shown that romidepsin is capable of inducing durable responses with manageable toxicities in patients with mature T‐cell lymphomas. This case study describes the successful use of romidepsin in combination with hyper‐CVAD in an adult patient with refractory T‐ALL and highlights the activity of romidepsin in the T‐cell lineage. The potential of romidepsin‐containing regimens in patients with T‐ALL/LBL deserves further study.     

microRNA与急性淋巴细胞性白血病关系的研究进展

microRNA是一类长度为19～25个核苷酸的内源性非编码小分子RNA,通过抑制靶基因的表达参与包括细胞增殖、分化、凋亡、炎症调节、干细胞发育等几乎所有重要的生物学过程,许多microRNA在肿瘤细胞中异常表达,提示可能与肿瘤的发生发展有关。急性淋巴细胞性白血病（ALL）是最常见的儿童肿瘤,临床表现、形态学、免疫表型及遗传学特征极具异质性。现已发现若干microRNA在ALL 中异常表达,且与其生物学特性以及临床特征、预后和治疗相关。对microRNA的了解有助于帮助人们更深入地认识ALL 的发病机理,有助于在寻找合适的诊断、判定预后的分子标志物以及潜在的治疗靶点方面取得新突破。      

Characterization of thymocytes expressing the common acute lymphoblastic leukemia antigen

We studied the relationship between CALLA + thymocytes and two known markers of T-lymphocyte differentiation, Tdt and the sheep erythrocyte receptor. Thymocytes were studied using double fluorochrome analysis (with monoclonal anti-CALLA antibody and anti-Tdt) before and after E rosette separation. We found that approx. 4% of unseparated thymocytes were CALLA + and that most CALLA + cells were also Tdt+. After E rosettes separation CALLA + Tdt + cells were found mostly in the ER- fraction (20% of ER- cells) while only 1.0% of ER + cells were CALLA +. The expression of CALLA on ER? Tdt + thymocytes suggests that CALLA may defined cells early in T-cell differentiation.     

急性淋巴细胞白血病化疗患者经外周静脉穿刺的中心静脉导管相关性感染影响因素的Logistic回归分析

目的探讨急性淋巴细胞白血病化疗患者经外周静脉穿刺的中心静脉导管(PICC)导管相关性感染影响因素的Logistic回归分析。方法选取120例急性淋巴细胞白血病化疗患者,整理、分析所有患者病历资料,如性别、年龄、化疗次数、穿刺部位、穿刺次数、置管时间、糖尿病、免疫功能等,分析PICC导管相关性感染的危险因素进行单因素和Logistic回归分析,探讨感染危险因素,并提出预防对策。结果120例急性淋巴细胞白血病化疗患者中,PICC导管相关性感染17例,感染率为14.17%;共检出17株病原菌,其中革兰氏阴性菌占比58.82%,革兰氏阳性菌占比41.18%。不同性别、穿刺部位急性淋巴细胞白血病化疗患者PICC导管相关性感染发生率比较,差异均无统计学意义(P﹥0.05);不同年龄、化疗次数、置管时间、免疫功能情况、糖尿病情况急性淋巴细胞白血病化疗患者PICC导管相关性感染发生率比较,差异均有统计学意义(P﹤0.05)。Logistic回归分析结果显示,年龄≥65岁、化疗次数≥11次、置管时间≥11 h、免疫功能低下、有糖尿病史是急性淋巴细胞白血病化疗患者PICC导管相关性感染的独立危险因素(P﹤0.05)。结论年龄≥65岁、化疗次数≥11次、置管时间≥11 h、免疫功能低下、有糖尿病史是急性淋巴细胞白血病化疗患者PICC导管相关性感染的独立危险因素,临床治疗应该选择合适的化疗方案,缩短置管时间,针对危险因素积极采取预防措施,从而减少PICC导管感染发生。