T-cell acute lymphoblastic leukemia following therapy of rhabdomyosarcoma

Multiple studies have documented an increased risk of secondary malignancies in patients receiving alkylating agents. Secondary leukemia following chemotherapy accounts for about 20% of all secondary neoplasms; most are acute nonlymphocytic. Secondary acute lymphoblastic leukemia has rarely been reported in either adult or childhood cancer. We report the development of acute T-cell lymphoblastic leukemia in a child following successful treatment of a paravertebral embryonal rhabdomyosarcoma (ERS). Southern blot analysis of DNA extracted from the T-cell lymphoblasts, using probes homologous to loci on the short arm of chromosome 11; P-calcitonin, P40.1 and H-ras, did not demonstrate the chromosomal loss of heterozygosity (LOH), a common feature of embryonal rhabdomyosarcoma. The data presented support the assumption that de novo leukemia emerged following treatment of the primary malignancy. © 1992 Wiley-Liss, Inc.     

Lack of mitogenic effects of growth hormone on human leukemic lymphoblasts

To determine whether human growth hormone (HGH) can cause proliferation of human leukemic lymphoblasts, we studied colony formation in semi-solid medium of MOLT 4, a cell line derived from an adolescent with acute lymphoblastic leukemia (ALL). Although exposure to single doses of HGH in supraphysiologic concentrations resulted in almost two-fold increases in number of colonies compared with control samples, physiologic concentrations had no effect. Similarly, physiologic concentrations of HGH had no effect on thymidine incorporation in short-term cultures of fresh lymphoblasts from children with ALL. In addition, total white blood cell and differential counts in 14 children with isolated growth hormone deficiency were reviewed pre- and post-treatment with HGH. In no case was there evidence of in vivo lymphocytosis or blastogenesis.Abbreviations HGH human growth hormone - ALL acute lymphoblastic leukemia - LCM leukocyte conditioned medium - PHA phytohemagglutinin - WBC white blood cell     

Receptors for sheep erythrocytes (E) and erythrocyte-antibody-complement complexes (EAC) on the lymphoblasts of childhood acute lymphoblastic leukemia

Two cell-surface markers, rosette formation with sheep erythrocytes (E-rosette) as a T-cell marker and rosette formation with bovine erythrocyte-antibody-complement complex (EAC-rosette) as a B-cell marker were determined on peripheral blood lymphocytes and lymphoblasts from normal and 89 children with acute lymphoblastic leukemia (ALL). In the majority of the patients (12/15 untreated patients and 6/11 patients in relapse), lymphoblasts exhibited neither E- nor EAC-rosette formation. Lymphoblasts from one untreated patient with mediastinal mass displayed E-(50%) and EAC-rosette formation (15%). In 3 of 11 patients in relapse, lymphoblasts displayed an increase in EAC-rosette formation with progressive disease. In the remaining patients with active disease, a small and variable proportion of lymphoblasts expressed E and/or EAC-rosette formation. In 63 patients in remission, percentages of E- and/or EAC-rosette were similar (p > 0.05) to those of control. The results indicate a wide heterogeneity with respect to expression of lymphocyte membrane markers in lymphoblasts and in normal lymphocytes in patients with active ALL.     

儿童急性淋巴细胞白血病DNA倍性与体内白血病细胞凋亡

目的：探讨儿童急性淋巴细胞白血病(急淋)肿瘤细胞DNA倍性与凋亡间的关系。方法：检测22例初治急淋患儿的DNA倍性及化疗前后体内白血病细胞的凋亡情况。结果：化疗前所有患儿体内白血病细胞均无明显凋亡,化疗后DNA指数为 1.16～1.6 的高二倍体组凋亡细胞比例为(22.06±8.98)%,较非高二倍体组(9.38±10.27)%显著升高(P<0.01)。结论：儿童高二倍体急性淋巴细胞白血病预后优于其它DNA倍性的病人与此类白血病细胞易凋亡、对化疗敏感有关。     

10岁以上儿童及青少年急性淋巴细胞性白血病的临床总结

目的总结64例年龄为10~17岁急性淋巴细胞性白血病(以下简称急淋)的临床疗效。方法64例患儿中男44例,女20例均接受99-XH-ALL方案治疗,随访1~116个月,平均随访时间为43个月,并应用SPSS 11.0软件进行无事件生存期和总生存期的分析。结果64例患儿中24例(37.5%)无不良临床特征,早期治疗反应良好,40例(62.5%)有不良临床特征及早期治疗反应不佳,64例患儿中58例达到CR,其中55例一疗程达到CR(85.94%),总CR率为90.63%,平均CR时间为38.45(25~56)天;13例复发(22.41%),平均复发时间为CR后15.77(2~58)个月;9例死亡(14.06%),其中4例死于感染,5例死于复发;随访中有21例失访,其中7例为复发后,10例为CR后,4例为未CR者,3例患儿接受移植,其中2例存活,1例死于移植后疾病复发,4例患儿出现并发症,占11.76%,其中1例乙肝(50个月),3例股骨头坏死(25、32、60个月),1例女孩4个月时发生第二肿瘤恶性葡萄胎,治愈存活至今。64例病人7年EFS:(37.31±7.23%),7年OS:(54.40±6.51%)。结论10岁以上儿童及青少年的急淋预后不良,长期生存率低。     

Lymphoblast morphology in predicting leukemic meningeal relapse with low chamber count and lymphoblasts

The diagnostic criteria for meningeal relapse (MR) of acute lymphoblastic leukemia (ALL) are a cerebrospinal fluid (CSF) chamber count of more than five leukocytes per microliter and a cytomorphological evaluation revealing lymphoblasts. A dilemma arises when confronted with a patient with a low CSF white blood cell (WBC) chamber count and lymphoblasts. We utilized a scoring system to review lymphoblast morphology in 12 such patients. A cell was defined as a lymphoblast if it could not be easily categorized as a lymphocyte, monocyte, histiocyte, or granulocyte. Each lymphoblast was scored on four parameters: presence of nucleoli, homogeneous distribution of chromatin, nucleocytoplasmic ratio greater than 75% and nuclear irregularity. Cells were scored without knowledge of the patients' out come. Seven patients eventually developed MR by current criteria and five patients never relapsed. The mean lymphoblast scores for patients that did and did not relapse were 2.35 and 1.53, respectively (P < .001). The percent of cells scored as lymphoblasts was also significantly higher in patients that relapsed, 36.9% vs. 19.4% (P = .01). Our study shows that careful cytomorphologic analysis can predict which patients with low chamber counts and “blasts” on cytocentrifuge examination will progress to meningeal relapse. We recommend reviewing the definition of MR and using a scoring system when confronted with blasts in a low chamber count cerebrospinal fluid specimen. Med. Pediatr. Oncol. 29:98–102, 1997. © 1997 Wiley-Liss, Inc.     

Immunodiagnosis of childhood all: Problems associated with the use of peripheral blood alone

The immunologic classification of acute lymphoblastic leukemia (ALL) based solely on peripheral blood (PB) cell phenotypes may lead to conflicting results. This was demonstrated by the simultaneous assay of five immunologic markers on PB and bone marrow (BM) cells from 13 children with untreated ALL. We assayed erythrocyte (E) rosettes at 4°C and 37°C, presence of membrane Ig(mIg), and binding of antisera raised against thymus (T), and E^? ALL blasts, respectively. At diagnosis, the PB of these children contained > 90% lymphoid cells with 0–48% E rosettes and 1-84% cells with T antigen(s). Of 7 children with WBC < 10,000/cu mm there were 4 who had 20% or more E rosettes and T-antigen-positive cells. Of 6 children with WBC > 10,000/cu mm there were only 2 who had more than 20% E rosettes and T-antigen-positive cells. Based on examination of PB alone, six children may have been classified as having T-like ALL. However, these results were due to the presence of circulating normal T lymphocytes, and assay of BM cells established that only one of the 13 children had T-like ALL and none had B-cell ALL. Bone marrow blasts from 12 patients did not form rosettes at 37°C, did not have mIg, and did not react with anti-T serum. A high proportion of BM blasts from these 12 patients (39-96%) did react with antiserum against E^? ALL blasts. Of these 12 patients 11 had a higher proportion of E^? ALL antiserum-positive blasts in the BM than PB. Thus, immunologic classification of ALL should be based on the study of BM blasts, or both PB and BM cells.     

Minimal requirements for the diagnosis,classification, and evaluation of the treatment of childhood acute lymphoblastic leukemia (ALL) in the “BFM family” cooperative group

Minimal requirements and their rationale for the diagnosis and the response to treatment in childhood acute lymphoblastic leukemia (ALL) were defined in the recently instituted “BFM-Family”-Group, in which the German, Austrian, Dutch, Italian, Belgian, French and Hungarian childhood leukemia study groups cooperate. ALL is defined as ≥ 25% lymphoblasts in the bone marrow; for confirmation of the diagnosis and classification the criteria of the French-American-British (FAB) criteria are retained. For determination of the extent of the disease at diagnosis or relapse the criteria by the Rome Workshop [1986] are recommended: An obligatory panel of monoclonal antibodies for immunophenotyping was defined, as well as criteria for precursor B-ALL and T-ALL. Cytogenetic studies may support the diagnosis and subtyping, and are essential to identify certain patients with a high risk of treatment failure (f.i. t(9;22), t(4;11)). The role of molecular genetics for the diagnosis and the characterization of leukemia and the value of its clinical application needs further elucidation. Relapse was defined as recurrence of evident leukemia in the blood, bone marrow (≥ 25% lymphoblasts) or at any other site (to be confirmed by histological examination). Bone marrow involvement combined with extramedullary relapse was defined as ≥ 5% lymphoblasts in the bone marrow. © 1992 Wiley-Liss, Inc.     

Eosinophilic Meningitis Preceding Meningeal Relapse in a Child with Acute Lymphoblastic Leukemia: Abnormal Nucleotide Content of Eosinophils

A case of eosinophilk meningitis 2 months before the appearance of lymphoblasts in the cerebrospinal fluid is described in a child with acute lymphoblastic leukemia (ALL). The peripheral blood showed no simultaneous eosinophilia. The child was successfully treated for her CNS relapse, and complete remission was easily obtained. The eosinophils and lymphoblasts disappeared quickly after the administration of intrathecal methotrexate. However, 3¹/₂ years later hypereosinophilia developed in the blood and bone marrow, heralding bone marrow relapse. Simultaneously, meningeal relapse was diagnosed and this time the cerebrospinal fluid showed a mixture of lymphoblasts and eosinophils. Treatment was reinstituted and complete remission was again obtained. Analysis of the blood eosinophils showed abnormal nucleotide patterns. Similar patterns were previously found in the lymphoblasts from other ALL patients.     

Augmented therapy improves outcome for pediatric high risk acute lymphocytic leukemia: results of Children's Oncology Group trial P9906

Background

The augmented BFM regimen improves outcome for children with NCI high acute lymphoblastic leukemia (ALL). Patient age, sex, and presenting white blood cell count (WBC) can be used to identify a subset of approximately 12% of children with B‐precursor ALL that had a 5‐year continuous complete remission (CCR) rate of only about 50% on earlier Pediatric Oncology Group (POG) trials.

Procedures

Children's Oncology Group trial P9906 evaluated a modified augmented BFM regimen in 267 patients with particularly high risk B‐precursor ALL. Minimal residual disease (MRD) was assessed in blood at day 8 and in marrow at day 29 of induction and correlated with outcome.

Results

The 5‐year CCR probability for patients in P9906 was significantly better than that observed for similar patients on POG trials 8602/9006 (62.2 ± 3.7% vs. 50.6 ± 2.4%; P = 0.0007) but similar to POG 9406 (63.5 ± 2.4%; P = 0.81). Interim analysis showed poor central nervous system (CNS) control, especially in patients with initial WBC ≥100,000/microliter. Day 29 marrow MRD positive (≥0.01%) vs. negative patients had 5 year CCR rates of 37.1 ± 7.4% vs. 72.6 ± 4.3%; day 8 blood MRD positive vs. negative patients had 5 year CCR rates of 57.1 ± 4.6% vs.83.6 ± 6.3%. End induction marrow MRD predicted marrow but not CNS relapse. In multivariate analysis, day 29 MRD > 0.01%, initial WBC ≥ 100,000/µl, male gender, and day 8 blood MRD > 0.01% were significant prognostic factors.

Conclusions

Augmented BFM therapy improved outcome for children with higher risk ALL. Day 8 blood and day 29 marrow MRD were strong prognostic factors in these patients. Pediatr Blood Cancer 2011; 57: 569–577. © 2011 Wiley‐Liss, Inc.

     

Phase II study of gemcitabine in children with relapsed acute lymphoblastic leukemia or acute myelogenous leukemia (ADVL0022): a Children's Oncology Group Report

BACKGROUND: To determine the response rate and toxicity to gemcitabine administered as 10 mg/m2/min x 360 min weekly for 3 weeks in children with relapsed acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML). Gemcitabine is a deoxycytidine analog that inhibits DNA synthesis and repair and has a broad spectrum of antitumor activity. PROCEDURE: From April 2001 to April 2003, 23 male and 9 female eligible patients were recruited for the Children's Oncology Group (COG) phase II study of Gemcitabine (ADVL0022). RESULTS: One of 20 evaluable patients with ALL and none of 10 evaluable patients with AML had complete responses to gemcitabine; there were no partial responses. Grade 3 or 4 hematologic toxicity and liver toxicity were common during therapy. Only one patient was alive 1 year after entry. The estimated 1-year overall survival probability for the 32 patients was 4% (SE = 3%). CONCLUSIONS: Gemcitabine at the dose and schedule in this trial was not effective for children with relapsed AML or ALL.     

Treatment of relapsed or refractory acute leukemia in childhood with bisantrene combined with high dose aracytine

Bisantrene is an anthracene derivative which has demonstrated activity in acute myeloblastic leukemia (AML) and in lymphoma. The present study was designed to assess the reinduction rate and toxicity of bisantrene (250 mg/m²/d × 5) associated with aracytine (1000 mg/m² twice a day × 5) in refractory and relapsed acute childhood leukemia. Patients who relapsed after bone marrow transplantation were eligible. Twenty-six children were included. Diagnoses were as follows: 13 AML, 9 acute lymphoblastic leukemia (ALL), and 4 undifferentiated leukemia (AUL). All patients had been very highly pretreated, especially with anthracyclines, and most of them were of poor prognosis. The overall response rate was 46% with a 95% confidence interval ranging from 27-65%. According to diagnosis, complete remission (CR) rates are: AML: 5/13, ALL: 5/9, and AUL: 2/4. Four children died, three from infection and one from acute lysis syndrome. The major toxicity was infection with grade 3 and 4 episodes occurring in 42% of patients. No significant cardiac toxicity was noted. Hepatic and renal toxicity were limited and transient. Bisantrene in association with aracytine is effective in both AML and ALL of childhood. Bisantrene should be evaluated with a five-day schedule in other pediatric malignancies. In children with acute leukemia previously treated with high dose aracytine, new combination regimen is warranted. © 1994 Wiley-Liss, inc.     

Survival of childhood leukemia in Singapore

The objective of this study was to evaluate the treatment outcome of children with acute leukemias at a university hospital in Singapore. Between January 1988 and January 1994, 66 children were treated, comprising 13 cases of acute myeloid leukemia (AML) and 53 of acute lymphoblastic leukemia (ALL). The 2-year disease-free survival (DFS) was computed according to the Kaplan-Meier method. The results showed that the survival for AML was poor, with a 2-year DFS of only 30%. The major cause of death for AML was leukemia and leukemia-related complications, such as hemorrhage and severe infections. In contrast, a 62% 2-year DFS was achieved for ALL. It was found that marked hepatosplenomegaly (enlarged liver and/or spleen ≥10 cm below the costal margin) at presentation correlated with a significantly shortened survival in our patients with ALL. The major cause for treatment failure in ALL was recurrence of disease. We conclude that the DFS for our patients with ALL at 2 years was fair. The treatment results for AML were poor, but the numbers are too small to make any definite conclusions. © 1996 Wiley-Liss, Inc.     

Stress lysis in childhood leukemia

Children with acute lymphoblastic leukemia (ALL) can experience a decrease in their white blood count (WBC) prior to chemotherapy, a phenomenon commonly attributed to the administration of allopurinol and hydration. We reviewed the records of 20 children with newly diagnosed ALL prior to the administration of allopurinol and found that 80% of patients experienced a decrease in their WBC (median decrease 14,000/mm(3)) in the less than 24-hr interval between evaluation at the referring center and admission to our hospital (P = 0.002). The basis for this often-observed phenomenon appears to be that leukemic cells rapidly lyse in response to the stress-induced release of endogenous corticosteroids.     

Receptors for sheep erythrocytes (E) and erythrocyte-antibody-complement complexes (EAC) on the lymphoblasts of childhood acute lymphocyblastic leukemia.

Two cell-surface markers, rosette formation with sheep erythrocytes (E-rosette) as a T-cell marker and rosette formation with bovine erythrocyte-antibody-complement complex (EAC-rosette) as a B-cell marker were determined on peripheral blood lymphocytes and lymphoblasts from normal and 89 children with acute lymphoblastic leukemia (ALL). In the majority of the patients (12/15 untreated patients and 6/11 patients in relapse), lymphoblasts exhibited neither E- nor EAC-rosette formation. Lymphoblasts from one untreated patient with mediastinal mass displayed E-(50%) and EAC-rosette formation (15%). In 3 of 11 patients in relapse, lymphoblasts displayed an increase in EAC-rosette formation with progressive disease. In the remaining patients with active disease, a small and variable proportion of lymphoblasts expressed E and/or EAC-rosette formation. In 63 patients in remission, percentages of E- and/or EAC-rosette were similar (p greater than 0.05) to those of control. The results indicate a wide heterogeniety with respect to expression of lymphocyte membrane markers in lymphoblasts and in normal lymphocytes in patients with active ALL.     

Acute transformation of chronic lymphocytic leukemia

A patient with chronic lymphocytic leukemia had typical cell morphology and a characteristic clinical course for 7 years. He then developed progressive disease with a rapidly rising WBC which proved resistant to chemotherapy. The cells resembled lymphoblasts. Immunoperoxidase studies demonstrated identical immunoglobulin light and heavy chains on the surface of both mature lymphocytes and lymphoblasts. Using a recently described monoclonal antibody, B5, a "blast" antigen was demonstrated on the lymphoblast cell surface, but not on the mature lymphocytes. On the basis of morphological and immunological studies, we suggest that the patient's malignant clone transformed from chronic lymphocytic leukemia to acute lymphoblastic leukemia.     

Value of Routine Bone Marrow Examination for Detection of Bone Marrow Relapse in Children with Standard Risk Acute Lymphoblastic Leukemia

The value of routine bone marrow examination (RBME) in children during and after treatment for standard risk acute lymphoblastic leukemia (SR-ALL) was Investigated. The clinical symptoms and peripheral blood findings at the time of bone marrow relapse of 28 children were reviewed and compared with those of 28 matched controls in continuous complete remission. Five (45%) children with bone marrow relapse during maintenance therapy and six (35%) after cessation of cytostatic treatment were asymptomatic at the time of relapse. Signs indicative of relapse duriny treatment were lymphoblast cells in the peripheral blood, thromhocytopenia, hepatomegaly, anemia, or leukopenia in decreasing order of frequency. Afer cessation of treatment these signs were lymphoblasts in the peripheral blood, hepatomegab, splenomegaly, thrombocytopenia, or leukocytosis. Except for one case with thrombocytopenia, no signs suspicious for relapse were found in the control groups. When each sign was evaluated separately only the presence of lymphoblasts in peripheral blood and hepatomegaly were significant symptoms for relapse after cessation of treatment. The mean percentage of lymphoblasts in the bone marrow at the time of relapse was significant& lower for patients with an unpredicted relapse (46.8%) than patients with clinical and/or laboratory evidence of relapse (79.5 %). When lymphoblasts were present in the peripheral blood the percentage of lymphoblasts in the bone marrow was always more than 40%, both during and after cessation of treatment. These data suggest a relation between clinical and laboratory symptom and progression of the disease. It is concluded that 467% of relapses are detected by RBME in the absence of clinical or laboratory symptoms. This early detection may have a positive prognostic influence with more effective treatment for relapsed ALL.     

NAD(P)H:quinone oxidoreductase 1 null genotype is not associated with pediatric de novo acute leukemia

BACKGROUND: NAD(P)H:quinone oxidoreductase1 (NQO1) is a two-electron reductase that detoxifies quinones derived from the oxidation of phenolic metabolites of benzene. Exposure to benzene metabolites increases the risk of hematotoxicity and leukemia. NQO1 enzyme activity protects the cells against metabolites of benzene. C to T base substitution at nucleotide 609 of NQO1 cDNA (C609T) results in loss of enzyme activity. Low NQO1 activity may play a role in etiology of acute leukemia. PROCEDURE: We analyzed NQO1 C609T gene polymorphism using the PCR-RFLP method in 273 patients with de novo acute leukemia (189 acute lymphoblastic leukemia (ALL), and 84 acute myeloid leukemia (AML) and 286 healthy volunteers to investigate the role of NQO1 polymorphism in the etiology of acute leukemia. RESULTS AND CONCLUSIONS: The frequency of homozygosity for NOQ1 C609T polymorphism was 3.5% in the healthy control population and 2.5% in pediatric acute leukemia. The NQO1 C609T allele frequency was not statistically different in the children with acute leukemia in comparison to the controls (odds ratio (OR), 0.76; 95% confidence interval (CI), 0.58-1.01; P = 0.06). The distribution of NQO1 genotypes among children with acute leukemia was not statistically different from the control group (P = 0.13). These findings do not support the role of NQO1 C609T polymorphism in the etiology of de novo pediatric acute leukemia.     

Central Nervous System Relapse Surveillance by Serial Beta2-Microglobulin Measurements in Childhood Acute Lymphoblastic Leukemia

ABSTRACT. Beta₂-microglobulin (β₂m) is synthesized particularly in lymphocytes. Its value for early detection of central nervous system (CNS) involvement in acute lymphoblastic leukemia in children was tested by serial determinations. Before 9 overt CNS relapses, the mean increase of the cerebrospinal fluid (CSF) β₂m concentration was 588 μg/l/month (range: -50 to +2020), which was significantly higher than the steady levels during maintenance treatment. Although the absolute value of CSF β₂m was increased to 1430 μg/l in the group with overt CNS relapse, individual variations in CSF β₂m before a relapse were so great that no difference was seen between samples from CSF with or without lymphoblasts. The ratio between β₂m in the CSF and in serum did not increase in serial samples prior to overt relapse, but the ratio was higher in patients with CNS relapse compared with a control group on maintenance therapy. In 9 children without CNS leukemia, the β₂m concentration in CSF and serum decreased to a nadir 4 weeks after the start of induction treatment. The subsequent increase of CSF β₂m was similar to the increase before a CNS relapse. Mean values of CSF β₂m changes differed between groups of children with and without CNS leukemia early in the induction phase and during the maintenance treatment, but the wide range in individual values made serial β₂m determinations unsuitable for detecting a CNS relapse.     

Treatment of young children with CNS‐positive acute lymphoblastic leukemia without cranial radiotherapy

Background

Due to the long‐term sequelae of cranial radiotherapy (CRT), contemporary treatment protocols for children with acute lymphoblastic leukemia (ALL) aim to limit the use of prophylactic CRT. For patients with central nervous system (CNS) involvement with ALL at diagnosis, the use of CRT remains common. Children <5 years of age are a particularly challenging subgroup in whom the consequences of CRT can be devastating.

Procedure

This study retrospectively describes the overall (OS) and event‐free survival (EFS) of young children (1–5 years) who were treated for CNS‐positive ALL at the Hospital for Sick Children between 2000 and 2013.

Results

Of a total of 19 patients, two were treated with upfront CRT, both as part of the conditioning regimen prior to HSCT. All patients received intensification of CNS‐directed chemotherapy by triple intra‐thecal chemotherapy (84.2%), use of dexamethasone in induction (57.9%) and maintenance (66.7%), and high‐dose methotrexate (77.8%). The OS was 84.2 ± 8.4% and EFS was 79.0 ± 9.4% with a median follow‐up time of 4.3 years (range, 2.6–8.2). The cumulative incidence of CNS relapse was 5.2 ± 5.1%.

Conclusions

We conclude that omission of CRT from the treatment of young children with ALL involving the CNS is associated with acceptable survival and avoids potentially devastating late effects in this group. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc.