Cranial computed tomographic findings in children with newly diagnosed acute lymphoblastic leukemia: A prospective follow-up study during treatment

Cranial computed tomography (CT) was performed on 40 consecutive children with newly diagnosed acute lymphoblastic leukemia (ALL) on admission before any chemotherapy, 5 months after CNS therapy (n = 39) and after 2 to 3 years of therapy (n = 31). Changes related to leukemia were found in only 10% of the patients at the time of diagnosis (4/40). These initial changes, two intracranial hemorrhages, one dural thickening and one contrast enhancement, all disappeared during therapy. The findings which persisted unchanged in the next two CT scans were thought to be normal variations or caused by earlier disorders. CNS therapy consisted of intrathecally and intravenously administered methotrexate in 20 standard risk (SR) patients and cranial irradiation in addition to chemotherapy in 19 intermediate risk (IR) or high risk (HR) patients. Four SR patients developed changes during therapy. Three had enlarged cerebrospinal fluid (CSF) spaces and one developed a focal low density area suggesting disturbances in brain blood circulation and also experienced disturbances in level of consciousness. Of the 19 IR or HR patients, eight developed changes related to the therapy, including four with white matter hypodensity areas, of whom three also had enlarged CSF spaces, and four others who developed enlarged CSF spaces. The medians of the widths of the cortical sulci (P < .001), insular cisterns (P < .01), third ventricles (P < .01), and frontal horns (P < .05), and also of Evans' ratios (P < .05) increased significantly after CNS therapy as compared with the findings at diagnosis in the patients who had received cranial irradiation. Most of these changes persisted during the follow-up. We conclude that the clinical value of CT scanning during therapy for ALL is restricted to patients with neurological symptoms or those who have undergone CNS irradiation. © 1992 Wiley-Liss, Inc.     

Immunohistochemical Detection of Post-Therapy Residual Testicular Lymphoblasts in Childhood Acute Lymphoblastic Leukemia (All)

The aim of this study was to evaluate the diagnostic value of immunohistochemistry with monoclonal antibodies (MoAbs) in detecting residual blast cells in testicular biopsies from children with acute lymphoblastic leukemia (ALL). In a prospective study of 26 patients, testicular biopsies were performed after completion of therapy, and the average follow-up after biopsies was 29 months. After immunostaining, seven patients with negative biopsies on routine histology showed scattered, strongly calla-positive cells as well as cells reacting with anti-B (CD22) MoAb. Among these seven patients with residual blast cells, four had relapsed either in testes (n = 1), bone marrow and testes (n = 1), or in the bone marrow (n = 2). In contrast, among the 15 patients without residual blast cells, all but 1 remained in complete remission. In four other cases no definite conclusion was possible after immunohistochemical study. Four testicular biopsies from patients with occult infiltration were used as positive controls. Negative controls consisted of testicular biopsies from children with testicular ectopia and postmortem testicular tissue specimens. Results suggest that the risk of relapse is significantly higher in patients with positive immunohistochemical findings indicating persistent residual blast cells. However, the predictive value of these findings requires confirmation on a larger number of cases to have therapeutic implications.     

Acute lymphoblastic leukemia clonal distribution between bone marrow and peripheral blood

Acute lymphoblastic leukemia (ALL) is often composed of numerous subclones. Here we test whether the clonal composition of the blood is representative of the bone marrow at leukemia onset. Using ultra‐deep IGH sequencing, we detected 28 clones across 16 patients; 5/28 were only in the marrow. In four patients, the most abundant clones differed between sites, including three in which the dominant medullary clones were minimally detectable in the blood. These findings demonstrate that the peripheral blood often underrepresents the genetic heterogeneity in a B‐ALL and highlight the potential impact of tissue site selection on the detection of minor subclones.     

SIRT1在急性髓系白血病患儿骨髓活检组织中的表达及临床意义

目的 了解SIRTl 在急性髓系白血病（AML）患儿骨髓活检组织中的表达水平,并分析其与AML 预后的相关性。方法 回顾性分析2009 年7 月至2012 年4 月确诊为AML 并于初诊时行骨髓活检检查的54 例患儿的临床资料。采用免疫组织化学染色方法检测患儿骨髓活检组织中SIRTl 的表达;根据SIRT1 的表达情况将病例分为SIRT1 阴性组（n=10）和SIRT1 阳性组（n=44）,再根据SIRT1 表达的阳性程度进一步将SIRT1 阳性组分为（+）组（n=8）、（2+）组（n=7）和（3+）组（n=29）,比较各组患儿的预后。Cox 多因素回归分析患儿长期生存的危险因素。结果 SIRT1（3+）组病死率明显高于SIRT1 阴性组（PPPP=0.045,危险系数绝对值=2.071,95%CI：1.017~4.219）。结论 部分AML患儿骨髓活检组织存在SIRTl表达增高情况,且SIRTl高表达与不良预后相关。     

Experience with generic pegylated L-asparaginase in children with acute lymphoblastic leukemia and monitoring of serum asparaginase activity

Abstract

Background: Pegylated asparaginase (P-Asp) though integral to acute lymphoblastic leukemia (ALL) therapy is often not accessible to patients in developing countries. We share our clinical experience with generic P-Asp along with monitoring of asparaginase activity. Methods: In this prospective observational study, patients ≤18?years of age with ALL were assigned to receive either generic P-Asp or native asparaginase (N-Asp) in a non-randomized manner. Treatment protocol was based on ALL BFM-95 backbone. The dose of P-Asp was 1500?IU/m² by intravenous route during induction (Ia) and re-induction (IIa) phase of therapy. Results: N-Asp or P-Asp was administered to 52 and 54 of the 106 eligible patients respectively. Demographic and disease characteristics were comparable in both arms. The mean trough levels for N-Asp and P-Asp were 156.87?±?22.35?IU/L and 216.03?±?73.40?IU/L, respectively (p value <0.001) and all patients achieved therapeutic levels during Ia. Incidence of asparaginase-attributable toxicity was similar in the two arms in both phases of treatment, although hospitalization due to noninfectious causes was more common in P-Asp arm during Ia (13% versus 0%, p value, 0.01). Clinical hypersensitivity and silent inactivation were not observed during Ia while these occurred in 13% and 5% of patients in the N-Asp arm and P-Asp arms of IIa, respectively. The 2-year event free survival for P-Asp and N-Asp groups was 84% and 80.7%, respectively (p value 0.85). Conclusion: Generic P-Asp was observed to be efficacious and well tolerated in our patients and adequate therapeutic levels were sustained for 2 weeks.     

CEREBROSPINAL FLUID OXIDATIVE STRESS DURING CHEMOTHERAPY OF ACUTE LYMPHOBLASTIC LEUKEMIA IN CHILDREN

In this study the authors addressed the question whether neurotoxicity due to the chemotherapy of acute lymphoblastic leukemia (ALL) is associated with cerebrospinal fluid (CSF) oxidative stress. Examination of 38 ALL patients revealed significant increases in 8-isoprostane concentration and important decreases in total antioxidative capacity of CSF during therapy. The mean 8-isoprostane level at diagnosis was 9.05 ± 1.62 pg/mL, and no correlations with initial leukocytosis, organomegaly, and lactate dehydrogenase levels were noted. 8-Isoprostane concentrations were increased on the 59th day of treatment (mean level: 24.85 ± 7.59 pg/mL [P < .01]) and remained elevated at 4 points of the consolidation phase (17.28 ± 2.16 pg/mL [P < .05]; 22.72 ± 6.04 pg/mL [P < .05]; 24.92 ± 6.31 pg/mL [P < .01]; 32.32 ± 7.94 pg/mL [P < .01]) as compared to their level at diagnosis. The mean total antioxidative capacity at diagnosis was 203.08 ± 6.17 μmol/L and was remarkably decreased on the 59th day of treatment (189.76 ± 1.9 μmol/L [P < .05]) and at one point of the consolidation phase (188.29 ± 3.46 μmol/L [P < .05]) as compared to the level at diagnosis. This study indicates that neurotoxicity of standard ALL treatment may be related to oxidative stress.     

KASABACH-MERRITT SYNDROME IN A JEHOVAH'S WITNESS INFANT

Although varicella is a benign self-limiting disease in healthy children, it can be fatal when it occurs in immunocompromised hosts. Despite that immunosuppressed children are suggested to require 2 doses of vaccine to achieve seroconversion, conflicting results are reported in the literature. The aim of this study was to investigate the seroconversion status and mean antibody titers at first year after single dose and double doses of varicella vaccination in acute lymphoblastic leukemia patients. Patients with leukemia in remission for at least 1 year who were seronegative for varicella-zoster virus immunoglobulin G (IgG) were vaccinated. Titers above the cutoff level (0.65) were accepted as seroconversion. Seventeen patients were vaccinated with single dose whereas 24 patients were vaccinated with double doses. Mean prevaccination antibody titers were 0.56 ± 0.05 in patients with single dose and 0.51 ± 0.08 in patients with double doses (P > .05, Student t test). The mean antibody titers at first year were 0.61 ± 0.05 in patients with single-dose vaccination (P > .05, Wilcoxon signed-rank test) and 1.48 ± 0.04 in patients with double doses (P < .001, Wilcoxon signed-rank test). Seroconversion after single-dose vaccination was achieved in 29% of patients (n = 5/17) and in 75% of patients with double doses (n = 18/24) at first year (P = .004, chi-square test). These results suggest that seroconversion after single-dose vaccination might not persist at first year in malignancy patients. Double doses should be applied in order to provide long-term seroconversion.     

Association of ABCC2 with levels and toxicity of methotrexate in Malaysian Childhood Acute Lymphoblastic Leukemia (ALL)

Abstract

Studies had shown that genetic polymorphism plays a significant role in the pharmacokinetics and pharmacodynamics variation of high dose methotrexate (MTX), 5000?mg/m² regimen. The objective of this study was to investigate the genetic variations associated with the serum level and toxicity of MTX in Malaysian children with acute lymphoblastic leukemia (ALL). Thirty-eight patients were genotyped for rs717620 (ABCC2), rs4948496 (ARID5B), rs1801133 (MTHFR) and rs4149056 (SLCO1B1). Serum levels of MTX at 48?h post 24?h of intravenous infusion were analyzed by high-performance liquid chromatography-mass spectrometry. The ABCC2 genotype was significantly associated with the serum levels of MTX at 48?h after treatment (p?=?0.017). Patients with CT and TT of rs717620 (ABCC2) and TC and CC of rs4948496 (ARID5B) were significantly associated with leukopenia grade I–IV (Fisher Exact Test; p?=?0.03 and 0.02, respectively). The three most common MTX related toxicities were leukopenia (60.5%), increased alanine aminotransferase enzyme (47.4%), and thrombocytopenia (47.4%). Our results demonstrate that by prescreening of patients for ABCC2 and ARID5B associated with the serum levels and adverse effects of MTX would identify patients at risk and therefore help a pediatric oncologist to personalize chemotherapy drugs for precision health.     

Immunohistochemical nuclear positivity for WT1 in childhood acute myeloid leukemia

Several studies have reported previously that acute myeloid leukemia (AML) may express WT1 detected by RT-PCR and/or Northern blotting. The diagnostic utility of WT1 expression in AML using immunohistochemistry has not been reported previously. Paraffin-embedded tissue sections from 55 AML, 12 acute lymphoblastic leukemia (ALL), and 10 normal bone marrow specimens were immunostained for WT1 (anti-N terminus antibody). 22/55 AML cases (40%) demonstrated nuclear immunopositivity for WT1, including 20/47 bone marrow trephines and 2/4 granulocytic sarcomas. All the ALL and normal bone marrow specimens were negative. A significant proportion of AML expresses nuclear immunostaining for WT1, a finding that has only been described previously in Wilms' tumor and desmoplastic small round cell tumor. This finding is important for the correct interpretation of immunohistochemical findings in the diagnosis of “small round cell” tumors of childhood, especially in cases of extramedullary deposits of AML, in which traditional myeloid markers may be negative.     

Decreased induction morbidity and mortality following modification to induction therapy in infants with acute lymphoblastic leukemia enrolled on AALL0631: A report from the children's oncology group

Background

Infants with acute lymphoblastic leukemia (ALL) have a poor prognosis. Intensification of therapy has resulted in fewer relapses but increased early deaths, resulting in failure to improve survival.

Procedure

AALL0631 is a Phase 3 study for infants (<366 days of age) with newly diagnosed ALL. Induction initially (Cohort 1) consisted of 3 weeks of therapy based on COG P9407. Due to excessive early mortality, induction was amended to a less intensive 5 weeks of therapy based on Interfant‐99. Additionally, enhanced supportive care guidelines were incorporated with hospitalization during induction until evidence of marrow recovery and recommendations for prevention/treatment of infections (Cohort 2).

Results

Induction mortality was significantly lower for patients in Cohort 2 (2/123, 1.6%) versus Cohort 1 (4/26, 15.4%; P = 0.009). All induction deaths were infection related except one due to progressive disease (Cohort 2). Sterile site infections were lower for patients in Cohort 2 (24/123, 19.5%) versus Cohort 1 (15/26, 57.7%; P = 0.0002), with a significantly lower rate of Gram positive infections during induction for patients in Cohort 2, P = 0.0002. No clinically significant differences in grades 3–5 non‐infectious toxicities were observed between the two cohorts. Higher complete response rates were observed at end induction intensification for Cohort 2 (week 9, 94/100, 94%) versus Cohort 1 (week 7, 17/25, 68%; P = 0.0.0012).

Conclusion

De‐intensification of induction therapy and enhanced supportive care guidelines significantly decreased induction mortality and sterile site infections, without decreasing complete remission rates. Pediatr Blood Cancer 2015;62:414–418. © 2014 Wiley Periodicals, Inc.     

Comparison of idarubicin to daunomycin in a randomized multidrug treatment of childhood acute lymphoblastic leukemia at first bone marrow relapse: A report from the Children's Cancer Group

The outcome of children with acute lymphoblastic leukemia (ALL) and bone marrow relapse has been unsatisfactory largely because of failure to present subsequent leukemia relapses. Ninety-six patients were enrolled and received vincristine, prednisone, L-asparaginase, and an anthracycline as reinduction therapy. Ninety-two patients were randomized to receive either daunomycin (DNR) or idarubicin (IDR). After achievement of second complete remission (CR2), maintenance chemotherapy included the same anthracycline, IDR or DNR, high-dose cytarabine, and escalating-dose methotrexate. Compared to DNR (45 mg/m²/week × 3), IDR (12.5 mg/m²/week × 3) was associated with prolonged myelosuppression and more frequent serious infections. Halfway through the study, the dose of IDR was reduced to 10 mg/m². Overall, second remission was achieved in 71% of patients. Reinduction rate was similar for IDR and DNR. Reasons for induction failure differed; none of 15, 1 of 5, and 5 of 7 reinduction failures were due to infection for DNR, IDR (10 mg/m²), and IDR (12.5 mg/m²), respectively. Two-year event-free survival (EFS) was better among patients who received IDR (12.5 mg/m²) (27 ± 18%) compared to DNR (10 ± 8%, P = 0.05) and IDR (10 mg/m²) (6 ± 12%, P = 0.02). However, after 3 years of follow-up, late events in the high-dose IDR group result in a similar EFS to the lower-dose IDR and DNR groups. In conclusion, IDR is an effective agent in childhood ALL. When used weekly at 12.5 mg/m² during induction, the EFS outcome during the first 2 years of treatment appears better than lower-dose IDR or DNR (45 mg/m²), although this difference was not sustained at longer periods of follow-up. Increased hematopoietic toxicity seen at this dose might be reduced through the use of supportive measures, such as hematopoietins and intestinal decontamination. © 1996 Wiley-Liss, Inc.     

Pulmonary Sequestration In A Child With Acute Myelold Leukemia

The article describes a relatively rare congenital anomaly that was difficult to diagnose in a 10–year-old child with acute nonlymphoblastic leukemia. Just at diagnosis of leukemia, the patient showed a pathologic chest radiograph because of a parenchymal thickening at the right lung apex. The presence of bronchopneumonia was suspected, and broad-spectrum antibiotic therapy was started with subsequent antifungal treatment for persistent fever and concurrent chemotherapy-induced marrow aplasia, which did not favor pulmonary infiltrate recovery. Continuous culture tests, including bronchial swab, proved negative for Koch-Weeks bacillus, fungal organisms, and other pathogens. Computed tomography, however, was suggestive of Aspergillus lung involvement, and apical sepmentectomy was performed. The anatomic pathologist suggested the diagnosis of intralobar sequestration. In summary, when pulmonary pathology with an excavation is found in a leukemic child, one must consider the possibility of pulmonary sequestration complicated by an infectious disease.     

贝林妥欧单抗治疗儿童复发/难治急性淋巴细胞白血病的安全性及近期疗效分析

目的 分析贝林妥欧单抗治疗儿童复发/难治急性淋巴细胞白血病的安全性及近期疗效。方法 以2021年8月—2022年8月接受贝林妥欧单抗治疗的6例复发/难治急性淋巴细胞白血病患儿作为研究对象,回顾性分析患儿临床数据。结果 6例患儿中,男女各3例,中位入组年龄为10.5 （范围：5.0～13.0）岁。1例为难治性,经多次化疗均未缓解;5例为第一次复发,从诊断至复发中位间隔时间为30 （范围：9～60）个月。治疗前骨髓微小残留病为15.50 （范围：0.08～78.30）%。治疗后3例完全缓解,其中骨髓微小残留病转阴2例。5例患儿发生细胞因子释放综合征,其中1级3例,2级2例。4例桥接了异基因造血干细胞移植,贝林妥欧单抗治疗结束至移植中位间隔时间为50 （范围：40～70） d。6例患儿中位随访时间为170 d,总生存率为41.7%(95%CI:5.6%～76.7%),中位生存时间为126 (95%CI:53～199) d。结论 贝林妥欧单抗治疗儿童复发/难治急性淋巴细胞白血病短期安全有效,长期疗效需扩大样本量进一步观察。[中国当代儿科杂志,2023,25 (4):374-380]     

Expression of antiapoptotic proteins livin and survivin in pediatric AML patients,as prognostic markers

Abstract

Objective: Survivin and livin are highly expressed in various malignancies and their expression levels may be related to unfavorable prognosis. The aim was to investigate the relationships of these two markers with some prognostic factors and with survival of the children with acute myeloid leukemia (AML). Methods: Livin and survivin expression was investigated quantitatively by immunohistochemistry staining technique in 43 primary formalin-fixed, paraffin-embedded bone marrow blocks in pediatric age group (<18 years). Results: Both survivin and livin were expressed in 81.4% of AML patients. Livin expression showed significant positive association with high level of primary WBC (p?=?.002). Survivin expression showed significant positive correlations with risk of relapse (p ≤ .001) and high level of primary WBC (p?=?.003). The relationship of overall survival (OS) of the patients with livin and survivin expression, were investigated separately in disease subtypes. Significant association was observed between survivin expression and shorter OS regardless of subtypes including acute promyelocytic (APL) (p?=?.01) and nonacute promyelocytic leukemia (non-APL) (p?=?.008). Also, significant association of livin expression with shorter OS was detected, but only in APL subgroup (p?=?.046). Nevertheless, in Cox regression model after adjusting for disease subtypes, stage and cytogenetics; survivin and livin showed no significant association with OS (p?>?.05). Conclusion: Livin and survivin showed significant associations with some poor prognostic factors of AML. Although survivin in both subtypes and livin in non APL subtype, showed a significant relationship with shorter OS, none of them was determined as independent prognostic factors. Further studies with larger sample size are suggested.     

Association of -24CT, 1249GA,and 3972CT ABCC2 Gene Polymorphisms with Methotrexate Serum Levels and Toxic Side Effects in Children with Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia patients after being treated with methotrexate, have differences in methotrexate serum levels and toxic side effects. One of the main determinants of these toxic side effects is the host pharmacogenetics. The aim of this study was to evaluate the association of -24CT, 1249GA, and 3972CT ABCC2 gene polymorphisms with serum levels, and toxic side effects of methotrexate in childhood acute lymphoblastic leukemia. Applying polymerase chain reaction and restriction fragment length polymorphism techniques, the prevalence of -24CT, 1249GA, and 3972CT ABCC2 gene polymorphisms was evaluated in 65 acute lymphoblastic leukemia patients. The relationship between polymorphisms and methotrexate serum levels and toxicities was studied. A reverse significant relationship was detected between 3972T allele carriers and hepatotoxicity (P = 0.01, OR = 0.25, 95% CI = 0.09–0.72). Also, 1249A allele carriers had increased rate of gastrointestinal toxicity (P = 0.05, OR = 3.47, 95% CI = 1.04–11.57). No significant relationship was detected between -24CT polymorphism and methotrexate toxic side effects. There was no significant relationship between these three polymorphisms and methotrexate serum levels. Genotyping for 3972CT and 1249GA ABCC2 gene variants maybe useful in acute lymphoblastic leukemia to optimize methotrexate therapy and reducing the associated toxicity.     

Bone marrow transplantation for hematological disorders—Shiraz experience

Objective : In the past 8 years, 120 cases of hematological disorders were transplanted from the HLA identical donors.Method: Using chemotherapy based conditioning regimen with cyclophosphamide 200 mg/kg and busulfan 15–16 mg/kg, 80 cases of β-thalassemia major and 35 cases of leukemia and five patients with aplastic anemia had received bone marrow transplantation.Result : The five-year-survival in thalassemic group was 72%, for leukemic group (acute and chronic) was 58%, and also for aplastic anemia 65%. Transplantation related mortality was the cause of death in 29 cases. The two major causes of death were acute graft versus host disease and poor medical condition of patients before marrow transplantation.Conclusion : At the present time, allogenic marrow transplantation is curative mode of treatment for many hematological diseases.     

Immunophenotyping to Detect and Characterize Acute Lymphocytic Leukemia in Testicular Biopsies

This study establishes the utility of immunophenotyping testicular biopsy specimens in patients with acute lymphoid leukemia. The value of immunophenotyping in detecting or excluding leukemic testicular infiltration is demonstrated in six children with acute lymphocytic leukemia. A panel of monoclonal antibodies was employed on snap-frozen testicular biopsies, allowing both detection and immunologic characterization of four neoplastic lymphocytic infiltrates. Two samples were proven both histologically and phenotypically negative for leukemic infiltration. One of the four leukemic cases was clinically silent and might have escaped detection except for phenotyping. One leukemic infiltrate was also suspected to possess a multidrug-resistant phenotype (-glycoprotein +); the latter possibility was excluded by an absence of reactivity with anti-p-glycoprotein monoclonal antibody. Thus, three clinically useful applications are demonstrated: (1) confirmation of testicular leukemic relapse, gaining assertion in histologically uncertain cases; (2) exclusion of clinically suspected disease relevant to cessation of therapy, and (3) detection/exclusion of drug-resistant phenotypes. Unexpectedly, we found expression of plasma cell-associated antigen in testicular germ cells, which may prove to be diagnostically useful in the future evaluation of germ cell tumors.     

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.     

Secondary acute non-lymphoblastic leukemia in two children following treatment with a cis-diamminedichloroplatinum-II-based regimen for osteosarcoma

Acute nonlymphocytic leukemia (ANLL) developed in 2 of 142 pediatric patients with osteosarcoma treated with a cis-diamminedichloroplatinum-II (CDP)-based regimen: acute monomyelogenous leukemia (M₄) with a normal female karyotype in one and acute myelogenous leukemia (M₂) with t (8,21) in the other. The ANLLs occurred, respectively, in each patient 3 and 4 years after the initial diagnosis of osteosarcoma. In contrast to most of the adult experience and consistent with the majority of reported ANLL in children, the disease was characterized by an absence of the smoldering phase and cytogenetic findings similar to those seen in de novo ANLL.     

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.