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.     

Osteonecrosis in children treated for acute lymphoblastic leukemia

The purpose of the study was to find out the prevalence of osteonecrosis in children with acute lymphoblastic leukemia (ALL) in complete bone marrow remission at the end of the treatment. Twenty-eight children with ALL underwent MRI of the upper and/or lower extremities. Bone marrow signal intensity was analyzed on T1-weighted images, where cir-cumscribed lesions with a rim of low signal intensity were considered typical of osteonecrosis. Osteonecrosis was found in 9 of the 28 children (32%, 95% CI 16% to 52%). Five of them were asymptomatic. They had been treated with high risk and intermediate risk protocols, both of which include a delayed intensification phase with dexamethasone. None of the patients with standard risk ALL were found to have developed osteonecrosis. Osteonecroses occurred unexpectedly in symptomless patients and in patients with mild transient symptoms treated with high risk and intermediate risk protocols. Our study suggests that the intensification phase of the treatment protocols with intensive dexamethasone medication might be responsible for the development of osteonecrosis. Med. Pediatr. Oncol. 29:260–265, 1997. © 1997 Wiley-Liss, Inc.     

儿童急性淋巴细胞白血病骨骼并发症研究进展

ALL是儿童最常见的恶性肿瘤,应用目前的联合化疗方法,5 a生存率超过80%.骨骼并发症可发生于ALL诊断时、治疗过程中和治疗结束后,影响ALL的治疗和生存.骨坏死(ON)是儿童ALL治疗过程中最严重的并发症之一,可影响高达1/3的接受治疗的儿童.ON的危险因素包括糖皮质激素的使用、诊断时年龄及放疗等.双膦酸盐治疗可减轻患者疼痛,减少止痛药用量及改善骨关节功能.间充质干细胞可提高手术治疗的疗效.     

Development of acute lymphoblastic leukemia following treatment for acute myeloid leukemia in children with Down syndrome: A case report and retrospective review of Children's Oncology Group acute myeloid leukemia trials

Children with Down syndrome have a 150‐fold increased risk of developing acute myeloid leukemia (AML) and 20‐fold increased risk of developing acute lymphoblastic leukemia (ALL). Although the risk of developing AML and ALL is significantly increased in children with Down syndrome, the development of both malignancies in the same patient is very rare. We describe a patient with Down syndrome who developed ALL 6 years after being diagnosed with AML. We performed a literature review and Children's Oncology Group query and discovered eight published cases and five cases of ALL following AML in pediatric patients with Down syndrome, as well as six cases of ALL following AML in non‐Down syndrome patients. There was a similar cumulative incidence of ALL after treatment for AML in the Down syndrome and non‐Down syndrome populations. Overall survival in patients with Down syndrome who developed ALL after treatment for AML was comparable to overall survival for patients with Down syndrome with de novo ALL with an average follow‐up of 7 years after ALL diagnosis. Clinical data collected were used to discuss whether this phenomenon represents a secondary leukemia, second primary cancer, or mixed‐lineage leukemia.     

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.     

Incidence of skeletal complications during treatment of childhood acute lymphoblastic leukemia: comparison of fracture risk with the General Practice Research Database

BACKGROUND: Skeletal complications during or after treatment of acute lymphoblastic leukemia (ALL) have been frequently reported and can cause substantial morbidity, yet their incidence is not well established. The present study assessed the incidence of fractures, osteonecrosis (ON), and bone pain during ALL treatment and compared the fracture incidence with age- and sex-specific reference data from the UK General Practice Research Database (GPRD). PROCEDURE: Medical records of 122 ALL patients diagnosed at our institution from 1992 to 2004 were reviewed for information on fractures, ON, bone pain, and their anatomical location, risk group, phase of antileukemic therapy, and time since diagnosis. Evaluation of skeletal complications was followed up until July 2005 or the patient's death. Thirteen children were excluded as they were transferred to other institutions shortly after diagnosis. RESULTS: Skeletal complications occurred at a 5-year incidence of 32.7%. The 5-year incidence of fractures, ON, and isolated bone pain was 13.5%, 12.1%, and 12.3%, respectively. The relative rate of fractures adjusted for age and sex was 2.03 (95% confidence interval 1.15-3.57) compared to the GPRD, with greatest rates in children <5 years. Thirty ON occurred in 10 patients with a 15 times greater incidence in children >10 years than in those <5 years. Nearly all skeletal complications occurred during maintenance therapy at a median of 14.92 months (range 0.0-53.8) after diagnosis and in weight-bearing bones. CONCLUSIONS: The doubled fracture rate and the high incidence of skeletal complications during the first years after diagnosis suggest the developing skeleton is very vulnerable in this period. Adolescents develop more ON whereas younger children may be more prone to fractures. Serious "immediate effects" of chemotherapy on bone appear of great concern and should entail preventative studies in this group of patients.     

MRI diagnosis of bone marrow relapse in children with ALL

Background Diffuse marrow replacement in acute leukemia is well known, but there are few reports describing the MRI features of pediatric leukemic relapse. Objective Our purpose was to describe the MRI appearance of pediatric leukemic relapse. Materials and methods A total of 53 consecutive children with a history of ALL were referred for musculoskeletal MRI from 1 January 1998 to 28 February 2007 at one center, and from 1 January 2000 to 2 May 2007 at a second center. From this group, 14 children seen at initial diagnosis of leukemia and 2 children who underwent MRI after therapy for relapse were excluded. The remaining 37 children, 8 with relapse and 29 in remission, were studied. Images of patients with relapse and in remission were reviewed for type and configuration of marrow infiltration; coexisting marrow alterations including osteonecrosis or stress reaction were also reviewed. Results All eight children with relapse demonstrated nodular lesions with well-defined margins. Coexisting osteonecrosis was present in three children (38%) and pathologic fracture in one. Among the 29 children in remission, 9 showed stress reaction/fracture, 14 showed osteonecrosis and 9 showed ill-defined nodules, and in 5 the marrow was completely normal. Conclusion Well-defined nodules in all patients with leukemic relapse suggest that this appearance is characteristic and distinct from the published findings of diffuse marrow replacement in acute leukemia.     

Childhood relapsed acute lymphoblastic leukemia: Biology and recent treatment progress

Acute lymphoblastic leukemia (ALL) is the most frequent cancer in children. Despite remarkable improvement in the prognosis of childhood ALL over the past few decades, the treatment of relapsed ALL is still challenging. The prognosis of first ALL relapse is associated with time of relapse after initial therapy, sites of relapse, and immunophenotype. More recently, response to treatment, which is evaluated by assessment of minimal residual disease (MRD), has been found to be clinically significant in relapsed ALL as well as in the initially diagnosed disease. Utilizing these factors, risk‐oriented treatment stratification for first ALL relapse has been established. In the standard‐risk group for first ALL relapse, intensification of conventional ALL‐type therapy can provide a cure in approximately 70% of patients. It is important to assess MRD after reinduction therapy to determine the indications for stem cell transplantation in the standard‐risk group. In contrast, no standardized therapy has been established for the high‐risk group, which accounts for more than half of relapsed ALL patients. Recent studies have shed light on the clonal origin of relapsed ALL, which usually exists as a minor subclone at the time of initial diagnosis. Clonal selection and evolution take place during chemotherapy, resulting in distinct genetic and epigenetic characteristics of relapsed ALL, some of which are linked to drug resistance, a common and problematic feature of ALL after relapse. To overcome resistance to standard ALL‐type therapy, and considering the heterogeneous biological background of high‐risk relapsed ALL, innovative therapies using new agents are necessary.     

Adrenal axis function after high-dose steroid therapy for childhood acute lymphoblastic leukemia

Background A 4‐week course of high‐dose glucocorticoids may cause prolonged adrenal suppression even after a 9‐day tapering phase. In this study, adrenal function and signs and symptoms of adrenal insufficiency were prospectively assessed in children with acute lymphoblastic leukemia (ALL) after induction treatment including high‐dose prednisone (PDN) or dexamethasone (DXM). Procedures Sixty‐four children with ALL, treated according to the AIEOP ALL 2000 Study protocol, underwent low dose ACTH (LD‐ACTH) stimulation 24 hr after the last tapered steroid dose. In those with impaired cortisol response, additional LD ACTH tests were performed every 1–2 weeks until cortisol levels normalized. Signs and symptoms of adrenal insufficiency were recorded during the observation period. Results All patients had normal basal cortisol values at diagnosis. Twenty‐four hours after last glucocorticoid dose, morning cortisol was reduced in 40/64 (62.5%) patients. LD‐ACTH testing showed adrenal suppression in 52/64 (81.5%) patients. At the following ACTH test 7–14 days later, morning cortisol values were reduced in 8/52 (15.4%) patients and response to the test was impaired in 12/52 (23%). Adrenal function completely recovered in all patients within 10 weeks. No difference was found between patients treated with PDN or DXM. Almost 35% of children with impaired cortisol values at the first test developed signs or symptoms of adrenal insufficiency. One child developed a severe adrenal crisis during adrenal suppression. Conclusions High‐dose glucocorticoid therapy in ALL children may cause prolonged adrenal suppression and related clinical symptoms. Laboratory monitoring of cortisol levels and steroid coverage during stress episodes may be indicated. Pediatr Blood Cancer 2008;50:537–541. © 2007 Wiley‐Liss, Inc.     

Reduced folate carrier and dihydrofolate reductase expression in acute lymphocytic leukemia may predict outcome: a Children's Cancer Group Study

PURPOSE: Methotrexate is a major component of current treatment regimens for children with acute lymphocytic leukemia (ALL). Potential mechanisms of methotrexate resistance include impaired drug uptake, decreased drug retention, and dihydrofolate reductase (DHFR) amplification. The purpose of this study was to assess whether reduced folate carrier (RFC) and DHFR expression in untreated leukemic blasts correlated with outcome. METHODS: Quantitative real-time RT-PCR was used to measure RFC and DHFR mRNA expression in leukemic blasts from 40 newly diagnosed patients with ALL obtained in a blinded fashion from Children's Cancer Group studies. RESULTS: Low RFC expression at diagnosis correlated significantly with an unfavorable event free survival. Surprisingly, low, not high, DHFR expression correlated significantly with an unfavorable event-free survival. Proliferative cell nuclear antigen (PCNA) expression demonstrated a weak inverse relationship between sample PCNA and DHFR or RFC expression, suggesting that DHFR and RFC expression may be markers for factors other than drug resistance. CONCLUSIONS: These results suggest that impaired transport may be an important mechanism of intrinsic methotrexate resistance in ALL, and DHFR expression also may be an important prognostic factor in ALL. Additional studies are necessary to clarify the mechanism for the correlation of low DHFR expression with poor outcome.     

Children's Oncology Group's 2013 blueprint for research: acute lymphoblastic leukemia

Approximately 90% of the 2,000 children, adolescents, and young adults enrolled each year in Children's Oncology Group acute lymphoblastic leukemia (ALL) trials will be cured. However, high‐risk subsets with significantly inferior survival remain, including infants, newly diagnosed patients with age ≥10 years, white blood count ≥50,000/µl, poor early response or T‐cell ALL, and relapsed ALL patients. Effective strategies to improve survival include better risk stratification, optimizing standard chemotherapy and combining targeted therapies with cytotoxic chemotherapy, the latter of which is dependent upon identification of key driver mutations present in ALL. Pediatr Blood Cancer 2013; 60: 957–963. © 2012 Wiley Periodicals, Inc.     

THE ROLE OF PARVOVIRUS B19 INFECTION IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA

The authors hypothesized that parvovirus B19 with its hematotropic effects has the potential to precipitate varying forms of cytopenia in patients prior to or at the diagnosis of acute lymphoblastic leukemia (ALL). Consequently, and in view of the increasing number of cases reported, this retrospective study evaluated, for the first time, the possible role of parvovirus B19 infection in pediatric patients suffering from ALL, by investigating the frequency and clinical relevance of this infection at the time of the malignant diagnosis or, when applicable, during a phase of pre-ALL. Furthermore, a review of reported parvovirus B19 infections in pediatric ALL patients is presented. The serum of 65 consecutive pediatric patients with a diagnosis of ALL was examined for possible parvovirus B19 infection employing the polymerase chain reaction and ELISA techniques. Specific IgG was demonstrated in 30% of the patients. One patient diagnosed with pre-ALL had evidence of parvovirus B19 DNA in the serum during pancytopenia 5 months prior to the onset of ALL. The results suggest that there is an insignificant chance of finding a parvovirus B19 infection in pediatric patients with ALL at the time of diagnosis. However, parvovirus B19 infection may infrequently serve as a prodrome to ALL.     

Value of flow cytometric analysis of peripheral blood samples in children diagnosed with acute lymphoblastic leukemia

Diagnostic procedures in children with acute lymphoblastic leukemia (ALL) are typically performed under general anesthesia. Anticipation of the diagnosis based on findings in peripheral blood allows scheduling of the first dose of intrathecal chemotherapy and diagnostic bone marrow (BM) aspirate during a single anesthetic. We retrospectively compared paired results of peripheral blood (PB) flow cytometric analysis and BM evaluation in 383 children with ALL diagnosed consecutively at a single center and found very high concordance of results between both tests. We conclude that PB flow cytometry may help streamline planning of procedure‐related anesthetics during diagnosis and early treatment of childhood ALL.     

Effects of chemotherapy on neurocognitive function in children with acute lymphoblastic leukemia: A critical review of the literature

Chemotherapy‐only treatment has increasingly become the standard of treatment for childhood acute lymphoblastic leukemia (ALL). The objective of this review is to assess the present state of knowledge of the neurocognitive effects of central nervous system (CNS)‐directed chemotherapy in children with ALL, and to formulate directions for future research. We performed a review of studies published since 1997, that included an ALL group treated with chemotherapy only and a control group. Twenty‐one studies met our inclusion criteria. There is evidence of subtle long‐term neurocognitive deficits survivors of childhood ALL after treatment with chemotherapy only. These involve mainly processes of attention and of executive functioning, while global intellectual function is relatively preserved. Young age at diagnosis and female sex emerged as risk factors. Pediatr Blood Cancer 2009;52:447–454. © 2008 Wiley‐Liss, Inc.     

A Persistent epidural mass in a child with B‐lineage ALL

Epidural spinal cord compression as the initial presentation of acute lymphoblastic leukemia (ALL) is a rare and serious complication. Extramedullary disease is rarely reported in patients with ALL. The most common sites are bone, followed by soft tissue, skin and lymph nodes. We describe a child with common B—lineage ALL who presented with a mass in the spinal epidural space. She was initially treated with intrathecal chemotherapy and intravenous dexamethasone with total resolution of her clinical symptoms but a persistent epidural mass. An open biopsy of the residual epidural mass was performed 7 months after diagnosis. The histological examination did not reveal any tumor infiltration, only fibrosis. We conclude that a persistent epidural mass in patients with ALL may not indicate resistant disease and may require over a year for resolution, even when response to therapy is adequate. Pediatr Blood Cancer. 2010;55:727–729. © 2010 Wiley‐Liss, Inc.     

An aggressive systemic juvenile xanthogranuloma clonally related to a preceding T‐cell acute lymphoblastic leukemia

Juvenile xanthogranuloma (JXG) is a disorder of disputed origin thought to be related to the dermal/interstitial macrophage. A 5‐year‐old female presented with an aggressive systemic JXG that developed 5 months after the diagnosis of T‐cell acute lymphoblastic leukemia (T‐ALL). Examination of the T‐cell receptor gamma (TCR‐γ) rearrangement in T‐ALL blasts, JXG infiltrated lymph node biopsies and micro‐dissected JXG histiocytes revealed an identical bi‐allelic TCR‐γ rearrangement in all samples, thus providing evidence for a clonal relationship between T‐ALL and JXG in this case. Pediatr Blood Cancer 2011;56:859–862. © 2011 Wiley‐Liss, Inc.     

A Case of T‐cell Acute Lymphoblastic Leukemia Relapsed As Myeloid Acute Leukemia

A 4‐year‐old male with the diagnosis of T‐cell acute lymphoblastic leukemia (T‐ALL) relapsed after 19 months with an acute myeloid leukemia (AML). Immunoglobulin and T‐cell receptor gene rearrangements analyses reveal that both leukemias were rearranged with a clonal relationship between them. Comparative genomic hybridization (Array‐CGH) and whole‐exome sequencing analyses of both samples suggest that this leukemia may have originated from a common T/myeloid progenitor. The presence of homozygous deletion of p16/INK4A, p14/ARF, p15/INK4B, and heterozygous deletion of WT1 locus remained stable in the leukemia throughout phenotypic switch, revealing that this AML can be genetically associated to T‐ALL.     

Negative correlation between cerebrospinal fluid tau protein and cognitive functioning in children with acute lymphoblastic leukemia

The aim of the study was to assess whether cerebrospinal fluid tau protein is associated with cognitive changes in children with acute lymphoblastic leukemia (ALL). Examination of 38 ALL patients revealed a statistically significant increase in tau protein on treatment day 59 and at two points during consolidation phase. Cognitive functioning was examined in 19 patients at an average of 3.7 years after diagnosis. The level of tau at the initiation of maintenance therapy was negatively correlated with verbal abilities measured on an intellectual scale. The study suggests that standard ALL treatment may cause a decline in cognitive functioning. Pediatr Blood Cancer 2009;53:105–108. © 2009 Wiley‐Liss, Inc.