Suppression of adrenal function in children with acute lymphoblastic leukemia following induction therapy with corticosteroid and other cytotoxic agents

OBJECTIVE: To evaluate adrenal function in children with acute lymphoblastic leukemia (ALL) after induction therapy with corticosteroid and other cytotoxic agents.Study design Children with ALL (N=24) were treated with prednisolone (40 mg/m(2) per day) for 28 days during the induction phase followed by 1 week of oral dexamethasone every 4 weeks. A low-dose (1 microg) adrenocorticotropin (ACTH) test was performed 2 weeks after discontinuation of prednisolone; it was repeated 2 weeks later and then every 4 weeks in patients with adrenal suppression until normal response was achieved. RESULTS: Adrenal suppression was found in 46% of patients at 2 weeks after discontinuation of prednisolone; it persisted in 38%, 29%, and 13% of patients through 4 weeks, 8 weeks, and 20 weeks, respectively. Adrenal suppression appeared to last significantly longer in children aged >or=5 years than in children aged <5 years. Four children developed febrile neutropenia; all belonged to the adrenal suppressed group and were unable to mount an adequate adrenal response to the stress. CONCLUSIONS: About 50% of children with ALL developed adrenal suppression 2 weeks after a 4-week induction therapy with prednisolone. The suppression could persist through 20 weeks and may hinder an adequate adrenal response during acute febrile illness.     

Height of children off therapy after acute lymphoblastic leukemia

A total of 290 children off therapy after acute lymphoblastic leukemia, in continuous complete remission for at least 2 years, were evaluated for height at the onset of the disease and at the most recent clinical visit (median time after suspension of treatment 4 years 4 months, range 2 years-11 years 3 months). All patients had been treated with multidrug schedules; intrathecal drugs had been given to 84% of the patients for prevention of CNS involvement, associated with radiotherapy. The height percentiles at the most recent examination were shifted downward significantly compared with the expected pattern (p less than 0.001). The effect on stature was much more marked in girls, with a reduction of height percentiles at most recent examination from expected and from diagnosis; in males there was a reduction from diagnosis to latest follow-up, but the values were within the limits of normal. The short stature was mostly observed in pubertal girls and in patients who had undergone radiotherapy.     

Low relapse rate in children with acute lymphoblastic leukemia after risk-directed therapy

PURPOSE: Even though acute lymphoblastic leukemia (ALL) responds well to chemotherapy, relapse remains the major problem. This study documents relapse and survival rates in 85 consecutive children (33 at good risk, 52 at high risk) with ALL diagnosed in 1991 to 1996. PATIENTS AND METHODS: Until 1993, the New York II protocol for the high-risk group and a combination of UKALL XI (induction) and R blocks of ALL-REZ BFM-87 (intensification) regimens for patients at good risk were used. To reduce toxicity, the protocols were subsequently modified. Consolidation treatment was the same for both groups, consisting of a lower cytarabine dose and methotrexate removal, whereas intensification was changed only for the high-risk group using the BB block of the NHL-BFM-90 protocol. The bone marrow clearance of leukemia was assessed on day 22, and minimal residual disease was detected using polymerase chain reaction analysis of Ig heavy-chain gene rearrangements. RESULTS: Seventy patients had common precursor B lineage ALL, six had pre-B-ALL, eight had T-ALL, and one had B-ALL. Two patients never achieved remission and died. Six patients died of consolidation-related complications. Four more patients died, two during induction and two during maintenance therapy. Two other children had relapse (2.3%), both of whom were treated with the earlier protocols and then underwent bone marrow transplantation. Four more children with morphologically complete remission showed minimal residual disease (which reached the levels of 1 leukemic cell among 10(2)-10(4) normal cells) with the use of clone-specific probes at several points of the study intervals, but never had relapse. The 5-year overall and event-free survival rates were 86% and 83%, respectively. The 5-year overall survival rates for good-risk and high-risk groups were 94% and 81%; the corresponding event-free rates were 91% and 78%. The 5-year event-free survival rate in the patients at high risk was significantly higher after the protocol change (90% vs. 65%, P = 0.04). CONCLUSIONS: The modification proved to be effective in diminishing the therapeutic toxicity and improving the efficacy, mainly for the high-risk group.     

Prevalence of obesity in children after therapy for acute lymphoblastic leukemia

To confirm an impression that many survivors of acute lymphoblastic leukemia (ALL) are overweight or obese, we retrospectively examined the medical records of 414 patients for height and weight at diagnosis, at completion of treatment, and at annual intervals thereafter. The body mass index, weight/height2, was used as a measure of fatness; population norms for the index were established from 9,003 people between the ages of 1 and 30 years who were examined in a national health survey. The percentile of each patient's index was determined at each observation date. At diagnosis, the study sample was skewed toward leanness; however, at cessation of therapy, the fatness distribution resembled population norms. Statistically significant increases in fatness occurred during the first year off therapy, at the end of which 35% of the children were above the 80th percentile (i.e., overweight) and 12% were above the 95th percentile (i.e., obese). Only 12% were below the 20th percentile. This skewed distribution persisted during the subsequent 4-year follow-up period. Cranial irradiation was associated with a large increase of fatness in one group available for comparisons. Our findings indicate that the first year following cessation of therapy is a time of excessive weight gain among pediatric ALL patients.     

Relapses after termination of therapy of acute lymphoblastic leukemia in children

In the past 16 years, 2004 children with acute lymphoblastic leukemia (ALL) have been treated in the Polish Pediatric Group centers. Eight hundred and eighty-seven (44.3%) of these patients discontinued treatment after the first remission. Acute lymphoblastic leukemia relapse occurred in 180 patients (20.3%). This group was analyzed for the method of treatment and its influence on long-term survival, the time between cessation of treatment and relapse, the character and localization of relapse and later follow-up. It was shown that the patients with the best chance of a second remission are those with late testicular relapse. The most frequent and prognostically poor are bone marrow (BM) relapses which warrant intensive chemotherapy with BM transplantation. Patients with ALL relapse still have the possibility of a second remission and long-term survival.     

BIM基因与儿童急性淋巴细胞白血病对糖皮质激素耐药的相关性

急性淋巴细胞白血病(ALL)是儿童时期最常见的恶性血液系统疾病。糖皮质激素作为ALL化疗方案中的主要用药,可通过多种途径诱导白血病细胞的凋亡,但仍有约10%的儿童ALL对糖皮质激素不敏感。研究发现糖皮质激素通过上调BIM基因表达介导ALL细胞的凋亡,BIM基因与儿童ALL对糖皮质激素耐药有关。本综述概括了近年关于儿童急性淋巴细胞白血病对糖皮质激素耐药相关研究,主要包括BIM基因及其表达产物在该过程中的作用。     

Endocrine function after antineoplastic therapy in 22 children with acute lymphoblastic leukaemia.

In 22 children who were in complete remission after acute lymphoblastic leukaemia endocrinological investigations were performed 5-12 weeks after cessation of therapy. The children had received central nervous system irradiation (tele-Co60, 850-1800 rad), and long term, aggressive cytostatic drug therapy during 21 to 36 months. Growth hormone, TSH, thyroxine, LH, FSH, cortisol secretion, and urinary concentrating capacity were found to be normal, with a few exceptions where borderline results were obtained.     

急性淋巴细胞性白血病患儿化疗后的脑MRI表现

目的总结儿童急性淋巴细胞性白血病治疗后的脑MRI表现。方法用MRI检查急性淋巴细胞性白血病患儿化疗后脑实质的改变。结果脑MRI显示4例患儿脑白质病变,表现为侧脑室旁脑白质内对称T1低信号、T2高信号。8例患儿脑萎缩,表现为脑室扩大和脑沟增深。结论MRI对于显示白血病治疗后的脑内异常改变很敏感,急性淋巴细胞性白血病患儿治疗中和治疗后可选择性行头颅MRI检查以便及时发现病变和指导治疗。     

急性淋巴细胞性白血病患儿化疗后的脑MRI表现

目的总结儿童急性淋巴细胞性白血病治疗后的脑MRI表现。方法用MRI检查急性淋巴细胞性白血病患儿化疗后脑实质的改变。结果脑MRI显示4例患儿脑白质病变，表现为侧脑室旁脑白质内对称T1低信号、T2高信号。8例患儿脑萎缩，表现为脑室扩大和脑沟增深。结论MRI对于显示白血病治疗后的脑内异常改变很敏感，急性淋巴细胞性白血病患儿治疗中和治疗后可选择性行头颅MRI检查以便及时发现病变和指导治疗。     

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 pulsatile growth hormone secretion in children after therapy for acute lymphoblastic leukemia

Basal growth hormone levels were measured every 20 minutes over 24 hours in eight long-term survivors of acute lymphoblastic leukemia and in 13 age- and pubertal stage-matched normal children. Among the patients, the median total basal growth hormone output (AUC) was 43 units, compared with 341 units in the normal control group (P less than 0.001). In the patients, mean pulse amplitude (6.9 ng/ml) and frequency (4.6) over 24 hours also were reduced, compared with the control values (32 ng/ml and 8.5, P less than 0.001 and P less than 0.05, respectively). In addition, normal children secreted more GH at night (median AUC 280) than during the day (113, P less than 0.001). However, this diurnal pattern was absent in three of the patients studied. These data suggest that perturbations of spontaneous pulsatile GH secretion are common after standard therapy for ALL and may be a sensitive means of detecting therapy-related neuroendocrine damage. Blunting of spontaneous pulsatile GH secretion may contribute to the abnormalities in growth seen in children with ALL.     

Acral eruptive nevi after chemotherapy in children with acute lymphoblastic leukemia

Eruptive melanocytic nevi have mainly been associated with blistering cutaneous diseases and with immunosuppression, particularly after renal allograft transplantation, hematological neoplasms, or HIV infection. Thus, immunosuppression has been suggested to increase the possibility of melanocyte proliferation. We report two cases of children with acute lymphoblastic leukemia who, after receiving chemotherapy, developed severe motor polyneuropathy, and sudden onset of multiple melanocytic nevi on the soles.     

儿童急性淋巴细胞白血病诱导化疗前后颅脑损伤的研究

目的 用头颅磁共振(MRI)探讨儿童急性淋巴细胞白血病(ALL)诱导化疗前后颅脑损伤的变化。方法 对2014 年3 月至2015 年6 月期间62 例ALL 患儿化疗前后的临床资料及头颅MRI 结果进行回顾性研究。结果 化疗前头颅MRI 提示,33 例(53%)颅骨骨髓浸润,其中WBC<20×10⁹/L 者(16 例,42%)明显少于WBC ≥ 20×10⁹/L 者(17 例,71%),P<0.05;高危组颅骨骨髓浸润发生率(71%)明显高于非高危组(44%),P<0.05。脑萎缩4 例(7%),感觉传导束异常信号2 例(3%)。28 例患儿化疗3 月后复查,新出现脑萎缩3 例(11%),1 例脑萎缩加重;11 例颅骨骨髓浸润消失。结论 ALL 患儿化疗前头颅MRI 提示有颅骨骨髓浸润、脑萎缩和感觉传导束异常信号等,以颅骨骨髓浸润为主,治疗后部分能恢复。     

急性淋巴细胞白血病并中枢神经系统白血病的诊断与治疗

目的：探讨急性淋巴细胞白血病（ALL）并中枢神经系统白血病（CNSL）的诊断与治疗及影响发病和预后的因素。方法：对1990－1999年收治117例临床资料进行回顾分析。结果：CNSL发生距确诊ALL的中位数时间为8个月,高危型组发生率（54．85）明显高于标危型组（23．7％）。31例CNSL中以脑脊液（CSF）异常作出诊断远比临床症状多。CNSL治疗效果显示,大剂量氨甲喋呤＋三联鞘注＋四组（CR＋IT）相当。结论：为避免诊断假阳性造成的过度治疗,CSF仅有幼稚细胞而白细胞计数政党者诊断CNSL应慎重,HDMTX＋IT＋FC是治疗CNSL的有效措施。     

Liver function studies in children with acute lymphocytic leukemia after cessation of therapy

We investigated liver function in 27 children with acute lymphocytic leukemia (ALL) after cessation of therapy. Induction therapy consisted of prednisolone + vincristine (VP regimen) alone (16 patients) or with addition of daunorubicin (4 patients) or L-asparaginase (7 patients). Patients treated with VP regimen short courses of VP regimen every 12 weeks for the first year of maintenance. Twenty-five patients remained in first complete remission and had completed 3-year maintenance therapy with methotrexate (MTX) and 6-mercaptopurine (6-MP) 1–7 years prior to this study. Twenty-three patients had transfusions of packed red blood cells or fresh whole blood (1–11 units; median: 2 units) but none had evidence of either hepatitis B or hepatitis C. Alanine aminotransferase (ALT), which was measured every 3 months during maintenance therapy, had values more than three times the upper limit of the normal range in 25% of the measurements in more than half of the patients. However, by 3 months after the completion of maintenance therapy, ALT had normalized in all patients and remained normal in all but two patients until the time of this study. Serum bilirubin, serum albumin, and prothrombin time were all within normal limits. Fasting and 2-hour postprandial total serum bile acids were high in 5 of 13 patients and in 6 of 13 patients, respectively. The ratio of cholic acids + deoxycholic acids to chenodeoxycholic acids + lithocholic acids was below 1 in all but two patients, whereas this ratio was above 1 in all controls. Our bile acid profile results indicate the necessity of careful long-term follow-up of survivors of ALL treated with hepatotoxic chemotherapy during childhood. © 1994 Wiley-Liss, Inc.     

Evaluation of renal function in Turkish children receiving BFM-95 therapy for acute lymphoblastic leukemia

This study examined renal function in 42 children with acute lymphoblastic leukemia (ALL) treated according to BFM-95 protocol. Fifteen (group 1) were investigated longitudinally at 3 time points: before (T1), 4 weeks after (T2), and 2-6 months after (T3) consolidation therapy with high-dose methotrexate (HDMTX). The frequency of abnormalities in glomerular and tubular tests were nil at T1 and ranged from 13 to 40% at T2 and 7 to 33% at T3 in group 1. Twenty percent of the patients (n = 10) in group 2, who were examined at a single time point 7-36 months after consolidation, had glomerular and tubular abnormalities. There was only mild tubular abnormality in 5.8% of patients (n = 17) in group 3, who were examined at a single time point a mean of 56.1 ± 12.5 months after completion chemotherapy. These data show that consolidation therapy with HDMTX is frequently associated with acute renal toxicity in children with ALL but does not leave clinically significant late sequelae.     

Cytomegalovirus disease in children with acute lymphoblastic leukemia

Viral infections are an underrecognized problem in children on standard chemotherapy for acute lymphoblastic leukemia (ALL). In countries with high baseline seroprevalence of cytomegalovirus (CMV) such as India, it may be an important pathogen leading to fever, end-organ damage, and cytopenia. Data regarding the incidence and manifestations of CMV disease in pediatric ALL patients are scanty. The authors prospectively assessed all children on chemotherapy for ALL with prolonged febrile neutropenia (FN) for CMV disease over a 3-year period. Children with end-organ damage, including pneumonia, retinitis, and colitis, were also evaluated. Quantitative and qualitative polymerase chain reaction (PCR) from blood, body fluids, or tissue was done along with ophthalmologic evaluation. CMV disease was detected in 10% of the children with prolonged FN. In addition, other children were identified due to end-organ damage, lung and eye being the common organs of involvement. Time of CMV reactivation was essentially during nonintense phase of chemotherapy. Lymphopenia was present in most children, and prolonged lymphopenia was associated with relapse of CMV infection after therapy. The authors conclude that CMV is an important pathogen in children on standard chemotherapy for ALL. It has a good outcome with early detection and directed therapy. Parenteral ganciclovir is needed for a period of 14–21 days to prevent recurrence.