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Dexamethasone-associated toxicity during induction chemotherapy for childhood acute lymphoblastic leukemia is augmented by concurrent use of daunomycin
Article first published online: 19 MAY 2003
Copyright © 2003 American Cancer Society
Volume 97, Issue 11, pages 2898–2903, 1 June 2003
How to Cite
Belgaumi, A. F., Al-Bakrah, M., Al-Mahr, M., Al-Jefri, A., Al-Musa, A., Saleh, M., Salim, M. F., Osman, M., Osman, L. and El-Solh, H. (2003), Dexamethasone-associated toxicity during induction chemotherapy for childhood acute lymphoblastic leukemia is augmented by concurrent use of daunomycin. Cancer, 97: 2898–2903. doi: 10.1002/cncr.11390
- Issue published online: 19 MAY 2003
- Article first published online: 19 MAY 2003
- Manuscript Accepted: 26 FEB 2003
- Manuscript Revised: 22 FEB 2003
- Manuscript Received: 18 NOV 2002
- acute lymphoblastic leukemia;
The goals of the current study were to examine the incidence and severity of toxicity resulting from dexamethasone and prednisone during induction therapy for children with precursor B-cell acute lymphoblastic leukemia (ALL) and to determine whether the addition of daunomycin affected toxicity.
Medical records of patients with precursor B-cell ALL from January 1996 through June 2000 were reviewed retrospectively for toxicity during the 4-week induction phase and the 2 weeks after the induction phase.
One hundred seventy-six patients age < 14 years were diagnosed with precursor B-cell ALL from January 1996 through June 2000. Of the 156 evaluable patients, 106 were treated with prednisone and 50 with dexamethasone. Fifty-two patients received steroids, L-asparaginase, and vincristine, whereas 104 high-risk patients received daunomycin in addition to these 3 agents. The incidence of gastritis was significantly higher among patients receiving dexamethasone (P = 0.01); incidence rates of hyperglycemia, hypertension, and myopathy were similar for all treatment groups. Dexamethasone led to more weight gain than did prednisone (+11.9% vs. +5.4%; P = 0.002). Serious infections were observed in 27 (25.5%) and 18 (36%) patients receiving prednisone and dexamethasone, respectively (P ≤ 0.2). Five patients, four of whom received prednisone and one of whom received dexamethasone, died of infection. The addition of daunomycin to treatment regimens increased overall toxicity (P < 0.01). When daunomycin was included in treatment regimens, toxicity was greater among patients receiving dexamethasone; in contrast, when daunomycin was not included, toxicity was equal for both treatment groups. Regardless of daunomycin use, there was no difference in the incidence of serious infection between the two groups. ALL treatment was not compromised by steroid-related toxicity in either group.
The addition of daunomycin led to a much larger increase in dexamethasone-related toxicity compared with the increase in prednisone-related toxicity. Although the use of daunomycin enhanced dexamethasone-related toxicity, this enhancement did not result in a higher mortality rate or the alteration of planned ALL therapy. Cancer 2003;97:2898–903. © 2003 American Cancer Society.
Glucocorticosteroids are important therapeutic agents for treatment of acute lymphoblastic leukemia (ALL) and are included in most pediatric ALL treatment protocols.1 Although the exact mechanism of leukemic blast cell kill is not known, glucocorticoids do induce apoptosis of these cells in vitro.2
The differential antileukemic activity of the two most widely used steroids, dexamethasone and prednisone, remains controversial, although most studies indicate that dexamethasone is the more effective agent. Kaspers et al.3 and Ito et al.4 have shown that dexamethasone is 5–16 times more cytotoxic than prednisone; however, the difference may be insignificant when the respective anti-inflammatory activities of both agents are taken into consideration.
The pharmacokinetics of the two agents also indicate that, at least for therapy that is directed at the central nervous system (CNS), dexamethasone may be the preferred steroid. Following bolus intravenous administration, the ratio of plasma concentration to cerebrospinal fluid (CSF) concentration is twice as high for dexamethasone, and the half-life of prednisone in the CSF is shorter.5 These differences are thought to be related primarily to dexamethasone's lower degree of protein binding and to the resultant increased availability of the free form for diffusion into the CSF. These findings may explain the lower rates of meningeal leukemia that have been observed in children receiving dexamethasone instead of prednisone for the treatment of ALL.1, 6
Dexamethasone and prednisone are not devoid of side effects and share several toxicities. Toxic side effects of these agents include altered fat distribution (Cushingoid facies), obesity, glucose intolerance, hypertension, gastritis, myositis and myopathy, avascular necrosis of bone, psychologic alterations, and immune suppression with a resultant increase in infections, particularly those of fungal etiology. As would be expected based on its more potent anti-inflammatory activity, dexamethasone also has a more intense toxicity profile than does prednisone.
Dexamethasone-related toxicities have limited the utility of this agent in adult leukemia treatment protocols. Nonetheless, these toxicities had not been reported to be significant among pediatric patients. Recently however, Hurwitz et al. reported a substantial increase in fatal or near-fatal sepsis in pediatric ALL patients who received dexamethasone during the induction phase of chemotherapy compared with patients who received prednisone.7
In December 1998, we opted to change the steroid used during induction chemotherapy from prednisone to dexamethasone, based on the evidence of dexamethasone's greater antileukemic activity and the paucity of data regarding its toxicity in children. All other features of the treatment, including chemotherapeutic agents, diagnostic procedures, and risk-stratification methodology, remained the same. Over the following 18 months, an increase in the frequency and severity of morbidity parameters was observed in ALL patients during the remission induction phase of treatment. The current study was a retrospective comparison of steroid-associated complications in patients treated with dexamethasone (from December 1998 onward) and patients treated with prednisone (before December 1998).
MATERIALS AND METHODS
Medical records of all patients age < 14 years with a diagnosis of precursor B-cell ALL from King Faisal Specialist Hospital and Research Center (Riyadh, Saudi Arabia) between January 1996 and June 2000 were reviewed retrospectively. Patient data included age and gender, presentation features such as white blood cell count and presence of CNS leukemia, risk assignment, treatment protocol, and details of steroid-associated complications (namely, weight gain, hyperglycemia, hypertension, gastritis, myopathy, and infection) that occurred during and for 2 weeks immediately following the 4-week remission induction phase of therapy. Risk stratification was based on parameters outlined in Table 1. The treatment protocol used for each patient was based on risk assignment. Table 1 also provides the details of induction therapy for standard and high-risk patients. Patients with T-cell ALL or biphenotypic leukemia, infants, and those with poor-risk cytogenetic markers (t[9;22], t[1;19], t[4;11]) or MLL gene rearrangement were categorized as poor-risk and were treated with various regimens. Poor-risk patients were not included in the current analysis unless they were treated with the high-risk regimen.
|Risk||Stratification criteria||Induction therapy|
|Standard||Age > 1 yr and < 10 yrs||Prednisone, 40 mg/m2/d, or dexamethasone, 6 mg/m2/d|
|WBC count < 50 × 109 L−1||L-asparaginase, 6000 U/m2 × 6 doses|
|DNA index ≥ 1.16 and ≤ 1.61||Vincristine, 1.5 mg/m2 weekly × 4 doses|
|High||Presence of any of the following features:||Prednisone, 60 mg/m2/d, or dexamethasone, 6 mg/m2/d|
|Age < 1 yr and > 10 yrs||L-asparaginase, 6000 U/m2 × 6 doses|
|WBC count ≥ 50 × 109 L−1||Vincristine, 1.5 mg/m2 weekly × 4 doses|
|DNA index < 1.16 and > 1.61||Daunomycin, 25 mg/m2 weekly × 4 doses|
|Presence of any leukemic blasts in the CSF, regardless of WBC count (CNS 2 or 3)|
In both protocols, steroid therapy was administered at full dose for 28 days and then reduced over the following 8–10 days. Toxicities were considered to be steroid-related if they occurred during the first 6 weeks of treatment. This time frame was chosen to include the period of dose reduction and establishment of normal glucocorticoid homeostasis in patients. Weight change was defined as the difference (as a percentage of weight at presentation) between weight at presentation and weight at the end of steroid therapy. Hyperglycemia was recorded only when it resulted in dietary restriction, dextrose withdrawal, or insulin use. Similarly, isolated episodes of elevated blood pressure were not considered significant, and elevated blood pressure was recorded only when it was sustained and required intervention (National Cancer Institute Common Toxicity Criteria Grade 3). The diagnosis of gastritis was clinical and was based on the presence of classic epigastric pain, with or without associated vomiting. Myopathy also was diagnosed clinically and was graded according to the system presented in Table 2.
|Hyperglycemia (%)||13 (12.3)||10 (20)||0.20|
|Insulin use||5 (38.5)||4 (40)|
|Gastritis (%)||25 (23.6)||23 (46)||0.005|
|Hematemesis||4 (16)||1 (4.3)|
|Hypertension (%)||13 (12.3)||5 (10)||0.7|
|Myopathya (%)||5 (4.7)||4 (8)||0.65|
|% Weight changeb (range)||+5.4 (−16.7 to +28.4)||+11.9 (−20.2 t +35.3)||0.002|
All febrile episodes during the study period were recorded. Infection was considered serious if bacteremia was documented on blood culture, if signs and symptoms of sepsis (such as hypotension, respiratory distress, and shock) occurred, or if there was other evidence of infection (e.g., pneumonia, abscess, meningitis, osteomyelitis, etc.). Fungal infection was confirmed if a fungal pathogen was isolated from normally sterile locations either by culture or by pathologic examination; infection was considered probable if there were classic radiologic changes on imaging studies but no confirmation by biopsy or culture.
The chi square test with continuity correction was used to assess the association of toxicities with the use of prednisone versus dexamethasone and with the use of daunomycin. The t test was used to compare the difference in weight gain between treatment groups. P values are reported for each test, with P < 0.05 indicating significance. Computations were performed using the SPSS statistical package (SPSS, Inc., Chicago, IL).
Between January 1996 and June 2000, 176 patients age < 14 years were diagnosed with precursor B-cell ALL and treated at King Faisal Specialist Hospital and Research Center. Of these patients, 20 were excluded from the analysis (12 were treated using a different induction protocol, 5 received previous steroid therapy and/or chemotherapy, and 3 had induction therapy discontinued for reasons that were not therapy-related or toxicity-related). Analysis of the results from the remaining 156 patients was performed. One hundred six patients received prednisone during induction therapy, whereas 50 received dexamethasone. Fifty- two patients were categorized as standard-risk and received induction therapy consisting of steroids, L-asparaginase, and vincristine; 104 patients were considered to be high-risk and received daunomycin in addition to the other 3 agents. There were significantly more standard-risk patients in the prednisone group than in the dexamethasone group (40.6% vs. 18%; P < 0.01).
The incidence of noninfectious toxicity is shown in Table 2. Hyperglycemia that required intervention was observed in 13 (12.3%) and 10 (20%) patients in the prednisone and dexamethasone groups, respectively. Significantly more episodes of gastritis occurred in the dexamethasone group; however, most patients had only epigastric pain that responded to antacid or ranitidine therapy. Hematemesis occurred in five patients, four of whom were receiving prednisone. One of these patients receiving prednisone required endoscopy.
Hypertension that required therapy occurred in 13 (12.2%) and 5 (10%) patients who received prednisone and dexamethasone, respectively. Ten of these patients received antihypertensive therapy on an as-needed basis, whereas the other eight eventually required scheduled antihypertensive therapy. Only one patient in the dexamethasone group required a fixed antihypertensive treatment schedule. In the majority of cases, hypertension resolved spontaneously, without any change in steroid therapy, over a period of 1–30 days (median, 7 days). For two patients who received prednisone, the steroid had to be discontinued prematurely; for one patient who initially received dexamethasone, the steroid was changed to prednisone to help control hypertension.
Myopathy occurred in 5 (4.7%) and 4 (8%) patients in the prednisone and dexamethasone treatment groups, respectively. In the prednisone group, 2 patients had Grade 1 myopathy and 3 had Grade 2 myopathy; in the dexamethasone group, 2 patients each had Grade 2 and Grade 3 myopathy. In all patients, the myopathy resolved without any intervention or early discontinuation of steroid therapy. Avascular necrosis of bone was not observed in any of the 156 patients.
The median weight change for patients receiving prednisone was +5.4% (range, −16.7% to +28.4%), whereas the median weight change for patients receiving dexamethasone was +11.9% (range, −20.2% to +35.3%). The difference between groups was statistically significant (P = 0.002).
The incidence of infection or possible infection (fever without any focus of infection) is shown in Table 3. Fever was the primary symptom for the majority of patients in both groups. Bacteremia or signs of sepsis (such as hemodynamic instability, respiratory distress, and chills and rigors with fever) occurred in 45 patients (27 [25.5%] in the prednisone group vs. 18 [36%] in the dexamethasone group; P = 0.17).
|Infection type||Prednisone (%)||Dexamethasone (%)||P|
|Any infection||71 (67)||35 (70)||0.7|
|With fever||68 (64.2)||34 (68)|
|Serious infection||27 (25.5)||18 (36)||0.17|
|Fungal infection||4 (3.8)||2 (4)|
|HSV infection||15 (14.1)||10 (20)|
Four patients in the prednisone group and two in the dexamethasone group were diagnosed with invasive fungal infections. Two patients in the prednisone group had documented infections with both an Aspergillus species and Candida albicans; one patient in the dexamethasone group had an Aspergillus infection, and the other had a yeast infection. The remaining two patients in the prednisone group had radiologic evidence of invasive pulmonary fungal infections. Mucositis complicated by herpes simplex Type-I infection was documented in 15 (14.1%) patients receiving prednisone and 10 (20%) patients receiving dexamethasone.
Overall, toxicity occurred in 89 (85.6%) of the 104 patients who were treated on the daunomycin-containing induction protocol and in 34 (65.4%) of the 52 who were treated without daunomycin (P ≤ 0.01) (Table 4). When we considered only patients who received daunomycin and compared the relative toxicities of dexamethasone and prednisone within this subset, we observed that the addition of daunomycin led to increased dexamethasone-related toxicity. Among patients receiving daunomycin, toxicity occurred in 50 of 63 (79.4%) patients in the prednisone group and in 39 of 41 (95.1%) patients in the dexamethasone group (P = 0.0001). No difference in toxicity between the 2 groups was observed when daunomycin was not used (67.4% vs. 55.6%; P = 0.77).
|Toxicity||Daunomycin (n = 104)||No daunomycin (n = 52)||P|
|Any toxicity (%)||89 (85.6)||34 (65.4)||0.004|
|Prednisone||50 (79.4)||29 (67.4)|
|Dexamethasone||39 (95.1)||5 (55.6)|
|P = 0.00001||P = 0.77|
|Serious infection (%)||35 (33.6)||10 (19.2)||0.06|
|Prednisone||19 (30.2)||8 (18.6)|
|Dexamethasone||16 (39.0)||2 (22.2)|
|P = 0.35||P = 0.83|
Of the 45 patients who developed bacteremia or signs of sepsis, 35 (77.8%) were receiving daunomycin. Serious infection occurred in 33.6% of patients who received daunomycin, compared with 19.2% of those who did not (P = 0.06). There was no difference in the incidence of serious infection between the dexamethasone and prednisone groups, regardless of whether or not daunomycin was used. Five patients died of infectious causes (four in the prednisone group and one in the dexamethasone group).
We further examined the incidence of toxicity in the dexamethasone group with and without concurrent daunomycin treatment. The incidence of toxicity increased significantly when daunomycin was included in the therapeutic regimen (Table 5).
|Toxicity||Daunomycin (n = 41)||No daunomycin (n = 9)||P|
|All toxicity (%)||39 (95.1)||5 (55.6)||0.006|
|Noninfectious toxicity (%)||32 (78)||5 (55.6)||0.33|
|Hyperglycemia||8 (19.5)||2 (22.2)||0.78|
|Gastritis||20 (48.8)||3 (33.3)||0.63|
|Hypertension||4 (9.8)||1 (11.1)|
|Myopathy||3 (7.3)||1 (11.1)|
|Infectious toxicity||29 (70.7)||3 (33.3)||0.08|
|Serious infections||16 (39)||2 (22.2)||0.57|
ALL treatment was compromised (either delayed, altered, or stopped) by steroid-related toxicity in 16 (15.1%) and 6 (12%) patients in the prednisone and dexamethasone groups, respectively (Table 6).
|Treatment compromiseda (%)||16 (15.1)||6 (12)||0.6|
|Toxic deathb (%)||4 (3.8)||1 (2)||0.92|
In addition to the report by Hurwitz et al.,7 which described an increase in serious infection rates among patients who received dexamethasone during induction therapy, studies conducted by the Dana Farber Cancer Institute ALL Consortium have reported the increased toxicity of dexamethasone in ALL patients when the agent is used in postinduction therapy. Dexamethasone also may have an affect on neurocognitive development, particularly as it relates to tasks with a memory demand.8 Furthermore, the cumulative incidence of bony morbidity, especially fractures, was found to be significantly higher in patients receiving dexamethasone compared with those receiving prednisone.9
Reilly et al. examined the effect of postinduction steroid therapy on energy intake, which leads to the excess weight gain observed in children who complete therapy for ALL.10 They observed an increase in energy intake that was associated with steroid use but saw no difference between dexamethasone and prednisone treatment groups.
In the current study, we attempted to study a wider spectrum of glucocorticoid-associated morbidity. Although toxicity was not documented prospectively, most patients received induction chemotherapy in the inpatient pediatric oncology ward and were monitored closely for the development of toxic effects. As a result of daily weight measurement, routine blood pressure monitoring, and daily blood chemistry evaluation (including serum glucose measurement), it is unlikely that any side effects related to these parameters were overlooked in the retrospective data retrieval.
To avoid overrepresentation, episodes of hypertension and hyperglycemia were considered evaluable only when they were judged to be significant enough to warrant an intervention. For the same reason, potentially spurious isolated episodes of increased blood pressure and serum glucose levels were excluded. It is noteworthy that we observed no increase in either incidence or severity of hypertension and hyperglycemia between the two steroid treatment groups.
There also was no significant difference in the incidence of myopathy between groups; however, there was a slight difference in the severity of myopathy, with Grade 3 myopathy observed in 2 patients receiving dexamethasone and in none of the patients receiving prednisone. With a larger patient sample, a clinically significant difference may be observable. It should be noted that any observed muscle weakness might not have been related primarily to the steroid. Patients with ALL frequently present with bone pain, do not feel well, and are unwilling to ambulate. The resultant inactivity could lead to disuse atrophy and weakness of the weight-bearing muscles in the proximal lower limbs. Routine muscle biopsy or electromyography probably would yield a more definitive diagnosis but would not be cost-effective or necessary, because most patients who experience myopathy recover spontaneously after steroid discontinuation.
It was not surprising that no patients developed osteonecrosis. Strauss et al. reported that none of the patients in their study developed osteonecrosis during induction, and the median time to development was 14 months.9 Similarly, a study of osteonecrosis in patients who were treated for malignancy at St. Jude Children's Research Hospital (Memphis, TN) reported a median time of occurrence of 25 months after diagnosis.11
The 4-week dexamethasone treatment led to a significant increase in weight compared with what was observed in patients receiving prednisone. Reilly et al. reported no difference in energy intake and subsequent weight gain between the 2 steroid treatment groups; however, patients in the study of Reilly et al. were receiving continuation therapy, with 5-day pulses of steroid treatment every 28 days.10 It is likely that the difference in weight gain grows more pronounced with increasing duration of steroid use.
In contrast with the report of Hurwitz et al.,7 we demonstrated no significant difference in the incidence of severe infection between the two steroid groups. The current study was expanded to examine fungal infections and infection by herpes simplex; again, the incidence was similar in both groups. We did observe a significant increase in toxicity when daunomycin was added to the treatment regimen, particularly when it was used in conjunction with dexamethasone. Even the incidence of serious infection was higher among patients who received daunomycin, although we did not demonstrate a correlation between serious infection and choice of steroid. The absence of a correlation with steroid choice could be related to the small number of patients in the analysis.
The increased incidence of serious infection that was observed by Hurwitz et al.7 may be explained by their use of daunomycin in all patients and by the fact that it was administered at a higher dose (30 mg/m2, compared with 25 mg/m2 in the current study) and given on 2 consecutive days. In the current study, patients received daunomycin on a weekly schedule for four doses. In addition, patients in the study of Hurwitz et al. received high-dose methotrexate (4 g/m2) immediately after the second dose of daunomycin; anthracycline- and methotrexate-induced mucosal breakdown, in association with the immunosuppressive effects of dexamethasone, might have resulted in the increased incidence of serious infection.
The most noteworthy finding of the current study was that although dexamethasone-related toxicity was more common than prednisone-related toxicity (especially when the steroids were used in conjunction with daunomycin), the choice of steroid did not affect our ability to administer planned therapy.
The current study adds to the ever-increasing body of evidence in the literature that substitution of prednisone with dexamethasone should be performed with extreme caution. Particular attention should be paid to nature of the agents used in combination with dexamethasone during induction therapy. Awareness of the potential for life-threatening complications when dexamethasone is used in conjunction with anthracyclines and the higher risk of long-term debilitating morbidity associated with dexamethasone use should encourage the development of better protocols for treatment of children with ALL.
The authors thank Ameurfina Silo for her work on data management and analysis.