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Journal of Clinical Oncology, Vol 21, Issue 8 (April), 2003: 1612-1617
© 2003 American Society for Clinical Oncology

Human Granulocyte Colony-Stimulating Factor in Children With High-Risk Acute Lymphoblastic Leukemia: A Children’s Cancer Group Study

John A. Heath, Peter G. Steinherz, Arnold Altman, Harland Sather, Suresh Jhanwar, Steven Halpern, Richard Pieters, Narayan Shah, Laurel Steinherz, Raymond Tannous, William Terry, Michael E. Trigg

From the Memorial Sloan-Kettering Cancer Center, New York, NY; Children’s National Medical Center, Washington, DC; Mayo Clinic, Rochester, MN; Children’s Hospital Los Angeles, Los Angeles; and Children’s Cancer Group, Arcadia, CA.

Address reprint requests to Peter G. Steinherz, MD, Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021; email: steinhep{at}mskcc.org.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: To investigate the effect of granulocyte colony-stimulating factor (G-CSF) on hematopoietic toxicities, supportive care requirements, time to complete intensive therapy, and event-free survival (EFS) and overall survival (OS) in children with high-risk acute lymphoblastic leukemia (HR-ALL).

Patients and Methods: A total of 287 children with HR-ALL were randomly assigned to intensive chemotherapy regimens (New York I [NY I] or NY II) as part of the Children’s Cancer Group (CCG)-1901 protocol. The induction phases consisted of five drugs (vincristine, prednisone, L-asparaginase, daunorubicin, and cyclophosphamide). Initial consolidation comprised six-agent chemotherapy combined with 18 Gy of total-brain irradiation. Patients were randomly assigned to receive G-CSF (5 µg/kg/day) during either induction or initial consolidation. A crossover study analysis was done on the 259 patients who completed both phases of therapy.

Results: The mean time to neutrophil recovery (>= 0.5 x 109/L) was reduced with G-CSF (16.7 v 19.1 days, P = .0003); however, patients who received G-CSF did not have significantly reduced episodes of febrile neutropenia (149 v 164, P = .41), positive blood cultures (57 v 61, P = .66), or serious infections (75 v 79, P = .62). Hospitalization (14.0 v 13.9 days, P = .87) and induction therapy completion times (NY I, 30.3 v 31.3 days, P = .11; NY II, 33.4 v 32.3 days, P = .40) were not significantly altered. There were no differences in 6-year EFS (P = .24) or OS (P = .54) between patients receiving or not receiving G-CSF on CCG-1901, NY I and NY II.

Conclusion: Children with high-risk ALL do not appear to benefit from prophylactic G-CSF.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
ACUTE LYMPHOBLASTIC leukemia (ALL) is the most common malignancy of childhood, with an annual incidence of approximately one per 10,000.1 With current modern chemotherapy regimens, overall cure rates of better than 70% can be expected.2 Attempts to further improve survival have led to increased intensity multiagent chemotherapy protocols for patients at high risk of relapse. The dose-limiting toxicity for many of these regimens is myelosuppression. Infectious complications during prolonged neutropenia are a major cause of morbidity and mortality. Slow neutrophil recovery can also delay timely delivery of further treatment, and hence affect response. Administration of recombinant growth factor granulocyte colony-stimulating factor (G-CSF) to children with ALL has had conflicting results to date, with no clear evidence of benefit in several small-scale studies.3–7 Therefore, we conducted a large-scale, prospective, open-label, randomized, crossover trial of G-CSF administered during either the remission induction (RI) or initial consolidation (CD) phase of treatment for high-risk ALL. We assessed its efficacy for decreasing incidence and duration of neutropenia, reducing fever and infectious complications, reducing duration of hospital stays, shortening time between chemotherapy cycles to increase dose-intensity, and improving event-free survival (EFS) and overall survival (OS).


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
We included patients with newly diagnosed ALL who were eligible for enrollment on Children’s Cancer Group (CCG)-1901. This study compared efficacy and morbidity of two treatment regimens, New York I [NY I]8 and NY II,9 in high-risk childhood ALL. Patients were between 1 and 21 years old and untreated and had initial WBC counts >= 50 x 109/L, hemoglobin >= 10 g/dL, or T-cell ALL and massive lymphadenopathy (> 3 cm), massive splenomegaly (below umbilicus), or a large mediastinal mass (more than a third of maximal transthoracic diameter). These groups are recognized to be at high risk of early relapse.10,11 Patients with French-American-British (FAB) classification L3 leukemia cell morphologies were not eligible for this study. Before registration, all patients or their parents or legal guardians signed written informed consent forms approved by the institutional review boards of the treating centers and in accordance with the Declaration of Helsinki.

Treatment Protocol
The treatment schedules and doses for the RI and first CD phases of NY I and NY II are outlined in Fig 1AGo and 1BGo. Both regimens comprised a five-drug induction (vincristine, prednisone, L-asparaginase, daunorubicin, and cyclophosphamide), with intrathecal cytarabine and methotrexate. The first consolidation therapy cycles consisted of combined prednisone, L-asparaginase, cytarabine, 6-thioguanine, methotrexate, and intrathecal methotrexate. Patients also received 18 Gy of irradiation to their craniums at commencement of consolidation on NY I and in a later phase of consolidation in NY II.



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  		Fig 1. A schematic representation of CCG-1901 remission induction and consolidation. (A) New York I regimen; (B) New York II regimen.

 
Study Design
A schema summarizing our randomized crossover study design is shown in Fig 2Go. At diagnosis, patients were assigned randomly to either regimen and then immediately assigned randomly to receive G-CSF during either RI or CD. G-CSF was administered as a daily subcutaneous injection of 5 µg/kg that commenced at least 24 hours after intravenous chemotherapy and continued until neutrophil counts exceeded 2.5 x 109/L for 2 consecutive days after nadir. Subsequent scheduled chemotherapy was started at least 48 hours after cessation of G-CSF, with absolute neutrophil counts >= 0.5 x 109/L. For those who did not receive G-CSF, chemotherapy commenced when neutrophil counts after nadir were >= 0.5 x 109/L. Platelet counts >= 100 x 109/L were required in both groups before the next cycle of chemotherapy was given. Complete and differential blood counts were measured at least twice weekly throughout the study.



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  		Fig 2. A schematic outline of the study design.

 
Supportive Care
Standard hospital policies were observed for all measures of supportive care. Patients had central venous catheters placed for administration of chemotherapy, irradiated blood products, and other supportive care as needed. Patients were given fluids, blood alkalizing agents, and allopurinol before induction therapy according to protocol requirements. We also gave patients prophylactic co-trimoxazole and nystatin. Packed RBC transfusions were given to patients whose hemoglobin counts were less than 80 g/L and platelet transfusions to those whose platelet counts were less than 10 x 109/L or had active bleeding. Patients with fevers (>= 38.0°C for 4 hours, or single recorded temperatures of >= 38.5°C) and neutropenia were hospitalized and treated with broad-spectrum intravenous antibiotics after appropriate culture samples were collected. Specific infections were treated according to available culture and sensitivities results. In patients without documented infections, antibiotics were given until patients remained afebrile more than 24 hours with absolute neutrophil count (ANC) >= 0.5 x 109/L. If fever persisted in a patient beyond 7 days of antibiotic therapy with no positive culture,amphotericin B was given. To be discharged from the hospital, children had to be clinically well, with no fever for 48 hours, negative blood cultures, and ANC >= 0.5 x 109/L. Children with positive blood cultures routinely received a 10-day course of intravenous antibiotics.

Organization of the Study
Four hundred fifteen patients from 92 participating centers (range, one to 17 patients) were enrolled on CCG-1901 between January 1991 and September 1994. Among those, 287 consecutive patients enrolled between June 1991 and June 1994 were assigned randomly to receive G-CSF during RI or CD. For the crossover design analyses, only 259 patients who successfully completed RI and CD were included. The review board at each institution approved the protocol before participation. All data collected on this study were submitted to the CCG Research Data Center on specified forms. CCG central data management personnel were responsible for quality assurance of data submitted. Eligibility criteria were verified for all patients, and the authors made complete evaluations of treatment, response, and toxicity.

Response Criteria
The primary study end point was time to ANC recovery (>= 0.5 x 109/L for 2 consecutive days). Secondary end points were time to platelet recovery (>= 50 x 109/L), number of days with febrile neutropenia, incidence of patients with positive blood cultures, number and types of documented infections, time to complete scheduled phases of therapy, and EFS and OS rates at 6 years. For calculation of days of neutropenia, days to recovery of platelet counts, days of febrile neutropenia, antibiotic use, and hospital stay, partial days were counted as whole days. Pneumonia was defined by compatible symptoms and clinical signs, with pulmonary infiltrates shown by radiography. A serious infection was defined as any proven systemic bacterial or fungal infection or any episode associated with hypotension or that required admission to an intensive care unit for supportive care.

Statistical Analysis
Analyses of the 259 patients who completed the two phases of treatment were conducted on an intention-to-treat basis, with inclusion of all patients assigned randomly in the data analysis, regardless of eligibility status or treatment received. Analysis of noncategorical data such as time to ANC recovery, time to platelet recovery, number of days hospitalized, and duration of treatment phase used standard analysis of variance (ANOVA) methods for analysis of crossover design data. The remaining secondary end points, including incidence of febrile neutropenia, incidence of positive blood cultures, incidence of documented pneumonia, cellulitis, abscess, or serious infections were converted to a binary form (patient experienced the variable event or not). A stratified crossover analysis accounting for chemotherapy regimen, treatment phase, and use of G-CSF was then employed.12 Comparison of times to complete each phase of therapy were made using a t statistic. EFS and OS rates were constructed using Kaplan-Meier survival curves and compared statistically using the log-rank test. Kaplan-Meier survival curves were also constructed for all patients who were assigned randomly to receive prophylactic G-CSF on either NY I or NY II. Comparisons with control groups consisting of 44 (NY I) and 46 (NYII) patients enrolled on the CCG-1901 protocol who did not receive prophylactic G-CSF and completed both phases of treatment (enrolled for 6 months before and 3 months after this study) were made using the log-rank test.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Baseline Clinical Features
We entered 287 consecutive eligible patients on study. Before starting induction therapy, 143 patients were assigned randomly to receive G-CSF during RI (71 patients on NY I and 72 patients on NY II) and 144 patients to receive G-CSF during first CD (71 patients on NY I and 73 patients on NY II). The four groups were well matched for clinical and biologic characteristics at the time of diagnosis (Table 1Go). The total number of patients who completed RI and CD and were available for the stratified two-treatment parametric crossover analysis was 259. Of these, 130 patients received G-CSF during RI (70 patients on NY I and 60 patients on NY II) and 129 patients received G-CSF during CD (62 patients on NY I and 67 patients on NY II). There were no detectable differences between all randomly assigned patients and those who did or did not complete RI and CD.


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  		Table 1. Clinical and Biological Characteristics of 287 Patients Enrolled on CCG-1901 and Randomly Assigned to Receive G-CSF in Remission Induction (Order 1) or Consolidation (Order 2)
 
End Points
Neutrophil recovery. The mean times to ANC recovery within the induction phase were 14.2 and 16.8 days for those who received G-CSF (NY I and NY II, respectively), compared with 18.5 (P = .03) and 18.8 days (P = .16), respectively, for control groups. The mean times for ANC recovery within the initial CD phase were 20.8 and 13.7 days for those who received G-CSF (NY I and NY II, respectively), compared with 22.0 (P = .62) and 17.6 (P = .03) days, respectively, for control groups. The ANC counts of three patients who received G-CSF during RI did not decrease below 0.5 x 109/L, compared with nine patients in control groups. The ANC counts of 13 patients who received G-CSF during CD did not decrease below 0.5 x 109/L during the initial CD phase, compared with 14 patients in the respective control groups. Overall, the mean time to ANC recovery was significantly shorter for those who received G-CSF compared with controls (16.3 compared with 19.2 days; P = .0003). There was no evidence of a carryover effect in the crossover analysis (P = .99).

Platelet Recovery
The mean times to platelet recovery within the RI phase were 13.8 and 15.1 days for those who received G-CSF (NY I and NY II, respectively), compared with 14.8 (P = .44) and 12.5 days (P = .10) for control groups. Mean times for platelet recovery within the initial CD phase were 16.7 and 13.2 days for those who received G-CSF (NY I and NY II, respectively), compared with 17.0 (P = .88) and 13.5 days (P = .84), respectively, for controls. The platelet counts of five patients who received G-CSF during RI did not decrease below 50 x 109/L, compared with 11 patients in the respective control groups. The platelet counts of 13 patients who received G-CSF during the initial CD phase and 13 respective controls did not decrease below 50 x 109/L. Overall, mean time to platelet recovery was not significantly longer for those who received G-CSF compared with controls (14.8 v 14.5 days; P = .70). There was no evidence of a carryover effect in the crossover analysis (P = .48).

Infectious Complications
A summary of infectious complications according to treatment regimen, treatment phase, and administration of prophylactic G-CSF is given in Table 2Go. The number of episodes of febrile neutropenia among those who received G-CSF was not statistically different from that of controls (149 v 164; P = .41). The number of serious infections was not significantly different for those who received G-CSF compared with controls (75 v 79; P = .66). There was no evidence of significant reduction in number of days of antibiotic usage (169 v 175; P = .30), positive blood cultures (57 v 61; P = .66), incidence of pneumonia (12 v 12; P = .14), cellulitis (12 v seven; P = .19), or abscesses (nine v nine; P = .97) with prophylactic G-CSF.


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  		Table 2. Number and Percentage of Patients With Infectious Complications
 
Hospitalization Time
The mean durations of hospitalization during the induction phase were 16.7 and 22.4 days for those who received G-CSF (NY I and NY II, respectively), compared with 20.7 (P = .04) and 20.0 days (P = .18), respectively, for control groups. The mean durations of hospitalization during the initial consolidation phase were 6.9 and 8.2 days for those who received G-CSF, compared with 6.8 days (P = .16) and 9.3 days (P = .35), respectively, for control groups. Overall, the mean duration of hospitalization was not significantly shorter for those who received G-CSF compared with controls (14.0 compared with 13.9 days; P = .87).

Treatment Duration
The mean times taken to complete the induction phase of therapy (G-CSF compared with controls) were 30.3 days compared with 31.3 days (P = .11) on NY I and 33.4 days compared with 32.3 (P = .40) on NY II. The mean times to complete the initial CD phase of therapy (G-CSF compared with controls) were 41.3 days versus 42.6 days (P = .49) on NY I and 31.2 days versus 30.8 days (P = .68) on NY II.

Survival
The median EFS for eligible patients (132 patients on NY I and 127 patients on NY II) were 68 and 69 months, respectively. EFS (NY I, P = .77; NY II, P = .72; overall, P = .91) and OS (NY I, P = .48; NY II, P = .83; overall, P = .78) rates through 6 years were not statistically different among the four treatment arms (Fig 3AGo and 3BGo). In addition, no difference was found in 6-year EFS (P = .24) or OS rates (P = .54) between those who received G-CSF on NY I and NY II and patients enrolled on the CCG-1901 protocol who were not assigned randomly (Fig 4AGo and 4BGo).



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  		Fig 3. Kaplan-Meier estimates for the survival of patients on New York I (NY I) and New York II (NY II) regimens receiving granulocyte colony-stimulating factor during either remission induction (Order 1) or initial consolidation (Order 2). (A) Event-free survival; (B) overall survival.

 


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  		Fig 4. Kaplan-Meier estimates for survival of patients on New York I (NY I) and New York II (NY II) regimen receiving and not receiving granulocyte colony-stimulating factor. (A) Event-free survival; (B) overall survival.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Although G-CSF shortened the duration of neutropenia after intensive RI and CD chemotherapy in children with high-risk ALL, we achieved no significant effect on clinically important outcomes. This finding was consistent across two separate intensive regimens for high-risk ALL. We believe this study, the largest cohort reported to date, helps to address some conflicting results reported in many adult and several smaller pediatric studies.

The first studies to examine the effect of prophylactic G-CSF in ALL were in adults. The initial prospective randomized trial, which examined its effect after induction chemotherapy for patients with refractory or relapsed leukemias, strongly indicated that an accelerated hematopoietic recovery was associated with reduced rates of infections.13 A subsequent study also was associated with more rapid completion of scheduled chemotherapy.14 A more recent randomized, placebo-controlled study that involved 198 adult patients also showed a trend toward higher complete response rates.15

The situation in pediatric patients has been far less clear, however, with most studies in children with ALL not showing these benefits. To date, the largest randomized trial of pediatric patients who received single courses of G-CSF after RI found a 2-day reduction in time to neutrophil recovery, associated with fewer documented infections, but no change in hospital admission rates, costs of supportive care, or overall survival rates.4 A more recent randomized study of prophylactic G-CSF after an intensification regimen in childhood ALL and T-cell–derived non-Hodgkin’s leukemia (Medical Research Council UKALL XI protocols) found a significant reduction in the rate of hospital readmission for management of febrile neutropenia.16 In contrast, a Pediatric Oncology Group pilot study in children with T-cell ALL and advanced-stage lymphoblastic lymphoma did not find any significant effects on duration of neutropenia, hospitalization, or delays in induction therapy. In that study, the only reduction in neutropenia duration was after two phases of consolidation chemotherapy.5

It has been suggested that beneficial clinical effects of prophylactic G-CSF only become apparent when myelosuppression is prolonged.17 In our study, the average length of neutropenia was more than 13 days for all cycles of therapy administered. Despite this intensity of myelosuppression, clinical benefit was not seen. This was probably because the nadir of neutropenia—the period of maximal risk—did not appear to be affected. Our study showed no decrease in patients who became neutropenic in either phase of treatment. It is possible that by commencing G-CSF on day 5 of treatment, only the time to postnadir recovery shortened. Interestingly, it has previously been shown in adult patients with ALL who received a hyper cyclophosphamide, doxorubicin, vincristine, and dexamethasone therapy and methotrexate/cytarabine regimen, G-CSF can be delayed until day 10 without increasing risk of treatment-related morbidity.18

Given the proven benefit of G-CSF in patients with established febrile neutropenia,19 it is important to note that in our study, administration of G-CSF was not associated with any detrimental effects. In particular, the time to platelet recovery after intensive chemotherapy was not prolonged, a critical factor enabling commencement of additional therapy. In addition, although leukemic cells can express G-CSF receptors20 and be stimulated by G-CSF in vitro,21 we observed no increase in relapse rates in those who received G-CSF (compared with a cohort of CCG-1901 patients who did not receive G-CSF; unpublished data).

Although many differences in outcomes from different studies might be attributable to differences in intensity of treatment regimens and variations in observed end points, it remains true that no study has ever shown a clear survival benefit for prophylactic G-CSF in children with leukemia. Without a definitive effect, a role for prophylactic G-CSF can only be justified on the basis of improved quality of life or financial savings on the cost of overall care. Our study, like others,4,7 did not show any reduction in amount of time patients spent hospitalized. The imposition of daily subcutaneous injections has a negative effect on children’s quality of life, and prophylactic G-CSF is not a cost-effective measure in children with ALL,6 even when rates of hospitalization appear to be reduced with its use.

In conclusion, we do not support the use of prophylactic G-CSF in RI or CD for children with high-risk ALL and recommend it only when serious infection in a neutropenic patient is documented or considered likely.


   ACKNOWLEDGMENTS
 
The authors thank Conway Gee for statistical advice and Mei La for editorial assistance.


   REFERENCES
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 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
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1. Pui CH. Childhood leukemias. N Engl J Med 332:1618–1630, 1995[Free Full Text]

2. Tubergen DG, Gilchrist GS, O’Brien RT, et al: Improved outcome with delayed intensification for children with acute lymphoblastic leukemia and intermediate presenting features: A Children’s Cancer Group phase III trial. J Clin Oncol 11:527–537, 1993[Abstract/Free Full Text]

3. Welte K, Reiter A, Mempel K, et al: A randomized phase III study of the efficacy of granulocyte colony-stimulating factor in children with high-risk acute lymphoblastic leukemia: Berlin-Frankfurt-Munster Study Group. Blood 87:3143–3150, 1996[Abstract/Free Full Text]

4. Pui CH, Boyett JM, Hughes WT, et al: Human granulocyte colony-stimulating factor after induction chemotherapy in children with acute lymphoblastic leukemia. N Engl J Med 336:1781–1787, 1997[Abstract/Free Full Text]

5. Laver J, Amylon M, Desai S, et al: Randomized trial of r-metHu granulocyte colony-stimulating factor in an intensive treatment for T-cell leukemia and advanced-stage lymphoblastic lymphoma of childhood: A Pediatric Oncology Group pilot study. J Clin Oncol 16:522–526, 1998[Abstract]

6. Clarke V, Dunstan FD, Webb DK: Granulocyte colony-stimulating factor ameliorates toxicity of intensification chemotherapy for acute lymphoblastic leukemia. Med Pediatr Oncol 32:331–335, 1999[CrossRef][Medline]

7. Michel G, Landman-Parker J, Auclerc MF, et al: Use of recombinant human granulocyte colony-stimulating factor to increase chemotherapy dose-intensity: A randomized trial in very high-risk childhood acute lymphoblastic leukemia. J Clin Oncol 18:1517–1524, 2000[Abstract/Free Full Text]

8. Steinherz PG, Gaynon P, Miller DR, et al: Improved disease-free survival of children with acute lymphoblastic leukemia at high risk for early relapse with the "New York" regimen: A new intensive therapy protocol. J Clin Oncol 4:744–752, 1986[Abstract/Free Full Text]

9. Steinherz PG, Redner A, Steinherz L, et al: Development of a new intensive therapy for acute lymphoblastic leukemia in children at increased risk of early relapse: The Memorial Sloan-Kettering New York-II protocol. Cancer 72:3120–3130, 1993[CrossRef][Medline]

10. Steinherz PG, Siegel SE, Bleyer A, et al: Lymphomatous presentation of childhood acute lymphoblastic leukemia: A subgroup at high risk of early treatment failure. Cancer 68:751–758, 1991[CrossRef][Medline]

11. Steinherz PG, Gaynon PS, Breneman JC, et al: Treatment of patients with acute lymphoblastic leukemia with bulky extramedullary disease and T-cell phenotype or other poor prognostic factors: Randomized controlled trial from the Children’s Cancer Group. Cancer 82:600–612, 1998[CrossRef][Medline]

12. Gee C: Stratified testing for crossover design analysis with binary data. Master’s thesis, University of Southern California Graduate School, Department of Preventive Medicine, Division of Biometry, 1998

13. Ottmann OG, Hoelzer D, Gracien E, et al: Concomitant granulocyte colony-stimulating factor and induction chemoradiotherapy in adult acute lymphoblastic leukemia: A randomized phase III trial. Blood 86:444–450, 1995[Abstract/Free Full Text]

14. Geissler K, Koller E, Hubmann E, et al: Granulocyte colony-stimulating factor as an adjunct to induction chemotherapy for adult acute lymphoblastic leukemia: A randomized phase III study. Blood 90:590–596, 1997[Abstract/Free Full Text]

15. Larson RA, Dodge RK, Linker CA, et al: A randomized controlled trial of filgrastim during remission induction and consolidation chemotherapy for adults with acute lymphoblastic leukemia: CALGB study 9111. Blood 92:1556–1564, 1998[Abstract/Free Full Text]

16. Little MA, Morland B, Chisholm J, et al: A randomized study of prophylactic G-CSF following MRC UKALL XI intensification regimen in childhood ALL and T-NHL. Med Pediatr Oncol 38:98–103, 2002[CrossRef][Medline]

17. Saarinen-Pihkala UM, Lanning M, Perkkio M, et al: Granulocyte-macrophage colony-stimulating factor support in therapy of high-risk acute lymphoblastic leukemia in children. Med Pediatr Oncol 34:319–327, 2000[CrossRef][Medline]

18. Weiser MA, O’Brien S, Thomas DA, et al: Comparison of two different schedules of granulocyte-colony-stimulating factor during treatment for acute lymphocytic leukemia with a hyper-CVAD (cyclophosphamide, doxorubicin, vincristine, and dexamethasone) regimen. Cancer 94:285–291, 2002[CrossRef][Medline]

19. Bennett CL, Stinson TJ, Lane D, et al: Cost analysis of filgrastim for the prevention of neutropenia in pediatric T-cell leukemia and advanced lymphoblastic lymphoma: A case for prospective economic analysis in cooperative trials. Med Pediatr Oncol 34:92–96, 2000[CrossRef][Medline]

20. Mitchell PL, Morland B, Stevens MC, et al: Granulocyte colony-stimulating factor in established febrile neutropenia: A randomized study of pediatric patients. J Clin Oncol 15:1163–1170, 1997[Abstract/Free Full Text]

21. Dibenedetto SP, Ragusa R, Ippolito AM, et al: Assessment of the value of treatment with granulocyte colony-stimulating factor in children with acute lymphoblastic leukemia: A randomized clinical trial. Eur J Haematol 55:93–96, 1995[Medline]

Submitted July 22, 2002; accepted January 21, 2003.




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