PEDIATRIC PHARMACOLOGY AND THERAPEUTICS

Combination treatment with azidothymidine and granulocyte colony-stimulating factor in children with human immunodeficiency virus infection Brigitta U. Mueller, MD, Freda J a c o b s e n , RN, Karina M. Butler, MBBCh, Robert N. Husson, MD, Linda L. Lewis, ME), a n d Philip A. Pizzo, MD From the Pediatric Branch, National Cancer Institute, Bethesda, Maryland Bone marrow suppression is the major dose-limiting toxic effect of zidovudine (azidothymidine, AZT) in children with human i m m u n o d e f i c i e n c y virus infection. We e v a l u a t e d the effect of subcutaneously administered g r a n u l o c y t e colonystimulating factor (G-CSF) in pediatric patients whose absolute neutrophil count was less than 0.8 • 109/L during AZT therapy despite d o s a g e reductions to 120 m g / m 2 every 6 hours. Nineteen patients b e t w e e n 6 months and 20 years of a g e were treated with AZT and G-CSF and monitored for 2 to 12 months. All had previously shown improvement while receiving AZT but had required d o s a g e reduction or discontinuation. By using a sliding dosing schedule of G-C$F, we a t t e m p t e d to maintain the absolute neutrophil count b e t w e e n 1.5 and 5.0 • 109/ L. Administration of G-CSF resulted in a significant increase in the median leukocyte count (2.0 • 109/L to 4.14 • 109/L; p = 0.004), and the median absolute neutrophil count (1.02 • 109/L to 2.96 • I09/I; p = 0.0006). G-CSF was well tolerated, but mild t h r o m b o c y t o p e n i a d e v e l o p e d in nine children. Administration of G-CSF and AZT was discontinued in two patients b e c a u s e of continuing neutropenia. With doses of G-CSF ranging from I to 20/~g/kg per day, 17 of 19 patients were a b l e to tolerate AZT at a dose of 120 to 180 m g / m 2 every 6 hours. We conc l u d e that G-CSF therapy enables patients who have had AZT-related neutropenia to receive therapeutic doses of AZT. (J PEDIATR1992;121:797-802)

Encephalopathy is one of the major problems in children with human immunodeficiency virus infection. Studies of children with symptomatic HIV infection who received azidothymidine (zidovudine) by the oral route at a dosage of 180 m g / m 2 every 6 hours showed improvement in neurocognitive function, ~ and a continuous infusion schedule that maintained steady-state concentrations of A Z T has shown significant benefit in children with encephalopathy. 2 These benefits may be dependent on the ability to deliver doses of A Z T that are higher than those currently given to adults. However, at these dosage levels, myelotoxic effects can eventually develop in up to 35% of children, l Submitted for publication April 13, 1992; accepted June 18, 1992. Reprint requests: Philip A. Pizzo, MD, Pediatric Branch, National Cancer Institute, Building 10, Room 13N240, Bethesda, MD 20892. 9/25/40329

Granulocyte colony-stimulating factor is a hematopoietic hormone that promotes the growth and maturation of myeloid precursor cells committed to the neutrophil lineage. It also induces the terminal differentiation of mature neuANC AZT G-CSF GM-CSF HIV MAI

Absolute neutrophil count Azidothymidine (zidovudine) Granulocyte colony-stimulating factor Granulocyte-macrophage colonystimulating factor Human immunodeficiency virus

Mycobacterium avium-intracellulare

trophils and enhances phagocytic activity and antibody-dependent cell-mediated cytotoxicity.35 Human G-CSF has been molecularly cloned, expressed in Escherichia coli, and purified, allowing the production of large quantities of recombinant material. G-CSF has been studied in patients with congenital or chemotherapy-induced neutropenia and 797

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9has been well tolerated, with bone pain as the only reported side effect. 6-11 We conducted a pilot study to evaluate the effects of subcutaneously administered recombinant G-CSF in HIV-infected children with a history ofneutropenia as a result of AZT therapy.

METHODS Patients. Children 3 months to 18 years of age with HIV infection who had previously had an absolute neutrophil count less than 0.8 • 109/L, despite reductions of the A Z T dose to 120 m g / m 2 every 6 hours orally or 360 m g / m 2 for 24 hours intravenously, were eligible to receive G-CSF. Patients were excluded from the study if they had acute opportunistic or other infections requiring intensive drug therapy at the time of entry, a serum creatinine concentration greater than 180 #mol/L (2.0 mg/ml) or a creatinine clearance less than 50 ml/min per 1.73 m 2, a serum bilirubin value more than three times normal, or liver aminotransferase values more than 10 times normal. Patients who had received immunomodulating agents other than immunoglobulins, or hormonal therapy, cytolytic chemotherapy, or radiation therapy within 30 days of entry into the study, were excluded. Patients with a history or evidence of any chronic hematologic disorder (other than coagulopathy) that was unrelated to HIV disease, or of anemia caused by chronic disease, were also not considered eligible. A parent or legal guardian had to be available to give informed consent. Study design. The study protocol was approved by the National Cancer Institute Human Experimentation Review Board, and written informed consent was obtained from the parent or legal guardian. Azidothymidine (zidovudine) was given at a dose of 180 m g / m 2 every 6 hours orally or 480 m g / m 2 for 24 hours intravenously. Therapy with subcutaneously administered G-CSF was initiated at a dose of 1 #g/kg per day and increased stepwise as necessary every 3 days to 2.5, 5, 7.5, 10, 15, or 20 #g/kg per day to maintain the A N C between 1.5 and 5.0 • 109/L. Recombinant methionyl human G-CSF was kindly supplied by Amgen, Inc. (Thousand Oaks, Calif.) in 2 ml vials as a 300 #g/ml clear, sterile solution without preservative. Parents or patients or both learned to inject G-CSF subcutaneously. The exact dose schedule of G-CSF and A Z T was adjusted individually for each patient according to his or her ANC. If, after the start of AZT therapy, the patient's A N C fell to less than 0.8 • 109/L, the dose of A Z T was decreased to 120 m g / m 2 every 6 hours orally, or to 360 m g / m 2 for 24 hours intr~tvenously. In general, such reductions were meant to be temporary; the goal was to maintain, if achievable, the full dose of A Z T (180 m g / m 2 every 6 hours orally or 480 m g / m 2 for 24 hours intravenously). Clinical and laboratory monitoring. Vital signs were

The Journal o f Pediatrics November 1992

monitored for 2 hours after the first subcutaneous injection of G-CSF. Hemoglobin, hematocrit, reticulocyte count, leukocyte count with differential cell count, and platelet count were measured daily for the first 7 days of G-CSF therapy. For the first 12 weeks of study, a complete blood cell count was obtained weekly and then at least biweekly. A chemistry profile and an immunologic assessment, including T-lymphocyte subsets and serum p24 antigen, were performed monthly. The parents were asked to maintain a diary of the administration of G-CSF and AZT, the blood cell counts, and any potentially treatment-related adverse events. Statistical analysis. Median hemoglobin level, platelet count, leukocyte count, and A N C at week 0 (baseline) and at week 10 were compared with the two-sided Wilcoxon signed rank test. The median A N C during previous treatment with A Z T was compared with the median A N C during G-CSF and A Z T therapy. The serum p24 antigen levels before and after treatment with G - C S F were also compared. The Wilcoxon signed rank test was used for analysis. RESULTS

Patient population. Nineteen patients who met the eligibility criteria and who received G-CSF for at least 1 month were evaluable. The study population included 12 boys and 6 girls between the ages of 6 months and 17 years 3 months; one 201A-year-old man with hemophilia was entered as a special exemption because of age. The median age was 9.5 years. Ten patients had acquired HIV infection by vertical transmission and eight by transfusion; in one patient the mode of transmission was not clear. All children were in class P-2, according to the classification system of the Centers for Disease Control (Atlanta, Ga.). 12 The median absolute CD4 count at the time of study entry was 4 cells/mm 3 (range, up to 304 cells) with a median percentage of 1% (range, up to 65%). Serum p24 antigen was detected in 15 children, with a median of 135 pg/ml (range, up to 3167 pg/ml). Eight chit~ren died during the study, but none of the deaths was considered to be related to the study drugs. Clinical course and laboratory response. The 19 patients entered into the study had previously received AZT for a median of 178 days (range, 15 to 696 days). Although most patients had initially been able to tolerate a dose of 180 m g / m 2 every 6 hours, the median dose that the patients were receiving before stopping A Z T therapy or entering the study was 100 m g / m 2 every 6 hours or an equivalent intravenous dose. The 19 children received G-CSF for a median of 109 days (range, 55 to 370 days), and seven of them continue to receive therapy (Table). The leukocyte count increased from a median of 2.0 x 109/L (range, 0.8 to 5.2 X 109/L) before study entry to 4.14 • 109/L (range, 1.5 to 11.3) (p -- 0.004) after 10 weeks of treatment with A Z T and G-CSF. The

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Table. Patients treated with AZT and G-CSF and their treatment course Patient No.

G-CSF (ug/kg)

1 2

1 daily 1-2.5 daily

3 4 5 6 7 8 9 10 11

1-5 daily 1-2.5 daily 1 daily 1 q3 days 1 daily 20 daily 15-20 daily 5 daily 5-12.5 daily

12 13

5-10 daily 1 daily

14 15 16 17 18 19

10 daily 1 daily 1 q3 days 1 daily 1 daily 2.5 daily

Reason for discontinuation of AZT therapy

Treatment course

AZT well tolerated* AZT dosage decreased for anemia, thromboeytopenia Mild thrombocytopeniat Anemia, mild thrombocytopenia$

Death Death

Anemia AZTwell tolerated Thrombocytopenia Thrombocytopenia AZT well tolerated AZT dosage decreased for anemia and thrombocytopenia Thrombocytopenia$

More G-CSF during acyclovir therapyt Mild thrombocytopenia:~ AZT well tolerated AZT well tolerated Thrombocytopenia before AZT therapy AZT well tolerated

Anemia, progressive HIV infection:~ Neutropenia, progressive HIV infection:~ Neutropenia~: Death Death Thrombocytopenia, severe nausea, progressive HIV infection

Death Death Death

*Ganciclovirfor retinitiscaused by cytomegalovirus. ]'Acyclovirfor recurrentherpes infection. $Infectionwith MAI. median ANC increased from 1.02 x 109/L (range, 0.15 to 3.85) to 2,96 • 109/L (range, 1.12 to 9.69) (p = 0.0006) after 10 weeks of AZT and G-CSF therapy (Fig. 1). Only 14 patients had an ANC less than 1.5 • 109/L when G-CSF was initiated; the others had been off the A Z T regimen long enough for their bone marrow to recover temporarily. There was considerable individual variation in both the optimal dose of G-CSF required to overcome neutropenia and the dose of AZT that was simultaneously tolerated. Two children (Nos. 6 and 16) were able to maintain their neutrophil counts at more than 1.5 • 109/L with less than daily injections of 1 #g/kg per dose of G-CSF, whereas five patients needed more than 10 #g/kg per day. Neutropenia did not occur in 17 of 19 patients. The coadministration of G-CSF allowed 10 patients to receive an AZT dose of 180 mg/m 2 every 6 hours, and seven other patients tolerated >_120 mg/m 2 every 6 hours; anemia or thrombocytopenia was the reason for the lower doses. The median ANC for all patients during treatment with G-CSF and A Z T was 2.97 • 109/L compared with 1.16 X 109/L during previous episodes of treatment with A Z T alone (p = 0.0002). However, two patients (Nos. 8 and 9) with concomitant Mycobacterium avium-intracellulare infection had to discontinue A Z T therapy because of unresolving neutropenia despite maximal doses of G-CSF. A significant decrease in the median platelet count, however, was observed by week 10 (p = 0.026) (Fig. 2).

Thrombocytopenia (platelet count ~ 1 5 0 • 109/L) developed in nine patients, but no episodes of bleeding were noted. One child had a decreased platelet count before receiving AZT and G-CSF, whereas nine others acquired mild to severe thromb0cytopenia during therapy, resulting in the discontinuation of A Z T therapy in one patient (No. 13). Five of these patients had concurrent MAI infection. Of our 19 patients, 9 received recombinant erythropoietin to treat anemia, but there was still a median decrease in the hemoglobin level of 0.8 gm/dl ( p = 0.019) for the whole group of patients. Two patients (Nos. 5 and 7) had to stop AZT therapy because of severe persistent anemia despite concomitant administration of erythropoietin. Our study group was too small and the patients too advanced in the course of their HIV infection to assess whether the higher doses of AZT resulted in clinical benefits. One patient (No. 17), in whom progressive encephalopathy developed during treatment with a decreased dose of AZT because of bone marrow suppression, improved rapidly after initiation of G-CSF therapy and a full dose of AZT. Adverse effects. Treatment with G-CSF was well tolerated. There was no adverse impact on hepatic aminotransferase or routine chemistry values, and the level of serum p24 antigen was not statistically different before or after the start of G-CSF therapy. On one occasion a child with hemophilia acquired a large hematoma at the site of the injection; the lesion resolved spontaneously. Another patient

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The Journal o f Pediatrics November 1992

cells/mm3 5000

median

ANC

4000

3000

2000

tJ

1000

12

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i

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weeks on study I=i9. 4. Median ANCs for all patients before and after initiation of G-CSF therapy (week 0 = protocol entry).

complained of burning with every injection, a previously unpublished observation, but improvement was marked when 5% dextrose in water was used to formulate a 1:1 dilution of G-CSF. DISCUSSION High doses of AZT are associated with bone marrow suppression, resulting in neutropenia and anemia. When these toxic effects occur, it is common practice to reduce the dose of AZT from 180 m g / m 2 every 6 hours to 120 mg/m 2 or even 90 mg/m 2 every 6 hours. Dosag6" reduction can, at least for a time, ameliorate the hematologic toxic effects, but the lower doses of A Z T may prove suboptimal for children who have evidence of, or are at risk for, encephalopathy. Thus the currently recommended oral dosage of AZT

for children remains4'80 mg/m 2 every 6 hours, even though this is substantially higher than the dosages currently being used for adults. 12, 13 Granulocyte colony-stimulating factor has been studied extensively in congenital6, ]o, 1l, 14 and chemotherapy-related neutropenia.7, 9, 15 One of its major advantages over granulocyte-macrophage colony-stimulating factor is the low incidence of side effects, bone pain being the only commonly encountered complaint.9' 16 Moreover, there is concern that GM-CSF, when used in patients with HIV infection, may enhance viral activity. 17 We have demonstrated that daily subcutaneous doses of recombinant G-CSF enable children with AZT-related bone marrow suppression to continue to receive AZT in therapeutic doses. There was marked individual variation in

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platelets/mm3 median

400

platelets

350

3OO

250

200

1 150

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weeks on study Fig. 9. Median platelet counts for all patients before and after initiation of G-CSF therapy (week 0 = protocol entry). both the dosage of G-CSF required to overcome neutropenia and the dosage of AZT that was tolerated. In 11 of 19 patients we were able to find multiple other causes for bone marrow compromise in addition to AZT-related suppression. Six patients with MAI infection appeared to have more hematologic problems, especially anemia and thrombocytopenia, than children without documented MAI. Two of them discontinued AZT and G-CSF therapy because of continued refractory neutropenia despite daily G-CSF doses of 20 #g/kg. The frequency of MAI infection is significant in children with low CD4 counts, is so this association is likely to assume greater magnitude in the future. Although thrombocytopenia has not been a side effect commonly observed with AZT, 1, 19 we noted precipitous drops in platelet counts shortly after treatment with AZT and G-CSF was started in several patients, none of whom

had previously had thrombocytopenia while receiving AZT. Whether this was a consequence of higher doses of AZT and a compromised bone marrow or whether it represented a side effect of G-CSF and A Z T remains to be determined. Dfihrsen et al. 4 described an increase of progenitor cells, including the megakaryocyte lineage, after 4 days of in vitro treatment with G-CSF. This finding suggests that G-CSF may cycle the megakaryocyte progenitors, rendering them more susceptible to the toxic effects of AZT. It has also been suggested that the thrombocytopenia observed during treatment with GM-CSF and A Z T may be due to stimulation of macrophages, which leads to an accelerated clearance of immunoglobulin-coated platelets. 2~ Weston et al. 21 described the occurrence of transient thrombocytopenia during treatment with G-CSF in a patient with myelokathexis. Our study allowed the concomitant use of erythropoietin

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for the treatment of anemia. However, only one of the nine children treated with erythropoietin had a reduction in transfusion frequency and a rise of her hemoglobin level into an age-appropriate range, despite the fact that all children had low (

Combination treatment with azidothymidine and granulocyte colony-stimulating factor in children with human immunodeficiency virus infection.

Bone marrow suppression is the major dose-limiting toxic effect of zidovudine (azidothymidine; AZT) in children with human immunodeficiency virus infe...
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