Bogner, Johannes R.

Chatterjee, M.

Ganser, A.

Goebel, Frank-Detlef

Helm, E. B.

Hoelzer, D.

Ottmann, O. G.

Seipelt, G.

English

Universität München: Elektronischen Publikationen

Internationale Zeitschrift für 
Krebsforschung und -behandlung Band 14, Heft 4, August 1991 
Inhalt Contents 
Ubersichtsarbeiten 
Proliferationskinetik und Prognose eines 
Nierenzellkarzinoms* 
de Riese, W.. Allhoff, E . , Werner, M . . Stief, C G . 
Atzpodien, J., Kirchner, Η 
Z u r Bewertung von Therapiestudien 
beim Mammakarzinom 
Sauerbrei, W., Schmoor, C , Schumacher, M . 
297 
303 
Review Articles 
Proliferation Kinetics and Prognosis 
of Renal Cell Carcinoma* 
de Riese. W. , Allhoff, E . , Werner. M . , Stief. C G . , 
Atzpodien, J., Kirchner. Η 
On the Assessment of Quality i n Breast Cancer 
Clinical Trials 
Sauerbrei. W.. Schmoor, C , Schumacher. Μ 
297 
303 
Originalarbeiten 
Etoposid, Leukovorin und 5-Flourouracil ( E L F ) beim 
fortgeschrittenen Magenkarzinom: Abschließende 
Ergebnisse einer Phase-II-Studie bei älteren 
Patienten oder Patienten mit kardialem Risiko* 
Stahl, M . , Wilke, H . , Preusser, P., Fink, U . , Achterrath, W., 
Schöber, C , Köhne-Wömpner , C . H . . Harstrick. Α . , 
Meyer, H.J . , Meyer, J., Lenaz, L . , Schmoll. H.J 314 
Einfluß von Rekombinantem Granulozyten-Makro-
phagen Kolonien-stimulierender Faktor (GM-CSF) 
auf Leukopenie bei A I D S : Eine Untersuchung bei 
sieben Patienten* 
Ottmann, O.G. , Goebel, F . -D. , Ganser, Α . . Bogner. J.R., 
Seipelt, G. , Chatterjee, M . , Helm, E .B . , Hoelzer, D 319 
Chirurgische Therapie bei großen Knochenmetastasen 
i m Becken 
Spring, W., Dit tmer. Η 322 
Prospektive multizentrische Phase-III-Studie m i t 
Doxi f lur id in (5 'dFUR) versus 5-Flourouracil bei 
Patienten mit fortgeschrittenem kolorektalen 
Karzinom* 
Schuster, D . . Heim, M . E . , Dombernowski, P., Wood, C , 
Q u e i ß e r , W 333 
Original Papers 
Etoposide, Leukovorin and 5-Flourouracil ( E L F ) in 
Advanced Gastric Carcinoma - Final Results of a 
Phase-Ii Study in Elderly Patients or Patients w i t h 
Cardiac Risk* 
Stahl. Μ. . Wilke. Η . , Preusser, P., Fink, U . , Achterrath. W.. 
Schöber , C . Köhne -Wömpner , C . H . , Harstrick, Α . , 
Meyer, H.J . , Meyer, J., Lenaz, L . , Schmoll, H.J 314 
Effect of Recombinant Granulocyte-Macrophage 
Colony-Stimulating Factor (GM-CSF) on Leukopenia 
in A I D S : A Study of Seven Cases* 
Ottmann, O.G. . Goebel, F . -D. . Ganser, Α . , Bogner, J.R., 
Seipelt. G. , Chatterjee. M . , Helm, E .B . , Hoelzer, D 319 
Surgical Therapie in Extensive Pelvic Bone 
Metastases 
Spring, W. . Dit tmer. Η 322 
Prospective Multicenter Phase-I l l Trial o f 
D o x i f l u r i d i n (5 'dFUR) versus 5-Flourouracil in 
Patients wi th Advanced Colorectal Carcinoma* 
Schuster, D . , Heim, Μ . Ε . , Dombernowski, Ρ , Wood, C , 
Q u e i ß e r . W 333 
Kurzmitteilungen 
Ansprechraten und Toxizität von Mitomycin-C, 
Mitoxantron und Methotrexat (3M) bei metastiertem 
Mammakarzinom* 
Porzsolt, F., Meuret, G 338 
Schmerztherapie: Vergleich zweier Bestrahlungs-
schemata bei schmerzhaften Knochenmetastasen* 
Karstens, J .H. , Blach. M . . Ammon. J 341 
Immunzytologische Differenzierung zwischen 
Leberzellkarzinom und metastasierendem 
extragonadalem Keimzel l tumor* 
Hastka, J.. Bohrer, M . H . , Hartum*, G. , Verbeke. C S 344 
Short Communications 
Response Rates and Toxicity of Mi tomycin -C , 
Mitoxantrone, and Methotrexate (3M) in Advanced 
Breast Cancer* 
Porzsolt, F., Meinet . G 338 
Pain Management Policy: Comparison of Two 
Irradiat ion Schedules in Metastatic Bone Pain* 
Karstens. J .H. , Blach. M . . Ammon. J 341 
Immunocytological Differentiation of Hepatocellular 
Carcinoma versus Estragonadal Ge r m Cell Tumor* 
Hastka. J.. Bohrer. Μ . Η . . Harums. G. . Verbeke. C S 344 
Onkologie 1991:14:319-321 
Effect of Recombinant Granulocyte-Macrophage Colony-Stimulating 
Factor (GM-CSF) on Leukopenia in AIDS: A Study of Seven Cases 
O.G. Ottmann", F.-D. Goebelb, A. Gamer", J.R. Bognerb, G. Seipelt", M. Chatterjee", E. B. Helm", D. Hoelzer" 
depar tments of Hematology and Infectious Diseases, Kl in ikum der Johann-Wolfgang-Goethe-Univers i tä t , Frankfurt 
bMedizinische Poliklinik der Ludwig-Maximilians-Universi tät , Munich 
Summary and Key Words 
Seven neutropenic patients with the acquired immunodeficiency syn­
drome (AIDS) or AIDS-related complex ( A R C ) were treated with 
recombinant human GM-CSF in an attempt to reverse their 
leukopenia. Overall, treatment was associated with a rapid, substan­
tial increase in neutrophilic granulocytes and a smaller increment in 
eosinophils and monocytes. No significant increase in platelets or 
reticulocytes was observed. Termination of treatment was associated 
with a rapid drop in the leukocyte count. While some patients with 
severely hypoplastic marrows did not respond to GM-CSF treatment, 
azidothymidine- or ganciclovir-induced neutropenia was reversed by 
concomitant administration of GM-CSF in others. This indicates that 
rhGM-CSF may be a valuable adjunct to antiviral therapy in A R C / 
A I D S and requires further testing in controlled trials. 
Colony-stimulating factor - AIDS · Leukopenia · GM-CSF 
Zusammenfassung und Schlüsselwörter 
Sieben neutropene Patienten mit dem erworbenen Immundefizienz-
syndrom (AIDS ) oder AIDS-related Complex wurden mit rekombi-
nantem humanen GM-CSF behandelt mit dem Zie l , ihre Leukopenie 
zu beheben. Insgesamt war die Behandlung assoziiert mit einem 
schnellen, ausgeprägten Anstieg der Neutrophilen und einer geringe­
ren Zunahme der Eosinophilen und Monozyten. Ein signifikanter 
Anstieg der Thrombozyten oder Retikulozyten wurde nicht beobach­
tet. Beendigung der Behandlung ging mit einem schnellen Abfall der 
Leukozytenzahl einher. Während einzelne Patienten mit ausgeprägt 
hypoplastischen Knochenmark nicht auf die rhGM-CSF Behandlung 
ansprachen, ließ sich eine Azidothymidin- oder Ganciclovir-induzierte 
Neutropenie durch gleichzeitige Gabe von rhGM-CSF bei anderen 
Patienten bessern. Diese Befunde deuten daraufhin, daß rhGM-CSF 
ein sinnvolles Adjuvans bei der antiviralen Therapie bei A R C / A I D S 
sein könn te , und eine weitere Überprüfung im Rahmen kontrollierter 
klinischer Studien erforderlich ist. 
Kolonien-Stimulierender Faktor · Leukopenie • AIDS • GM-CSF 
Infection with the human immunodeficiency virus ( H I V ) leads 
to a destruction of the immune defense system resulting in 
various opportunistic and viral infections [ 1 , 2]. Granulocyto­
penia, anemia and thrombocytopenia as additional hematolo­
gic manifestations of the HIV-infektion [3, 4] frequently pre­
clude the use of antiviral, antibiotic and antineoplastic agents 
which by themselves are myelosuppressive. For example, ad­
ministration of A Z T , ganciclovir (DHPG) and trimethoprim-
sulfamethoxazol (Bactrim), is associated with severe hemato-
toxicity in the majority of patients [5-7]. Recombinant human 
granulocyte-macrophage colony-stimulating factors (CSF), 
(rhGM-CSF) stimulates multipotential and various lineage 
restricted progenitor cells in vitro, and enhances the functional 
activity of mature granulocytes and monocytes, and may thus 
function as an integral part of the host's response to infectious 
and immunological challenge [8]. In patients with the acquired 
immune deficiency syndrome ( A I D S ) , administration of 
rhGM-CSF resulted in a dose-dependent increase of periphe­
ral blood leukocyte counts which persisted during the period 
of administration [9]. In a separate study of severely neutrope­
nic patients with CMV-retinitis, the concomitant administra­
tion of rhGM-CSF mitigated the leukopenia and facilitated 
prolonged treatment with ganciclovir with prevention of pro­
gression of retinitis in virtually all patients [10]. This evidence 
supporting a beneficial effect of rhGM-CSF on the hemopoie­
tic function in patients infected with H I V provided the rationa­
le for treating neutropenic patients with A R C / A I D S with 
rhGM-CSF in an attempt to reverse their leukopenia. 
Patients and Methods 
Patients above 18 years of age with a proven HIV-infection were 
eligible for the study after having given informed written consent; the 
study was approved by the local ethics committee. Six of the seven 
currently evaluable patients (five male, two female) had A I D S , one 
patient was in the stage of A R C . The median age was 37 years with a 
range of 29 to 54 years (Table 1). Cause of the leukopenia was prior 
treatment with A Z T (n-3), D H P G (n-2), one patient each had receiv­
ed Cotrimoxazol and no treatment immediately prior to the study, 
respectively. RhGM-CSF (Behringwerke A G , Marburg, FRG) was 
expressed in yeast and given at a dose of 150 Mg/m2 as a daily i. v. 
infusion over 8 hours. Three patients received one, and four patients 
received 2 treatment cycles; the duration of each cycle ranged from 
two to 25 days (Table 2). 
Results and Discussion 
Treatment with rhGM-CSF was associated with a mean 3.4-
fold increase of leukocytes from 1580±220/μ1 pre-treatment to 
5345±100/μ1 after treatment. This increase was due predomi­
nantly to an increase of segmented neutrophilic granulocytes 
320 Ottman/Goebel/Ganser/Bogner/Seipelt/Chatterjee/Helm/Hoelzer 
Table 1. Patient characteristics 
Number of Patients 7 
male/female 5/2 
Age (years): median 37 
range (29-54) 
Stage: A R C 1 
A I D S 6 
Concomitant therapy: 
A Z T 3 
D H P G 2 
Cotrimoxazol 1 
A R C : AIDS-related complex: A I D S : acquired immunedeficiency 
syndrome; A Z T : azidothymidine; D H P G : Ganciclovir. 
from 1115±174/μ1 to 4521±100/μ1 (mean ± SEM). The effect 
of rhGM-CSF on the different leukocyte subpopulations and 
the response kinetics are exemplified in figure 1: there was a 
small increment in bands, eosinophils and monocytes, the 
major response resulting from the increase in mature neutro­
phils. There was no significant increase in platelets or reticulo­
cytes. Typically, the increase in WBC was rapid, occurring 
within a few days of rhGM-CSF administration; after termina­
tion of treatment, there was a rapid decline of the WBC. 
Essentially no response was seen in three patients who receiv­
ed one treatment cycle (F10, F14, F15) and during the first of 
two cycles in one additional patient (M2) (Table 2). While 
rhGM-CSF was given for only 2 days in one of these patients, 
the lack of response can not be attributed to an insufficient 
treatment duration in the others. A l l of these patients had 
severely hypoplastic bone marrows, however, suggesting that 
the degree of pre-existing bone marrow damage may deter­
mine the response to rhGM-CSF. In addition, A Z T or Cotri­
moxazol given as concomitant medication during the treat­
ment could have been responsible for the lack of hematologi­
cal response. Since progenitor cells in A I D S have been shown 
to be more sensitive to inhibition by A Z T and appear to 
require higher concentrations of GM-CSF than progenitors 
Table 2. Response to treatment with rhGM-CSF 
Pat. Dose Days WBC/μΙ Neutroph. /μ ΐ 
before after before after 
F10 150 2 1.4 1.7 1.04 1.07 
F14 150* 10 1.2 1.8 0.73 0.66 
F15 150* 8 2.4 2.6 1.68 1.38 
M l 150* 25 1.5 11.2 0.65 9.97 
150* 5 1.9 8.4 1.58 7.48 
M2 150** 14 0.9 0.7 0.59 0.29 
150 7 1.5 7.7 1.26 6.51 
M3 150*** 14 1.2 4.6 0.97 3.50 
150*** 6 3.3 5.5 2.41 4.84 
M4 150*** 14 0.9 6.7 0.54 6.60 
150*** 7 1.2 7.9 0.82 7.43 
Concomitant medication: * A Z T ; **Cotrimoxazole; ***DHPG 
from healthy controls [11-13], some initially unresponsive 
leukopenic patients receiving A Z T might have benefitted from 
rhGM-CSF administration at a higher dose level. The feasibili­
ty of reversing granulocytopenia during concomitant treat­
ment with myelotoxic antiviral agents is clearly demonstrated 
by the patients receiving D H P G (M3, M4) or A Z T (M2) 
(Table 2), each of whom responded with a pronounced increa­
se of granuloctes during two successive cycles of rhGM-CSF, 
with a return to near baseline levels after termination of 
rhGM-CSF. Mi ld fever and prostration (WHO-grade I - I I ) 
were the predominant side effects. More severe reactions 
(fever to 40°C, chills and rigors) were observed only rarely and 
appeared to occur primarily in patients with concurrent infec­
tions. Since GM-CSF given alone might potentiate viral pro­
duction in monocytes yet enhances the antiviral activity of 
A Z T [14], GM-CSF therapy should probably be combined 
with A Z T whenever possible. 
Overall, these data in addition to the results reported by 
Groopman et al. [9] indicate that rhGM-CSF is a potentially 
valuable adjunct to antiviral therapy in patients with A R C / 
A I D S , and requires further testing in controlled trials. 
Days 
Fig. 1. Typical example of the W B C response in a patient treated with 
rhGM-CSF. The open bar at top of the figure indicates administration 
of rhGM-CSF, given as a slow i.v. infusion. Vertical axis reflects the 
leukocyte count x 103/μ,1. A pronounced increase in total leukocytes, 
predominantly segmented neutrophils, occurs within days of initiation 
of rhGM-CSF. Smaller increments are seen for bands, eosinophils and 
neutrophils. 
References 
1 Fauci AS: The human immunodeficiency virus: Infectivity and 
mechanisms of pathogenesis. Science 1988;239:617. 
2 Center For Disease Control. : Revision of the case definition for 
acquired immunodeficiency syndrome. M M W R 36:IS, 1987. 
3 Ganser A : Abnormalities of hematopoiesis in the aquired im­
munodeficiency syndrome. Blut 1988;56:49. 
4 Zon L I , A r k i n C, Groopman JE: Hematologic manifestations of 
the human immune deficiency virus ( H I V ) . Br J Haematol 
1987:66:251. 
5 Fischl M A , Richman D D , Grieco M H , Gottlieb MS, Volberding 
PA, Laskin O L , Leedom J M , Groopman JE, Mildvan D , Schooley 
RT, Jackson JJ, Durack DT, King D , and A Z T Collaborative 
Working Group: The efficacy of azidothymidine ( A Z T ) in the 
treatment of patients with A I D S and AIDS-related complex. 
Ν Engl J Med 1987:317:185. 
6 Richman D D , Fischl M A , Grieco M H , Gottlieb MS, Volberding 
PA, Laskin O L , Leedom J M , Groopman JE, Mildvan D , Hirsch 
MS, Jackson G G , Durack DT, Nusinoff-Lehrman S, and the A Z T 
Collaborative Working Group: The toxicity of azidothymidine 
( A Z T ) in the treatment of patients with A I D S and AIDS-related 
complex. Ν Engl J Med 1987;317:192. 
Effect of Recombinant GM-CSF on Leukopenia in A I D S 
7 Jaffe HS, Abrams D I , Ammann A J , Lewis BJ, Golden JA: 
Complications of co-trimoxazole in treatment of AIDS-associated 
Pneumocystis carinii pneumonia in homosexual men. Lancet 
1983;ii:1109. 
8 Weisbart R H , Golde D W , Clark SC, Wong GC, Gasson JC: 
Human granulocyte-macrophage colony-stimulating factor is a 
neurophil activator. Nature 1985;314:361. 
9 Groopman JE, Mitsuyasu RT, DeLeo M J , Oette D H , and Golde 
D W : Effect of recombinant human granulocyte-macrophage colo­
ny-stimulating factor on myelopoiesis in the acquired immunodefi­
ciency syndrome. Ν Engl J Med 1987;317:593. 
10 Grossberg HS, Bonnern E M , Bühles W C Jr: GM-CSF with 
ganciclovir for the treatment of C M V retinitis in A I D S (letter). 
Ν Engl J Med 1989;320:1560. 
11 Carlo-Stella C, Ganser A , Hoelzer D : Defective in vitro growth of 
the hemopoietic progenitor cells in the acquired immunodeficiency 
syndrome. J Clin Invest 1987;80:286. 
12 Ganser A , Greher J, Völkers Β , Staszewski S, Hoelzer D : Azido-
thymidine in the treatment of A I D S . Ν Engl J Med 1988;318:250. 
13 Ganser A , Greher J, Völkers Β , Staszewski S, Hoelzer D : Inhibi­
tory effect of azidothymidine, 2'-3'-dideoxyadenosine and 2'-3'-
dideoxycytidine on in vitro growth of hematopoietic progenitor 
cells from normal persons and from patients with A I D S . Exp 
Hematol 1989;17:321. 
14 Perno CF, Yarchoan R, Cooney D A , Hartmen NR, Webb D S A , 
Hao Z , Mitsuya H , Johns D G , Brodre S: Replication of human 
immunodeficiency virus in monocytes: Granulocyte/macrophage 
colony stimulating factor (GM-CSF) potentiates viral production 
yet enhances the antiviral effect mediated by 3'-azido-2\ 3'-
dideoxythymidine ( A Z T ) and other dideoxynucleoside congeners 
of thymidin. J Exp Med 1989; 169:933. 
Requests for reprints to: 
Dr . O.G. Ottmann 
Abteilung für Hämatologie 
Zentrum der Inneren Medizin 
Klinikum der Johann-Wolfgang-Goethe-Univers i tä t 
Theodor-Stern-Kai 7 
D-6000 Frankfurt 70 (FRG) 


Effect of remobinant granulocyte-macrophage colony stimulating factor (GM-CSF) on leukopenia in AIDS

Open Access LMU

Internationale Zeitschrift für Krebsforschung und -behandlung Band 14, Heft 4, August 1991 Inhalt Contents Ubersichtsarbeiten Proliferationskinetik und Prognose eines Nierenzellkarzinoms* de Riese, W.. Allhoff, E . , Werner, M . . Stief, C G . Atzpodien, J., Kirchner, Η Z u r Bewertung von Therapiestudien beim Mammakarzinom Sauerbrei, W., Schmoor, C , Schumacher, M . 297 303 Review Articles Proliferation Kinetics and Prognosis of Renal Cell Carcinoma* de Riese. W. , Allhoff, E . , Werner. M . , Stief. C G . , Atzpodien, J., Kirchner. Η On the Assessment of Quality i n Breast Cancer Clinical Trials Sauerbrei. W.. Schmoor, C , Schumacher. Μ 297 303 Originalarbeiten Etoposid, Leukovorin und 5-Flourouracil ( E L F ) beim fortgeschrittenen Magenkarzinom: Abschließende Ergebnisse einer Phase-II-Studie bei älteren Patienten oder Patienten mit kardialem Risiko* Stahl, M . , Wilke, H . , Preusser, P., Fink, U . , Achterrath, W., Schöber, C , Köhne-Wömpner , C . H . . Harstrick. Α . , Meyer, H.J . , Meyer, J., Lenaz, L . , Schmoll. H.J 314 Einfluß von Rekombinantem Granulozyten-Makro-phagen Kolonien-stimulierender Faktor (GM-CSF) auf Leukopenie bei A I D S : Eine Untersuchung bei sieben Patienten* Ottmann, O.G. , Goebel, F . -D. , Ganser, Α . . Bogner. J.R., Seipelt, G. , Chatterjee, M . , Helm, E .B . , Hoelzer, D 319 Chirurgische Therapie bei großen Knochenmetastasen i m Becken Spring, W., Dit tmer. Η 322 Prospektive multizentrische Phase-III-Studie m i t Doxi f lur id in (5 'dFUR) versus 5-Flourouracil bei Patienten mit fortgeschrittenem kolorektalen Karzinom* Schuster, D . . Heim, M . E . , Dombernowski, P., Wood, C , Q u e i ß e r , W 333 Original Papers Etoposide, Leukovorin and 5-Flourouracil ( E L F ) in Advanced Gastric Carcinoma - Final Results of a Phase-Ii Study in Elderly Patients or Patients w i t h Cardiac Risk* Stahl. Μ. . Wilke. Η . , Preusser, P., Fink, U . , Achterrath. W.. Schöber , C . Köhne -Wömpner , C . H . , Harstrick, Α . , Meyer, H.J . , Meyer, J., Lenaz, L . , Schmoll, H.J 314 Effect of Recombinant Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) on Leukopenia in A I D S : A Study of Seven Cases* Ottmann, O.G. . Goebel, F . -D. . Ganser, Α . , Bogner, J.R., Seipelt. G. , Chatterjee. M . , Helm, E .B . , Hoelzer, D 319 Surgical Therapie in Extensive Pelvic Bone Metastases Spring, W. . Dit tmer. Η 322 Prospective Multicenter Phase-I l l Trial o f D o x i f l u r i d i n (5 'dFUR) versus 5-Flourouracil in Patients wi th Advanced Colorectal Carcinoma* Schuster, D . , Heim, Μ . Ε . , Dombernowski, Ρ , Wood, C , Q u e i ß e r . W 333 Kurzmitteilungen Ansprechraten und Toxizität von Mitomycin-C, Mitoxantron und Methotrexat (3M) bei metastiertem Mammakarzinom* Porzsolt, F., Meuret, G 338 Schmerztherapie: Vergleich zweier Bestrahlungs-schemata bei schmerzhaften Knochenmetastasen* Karstens, J .H. , Blach. M . . Ammon. J 341 Immunzytologische Differenzierung zwischen Leberzellkarzinom und metastasierendem extragonadalem Keimzel l tumor* Hastka, J.. Bohrer, M . H . , Hartum*, G. , Verbeke. C S 344 Short Communications Response Rates and Toxicity of Mi tomycin -C , Mitoxantrone, and Methotrexate (3M) in Advanced Breast Cancer* Porzsolt, F., Meinet . G 338 Pain Management Policy: Comparison of Two Irradiat ion Schedules in Metastatic Bone Pain* Karstens. J .H. , Blach. M . . Ammon. J 341 Immunocytological Differentiation of Hepatocellular Carcinoma versus Estragonadal Ge r m Cell Tumor* Hastka. J.. Bohrer. Μ . Η . . Harums. G. . Verbeke. C S 344 Onkologie 1991:14:319-321 Effect of Recombinant Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) on Leukopenia in AIDS: A Study of Seven Cases O.G. Ottmann", F.-D. Goebelb, A. Gamer", J.R. Bognerb, G. Seipelt", M. Chatterjee", E. B. Helm", D. Hoelzer" depar tments of Hematology and Infectious Diseases, Kl in ikum der Johann-Wolfgang-Goethe-Univers i tä t , Frankfurt bMedizinische Poliklinik der Ludwig-Maximilians-Universi tät , Munich Summary and Key Words Seven neutropenic patients with the acquired immunodeficiency syn­drome (AIDS) or AIDS-related complex ( A R C ) were treated with recombinant human GM-CSF in an attempt to reverse their leukopenia. Overall, treatment was associated with a rapid, substan­tial increase in neutrophilic granulocytes and a smaller increment in eosinophils and monocytes. No significant increase in platelets or reticulocytes was observed. Termination of treatment was associated with a rapid drop in the leukocyte count. While some patients with severely hypoplastic marrows did not respond to GM-CSF treatment, azidothymidine- or ganciclovir-induced neutropenia was reversed by concomitant administration of GM-CSF in others. This indicates that rhGM-CSF may be a valuable adjunct to antiviral therapy in A R C / A I D S and requires further testing in controlled trials. Colony-stimulating factor - AIDS · Leukopenia · GM-CSF Zusammenfassung und Schlüsselwörter Sieben neutropene Patienten mit dem erworbenen Immundefizienz-syndrom (AIDS ) oder AIDS-related Complex wurden mit rekombi-nantem humanen GM-CSF behandelt mit dem Zie l , ihre Leukopenie zu beheben. Insgesamt war die Behandlung assoziiert mit einem schnellen, ausgeprägten Anstieg der Neutrophilen und einer geringe­ren Zunahme der Eosinophilen und Monozyten. Ein signifikanter Anstieg der Thrombozyten oder Retikulozyten wurde nicht beobach­tet. Beendigung der Behandlung ging mit einem schnellen Abfall der Leukozytenzahl einher. Während einzelne Patienten mit ausgeprägt hypoplastischen Knochenmark nicht auf die rhGM-CSF Behandlung ansprachen, ließ sich eine Azidothymidin- oder Ganciclovir-induzierte Neutropenie durch gleichzeitige Gabe von rhGM-CSF bei anderen Patienten bessern. Diese Befunde deuten daraufhin, daß rhGM-CSF ein sinnvolles Adjuvans bei der antiviralen Therapie bei A R C / A I D S sein könn te , und eine weitere Überprüfung im Rahmen kontrollierter klinischer Studien erforderlich ist. Kolonien-Stimulierender Faktor · Leukopenie • AIDS • GM-CSF Infection with the human immunodeficiency virus ( H I V ) leads to a destruction of the immune defense system resulting in various opportunistic and viral infections [ 1 , 2]. Granulocyto­penia, anemia and thrombocytopenia as additional hematolo­gic manifestations of the HIV-infektion [3, 4] frequently pre­clude the use of antiviral, antibiotic and antineoplastic agents which by themselves are myelosuppressive. For example, ad­ministration of A Z T , ganciclovir (DHPG) and trimethoprim-sulfamethoxazol (Bactrim), is associated with severe hemato-toxicity in the majority of patients [5-7]. Recombinant human granulocyte-macrophage colony-stimulating factors (CSF), (rhGM-CSF) stimulates multipotential and various lineage restricted progenitor cells in vitro, and enhances the functional activity of mature granulocytes and monocytes, and may thus function as an integral part of the host's response to infectious and immunological challenge [8]. In patients with the acquired immune deficiency syndrome ( A I D S ) , administration of rhGM-CSF resulted in a dose-dependent increase of periphe­ral blood leukocyte counts which persisted during the period of administration [9]. In a separate study of severely neutrope­nic patients with CMV-retinitis, the concomitant administra­tion of rhGM-CSF mitigated the leukopenia and facilitated prolonged treatment with ganciclovir with prevention of pro­gression of retinitis in virtually all patients [10]. This evidence supporting a beneficial effect of rhGM-CSF on the hemopoie­tic function in patients infected with H I V provided the rationa­le for treating neutropenic patients with A R C / A I D S with rhGM-CSF in an attempt to reverse their leukopenia. Patients and Methods Patients above 18 years of age with a proven HIV-infection were eligible for the study after having given informed written consent; the study was approved by the local ethics committee. Six of the seven currently evaluable patients (five male, two female) had A I D S , one patient was in the stage of A R C . The median age was 37 years with a range of 29 to 54 years (Table 1). Cause of the leukopenia was prior treatment with A Z T (n-3), D H P G (n-2), one patient each had receiv­ed Cotrimoxazol and no treatment immediately prior to the study, respectively. RhGM-CSF (Behringwerke A G , Marburg, FRG) was expressed in yeast and given at a dose of 150 Mg/m2 as a daily i. v. infusion over 8 hours. Three patients received one, and four patients received 2 treatment cycles; the duration of each cycle ranged from two to 25 days (Table 2). Results and Discussion Treatment with rhGM-CSF was associated with a mean 3.4-fold increase of leukocytes from 1580±220/μ1 pre-treatment to 5345±100/μ1 after treatment. This increase was due predomi­nantly to an increase of segmented neutrophilic granulocytes 320 Ottman/Goebel/Ganser/Bogner/Seipelt/Chatterjee/Helm/Hoelzer Table 1. Patient characteristics Number of Patients 7 male/female 5/2 Age (years): median 37 range (29-54) Stage: A R C 1 A I D S 6 Concomitant therapy: A Z T 3 D H P G 2 Cotrimoxazol 1 A R C : AIDS-related complex: A I D S : acquired immunedeficiency syndrome; A Z T : azidothymidine; D H P G : Ganciclovir. from 1115±174/μ1 to 4521±100/μ1 (mean ± SEM). The effect of rhGM-CSF on the different leukocyte subpopulations and the response kinetics are exemplified in figure 1: there was a small increment in bands, eosinophils and monocytes, the major response resulting from the increase in mature neutro­phils. There was no significant increase in platelets or reticulo­cytes. Typically, the increase in WBC was rapid, occurring within a few days of rhGM-CSF administration; after termina­tion of treatment, there was a rapid decline of the WBC. Essentially no response was seen in three patients who receiv­ed one treatment cycle (F10, F14, F15) and during the first of two cycles in one additional patient (M2) (Table 2). While rhGM-CSF was given for only 2 days in one of these patients, the lack of response can not be attributed to an insufficient treatment duration in the others. A l l of these patients had severely hypoplastic bone marrows, however, suggesting that the degree of pre-existing bone marrow damage may deter­mine the response to rhGM-CSF. In addition, A Z T or Cotri­moxazol given as concomitant medication during the treat­ment could have been responsible for the lack of hematologi­cal response. Since progenitor cells in A I D S have been shown to be more sensitive to inhibition by A Z T and appear to require higher concentrations of GM-CSF than progenitors Table 2. Response to treatment with rhGM-CSF Pat. Dose Days WBC/μΙ Neutroph. /μ ΐ before after before after F10 150 2 1.4 1.7 1.04 1.07 F14 150* 10 1.2 1.8 0.73 0.66 F15 150* 8 2.4 2.6 1.68 1.38 M l 150* 25 1.5 11.2 0.65 9.97 150* 5 1.9 8.4 1.58 7.48 M2 150** 14 0.9 0.7 0.59 0.29 150 7 1.5 7.7 1.26 6.51 M3 150*** 14 1.2 4.6 0.97 3.50 150*** 6 3.3 5.5 2.41 4.84 M4 150*** 14 0.9 6.7 0.54 6.60 150*** 7 1.2 7.9 0.82 7.43 Concomitant medication: * A Z T ; **Cotrimoxazole; ***DHPG from healthy controls [11-13], some initially unresponsive leukopenic patients receiving A Z T might have benefitted from rhGM-CSF administration at a higher dose level. The feasibili­ty of reversing granulocytopenia during concomitant treat­ment with myelotoxic antiviral agents is clearly demonstrated by the patients receiving D H P G (M3, M4) or A Z T (M2) (Table 2), each of whom responded with a pronounced increa­se of granuloctes during two successive cycles of rhGM-CSF, with a return to near baseline levels after termination of rhGM-CSF. Mi ld fever and prostration (WHO-grade I - I I ) were the predominant side effects. More severe reactions (fever to 40°C, chills and rigors) were observed only rarely and appeared to occur primarily in patients with concurrent infec­tions. Since GM-CSF given alone might potentiate viral pro­duction in monocytes yet enhances the antiviral activity of A Z T [14], GM-CSF therapy should probably be combined with A Z T whenever possible. Overall, these data in addition to the results reported by Groopman et al. [9] indicate that rhGM-CSF is a potentially valuable adjunct to antiviral therapy in patients with A R C / A I D S , and requires further testing in controlled trials. Days Fig. 1. Typical example of the W B C response in a patient treated with rhGM-CSF. The open bar at top of the figure indicates administration of rhGM-CSF, given as a slow i.v. infusion. Vertical axis reflects the leukocyte count x 103/μ,1. A pronounced increase in total leukocytes, predominantly segmented neutrophils, occurs within days of initiation of rhGM-CSF. Smaller increments are seen for bands, eosinophils and neutrophils. References 1 Fauci AS: The human immunodeficiency virus: Infectivity and mechanisms of pathogenesis. Science 1988;239:617. 2 Center For Disease Control. : Revision of the case definition for acquired immunodeficiency syndrome. M M W R 36:IS, 1987. 3 Ganser A : Abnormalities of hematopoiesis in the aquired im­munodeficiency syndrome. Blut 1988;56:49. 4 Zon L I , A r k i n C, Groopman JE: Hematologic manifestations of the human immune deficiency virus ( H I V ) . Br J Haematol 1987:66:251. 5 Fischl M A , Richman D D , Grieco M H , Gottlieb MS, Volberding PA, Laskin O L , Leedom J M , Groopman JE, Mildvan D , Schooley RT, Jackson JJ, Durack DT, King D , and A Z T Collaborative Working Group: The efficacy of azidothymidine ( A Z T ) in the treatment of patients with A I D S and AIDS-related complex. Ν Engl J Med 1987:317:185. 6 Richman D D , Fischl M A , Grieco M H , Gottlieb MS, Volberding PA, Laskin O L , Leedom J M , Groopman JE, Mildvan D , Hirsch MS, Jackson G G , Durack DT, Nusinoff-Lehrman S, and the A Z T Collaborative Working Group: The toxicity of azidothymidine ( A Z T ) in the treatment of patients with A I D S and AIDS-related complex. Ν Engl J Med 1987;317:192. Effect of Recombinant GM-CSF on Leukopenia in A I D S 7 Jaffe HS, Abrams D I , Ammann A J , Lewis BJ, Golden JA: Complications of co-trimoxazole in treatment of AIDS-associated Pneumocystis carinii pneumonia in homosexual men. Lancet 1983;ii:1109. 8 Weisbart R H , Golde D W , Clark SC, Wong GC, Gasson JC: Human granulocyte-macrophage colony-stimulating factor is a neurophil activator. Nature 1985;314:361. 9 Groopman JE, Mitsuyasu RT, DeLeo M J , Oette D H , and Golde D W : Effect of recombinant human granulocyte-macrophage colo­ny-stimulating factor on myelopoiesis in the acquired immunodefi­ciency syndrome. Ν Engl J Med 1987;317:593. 10 Grossberg HS, Bonnern E M , Bühles W C Jr: GM-CSF with ganciclovir for the treatment of C M V retinitis in A I D S (letter). Ν Engl J Med 1989;320:1560. 11 Carlo-Stella C, Ganser A , Hoelzer D : Defective in vitro growth of the hemopoietic progenitor cells in the acquired immunodeficiency syndrome. J Clin Invest 1987;80:286. 12 Ganser A , Greher J, Völkers Β , Staszewski S, Hoelzer D : Azido-thymidine in the treatment of A I D S . Ν Engl J Med 1988;318:250. 13 Ganser A , Greher J, Völkers Β , Staszewski S, Hoelzer D : Inhibi­tory effect of azidothymidine, 2'-3'-dideoxyadenosine and 2'-3'-dideoxycytidine on in vitro growth of hematopoietic progenitor cells from normal persons and from patients with A I D S . Exp Hematol 1989;17:321. 14 Perno CF, Yarchoan R, Cooney D A , Hartmen NR, Webb D S A , Hao Z , Mitsuya H , Johns D G , Brodre S: Replication of human immunodeficiency virus in monocytes: Granulocyte/macrophage colony stimulating factor (GM-CSF) potentiates viral production yet enhances the antiviral effect mediated by 3'-azido-2\ 3'-dideoxythymidine ( A Z T ) and other dideoxynucleoside congeners of thymidin. J Exp Med 1989; 169:933. Requests for reprints to: Dr . O.G. Ottmann Abteilung für Hämatologie Zentrum der Inneren Medizin Klinikum der Johann-Wolfgang-Goethe-Univers i tä t Theodor-Stern-Kai 7 D-6000 Frankfurt 70 (FRG) 

Abnormalities of hematopoiesis in the aquired im munodeficiency syndrome. Blut

and AZT Collaborative Working Group: The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex.

and the AZT Collaborative Working Group: The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex.

Bühles WC Jr: GM-CSF with ganciclovir for the treatment of CMV retinitis in AIDS (letter).

Disease Control.: Revision of the case definition for acquired immunodeficiency syndrome.

Effect of recombinant human granulocyte-macrophage colo ny-stimulating factor on myelopoiesis in the acquired immunodefi ciency syndrome.

Groopman JE: Hematologic manifestations of the human immune deficiency virus (HIV).

Hoelzer D: Azidothymidine in the treatment of AIDS.

Hoelzer D: Defective in vitro growth of the hemopoietic progenitor cells in the acquired immunodeficiency syndrome.

Hoelzer D: Inhibi tory effect of azidothymidine, 2'-3'-dideoxyadenosine and 2'-3'-dideoxycytidine on in vitro growth of hematopoietic progenitor cells from normal persons and from patients with AIDS. Exp Hematol

JA: Complications of co-trimoxazole in treatment of AIDS-associated Pneumocystis carinii pneumonia in homosexual men.

JC: Human granulocyte-macrophage colony-stimulating factor is a neurophil activator.

The human immunodeficiency virus: Infectivity and mechanisms of pathogenesis.

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Effect of remobinant granulocyte-macrophage colony stimulating factor (GM-CSF) on leukopenia in AIDS

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