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Granulocyte colony-stimulating factor and congenital neutropenia-risk of leukemia?
The Journal of Pediatrics Volume 129, Number 1
Editorial correspondence
range; both infants had a very prolonged capillary filling time (>5 seconds). Because of the cardiomegaly and the poor ejection fraction, the patients were given dopamine at an initial infusion rate of 3 pg/kg per hour. Both infants had a more severe hypertension and had increasing oxygen requirements; additional echocardiograms revealed a disappearance of the left-to-right shunting, with an exclusive right-to-left shunting. We subsequently treated both infants with afterload reducing agents (nitroprusside) for several days; we observed a significant and immediate improvement of the hypertension, with a reversal of the shunting from a right-to-left shunt to a left-to-right shunt; the cardiac function also improved, with rapid increases in the ejection fraction. Oxygen requirements decreased and the infants were weaned from the ventilator within a few days. Ductal closure occurred spontaneously, also within a few days. Both infants survived and were discharged after several weeks with adequate cardiac function. We suspect that during chronic TTS the recipient twin may have significant vasoconstriction (both pulmonary and systemic), presumably in an attempt to resist chronic hypervolemia. The cardiac hypertrophy that develops prenatally is a response to this high peripheral vascular resistance. We hypothesize that our initial management with inotropic agents led to further vasoconstriction, aggravating the systemic and, even more so, the pulmonary hypertension. In contrast, the use of afterload reducers may be the management of choice in such patients because it produces a pro;ressive systemic and pulmonary vessel relaxation, with subsequent maprovement in cardiac function. These difficult-to-treat patients can be identified prenatally by paying careful attention to cardiac findings in the recipient. 2 By doing so, proper management can be effected soon after birth.
Francis B. Mimouni, MD Department of Pediatrics Maimonides Medical Center Brooklyn, NY 11219 F. S. Sherman, MD Magee Women's Hospital Pittsburgh, PA 15217 9/35/73303 REFERENCES
1. Lopriore E, Vandenbussche FPHA, Tiersma ESM, de Beaufort AJ, de Leeuw JP. Twin-to-twin transfusion syndrome: new perspectives. J Pediatr 1995;127:675-80. 2. Molina RD, Sherman FS, Laifer S. Fetal echocardiography in the twin transfusion syndrome (TTS) [abstract]. Am J Obstet Gynecol 1993;168:382A.
Granulocyte colony-stimulating factor and congenital neutropenia--risk of leukemia? To the Editor." We wish to describe a child in whom monosomy 7 developed during therapy with granulocyte colony-stimulating factor (G-CSF) for severe congenital neutropenia (SCN). This child's case and re-
187
cent published reports 1' 2 should raise further concern about the safety of hematopoietic growth factors in patients with a dysfunctional bone marrow. A 14-year-old boy was diagnosed in the neonatal period with Kostmann syndrome (severe congenital neutropenia). His leukocyte count was 5.5 × 103/ram 3, with an absolute neutrophil count of 55/ mm 3. After 8 years complicated by recurrent oral infections treated with antibiotics, a regimen of recombinant human G-CSF was begun. A bone marrow examination performed before the start of this therapy had a normal 46,XY karyotype. Five years later, anemia and thrombocytopenia developed in association with splenomegaly. A bone marrow biopsy showed hypercellularity with 10% blasts. The karyotype was 46,XY,-7,+21[ll]/46,XY[7] (reference 3). Two months after G-CSF therapy was stopped, the karyotype was 46,XY[15]/46,XY,-7,+21[I]. Seven months after cessation, acute myelogenous leukemia was present, with the dominant karyotype showing monosomy 7 and trisomy 21. The patient was subsequently treated with allogeneic bone marrow transplantation and reestablishment of a normal karyotype. He then died of complications associated with chronic graft-versus-host disease. It is not known whether the children reported by Weinblatt et al.1 or Smith et al.2 had abnormal G-CSF receptors, which might have served as a "first hit" for possible G-CSF-accelerated leukemogenesis. In our patient, reverse-transcribedpolymerase chain reaction amplification of the transmembrane and cytosolic domains was performed, and DNA sequencing showed a silent polymorphism. Therefore our patient with SCN did not have a "first hit," which would increase the risk of leukemogenesis. It is possible that he had a genetic defect in some other critical granulopoietic signaling molecule. On the basis of the patients with SCN in whom leukemia developed during G-CSF therapy in association with congenital mutant G-CSF receptors,4 those who acquired monosomy 7,1, 2 and our own experience with an affected child, we cannot be as sanguine as the New England Journal of Medicine editorial that clinical benefits of G-CSF "clearly outweigh" the hazards of leukemogenesis. 5 Further studies into the basic mechanisms of granulopoiesis and the use of an animal model to compare the effects of G-CSF versus granulocyte-macrophage colony-stimulating factor are warranted. Until then, these data should give pause to clinicians administering growth factor to patients with congenital bone marrow failure syndromes. Until an animal model can address the effect of G-CSF on a mutated receptor, patients with SCN and mutation of the G-CSF receptor should be given GM-CSF. This may not necessarily prevent the development of monosomy 7.
Seth J. Corey, MD, MPH Assistant Professor of Pediatrics and Pharmacology Michael R. Wollman, MD Associate Professor of Pediatrics Children's Hospital of Pittsburgh University of Pittsburgh School of Medicine Pittsburgh, PA 15213-2583 Rajendra V. Deshpande, PhD James Ewing Laboratory of Developmental Hematopoiesis Memorial Sloan-Kettering Cancer Center New York, NY 10021 9/35/73470
18 8
Editorial correspondence
The Journal of Pediatrics July 1996
REFERENCES
1. Weinblatt ME, Scimeca P, James-Herry A, Sahdev I, Kochen J. Transformationof congenital neutropenia into monosomy 7 and acute nonlymphoblastic leukemia in a child treated with granulocyte colony-stimulating factor. J Pediatr 1995;126: 263-5. 2. Smith OP, Reeves BR, Kempski HM, Evans JP. Kostmann's disease, recombinantHuG-CSF,monosomy7 and MDS/AML. Br J Haematol 1995;91:150-3. 3. Shekhter-Levin S, Penchansky L, Wollman MR, Shere ME, Wald N, Gotlin SM. An abnormalclone with monosomy 7 and
trisomy 21 in the bone marrow of a child with congenitalagranulocytosis (Kostmanndisease) treated with granulocytecolonystimulatingfactor. Cancer Genet Cytogenet. 1995;84:99-104. 4. Dong F, Byrnes RK, Tidow N, Welte K, Lowenberg B, Touw IP. Mutations in the gene for the granulocyte colony-stimulating factor receptor in patients with acute myeloid leukemia preceded by severecongenitalneutropenia.N Engl J Med 1995; 333:487-93. 5. Naparstek E. Granulocyte colony-stimulatingfactor, congenital neutropenia, and acute myeloid leukemia. N Engl J Med 1995;333:516-8.
CORRECTION In the article "Comparative Safety and Efficacy of Two Immune Globulin Products in Kawasaki Disease," by Rosenfeld et al., which appeared in the June 1995 issue of The Journal (volume 126, pages 1000 to 1003), Table I contains two errors under the column head "Product A": The preparation of Product A should read as follows: "Cold ethanol-PEG fractionation, DEAE-Sephadex treatment, not plasmin digested." The formulation of Product A should read as follows: "5% IgG with 2% manitol, 1% albumin; lyophilized."
Editorial correspondence
range; both infants had a very prolonged capillary filling time (>5 seconds). Because of the cardiomegaly and the poor ejection fraction, the patients were given dopamine at an initial infusion rate of 3 pg/kg per hour. Both infants had a more severe hypertension and had increasing oxygen requirements; additional echocardiograms revealed a disappearance of the left-to-right shunting, with an exclusive right-to-left shunting. We subsequently treated both infants with afterload reducing agents (nitroprusside) for several days; we observed a significant and immediate improvement of the hypertension, with a reversal of the shunting from a right-to-left shunt to a left-to-right shunt; the cardiac function also improved, with rapid increases in the ejection fraction. Oxygen requirements decreased and the infants were weaned from the ventilator within a few days. Ductal closure occurred spontaneously, also within a few days. Both infants survived and were discharged after several weeks with adequate cardiac function. We suspect that during chronic TTS the recipient twin may have significant vasoconstriction (both pulmonary and systemic), presumably in an attempt to resist chronic hypervolemia. The cardiac hypertrophy that develops prenatally is a response to this high peripheral vascular resistance. We hypothesize that our initial management with inotropic agents led to further vasoconstriction, aggravating the systemic and, even more so, the pulmonary hypertension. In contrast, the use of afterload reducers may be the management of choice in such patients because it produces a pro;ressive systemic and pulmonary vessel relaxation, with subsequent maprovement in cardiac function. These difficult-to-treat patients can be identified prenatally by paying careful attention to cardiac findings in the recipient. 2 By doing so, proper management can be effected soon after birth.
Francis B. Mimouni, MD Department of Pediatrics Maimonides Medical Center Brooklyn, NY 11219 F. S. Sherman, MD Magee Women's Hospital Pittsburgh, PA 15217 9/35/73303 REFERENCES
1. Lopriore E, Vandenbussche FPHA, Tiersma ESM, de Beaufort AJ, de Leeuw JP. Twin-to-twin transfusion syndrome: new perspectives. J Pediatr 1995;127:675-80. 2. Molina RD, Sherman FS, Laifer S. Fetal echocardiography in the twin transfusion syndrome (TTS) [abstract]. Am J Obstet Gynecol 1993;168:382A.
Granulocyte colony-stimulating factor and congenital neutropenia--risk of leukemia? To the Editor." We wish to describe a child in whom monosomy 7 developed during therapy with granulocyte colony-stimulating factor (G-CSF) for severe congenital neutropenia (SCN). This child's case and re-
187
cent published reports 1' 2 should raise further concern about the safety of hematopoietic growth factors in patients with a dysfunctional bone marrow. A 14-year-old boy was diagnosed in the neonatal period with Kostmann syndrome (severe congenital neutropenia). His leukocyte count was 5.5 × 103/ram 3, with an absolute neutrophil count of 55/ mm 3. After 8 years complicated by recurrent oral infections treated with antibiotics, a regimen of recombinant human G-CSF was begun. A bone marrow examination performed before the start of this therapy had a normal 46,XY karyotype. Five years later, anemia and thrombocytopenia developed in association with splenomegaly. A bone marrow biopsy showed hypercellularity with 10% blasts. The karyotype was 46,XY,-7,+21[ll]/46,XY[7] (reference 3). Two months after G-CSF therapy was stopped, the karyotype was 46,XY[15]/46,XY,-7,+21[I]. Seven months after cessation, acute myelogenous leukemia was present, with the dominant karyotype showing monosomy 7 and trisomy 21. The patient was subsequently treated with allogeneic bone marrow transplantation and reestablishment of a normal karyotype. He then died of complications associated with chronic graft-versus-host disease. It is not known whether the children reported by Weinblatt et al.1 or Smith et al.2 had abnormal G-CSF receptors, which might have served as a "first hit" for possible G-CSF-accelerated leukemogenesis. In our patient, reverse-transcribedpolymerase chain reaction amplification of the transmembrane and cytosolic domains was performed, and DNA sequencing showed a silent polymorphism. Therefore our patient with SCN did not have a "first hit," which would increase the risk of leukemogenesis. It is possible that he had a genetic defect in some other critical granulopoietic signaling molecule. On the basis of the patients with SCN in whom leukemia developed during G-CSF therapy in association with congenital mutant G-CSF receptors,4 those who acquired monosomy 7,1, 2 and our own experience with an affected child, we cannot be as sanguine as the New England Journal of Medicine editorial that clinical benefits of G-CSF "clearly outweigh" the hazards of leukemogenesis. 5 Further studies into the basic mechanisms of granulopoiesis and the use of an animal model to compare the effects of G-CSF versus granulocyte-macrophage colony-stimulating factor are warranted. Until then, these data should give pause to clinicians administering growth factor to patients with congenital bone marrow failure syndromes. Until an animal model can address the effect of G-CSF on a mutated receptor, patients with SCN and mutation of the G-CSF receptor should be given GM-CSF. This may not necessarily prevent the development of monosomy 7.
Seth J. Corey, MD, MPH Assistant Professor of Pediatrics and Pharmacology Michael R. Wollman, MD Associate Professor of Pediatrics Children's Hospital of Pittsburgh University of Pittsburgh School of Medicine Pittsburgh, PA 15213-2583 Rajendra V. Deshpande, PhD James Ewing Laboratory of Developmental Hematopoiesis Memorial Sloan-Kettering Cancer Center New York, NY 10021 9/35/73470
18 8
Editorial correspondence
The Journal of Pediatrics July 1996
REFERENCES
1. Weinblatt ME, Scimeca P, James-Herry A, Sahdev I, Kochen J. Transformationof congenital neutropenia into monosomy 7 and acute nonlymphoblastic leukemia in a child treated with granulocyte colony-stimulating factor. J Pediatr 1995;126: 263-5. 2. Smith OP, Reeves BR, Kempski HM, Evans JP. Kostmann's disease, recombinantHuG-CSF,monosomy7 and MDS/AML. Br J Haematol 1995;91:150-3. 3. Shekhter-Levin S, Penchansky L, Wollman MR, Shere ME, Wald N, Gotlin SM. An abnormalclone with monosomy 7 and
trisomy 21 in the bone marrow of a child with congenitalagranulocytosis (Kostmanndisease) treated with granulocytecolonystimulatingfactor. Cancer Genet Cytogenet. 1995;84:99-104. 4. Dong F, Byrnes RK, Tidow N, Welte K, Lowenberg B, Touw IP. Mutations in the gene for the granulocyte colony-stimulating factor receptor in patients with acute myeloid leukemia preceded by severecongenitalneutropenia.N Engl J Med 1995; 333:487-93. 5. Naparstek E. Granulocyte colony-stimulatingfactor, congenital neutropenia, and acute myeloid leukemia. N Engl J Med 1995;333:516-8.
CORRECTION In the article "Comparative Safety and Efficacy of Two Immune Globulin Products in Kawasaki Disease," by Rosenfeld et al., which appeared in the June 1995 issue of The Journal (volume 126, pages 1000 to 1003), Table I contains two errors under the column head "Product A": The preparation of Product A should read as follows: "Cold ethanol-PEG fractionation, DEAE-Sephadex treatment, not plasmin digested." The formulation of Product A should read as follows: "5% IgG with 2% manitol, 1% albumin; lyophilized."