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Allogeneic bone marrow transplantation for erythrophagocytic lymphohistiocytosis
volume 108 Number 2
In our patient, electrical dysrhythmias most frequently appeared after feeding. This is surprising because gastric dysrhythmias have been described to occur only in the fasting state and to disappear after food intake.J2 Increased vagal activity usually occurs in the postprandial period. The possibility that an uncontrolled postprandial release of acetylcholine would be responsible for the gastric electrical disturbances remains entirely speculative. 13 Previous studies have demonstrated that surgical procedures, such as gastric transection or vagotomy, can give rise to electrical abnormalities? 4' ~s The previous surgical interventions in our patient may therefore have played a role in the production of the dysrhythmias. It is not clear whether gastric electrical disturbances can be explained by anatomic lesions detectable at the microscopic level.l' 3.4,7 In the present case, microscopic examination revealed only a disordered arrangement of the oblique muscular fibers of the muscularis propria. Myoelectric abnormalities of the gastric antrum may account for unexplained symptoms of upper gastrointestinal dysfunctions in children. Gastric myoelectrical activity can be recorded successfully in children as well as in adults by noninvasive peroral electrodes. We thank iechnicians Jan Servaes and Ton De Greef for their excellent assistance.
Clinical and laboratory observations
4.
5.
6.
7
8.
9.
10.
tl
12. 13
REFERENCES
1. You CH, Lee KY, Chey WY, Menguy R. Electrogastrographic study of patients with unexplained nausea, bloating and vomiting. Gastroenterology 1980;79:311. 2. You Ch, Chey WY, Lee KY, Menguy R, Bortoff A. Gastric and small intestinal dysrhythmia associated with chronic intractable nausea and vomiting. Ann Intern Med 1981; 95:449. 3. Chey WY, You CH, Lee KY, Menguy, R. Gastric dysrhythmia: clinical aspects. In: Chey WY, ed. Functional disorders
14.
15.
267
of the digestive tract. New York: Raven Press, 1983;175181. You CH, Lee KY, Chey WY. Gastric electromyography in normal and abnormal states in humans, ln: Chey WY. ed. Functional disorders of the digestive tract. New York. Raven Press. 1983:167-173. Lee KY. Park HJ. Chey WY. Studies on mechanism of retching and vomiting in dogs. Effect of peripheral dopamine blocker on myoelectric changes in antrum and upper small intestine. Dig Dis Sci 1985:30:22. Vantrappen G. Schippers E, Janssens J. Vandeweerd M What is mechanical correlate of g~istric dysrhythmia? Gastroenterology 1984:86:1288. Kelly KA. Motility of the stomach and gastroduodenal junction. In: Johnson LR. ed. Physiology of gastrointestinal tract. New York: Raven Press. 1981:393-410. Weber J. Kohatsu S. Pacemaker localization and electrical conduction patterns in the canine stomach. Gastroenterology 1970:59:717. Kelly KA. Differential responses of the canine gastric corpus and antrum to electrical stimulation. Am J Physiol 1974: 226:230. You CH. Chey WY: Study of electromechanical activity of the stomach in humans and in dogs with particular attention to tachygastria. Gastroenterology 1984:86:1460. Telander R. Morgan KG. Kreulen DE. Schmalz PF. Kelly KA. Szursewski JH. Human gastric atony with tachygastria and gastric retention Gastroenterology 1978:75:497. Code CF. Marlett JA: Canine tachygastria. Mayo Clin Proc 1974:49:325. Sarna SK. Daniel EE. Vagal control of gastric electrical control acnvity and motility. Gastroenterology t975:68:301 Kelly KA. Code CF. Effect of transthoracic vagotomy on canine gasmc electrical activity. Gastroenterology 1969: 57:51. Ormsbee HS. Mason GR. Bass P. Effects of pyloroplasty on the electrical activity of the canine gastroduodenal junction. In: Vantrappen G. ed. Proceedings of the Fifth International Symposium on Gastrointestinal Motility. Herentals. Typoff, 1975;293-299.
AIIogeneic bone marrow transplantation for erythrophagocytic lymphohistiocytosis A. Fischer, M.D., N. Cerf-Bensussan, M.D., S. Blanche, M.D., F. Le Deist, M.D., C. Bremard-Oury, M.D., G. Leverger, M.D., G. Schaison, M.D., A. Durandy, M.D., and C. Griscelli, M.D. From the Department of Pediatrics, H6pital des Enfants Malades, and the Pediatric Hematology UniL H(Spital Saint-Louis, Paris Cedex, France Submitted for publication May 22, 1985; accepted July 30, 1985. Reprint requests: Alain Fischer, M.D, INSERM U 132, D6partement de P6diatrie, H6pital des Enfants Malades, 149 rue de S6vres, 75 730 Paris Cedex 15, France.
Familial erythrophagocytic lymphohistiocytosis is characterized by rapidly progressive visceral and central nervous system infiltration by lymphocytes and erythrophagocytic histiocytes? -3 The disease is transmitted as an autosomal recessive trait, 1,3 and usually is noted within the first years
268
The Journal of Pediatrics February 1986
Clinical and laboratory observations
FEL GVHD NK
Familial erythrophagocytic lymphohistiocytosis Graft-versus-host disease Natural killer
of life. Until recently, therapeutic approaches have failed to cure the disease, "~ and outcome has been fatal within 3 months of presentation. The use of epipodohyllotoxin (VP 16-213) in combination with steroids, intrathecal methotrexate, and cranial irradiation has led to remission lasting longer than 2 years in some patients?. 7 Despite use of such therapy or other intensive chemotherapy regimens, s F E L is sometimes primarily resistant or subject to relapse, eventually leading to death in some patients. 3~6.s H L A - m a t c h e d bone marrow transplantation can cure a number of bone marrow~lerived inherited disorders, 9 including ChediakHigashi syndrome, a disorder characterized in its accelerated phase by a syndrome very similar to FEL. 1~ We report the case of a boy with chem0therapy-resistant F E L who received an H L A - m a t c h e d marrow transplant after conditioning with combination chemotherapy. Progressive control of the disease was achieved within 3 months, and the patient has remained disease free.
METHODS Suspensions of mononuclear cells were prepared from heparinized peripheral blood by Ficoil-Hypaque centrifugation. Natural killer activity was assayed as previously described. 12 CASE REPORT The patient was the third child of unrelated parents. Growth and development were normal until 14 months of age, when he was noted to have transient edema of both legs. Bouts of fever, diarrhea, and vomiting oCcurred during the following 4 months. Skin rash, ataxia, and hepatosplenomegaly were then noted. Erythropbagocytic lymphohistiocytosis was diagnosed on evidence of pancytopenia, profound fibrinopenia, and increased triglyceridemia, and histiocytic hyperplasia with fiemophagocytosis on bone marrow smears. Culture and serology for microorganisms, including Salmonella, Toxoplasma, measles, rubella, cytomegalovirus, and Epstein-Barr virus, were repeatedly negative. Cerebrospinal fluid was normal. T-lymphocyte markers, lymphoCyte proliferation to mitogens, and B-lymphocyte markers on blood mononuclear cells were normal. Serum immunogiobulin levels were within the normal range. Natural killer activity was absent and could not be induced by incubation with ~,-interferon (700 U/ml). The patient was given VM 26, steroids, and then VP 16-213 (200 mg/m 2 on 3 consecutive days). This therapy had mild effect on the fever and hepatosplenomegaly, but the edema and ataxia resolved (Fig. 1). However, despite repeated infusions of VP 16-2l 3, with increasing dosage up to 250 mg/m 2 (3 consecutive days every 3 weeks),
fever, pancytopenia, and hypertriglyceridemia persisted, with progressive liver and spleen enlargement. After 41/2 months of treatment , mononuclear cells (20/mm 3, including histiocytes and lymphocytes ) in the CSF were first noted. The patient was referred to H6pital des Enfants Malades for bone marrow transplantation at 25 months of age. A partial splenectomy was performed first, because chemotherapy alone did not reduce spleen size. Histology of the spleen showed histiocytic cell and lymphocyte infiltration with hemophagocytosis. A 5-day course of VP 16-213 (200 mg/m 2) was then given, together with six intrathecal injections of methotrexate. Although this treatment had a partial effect, complete remission of the disease could not be obtained(Fig. 1). The preparative regimen for the transplantation consisted of VP 16-213 (300 mg/m 2) on days -14 through -12, araeytine (1 gm/m 2) on days -11 and -10, bnsulfan (4 mg/kg) on days - 9 through -6, and cyclophosphamide (50 mg/kg) on days - 5 through -2. Bone marrow was transplanted from the patient's 16-year-old-brother, Who was HLA-A, B, D-DR identical. The graft-versus-host preventive regimen consisted of T ceil depletion of the harvested bone marrow by one cycle of rosetting with neuraminidase-treated sheep red cells. 13 This procedure resulted in the reduction of OKT3+ T cells from 26.5% to 0.5%. The patient received 1.5 • 109 cells (1.5 • 10s kg). Cyclosporine A was given by continuous intravenous infusion from day - 1.5 The patient was maintained in a sterile isolator (La Calh6ne, Paris) from d a y - 1 0 to day 87 and received nonabsorbable aiatibiotics and ketoconazole. Complete remission of the disease has been maintained for >1 year since transplant. The child is doing well, with no therapy but penicillin administered orally. RESULTS The posttransplant course was marked by quick hematologic reconstitution (granulocytes > 5 0 0 / m m 3 on day 21, last platetet transfusion required on day 30). Transient positive water and sodium balance necessitated cessation of cyelosporine A infusion (day 28). There was no infection nor signs of graft-versus-host disease. Clinical and biologic manifestations o f the lymphohistiocytosis disappeared slowly. As early as day 35, natural killer activity of peripheral blood mononuclear cells was restored. It thereafter remained present, although at a lower level (Fig. 2). The hepatomegaly persisted for 3 months, and the hypertriglyceridemia, which increased after transplant to 10 n m o l / L , continued until day 60. After day 90, blood counts were normal, as were serum fibrinogen and triglyceride levels. The C S F and bone marrow smears were normal. The only evidence o f engraftment was provided by immunoglobulin allotype studies, because there was no difference between donor and recipient in erythrocyte and granulocyte phenotypes. Immunoglobulin allotype studies performed 8 months after transplant indicated full chimerism.
Volume 108 Number 2
Clinical and laboratory observations
Fever
4.
4. 4 . -
-
t
4. 4.
§
-
§
-
4.-
269
-
Partial splenectomy 9
Splenomegaly I~[
15 Hepatomegaly
1~f
0L 4000 3000 PMN/mm3 2000 1000
~
0
10
1 i
0
Triglycerides
(mmol/I) o
30 Platelets/mm3 20 ~10_4 o 10
6
43 Fibrinogen
4
(g/I) 9
2 0
VP16 (rng/m2)
'~176
'~
"~
II
nllllllllRI
~VM26 ~
IlAra'C~.~Cyc,ospor,nA 11
Steroids
t__
I
D-30 AUGSEP OCT NOV DECJAN 1983
DO FEB
i
I
D30
060
I
D90
.~
I
.:.
I
.~
D150 0240 D360
Fig. t. Clinical course in patient with familial erythrophagocytic lymphohistiocytosis. Ara-C, aracytine; Bu. busulfan; Cy. cyclophosphamide; VPI 6, epipodophylotoxin.
50=1 so
25=1
12=1
[/K, - I
, a30
, n60
, a90
-"'---..~ 6=1 a3OOOa~
BMT Fig. 2. Natural killer activity in our patient. NK activity was absent 1 month before transplantation, and could not be induced by incubation with interferon. 50 = 1, 25 = l, 12 = l, 6 = 1, Ratios of effector/target cells (K 562). Normal values (mean _+ 1 SEM, n = 30): 50 = 1, 53% _+ 21%; 25 = 1, 41% -+ 19%; 12 = I, 27% +_ 16%; 6 = 1, 17% _+ 13%. BMT, bone marrow transplantation.
DISCUSSION A stable remission o f e r y t h r o p h a g o c y t i c l y m p h o h i s t i o c y -
t h r o u g h an intensive c o u r s e o f c h e m o t h e r a p y followed by an H L A - m a t c h e d allogeneic bone m a r r o w - t r a n s p l a n t .
tosis r e s i s t a n t to c h e m o t h e r a p y alone has b e e n a c h i e v e d
E r y t h r o c y t i c l y m p h o h i s t i o c y t o s i s has also been d e s c r i b e d
270
Clinical and laboratory observations
in association with several viral infections. TM Inasmuch as there was no family history in the case of our patient, the possibility of a viral-associated hemophagocytic syndrome was considered, but rejected because negative searches for viral infections made it unlikely. Varying immunologic abnormalities associated with F E L have been described, 4,5 including defective natural killer activity. 12 This defect is not a primary characteristic of the disease, however, as it is in Chediak-Higashi syndrome. 15 Indeed, stable remission achieved by VP 16-213 therapy has been shown to be marked by a correction of N K activity. 12 Thus the normal N K activity found in our patient after transplantation could reflect either disease control or donor cell engraftment or both. That F E L can be treated with allogeneic bone marrow transplantation indicates either that the disease stems from the hematopoietic system, although the typical infiltrating cells have not been precisely characterized, 1,3 or that the causal abnormality is found in all cells but can be corrected by transplantation of the hematopoietic system, as can some metabolic inherited diseases. 9 The conditioning regimen used in our patient was intensive, and included VP16-213, a drug known to be effective in FEL, 6-7 and busulfan, aracytine, and cyclophosphamide, proved to have strong myeloablative and immunosuppressive effects. High doses of busulfan associated with cyclophosphamide allow engraftment of allogeneic bone marrow in patients with inherited disorders and hyperactive bone marrow, although some failures have been observed. 9,~6 Chemotherapy was preferred to total body irradiation in this patient because of his young age and because of doubt as to the effectiveness of irradiation on the infiltrating histiocytic cells. T cell depletion of the harvested bone marrow was performed to prevent the risk of G V H D . This method has proved efficient in preventing the occurrence of G V H D in high-risk patients (older patients or those receiving partially mismatched bone marrow). 13 E-rosetting for T cell depletion of the bone marrow in patients with severe combined immunodeficiency has previously been used successfully. ~3 Allogeneic bone marrow transplantation associated with intensive chemotherapy can induce stable remission of drug-resistant F E L and should be considered for chemotherapy-resistant F E L and in patients in relapse. We thank O. Journet, C. Harre, and P. Zanoni for technical assistance, and M. Levinson for reviewing the manuscript.
The Journal of Pediatrics February 1986
REFERENCES
1. Farquhar JW, Claireaux AE. Familial haemophagocytic reticulosis. Arch Dis Child 1952;27:519. 2. Perry MC, Harrison EG, Burgert EO, Gilchrist GS. Familial erythrophagocytic lymphohistiocytosis: report of two cases and clinicopathologic review. Cancer 1976;38:209. 3. Janka GE. Familial hemophagocytic lymphohistiocytosis. Eur J Pediatr 1983,140:221. 4. Ladisch S, Ho W, Matheson D, Pilkington R, Hartman G. Immunological and clinical effects of repeated blood exchange in familial erythrophagocytic lymphohistiocytosis. Blood 1982;60:814. 5. De Victor D, Fischer A, Mamas S, De Saint Basile G, Durandy A, Buriot D, Griscelli C. Etude immunologique de la lymphohistiocytose familiale. Arch Fr Pediatr 1982;39:135. 6. Ambruso DR, Hays T, Zwartjes W J, Tubergen DG, Favara BE. Successful treatment of lymphohistiocytic reticulosis with phagocytosis with epipodophyllotoxin VP 16-213. Cancer 1980;45:2516. 7. Fischer A, Virelizier JL, Arenzana-Seisdedos F, Perez N, Nezelof C, Griscelli C. Treatment of four patients with erythrophagocytic lymphohistiocytosis by a combination of epipodophyllotoxin, steroids, intrathecal methotrexate and cranial irradiation. Pediatrics 1985;76:263, 8. Delaney MM, Shafford EA, Al-Attar A, Pritchard J. Familial erythrophagocytic reticulosis: complete response to combination chemotherapy. Arch Dis Child 1984;59:173. 9. O'Reilly R J, Brochstein J, Dinsmore R, Kirkpatrick D. Marrow transplantation for congenital disorders. Semin Haematol 1984;21:188. 10. Virelizier JL, Lagrue A, Durandy A, Arenzana F, Oury C, Griscelli C, Reinert P. Reversal of natural killer defect in a patient with Chediak-Higashi syndrome after bone marrow transplantation. N Engl J Med 1982;306:1055. 11. Blume RS, Wolff SM. The Chediak-Higashi syndrome: studies in four patients and a review of the literature. Medicine 1972;51:247. 12. Perez N, Virelizier JL, Arenzana-Seisdedos F, Fischer A, Griscelli C. Impaired natural killer activity in lymphohistiocytosis syndrome. J PEDIATR 1984;104:569. 13. Fischer A, Durandy A, De Villartay JP, Vilmer E, Griscelli C. HLA-haploidentical bone marrow transplantation for severe combined immunodeficiency using E-rosette fractionation and cyclo~porin A. Transplant Proc 1985;17:447. 14. Risdall R J, McKenna RW, Nesbit MR, Krivitt W, Balfour HH, Simmons RL, Brunning RD. Virus-associated hemophagocytic syndrome. Cancer 1979;44:993. 15. Roder JC, Haliotis T, Klein M, et al. A new immunodeficiency disorder in humans involving NK cells. Nature 1980;284:553. 16. Parkman R, Rappeport JM, Hellman S, Lipton J, Smith B, Geha R, Nathan DG. Busulfan and total body irradiation as antihematopoietic stem cell agents in the preparation of patients with congenital bone marrow disorders for allogeneic bone marrow transplantation. Blood 1984;64:852.
In our patient, electrical dysrhythmias most frequently appeared after feeding. This is surprising because gastric dysrhythmias have been described to occur only in the fasting state and to disappear after food intake.J2 Increased vagal activity usually occurs in the postprandial period. The possibility that an uncontrolled postprandial release of acetylcholine would be responsible for the gastric electrical disturbances remains entirely speculative. 13 Previous studies have demonstrated that surgical procedures, such as gastric transection or vagotomy, can give rise to electrical abnormalities? 4' ~s The previous surgical interventions in our patient may therefore have played a role in the production of the dysrhythmias. It is not clear whether gastric electrical disturbances can be explained by anatomic lesions detectable at the microscopic level.l' 3.4,7 In the present case, microscopic examination revealed only a disordered arrangement of the oblique muscular fibers of the muscularis propria. Myoelectric abnormalities of the gastric antrum may account for unexplained symptoms of upper gastrointestinal dysfunctions in children. Gastric myoelectrical activity can be recorded successfully in children as well as in adults by noninvasive peroral electrodes. We thank iechnicians Jan Servaes and Ton De Greef for their excellent assistance.
Clinical and laboratory observations
4.
5.
6.
7
8.
9.
10.
tl
12. 13
REFERENCES
1. You CH, Lee KY, Chey WY, Menguy R. Electrogastrographic study of patients with unexplained nausea, bloating and vomiting. Gastroenterology 1980;79:311. 2. You Ch, Chey WY, Lee KY, Menguy R, Bortoff A. Gastric and small intestinal dysrhythmia associated with chronic intractable nausea and vomiting. Ann Intern Med 1981; 95:449. 3. Chey WY, You CH, Lee KY, Menguy, R. Gastric dysrhythmia: clinical aspects. In: Chey WY, ed. Functional disorders
14.
15.
267
of the digestive tract. New York: Raven Press, 1983;175181. You CH, Lee KY, Chey WY. Gastric electromyography in normal and abnormal states in humans, ln: Chey WY. ed. Functional disorders of the digestive tract. New York. Raven Press. 1983:167-173. Lee KY. Park HJ. Chey WY. Studies on mechanism of retching and vomiting in dogs. Effect of peripheral dopamine blocker on myoelectric changes in antrum and upper small intestine. Dig Dis Sci 1985:30:22. Vantrappen G. Schippers E, Janssens J. Vandeweerd M What is mechanical correlate of g~istric dysrhythmia? Gastroenterology 1984:86:1288. Kelly KA. Motility of the stomach and gastroduodenal junction. In: Johnson LR. ed. Physiology of gastrointestinal tract. New York: Raven Press. 1981:393-410. Weber J. Kohatsu S. Pacemaker localization and electrical conduction patterns in the canine stomach. Gastroenterology 1970:59:717. Kelly KA. Differential responses of the canine gastric corpus and antrum to electrical stimulation. Am J Physiol 1974: 226:230. You CH. Chey WY: Study of electromechanical activity of the stomach in humans and in dogs with particular attention to tachygastria. Gastroenterology 1984:86:1460. Telander R. Morgan KG. Kreulen DE. Schmalz PF. Kelly KA. Szursewski JH. Human gastric atony with tachygastria and gastric retention Gastroenterology 1978:75:497. Code CF. Marlett JA: Canine tachygastria. Mayo Clin Proc 1974:49:325. Sarna SK. Daniel EE. Vagal control of gastric electrical control acnvity and motility. Gastroenterology t975:68:301 Kelly KA. Code CF. Effect of transthoracic vagotomy on canine gasmc electrical activity. Gastroenterology 1969: 57:51. Ormsbee HS. Mason GR. Bass P. Effects of pyloroplasty on the electrical activity of the canine gastroduodenal junction. In: Vantrappen G. ed. Proceedings of the Fifth International Symposium on Gastrointestinal Motility. Herentals. Typoff, 1975;293-299.
AIIogeneic bone marrow transplantation for erythrophagocytic lymphohistiocytosis A. Fischer, M.D., N. Cerf-Bensussan, M.D., S. Blanche, M.D., F. Le Deist, M.D., C. Bremard-Oury, M.D., G. Leverger, M.D., G. Schaison, M.D., A. Durandy, M.D., and C. Griscelli, M.D. From the Department of Pediatrics, H6pital des Enfants Malades, and the Pediatric Hematology UniL H(Spital Saint-Louis, Paris Cedex, France Submitted for publication May 22, 1985; accepted July 30, 1985. Reprint requests: Alain Fischer, M.D, INSERM U 132, D6partement de P6diatrie, H6pital des Enfants Malades, 149 rue de S6vres, 75 730 Paris Cedex 15, France.
Familial erythrophagocytic lymphohistiocytosis is characterized by rapidly progressive visceral and central nervous system infiltration by lymphocytes and erythrophagocytic histiocytes? -3 The disease is transmitted as an autosomal recessive trait, 1,3 and usually is noted within the first years
268
The Journal of Pediatrics February 1986
Clinical and laboratory observations
FEL GVHD NK
Familial erythrophagocytic lymphohistiocytosis Graft-versus-host disease Natural killer
of life. Until recently, therapeutic approaches have failed to cure the disease, "~ and outcome has been fatal within 3 months of presentation. The use of epipodohyllotoxin (VP 16-213) in combination with steroids, intrathecal methotrexate, and cranial irradiation has led to remission lasting longer than 2 years in some patients?. 7 Despite use of such therapy or other intensive chemotherapy regimens, s F E L is sometimes primarily resistant or subject to relapse, eventually leading to death in some patients. 3~6.s H L A - m a t c h e d bone marrow transplantation can cure a number of bone marrow~lerived inherited disorders, 9 including ChediakHigashi syndrome, a disorder characterized in its accelerated phase by a syndrome very similar to FEL. 1~ We report the case of a boy with chem0therapy-resistant F E L who received an H L A - m a t c h e d marrow transplant after conditioning with combination chemotherapy. Progressive control of the disease was achieved within 3 months, and the patient has remained disease free.
METHODS Suspensions of mononuclear cells were prepared from heparinized peripheral blood by Ficoil-Hypaque centrifugation. Natural killer activity was assayed as previously described. 12 CASE REPORT The patient was the third child of unrelated parents. Growth and development were normal until 14 months of age, when he was noted to have transient edema of both legs. Bouts of fever, diarrhea, and vomiting oCcurred during the following 4 months. Skin rash, ataxia, and hepatosplenomegaly were then noted. Erythropbagocytic lymphohistiocytosis was diagnosed on evidence of pancytopenia, profound fibrinopenia, and increased triglyceridemia, and histiocytic hyperplasia with fiemophagocytosis on bone marrow smears. Culture and serology for microorganisms, including Salmonella, Toxoplasma, measles, rubella, cytomegalovirus, and Epstein-Barr virus, were repeatedly negative. Cerebrospinal fluid was normal. T-lymphocyte markers, lymphoCyte proliferation to mitogens, and B-lymphocyte markers on blood mononuclear cells were normal. Serum immunogiobulin levels were within the normal range. Natural killer activity was absent and could not be induced by incubation with ~,-interferon (700 U/ml). The patient was given VM 26, steroids, and then VP 16-213 (200 mg/m 2 on 3 consecutive days). This therapy had mild effect on the fever and hepatosplenomegaly, but the edema and ataxia resolved (Fig. 1). However, despite repeated infusions of VP 16-2l 3, with increasing dosage up to 250 mg/m 2 (3 consecutive days every 3 weeks),
fever, pancytopenia, and hypertriglyceridemia persisted, with progressive liver and spleen enlargement. After 41/2 months of treatment , mononuclear cells (20/mm 3, including histiocytes and lymphocytes ) in the CSF were first noted. The patient was referred to H6pital des Enfants Malades for bone marrow transplantation at 25 months of age. A partial splenectomy was performed first, because chemotherapy alone did not reduce spleen size. Histology of the spleen showed histiocytic cell and lymphocyte infiltration with hemophagocytosis. A 5-day course of VP 16-213 (200 mg/m 2) was then given, together with six intrathecal injections of methotrexate. Although this treatment had a partial effect, complete remission of the disease could not be obtained(Fig. 1). The preparative regimen for the transplantation consisted of VP 16-213 (300 mg/m 2) on days -14 through -12, araeytine (1 gm/m 2) on days -11 and -10, bnsulfan (4 mg/kg) on days - 9 through -6, and cyclophosphamide (50 mg/kg) on days - 5 through -2. Bone marrow was transplanted from the patient's 16-year-old-brother, Who was HLA-A, B, D-DR identical. The graft-versus-host preventive regimen consisted of T ceil depletion of the harvested bone marrow by one cycle of rosetting with neuraminidase-treated sheep red cells. 13 This procedure resulted in the reduction of OKT3+ T cells from 26.5% to 0.5%. The patient received 1.5 • 109 cells (1.5 • 10s kg). Cyclosporine A was given by continuous intravenous infusion from day - 1.5 The patient was maintained in a sterile isolator (La Calh6ne, Paris) from d a y - 1 0 to day 87 and received nonabsorbable aiatibiotics and ketoconazole. Complete remission of the disease has been maintained for >1 year since transplant. The child is doing well, with no therapy but penicillin administered orally. RESULTS The posttransplant course was marked by quick hematologic reconstitution (granulocytes > 5 0 0 / m m 3 on day 21, last platetet transfusion required on day 30). Transient positive water and sodium balance necessitated cessation of cyelosporine A infusion (day 28). There was no infection nor signs of graft-versus-host disease. Clinical and biologic manifestations o f the lymphohistiocytosis disappeared slowly. As early as day 35, natural killer activity of peripheral blood mononuclear cells was restored. It thereafter remained present, although at a lower level (Fig. 2). The hepatomegaly persisted for 3 months, and the hypertriglyceridemia, which increased after transplant to 10 n m o l / L , continued until day 60. After day 90, blood counts were normal, as were serum fibrinogen and triglyceride levels. The C S F and bone marrow smears were normal. The only evidence o f engraftment was provided by immunoglobulin allotype studies, because there was no difference between donor and recipient in erythrocyte and granulocyte phenotypes. Immunoglobulin allotype studies performed 8 months after transplant indicated full chimerism.
Volume 108 Number 2
Clinical and laboratory observations
Fever
4.
4. 4 . -
-
t
4. 4.
§
-
§
-
4.-
269
-
Partial splenectomy 9
Splenomegaly I~[
15 Hepatomegaly
1~f
0L 4000 3000 PMN/mm3 2000 1000
~
0
10
1 i
0
Triglycerides
(mmol/I) o
30 Platelets/mm3 20 ~10_4 o 10
6
43 Fibrinogen
4
(g/I) 9
2 0
VP16 (rng/m2)
'~176
'~
"~
II
nllllllllRI
~VM26 ~
IlAra'C~.~Cyc,ospor,nA 11
Steroids
t__
I
D-30 AUGSEP OCT NOV DECJAN 1983
DO FEB
i
I
D30
060
I
D90
.~
I
.:.
I
.~
D150 0240 D360
Fig. t. Clinical course in patient with familial erythrophagocytic lymphohistiocytosis. Ara-C, aracytine; Bu. busulfan; Cy. cyclophosphamide; VPI 6, epipodophylotoxin.
50=1 so
25=1
12=1
[/K, - I
, a30
, n60
, a90
-"'---..~ 6=1 a3OOOa~
BMT Fig. 2. Natural killer activity in our patient. NK activity was absent 1 month before transplantation, and could not be induced by incubation with interferon. 50 = 1, 25 = l, 12 = l, 6 = 1, Ratios of effector/target cells (K 562). Normal values (mean _+ 1 SEM, n = 30): 50 = 1, 53% _+ 21%; 25 = 1, 41% -+ 19%; 12 = I, 27% +_ 16%; 6 = 1, 17% _+ 13%. BMT, bone marrow transplantation.
DISCUSSION A stable remission o f e r y t h r o p h a g o c y t i c l y m p h o h i s t i o c y -
t h r o u g h an intensive c o u r s e o f c h e m o t h e r a p y followed by an H L A - m a t c h e d allogeneic bone m a r r o w - t r a n s p l a n t .
tosis r e s i s t a n t to c h e m o t h e r a p y alone has b e e n a c h i e v e d
E r y t h r o c y t i c l y m p h o h i s t i o c y t o s i s has also been d e s c r i b e d
270
Clinical and laboratory observations
in association with several viral infections. TM Inasmuch as there was no family history in the case of our patient, the possibility of a viral-associated hemophagocytic syndrome was considered, but rejected because negative searches for viral infections made it unlikely. Varying immunologic abnormalities associated with F E L have been described, 4,5 including defective natural killer activity. 12 This defect is not a primary characteristic of the disease, however, as it is in Chediak-Higashi syndrome. 15 Indeed, stable remission achieved by VP 16-213 therapy has been shown to be marked by a correction of N K activity. 12 Thus the normal N K activity found in our patient after transplantation could reflect either disease control or donor cell engraftment or both. That F E L can be treated with allogeneic bone marrow transplantation indicates either that the disease stems from the hematopoietic system, although the typical infiltrating cells have not been precisely characterized, 1,3 or that the causal abnormality is found in all cells but can be corrected by transplantation of the hematopoietic system, as can some metabolic inherited diseases. 9 The conditioning regimen used in our patient was intensive, and included VP16-213, a drug known to be effective in FEL, 6-7 and busulfan, aracytine, and cyclophosphamide, proved to have strong myeloablative and immunosuppressive effects. High doses of busulfan associated with cyclophosphamide allow engraftment of allogeneic bone marrow in patients with inherited disorders and hyperactive bone marrow, although some failures have been observed. 9,~6 Chemotherapy was preferred to total body irradiation in this patient because of his young age and because of doubt as to the effectiveness of irradiation on the infiltrating histiocytic cells. T cell depletion of the harvested bone marrow was performed to prevent the risk of G V H D . This method has proved efficient in preventing the occurrence of G V H D in high-risk patients (older patients or those receiving partially mismatched bone marrow). 13 E-rosetting for T cell depletion of the bone marrow in patients with severe combined immunodeficiency has previously been used successfully. ~3 Allogeneic bone marrow transplantation associated with intensive chemotherapy can induce stable remission of drug-resistant F E L and should be considered for chemotherapy-resistant F E L and in patients in relapse. We thank O. Journet, C. Harre, and P. Zanoni for technical assistance, and M. Levinson for reviewing the manuscript.
The Journal of Pediatrics February 1986
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