American Journal of Hematology 39:208-211 (1992)
Cyclosporin A Treatment for Diamond-Blackfan Anemia James Splain and Brian W. Berman Division of Pediatric HematologyiOncology, Department of Pediatrics, Case Western Reserve University School of Medicine, Rainbow Babies and Childrens Hospital, Cleveland, Ohio
Diamond-Blackfananemia (DBA) is characterized by a variable response to corticosteroid therapy. Patients poorly responsive to acceptable doses of steroid treatment require long-termtransfusion therapy. We have treated three patients with DBA with the immunosuppressive agent cyclosporin A with limited success. Patients 1 (DS) and 2 (LS), halfsiblings, were 13 and 9 years old, respectively, and remainedtransfusion independentfor many years on steroid therapy. Both patients manifest steroid-associatedgrowth failure and osteopenia, with resultant orthopedic complications. Oral cyclosporin therapy sufficient to achieve trough serum levels of 100-200 ng/ml was associated with a brisk 50100% increase in hematocrit within 1 month of initiation of treatment and allowed for a gradual tapering of prednisone dose to approximately 20% of prior established maintenance dose. After 7-8 months, both patients developed progressive decline in hematocrit level requiring increased prednisone dose and, ultimately, transfusion support. Patient 3 (RD), a 5-year-old child with steroid refractory, transfusion-dependent DBA, was entirely unresponsive to cyclosporin therapy. No cyclosporin-associatedtoxicity occurred. Our observations indicate that cyclosporin A can transiently ameliorate the hematologic course of some patients with DBA. Further studies are in order to determine its mechanism of action and potential clinical utility in patients unresponsiveto acceptabledoses of steroid. Key words: congenital hypoplastic anemia, corticosteroids, DBA, steroid therapy, immunosuppression
INTRODUCTION
CASE REPORTS
Diamond Blackfan anemia (DBA) is an uncommon, constitutional, pure red blood cell aplasia syndrome. Because of variable inheritance patterns, inconsistent results of in vitro studies of erythroid progenitor cell proliferation, and variety of responses to therapy, DBA is believed to represent a common phenotypic expression of several potential pathophysiologic mechanisms [ 11. Approximately 70% of patients initially respond to corticosteroid therapy; many require chronic high-dose treatment, while others develop progressive resistance to therapy [2]. Patients unresponsive to acceptable doses of steroids must be maintained on transfusion therapy. Because of the risks and potential side effects of long-term high-dose steroid and transfusion therapies, other useful treatment approaches have been sought. Several patients have been reported to have responded to the immunosuppressive agent cyclosporin A [3-61. We report three additional patients with DBA treated with cyclosporin A, two of whom manifested a marked, but unsustained, response.
Patient 1 (D.S.), a 13-year-old male and patient 2 (L.S.), a 9-year-old female, are half-siblings with a common hematologically normal mother. This family has been previously reported in relation to this unusual pattern of inheritance 171. Both patients presented at approximately 4 months of age with profound anemia, reticulocytopenia, and bone marrow erythroid aplasia. Both children demonstrated a brisk and sustained response to steroid therapy. For several years prior to the trial of cyclosporin, hematocrits were maintained in the 18-25% range, with therapy consisting of 1-2 mg of prednisone per kilogram on alternate days (q.o.d.), with 2-3 week courses of daily prednisone required at about 3-4 month intervals to maintain an acceptable hematocrit level. Very
0 1992 Wiley-Liss, Inc.
Received for publication May 17, 1991; accepted September 26, 1991. Address reprint requests to Brian W. Berman, MD, Division of Pediatric Hematology/Oncology, Rainbow Babies & Childrens Hospital, Cleveland. OH 44106.
209
Case Report: Diamond-Blackfan Anemia D.S.
G
I
20. 10-
Duration of CyclsporineTherapy
0 1 unrtpRBC
Duration of CyclosporineTherapy
:I, 50 i
I
n
d,u$l
1
n
tt
OJ
8
10122/ 4 88
6
8
101221 4 89
6
8
1012
8
10122/ 4 88
Months
6
8
101221 4
6
8
1012
89
Months
Fig. 1. Clinical course of patient 1 (D.S.).
Fig. 2. Clinical course of patient 2 (L.S.).
infrequent blood transfusions were required. Both patients exhibited significant steroid-associated side effects in the form of severe growth retardation, Cushingoid body habitus, and profound osteopenia with resultant orthopedic complications (pathologic fractures and aseptic necrosis of the humoral head in the case of L.S., and slipped capital femoral epiphysis in the case of D .S.). In an attempt to decrease or eliminate steroid dependency, single-daily-dose oral cyclosporin A therapy sufficient to maintain trough serum levels of 100-200 ng/ml was initiated. Treatment was begun at a dose of 7 mg/kg/day and modified appropriately to achieve the desired trough level (based on a whole-blood high-pressure liquid chromatography method). Ranges of dosage for patients 1 and 2 were 7-15 mglkglday and 3-7 mgtkglday, respectively. As depicted in Figures 1 and 2, both patients responded with a brisk reticulocytosis and a 50-100% increase in hematocrit during the first month of therapy. Over the initial 8 months of therapy, prednisone doses were rapidly tapered to approximately 20% of previous established maintenance dosage, while hematocrits were maintained at or above previous baseline values. No daily prednisone or transfusions were required during this period. After this initial 8 month period, both patients exhibited progressive decline of hematocrit and an increasing prednisone requirement and eventually required transfusional support. After approximately 21 months of cyclosporin therapy, treatment was discontinued because of the lack of sustained response. Neither patient experienced cyclosporin-associated toxicity. Both children are currently maintained on a chronic red blood cell transfusion program in an effort to avoid further steroid-associated side effects. Patient 3 (R.D.) was a 5-year-old male who presented at approximately 6 months of age with profound anemia, reticulocytopenia, and bone marrow erythroid aplasia. He was unresponsive to multiple courses of prednisone at
doses of 2 mg/kg/day and has been transfusion dependent since infancy. A 3 month course of oral cyclosporin A therapy sufficient to maintain trough serum levels of 100-200 nglml (dosage range 9- 12.5 mg/kg/day) resulted in no hematologic response. He is currently maintained on a long-term chronic transfusion program and desferoximine iron chelation treatment. DISCUSSION
First described in 1938, Diamond-Blackfan anemia (DBA) is a rare, constitutional, aregenerative anemia characterized by reticulocytopenia and a bone marrow examination demonstrating isolated profound erythroid hypoplasia [8,9]. Most cases are sporadic, but as many as 20% have a family history suggestive of either autosomal recessive or autosomal dominant inheritance [2]. Many pathophysiologic mechanisms have been suggested and investigated. Some studies have suggested the existence of humeral or cellular inhibitors of erythropoiesis, but findings have not been consistently reproducible [ 10131. A growing body of laboratory data and the response of several patients to bone marrow transplantation support the concept of an intrinsic erythroid stem cell defect [13]. Approximately 70% of DBA patients initially respond to corticosteroid therapy [21. Patients unresponsive to corticosteroid therapy and those requiring unacceptably high doses of steroid must be maintained on chronic transfusion programs. Because of the risks and potential side effects of chronic steroid and transfusion therapies, other modalities, including cyclosporin A, have been attempted in some patients [3-6]. Cyclosporin A is a potent immunosuppressive agent used extensively to treat graft rejection in kidney transplantation and graft vs. host disease in bone marrow transplantation recipients [ 141. Cyclosporin appears to interfere with T-cell function by inhibiting the
210
Case Report: Splain and Berman
TABLE 1. Literature Review of Diamond-Blackfan Anemia Patients Treated With Cyclosporin A*
Study
Steroid responders (cyclopsorin responders/ total treated)
Steroid nonresponders (cyclosporin respondersltotal treated)
Seip and Zanussi [ 5 ] Leonard e t a ] . 13) Totterman et al. [4] Finlay and Shahidi [6] Present report
2/2 111 212
o/ 1
Total
818
1I9
212 1/1
118
*Note high response rate in patients responsive to steroid therapy.
activation cascade that generates T-cell-mediated responses [14]. In contrast to T-cell functions, B-cell responses are minimally affected by cyclosporin [ls].Cyclosporin is metabolized by the liver and competes with prednisone for common metabolizing enzymes. It has been suggested by some investigators that cyclosporin inhibits the metabolic elimination of prednisone, but this has been disputed by others [ 16191. As is noted in Table I, of the 17 DBA patients reported to have been treated with cyclosporin, eight had previously responded to corticosteroid therapy, while nine were previously refractory to steroid treatment [3-61. All eight steroid responders have been reported to have responded to the addition of cyclosporine to the treatment regimen 13-61. Four of these patients have displayed an unsustained response; one patient responded for 15 months, at which time cyclosporine was discontinued because of toxicity, and the remaining three patients had continued responses at the time of publication (3, 6, and 12 months) 13-61 (N. Shahidi and N. Young, personal communication). Of the nine patients previously refractory to steroids, one was treated with cyclosporin alone and eight were treated with cyclosporin followed by cyclosporin and prednisone. One of these patients manifested an unsustained response to the combination of cyclosporin and prednisone; the remaining eight patients exhibited no response [3] (N. Young, personal communication). The mechanism of action of cyclosporin in DBA is unclear. The immunosuppressive activity of cyclosporin suggests a possible T-cell-inhibitory role in the pathogenesis of this disease in some patients. Consistent with this, several in vitro studies have suggested a role for cellular inhibitors of erythropoiesis in some patients 112,131. There is at this time, however, no conclusive evidence for a T-cell role in the pathogenesis of DBA. The observation that nine patients responsive to cyclosporin demonstrated a response and that eight patients unresponsive to cyclosporin were previously unresponsive to steroid therapy suggests that cyclosporin is efficacious in DBA only in
conjunction with steroid therapy. Corticosteroids are believed to act in DBA by increasing the sensitivity of erythroid stem cells to the action of erythropoietin, but the exact mechanism of action is unclear [ 131. Cyclosporin may somehow potentiate the action of steroids, or it may increase the bioavailability of steroids by competing for common hepatic metabolizing enzymes. Another possibility is that cyclosporin directly stimulates erythropoiesis by unknown mechanisms. It is unclear why the responses to cyclosporin in our patients, as well in at least two other patients reported, were unsustained. If cyclosporin works in conjunction with steroids, it is possible that the response was lost because steroid dosages were reduced too markedly. One would have expected, however, a return of cyclosporin’s effects with the reinstitution of higher steroid dosages. This did not occur in our patients. If cyclosporin works by increasing steroid bioavailability, the unsustained response could be explained by transient inhibition of hepatic metabolism of steroids. The clinical course of patient 2, who had higher cyclosporin levels (approximately 200-400 ng/ml) during the first several months of therapy and lower levels (100-200 ng/ml) throughout the remainder of therapy, raises the possibility that the cyclosporin therapeutic range in DBA may be higher than the 100-200 ng/dl levels sought in our patients. The patients reported by Leonard et al. 131, however, were treated to attain cyclosporin levels of 2 0 0 4 0 0 ng/ml, and the responses of their patients were also unsustained. We conclude that cyclosporin therapy had a definite, but unsustained, effect on two steroid-dependent DBA patient and no effect on one steroid-refractory DBA patient. This, in addition to cases previously reported, suggests that cyclosporin may be a useful therapeutic agent in DBA, probably in conjunction with steroid therapy. If cyclosporin’s mechanism of action in this disease is to increase the bioavailability of steroids, then its usefulness in DBA is doubtful. A trial of cyclosporin therapy may be warranted in those DBA patients unresponsive to acceptable doses of corticosteroids. REFERENCES I . Alter BP: The bone marrow failure syndromes. In Nathan DG, Oski FA (eds). “Hematology of Infancy and Childhood.” Philadelphia: WB Saunders Company, 1987, pp 195-205. 2. Halperin DS, Freedman MH: Diamond-Blackfan anemia: Etiology, pathophysiology, and treatment. Am J Pediatr Hematol Oncol 11:38& 394, 1989. 3. Leonard EM, Raefsky E, Griffith P: Cyclosporine therapy of aplastic anemia, congenital and acquired red cell aplasia. Br J Hematol 72:278-284, 1989. 4. Totterman TH, Nisell J , Killander A, et al.: Successful treatment of pure red-cell aplasia with cyclosporin. Lancet 2:693, 1984. 5. Seip M , Zanussi GF: Cyclosporine in steroid-resistant DiamondBlackfan anemia. Acta Pediatr Scand 77:46&466, 1988. 6. Finlay JL, Shahidi NT: Cyclosporin A induced remission in DiamondBlackfan anemia. Blood 64[Suppl 1]:104, 1984.
Case Report: Diamond-Blackfan Anemia 7. Altman AC, Gross S: Severe congenital hypoplastic anemia transmission from a healthy female to opposite sex step-siblings. Am J Pediatr Hematol Oncol5:99-100, 1983. 8. Diamond LK, Blackfan KD: Hypoplastic anemia. Am J Dis Child 56:464-467, 1938. 9. Diamond LK, Wang WC, Alter B P Congenital hypoplastic anemia. Adv Pediatr 22:349-378, 1976. 10. Ortega JA, Shore NA: Congenital hypoplasic anemia inhibition of erythropoiesis by sera from patients with congenital hypoplastic anemia. Blood 45:83-89, 1975. 11. Freedman MH, Amato D, et al.: Haem synthesis in the DiamondBlackfan syndrome. Br J Heamatol31:515-520, 1975. 12. Hoffman R, Zanjani ED, et al.: Diamond-Blackfan syndrome: Lymphocyte-mediated suppression of erythropoiesis. Science 193:899900, 1976. 13. Nathan DG, Clarke BJ, et al.: Erythroid precursors in congenital
211
hypoplastic anemia. J Clin Invest 61:489-489, 1978. 14. Kahan B D Cyclosporine. N Engl J Med 321:1725-1736, 1989. 15. Shevach EM: The effects of cyclosporin A on the immune system. Annu Rev Immunol3:397-423, 1985. 16. Langhoff E, Madsen S, Flachs H, et al.: Inhibition of prednisolone metabolism by cyclosporine in kidney-transplanted patients. Transplantation 39:107-109, 1985. 17. Ost L. Effects of cyclosporine on prednisolone metabolism. Lancet 1:451, 1984. 18. Rocci ML, Tietye KJ, Lee J, et al.: The effect of cyclosporine on the pharmacokinetics of prednisolone in renal transplant patients. Transplantations 45:65&660, 1988. 19. Frey FJ, Schnetyer A, Horber FF, et al.: Evidence that cyclosporine does not affect the metabolism of prednisolone after renal transplantation. Transplantation 43:494-498, 1987.
Cyclosporin A Treatment for Diamond-Blackfan Anemia James Splain and Brian W. Berman Division of Pediatric HematologyiOncology, Department of Pediatrics, Case Western Reserve University School of Medicine, Rainbow Babies and Childrens Hospital, Cleveland, Ohio
Diamond-Blackfananemia (DBA) is characterized by a variable response to corticosteroid therapy. Patients poorly responsive to acceptable doses of steroid treatment require long-termtransfusion therapy. We have treated three patients with DBA with the immunosuppressive agent cyclosporin A with limited success. Patients 1 (DS) and 2 (LS), halfsiblings, were 13 and 9 years old, respectively, and remainedtransfusion independentfor many years on steroid therapy. Both patients manifest steroid-associatedgrowth failure and osteopenia, with resultant orthopedic complications. Oral cyclosporin therapy sufficient to achieve trough serum levels of 100-200 ng/ml was associated with a brisk 50100% increase in hematocrit within 1 month of initiation of treatment and allowed for a gradual tapering of prednisone dose to approximately 20% of prior established maintenance dose. After 7-8 months, both patients developed progressive decline in hematocrit level requiring increased prednisone dose and, ultimately, transfusion support. Patient 3 (RD), a 5-year-old child with steroid refractory, transfusion-dependent DBA, was entirely unresponsive to cyclosporin therapy. No cyclosporin-associatedtoxicity occurred. Our observations indicate that cyclosporin A can transiently ameliorate the hematologic course of some patients with DBA. Further studies are in order to determine its mechanism of action and potential clinical utility in patients unresponsiveto acceptabledoses of steroid. Key words: congenital hypoplastic anemia, corticosteroids, DBA, steroid therapy, immunosuppression
INTRODUCTION
CASE REPORTS
Diamond Blackfan anemia (DBA) is an uncommon, constitutional, pure red blood cell aplasia syndrome. Because of variable inheritance patterns, inconsistent results of in vitro studies of erythroid progenitor cell proliferation, and variety of responses to therapy, DBA is believed to represent a common phenotypic expression of several potential pathophysiologic mechanisms [ 11. Approximately 70% of patients initially respond to corticosteroid therapy; many require chronic high-dose treatment, while others develop progressive resistance to therapy [2]. Patients unresponsive to acceptable doses of steroids must be maintained on transfusion therapy. Because of the risks and potential side effects of long-term high-dose steroid and transfusion therapies, other useful treatment approaches have been sought. Several patients have been reported to have responded to the immunosuppressive agent cyclosporin A [3-61. We report three additional patients with DBA treated with cyclosporin A, two of whom manifested a marked, but unsustained, response.
Patient 1 (D.S.), a 13-year-old male and patient 2 (L.S.), a 9-year-old female, are half-siblings with a common hematologically normal mother. This family has been previously reported in relation to this unusual pattern of inheritance 171. Both patients presented at approximately 4 months of age with profound anemia, reticulocytopenia, and bone marrow erythroid aplasia. Both children demonstrated a brisk and sustained response to steroid therapy. For several years prior to the trial of cyclosporin, hematocrits were maintained in the 18-25% range, with therapy consisting of 1-2 mg of prednisone per kilogram on alternate days (q.o.d.), with 2-3 week courses of daily prednisone required at about 3-4 month intervals to maintain an acceptable hematocrit level. Very
0 1992 Wiley-Liss, Inc.
Received for publication May 17, 1991; accepted September 26, 1991. Address reprint requests to Brian W. Berman, MD, Division of Pediatric Hematology/Oncology, Rainbow Babies & Childrens Hospital, Cleveland. OH 44106.
209
Case Report: Diamond-Blackfan Anemia D.S.
G
I
20. 10-
Duration of CyclsporineTherapy
0 1 unrtpRBC
Duration of CyclosporineTherapy
:I, 50 i
I
n
d,u$l
1
n
tt
OJ
8
10122/ 4 88
6
8
101221 4 89
6
8
1012
8
10122/ 4 88
Months
6
8
101221 4
6
8
1012
89
Months
Fig. 1. Clinical course of patient 1 (D.S.).
Fig. 2. Clinical course of patient 2 (L.S.).
infrequent blood transfusions were required. Both patients exhibited significant steroid-associated side effects in the form of severe growth retardation, Cushingoid body habitus, and profound osteopenia with resultant orthopedic complications (pathologic fractures and aseptic necrosis of the humoral head in the case of L.S., and slipped capital femoral epiphysis in the case of D .S.). In an attempt to decrease or eliminate steroid dependency, single-daily-dose oral cyclosporin A therapy sufficient to maintain trough serum levels of 100-200 ng/ml was initiated. Treatment was begun at a dose of 7 mg/kg/day and modified appropriately to achieve the desired trough level (based on a whole-blood high-pressure liquid chromatography method). Ranges of dosage for patients 1 and 2 were 7-15 mglkglday and 3-7 mgtkglday, respectively. As depicted in Figures 1 and 2, both patients responded with a brisk reticulocytosis and a 50-100% increase in hematocrit during the first month of therapy. Over the initial 8 months of therapy, prednisone doses were rapidly tapered to approximately 20% of previous established maintenance dosage, while hematocrits were maintained at or above previous baseline values. No daily prednisone or transfusions were required during this period. After this initial 8 month period, both patients exhibited progressive decline of hematocrit and an increasing prednisone requirement and eventually required transfusional support. After approximately 21 months of cyclosporin therapy, treatment was discontinued because of the lack of sustained response. Neither patient experienced cyclosporin-associated toxicity. Both children are currently maintained on a chronic red blood cell transfusion program in an effort to avoid further steroid-associated side effects. Patient 3 (R.D.) was a 5-year-old male who presented at approximately 6 months of age with profound anemia, reticulocytopenia, and bone marrow erythroid aplasia. He was unresponsive to multiple courses of prednisone at
doses of 2 mg/kg/day and has been transfusion dependent since infancy. A 3 month course of oral cyclosporin A therapy sufficient to maintain trough serum levels of 100-200 nglml (dosage range 9- 12.5 mg/kg/day) resulted in no hematologic response. He is currently maintained on a long-term chronic transfusion program and desferoximine iron chelation treatment. DISCUSSION
First described in 1938, Diamond-Blackfan anemia (DBA) is a rare, constitutional, aregenerative anemia characterized by reticulocytopenia and a bone marrow examination demonstrating isolated profound erythroid hypoplasia [8,9]. Most cases are sporadic, but as many as 20% have a family history suggestive of either autosomal recessive or autosomal dominant inheritance [2]. Many pathophysiologic mechanisms have been suggested and investigated. Some studies have suggested the existence of humeral or cellular inhibitors of erythropoiesis, but findings have not been consistently reproducible [ 10131. A growing body of laboratory data and the response of several patients to bone marrow transplantation support the concept of an intrinsic erythroid stem cell defect [13]. Approximately 70% of DBA patients initially respond to corticosteroid therapy [21. Patients unresponsive to corticosteroid therapy and those requiring unacceptably high doses of steroid must be maintained on chronic transfusion programs. Because of the risks and potential side effects of chronic steroid and transfusion therapies, other modalities, including cyclosporin A, have been attempted in some patients [3-6]. Cyclosporin A is a potent immunosuppressive agent used extensively to treat graft rejection in kidney transplantation and graft vs. host disease in bone marrow transplantation recipients [ 141. Cyclosporin appears to interfere with T-cell function by inhibiting the
210
Case Report: Splain and Berman
TABLE 1. Literature Review of Diamond-Blackfan Anemia Patients Treated With Cyclosporin A*
Study
Steroid responders (cyclopsorin responders/ total treated)
Steroid nonresponders (cyclosporin respondersltotal treated)
Seip and Zanussi [ 5 ] Leonard e t a ] . 13) Totterman et al. [4] Finlay and Shahidi [6] Present report
2/2 111 212
o/ 1
Total
818
1I9
212 1/1
118
*Note high response rate in patients responsive to steroid therapy.
activation cascade that generates T-cell-mediated responses [14]. In contrast to T-cell functions, B-cell responses are minimally affected by cyclosporin [ls].Cyclosporin is metabolized by the liver and competes with prednisone for common metabolizing enzymes. It has been suggested by some investigators that cyclosporin inhibits the metabolic elimination of prednisone, but this has been disputed by others [ 16191. As is noted in Table I, of the 17 DBA patients reported to have been treated with cyclosporin, eight had previously responded to corticosteroid therapy, while nine were previously refractory to steroid treatment [3-61. All eight steroid responders have been reported to have responded to the addition of cyclosporine to the treatment regimen 13-61. Four of these patients have displayed an unsustained response; one patient responded for 15 months, at which time cyclosporine was discontinued because of toxicity, and the remaining three patients had continued responses at the time of publication (3, 6, and 12 months) 13-61 (N. Shahidi and N. Young, personal communication). Of the nine patients previously refractory to steroids, one was treated with cyclosporin alone and eight were treated with cyclosporin followed by cyclosporin and prednisone. One of these patients manifested an unsustained response to the combination of cyclosporin and prednisone; the remaining eight patients exhibited no response [3] (N. Young, personal communication). The mechanism of action of cyclosporin in DBA is unclear. The immunosuppressive activity of cyclosporin suggests a possible T-cell-inhibitory role in the pathogenesis of this disease in some patients. Consistent with this, several in vitro studies have suggested a role for cellular inhibitors of erythropoiesis in some patients 112,131. There is at this time, however, no conclusive evidence for a T-cell role in the pathogenesis of DBA. The observation that nine patients responsive to cyclosporin demonstrated a response and that eight patients unresponsive to cyclosporin were previously unresponsive to steroid therapy suggests that cyclosporin is efficacious in DBA only in
conjunction with steroid therapy. Corticosteroids are believed to act in DBA by increasing the sensitivity of erythroid stem cells to the action of erythropoietin, but the exact mechanism of action is unclear [ 131. Cyclosporin may somehow potentiate the action of steroids, or it may increase the bioavailability of steroids by competing for common hepatic metabolizing enzymes. Another possibility is that cyclosporin directly stimulates erythropoiesis by unknown mechanisms. It is unclear why the responses to cyclosporin in our patients, as well in at least two other patients reported, were unsustained. If cyclosporin works in conjunction with steroids, it is possible that the response was lost because steroid dosages were reduced too markedly. One would have expected, however, a return of cyclosporin’s effects with the reinstitution of higher steroid dosages. This did not occur in our patients. If cyclosporin works by increasing steroid bioavailability, the unsustained response could be explained by transient inhibition of hepatic metabolism of steroids. The clinical course of patient 2, who had higher cyclosporin levels (approximately 200-400 ng/ml) during the first several months of therapy and lower levels (100-200 ng/ml) throughout the remainder of therapy, raises the possibility that the cyclosporin therapeutic range in DBA may be higher than the 100-200 ng/dl levels sought in our patients. The patients reported by Leonard et al. 131, however, were treated to attain cyclosporin levels of 2 0 0 4 0 0 ng/ml, and the responses of their patients were also unsustained. We conclude that cyclosporin therapy had a definite, but unsustained, effect on two steroid-dependent DBA patient and no effect on one steroid-refractory DBA patient. This, in addition to cases previously reported, suggests that cyclosporin may be a useful therapeutic agent in DBA, probably in conjunction with steroid therapy. If cyclosporin’s mechanism of action in this disease is to increase the bioavailability of steroids, then its usefulness in DBA is doubtful. A trial of cyclosporin therapy may be warranted in those DBA patients unresponsive to acceptable doses of corticosteroids. REFERENCES I . Alter BP: The bone marrow failure syndromes. In Nathan DG, Oski FA (eds). “Hematology of Infancy and Childhood.” Philadelphia: WB Saunders Company, 1987, pp 195-205. 2. Halperin DS, Freedman MH: Diamond-Blackfan anemia: Etiology, pathophysiology, and treatment. Am J Pediatr Hematol Oncol 11:38& 394, 1989. 3. Leonard EM, Raefsky E, Griffith P: Cyclosporine therapy of aplastic anemia, congenital and acquired red cell aplasia. Br J Hematol 72:278-284, 1989. 4. Totterman TH, Nisell J , Killander A, et al.: Successful treatment of pure red-cell aplasia with cyclosporin. Lancet 2:693, 1984. 5. Seip M , Zanussi GF: Cyclosporine in steroid-resistant DiamondBlackfan anemia. Acta Pediatr Scand 77:46&466, 1988. 6. Finlay JL, Shahidi NT: Cyclosporin A induced remission in DiamondBlackfan anemia. Blood 64[Suppl 1]:104, 1984.
Case Report: Diamond-Blackfan Anemia 7. Altman AC, Gross S: Severe congenital hypoplastic anemia transmission from a healthy female to opposite sex step-siblings. Am J Pediatr Hematol Oncol5:99-100, 1983. 8. Diamond LK, Blackfan KD: Hypoplastic anemia. Am J Dis Child 56:464-467, 1938. 9. Diamond LK, Wang WC, Alter B P Congenital hypoplastic anemia. Adv Pediatr 22:349-378, 1976. 10. Ortega JA, Shore NA: Congenital hypoplasic anemia inhibition of erythropoiesis by sera from patients with congenital hypoplastic anemia. Blood 45:83-89, 1975. 11. Freedman MH, Amato D, et al.: Haem synthesis in the DiamondBlackfan syndrome. Br J Heamatol31:515-520, 1975. 12. Hoffman R, Zanjani ED, et al.: Diamond-Blackfan syndrome: Lymphocyte-mediated suppression of erythropoiesis. Science 193:899900, 1976. 13. Nathan DG, Clarke BJ, et al.: Erythroid precursors in congenital
211
hypoplastic anemia. J Clin Invest 61:489-489, 1978. 14. Kahan B D Cyclosporine. N Engl J Med 321:1725-1736, 1989. 15. Shevach EM: The effects of cyclosporin A on the immune system. Annu Rev Immunol3:397-423, 1985. 16. Langhoff E, Madsen S, Flachs H, et al.: Inhibition of prednisolone metabolism by cyclosporine in kidney-transplanted patients. Transplantation 39:107-109, 1985. 17. Ost L. Effects of cyclosporine on prednisolone metabolism. Lancet 1:451, 1984. 18. Rocci ML, Tietye KJ, Lee J, et al.: The effect of cyclosporine on the pharmacokinetics of prednisolone in renal transplant patients. Transplantations 45:65&660, 1988. 19. Frey FJ, Schnetyer A, Horber FF, et al.: Evidence that cyclosporine does not affect the metabolism of prednisolone after renal transplantation. Transplantation 43:494-498, 1987.
