Comparison between bone marrow transplantation and antithymocyte globulin in treatment of young patients with severe aplastic anemia

Comparison between bone marrow transplantation and antithymocyte globulin in treatment of young patients with severe aplastic anemia

Fifty-seven patients younger than 25 years with severe aplastic anemia underwent either bone marrow transplantation or antithymocyte globulin therapy (A TG) to ascertain which approach should be used in young patients. Thirty-five patients who had an HLA-identical sibling donor underwent bone marrow transplantation after conditioning with cyclophosphamide and low-dose total-body radiation. Twenty-two patients who did not have an HLA-identical donor received ATG. The 2-year actuarial survival o f patients after transplant is 72% (95%, C1 64% to 80%), versus 45% (95%, CI 29% to 61%) in those given ATG therapy (P = 0.18). In those patients surviving 6 months after treatment, return o f peripheral blood counts to normal values was more common in patients who received marrow transplant compared with those given A TG therapy (P < 0.001). Furthermore, 24 o f 26 transplant survivors had Karnofsky performance scores >90 %, compared with only five o'f 13 A TG survivors. These data suggest that bone marrow transplantation is the preferred therapy for severe aplastic anemia in young patients who have an HLA-identical sibling donor. A TG should be reserved for those young patients with severe aplastic anemia who do not have a histocompatible marrow donor. (J PEDIATR 103:920, 1984)

Eliel Bayever, M.D., Richard Champlin,M.D., Winston Ho, M.D., Carl Lenarsky, M.D., Susan Storch, M.D., Stephan Ladisch, M.D., Robert P. Gale, M.D., and Stephen A. Feig, M.D. Los Angeles, California

From the Gwynne Hazen Cherry Memorial Laboratories, the Bone Marrow Transplant Team, and the Departments o f Pediatric~ and Medicine, UCLA School o f Medicine. Supported in part by Grant CA 23175from the National Cancer Institute, National Institutes o f Health, and by Grant RR-865 from the U.S. Public Health Service. Dr. Champlin is the recipient o f a New Investigator Research Award from the National Institute o f Arthritis, Diabetes, Digestive and Kidney Disease; Dr. Lenarsky is a Junior Faculty Clinical Fellow o f the American Cancer Society; Dr. Ladisch is the recipient o f Research Career Development Award CA 00821 from the National Cancer Institute, and a Scholar o f the Leukemia Society o f America. Presenied in part in abstract form, Clin Res 31:115A, 1983, and Pediatr Res 17-229A, 1983. Submitted for publication Dec. 27, 1983; accepted June 1, 1984. Reprint requests: S. A. Feig, M.D., Department o f Pediatrics, Division o f Hematology-Oncology, UCLA School o f Medicine, 10833 Le Conte, Los Angeles, CA 90024.

920

TheJournalofPEDIATRICS

APLASTIC ANEMIA is characterized by pancytopenia resulting from bone marrow failure. In its severe form it is associated with high morbidity and mortality, particularly within the first year? -3 In recent years, although supportive care has been improved by the use of new antibiotics and ALG ATG CI GVHD HLA

Antilymphocyte globulin Antithymocyte globulin Confidence interval Graft-versus-host disease Human leukocyte antigen

the transfusion of selected blood components, there has been no substantial improvement in the survival of patients with severe aplastic anemia. Androgens have been reported to be beneficial in rare individuals but have little impact on overall morbidity and mortality (reviewed in references 4

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Treatment o f aplastic anemia in young patients

to 7). More recently, bone marrow transplantation from an HLA-identical sibling has been used successfully, especially in young patients; recent series report survival rates of approximately 50% to 80% in patients younger than 25 years5,5 Many patients, however, do not have an HLA-identical donor. Treatment of these patients with A L G or ATG, with or without androgens or the infusion of HLAhaploidentical bone marrow, has been shown in nonrandomized trials to improve their peripheral blood counts.~6:~ Two recent large prospective randomized trials 2z'23demonstrate the efficacy of ATG, compared with supportive care only, in the treatment of severe aplastic anemia. The risks of bone marrow transplantation, particularly graft rejection, graft-versus-host disease, and opportunistic infections, may be severe or even fatal. In contrast, the complications of A T G therapy, particularly serum sickness, are usually mild or easily treated. We therefore sought to determine whether treatment with ATG should be the primary therapeutic approach in all young patients regardless of availability of an HLA-identical sibling. We analyzed the outcome in young patients with severe aplastic anemia, both with respect to survival and recovery from disease, who concurrently underwent therapy at U C L A with either bone marrow transplantation or ATG. We present this interim report to compare the outcome of ~:reatment in young patient s who were previously reported as part of a larger'group of patients of all agesJ 4

Table I. Demographic characteristics of patients with severe aplastic anemia

METHODS

Fifty-seven consecutive patients younger than 25 years with severe aplastic anemia underwent treatment at UCLA between November 1977 and October 1982 (Table I). The experimental use of ATG was approved by the UCLA Human Subject Protection Committee. Informed consent was obtained from all patients or their representatives prior to the initiation of therapy. Criteria for the diagnosis of severe aplastic anemia were those defined by the International Aplastic Anemia Study Group4: (1)bone marrow cellularity <25% (with <30% myeloid cells); and (2) peripheral counts, taken on three 6ccasions 24 hours apart, including at least two of the following: granulocytes <0.5 X 109/L, platelets <20 x 109/L, reticulocytes <20 X 109/L. All 35 patients who had an HLA-identical donor underwent bone marrow transplantation. The 22 patients without an HLA-identical donor received ATG therapy. This high proportion of patients who underwent transplantation reflects the local referral pattern rather than the proportion of patients with an HLA-identieal donor in the general population.

921

Treatment Bone marrow Antilhymocyte transplantation globulin

Number of patients Sex (M/F) Age (yr) Median Range Interval from diagnosis to treatment (day) Median Range Cause of aplasia Idiopathic Hepatitis Chemical/drug Paroxysmal nocturnal hemogtobinuria

35 23/12

22 15/7

17 2 to 24

15 1 to 23

60 9 to 2520

58 8 to 2669

25 5 5 0

17 3 1 1

Conditioning for transplantation included cyclophosphamide 50 m g / k g / d a y on days - 5 , - 4 , - 3 , and - 2 , followed by total-body radiation (3 Gy) on the day before transplantation. 9,t5 The median dose of bone marrow administered was 2 x 108 (range 0.4 to 6.0 x 108 nucleated ceils per kilogram recipient body weight. Methotrexate was given to modify or prevent GVHD, as described.25 Patients who developed acute GVHD of grade >_22~ were given corticosteroids (prednisone 2 m g / k g / d a y or parenterally administered equivalent). Nine patients who received transplants were given transfusions of cytomegalovirus immune plasma, and three received immune globul i n intravenously in an attempt to prevent or modify interstitial pneumonia. 27 Treatment with ATG consisted of eight daily doses of equine anti-human thymocyte globulin (Upjohn, Kalamazoo, Mich.; lot 1790, 20 m g / k g / d a y iv over 4 to 6 hours), and prednisone (40 mg/mZ/day for 5 days beginning on the last day of ATG treatment) to abrogate the manifestations of serum sickness. Patients given A T G did not receive bone marrow infusion or androgens. Criteria for response to ATG, defined prospectively, were a sustained increment above pretreatment levels by 3 months after therapy of granulocytes by >0.5 x 109/L or platelets by >30 • 109/L or complete resolution of red cell transfusion requirements. Granulocytopenic patients with fever or documented infections were given broad-spectrum antibiotics parenterally. Documented or presumed fungal infections were treated with amphotericin B. Herpes simplex and zoster

922

Bayever et al.

The Journal o f Pediatrics December 1984

Table II. Hematologic recovery 6 months after treatment Treatment Bone marrow transplantation

Antithymocyte globulin

26/28 27/28 24/28 24/28 (86%)

Hemoglobin >_12 gm/dl Granuloeytes >_2 X 109/L Platelets >_100 X 109/L Recovery in all three cell lines

4/18

4/18 3/18 3/18 (14%)

P <0.001 <0.001 <0.001 <0.001

Data representnumberof patientsshowingrecovery/numbersurviving6 monthsafter treatment.

Table III. Comparison of complications and causes of death after treatment Treatment

Complications Acute or chronic GVHD, interstitial pneumonia Serum sickness Hypertension Causes of death Hemorrhage Infection Graft rejection Liver toxicity (veno-occulusive disease) Acute GVHD and infection, interstitial pneumonia Chronic GVHD and infection Total deaths

Bone marrow transplantation

Antithymocyte globulin

17/33"1

NA

NA NA

22/22 3/22

0 1 1 1

4 5 NA 0

3

NA

3

NA

9/35*

9/22

*Data representnumberof patientsaffected/numbertreated. tThe patientwho died of sepsis 1 day after transplantand the patientwho rejected the graft are excluded. NA, Not applicable.

infections were treated with acyclovir. Blood products were irradiated (15 Gy) prior to administration. Criteria for transfusion have been previously described. 22 Comparable supportive care was provided to both treatment groups. Statistical Analysis. Survival curves were estimated by the standard Kaplan-Meier method of life table analysis.28 Survival curves were compared by Generalised Savage (Mantel-Cox) test 28 and Fisher exact test (two tailed). 29 Hematologic responses were compared using chi-square with Yates continuity correction. RESULTS Response. Twenty-eight of 35 patients who underwent marrow transplantation and 18 of 22 given ATG therapy

survived 6 months after treatment. Twenty-four of the 28 patients with transplants had complete and sustained hematologic recovery with normal peripheral blood counts within 6 months of treatment (Table II). Eight (36%) of the 22 patients who received ATG showed a response at 3 months according to the criteria defined above. Patients who had no response within 3 months of receiving ATG did not subsequently improve. One patient showed improvement in granulocyte count, another in red ceil transfusion requirements; one each responded in both granulocytes and platelets, granulocytes and red cell transfusion requirements, and platelets and red cell transfusion requirements; and three responded in all three cell lines. The two patients who responded in only one cell line continued to fulfill the criteria for severe aplastic anemia. Four of eight responders whose counts we were able to monitor for 1 year continued to improve: granulocyte count in four, platelet count in two, and red cell transfusion requirements in one. Three of t8 survivors showed full hematologic recovery with normal peripheral blood counts 6 months after ATG therapy (Table II). Response to ATG appeared to be independent of age, sex, cause of aplasia, number of transfusions prior to treatment, and time from diagnosis to treatment, but the patient numbers were too small for statistical analysis. No clinical predictors of response to ATG could be identified. Complications of therapy. The major complications (Table III) of bone ma~ow transplantation were GVHD and interstitial pneumonia, which were observed in moderate or severe form in 17 patients. Serum sickness was observed in all patients given ATG but was usually mild and responded promptly to brief treatment with corticosteroids. Three patients given ATG developed severe hypertension during therapy before the initiation of corticosteroid therapy and required aggressive pharmacologic management for 7 to 14 days. The cause of the hypertension is unknown but was temporally related to the administration of ATG. Survival. The l- and 2-year actuarial survival in the 35 patients who underwent transplantation are 82% (95%, CI

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Treatment of aplastic anemia in young patients

923

100 -~ Transplant 6O

:---

! I

22

:_--2_

I I I l e - - - -i . . . . . . . . . . .

-6

40

U')

30

,4 ....

-i

ATG

2O I

I

25

50

I

75

Time (months) Fig. 1. Product limit analysis of percent survivaF7of patients with severe aplastic anemia treated with horse anti-human antithymocyte globulin therapy (ATG) or bone marrow transplantation.

76% to 88%) and 72% (95%, CI 64% to 80%), respectively (Fig. 1), and of the 22 patients who received ATG therapy are 60% (95%, CI 49% to 71%) and 45% (95%, CI 29% to 61%), respectively (P = 0.18). All eight patients with severe aplastic anemia who responded after ATG therapy are alive. One of the responders has relapsed but still survives, with supportive care only, 51/2 years after receiving ATG. Nine of the 14 nonresponders died at a median of 180 days after receiving ATG. The difference in survival between responders and nonresponders is highly significant (p = 0.005). The five nonresponders who are still alive account for the difference between ATG response rate (36%) and the 2-year actuarial survival rate (47%). There were nine deaths in each treatment group (Table III). Among the patients who received transplants, one died of infection, one because of graft rejecUon, and seven deaths were related to complications of the transplantation procedure. All deaths among the patients given ATG therapy resulted from hemorrhage or sepsis and were related to the underlying aplasia. Quality of Life. Karnofsky performance scores 3~ were assessed for all patients at the end of follow-up (Fig. 2) to determine the quality of life. Briefly, those able to carry on normal activity and to work are scored between 71% and 100%, those unable to work from 41% to 70%, and those unable to care for themselves 1% to 40%. 29Only two of the 26 patients surviving transplantation had scores <90%. One patient with a score of 70% had moderately severe chronic GVHD, and the other was receiving therapy for a T cell lymphoma diagnosed 8 months after transplant, the

(20)

7

4oi o 5o >

og

(3)

20

(3)

(2)

10 (1)

4'o

50

do

70

8'0

go

lOO

Karnofsky Score (%)

Fig. 2. Karnofsky performance scores of patients with severe aplastic anemia surviving to date of analysis after bone marrow transplantation (open bars) or antithymocyte globulin therapy (hatched bars). Ordinate represents percentage of surviving patients from each group at each Karnofsky Score. Numbers in parentheses indicate actual number of patients in group.

genetic origin of which was not determined. I n contrast, among the surviving 13 patients who received ATG therapy, seven had scores _<70%, which reflected persistent complications of aplastic anemia. DISCUSSION Previous prospective trials of ATG therapy 22,23 comprised patients of all ages; however, the study of Camitta et al. 23had a preponderance of young patients (median age of

924

Bayever et al.

treatment group 16 years, median age of concurrent controls 19 years, median age of historical controls 13 years). Inasmuch as the relevance of ATG therapy in children was reasonably established and the morbidity of ATG therapy is less intense than that of transplantation, our study was undertaken to compare the outcome of transplantation and ATG therapy. If comparable survival and recovery were achieved, the less invasive therapy (ATG) would be preferable, even if a marrow donor were available. The major complications of bone marrow transplantation are GVHD and interstitial pneumonia, which were observed in moderate or severe form in 10 patients. There is no effective treatment of severe GVHD, and there is substantial mortality in the severe cases. 26 In contrast, the complications of ATG treatment are generally milder and easier to control. Although the survival in patients who received transplants was not significantly improved, the rapidity and completeness of hematologic recovery was better than observed in patients given ATG therapy. Thus surviving transplant patients experienced less morbidity than surviving ATG-treated patients. Previous comparisons of bone marrow transplantation and ATG therapy in severe aplastic anemia have reached contradictory conclusions. Gratwohl et al? t'32 observed 50% survival after bone marrow transplantation and 75% survival after antilymphocyte globulin in a study involving 79 patients of all ages. They concluded that ALG with androgens was superior. However, the incidence of graft rejection was high (18%), possibly because of the use of a conditioning regimen with cyclophosphamide alone. Gluckman et alfl 2"33 reported data similar to ours. They concluded that for young patients bone marrow transplantation remains the treatment of choice. However, theirs was a multicenter trial, making it difficult to ensure c6mparability of care. Our data, obtained at a single institution and demonstrating an improved quality of survival in patients who underwent marrow transplantation compared with those who received ATG therapy, support Gluckman's conclusion. Only one lot of ATG was used in our study. Other lots may give different results, 34 although published reports using other types of ATG have been comparable. ~6-2~ Camitta et alfl3 reported an overall survival of 76% in 29 patients given anti-thoracic duct lymphocyte globulin, HLA-haploidentical marrow, and androgen, but only a 67% survival in 21 of those patients younger than 20 years, which is similar to our survival rates in young patients receiving ATG alone. Although age does not appear to affect mortality after ATG therapy 22 the mortality after bone marrow transplantation increases with age. 15 Therefore our recommendation should apply only to patients younger than 25 years of age.

The Journal of Pediatrics December 1984

A number of considerations require further study and may affect future recommendations regarding treatment. The analysis of long-term side effects of current treatment modalities must be awaited. In one of our patients a lymphoma developed 8 months after bone marrow transplantation. The interval between bone marrow transplantation and diagnosis of lymphoma was shorter than one would expect for the development of a secondary malignancy, but this risk must be evaluated with further transplant experience. Growth and development in pediatric patients are also of special concern. Sanders 8 reported little deleterious effect on growth and development in an 11-year experience with bone marrow transplantation in 59 survivors with aplastic anemia who received cyclophosphamide conditioning alone. Thirty-six percent of the patients given ATG therapy responded. Although response to ATG could not be predicted by clinical features, several in vitro methods for making such a prediction have been proposed. 3~,36Thus, in the future it may become possible to identify a group of patients for whom ATG should be the primary treatment even if an HLA-identical donor is available. Our data indicate that there is currently an advantage to performing bone marrow transplantation as the primary therapy in those young patients with severe aplastic anemia who have an HLA-identical donor, whereas ATG may be used when an HLA-identical donor is not available. We thank Ms. Priscilla Ireland and Ms. Nancy Lyddane for administrative support; Ms. Fran Wiley for nursing assistance; Ms. Donna Lopez for secretarial help; Dr. Mario Barras and Dr. Elliot Landaw for their help with the statistical analysis; and the nurses and house staff of the pediatric and adult bone marrow transplant units for their effort and cooperation.

REFERENCES 1. Li PF, Alter BP, Nathan DG: The mortality of aplastic anemia in children. Blood 40:153, 1972. 2. Lynch RE, Williams DM, Reading JC, Cartwright GE: The prognosis in aplastic a~emia. Blood 45:517, 1975. 3. Rozman C, Marin P, Granena A, Nomdedeu B, Montserrat E, Feliu E, Vives-CorronsJ-L: Prognosis in acquired aplastic anemia: A multivariate statistical analysis of 80 cases. Scand J Haematol 26:321, 1981. 4. Camitta BM, Thomas ED, Nathan DG, Gale RP, Kopecky KJ, Rappeport JM, Santos G, Gordon-Smith EC, Storb R: A prospective study of androgens and bone marrow transplantation for treatment of severe aplastic anemia. Blood 53:504, 1979. 5. Najean Y:, Long-term follow-up in patients with aplastic anemia: A study of 137 androgen-treated patients surviving more than two years. Am J Meal 71:543, 1981. 6. Gale RP, Feig SA, Champlin R, Fitchen JH: Aplastic anemia: Biology and treatment. Ann Intern Med 95:477, 1981. 7. Camitta BM, Storb R, Thomas ED: Aplastic anemia: Patho-

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8. 9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

genesis, diagnosis, treatment and prognosis. N Engl J Med 306:645, 1982. Sanders J: Eleven years of marrow transplantation for children with aplastic anemia [abstract]. Blood 60:172a, 1982. UCLA Bone Marrow Transplant Team: Prevention of rejection following bone marrow transplantation. Blood 57:9, 1981. Storb R, Doney KC, Thomas ED, Appelbaum F, Buckner CD, Cliff RA, Deeg H J, Goodell BW, Hackman R, Hansen JA, Sanders J, Sullivan K, Weiden PL, Witherspoon RP: Marrow transplantation with or without donor buffy coat cells for 65 transfused aplastic anemia patients. Blood 59:236, 1982. Gordon-Smith EC, Fairhead SM, Chipping PM, Hows J, James DCO, Dodi A, Batchelor JR: Bone-marrow transplantation for severe aplastic anemia using histocompatible unrelated volunteer donors. Br Med J 285:835, 1982. Gluckman E, Barrett A J, Arcese W, Devergie A, Degoulet P: Bone marrow transplantation in severe aplastic anemia: A survey of the European Group for Bone Marrow Transplantation (EGBMT). Br J Haematol 49:165, 1981. Storb R: Recent developments on allogeneic marrow transplantation for the treatment of severe aplastic anemia. Blur 43:339, 1981. Ramsay NKC, Kim TH, McGlave P, Goldman A, Nesbit ME, Krivit W, Woods WG, Kersey JH: Total lymphoid irradiation and cyclophosphamide conditioning prior to bone marrow transplantation for patients with severe aplastic anemia. Blood 62:622, 1983. Feig SA, Champlin R, Arenson E, Yale C, Ho W, Tesler A, Gale RP: Improved survival following bone marrow transplantation for aplastic anemia. Br J Haematol 54:509, 1983. Jansen J, Zwaan FE, Haak HL, te Velde J, Guiot HFL, Sabbe LJM, Eernisse JG, Tricot GJK, van Rood J J: Antithymocyte globulin treatment aplastic anemia. Scand J Haematol 28:341, 1982. Jansen J, Zwaan FE, Guiot FL, Simonis RFA, Haak HL: Anti-lymphocyte globulin treatment of aplastic anemia. Exp Hematol 10(suppl 10):21, 1983. European Group of Bone Marrow Transplant (EGBMT): Results of immunosuppression of 170 cases of severe aplastic anemia. Br J Haematol 51:541, 1982. Doney KC, Weiden PL, Buckner CD, Storb R, Thomas ED: Treatment of severe aplastic anemia!.using antithymocyte globulin with or without an infusion of HLA-haploidentical marrow. Exp Hematol 9:829, 1981. Fairhead SM, Chipping PM, Gordon-Smith EC: Treatment of aplastic anemia with antilymphocyt~ globulin (ALG). Br J Haematol 55:7, 1983. Miller W J, Branda RF, Flynn PJ, Howe RB, Ramsay NKC, Condie RM, Jacob HS: Antithymocyte globulin treatment of severe aplastic anemia. Br J Haematol 55:17, 1983. Champlin RC, Ho W, Gale RP: Antithymocyte globulin treatment in patients with aplastic anemia: A prospective randomized trial. N Engl J Med 308:113, 1983.

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23. Camitta B, O'Reilly R J, Sensenbrenner L, Rappeport J, Champlin R, Doney K, August C, Hoffman RG, Kirkpatrick D, Stuart R, Santos G, Parkman R, Gale RP, Storb R, Nathan D: Antithoracic duct lymphocyte globulin therapy of severe aplastic anemia. Blood 62:883, 1983. 24. Champlin R, Ho W, Bayever E, Winston D J, Lenarsky C, Feig SA, Gale RP: Treatment of aplastic anemia: Results with bone marrow transplantation, antithymocyte globulin, and a monoclonal anti T cell antibody. In Young NS, Levine AS, Humphries RK, editors: Aplastic anemia: Stem celt biology and advances in treatment. Proceedings of the Third International Conference on Aplastic Anemia. New York, 1984, Alan R. Liss, pp 227-238. 25. Thomas ED, Storb R, Clift RA, Fefer A, Johnson FL, Neiman PE, Lerner KG, Glucksberg H, Buckner CD: Bone marrow transplantation. N Engl J Med 292:832, 895, 1975. 26. Hershko C, Gale RP: GVHD scoring system in predicting survival and specific mortality in bone marrow transplant recipients. In Gale RP, editor: Biology of bone marrow transplantation. UCLA symposia on molecular and cellular biology, vol 17. New York, 1980, Academic Press, p 59. 27. Winston D, Pollard R, Ho W, Gallagher JG, Rasmusson LE, Huang SN, Lin C, Gossett T, Merigan TC, Gale RP: Cytomegalovirus immune plasma in bone marrow transplant recipients. Ann Intern Med 97:1 l, 1982. 28. Miller R: The survival analysis. New York, 1981, Wiley, pp 46, 82. 29. Fleiss L: Statistical methods for rates and proportions. New York, 1973, Wiley, p 20. 30. Karnofsky DA, Burchenal JH: The clinical evaluation of chemotherapeutic agents in cancer. In MacClcod CM, editor: EvaIuation of chemotherapeutic agents. New York, 1949, Columbia University Press, p 191. 31. Speck B, Gratwohl A, Nissen C, Leibundgut U, Ruggero D, Osterwalder B, Burri HP, Cornu P, Jeannet M: Treatment of severe aplastic anemia with antilymphocyte globulin or bone marrow transplantation. Br Med J 282:860, 1981. 32. Gratwohl A, Miller M, Osterwalder B, Nissen C, Speck B: Update of the Basel prospective study comparing BMT with ALG in severe aplastic anemia. Exp Hematol 10(suppl 10):24, 1983. 33. Gluckman E: Report of the EGBMT working party on severe aplastic anemia. Exp Hematol 10(suppl 10):14, 1983. 34. O'Reilly RE, Camitta B, Nathan DC: Antithoracic duct lymphocyte globulin [letter]. Blood 62:1304, 1983. 35. Nagasawa T, Abe T, Hanada T: .Inhibitory effects of T cells on in vitro granulopoiesis, erythropoeisis, and immunoglobulin production in patients with aplastic anemia. Scand J Haematol 28:389, 1982. 36. Glassetti A, Faille A, Balitrand N, Gluckman E, Devergie A, Dresch C: Inhibitory effects of peripheral blood cells on in vitro colony formation by autologous bone marrow in aplastic anemia: Relation with response to immunosuppressive therapy. J Clin Pathol 35:1316, 1982.