British journal oj Huematologg, 1991, 77, 502-508

ADONIS

000710489100081 Y

Danazol treatment of myelodysplastic syndromes EDWARD A . STADTMAUER. PETERA . CASSILETH,MARIANEDELSTEIN,J A N E T ABRAHM,A L A ND . S C H R E I B E K , PETERC. NOWELL A N D DOUGLAS B. CINESSection of HematologylOncology, Department of Medicine, Cancer Center, and Department oJ Pathology and Laboratory Medicine of the University of Pennsylvania School of Medicine

Received 12 July 1990; accepted for publication 1 9 November 1990

Summary. Peripheral cytopenias are common in patients with myelodysplastic syndromes. We previously successfully treated three such patients with improvement of some cytopenias with the impeded androgen danazol. To confirm this finding and elucidate the mechanism of response, we treated an additional 22 patients with myelodysplasia with oral danazol(600-800 mg daily) for 3-12 months. Eleven of 22 evaluable patients taking danazol met our criteria for improvement of peripheral counts, mainly thrombocytopenia. Chromosome analysis, marrow culture studies and serial bone marrow biopsies revealed no alteration of the abnormal clone or normal haematopoiesis in patients on danazol therapy. This suggested that improvement in blood counts was not related to modulation of ineffective haematopoiesis. Investigation of the thrombocytopenia in these patients

revealed that most patients presented with markedly elevated platelet associated IgG (PAIgG). elevated plasma plateletbindable IgG (PBIgG), and a n elevated number of monocyte Fcy receptors. Treatment with danazol was associated with a decline in monocyte Fcy receptor number without significantly altering the elevated PAIgG or PBIgG levels. These results are similar to our observations in patients treated with danazol for chronic idiopathic thrombocytopenia purpura (ITP).Our data suggest that a component of the thrombocytopenia occurring in patients with myelodysplasia may be due to enhanced peripheral blood cell destruction by abnormal macrophages. Danazol may modulate cytopenia by decreasing the number of monocyte Fcy receptors. Danazol treatment was associated with minimal toxicity, but clinically meaningful responses were rare.

Myelodysplastic syndromes are heterogeneous disorders characterized by variable degrees of peripheral cytopenias which are generally believed to result from disordered and ineffective haematopoiesis by an abnormal clone of haematopoietic stem cells (Bennett et a / . 1982:Greenberg, 1983).The extent to which peripheral destruction of these cells may contribute to the cytopenias is. however, unclear. The natural history of myelodysplasia differs from patient to patient, ranging from stable asymptomatic depression of one or more peripheral blood counts to severe pancytopenia (Koeffler & Golde. 1980).Patients with myelodysplasia have considerable morbidity and mortality from bleeding, infection and evolution into frank leukaemia (Foucar et a/, 1985). Treatment for myelodysplastic syndromes has been unsatisfactory, limited primarily to supportive care in this largely elderly patient population (Buzaid et al. 1986:Tricot et al. 1987:Larson. 1985).Therapy with corticosteroids (Bagby. 1985).cis-retinoic acid (Swanson et a/, 1986:Abrahm et al. 1986:Greenberg et a / , 1985:Picozzi et a/. 1986),low-dose

cytosine arabinoside (Wisch et a / , 1983:Winter et a / , 1985: Bolwell et al. 1987: Griffin et a/. 1985). intensive antileukaemic therapy or bone marrow transplantation (Buzaid et al, 1986: Larson. 1985:Bagby, 1985;Applebaum et a/, 1984:Stuart & Mangan. 1986)have had limited success or applicability and considerable toxicity. We previously reported three patients with myelodysplasia who had been successfully treated with the synthetic. attenuated androgen, danazol. with a sustained improvement in their platelet counts throughout the continued administration of the drug (Cines et al. 1985).The mechanism by which danazol caused an increase in the platelet count in these three patients was uncertain, but may be similar to its mode of action in immune thrombocytopenia and immune haemolytic anaemia (Ahn et al. 1983. 1985). Our previous studies on immune thrombocytopenia suggested that danazol may impair the clearance of IgG sensitized cells by modulating the number of monocyte Fcy receptors (Schreiber et a/. 1987).We therefore initiated a clinical trial of daily oral danazol in a larger number of patients with myelodysplasia in order to determine whether immune-mediated clearance of peripheral blood cells contributes to the cytopenias in this disorder.

Correspondence: Dr Edward Stadtrnauer. University of Pennsylvania Cancer Center, h Penn Tower, Hospital of the University of Pennsylvania. Philadelphia, PA 191 04. I1.S.A.

502

Danazol and Myelodysplastic Syndromes MATERIALS AND METHODS Patients. Twenty-two patients with myelodysplastic syndromes were treated between February 198 5 and June 1989. The treatment protocol was approved by the IRB of the University of Pennsylvania and informed consent was obtained from all patients. The patients were subclassified according to the FAB classification (Bennett et ul, 1982). All patients were treated with danazol at a dose of either 600 or 800 mg orally in three or four divided doses if their weight was < or > 140 Ib respectively. Patients with inadequate liver function (direct bilirubin > 1 . 5 mg/dl, alkaline phosphatase > 2 x normal, transaminase > 3 x nor mal). inadequate renal function (serum creatinine > 1 . 5 mg/ dl). pregnancy. dysfunctional uterine bleeding, congestive heart failure. diabetes mellitus and those taking oral anticoagulants were ineligible. Treatment was continued for up to 12 months provided that some evidence of benefit was apparent after 3 months follow-up, liver function tests did not worsen, the disease did not evolve into frank leukaemia, and the patient was willing to continue treatment. Response was defined as one or more of the following criteria ifsustained over a 2-month time interval: a rise in the platelet count greater than 2 5 x 1OY/I over pre-treatment levels if the pre-treatment count was less than 1 5 0 x 10y/l, an increase in haemoglobin greater than 2 g/dl or disappearance of a previous requirement for red blood cell transfusion, or a n increase in absolute neutrophil count greater than 0.5 x 1 Oy/I if the pre-treatment value was less than 2 x 1OY/1. All patients received packed red blood cell transfusions to maintain haemoglobin greater than 8.0 g/dl and random donor platelet transfusions to maintain platelet count greater than 2 0 x 10"/1.Patients received intravenous or oral antibiotics as needed for neutropenic fever. A number of laboratory studies, described below, were performed prior to and during treatment with danazol. Platelet untiglobulin test. Platelet associated IgG (PAIgG) and plasma platelet-bindable IgG (PBIgG) were determined using the radiolabelled antiglobulin test (Cines et al, 1982: Schreiber et ul. 1987). Values > 2 SD above the mean of the IgG on the platelet surface or deposited on the platelet by the plasma of > 200 normal donors was considered to represent a positive test. Monocyte F r j receptor assay. Monocytes were isolated from peripheral blood by density centrifugation followed by adherence to serum treated flasks (Chien et al, 1988). Monomeric IgG was labelled with 1151 and binding of IZ5I-IgGmonomer to monocytes at equilibrium was then measured (Schreiber et al. 1987: Kossman et 01, 1986). Specific binding was defined as the cell-associated radioactivity inhibited by 100-fold excess unlabelled IgG. The number of IgG binding sites and the affinity of the IgG binding to monocytes were determined by Scatchard analysis using a linear regression program (Kossman et al. 198h). Student's t-test was used to determine whether differences between two monocyte-donor populations were statistically significant. Chromosome anulysis and marrow cultures. Approximately 1 ml of bone marrow aspirate was obtained for karyotype analysis and marrow culture. Direct preparations from

50 3

colchicine-treated cells and preparations made after 24 h in culture without mitogenic stimulation were stained by the Trypsin-Giemsa banding method (Abrahm. 1983). A total of 20-40 chromosome counts and at least three karyotypes were analysed in each case. Repeat marrow aspiration for karyotype evaluation was performed after each patient had taken danazol for a minimum of 3 months. In a n attempt to correlate danazol-induced responses to in vitro marrow growth characteristics. bone marrow granulocyte-macrophage colony forming units (CFU-GM) were evaluated before and after treatment with danazol. Marrow cells were cultured alone or with therapeutic concentrations of danazol and assayed for the formation of granulocyte and monocyte colonies as per methods previously described (Aye et al, 1974: Abrahm & Smiley. 198 1 ). RESULTS Clinical characteristics of patients Table I lists the clinical characteristics of the 22 patients that we studied. They ranged in age from 28 to 8 4 years (median = 65 years). Seventeen patients required frequent red blood cell transfusions because of symptomatic anaemia and four required regular platelet transfusions because of lifethreatening thrombocytopenia. One patient had previously received chemotherapy for Hodgkin's disease. No other patient had a known exposure to a toxin believed to cause myelodysplasia. Five patients had been treated previously with other androgens and nine patients had received prednisone. The distribution of FAB types included seven patients with RA. six RARS, seven RAEB and two RAEBT (abbreviations are explained in Table I). There were no patients with CMMOL in our series. Median overall survival from time of enrolment on this study was 12 months (range 1-53+ months). Nine patients (40%)died as a result of progression to AML. This represented four of 1 3 patients (30%) with RA or RARS and five of nine patients ( 5 5 % ) with RAEB or RAEBT. Seven patients died from medical complications, including bacterial sepsis (two). bleeding (one), heart failure (two) and hepatic failure from non-A non-B hepatitis (two). Clinical outcome The results of therapy with danazol are listed in Table I. Eleven of 22 cases (50%) met our criteria for a clinical response including six (27%)with an increase in absolute granulocyte count and eight (36%) with an increase in platelet count. One patient no longer required transfusion with red blood cells. No significant decrease in percentage of bone marrow blasts, degree of dyspoiesis, or change in cellularity was observed following danazol treatment in any patient. Responding patients continued to respond for the duration of treatment with danazol (3-12 months). Among the responding patients, the median survival from initiating danazol was 15.7 months (range 5-37+ months) while the median survival time of non-responding patients was 29 months (range 4 - 5 3 + months). The difference in survival was not statistically significant. The toxicity of danazol treatment in this series of patients was mild. Danazol was not discontinued in any patient

Edward A. Stadtmauer et a1

504

Table I. Clinical characteristics, response and survival data of 22 patients with myelodysplastic syndromes treated with danazol Survival (months)

Diagnosis*

Age/sex

Karyotype

Responset

1

RAEB

65/M

44.XY. - 5,+ 6q-, - 7.- 12,- 17,+ring

NR

8

2

RA

77/M

47,XY,+8

NR

12

3 4 5 6 7

RA RAEBT RA RARS RAEB

5 5/F 28/M 73/M 74/F 84/F

46.XX 46,XY 46,XY 46.XX 46,XX

NR RP RP NR RE

53+ 17 16 34 15

Patient

9

8

RAEB

9

RAEB

7 3/M 60/F

46,XY 46.XX

RG RPG

18

10

11

RARS RA

72/F 82/M

45,xx. - 9.1 1p -q 45.x.-Y

NR RPG

47 + 6

12

RAEBT

58/M

46.XY

NR

4

13

RA

63/M

46,XY

RPG

14

14 15 16

RARS RARS RA

70/M 69/M 70/M

46.XY.20q46,XY 43.X. -Y. -2. - 7. - 20,Sq- .12p+, +mar

NR NR RG

44

17

RAEB

5 3/M

46.XY

RPG

16

18

RAEB RARS RA RARS RAEB

78/F 61/M 66/M 54/M 65/M

46.XX.iso( 17q) 46,XY 46,XY 46,XY 46.XY

RPG NR RP NR NR

37+ 35+ 27+ 23 23

19 20 21 22

+

5 6

Cause of death Acute leukaemia or progressive disease Acute leukaemia or progressive disease Alive Sepsis Bleeding Heart failure Acute leukaemia or progressive disease Hepatic failure Acute leukaemia or progressive disease Alive Acute leukaemia or progressive disease Acute leukaemia or progressive disease Acute leukaemia or progressive disease Alive Hepatic failure Acute leukaemia or progressive disease Acute leukaemia or progressive disease Alive Alive Alive Heart failure Sepsis

* FAB classification: refractory anaemia (RA): refractory anaemia with ringed sideroblasts (RARS):refractory anaemia with excess blasts (RAEB):refractory anaemia with excess blasts in transformation (RAEBT). t NR = No response. RG =Met criteria for granulocyte response. RP = Met criteria for platelet response. RE = Met criteria for erythroid response. RPG =Met criteria for granulocyte and platelet response. because of toxicity. Patient 21 developed a maculopapular rash. Mildly increased serum transaminase levels were observed in seven of the 2 2 evaluable patients. Serial chromosome analysis We performed chromosome analysis pre-therapy and during therapy whenever possible (Table I). Seven of 22 patients

(31%) had clonal karyotype abnormalities detected when first studied. Patients with unfavourable myelodysplasia (RAEB. RAEBT) exhibited chromosomal abnormalities (22% v. 38%)less frequently than did patients with more favourable histologies (RA or RARS) but this difference was not statistically significant. Nineteen patients had serial chromosome analyses performed while taking danazol. Patient 1 3

Table 11. P A W , PBIgG, and Fcy receptor number prior to treatment with danazol ~

~~

Test

Patients

Normal

PAIgG* PBIgG* Fcy receptorst

0.48f0.38 (n=19) 1 . 5 1 f 0 . 8 8 (n=19) 4 5 2 0 0 f 10600 ( n = 10)

0.08f0.08( n = 4 1 ) P=0.03 0.60f0.20 (n=60) P = 0 . 0 4 26200f 5900 ( n = 6 0 ) P=0.01

'Per cent platelet associated t Sites/cell ( f 1 SD).

Iz5I

anti-IgC ( f 1 SD).

developed a clone with a n extra abnormal chromosome that could not be further identified. Patient 2 1 developed a new chromosomal marker ( 7 q + ) 3 months after taking danazol which persisted after withdrawal of the drug. No chromosomally-abnormal clone disappeared on danazol treatment. The presence of a normal or abnormal karyotype did not correlate with survival or response to danazol. Marrow culture studies Abnormal proliferation of myeloid precursors in agar cultures occurs in patients with myelodysplastic syndromes (Abrahm ct (11. 1986).Addition ofdanazol to marrow cultures did not alter colony number or the relative distribution of granulocyte or monocyte colonies. No change in marrow growth characteristics occurred while patients were receiving danazol therapy. (Data not shown). Platelet and monocytc riwptor stui1ic.s Serial measurement of platelet count, direct and indirect platelet antiglobulin test and quantification of monocyte Fcy receptors were made to define more precisely the mechanism by which danazol caused an increase in the platelet count in some patients. A t presentation. increased platelet associated IgG (PAIgG) was detected in 15/19 patients with a mean value of 0 . 4 8 f0.38% (normal 0 . 0 8 fOW3%,) (Table 11). Increased plasma platelet bindable IgC (PBIgG) was detected in 15/19 patients with a mean of 1 . 5 1 f 0 . 8 8 x (normal 0 . 6 0 f 0 . 2 0 % ) . The number Fcy receptors/monocyte was elevatedin sixof l O p a t i e n t s w i t h a m e a n o f 4 5 2 0 0 ~1 0 6 0 0 sites/cell (normal 26 2 0 0 f 5900). No change in the level of PAIgC (mean pre-treatment 0.48f0.38%lversus on treatment 0 . 38f0.16'%,.P = 0 . 6 6 ) or PBIgC (pre-treatment 1.5 1 f 0 . 8 8 ~versus l on treatment 1.80fO. 30(j(,. P = O . I 7) was noted in the 19 patients in whom serial measurements were made. In contrast. the number of surface Fcy receptors/monocyte measured decreased in seven of 1 0 patients in whom serial measurements were performed from a pre-treatment mean of 45 20Of 10 600 sites/monocyte t o 2 2 600f 3900 sites/

Danazol and Myelodysplastic Syndromes 1wow

-

80000

t

-

0

5 c 0

T

60000-

c

n 0 0

p

40000-

?-

u

LL

20000

-

0 '

Pretreatment

Treatment

Fig 1 . Effect of danazol therapy on Fcy receptor levels. The number of Fc;. receptors/monocyte before treatment and the minimum during treatment are indicated.

monocyte. P = 0 . 0 4 , on treatment (Fig 1 ). The number of monocyte Fcy receptors was elevated in five ofsix thrombocytopenic patients in whom measurements were made prior to therapy, four of whom responded to danazol with a fall in receptor number (Table 111). One patient in whom normal Fcy receptor numbers were measured before treatment did not respond with an increment in platelet count. The clinical course of patient 20. shown in Fig 2 . is representative of responding patients. Prior to treatment, he was moderately thrombocytopenic with elevated PAIgC.

-5

-4

-3

-2

PA IgG -1

- r

0

7

1

5

-

I

10

-

Time (months)

I

15

-

5 05

PB IgG Plt Count FcR

I "

20

Fig 2. Clinical course in patient 20.

506

Edward A. Stadtrnauer et a1

Table 111. Response to danazol platelet count (x

FCY

receptors/monocyte'

lO'/I)

PreRx

Post Rx

Clinical response to danazol treatment

43 101 140 87 96 76

23 91 173 122 206 161

No No Yes Yes Yes Yes

Pre Rx

Post Rx

15800 58400 57500 89000 98000 78600

4900 N.D. N.D.

13400 33500 46000

'Normal = 262OOf 5900 (meanf SD).

normal PBIgG, and his monocytes expressed an increased number of Fcy receptors/monocyte compared with cells from healthy donors. His platelet count rose, the number of Fcy receptor/monocyte decreased, PAIgG did not change and PBIgG increased after treatment for 12 months. His response persisted until danazol was discontinued, after which his platelet count returned to pretreatment levels. DISCUSSION Despite their morphologic and clinical heterogeneity, the myelodysplastic syndromes all appear to arise as a clonal disorder of haematopoietic stem cells that leads to ineffective haematopoiesis. The syndromes also share the potential to evolve into acute leukaemia. Treatment has been directed at the abnormal clone to restore normal haematopoiesis and prevent transformation to acute leukaemia. Results of treatment with cis-retinoic acid, low-dose cytosine arabinoside. combination chemotherapy, and bone marrow transplantation have been disappointing because the responses are infrequent, incomplete, short lived or can be associated with substantial toxicity (Buzaid et al, 1986: Tricot et al. 1987: Larson, 1985: Bagby. 1985). Supportive care (transfusion of platelets and red blood cells and treatment with antibiotics) remains the cornerstone of therapy for this group of patients who are often elderly and have other medical disorders. We previously treated three patients (Cines et al, 1985) with stable myelodysplasia and troublesome thrombocytopenia with danazol. because the drug had been shown to be effective in immune thrombocytopenia (Ahn et al. 1983) and immune haemolytic anaemia (Ahn et aL 1985). Two of these patients were refractory to random donor and HLA-matched platelets and one had haemolytic anaemia and thrombocytopenia unresponsive to splenectomy. In each patient therapy with danazol was associated with an increase in the platelet count and decrease in the red blood cell transfusion requirements. The mechanism by which danazol led to a rise in the platelet count in these patients was uncertain. In immune thrombocytopenia purpura we observed that danazol therapy is associated with a decrease in the number ofFcy receptors on human monocytes (Schreiber et aJ. 1987). The current study was initiated in order to ( 1 ) determine the frequency with which danazol would improve cytopenias in

additional patients with myelodysplasia, (2) determine the relative contribution of increased peripheral destruction versus ineffective haematopoiesis to cytopenias, and ( 3 ) study the mechanism by which danazol improves cytopenias. The 22 patients with myelodysplasia evaluated in this study were clinically heterogenous. The median age of 65 years and the median survival of 12 months is similar to the clinical presentation and outcome observed by others (Buzaid et al, 1986). Improvement in peripheral granulocyte and/or platelet counts occurred in 50% of patients who continued danazol for a minimum of 3 months. Responses were generally durable as long as danazol was continued. Unfortunately, responses were modest in degree and only a few were clinically significant. Many of these patients had had a lengthy history (months or years) of myelodysplasia prior to entry in this study and were referred for treatment because of worsening cytopenias after periods of relatively stable disease. The short survival and moderate response rate to danazol therapy shown here may therefore be related, in part. to a population of patients with advanced, unstable disease. In this study, danazol appeared to benefit only a small subset of patients with relatively stable myelodysplasia and generally without increased numbers of marrow blasts. Although the precise mechanism of danazol's action in myelodysplasia is not certain, this study provides some insights. Karyotype analysis showed little evidence that danazol altered the abnormal clone even in patients who responded. Danazol did not alter number or distribution of granulocyte or monocyte colonies cultured from the patient's marrow. There was no evidence, therefore, that danazol therapy altered proliferation of the abnormal clone or enhanced the growth of residual normal marrow cells in responding patients. Immunological abnormalities in myelodysplastic syndromes have been reported previously, including: accelerated platelet clearance (Malpass et al, 1984): polyclonal increase in IgG (Solal-Cellgny el al, 1984):abnormalities of B lymphocyte surface receptors (Volsky & Anderson, 1983: Anderson et aJ. 1983): increased platelet associated IgG (Colonbat et al. 1988: Hall et al, 1987: Mufti et al. 1986) and autoimmune haemolytic anaemia (Sokol et al. 1989). Platelet membrane glycoprotein abnormalities including increased numbers of platelet Fcy receptors have been reported to occur in myeloproliferative disorders (Moore & Nachman, 198 1 : Clezardin et al. 1985). No patient in this study had a positive direct or indirect red cell antiglobulin test, but plateletassociated IgG (PAIgG) were markedly elevated in most patients and elevated numbers of Fcy receptors/monocyte were observed in these patients prior to starting danazol therapy. These data suggest that the cells derived from a n abnormal clone may display alterations in surface phenotype and function. Surface membrane alterations may allow platelets to bind increased levels of immunoglobulin and alter the capacity of the malignancy monocyte to bind and ingest IgG-coated cells. The increased levels of PAIgG and PBIgC did not change after treatment with danazol, but the number of monocyte Fcy receptors was reduced. These results are similar to those obtained in patients with chronic immune thrombocytopenia (Schreiber et al. 1987). in whom acceler-

Danazol and Myelodysplastic Syndromes ated clearance of IgG coated platelets by macrophages is k n o w n to occur. We conclude from these studies that increased PAIgG. PBlgG and increased numbers of Fcy receptors on peripheral blood monocytes are found in many patients with myelodysplasia. By analogy to the findings in chronic immune thrombocytopenia. our results suggest that a component of thrombocytopenia in myelodysplasia is due to enhanced peripheral destruction. We hypothesize that the abnormal clone in myelodysplasia is responsible for the membrane alterations that lead to the increase in monocyte Fcy receptors and platelet-bound IgG, although it is possible that such changes are due to the release of cytokines or other biologically reactive molecules either from the abnormal clone or by normal cells in response to the abnormal clone. Danazol therapy does not appear to improve haematopoiesis. ablate the malignant clone, or modify PAIgG or PBIgG. but does induce a decline in the monocyte Fcy receptor number. Patients with RA and KAKS with moderate thrombocytopenia were most likely to respond to danazol. Further investigation of the surface membranes of myelodysplastic cells will help to define their altered biology and may direct future therapy. ACKNOWLEDGMENTS We thank Toby Laiken for her expert assistance in preparing the manuscript for publication. Presented in part at the 30th annual meeting of the American Society of Hematology in San Antonio. Texas. on 3 December 1988. Supported by grants CA42868, CA42232, HL-27068 and AI-22 193 from the National Institutes of Health and the Paul F. Miller, ]r Research Fund. KEFEKENCES Abrahm. 1.1.. (1983) Role of normal human T cell subsets in colony stimulating activity production. Cliriiral Research. 31, 307A. Abrahm. J., Besa. E.C.. Hyzinski. M.. Finan, J. & Nowell. P. (1986) Disappearance of cytogenetic abnormalities and clinical remission during therapy with 13-cis-retinoic acid in a patient with myelodysplastic syndrome: inhibition of growth of the patient's malignant monocytoid clone. Blood. 67, 1323-1 327. Abrahm. J. & Smiley. R. (1981) Modification of normal human myelopoiesis by 1 2-0-tetradecanoyl phorbol-1 3-acetate (TPA). Blood. 58, 1 1 19-1 126. Ahn. Y.S.. Harrington. W.J.. Mylvaganam. R.. Ayub. J. & Pall. L.M. (1985) Danadol therapy for autoimmune hemolytic anemia. Atinals of Infernal Medicinr. 102, 298-301. Ahn. Y.S.. Harrington. W.J..Simon, S.R.. Mylvaganam. R.. Pall, C.M. & So. A.G. ( 1 9 8 3 ) Danazol for the treatment of idiopathic thrombocytopenla purpura. New Erigland Journal of Medicine. 308, 1396-1 399. Anderson. d.W.. Volsky, D.J..Creenberg. B.. Knox. S.J..Bechtold. T.. Kuszynski, C.. Harada. S. & Purtilo. D.T. (1983) Lymphocyte abnormalities in preleukemia. I. Decreased NK activity. anomalous immunoregulatory cell subsets and deficient EBV receptors. kukemia Krsrarch. 7, 389-395. Appelbaum. F.R.. Storb. R.. Ramberg. R.E.. Shulman. H.M.. Buckner. C.D.. Clift. R.A.. Deeg. H.J.. Fefer. A,. Sanders, 1.. Stewart. P..

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