American Journal of Hematology 415-12 (1992)

Cyclosporine and Prednisone Therapy for Pure Red Cell Aplasia in Patients With Chronic Lymphocytic Leukemia G. Chikkappa, D. Pasquale, M.H. Zarrabi, R.J. Weiler, M. Divakara, and M.F. Tsan Medical and Research Services, Department of Veterans Affairs Medical Centers, Albany and Northport, New York (G.C., D.P., M.H.Z., M.D., M.F.T.); Department of Medicine, Albany Medical College, Albany, New York (D.P.;M.D., M.F.T.); Health Sciences Center, SUNY at Stony Brook, New York (M.H.Z.); and Lovelace Medical Center, Albuquerque, New Mexico (R.J.W.)

We describe the characteristics of response to treatment with cyclosporine (CYA) plus prednisone in seven episodes of pure red cell aplasia (PRCA) in four patients with 6 cell chronic lymphocytic leukemia (CLL). Fourteen episodes of PRCA occurred in four patients with CLL. Eleven episodes were treated with conventional therapies which included an alkylating agent and prednisone. Four episodes that failed to respond to conventional therapies and an additional three episodes were treated with CYA and prednisone. Six of the seven episodes, including three of four which had failed conventional therapies, responded to CYA plus prednisone compared with six of eleven episodes treated with conventionaltherapies. Response to CYA and prednisoneoccurred without a reduction in leukemic mass. In contrast, PRCA remission did not occur until after leukemic mass reduction in three of four patients treated successfully with conventional therapies. Time to response was shorter (14 3 days) with CYA plus prednisone than with conventional therapies (154 2 97 days) in three of four patients. These results indicate that CYA plus prednisone is an effective therapy for the induction of remission from PRCA in patients with CLL. o 1992 Wiley-Liss, Inc.

*

Key words: cyclosporine, prednisone, aplasia

INTRODUCTION

tional therapies which successfully induced remission in six other episodes of PRCA in the same four patients.

Pure red cell aplasia (PRCA) is a well-defined entity that occurs in about 6% of patients with B cell chronic lymphocytic leukemia (CLL) [I]. The features of PRCA MATERIALS AND METHODS include anemia with < 21% Hct, uncorrected reticulo- Patients cyte count < 0.5% (or absolute reticulocyte count < 14 Four patients data were retrospectively analysed X 103/pl), absence of neutropenia or thrombocytopenia, (Table I). Patients 1 (WL) and 2 (CF) were managed at and complete or almost complete absence of normoblasts the VA Medical Center, Albany, NY, patient 3 (SK) at in the presence of adequate numbers of granulocytic se- the VA Medical Center, Northport, NY, and patient 4 ries and megakaryocytes in the bone marrow [1,2]. In (GC) at the Lovelace Medical Center, Albuquerque, NM. several patients an abnormal T cell population was described to be responsible for the pathogenesis of PRCA CIinical Assessment [3,4]. We previously reported the successful induction of The size of lymph nodes (graded &3+, 0 being no remission from PRCA by administration of immunosup- enlargement and 1, 2, and 3 + indicating mild, moderate, pressive agents cyclosporine (CYA) and prednisone in a and severe enlargement of palpable nodes) and spleen patient with CLL [ 5 ] . Since then three other cases have been published showing induction of remission of their PRCA by CYA [6-81. We describe here results of six successfully treated episodes of PRCA (including our Received for publication September 6, 1991; accepted January 30, 1992. previously reported case [ 5 ] )with CYA and prednisone in four B cell CLL patients. Results of therapy with CYA Address reprint requests to Dr. G. Chikkappa, ( I I IJ), VA Medical plus prednisone are compared with results of conven- Center, 113 Holland Avenue, Albany, N . Y . 12208. 0 1992 Wiley-Liss, Inc.

Chikkappa et at.

6

TABLE 1. Clinical and Laboratory Features at Diagnosis of PRCA in Patients With CLL*

PT WL

PRCA episode

Age

Sex

Date

HCT, %

Xl,OOO/pl

Retic

Lymph Xl,OOO/pI

Spleen CM

LN (0-3+)

1

64

M

8/79 10179 3/82 12/87 6/88 8/88

15 13 21 21 15 20

0 0 0 4 4 5

131 2 21 55 I42 3 18

4.5 4.5 3.0 8.0 10.0 14.0

1

1 0 2 2 3

2 3 4 5 6

Cell markers SIg+ 79%

CF

1 2 3 4

59

M

4/83 1/86 3/87 5/87

13 21 21 19

0 0 0 0

120 41 127 359

14.0 12.0 5.0 12.0

3 3 2 3

SIg+ 57%

SK

1 2

72

M

1 184 4/89

13 23

2 12

123 64

4.0 7.0

2 2

SIg+ 5 1 %

1 2

63

M

12/85 6/87

18 21

0 0

50 16

5 .0 0.0

2

B4(CD 19)' 65%

GC ~

0

~

*HCT, hematocrit; Retic, reticulocyte count; lymph, lymphocyte count; CM, CM below coastal margin; LN, lymph node; LN 0-3+, size 0 no adenopathy, and 1, 2, and 3 signify mild, moderate, and severe adenopathy; SIg (mouse anti-human IgC), surface immunoglobulin binding B cells; B4,

(cm below costal margin in midclavicular line), and the blood lymphocyte counts were used to assess the leukemic mass. Diagnosis of B cell CLL was established due to the presence of persistent peripheral blood lymphocytosis with a capacity to bind with a mouse anti-human Ig or B, (CD,,+) antibody, and Iymphocytosis in the bone marrow (assessed by morphological studies of the marrow aspirate and/or biopsy samples) [9]. The diagnosis of PRCA was made by the blood and bone marrow studies. The initial clinical course of the first three patients, including evaluation of pathogenesis of PRCA, have been previously reported (WL is patient 3 of ref. 4 and patient 2 of ref. 1 , CF is patient 3 in ref. 1 and the patient of ref. 5, and SK is patient 4 of ref. 1). Those reported studies of pathogenesis of PRCA indicated that during PRCA blood early erythroid progenitors (BFU-E) of WL [4] and bone marrow late erythroid progenitors (CFU-E) of CF [5] were markedly reduced. Unlike the normal blood T cells [lo], the T cells of WL failed to promote the growth of autologous blood BFU-E. The blood T cells obtained from CF during PRCA suppressed the growth of autologous bone marrow CFU-E, while his T cells obtained after remission had no inhibitory activity. Sera (and purified IgG of WL) obtained during PRCA from these two patients did not inhibit autologous and normal allogeneic bone marrow CFU-E or blood BFU-E [3,5]. Serum from SK also failed to inhibit normal allogeneic bone marrow CFU-E and BFU-E and blood BFU-E (unpublished observation). These results suggested that an abnormal population of T cells was responsible for the pathogenesis of PRCA in

WL and CF, and PRCA was not due to a serum factor in WL, CF, or SK. CYA (Sandimmune) Therapy

CYA was administered only when there was a contraindication for administration of cyclophosphamide or when the patient had not responded to conventional therapy containing cyclophosphamide. After establishing that renal and liver functions were normal, informed consent was obtained from each patient, and CYA was given, initially at 7-12 mg/kg daily, in single dose with breakfast. The CYA dosage was titrated to maintain the whole blood trough level (24 hr after the last dose) at 20&700 ng/ml or plasma level of 40-200 ng/ml. The drug was measured by radioimmunoassay [ 11,121. Prednisone was given at 40-60 mg daily along with CYA. Prior Conventional Therapies

Two basic regimens were used. 1) Cyclophosphamide plus prednisone were given as a) daily oral doses of 100-150 mg cyclophosphamide and 40-60 mg prednisone, or b) cyclophosphamide 1.5 g and vincristine 2 mg I.V. on day I , and prednisone 150 mg P.O. daily on days 1 through 5 (CVP regimen), repeated at 3 4 week intervals. 2) Chlorambucil and prednisone combination therapy was given for the 1st episode of WL only. Chlorambucil was given P.O. at 4-8 mg daily for 11 days at which time reticulocyte response was noted. Prednisone was initiated at day 1 and given at 60 mg daily for 3.5 weeks by then his Hct was 32%.

Cyclosporine and Prednisone Therapy

7

TABLE II. Clinical and Laboratory Features After Treatment of PRCA in Patients With CLL With CYA Plus Prednisone or Conventional Therapy?

PT WL

CF

SK

GC

PRCA episode 1 2 3 4 5 6 1 2 3 4 1 2 1

2

Treatment

Responded yesino

LfP CfP CSP CYASP CYA+P SPL RT+CYA*+P C S P f S P L RT P CYAfP CYASP C f B S P f V S S P L RT C+P CfP CYAfP P C+VSP AfCtVSP CYASP

Y Y Y Y Y N Y N Y Y N Y N Y N N Y Y

Time to response (days)

Remission duration (months) 1 15 62 6 2

HCT

Retic

Lymph

%

Xl,OOO/pl

Xl,OOO/pl

Spleen (CM)

(0-3f)

32 45 48 40

305 340 360 369 167

23 15 4 56 170 5 3 20 60 24 1 5 7 11 26 120 8 13 15

4.5 4.5 1.o 10.0 10.0 4.0 6.0 6.0 2.5 5.0 1.o 0.0 4.0 1.o 3.5 4.0 0.0 1.5

0 0 0 1 2 1 1 2 0 2 0 0 1 0 1 1 0 0

-

GI Bleed GI Bleed

12

47

-

Tx

11 1

40 27

-

Tx

9 1

50

-

11 31S

Tx 40 20 21 40 47

0.05).

response are not significant ( P > 0.05). These results indicated that neither therapy influenced the neutrophil or platelet counts significantly. At initial diagnosis of PRCA, mild thrombocytopenia (86 X 103/pl)was seen in one patient. We believe it was due to platelet pooling in his enlarged spleen (14 cm below the costal margin). However, with time, the platelet counts of all four patients decreased and remained low in spite of reticulocyte response and rising Hct. The exact cause for thrombocytopenia is not clear. No adverse effects, in the form of abnormal renal or liver functions or increased incidence of infections, were appreciated in our patients due to CYA therapy, with the possible exception of Pneumocystis carinii pneumonia in one patient (SK). DISCUSSION

We believe that PRCA in B cell CLL patients is an under-recognized entity. Anemia of PRCA may be mistakenly attributed to suppression of erythropoiesis by drug(s) given to treat leukemia, replacement of erythroid tissue in the bone marrow by the leukemic cells, sequestration and destruction of red cells by the enlarged spleen, and/or “anemia of malignancy.” The incorrect assumption of pathogenesis of the anemia is likely due to a lack of awareness of the condition, PRCA, coupled with infrequent measurements of the reticulocyte count and bone marrow evaluation. The exact incidence of PRCA in B cell CLL patients is not known. Our retrospective evaluation of 82 patients suggested that about 6% of them develop PRCA during the course of their CLL [I]. The disease has a tendency to relapse when an effective maintenance therapy is not given. We studied 14 episodes of PRCA in 4 patients with B cell CLL. Seven of these episodes were treated with CYA plus prednisone, six of which responded. The failure of the single episode (sixth episode in WL) was associated

with inadequate therapy with CYA. In this series, CYA was given in association with prednisone. We believe that CYA was responsible for induction of remission, since all patients were receiving prednisone prior to the addition of CYA. Whether CYA alone would have induced remission was not evaluated. However, there are reports of three patients with PRCA, two in association with B cell CLL [7,8] and another with CLL of undetermined cell type [6], who have responded to therapy with CYA alone. Maintenance of PRCA in remission induced by CYA plus prednisone may be achieved by continued administration of CYA and/or prednisone. The pattern of remission induced by CYA and prednisone is markedly different from that induced by modalities containing an alkylating agent. Remission due to an alkylating agent containing therapy occurred in most cases (three of four cases) after a perceptible reduction in leukemic mass, which took > 84 days. In contrast, a reduction in leukemic mass is not a prerequisite for the development of remission of PRCA in response to CYA plus prednisone, and remissions occurred within < 17 days. These differences, we believe, reflect differences in the mechanism of action of alkylating agents and CYA. Similar to our cases, the rate of response to CYA in two of the three reported cases was also fairly quick, 7 and 35 days, [6,7], no information was provided of the third case [8]. In several reported cases of PRCA in association with B cell CLL, including our patients WL and CF, an abnormal T cell population was found which failed to promote the growth of peripheral blood BFU-E in normal fashion [lo] and/or inhibited the growth of the bone marrow CFU-E [3,4]. CYA is known to down-regulate induction of interleukin-2 (IL-2) [13-151 and generation of IL-2 receptors [ 16,171 from CD4+ cells, and to inhibit T cell proliferation induced by IL-2 [ 181. The functions of IL-2 include induction of proliferation of T cells (CD4+ and CD8+ cells) and natural killer cells (CDl6+ cells) (NK cells). The IL-2 effect is direct and also occurs through induction of IL-4 production from activated CD4+ cells [ 19-22]. We speculate that the lack of or decreased production of IL-2, IL-4, and IL-2 receptors from CD4+ cells under the influence of CYA results in decreased proliferation of T cells, including the abnormal T cells. A reduced number of IL-2 receptor positive T cells in association with CYA treatment has been demonstrated in a patient with PRCA and B cell CLL [7]. However, the speculated reduction in abnormal T cell number or its functions in response to CYA treatment has not been demonstrated in PRCA B cell CLL patients. Such a reduction in the number of abnormal T cells, or interruption in their influence, is expected to allow for resumption of normal growth of erythroid progenitors and remission of PRCA . Whether CYA promotes erythroid progenitor proliferation, acting directly or through production of a

Cyclosporine and Prednisone Therapy

BFU-E growth stimulating factor from accessory cells, has not been fully elucidated 1231. Interferon-gamma (y-IFN) is a known in vitro inhibitor of BFU-E [24,25]. CYA not only decreases T cell and NK cell mass, which are sources of y I F N , but also actually inhibits production of y-IFN in a dose-dependent fashion 1261. Thus it is possible that recovery from PRCA may in part be related to a decreased production of y I F N in response to CYA therapy. However, no study has been published showing that y-IFN is the cause for PRCA and CYA effect is mediated by the reduced production of the cytokine. Prednisone may complement the CYA effect by inhibiting the production of IL- 1 from monocytes/macrophages [27] and by decreasing the proliferation of T cells [28,29]. IL- 1 is a comitogen for T cells which produce IL-2 and IL-4 [27]. Therefore, the decreased production of IL-1 is expected to result in an effect similar to that observed by the decreased production of IL-2 and IL-4 with respect to T cell proliferation. Furthermore, glucocorticoids may have a direct inhibitory effect on T cell proliferation and inhibition of y-IFN production [28-3 11, which in concept should also contribute to the recovery from PRCA. However, no study has been performed showing the occurrence of reduced number of abnormal T cells or decreased in vivo production of y-IFN in response to a glucocorticoid treatment in patients with PRCA and B cell CLL. Findings of this study asserts earlier report that remission of PRCA in response to treatment with an alkylating agent plus prednisone occurs in most cases after a perceptible reduction in leukemic mass [ 11. Such a reduction in leukemic mass has been shown to be associated with a reduction in the number of abnormal T cells [4,5]. Maintenance of remission is also possible by continued administration of adequate doses of cyclophosphamide and/or prednisone, as asserted earlier [ 11. Relapses of PRCA occurred in all four patients after variable periods after discontinuation of or reduction in the dosages of maintenance therapy. Relapses occurred in WL (episodes 2 and 3) in the absence of a perceptible increase in leukemic mass, supporting the previous suggestion that the pathogenesis of PRCA is not directly related to leukemic cells or leukemic cell mass [ 1,3,4]. PRCA of WL behaved differently from that of other three patients in terms of its response to cyclophosphamide plus prednisone. The response was quick, < 12 days, in WL as opposed to > 84 days in others. Also, leukemic mass reduction did not occur in WL before the occurrence of remission of PRCA, as it did in the other three patients. The reason for these differences is not clear. CYA treatment has been reported to increase incidence of Herpes zoster, Epstein-Barr virus, cytomegalovirus, Legionella pneumophilia, and Pneumocystis carinii infections in patients with autoimmune disorders and in

11

patients transplanted with organs [32]. Discerning the occurrence of increased frequency of infection in association with CYA therapy in patients who already are ill and receiving other immunosuppressive agents, or potentially immunosuppressive agents, is difficult. One of our patients (SK) died of Pneumocystis carinii infection after being on CYA for about 6 weeks and while his PRCA was in complete remission. Whether his infection was a direct consequence of CYA therapy is difficult to be sure. CYA therapy in post-transplant patients has been shown to be associated with B cell and skin malignancies 133,341. We feel the use of CYA was justified in our patients since their PRCA was not responding to other therapies or they could not be used. Furthermore, the dosage of CYA used in our patients was less than that used in most patients in whom a malignancy was developed [35]. In fact there was no obvious evidence of malignancies, other than B cell CLL, in our patients. In conclusion, the results presented in this paper suggest that CYA plus prednisone is an effective therapy for treatment of PRCA in patients with B cell chronic lymphocytic leukemia. REFERENCES I. Chikkappa G, Zarrabi MH, Tsan MF: Pure red cell aplasia in patients

with chronic lymphocytic leukemia. Medicine 65:339,1986. 2. Krantz SB, Kao V: Studies on pure red cell aplasia. I . Demonstration of plasma inhibitor to heme synthesis and an antibody to erythroblast nuclei. Proc Natl Acad Sci USA 58:439, 1967. 3. Mangan KF, Chikkappa G , Farley PC: T gamma (Tr) cells suppress growth of erythroid colony-forming units in vitro in the pure red cell aplasia of B-cell chronic lymphocytic leukemia. J Clin Invest 70: I 148, 1982. 4. Mangan KF, Chikkappa G , Scharfman WB, DesForges JF: Evidence for reduced erythroid burst (BFU-E) promoting function of T lymphocytes in the pure red cell aplasia of chronic lymphocytic leukemia. Exp Hematol9:489, 1981 . 5 . Chikkappa G, Pasquale D, Phillips PG, et al.: Cyclosporin-A for the treatment of PRCA in a patient with chronic lymphocytic leukemia. Am J Hematol 26:179, 1987. 6 . Tura S, Finelli C , Bandini G, Cava M, Gobbi M: Cyclosporin-A in the treatment of CLL associated PRCA and bone marrow hypoplasia. Nouv Rev Fr Haematol30:479, 1988. 7. Reid IS: Reversal of pure red cell aplasia by Cyclosporin-A in a patient with chronic lymphocytic leukemia. J Arkansas Med Soc 85:253, 1988. 8. Christen R, Morant R, Fehr J . Cyclosporine-A therapy of pure red cell aplasia in a patient with B-cell chronic lymphocytic leukemia. Eur J Heamatol42:303, 1989. 9. Committee on International Workshop o n Chronic Lymphocytic Leukemia: Chronic lymphocytic leukemia: Recommendations for diagnosis, staging, and response criteria. Ann Int Med 110236, 1989. 10. Mangan KF, Chikkappa G, Bieler LZ, Scharfman WB, Parkinson DR: Regulation of human blood erythroid burst-forming unit (BFU-E) proliferation by T-lymphocyte subpopulations defined by Fc receptors and monoclonal antibodies. Blood 59:990, 1982. I I. Robinson WT, Schran HF, Barry EP: Methods to measure cyclosporine levels: High pressure liquid chromatography, radioimmunoassay, and correlation. Transpl Proced 15:2403, 1983. 12. Pincus MR, Abraham NZ: Toxicology and therapeutics drug monitor-

12

Chikkappa et al.

ing. In Henry JB (ed): “Clinical Diagnosis and Management by Laboratory Methods,” 18th Ed. Philadelphia: Saunders, 1991, p. 371. 13. Elliot JF, Lin Y , Mizel S, Bleackley RE, Harnish DG, Faetkau V: Induction of interleukin-2 messenger RNA inhibited by Cyclosporin-A. Science 226: 1439, 1984. 14. Kronke M, Leonard WJ, Depper JM. Arya SK, Wong-Staal F, Gallo RC, Waldmann TA, Greene TC: Cyclosporin A inhibits T-cell growth factor gene expression at the level of m-RNA transcription. Proc Natl Acad Sci USA 8 I 5 2 14, 1984. 15. Lillehqj H, Shevach EM: A comparison of the effect of cyclosporin A, dexamethasone, and oubain on the interleukin-2 cascade. J Immunopharmac 7:267, 1985. 16. Prince HE, John JK: Cyclosporine inhibits the expression of receptors for interleukin-2 and transfenin on mitogen-activated human T lymphocytes. Immunol Invest 15:463, 1986. 17. Gauchat JF, Khadjian EW, Weil R: Cyclosporin A prevents induction of the interleukin-2 receptor gene in cultured murine thymocytes. Proc Natl Acad Sci USA 83:6430, 1986. 18. Hess AD, Tutschka PJ, Santos GW: Effect of cyclosporine on the induction of cytotoxic T lymphocytes: Role of interleukin- I and interleukin-2. Transpl Proc 15:2248, 1983. 19. Cantrell DA, Smith KA: The interleukin-2 T-cell system: A new cell growth model. Science 224: 1312, 1984. 20. Taniguchi T, Matsui H, Fujita T, Takaoka C, Kashima N, Yoshimoto R, Hamuro J: Structure and expression of a cloned cDNA for human interleukin-2. Nature 302:305, 1983. 21. Grabstein KH, Park LS, Morrisey PJ, Sassenfeld H, Price V. Urdal DL, Widmer MB: Regulation of murine T cell proliferation by B cell stirnulatory factor-I. J lmmunol 139:l 148, 1987. 22. Swain SL, McKenzie DT, Weinberg AD, Hancock W: Characterization or T helper I and 2 cell subsets in normal mice: Normal T cells responsible for IL-4 and IL-5 production are present as precursors that require priming before they develop into lymphokine secreting cells. J lmmunol 1413445, 1988. 23. Chikkappa G, Pasquale D, Berkowitz J: Cyclosporin (CYS) promotes proliferation of normal human granulocyte-macrophage (CFU-GM) and erythroid burst forming unit (BFU-E) progenitors. Blood 74:3030, 1989.

24. Broxmeyer HE, Lu L, Platzer E, Feit C, Juliano L, Rubin BY: Comparitive analysis of the influences of human gamma, alpha and beta interferons on human multipotential (CFU-GEMM), erythroid (BFU-E) and granulocyte-macrophage (CFU-GM) progenitor cells. J Immunol 131:1300, 1983. 25. Mamus SW, Beck-Schroeder S , Zanjani ED: Suppression of normal human erythropiesis by gamma-interferon in vitro: Role of monocytes and T lymphocytes. J Clin Invest 75: 1496, 1985. 26. Reem GH, Cook LA. Vilcek J: Gamma interferon synthesis by human thyinocytes and T lymphocytes inhibited by cyclosporin A. Science 221:63, 1983. 27. Besedovsky H, Delrey A, Sookin E, Dinarello CA: Immunoregulatory feedback between interleukin-I and glucocorticoid hormones. Science 233:652, 1986. 28. Larsson EL: Cyclosporin A and dexamethasone suppress T-cell responses by selectively acting at distinct sites of the triggering process. J lmmunol 124:2828, 1980. 29. Gordon D, Nouri AME: Comparison of the inhibition by glucocorticoids and cyclosporin A of mitogen-stimulated human lymphocyte proliferation. Clin Exp Immunol 44:287. 1981. 30. Ding JY, Yang SK, Yu RB: The inhibitory effect of hydrocortisone on interferon production by rat spleen cells. J Steroid Biochem 33:l 139, 1989. 31. Gyre PM, Girart MT: Glucocorticoid effects on the production and actions of immune cytokines. J Steroid Biochem 30:89, 1988. 32. Kim JH, Perfect J R : Infection and cyclosporine. Rev Infectious Dis 11:677, 1989. 33. Cockburn 1: Assesment of the risk of malignancy and lymphomas developing in patients using Sandimmune. Trnsplant Proc 19:1804, 1987. 34. Penn I: Cancers following cyclosporine therapy. Transplant Proc 19:221I , 1987. 35. Starzl TE, Nalesnik MA, Ho M, lwatsuki S, Griffith BP, Rosenthal JT, Hakala TR, Shaw BM Jr, Hardesty RL, Atchison RW, Jaffe R, Bahnson HT: Reversibility of lymphomas and lymphoproliferative lesions developing under cyclosporin-steroid therapy. Lancet 1583, 1984.

Cyclosporine and prednisone therapy for pure red cell aplasia in patients with chronic lymphocytic leukemia.

We describe the characteristics of response to treatment with cyclosporine (CYA) plus prednisone in seven episodes of pure red cell aplasia (PRCA) in ...
751KB Sizes 0 Downloads 0 Views