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March 2001, Volume 15, Number 3, Pages 465-467
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Open Forum
Pros and cons of splenectomy in patients with myelofibrosis undergoing stem cell transplantation
Z Li and H J Deeg

Fred Hutchinson Cancer Research Center and the University of Washington, Seattle, WA, USA

Correspondence to: H J Deeg, Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, D1-100, Seattle, WA 98109, USA; Fax: 206 667 6124

Abstract

During fetal development, the spleen is a major hemopoietic organ. In the adult human, this task is relinquished to the bone marrow. However, under the stress of certain pathologic conditions, extramedullary hemopoiesis may again occur in the spleen. This is especially true for diseases of the marrow, in particular, myeloproliferative disorders such as agnogenic myeloid metaplasia, which is associated with severe fibrosis of the marrow space. At the same time, the spleen sequesters blood cells and contributes to peripheral blood cytopenias, which may improve following splenectomy. However, success is unpredictable, and the operative mortality of splenectomy is on the order of 10%. As a growing number of patients undergo hemopoietic stem cell transplantation as definitive therapy for myelofibrosis, the decision on splenectomy has additional ramifications since the spleen plays an important role in the kinetics of engraftment of donor cells and in immune reconstitution. We conclude from our analysis of available information that the benefit of splenectomy is difficult to predict, although after transplantation splenectomized patients have faster hemopoietic recovery. It appears that the most important indication for splenectomy in these patients is the relief of symptoms from massive spleen enlargement. Leukemia (2001) 15, 465-467.

Keywords

myelofibrosis; splenectomy; hemopoietic stem cell transplantation

Introduction

Agnogenic myeloid metaplasia (AMM) and other disorders, such as the spent phase of polycythemia vera (P vera) or essential thrombocythemia (ET) are typically associated with myelofibrosis (MF) and splenomegaly as a result of extramedullary hematopoiesis.1 Severe splenomegaly may be complicated by splenic infarcts, blood cell sequestration, and hemolysis and may cause considerable discomfort to the patient. The management of this situation has remained controversial.2,3 As a growing number of patients with myeloproliferative disorder and splenomegaly are undergoing marrow or peripheral blood stem cell transplantation, this question has been further accentuated. It is uncertain to what extent the spleen is involved in post-transplant immune reconstitution and whether splenectomy is associated with improved clinical outcome. Prospective randomized trials are not available, and in any event, would be difficult to perform due to the heterogeneity of the underlying diseases, and the operative morbidity and mortality associated with splenectomy. Firm recommendations to guide clinicians in regards to a decision on splenectomy are lacking. Here, we review this controversial issue in the current literature, highlight our own experience at the Fred Hutchinson Cancer Research Center, consider the possible immunological consequences of splenectomy, and discuss factors that may influence the decision on splenectomy in the management of myelofibrosis.

Clinical controversies

Surgical splenectomy and splenic irradiation have been part of the management of AMM for two reasons: firstly, to relieve symptoms associated with splenomegaly, and secondly, to possibly slow disease progression, although this notion is not well supported by data. In fact, some reports suggest that in patients with AMM, splenectomy is associated with an increased risk of blast transformation.4 Tefferi and colleagues2 recently reported the Mayo Clinic experience with splenectomy in 223 patients with AMM. The indications for surgery were anemia, symptoms related to splenomegaly, portal hypertension or severe thrombocytopenia. Pre-splenectomy thrombocytopenia and the absence of a cellular marrow were risk factors for decreased survival. No durable remissions of thrombocytopenia were achieved. The rate of blast transformation was 16%; the rate was higher in patients with thrombocytopenia and increased spleen mass, but blast transformation did not affect survival. The authors surmised that thrombocytopenia was a surrogate for advanced disease. Overall, the data suggested that splenectomy was beneficial for the treatment of severe constitutional symptoms and portal hypertension, and the improved quality of life may justify the procedure despite an operative mortality of approximately 10%. With regards to the management of anemia, patients with a hypercellular marrow may require fewer transfusions post-splenectomy and may enjoy prolonged survival. Importantly, however, other than being associated with increased blast transformation in thrombocytopenic patients, splenectomy neither retarded nor hastened the progression of AMM. In an earlier study from the same institutions, investigators had shown that among 23 patients treated with 277.5 cGy of irradiation to the spleen, significant cytopenias occurred in 10 (43.5%), including six patients (26%) with prolonged life-threatening pancytopenia.5

While these data overall are in agreement with earlier reports,6,7 others advise cautious judgment because of uncertain benefits and considerable morbidity and mortality associated with splenectomy.3 Conclusions from these and other reports are summarized in Table 1.

As more patients with myelofibrosis are being treated by hemopoietic stem cell transplantation, the question arises as to whether pre-transplant splenectomy is beneficial or detrimental in regard to post-transplant outcome. Only limited data have been reported (Table 1). Guardiola et al8 recently presented results in 55 patients with AMM who were transplanted from HLA-matched related (n = 49) or alternative (n = 6) donors. The 5-year probability of survival was 47% for the overall group, and 54% for patients receiving an unmanipulated HLA-matched related transplant. Splenectomy prior to transplant was associated with significantly faster recovery of neutrophil and platelet counts. There was no correlation with acute or chronic GVHD, and there was no difference between patients with (n = 27) and without (n = 28) splenectomy prior to transplant with regard to 1-year transplant-related mortality (30% vs 25%) or 5-year overall survival (48% vs 46%).

We recently analyzed the impact of pre-transplant splenectomy on post-transplant outcome in 26 patients transplanted at the Fred Hutchinson Cancer Research Center for AMM (n = 17) or fibrosis associated with the spent phase of P vera or ET (n = 9).9 Patients were 18.2 to 55.3 (median 37) years old at the time of transplant. They had been followed for 1.5 to 10 (median 2.6) years. Eleven of these patients (44%) had undergone splenectomy prior to transplant, and 15 (56%) had an intact spleen. Patients with splenectomy were older (median 44 vs 36 years) and had longer disease duration before transplant, albeit not significantly so, than patients without splenectomy (median 37.5 vs 14 months). Overall post-transplant mortality was comparable in splenectomized (25%) and non-splenectomized patients (33%). As suggested by previous reports,10,11 post-transplant granulocyte recovery was faster among splenectomized patients (14-51 (median 18) days to reach 0.5 ´ 109/l, compared to 19-85 (median 23) days among patients with intact spleen) (P = 0.04), and the need for both red blood cell and platelet transfusions was greater among patients who had their spleens intact (mean 9.8 vs 6.1 units for red blood cells, and 21.7 vs 16 units for platelets). The 3-year probability of disease-free survival was 73% for splenectomized patients and 64% for patients without splenectomy (not significant).9

Theoretical considerations

Splenomegaly in AMM or other hemopoietic disorders may be a reflection of an expansion of the underlying malignant clone. Splenectomy should, therefore, not be expected to change the natural history of a hemopoietic stem cell disorder. However, such a view is difficult to test experimentally. Therefore, it may be useful to consider various possible consequences of splenectomy.

The spleen is the largest lymphoid organ in the body, accounting for about 25% of the body's lymphocytes.12 It is a reservoir of both effector and memory T and B lymphocytes. It is one of the sites in which B and T cells initially encounter blood-borne pathogens. The spleen plays an important role in the clearance of microorganisms, the synthesis of antibodies, and the provision of opsonins required for antibody-dependent cytotoxicity. Furthermore, the spleen, specifically the splenic outer periarteriolar lymphoid sheath (PALS), is a critical site where B cells undergo antigen-driven selection, activation and deletion, and where long-lived memory B cells are selected.13 In response to T cell dependent antigens, the proliferating B cells undergo plasma cell differentiation either within the outer PALS, or in the follicles after migration. In the absence of T cell help, B cells involved in T cell dependent responses die, but B cells involved in T cell independent antigen responses differentiate into plasma cells in the outer PALS. The outer PALS is also the site of inactivation and elimination of autoreactive B cells, although the mechanism remains incompletely defined. Taken together, the spleen plays a pivotal role in the initiation of B cell responses, the generation of long-term memory B cells, and the elimination of autoreactive B cell clones. It is unclear what role the spleen has in the reconstitution of the immune system post stem cell transplantation. It is safe to state, however, that the increased incidence of fatal bacteremia associated with asplenism is not simply the consequence of diminished opsonization, but is due to significant dysregulation of the immune response. In view of these considerations, it is not surprising that a role of the spleen in GVHD and immune reconstitution post- transplant has been considered.14,15,16,17,18

Practical approach

Given the lack of convincing data that would favor splenectomy in the management of AMM and the important role of the spleen in humoral immunity, splenectomy cannot be recommended as a routine procedure. Splenomegaly by itself is not necessarily a sign of disease progression and cannot serve as a prognostic marker. The clinical decision about splenectomy should be made on an individual basis. If transplantation is not an option for such a patient, the decision on splenectomy should probably be made primarily on the basis of patient symptomatology as recently discussed by Tefferi et al2 and in our own study.9 Symptoms from splenomegaly may also justify splenectomy in patients who proceed to hemopoietic stem cell transplantation. Splenectomized patients tend to have faster hemopoietic recovery and require fewer transfusions. However, the risk of overwhelming infections and impaired immune recovery has to be considered.

Conclusions

Despite considerable clinical interest, it is still controversial whether and when splenectomy should be performed in patients with myelofibrosis. This controversy is mainly due to a complete lack of prospective randomized studies and our incomplete knowledge of the role of the spleen in the pathogenesis of myelofibrosis and myeloid metaplasia. Retrospective studies have shown little, if any, advantage of splenectomy for clinical outcome. This fact, coupled with the importance of the spleen in the body's immune response, caution against routine splenectomy in patients with AMM or myelofibrosis of different etiologies.

Acknowledgements

This study was supported in part by PHS grants HL36444, CA18029, and CA87948. HJD is also supported by a grant from the Gabrielle Rich Leukemia Fund. We thank H Crawford and B Larson for help with manuscript preparation. The current address of ZL is Center for Immunotherapy, MC 1601, University of Connecticut Health Center, Farmington, CT 06030-1601.

References

1 Tefferi A. Myelofibrosis with myeloid metaplasia (review). N Engl J Med 2000; 342: 1255-1265, MEDLINE

2 Tefferi A, Messa RA, Nagorney DM, Schroeder G, Silverstein MN. Splenectomy in myelofibrosis with myeloid metaplasia: a single-institution experience with 223 patients. Blood 2000; 95: 2226-2233, MEDLINE

3 Benbassat J. Myelofibrosis with myeloid metaplasia. N Engl J Med 2000; 343: 659, MEDLINE

4 Barosi G, Ambrosetti A, Centra A, Falcone A, Finelli C, Foa P, Grossi A, Guarnone R, Rupoli S, Luciano L, Petti MC, Pogliani E, Russo D, Ruggeri M, Quaglini S. Splenectomy and risk of blast transformation in myelofibrosis with myeloid metaplasia. Blood 1998; 91: 3630-3636, MEDLINE

5 Elliott MA, Chen MG, Silverstein MN, Tefferi A. Splenic irradiation for symptomatic splenomegaly associated with myelofibrosis with myeloid metaplasia. Br J Haematol 1998; 103: 505-511, MEDLINE

6 Brenner B, Nagler A, Tatarsky I, Hashmonai M. Splenectomy in agnogenic myeloid metaplasia and postpolycythemic myeloid metaplasia. A study of 34 cases. Arch Intern Med 1988; 148: 2501-2505, MEDLINE

7 Coon WW, Liepman MK. Splenectomy for agnogenic myeloid metaplasia. Surg Gynecol Obstet 1982; 154: 561-563, MEDLINE

8 Guardiola P, Anderson JE, Bandini G, Cervantes F, Runde V, Arcese W, Bacigalupo A, Przepiorka D, O'Donnell MR, Polchi P, Buzyn A, Sutton L, Cazals-Hatem D, Sale G, De Witte T, Deeg HJ, Gluckman E, for the International Collaboration for Transplantation in Agnogenic Myeloid Metaplasia. Allogeneic stem cell transplantation for agnogenic myeloid metaplasia: a European Group for Blood and Marrow Transplantation, Société Française de Greffe de Moelle, Gruppo Italiano per il Trapianto del Midollo Osseo, and Fred Hutchinson Cancer Research Center collaborative study. Blood 1999; 93: 2831-2838, MEDLINE

9 Li Z, Gooley T, Appelbaum FR, Deeg HJ. Splenectomy and hemopoietic stem cell transplantation for myelofibrosis (letter). Blood (in press)

10 Martino R, Altes A, Muniz-Diaz E, Brunet S, Sureda A, Domingo-Albos A, Madoz P. Reduced transfusion requirements in a splenectomized patient undergoing bone marrow transplantation. Acta Haematol 1994; 92: 167-168, MEDLINE

11 von Bueltzingsloewen A, Bordigoni P, Dorvaux Y, Witz F, Schmitt C, Chastagner P, Sommelet D. Splenectomy may reverse pancytopenia occurring after allogeneic bone marrow transplantation (letter). Bone Marrow Transplant 1994; 14: 339-340, MEDLINE

12 Brown AR. Immunological functions of splenic B-lymphocytes (review). Crit Rev Immunol 1992; 11: 395-417, MEDLINE

13 Liu YJ. Sites of B lymphocyte selection, activation, and tolerance in spleen (review). J Exp Med 1997; 186: 625-629, MEDLINE

14 Ringden O, Nilsson B. Death by graft-versus-host disease associated with HLA mismatch, high recipient age, low marrow cell dose, and splenectomy. Transplantation 1985; 40: 39-44, MEDLINE

15 Michallet M, Corront B, Bosson JL, Molina L, Peissel B, Maraninchi D, Reiffers J, Chabannon C, Gaspard MH, Stoppa AM, Blaise D, Marit G, Hollard D, Carcassone Y, Broustet A, Demongeot J. Role of splenectomy in incidence and severity of acute graft-versus-host disease: a multicenter study of 157 patients. Bone Marrow Transplant 1991; 8: 13-17, MEDLINE

16 Boström L, Ringdén O, Jacobsen N, Zwaan F, Nilsson B. A European multicenter study of chronic graft-versus-host disease. The role of cytomegalovirus serology in recipients and donors, acute graft-versus-host disease, and splenectomy. Transplantation 1990; 49: 1100-1105, MEDLINE

17 Kalhs P, Schwarzinger I, Anderson G, Mori M, Clift RA, Storb R, Buckner CD, Appelbaum FR, Hansen JA, Sullivan KM. A retrospective analysis of the long-term effect of splenectomy on late infections, graft-versus-host disease, relapse, and survival after allogeneic marrow transplantation for chronic myelogenous leukemia. Blood 1995; 86: 2028-2032, MEDLINE

18 Tollemar J, Ringden O, Bostrom L, Nilsson B, Sundberg B. Variables predicting deep fungal infections in bone marrow transplant recipients. Bone Marrow Transplant 1989; 4: 635-641, MEDLINE

19 Jarvinen H, Kivilaakso E, Ikkala E, Vuopio P, Hastbacka J. Splenectomy for myelofibrosis. Ann Clin Res 1982; 14: 66-71, MEDLINE

Tables

Table 1  Controversies surrounding splenectomy in the management of myelofibrosis

Received 12 October 2000; accepted 31 October 2000
March 2001, Volume 15, Number 3, Pages 465-467
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