Splenectomy in Advanced Chronic Lymphocytic Leukemia: A Single Institution Experience With 50 Patients THOMASF. NEAL, JR., M.D., AYALEWTEFFERI,M.D., THOMASE. WITZIG, M.D., JOHN Su, Ph.D., ROBERTL. PHYLIKY,M.D., DAVIDM. NAGORNEY,M.D., Rochester, Minnesota

PURPOSE:To assess the efficacy of splenectomy in the treatment of refractory cytopenias associated with advanced chronic lymphocytic leuhemia (CIA). PATIENTSANDME~HODS~T~~~~~~Q~~~~ of57patienta with CLL who underwent splenectomy at the Mayo Clinic between 1975 and 1991 were retrospectively reviewd Of the 57 patients, 50 tmderwent splenectomy for reasons directly related to their disease process such as cytopenias or symptomatic splenomegaly. The histories from these 50 patients were studied to assess the response to splenectomy and the operative morbidity and mortality. FUNJLTSZ Ninety-four percent of patients were in Rai stage III or IV with extensive marrow infiltration, massive splenomegaly, and cytopenias refractory to chemotherapy. A positive response to splenectomy was defined at 3 months of follow-up 88: (1) a hemoglobin level of 11 g/dL or greater in a patient with a preoperative value less than 11 g/W or (2) a platelet count of 100 X W/mm3 or greater in a patient with a preoperative value less than 100 x 103/mm3. A positive response was achieved in 77% of patients with an& 70% of patients with thrombocytoper& and 54% of patients with both anemia and thrombocytoper& The response was sustained at 1 year of follow-up in 86%, 84%, and 85% of the patiente, respectively. Postoperative transfusion requirements decreased correspondingly. The operative morbidity was 26%, and the operative mortality was 4%. The mean duration of hospitalization was 9.8 days (median: 9 days; range: 5 to 24 days). The actuarial median survival after splenectomy was 41 months in responders and 14 months in nonresponders. We found no preoperative parameters that were clearly predictive of a poor hematologic reFrom the Department of Internal Medicine (TFN). Department of Internal Medicine and Division of Hematology (AT, TEW. RLP). Department of Epidemiology (IS), and Department of Surgery (DMN). Mayo Clinic, Rochester, Minnesota. Requests for reprints should be addressed to Ayalew Tefferi, M.D., Department of Hematology, Mayo Clinic, Rochester, Minnesota 55905. Manuscript submitted December 30. 1991, and accepted in revised form March 23.1992.

sponse. In particular, outcome was not affected by preoperative spleen size or the degree of marrow infiltration by CLL All patients with symptomatic splenomegaly had an improved sense of well-beii. CONCLUSION:Inthis,thelargegtsingleinstitu-

tion study to date, we found splenectomy to be efficacious in providing durable remissions of refractory cytopenias and in relieving symptomatic splenomegaly in the majority of patients with CLL The procedure is associated with a low perioperative mortality. Although the impact on survival is uncertain, the improved peripheral blood counts may allow the admG&ation of adequate doses of myelosuppressive chemotherapy.

hronic lymphocytic leukemia (CLL) is a disC ease of widely variable clinical severity characterized by the progressive accumulation of relatively mature but functionally incompetent lymphocytes [1,2]. The Rai staging system [3], introduced in 1975, was an important advance in the study of CLL in that it provided a link between clinical findings and survival and a reproducible way to randomize patients in clinical trials. However, despite a better understanding of the pathophysiology of CLL and the factors related to longterm prognosis, very little impact has been made on changing the natural history of the disease [4]. None of the current therapeutic interventions are curative and, therefore, must be considered paIliative-targeted primarily at alleviating symptoms and slowing disease progression. One such palliative intervention is splenectomy. The usual indications are either refractory cytopenias in the presence of an enlarged spleen or symptomatic splenomegaly. Several studies have shown a beneficial effect of splenectomy in reversing cytopenias associated with Rai stages III and IV disease [5-121. Some authors have suggested a favorable outcome on survival [5,9,13], whereas others have found no relationship [6]. The purpose of the current study was to review the largest clinical experience at a single institution in patients with CLL who have undergone splenectomy.

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CL1 AND SPLENECTOMY / NEAL ET AL -

-~

-.__-

-

---~___-_

-__

TABLE I Preoperative Clinical Features -.

_--.

No. of patients If

3”; 17

Mean age (Y) (range) Y MO from diagnosis to splenectomy (median)

51

Rai stage Stage II Stage III Stage IV

35 (70%)

Bone marrow lymphocytes (n = 31) < 50% lymphocytes 50%-75% lymphocytes > 75% lymphocytes

4 (13%) 5 (16%) 22 (71%)

Medical therapy at time of surgery None Prednisone Chlorambucil Chlorambucil and prednisone Other Spleen size “lOcm Liver size Not palpable 55cm 6-10 cm >lOcm

26 (52%) 22 (22%) 1 (2%) 1 (2%)

Response Criteria A positive hematologic response to splenectomy was defined as follows: (1) anemia; patients with a preoperative hemoglobin level less than 11 g/dL that increased to 11 g/dL or greater at 3 months of follow-up; (2) thrombocytopenia; patients with a preoperative platelet count of less than 100 X 103/mm3 that increased to 100 X 103/mm3 or greater at 3 months’ follow-up.

Performance status (ECOG) Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 DG = EasternCooperativeOncology Group.

PATIENTS AND METHODS Preoperative Data The charts of 57 patients with B-cell CLL who underwent splenectomy at the Mayo Clinic between January 1, 1975, and January 1, 1991, were reviewed. The diagnosis of CLL was based upon examination of the peripheral blood or bone marrow aspiration according to standard criteria [14]. Preoperative data obtained included: date of diagnosis of CLL, Eastern Cooperative Oncology Group (ECOG) performance status, Rai clinical stage of disease at the time of splenectomy, reason for splenectomy, frequency of packed red blood cell (PRBC) transfusion, medications, hemoglobin level, white blood cell (WBC) count, platelet count, bilirubin, aspartate aminotransferase (AST), alkaline phosphatase, y-globulin, direct Coombs’ test, antiplatelet antibodies, spleen size, liver size, and bone marrow biopsy results. 436

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Operative Data To assess operative morbidity and mortality, the following data were obtained: intraoperative and immediate postoperative transfusion requirements (including PRBC, platelets, cryoprecipitate, and fresh frozen plasma), surgical and postoperative complications, and length of hospitalization from the day of surgery. Follow-Up Data To assess the response to splenectomy, the following information was obtained at 3 months, 1 year, and at last follow-up: ECOG performance status, transfusion requirements, hemoglobin level, WBC count, platelet count, AST, bilirubin, alkaline phosphatase, r-globulin, and liver size. If a Richter’s transformation had taken place, this was noted, as were the date and cause of death. Those patients dying within 1 year of splenectomy were not included in the last follow-up data. In most instances, the last follow-up was at the time of death, but in those patients who are still alive, it is the most recent follow-up.

12 (24%)

1(2%) 11(22%) 11(22%) 27 (54%)

-

Statistical Methods Survival was calculated by the Kaplan-Meier method [15]. The associations of age, spleen size, liver size, performance status, and degree of bone marrow infiltration with response and survival were analyzed using a logistical regression model and the Cox proportional hazards model [16], respectively.

RESULTS Preoperative Data Of the 57 patients who underwent splenectomy, there were 50 who had splenectomy performed for reasons directly related to their disease. The remainder of this article will focus on these 50 patients. The preoperative characteristics of the 50 patients are summarized in Table I. The group consisted of 33 men and 17 women (mean age: 62.9 years; range: 32 to 79 years). The mean interval from the diagnosis of CLL to the time of splenectomy was 62 months (median: 51 months; range: 0 to 244 months). Bone marrow examination was done within 1 month of splenectomy in 62% (31 of 50) of

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CL1 AND SPLENECTOMY / NEAL ET AL TABLE II Operative Transfusion Requirements

9lwd Product PRBC FFP Platelets Cryoglobulin

TABLE III Operative Morbidity and Mortality

lntraoperative No. Mean Patients No. Units Requiring (range)

Postoperative No. Mean Patienk No.Units Requiring (range)

25 1 25 2

16 4 8 2

(50%) (2%) (50%) (4%)

2;

(l-9)

8.8 (2-26)

9.5 (9-10)

(32%) (8%) (16%) (4%)

3.4 3.3 17.3 5.0

Complication Bleeding Requiring transfusion Requiring surgery

(l-15) (2-6) (4-49) (4-6)

NC = packed red blood cells; FFP = fresh frozen plasma.

the patients. The bone marrow morphologic examination revealed greater than 75% lymphocytes in 71% (22 of 31) of cases. A direct Coombs’ test was done in 68% (34 of 50) of the patients and was negative in 71% (24 of 34). Antiplatelet antibody testing was performed in 20% (10 of 50) of the patients and was negative in 80% (8 of 10). The mean y-globulin level was 0.6 g/dL (median: 0.5 g/dL; range: 0.2 to 1.6 g/dL). The spleen was palpable in 98% (49 of 50) of patients and was greater than or equal to 10 cm below the left costal margin in 54% (27 of 50). The liver was palpable in 48% (24 of 50) of the patients and was greater than or equal to 10 cm below the right costal margin in only 2 patients. At the time of splenectomy, 94% of the patients (47 of 50) were in Rai stage III or IV, and 6% (3 of 50) were in Rai stage II. The primary reason for splenectomy was thrombocytopenia in 28% (14 of 50); anemia in 16% (8 of 50); anemia and thrombocytopenia in 20% (10 of 50); a cytopenia combined with symptomatic splenomegaly in 28% (14 of 50); and leukopenia secondary to hyperaplenism, which was preventing further myelosuppressive chemotherapy, in 2% (1 of 50). Operative Findings/Operative Morbidity and Mortality The average spleen weight was 2,233 g (median: 1,678 g; range: 240 to 11,000 g). The spleen pathologic findings were consistent with a low-grade lymphoproliferative disorder in 98% (49 of 50) of cases and a large cell lymphoma (Richter’s transformation) in 2% (1 of 50). At the time of surgery, one patient was noted to have portal hypertension, ascitea, and esophageal varices believed to be secondary to massive splenomegaly from CLL. Two additional patients were noted to have ascites. Intraoperative and postoperative transfusion requirements are outlined in Table II. The mean length of hospitalization from the day of surgery to discharge was 9.8 days (median: 9 days; range: 5 to 24 days). Information on operative morbidity (26%) and mortality (4%) is summarized in Table III. Neither the age

No.(%)

:I;;

Infection Fever of unknown origin Pneumonia Wound infection

4 (8) 3 (6)

Cardiac Congestive heart failure

1 (2)

Other Gout Respiratory arrest Portal vein thrombosis Portal and splenic vein thromboses Hydropneumothorax

:i;i 1 (2) 1 (2) 1 (2)

Death in hospital Death within 1 month of surgery Overall morbidity Overall mortality

1 (2)

0 2 13 2

(0) (4) (26) (4)

nor the performance status at the time of splenectomy was associated with an increased operative morbidity. Furthermore, the platelet count in the four patients who experienced postoperative bleeding complications was not significantly lower than that of the group as a whole (mean: 66 versus 77 X 103/mm3, respectively). No patient died during the initial hospitalization, but there were two deaths within 1 month of discharge from the hospital. One of these patients died suddenly in the nursing home. She was 74 years of age, and her clinical course and spleen pathologic findings were consistent with a Richter’s transformation. The other patient was 79 years of age and died of sepsis 5 days after discharge from the hospital. Hematologic Response At 3 months of follow-up, 96% (48 of 50) of the patients were still alive; of these, follow-up data were available in 94% (45 of 48). At 1 year of followup, 82% (41 of 50) of the patients were still alive; of these, follow-up data were available in 88% (36 of 41). The mean time to last follow-up was 43 months (median: 37 months; range: 13 to 143 months). Of the 41 patients who met the criteria for last followup, data were available for all 41. The overall hematologic response for each parameter evaluated is summarized in Table IV. The mean hemoglobin level prior to splenectomy was 9.5 g/dL (median: 9.4 g/dL; range: 4.6 to 16.2 g/dL). At 3 months of follow-up, the mean hemoglobin level

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m

I -

Hematologic Responseto Splenectomy

WBCcount (xlOg/L) Hemoglobin (g/dL)f Platelet count (x 103/mm3) Performance status*

32.2

50.9

38.5

9.4 62

12.6

13.3

10.5

256 0.5

211 0.6

105 2.0

1.1

Ail patients Good responders Nonresponders Bsldsd log-rank P value=O.W7

39.3

I

WBC = white blood cell. *The median time to last follow-up was 36.5 months.

tThe percentagesof patients that had received at least one blood transfusion wdhin several months of each consecutive follow-up were 46%, 16X, 1496,and 50%, respectively. #Mean EasternCooperativeOncology Group performance status.

0

2

4

6

6

10

Years after splenectomy Figure 1. Kaplan-Meier

was 12.2g/dL (median:12.6g/dL; range:7.2to 16.5 g/dL), at 1 yearof follow-up, it was13.1g/dL (median: 13.3g/dL; range:9.0 to 16.7g/dL), and, at last follow-up, it was 10.8 g/dL (median: 10.5 g/dL; range: 7.3 to 15.8 g/dL). The transfusion requirements decreasedcorrespondingly.Prior to surgery, 46% of the patients were receiving regular blood transfusions;the correspondingvaluesat 3 months, 1 year, and last follow-up were 16%,14%,and 50%, respectively. In reviewing the 36 patients with a preoperativehemoglobin level of lessthan 11g/dL (median:8.7g/dL; range:4.6to 10.8g/dL), wefound that 77%of the evaluablepatients had an increase in their hemoglobinlevel to 11 g/dL or greaterat 3 months of follow-up. This increasewassustainedin 86%of the patients at 1 year. The mean platelet count prior to splenectomy was 77 X 10a/mm3(median: 62 X 103/mm3;range: 6 to 245 X 103/mm3).The meanplatelet count at 3 months of follow-up was 265 X 103/mm3(median: 256 X 103/mm3;range: 10 to 660 X 103/mm3);at 1 year of follow-up, it was 247 X 103/mm3(median: 211 X 103/mm3;range:11 to 986 X 103/mm3)and, at last follow-up, it was 144 X 10a/mm3(median: 105 X 10Vmm3;range:7 to 483 X 103/mm3).In reviewing the 35 patients with a preoperativeplatelet count of less than 100 X 103/mm3(median: 39 X 103/mm3;range:6 to 92 X 10s/mm3),we found that 70%of the evaluablepatients had an increase in their platelet count of 100 X 10a/mm3or greater at 3 months’ follow-up. This increasewas sustained in 84% of the patients at 1 year. In reviewing the 23 patients with both anemia and thrombocytopenia, we found that 64% of the evaluablepatients increasedtheir hemoglobinlevel and their platelet count to 11 g/dL or greater and 100 X 103/mm3or greater, respectively. This increasewassustainedin 85%of the patients at 1 year. The lone patient with leukopenia, which was thought to be secondaryto hypersplenismand that

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survival

curve

after

splenectomy.

prevented further myelosuppressivechemotherapy, had an increasein the WBC count from 3.8 X 103/pLpreoperativelyto 10.5 X 103/~L at 3 months of follow-up. The mean WBC count prior to splenectomywas 70.0 X 10s/L (median: 32.2 X 10s/L; range:2.4 to 491 X log/L). At 3 months of follow-up, the mean WBC count was 94.1 X log/L (median: 50.9 X 10s/L; range: 3.7 to 514.8 X log/L); at 1 year of follow-up, it was 74.2 X 10s/L (median: 38.5 X log/L; range:5.1to 446.8X 10s/L),and, at last follow-up, it was 91.8 X 10s/L (median: 39.3 X 10s/L; range:2.9 to 680.1 X 10s/L). There wasno associationbetweenthe hematologic responseto splenectomy and spleen size, liver size, performance status, degree of bone marrow infiltration, or age.We did find a trend toward degree of cytopenia, spleenweight, and responseto splenectomy,but it wasnot statistically significant. Performance Status

An ECOG performancestatus (grades0 through 4) wasestimatedfor eachpatient prior to splenectomy, at 3 months, 1 year, and at last follow-up. The meanvaluesfor eachof thesedateswas 1.1,0.5,0.6, and 2.0,respectively.At the 3 month follow-up, 52% of the patients had an improved ECOG performance status, 38% had no change,and 5% had a worseECOG performancestatus. At 1 year of follow-up, the correspondingvalues were 52%, 38%, and lO%, respectively. Survival

The 3-month and l-year crude survival rates after splenectomy were 96% and 822, respectively. The 5-yearactuarial survival rate was 27% (Figure 1). To date, 37 patients have died with a median

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survival, from the time of splenectomy, of 20 months (range: 0.4 to 94 months). Overall survival was not affected by preoperative performance status, but the effect of age on survival did approach statistical significance (p = 0.10). The most frequent cause of death was an infectious event (22 of 37 patients). Bleeding complications as a cause of death were relatively infrequent, occurring in only 4 of 37 patients. In the majority of the remaining patients, CLL was related to or contributed to the cause of death. Three of the original 50 patients have had a documented Richter’s transformation, and all 3 have died.

COMMENTS Splenectomy has long been recognized as a valid, although controversial, therapeutic option in patients with lymphoproliferative disease [17]. Initial reports were characterized by high operative mortality and seemingly little beneficial effect. However, with improved surgical techniques and a better understanding of the indications for splenectomy in these patients, the initial negative results have required reevaluation. This study confirms the findings of other recent studies showing splenectomy to be effective in improving cytopenias in most and alleviating symptomatic splenomegaly in essentially all patients [5,7-111. Most patients in this study were in Rai stage III or IV with extensive marrow infiltration and one or more cytopenias refractory to medical management. Despite the advanced stage of disease, 77% of patients with anemia, 70% of patients with thrombocytopenia, 64% of patients with both anemia and tbrombocytopenia, and the single patient with leukopenia had a positive response to splenectomy. Furthermore, the response was sustained in 86%, 84%, and 85% of the patients in each of these groups at 1 year. The results at 1 year, and even more so at the last followup, are difficult to interpret in that some patients were concurrently receiving some form of medical therapy for disease progression. Nevertheless, there is little doubt as to the positive effect of splenectomy in contributing to the improved blood counts, increased sense of well-being, and decreased transfusion requirements in this group of patients. In examining the response to splenectomy, we explored the predictive potential of several presplenectomy parameters including degree of marrow infiltration, age, spleen size, and degree of cytopenia. Similar to Adler et al [12], we found no preoperative parameters that were clearly predictive of an unfavorable response. Furthermore, responsiveness to splenectomy was not dependent upon the particular kind of cytopenia or whether the cyto-

penia was isolated or combined. We did find a trend in the degree of cytopenia, spleen weight, and response to splenectomy, but it was not statistically significant [8,9,12]. These findings indicate that the only way to ascertain the role of the enlarged spleen in anemia or thrombocytopenia in patients with CLL is to remove the spleen [7,12]. Although evidence for splenic sequestration of chromium-51labeled erythrocytes provides strong support for a positive response to splenectomy [18,19], the converse is not necessarily true [12]. Because of this discrepancy, labeling studies are not routinely performed at our institution to aid in the decisionmaking process. The operative morbidity and mortality reported in this study are consistent with the recent literature in estimating these values to be 20% to 35% and 0% to lo%, respectively [5,6,8,10,11,20,21]. The median length of hospitalization was 9 days, which is consistent with other studies [B,lO,ll]. These findings indicate that although there is an increased surgical risk in patients with CLL, the risks are not prohibitive in appropriately selected patients and with experienced surgeons. Other treatment modalities that may alleviate cytopenias and symptomatic splenomegaly in CLL include splenic irradiation [22,23] and leukapheresis [24]. Leukapheresis is an efficient method for reducing a high lymphocyte count, but it has a minimal role in improving severe cytopenias [24]. Splenic irradiation compares favorably with splenectomy in pain management and has the added advantage of controlling lymphocytosis [23]. However, resolution of significant cytopenias occurs in less than 25% of the patients, and, in some, it may worsen thrombocytopenia [23]. Nevertheless, these alternative measures may be appropriate for patients who are poor surgical risks. Considerable controversy exists regarding the effect of splenectomy on survival [5,6,9,13]. The overall median survival for our group of patients as a whole was 36 months, which is greater than the normally expected 19 months in patients with such advanced disease [3]. It would be presumptuous to draw conclusions from this comparison due to the retrospective nature of our study. It can, however, be concluded that patients with a poor response to splenectomy have a significantly shorter median survival time (14 months) than responders (41 months). In this respect, the response to splenectomy may be useful as a prognostic parameter. In summary, we believe that splenectomy should be considered an efficacious therapeutic option in patients with CLL and refractory cytopenias or symptomatic splenomegaly. The surgical risks are

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not prohibitive in appropriately selected patients, and the beneficial effects may be quite durable. Although the impact on survival is uncertain, the improved peripheral blood counts may allow the administration of adequate doses of myelosuppressive chemotherapy.

REFERENCES 1. Damesheck W. Chronic lymphocytic leukemia: an accumulative disease of immunologically incompetent lymphocytes. Blood 1967; 29: 566-83. 2. Galton D. The pathogenesis of chronic lymphocytic leukemia. Can Med Assoc J 1966; 94: 1005-10. 3. Rai K, Sawitsky A. Cronkite E. Clinical staging of chronic lymphocytic leukemia. Blood 1975; 46: 219-34. 4. Rai K. Sawitsky A. Diagnosis and treatment of chronic iymphocytic leukemia. In: Wiernik P. Candles G, Kyle R. Schiier C, editors. Neoplastic diseases of the blood. 2nd ed. New York: Churchill Livingstone, 1991: 97-109. 5. Stein R. Weidert D. Reynolds V, Greer J. Flexner J. Splenectomyfor end-stage chronic lymphocytic leukemia. Cancer 1987: 59: 1815-8. 6. Ferrant A, Michauz J, Sokal G. Splenectomy in advanced chronic lymphocytic leukemia. Cancer 1986; 68: 2130-5. 7. Delpero J, Gastaut J, Letreut Y, et al. The value of spknectomy in chronic lymphocytic leukemia. Cancer 1987; 59: 340-5. 8. Delparo J. Houvenaeghel G. Gastaut J, Orsoni P. Blanche J, Carcassonne Y. Splenectomy for hypersplenism in chronic lymphocytic leukaemia and maliinant non-Hodgkin’s lymphoma. Br J Surg 1990; 77: 443-9. 9. Gallhofer G, Melo J. Spencer J, Catovsky D. Splenectomy in advanced chronic lymphocytic leukemia. Acta Haematol (Basel) 1987; 77: 78-82. 10. Thiruvengadam R. Piedmonte M. Barcos M, HanT, Henderson D. Splenecto-

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lymphocytic leukemia. Leukemia 1990; 4: 758-60. M. Goldberg J, Gottlied A. Splenectomy for thrombocytopenia in chronic lymphocytic leukemia. Am J Hematol 1983; 15: 253-9. 12. Adler S. Stutzman L. Sokal J. Mittelman A. Splenectomy for hematologic depression in lymphocytic lymphoma and leukemia. Cancer 1975; 35: 521-8. 13. Christensen 8. Hansen M. Videbaek A. Splenectomy in chronic lymphocytic leukemia. Stand J Haematol 1977; 18: 279-87. 14. Cheson B, Bennett J. Rai K. eta/. Guidelines for clinical protocols for chronic lymphocytic leukemia: recommendations of the National Cancer Institute-Sponsored Working Group. Am J Hematol 1988; 29: 152-62. 15. Kaplan E. Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457-81. 16. Cox D. Regression models and life tables. J R Stat Sot Ser B 1972; 34: my in advanced

chronic

11. Merl S. Theodorakis

187-220. 17. Fisher J. Welch C, Dameshek W. Splenectomy in leukemia and leukosarcoma. N Engl J Med 1952; 246: 477-84. 18. Jandl J, Greenberg M. Yonemoto R, Castle W. Clinical determination of the sites of red cell sequestration in hemolytic anemias. J Clin Invest 1956; 35: 84267. 19. McCurdy P, Rath C. Splenectomy in hemolytic anemia. N Engl J Med 1958; 259: 459-63. 20. Mentzer S. Starnes H, Canellos G. eta/. Splenic enlargement and hyperfunction as indications for splenectomy in chronic lymphocytic leukemia. Ann Surg

1987; 205: 13-7. 21. Pegourie B. Sotto J. Hollard D, Michallet M, Sotto M. Splenectomy during chronic lymphocytic leukemia. Cancer 1987; 59: 1626-30. 22. Byhardt R, Brace K. Wiernick P. Role of splenic irradiation in chronic lymphocytic leukemia. Cancer 1975; 35: 1621-5. 23. Guiney M, Liew K, Quong G. Cooper I. Astudy of splenic irradiation in chronic lymphocytic leukemia. Int J Radiat Oncol Biol Phys 1989; 16: 225-9. 24. Goldfinger D, Capostagno V, Lowe C. Sacks H, Gatti R. Use of long-term leukapheresis in the treatment of chronic lymphocytic leukemia. Transfusion

1980; 20: 450-4.

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