REVIEW

Splenectomy in Chronic Myeloid Leukemia DAVID

J. WOLF,

M.D.; RICHARD

T.

SILVER,

M.D.; and MORTON

COLEMAN, M.D.;

New York, New York

We review splenectomy in chronic myeloid leukemia, emphasizing recent studies that have evaluated early splenectomy during the chronic phase of the disease. Despite current interest in splenectomy in chronic myeloid leukemia, uncontrolled clinical trials to date suggest that the operation during the early phase neither delays the onset of blastic transformation nor prolongs survival. Immediate operative mortality of splenectomy during the chronic phase is low, generally less than 1 % . The morbidity of the procedure, however, remains formidable due to infectious and thromboembolic complications. Splenectomy during chronicphase chronic myeloid leukemia permits easier control of the disease in patients who are thrombocytopenic due to busulfan toxicity or sensitivity. Splenectomy during the chronic phase may also palliate those patients who suffer from acute splenic events or massive splenomegaly. Splenectomy in blast-phase disease should be considered a heroic measure providing little benefit to most patients.

T H E R O L E O F S P L E N E C T O M Y in chronic myeloid leuke-

mia remains controversial. Early splenectomy, during chronic-phase chronic myeloid leukemia has been included as part of vigorous programs to eradicate the Philadelphia chromosome (1) and to delay the subsequent onset of blastic transformation (2-6). Cytogenetic, kinetic, and morphologic studies of extramedullary hematopoietic tissue contained in spleens of patients with chronic myeloid leukemia constitute the basis for such programs, since blast-phase transformation in the spleen may antedate that in the marrow (7-9). Splenectomy has also been recommended during chronic-phase chronic myeloid leukemia for the management of symptomatic splenomegaly, for cytopenias due to hypersplenism, and for cytopenias related to busulfan toxicity (10-18). Although spleen size during the chronic phase can be generally controlled with chemotherapy, an enlarging spleen during the aggressive phase of chronic myeloid leukemia may lead to morbidity by causing pain or by limiting food intake (17, 19). Thus, it has been also suggested that early splenectomy may prophylactically alleviate the problems subsequently re• From the Oncology Service, Division of Hematology-Oncology, Department of Medicine, The N e w York Hospital-Cornell Medical Center; N e w York, N e w York.

684

lated to splenomegaly during the aggressive phase. Accordingly, two major questions concerning splenectomy have emerged in recent years. First, can early splenectomy combined with intensive chemotherapy prolong survival by delaying the onset of the aggressive phase of chronic myeloid leukemia? Second, does either early or late splenectomy provide sufficient palliation during the aggressive phase to justify the morbidity of the procedure? We shall attempt to answer these questions here. Brief History of Splenectomy in Chronic Myeloid Leukemia

In 1865 Lissauer (20) first reported improvement of patients with chronic myeloid leukemia after arsenic therapy. The following year, in London, Thomas Bryant (21) did the first recorded splenectomy in a patient with leukemia, a 20-year-old man who probably had acute myelocytic leukemia. The patient died 2 h and 20 min postoperatively from hemorrhage. During the latter part of the 19th and the first decades of the 20th centuries, splenectomy for acute and chronic leukemias resulted in an immediate postoperative mortality averaging 8 0 % to 9 0 % (22-25). Because of this, splenectomy fell into disrepute until 1928 when Mayo (26) described a new technique reducing the surgical mortality of splenectomy to about 2 5 % . Mayo's experience, however, indicated that splenectomy and radiation therapy offered no advantage over splenic irradiation alone. Splenic irradiation therefore remained the standard therapy for chronic myeloid leukemia (27, 28) until busulfan was introduced during the early 1950s (29). In 1939 Ferrati and Fieschi (12) were among the first to state clear indications for splenectomy in leukemic patients. Splenectomy was recommended for cytopenias due to hyperplenism and to improve the discomfort and pain that resulted from splenomegaly and splenic infarction. Surgical mortality, however, remained high. When Strumia, Strumia, and Bassert (30) reviewed the results of splenectomy in chronic myeloid leukemia from 1940 through 1966, the operative mortality still averaged 23.5%. At present, splenectomy is done in early chronic myeloid leukemia after spleen size and hematologic variables have been controlled with chemotherapy (1-6). Such control combined with the availability of platelet concentrates has greatly reduced the morbidity and mortality of

Annals of Internal Medicine 89(Part l):684-689, 1978

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©1978 American College of Physicians

the operation during the chronic phase. According to several studies, operative mortality now averages less than 1% (1-6, 31). Role of the Spleen in Chronic Myeloid Leukemia

During the chronic phase of chronic myeloid leukemia, myeloid activity is present in extramedullary sites, particularly the spleen and liver (7, 8). Cells containing the Philadelphia chromosome (Ph) have been found in the spleen (32), and some of the granulocytes circulating in the blood of patients with chronic myeloid leukemia are produced in the spleen (33). Whether hematopoietic cells in the spleen merely represent the expansion of the entire leukemic cell population or rather a subpopulation of leukemic cells that qualitatively differs from that in the marrow is both theoretically interesting and of potential practical importance. If the myeloid cells in the spleen represent an accumulation of leukemic cells similar to those in the marrow, then removal of the spleen would not be expected to significantly alter the natural history of the disease. However, if the spleen either selectively traps myeloid cells with a high malignant potential or provides a microenvironment that promotes malignant transformation of myeloid cells, then the spleen could be an initial site of blastic transformation. Hence early splenectomy would be expected to delay the appearance of the blast phase. Morphologic and replicative features of extramedullary hematopoiesis during the chronic phase suggest a role for the spleen as a possible initial site for the development of blastic transformation. In 1949, Rohr (34) first suggested that the spleen could be the initial site of blastic transformation when he described two patients with morphologic blastic transformation in the spleen predating its appearance in the marrow. In more recent studies, the composition, structure, and proliferative activity of splenic hematopoietic tissue in chronic myeloid leukemia have been examined (8, 35). The mitotic indexes of granulopoietic and erythropoietic precursor cells are significantly lower in the spleen compared with the marrow, often as low as those generally occurring in marrow blast cells in acute myeloid leukemia (36). Granulopoiesis also shifts toward a relative increase in earlier granulopoietic precursor cells in the spleen compared with the marrow. Kaur and colleagues (37, 38) found that the spleen in chronic myeloid leukemia contains an excessive proportion of T lymphocytes that presumably are terminal deoxynucleotidyl transferasepositive during the chronic phase. Perhaps splenic lymphocytes participate in those instances of blastic transformation characterized by blasts with lymphoid cell markers. Most marrow myeloid cells contain the Philadelphia chromosome during chronic-phase disease (39). Additional chromosomal abnormalities, particularly hyperdiploidy, eventually develop in the marrow before the appearance of morphologic blastic transformation (40, 41). The cytogenetic features of splenic myelopoiesis have not been examined as thoroughly as those in the marrow. Nevertheless, Ph ( + ) aneuploid cells have been found in

the spleen (8, 32, 42, 43). Moreover, Gomez, Hossfeld, and Sokal (44) have reported a higher frequency of Ph ( + ) cells with additional karyotypic abnormalities in the spleen compared to the marrow when examined on the same occasion. At present, hyperdiploidy in the spleen preceding its appearance in the marrow constitutes the strongest evidence for the spleen as the initial site of blastic transformation (9). The proliferative and morphologic features of hepatic myeloid tissue are similar to those of the spleen during the chronic phase (8, 35). The liver is therefore an additional potential site of origin for blastic transformation. Furthermore, myeloblastic tumors have been reported to occur in lymph nodes (45-49), soft tissues (50, 51), and leptomeninges (52) when the marrow indicates chronicphase disease. Thus, extramedullary sites other than the spleen may also be the site of origin of blastic transformation. Theoretically, early splenectomy in chronic myeloid leukemia may be expected to exert a major impact only on those patients who are destined to have blastic transformation first occurring in the spleen rather than in the marrow or some other extramedullary site. Because there is insufficient knowledge at present to predict the site of origin of blastic transformation early in the disease in any given patient, and because extramedullary blastic transformation may occur in many sites other than the spleen, routine splenectomy hardly seems justified on the theoretical considerations just discussed. Clinical Trials of Early Splenectomy in Chronic Myeloid Leukemia

In recent years there have been five major clinical trials evaluating early splenectomy in chronic myeloid leukemia (2-5, 31). None were randomized, and three of the five studies did not have concurrent, nonsplenectomized control groups. Nevertheless, analysis of these results provides some information on the outcome in patients undergoing splenectomy during remission in the chronic phase. Pertinent data from these five major clinical trials are summarized in Tables 1 and 2. FRENCH CLINICAL TRIAL

In 1973 Schwarzenberg and associates (4) reported the first clinical trial of early splenectomy in chronic myeloid leukemia. Of 43 patients, 18 underwent splenectomy after initial remission induction with hydroxyurea. The only criterion for splenectomy was the patient's consent for the operation. The age distribution of the splenectomized and nonsplenectomized groups was similar. The median survival of the group undergoing splenectomy was slightly longer than that of the group that did not (43 months and 37 months, respectively). There were three postoperative deaths due to infection. Six patients developed postoperative thrombocytosis, and two of these six sustained thrombotic complications. All 15 patients who survived splenectomy eventually died in the blast phase. The median duration of survival in the blast phase in nonsplenectomized and splenectomized groups was 1 and 2 months, respectively. Of 13 patients treated for blast-phase disWolf et al. • Splenectomy and Leukemia

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685

Table 1. Clinical Trial s Evaluating Early Splenectomy' in Chronic Myeloid Leukemia Author (Reference)

Location

Schwarzenberg et al (4) Spiers et al (2)

France England

Tura et al (5)

Patients Splenectomized

Duration of Chronic Myeloid Leukemia Before Splenectomy

Time from Splenectomy to Blast Phase

Median Survival of All Patients

Actuarial Median Survival for Patients Splenectomized Within 1 Year After Diagnosis of Chronic Myeloid Leukemia

'.

no.

NS*

26

"After first remission" 2-56 (mean, 11)

Median NYRt

Italy

56

2-12

Ihde et al (3)

USA

32

2t

McBride and Hester (31)

USA

31

4-59 (median, 10)

Median NYR Median NYR Median

18

Duration of Blast Phase

months — 2

43

39.6

1.5-14 (mean, 6.7)

NYR

40

NS

NYR

NS

4

60

44

6-7

NYR

NS

NYR

* NS = not stated. t NYR = not yet reached. t More than 50% of patients within 2 months.

ease, only two had a complete remission. The results of this nonrandomized study suggest that early splenectomy cannot prevent blastic transformation. In view of the three postsplenectomy deaths due to infection, Schwarzenberg and associates recommend that patients be kept in an aseptic environment for 1 month after splenectomy.

trol group. The authors concluded that the quality of life during the blast phase was improved by early splenectomy because symptoms of splenic pain were absent, fewer blood and platelet transfusions were required, tolerance to chemotherapy was improved, and patients spent less time in the hospital.

ENGLISH CLINICAL TRIAL

In 1975 Spiers and coauthors (2) reported the results of elective splenectomy in 26 patients after initial remission with chemotherapy. The criteria for splenectomy included an unequivocal diagnosis of chronic-phase Ph ( + ) chronic myeloid leukemia, a prior satisfactory hematologic and clinical response to initial treatment (which was most often with busulfan), age under 65 years, and the patient's consent for the operation. Before splenectomy the platelet count was reduced to less than 200 000/mm 3 by chemotherapy. There were no intraoperative deaths. Three patients sustained significant postoperative complications (pulmonary embolism, peritonitis, and delayed wound healing). A transient rise in the leukocyte count to the preoperative level within 48 to 72 h postsplenectomy was observed in most patients. The platelet count rose more slowly, peaking 7 to 10 days postsplenectomy and requiring weeks to months to return to preoperative levels. Postoperative platelet counts greater than 1 000 0 0 0 / mm 3 occurred in 14 patients who were then treated with heparin, aspirin, busulfan, and transfusion. Only one patient sustained a thrombotic complication, a nonfatal pulmonary embolus. At the time of Spiers' report, two of the 26 splenectomized patients had died in the blast phase, two were alive in the blast phase, and three had died of causes unrelated to chronic myeloid leukemia. Overall median survival had not been reached. Postoperative follow-up was less than 2 years for two thirds of the living patients. The onset of the blast phase from diagnosis was said to be delayed in splenectomized patients compared to 48 patients treated with busulfan before 1968. However, there was no difference in survival when the actuarial survival of the 19 subjects splenectomized within 1 year of diagnosis was compared with this same historical con686

ITALIAN CLINICAL TRIAL

In 1975 the Italian Cooperative Study Group on Chronic Myeloid Leukaemia (5) reported the results of a clinical trial conducted between February 1973 and October 1974 that evaluated early splenectomy, hydroxyurea, cyclic cytarabine, vincristine, and prednisone. Of 139 patients with newly diagnosed chronic myleoid leukemia admitted to the trial, 56 underwent splenectomy after initial remission with hydroxyurea. More than half of the splenectomized patients underwent splenectomy within 2 months after diagnosis, and all splenectomies were done within 1 year after diagnosis. Patients were placed in the splenectomy or nonsplenectomy group on a nonrandom basis. In some cooperative institutions all patients underwent splenectomy, whereas in others no splenectomies were done. To be eligible for splenectomy a patient had to be between 15 and 60 years old, have a normal clinical condition unrelated to chronic myeloid leukemia, and give informed consent for the operation. Of the 139 patients, 60% were Ph ( + ); 4% were Ph ( —); and 36% had no chromosome studies done. Of four patients with early postsplenectomy infections, one died. Nine other splenectomized patients had minor postoperative complications. Early postoperative complications were observed more frequently in patients with a platelet count in excess of 500 000/mm 3 at diagnosis. Eighteen percent of patients had a platelet count greater than 500 000/mm 3 postoperatively. Four patients had delayed thromboembolic complications, two of which were fatal. After splenectomy, maintenance hydroxyurea therapy was employed. Every 2 months a 4-day course of cytarabine was alternated with a 2-week course of vincristine and prednisone. The nonsplenectomized group received this same chemotherapy regimen.

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Although at the time of their report median survival had not yet been reached, the frequency of blastic crisis within the first 3 years from diagnosis was similar in the splenectomized and nonsplenectomized groups. The platelet count at diagnosis positively correlated with the mean standard platelet count after splenectomy. Similar to the observations of Spiers and colleagues (2), splenectomy did not result in a sustained elevation of the leukocyte count. The results of this trial also suggested that splenectomy did not delay the onset of blastic transformation. A platelet count greater than 500 000/mm 3 at diagnosis was associated with increased infectious and thromboembolic complications after splenectomy. A M E R I C A N CLINICAL TRIALS

In 1976 Ihde and coworkers (3) reported the results of elective splenectomy in 24 patients in hematologic remission after treatment with busulfan or dibromomannitol. Eight additional patients in the chronic phase underwent splenectomy for busulfan-induced thrombocytopenia. All but one patient was Ph ( + ). The duration of chronic myeloid leukemia from diagnosis to the time of splenectomy ranged from 1 year or less for 11 patients to more than 3 years for nine patients. The spleen weighed less than 500 g in 21 patients at the time of surgery. There were no postoperative deaths or severe infections. Splenectomy was totally uncomplicated in 22 of 32 patients. Of the remaining patients, one required re-exploration for abdominal bleeding, and minor complications occurred in nine. In the elective splenectomy group only four of 24 patients had a platelet count greater than 1 000 000/mm 3 postoperatively. N o postoperative thromboembolic complications occurred. At the time of Ihde's report, eight of the 32 splenectomized patients were alive. The median survival of patients who underwent splenectomy was 60 months, longer than the median survival of approximately 3 years usually observed in chronic myeloid leukemia. However, a bias in favor of longer survival would be anticipated in the splenectomy group because patients with poor responses to initial chemotherapy or in early blastic transformation were excluded from splenectomy. The median survival of patients who underwent splenectomy within 1

year of diagnosis was 44 months, not significantly different from that of a large, nonrandomized control group at the same institution. N o delay occurred in the onset of blastic crisis in patients who underwent splenectomy. Of 32 splenectomized patients, 22 developed blast-phase disease. Of these 22, 18 developed blast-phase disease within the first 2 years after splenectomy, three within 3 years, and one within 5 years. Nineteen patients were treated with combination chemotherapy after blastic transformation. One achieved a complete remission, five had a partial remission, and 13 had no response. Although the response to blast-phase chemotherapy was no better than that usually observed, the median survival of splenectomized patients from the onset of blast crisis was slightly longer than the median survival in blastic transformation observed for a historical control group at the same institution (4.0 and 2.5 months, respectively). Splenectomy seemed to eliminate morbidity due to untoward splenic events during the blast phase and improved the response to platelet transfusions. This study suggests that although the duration of survival or response to blast-phase chemotherapy is not improved, early splenectomy may reduce morbidity and facilitate management of the blast phase. Recently, McBride and Hester (31) studied 31 patients who had splenectomies during the chronic phase after remission induction, usually with doxorubicin and cytarabine. The median preoperative granulocyte count was 8300/mm 3 and the median platelet count 299 000/mm 3 . There were no postoperative deaths. Five patients developed postoperative infectious complications. Two patients were re-explored for postoperative hemorrhage. McBride and Hester compared these patients with a group of 27 splenectomized patients with chronic myeloid leukemia prior to 1972 who had a 26% operative mortality. They attributed the marked improvement in mortality to the liberal use of platelet concentrates and preoperative normalization of hematologic variables. At the time of their report, the median survival of patients who underwent splenectomy after 1972 had not yet been reached. However, 14 of the 31 patients had entered blastic crisis. At least two vigorous therapeutic programs designed

! Table 2. Complicaltions of Early Splenectomy in Chnonic Myeloid Leuk emia Author (Reference)

Location

Patients Splenectomized

Immediate Postoperative Deaths

Major Infectious Complications • •

Schwarzenberg et al (4) Spiers et al (2) Tura et al (5) Ihde et al (3) McBride and Hester (31) Total

France England Italy USA USA

Thromboembolic Complications

Major Postoperative Hemorrhagic Thrombocytosis Complications

%

no.

18 26 56 32

3* 0 1* 0

3 2 4 0

2 1 4 0

0 0 0 1

33 54t 18* 23

31 163

0 4

5 14

0 7

2 3

NS§

* Due to infectioii. t Greater than 1 ()00 000/mm 8 . t Greater than 500 000/mm 3 . § NS = not statec1. Wolf et al. • Splenectomy and Leukemia

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6 8 7

to eliminate the Ph ( + ) chromosome have included early splenectomy. Clarkson and associates (1) treated 21 adults who had chronic myeloid leukemia with an intensive protocol consisting of splenic irradiation preceding splenectomy followed by intensive chemotherapy with cytarabine, thioguanine, L-asparaginase, and vincristine. Two patients developed blastic transformation at 13 months, and another died of hemorrhage at 39 months. At the time of their report, median survival had not yet been reached. Follow-up data have not been published. Brodsky and coauthors (6) evaluated eight patients who underwent splenectomy after remission induction with busulfan. Splenectomy was then followed by intensive chemotherapy. There were no significant operative morbidity and no postoperative deaths. At the time of their report, no patient had entered the blast phase, and all were alive. Canellos, Nordland, and Carbone (18) identified an additional and probably significant palliative role for splenectomy in patients in chronic-phase disease who were thrombocytopenic due to busulfan myelosuppression or whose inordinate platelet sensitivity to chemotherapy prevented control of disease. Of six such patients, five derived significant benefit from splenectomy. Splenectomy in Late Chronic Myeloid Leukemia

Little information is available on the results of splenectomy during the later stages of chronic myeloid leukemia. Although the enlarging spleen of the aggressive phase may result in morbidity by causing pain, contributing to cytopenia, and limiting nourishment, little evidence exists that the operation palliates the symptoms of patients with terminal-phase disease. Moreover, the procedure has generally been considered too dangerous in this setting (18, 53). Because, at present, patients with terminal-phase disease have a median survival of about 3 months (19), we question whether major surgery is warranted for patients with such a dismal prognosis. Nevertheless, Gomez and colleagues (17) recently reported the results of splenectomy in 60 patients in late-stage chronic myeloid leukemia, 45 meeting the criteria of Karanas and Silver (19) for the "terminal phase" of chronic myeloid leukemia. Indications for splenectomy included splenic infarction, persistent abdominal discomfort due to massive splenomegaly, thrombocytopenia, and anemia requiring frequent transfusions. Of 50 patients splenectomized between 1964 and 1974, only two died postoperatively. The authors attributed the low operative mortality of 4% to management by a single medical-surgical team and the preoperative use of epsilon aminocaproic acid. Both significant improvement of hematologic variables and clinical benefit followed splenectomy in slightly more than half of their patients. Improvement of anemia was observed for those patients with the largest spleens. The operation, however, did not significantly prolong survival of most patients. The median survival after the operation was 6 months. Although long-term improvement occurred in 10% to 15% of patients, there were no preoperative criteria that could predict such results. Further, there must be skepticism about splenectomy as the cause of long-term im688

provement in this small group of patients. McBride and Hester (31) reported no postoperative deaths from 13 splenectomies done during blast-phase disease. Thus, these recent experiences suggest that splenectomy during the terminal phase of chronic myeloid leukemia is not as dangerous as was once thought. Until better definitive treatment for the terminal phase of chronic myeloid leukemia becomes available, however, we question whether a major surgical procedure is justified for patients with blast-phase disease whose median survival is about 3 months. Discussion

Whether early splenectomy significantly prolongs the duration of the chronic phase of chronic myeloid leukemia cannot be unequivocally stated from the inadequately controlled clinical trials described above. However, in these trials the actuarial median survival of patients undergoing splenectomy within 1 year of diagnosis was not substantially longer than the anticipated median survival of about 3 years for patients with chronic myeloid leukemia who were not splenectomized (19). As shown in Table 1, the median survival of patients splenectomized within 1 year of diagnosis in the French, British, and American trials was 39.6, 40, and 44 months, respectively. Early splenectomy did not permit significant reduction in postoperative dosages of chemotherapeutic drugs in these trials. Moreover, both the French and American trials suggest that the response to blast-phase chemotherapy was not influenced by prior splenectomy. The English and American trials do suggest, however, that early splenectomy may reduce morbidity during the blast phase by eliminating splenic pain, improving nutrition, and decreasing requirements for blood products. These trials also indicate that death is now infrequent after splenectomy early in remission during chronicphase chronic myeloid leukemia. As shown in Table 2, four of 163 splenectomies resulted in immediate postoperative deaths, each due to infection. Three of these four deaths, however, complicated 18 splenectomies in the French trial. The mortality rate in that trial was particularly high and was not the same as the others. If the patients in the French trial are excluded, only one immediate postoperative death complicated a total of 145 splenectomies. Nine percent of splenectomized patients in these trials, however, sustained major, nonfatal, infectious postoperative complications. In all five trials evaluating early splenectomy, initial remission induction with chemotherapy preceded splenectomy in order to lower the platelet count and thus prevent the postoperative, thombotic, and hemorrhagic complications associated with thrombocytosis. Despite successful normalization of preoperative platelet counts, postoperative thrombocytosis occurred in 18% to 54% of splenectomized patients. Seven thromboembolic and three hemorrhagic postoperative complications occurred in 163 patients. Although one of seven thromboembolic events resulted in immediate postoperative deaths, two of four that occurred months after surgery were fatal. Thus, despite a low postoperative mortality

November 1978 • Annals of Internal Medicine • Volume 89 • Number 5 (Part 1)

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from splenectomy during early-phase disease, the morbidity from infectious and thromboembolic complications is much higher. ACKNOWLEDGMENTS: This investigation was supported by Grant CA 07968 from the National Cancer Institute and grants from Research for Blood, Inc., The Fund for Blood and Cancer Research, The Arnold R. Krakower Hematology Foundation, The Sadinoff Family, and The Amerio Foundation.

24. C A R T W R I G H T GE, F I N C H CA, L O E B V, M O O R E CV, SINGER K, D A M -

25.

26. 27.

• Requests for reprints should be addressed to Richard T. Silver, M.D.; Division of Hematology-Oncology, The New York Hospital-Cornell Medical Center, 525 East 68th St.; New York, NY 10021.

28.

Received 27 January 1978; revision accepted 22 May 1978.

29.

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• Splenectomy and Leukemia

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Splenectomy in chronic myeloid leukemia.

REVIEW Splenectomy in Chronic Myeloid Leukemia DAVID J. WOLF, M.D.; RICHARD T. SILVER, M.D.; and MORTON COLEMAN, M.D.; New York, New York We...
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