Second Era 19241973 Initial Clinical Investigations Into CLL 221 Major Contributors

2.2.1.1. Ward: 1917. In the first era, CLL was separated from leukemia, and its separation from lymphomas was initiated. The second era, between 1924 and 1973, was marked by significant contributions to our understanding of the natural history of the disease, the diagnosis, and (as poor as they were) the various treatments for this disease. It should be noted that chronic leukemia was often the subject of a given report and that both forms (myelogenous and lymphocytic) were studied.

Just before the start of the second era in 1917, Ward (22), a military officer, analyzed 1457 cases of leukemia of all varieties. He compared the age and sex incidences of 398 cases of acute leukemia, 247 cases of chronic myelemia, and 84 cases of chronic lymphemia (CLL). Most of the CLL pateints were between 45 and 60 yr of age, and 73-80% were males (Figs. 9 and 10). He concluded that the marked preferences for a particular sex and age of onset argued for a noninfectious etiology of leukemia, resembling metabolic diseases and cancer.

2.2.1.2. Minot and Isaacs: 1924. In the first comprehensive report on CLL in 1924, Minot (Fig. 11) and Isaacs (23) compared their series of 92 CLL patients with 84 CLL patients reported by Ward. Figures 12 and 13 are extracted from their report. They showed that most cases of CLL occurred at 45-54 yr of age. The male/female ratio was 3:1, symptoms were usually present 9 mo before the patient presented, and another 6 mo more was required to confirm the diagnosis. Minot and Isaacs (23) further report on 50 patients who received irradiation and 30 patients who did not and who served as controls. The source of irradiation was radium, administered over the lymph nodes and spleen. They noted that there was no difference in the duration of life span for the two groups: 3.45 yr (40 mo). We have taken the liberty of using their data to draw Fig. 14. However, they did note that individual patients did benefit if the irradiation was given at 1 or more years prior to death. Although there seemed to be an improvement in the patients' efficiency and/or a decrease in metabolic rate, improvement in formed blood elements was not the rule. Lymph nodes and spleen size showed the greatest effect. Irradiation usually had no effect if the hemoglobin level was below 50%, if thrombocytopenia and purpura were present, or if the blood contained immature and atypical lymphocytes. In Rai's opinion (2), the formal beginnings of CLL as a recognized and well-described clinical entity should be considered to have occurred in 1924 with this report by Minot and Isaacs.

In 1938, Leavell (24) reported the incidence and factors influencing survival times for 128 CLL patients seen in three large city clinics between 1917 and 1936 and reported similar findings. The greatest number of cases occurred between ages 45 and 55 yr, with 60% being male and an average duration of life of 3.6 yr. Patients with marked anemia had a shorter course, and the duration of life was slightly longer in patients with lower white counts. The number of patients with a history of bleeding was too small to be significant. Skin involvement in CLL

Chronic Lymphaemia

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Fig. 9. Age incidence of CLL arranged in 5-yr periods. (From ref. 22, Ward, 1917; The "Chronic Lymphaemia" chart was extracted from Fig. 1.)

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Fig. 10. Proportions of males with CLL at each age period. (From ref. 22, Ward, 1917; The "Chronic Lymphaemia" curve was extracted for clarity from Fig. 3.)

Fig. 10. Proportions of males with CLL at each age period. (From ref. 22, Ward, 1917; The "Chronic Lymphaemia" curve was extracted for clarity from Fig. 3.)

seemed to have no effect on the duration of disease compared with those CLL patients without specific skin lesions.

2.2.1.3. Wintrobe and Hasenbush: 1939. The early phase of the disease was emphasized in a report published in 1939 by Wintrobe and Hasenbush (25) containing clinical data on 86 cases of chronic (myeloid and lymphoid) leukemia from the Department of Medicine, John Hopkins University. They studied 47 CLL patients of whom 39 were men (83%) seen between 1926 and 1938. The age of disease onset was 60-65 yr for 61.7% of the CLL patients. A representative figure from this work is shown in Fig. 16. Examples of patient presentation included three men with prostatic hypertrophy, one patient with sugar in the urine, one patient with a psychoneurotic disorder, and one patient with indigestion. One-third of their patients presented with an unexplained leukocytosis, and one-third had glandular enlargement. A distinct absolute lymphocyto-sis with a normal or low-normal white blood count (WBC) was frequently seen. Only one patient had splenomegaly. They observed an average life span of 2.33 yr but noted great variation in their patients and in the literature. Infections were common in CLL and did not correlate with spon-

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A^e Incidence of Chronic Lympta+ic Leukemia.

Fig. 12. Age incidence of CLL in the American and English population. (From ref. 23, Minot and Issacs, 1924; the curves were extracted for clarity from Fig. 1. Copyright © 1924, Massachusetts Medical Society.)

Ofol I taZ Ito J }ib4 4*5 5 K>b i *>7 7*8 0*>9 9MO DUQATlON IN YEA BJ

Fig. 13. Frequency of duration of CLL (87 cases). (From ref. 23, Minot and Isaacs, 1924, Fig. 5. Copyright © 1924, Massachusetts Medical Society.)

Ofol I taZ Ito J }ib4 4*5 5 K>b i *>7 7*8 0*>9 9MO DUQATlON IN YEA BJ

Fig. 13. Frequency of duration of CLL (87 cases). (From ref. 23, Minot and Isaacs, 1924, Fig. 5. Copyright © 1924, Massachusetts Medical Society.)

30 n

30 n

Otol 1to2 2to3 31o4 4to5 5io6 6to7 71o8 8to9 9to10 Duration in Years

Fig. 14. Frequency of duration of CLL. (Redrawn from the data of ref. 23, Minot and Isaacs, 1924. Copyright © 1924, Massachusetts Medical Society.)

Otol 1to2 2to3 31o4 4to5 5io6 6to7 71o8 8to9 9to10 Duration in Years

Fig. 14. Frequency of duration of CLL. (Redrawn from the data of ref. 23, Minot and Isaacs, 1924. Copyright © 1924, Massachusetts Medical Society.)

taneous remissions. These investigators also found no benefit from irradiation or the use of potassium arsenite solutions with CLL.

2.2.1.4. Boggs et al.: 1966. Boggs et al. (26) followed 130 CLL patients from 1945 to 1964 in the Hematology Clinic, University of Utah and reported their findings in 1966. Patients with "aleukemic" CLL and lymphosarcoma were excluded. Seventy-four had died, 46 were alive, and 10 were lost to follow-up. Death owing to CLL was caused by infection (23 patients), thrombocytopenic hemorrhage (2 patients), meningeal leukemic infiltrates (1 patient), and congestive heart failure (CHF) with acute myocardial infarction (AMI) and autoimmune hemolytic anemia (AIHA; 1 patient). Deaths unrelated to CLL consisted of AMI and CHF (five patients), pulmonary embolus (PE; two patients), cancer [three patients: prostate cancer, bile duct carcinoma, and Hodgkin's disease (HD)], and diabetes and uremia (two patients), as well as perforated ulcer, cerebral vascular thrombosis, and automobile accident in one patient each. Treatment-related deaths occurred in eight patients (see Table 1 of their report for a summary of deaths). The mean age of this CLL group was 59.5 yr, and 74% were male. Most patients were symptomatic,

Fig. 16. Age at onset of symptoms in 47 cases of chronic lymphogenous leukemia. (From ref. 25, Wintrobe and Hasenbush, 1939; extracted from Chart 1. Copyrighted 1939, American Medical Association.)

complaining of fatigue (76%), enlarged lymph nodes (39%), recent infection (25%), and easy bruising or minor bleeding (6%). In 25% there were no symptoms referable to CLL, and the patient was being seen either for a routine visit or for complaints unrelated to CLL. The duration of symptoms was 12.9 mo. Physical findings consisted of lymphadenopathy and splenomegaly in more than 75% of patients, with hepatomegaly and sternal tenderness in 45% and 27%, respectively. Palpable retroperitoneal (mesenteric or pelvic?) lymph nodes (three patients) and skin infiltrates (two patients) were also seen. An absolute lymphocytosis (7000-978,000), was noted in 100% of patients, with 32% showing greater than 100,000; anemia, thrombocytopenia, and neutropenia, were seen in 55%, 39%, and 23 % respectively. Triethylenemelamine, chlorambucil,

Fig. 17. Survival from onset of symptoms (A) or from time of diagnosis (B) considering deaths from all causes and deaths related to CLL. Calculations from which this figure was derived are listed in Tables IV and V of ref. 26. (From ref. 26, Boggs et al.,1966, Fig. 1. Copyright 1966, with permission frtom Excerpta Medica Inc.)

Fig. 17. Survival from onset of symptoms (A) or from time of diagnosis (B) considering deaths from all causes and deaths related to CLL. Calculations from which this figure was derived are listed in Tables IV and V of ref. 26. (From ref. 26, Boggs et al.,1966, Fig. 1. Copyright 1966, with permission frtom Excerpta Medica Inc.)

Fig. 18. Survival of 31 patients in whom the diagnosis was made before symptoms attributable to CLL developed. Calculations from which this figure was derived are listed in Table VI of ref. 26. (From ref. 26, Boggs et al., 1966, Fig. 4. Copyright 1966, with permission from Excerpta Medica Inc.)
Fig. 19. Professor D. A. G. Galton. (Digital image kindly provided by Professor Daniel Catovsky.)

Fig. 20. William Dameshek. Courtesy of the National Library of Medicine (http://www.nlm.nih.gov/).

and prednisone were used in the treatment of these patients. Treatment was associated with a reduction in lymphoid tissue, but often there was no improvement or there was a worsening of anemia, thrombocytopenia, and neutropenia. In addition, prednisone was associated with compression fractures, diabetes, and severe infections. Their analysis of survival (Fig. 18) suggests a median survival of 6 yr from time of diagnosis to death, 9 yr if non-CLL causes of death are excluded, and 10 yr for asymptomatic CLL. In their series, untreated patients lived as long or longer than treated patients.

2.2.1.5. Galton: 1960s. In his 1963 thesis on "The natural history of chronic lymphocytic leukemia" and in a later (1966) paper, Galton (27) summarized much of his experience and understanding of CLL. In his description of the natural history of CLL lay the beginning of a staging system that would later be used by Rai and Binet. His attention to the rediscovered patterns of lymphocytosis would also lead to a valuable prognostic indicator, i.e., the lymphocyte doubling time (LDT). Later, he also made seminal observations not only of the differential diagnosis of CLL but also the subclassification of CLL. In his observations of 88 cases over 15 yr, he starts by noting the need to evaluate and intergrate the presence or absence of symptoms, and physical and laboratory findings. Most importantly, he stressed the desirability of evaluating the hematological and blood film findings in conjunction with the histopathology of both the lymph node and bone marrow biopsies. An increase in symptoms and physical findings tends to be associated with a higher absolute lymphocyte count (ALC) and decreased normal marrow function. Marked marrow infiltration with normal function was often noted with isolated splenomegaly, i.e., so-called splenomegalic CLL.

In addition, he defined three patterns (trends) of ALC evolution in CLL. In the type I trend, the ALC continued to increase constantly during the period of observation. In the type IIa trend, the ALC rose to a certain level, reached a plateau, and remained relatively constant during the period of observation. Today CLL patients with type I and IIa patterns would be thought to have LDTs of less than 6-12 mo and more than 12 mo, respectively. A third pattern, type IIb, showed a fluctuation around a mean, which Galton interpreted to mean the stationary phase of type IIa. However, it could just as well be that the type IIb pattern could precede the type IIa pattern, as seen in early CLL. Regardless of these subtleties in the etiology of the type IIb pattern, Galton appropriately noted that the type II pattern favored superior survival and the type II trend was thus associated with slowly progressive disease. Parenthetically, Galton further notes: "The patterns shown by the lymphocyte counts in these cases were clearly seen when they were plotted on a semilogarithmic scale, on which the amplitude of fluctuations about the mean values does not increase as the mean counts rise." Thus he was able to define two groups of patients on the basis of their ALC: one whose absolute lymphocyte counts rose throughout the observation period and another in which the absolute lymphocyte count stabilized around a mean value and was associated with a more benign form of the disease. How strikingly similar these observations are to the recent correlation of Ig gene mutational status and CD38 expression correlating with two variants of CLL! Galton's speculations on the pathogenesis of CLL begin with his observations on the evolution of CLL: the gradual accumulation of aged, small, mature, well-differentiated lymphocytes as seen on blood films that are fragile (smudge cells) in the blood, lymph nodes, spleen, and bone marrow. This lymphocytosis is further characterized as having a low mitotic index and being poorly responsive to several mitogenic stimuli.

2.2.1.6. Dameshek: 1960s. In 1967, William Dameshek, attending hematologist at The Mount Sinai Hospital and Medical School, published a special article in Blood entitled: "Chronic Lymphocytic Leukemia—an Accumulative Disease of Immunologically Incompetent Lymphocytes" (28). Dameshek drew attention to several features of CLL. First he proposed a clinical stratification of CLL into four stages similar to those of Galton as follows: stage I, the patient is entirely asymptomatic, with a blood and marrow lymphocytosis; stage II, a year or decade later, the patient would develop night sweats, generalized lymphadenopathy, and variable splenomegaly (here recognized isolated splenomegalic CLL); stage III, the patient was increasingly symptomatic, with palpable intra-abdominal lymph nodes and frequent bouts of infection; and stage IV, "bouts of fever, frequent infections, disturbances referable to various organs such as nasal sinuses, the lung, the skin, various autoimmune disorders and increasing anemia take place often in rapid succession." Anemia was increasingly marked and associated with stages III and IV, as was a packed non-aspiratable marrow. Hypogammaglobulinemia was already recognized at that time, and the findings of autoimmunity (AIHA and idiopathic thrombocytopenia [ITP]) were beginning to emerge. The manifestations of autoimmunity and a reduced or absent response to common bacterial antigens led to the second concept of immune incompetence. The lack of skin graft rejection, fatal viral infections, the dissemination of live vaccines, and allergic reactions to insect bites suggested that there were defects in both the humoral and cellular immune systems. Although better understood today, the lack of a response to the plant mitogen phytohemagglutinin (PHA) led to the concept of a "block in differentiation" in this lymphoproliferative disorder of the CLL lymphocyte. He was also aware of familial CLL. In addition, Dameshek drew attention to the use of large-dose corticosteroids (prednisone 50-150 mg daily) and the pattern of response. Thus he defined CLL as an abnormal, generalized, self-perpetuating proliferation of small lymphocytes with a variety of immunological aberrations resulting in immunoincompetency.

2.2.1.7. Hansen: 1973. In 1973 Hansen (29) presented detailed clinical data on 189 patients with CLL followed for a long time in his department in Copenhagen. This report, along with Galton's thesis should be required reading for all students of CLL. This stand-alone report, a single issue of the Scandinavian Journal of Haematology devoted to CLL, is not unlike the early editions of Dameshek and Gunz's Leukemia (30). Because of the wealth of clinical material in this publication, a brief summary follows.

In Hansen's historical review (29), he notes that Hayhoe (31) assigns the first reported case of CLL to Craigie. The spleen of Craigie's 30-yr-old patient weighed 7 pounds, 3.5 ounces. He also notes the early recognition of splenic and lymphatic leukemia that was subsequently corrected by Neumann (32), who described bone marrow changes in leukemia as " 'pyoid' hyperplasia, predominated by highly granulated cells and 'lymphadenoid' hyperplasia, predominated by cells having pale homogeneous cytoplasm." Hansen aptly notes that difficulties in diagnosis led to a profusion of such terms as lymphosarcoma and leukosarcoma leukemia, to be differentiated from CLL. Hansen defined CLL as an increasing accumulation and infiltration of small lymphocytes with the characteristic presence of "smudge cells" or Gumprecht shadows. If the typical presentation of lymphadenopathy or splenomegaly with a leukemic blood picture is lacking, then either a lymph node and or bone marrow biopsy is required to document the typical lymphoid infiltrate. Generalized lymph node enlargement was defined as clinical or radiological evidence of enlarged lymph nodes in at least three regions. The WBC was required to be more than 10,000 cells/^L, with at least 60% lymphocytes (mostly mature forms) and a hypercellular marrow with more than 40% mature lymphocytes.

The 189 cases reported by Hansen came from three institutions in Denmark during the time period 1954-1963. When the analysis was completed in 1966/1967, 28 patients were still alive and had been followed for at least 3 yr. Autopsy reports were available on 109 of 161 deceased CLL patients (68%). It was felt that these cases represented 15% of all cases of CLL in Denmark during the period 1954-1963. The sex and age distribution is shown in Fig. 21; the mean age at diagnosis was 63.3 yr, and the overall male/female ratio was 1.8:1. Initial symptoms are shown in Table 1, and causes of death are listed in Table 2. Lymph node enlargement was present in 91%, splenomegaly in 47%, hepatomegaly in 30%, leukemic skin infiltrates in 6-7%, and herpes zoster in 13%. Mediastinal and or hilar lymphadenopathy was 27%, rising to 38% during the course of disease, whereas plural effusions were unusual, seen in only 2% at presentation but during the course of the disease in 17%. Microscopic pulmonary leukemia infiltrates were seen in 52% of

Fig. 21. Sex and age distribution at diagnosis. (From ref. 29, Hansen, 1973, Fig. 1. With permission from the European Journal of Hematology.)

Fig. 21. Sex and age distribution at diagnosis. (From ref. 29, Hansen, 1973, Fig. 1. With permission from the European Journal of Hematology.)

autopsy samples—gross leukemic gastrointestinal infiltrates were seen in 9% of patients and were generally clinically silent. Gross renal leukemic infiltrates were seen in 18%, with 70% microscopic involvement. Fatal uremia was seen in 2%, with urolithiasis in 7-8%. Skeletal changes consisted primarily of osteoporosis and vertebral body collapse. Osteosclerosis was seen less frequently, and lytic lesions were not seen. At presentation, 45% of the patients had a normal hemoglobin level, but 21% were Coombs test positive, and 47% had a normal platelet count. Normal marrow function persisted even though more than 80% of the marrow was involved with a leukemic infiltrate. Median survival was estimated at 3 yr and the single survival curve from this study is shown in Fig. 22. This extensive clinical review is followed by individual case reports and graphic presentations of each patient.

Rai (2) and Hamblin (5) both note in their reviews that Galton and Dameshek, virtually simultaneously but independently of each other, concluded that the primary pathology in CLL was the progressive accumulation (rather than an abnormally rapid proliferation) of lymphocytes. It is further noted that both of these leaders in hematology recognized that CLL lymphocytes were functionally incompetent and did so before the era of immunotyping and the classification of lymphoid neoplasms according to their T- and B-cell origin. Although Hansen did not propose a staging system, he seems to be the first to have laid down extensive criteria for the diagnosis of CLL. Hansen's extensive clinical description confirmed the patterns that Galton described. These observations, combined with Dameshek's symptomatic stages, set the stage for Rai and later Binet to develop clinical staging systems.

In his book Leukemia: Research and Clinical Practice published in 1960, Hayhoe (31) provided a comprehensive description of the clinical aspects of CLL prior to Hansen's report. Hamblin in his review (5) felt that Hayhoe's description remained the most up-to-date summary of knowledge of CLL nearly 35 yr later. Hayhoe's description of the latent autoimmune sensitization of

Table 1

Initial Symptoms of Chronic Lymphocytic Leukemia in 188 Patients

Patients

Table 1

Initial Symptoms of Chronic Lymphocytic Leukemia in 188 Patients

Patients

Lymph node enlargement

84

(45)

Symptoms of anemia

48

(26)

Sweating

38

(20)

Fever

22

(12)

Complaints owing to an enlarged liver or spleen

20

(11)

Cutaneous or mucosal hemorrhages

11

(6)

Itching

11

(6)

Accidental finding

30

(16)

From ref. 29, 1973, Table 4. With permission from the European Journal of Hematology.

From ref. 29, 1973, Table 4. With permission from the European Journal of Hematology.

Table 2

Causes of Death in 161 Patients With Chronic Lymphocytic Leukemia

Patients

Table 2

Causes of Death in 161 Patients With Chronic Lymphocytic Leukemia

Patients

Cause

No.

(%)

Infection

101

(63)

Other disease

31

(19)

Cachexia

22

(14)

Anemia

14

(9)

Hemorrhage

5

(3)

Uncertain

21

(13)

From ref. 29, 1973, Table 5. With permission from the European Journal of Hematology.

From ref. 29, 1973, Table 5. With permission from the European Journal of Hematology.

red cells (macrocytosis, anisocytosis, and sometimes spherocytosis with polychromatophilia) is particularly apt in the absence of a slight rise in the serum bilirubin and when reticulocytes are not noticeably increased. For reviews of the etiology of anemia in CLL, which is beyond the scope of this report, see Dameshek and Schwartz, 1938 (33), Berlin, 1951 (34), Coons et al., 1955 (35), Wasserman et al., 1955 (36), Troup et al., 1960 (37), Videbaek, 1962 (38), Myint et al., 1995 (39), and Casadevall et al., 2002 (40). His distinction between "amegakaryocytic thrombocytopenia" and "megakaryocyte thrombocytopenia" remains relevant today. In his chapter on CLL, Hayhoe references the early work (1957) of Scott (41). Three figures have been selected from that report and are shown here (Figs. 23, 24, and 25). Our summary of this second era in the history of CLL might best be closed with a discussion of the discovery and use of chlorambucil and steroids in the treatment of CLL.

2.2.2. Therapies of the Second Era

2.2.2.1. Chlorambucil (CB1348). In 1955, a landmark paper in the history of CLL, "Clinical Trials of p(DI-2-Chloroethylamino)-phenylbutyric Acid (CB 1348) in Malignant Lymphoma," Galton et al. (42) gave the first report of the treatment of patients with CLL with chlorambucil.

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Fig. 22. Single survival curve from Hansen's study. (From ref. 29, Hansen, 1973, Fig. 6. With permission from the European Journal of Hematology.)

Years after diagnosis

Fig. 22. Single survival curve from Hansen's study. (From ref. 29, Hansen, 1973, Fig. 6. With permission from the European Journal of Hematology.)

Fig. 23. Age at onset of symptoms in CLL. (From ref. 41, Scott, 1957, Fig. 9. Reprinted with permission from Elsevier, The Lancet.)

Ironically, the use of chlorambucil, a water-soluble aromatic nitrogen mustard, followed a fairly intensive study of mustard gas as a result of World War II. This drug was found to be a powerful inhibitor of the transplanted Walker rat tumor 256 and was therefore submitted to clinical trials.

Enlarged lymph-nodes Lassitude

Loss of weight n

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Angina SB Spontaneous hamorrhages 9

Abdominal tumour a

Ankle oedema a

Routine blood-count

Fig. 24. Presenting symptoms in 212 patients with CLL. (From ref. 41, Scott, 1957, Fig. 10. Reprinted with permission from Elsevier, The Lancet.)

Fig. 25. Survival from onset of symptoms in CLL. (From ref. 41, Scott, 1957, Fig. 12. Reprinted with permission from Elsevier, The Lancet.)

We quote liberally from this report as it provides the first description of how the drug chlorambucil was used for over 40 yr, before the discovery of fludarabine. In this first study, 93 patients suffering from advanced carcinoma and from lymphoma were treated with chlorambucil. The report was restricted to those patients with malignant lymphoma of which there were 62 including 23 with HD, 20 with lymphocytic lymphoma (including 8 patients with CLL), 11 with reticulum cell sarcoma, and 6 with follicular lymphoma. The oral dose ranged from 2 to 20 mg/d (0.03-0.34 mg/kg/body weight), and in most cases it was either 0.1 or 0.2 mg/kg daily or 6 or 12 mg for a patient weighing approx 10 stone (63.5 kg). The course of treatment usually lasted for 3-6 wk.

Results were summarized by the presence of "benefit," "some effect," or "no effect." The CLL cases are summarized in Table 2 of that report; 4 of the 8 CLL patients had a benefit, and 7 of 12

Fig. 24. Presenting symptoms in 212 patients with CLL. (From ref. 41, Scott, 1957, Fig. 10. Reprinted with permission from Elsevier, The Lancet.)

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Fig. 26. Overall survival of patients treated with chlorambucil, triethylenemelamine (TEM), and radioactive phosphorus (P32). It is to be noted that the administration of P32 ended at yr 4. (For an early study on the use of P32 in CLL, see ref. 45, Lawrence et al., 1949). (From ref. 43, Huguley, 1970, Fig. 4, as cited in ref. 44 by Rundles in Williams et al. [eds.] Hematology, 2nd and 3rd editions. With permission from Elsevier.)

Fig. 26. Overall survival of patients treated with chlorambucil, triethylenemelamine (TEM), and radioactive phosphorus (P32). It is to be noted that the administration of P32 ended at yr 4. (For an early study on the use of P32 in CLL, see ref. 45, Lawrence et al., 1949). (From ref. 43, Huguley, 1970, Fig. 4, as cited in ref. 44 by Rundles in Williams et al. [eds.] Hematology, 2nd and 3rd editions. With permission from Elsevier.)

patients with a lymphocytic lymphoma (subleukemic), also had a benefit. These benefits were associated with increases in hemoglobin and platelet counts and decreases in size of splenomegaly and degree of lymphadenopathy. The toxic effects of chlorambucil on blood elements included lymphopenia, which was slowly progressive and continued as long as the drug was given. Most patients showed some neutropenia after the third week of treatment. Severe neutropenia was closely related to the dosage of chlorambucil. All but one patient received a total dose of 6.5 mg/kg or more (450-550 mg) in one course. About one-fourth of all patients receiving 6.5 mg/kg may be expected to develop severe neutropenia, and if this dose is taken in 8 wk or less, the proportion approaches one-third. It may be significant that 16 of the 20 patients who derived most benefit from treatment received comparatively small doses suggesting that administration of chlorambucil need not be pushed to its limits of tolerance to achieve the best therapeutic results. In the lymphoma group, most patients who developed severe neutropenia and thrombocytopenia had infiltration of the bone marrow, but others who tolerated the drug well had similar infiltrations. The administration need not be discontinued as soon as the neutrophil count begins to fall, but it should be remembered that the fall may continue for 10 d after the last dose and that as the total dose is approached (6.5 mg/kg), there is a real risk of causing irreversible bone marrow damage. With regards to platelets, platelet depression was rarely serious in patients treated with chlorambucil.

In summary, 62 patients suffering from malignant lymphoma were treated with chlorambucil. Striking remissions were obtained in four cases of HD, seven of lymphocytic lymphoma, four of CLL, and of five follicular lymphoma. Chlorambucil therapy is relatively free from gastrointes-

Fig. 27. Overall survival of asymptomatic and symptomatic patients comparing continuous and intermittent regimens. (From ref. 43, Huguley, 1970, Fig. 4, as cited in ref. 44 by Rundles in Williams et al. [eds.] Hematology, 2nd and 3rd editions. With permission from Elsevier.)

tinal side effects and has proved to be less damaging to hemopoietic tissue than the cytotoxic agents heretofore available for the treatment of malignant lymphoma.

The introduction of chlorambucil led to clinical trials evaluating continuous vs intermittent therapy and a single large oral vs the same dose divided over 4 d. The addition of prednisone was also evaluated. Clorambucil became the mainstay of treatment in CLL. More importantly, clinical trials led to the discontinuation of the use of radioactive P32 owing to increased deaths compared with chlorambucil. This development is illustrated in Figs. 26 and 27.

2.2.2.2. Steroids. In 1961 Shaw et al. (46) reported on a National Cancer Institute (NCI) sponsored study of prednisone therapy to define its antileukemic effect and ascertain its effect on the frequency and/or character of infections in CLL. Eighteen patients were randomized to (1) prednisone for 12 wk followed by a 12-wk control period or (2) a control period of12 wk followed by prednisone for 12 wk. Prednisone was given at 1 mg/kg for 4 wk. At the end of 4 wk, it was reduced to 0.5 mg/kg for 4 wk, and after 8 wk it was reduced to 0.25 mg/kg. At the end of 12 wk, prednisone was discontinued. No other anti-eukemic therapy was given and antacids were not routinely administered.

This study showed an improved sense of well-being and increased strength and appetite in all subjects. There was a dramatic reduction in splenomegaly, with a comparable decrease in lym-phadenopathy and hepatomegaly in most of patients. (Figure 28 shows the reduction in spleen size.) There was an initial increase in the WBC ("paradoxical lymphocytosis") with a subsequent decrease. Improvements in hemoglobin, platelet, and absolute granulocyte counts were also chronic lymphocytic leukemic effect of prednisone on spleen size

T-1-1-!-,-1-1-j-1-,-,-,-1-1-1-,-1-r chronic lymphocytic leukemic effect of prednisone on spleen size

WEEKS OF THERAPY

Fig. 28. Effect of prednisone on spleen size in CLL. (From ref. 46, Shaw et al., 1961, Fig. 1. Copyright American Society of Hematology, used with permission.)

WEEKS OF THERAPY

Fig. 28. Effect of prednisone on spleen size in CLL. (From ref. 46, Shaw et al., 1961, Fig. 1. Copyright American Society of Hematology, used with permission.)

noted. All these changes were transient. Although there was no statistically significant increase in fever and infections during the prednisone period compared with the control period, infections in the prednisone-treated subjects were more severe and more difficult to treat.

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