Refer to: Chronic lymphocytic leukemia-Medical Staff Conference, University of California, San Francisco. West J Med 127:221-228, Sep 1977
Medical Staf Conference
Chronic Lymphocytic Leukemia These discussions are selected from the weekly staff conferences in the Department of Medicine, University of California, San Francisco. Taken from transcriptions, they are prepared by Drs. David W. Martin, Jr., Associate Professor of Medicine, and Robert C. Siegel, Associate Professor of Medicine and Orthopaedic Surgery, under the direction of Dr. Lloyd H. Smith, Jr., Professor of Medicine and Chairman of the Department of Medicine. Requests for reprints should be sent to the Department of Medicine, University of California, San Francisco, CA 94143.
DR. SMITH: * It has been our custom to ask our chief medical residents at Moffitt Hospital to discuss a topic at Medical Grand Rounds near the conclusion of their residency year. We have been privileged to have Dr. Janet Abrahm as chief resident during this past year. She will discuss the topic of chronic lymphocytic leukemia. DR. ABRAHM:t The first description of leukemia was published simultaneously in 1845 by Craigie in Edinburgh and Virchow in Berlin. In 1905 acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL) and "myelogenous" leukemias were first officially distinguished. The process of discovering and defining the different types of leukemic cell is still continuing. Before describing to you some of what we know about the leukemic cell in CLL, I would like to briefly review the characteristics and functions of normal T and B cells."2 T, or thymus derived, cells are distinguished from B, or bone marrow derived, cells by immunologic characteristics. The former make up most of the circulating lymphocyte population and are located in characteristic areas of lymph nodes and spleen. Their functions are still being *Lloyd H. Smith, Jr., MD, Professor and Chairman, DeparttJanet L. Abrahm, MD, Chief Resident.
ment of Medicine.
discovered, but it is felt, from studies in patients devoid of them, that T cells ( 1 ) are key mediators of cellular immune responses, including delayed hypersensitivity reactions, (2) may modulate B cell responses to antigens both as facilitators, so called "helper" T cells, and possibly as inhibitors, so called "suppressor" T cells. Patients without functional T cells, therefore, are prone to fungal, parasitic and intracellular bacterial infections. Their role in viral disease is still unclear, although they are clearly involved in the response to viruses that spread directly from cell to cell, such as in herpes zoster. B cells are major antigen recognizers and antibody producers. Patients who lack them are plagued by extracellular bacterial infections, as most bacteria must be coated by opsonizing antibody in order to be subject to optimal phagocytosis and clearing from the blood stream. Antibody also seems to affect the infectivity and dissemination of several viruses by inhibiting attachment, penetration or replication, especially of those that produce systemic infection. In patients with CLL there remain some functional, normal B cells and a normal T cell pool.3'4 But the leukemic B cell is the predominant cell in 98 percent of the cases of CLL. Moreover, it now seems clear that CLL is due to the proliferation of THE WESTERN JOURNAL OF MEDICINE
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CHRONIC LYMPHOCYTIC LEUKEMIA CLL
NORMAL ABBREVIATIONS USED IN TEXT = ALL acute lymphocytic leukemia AIHA=autoimmune hemolytic anemia CLL=chronic lymphocytic leukemia CLSL=chronic lymphosarcoma cell leukemia DNA= deoxyribonucleic acid HL-A=histocompatibility locus A ITP = idiopathic thrombocytopenic purpura SLE=systemic lupus erythematosus
clone of cells. The surface immunoglobulin produced by the malignant cells of CLL has been shown to be monoclonal, with single antibody specificity and single idiotype (variable region).5,6 The cells of CLL are structurally and functionally abnormal in several ways (including different specificity of C3 receptors, different scanning EM morphology) but the most clinically significant abnormalities involve their immunologic responsibilities. In vitro, the cells have delayed antibody secretion and delayed, if any response, to normal mitogens. In vivo studies in patients with CLL show an inability to produce antibodies to new antigens, to remember old antigens and produce antibodies to them, and to develop a delayed hypersensitivity response to an antigen to which the organism had not previously been exposed. Significantly, the delayed hypersensitivity (skin test) response to old antigens is retained. How might we explain these in vivo findings? Figure 1 schematically illustrates what happens to the lymphocyte pools in a patient with CLL. The sizes of the normal B and T cell pools remain unchanged, but the total pool size is greatly increased by the leukemic B cells. In addition, the presence of the abnormal B cells in the lymph nodes and splenic channels may impair contact between T cells and B cells. Moreover, the leukemic B cells may have receptors for the normal T cells, and so, by competitive inhibition, interfere with normal T-B cell interaction. This functional dilution of T-B cell interaction might explain the observed inability to produce antibody to new antigens. The dilution of normal T or B cells themselves in the lymph nodes and spleen might sufficiently decrease contact with new or old, frequently occurring antigens so as to lead both to impaired ability to mount a hypersensitivity response to a new antigen and to a general decrease of antibody production. This might then explain the hypogammaglobulinemia found in the majority of patients with disease of greater than five years. The standard skin tests remain posiSEPTEMBER 1977
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3
T
cell i
Figure 1.-Proposed dilution of normal B cell and T cell interactions by leukemic B cells of chronic lymphocytic leukemia (CLL).
one
222
leukemic B
B
B+T CELL POPULATION X factor
? genetic ? pathogen ALTERED IMMUNE COMPETENCE
ACQUIRED HYPOGAMMA
? pathogen(s)
NEOPLASTIC TRANSFORMED B CELLS etc. Waldenstrom's macroglobulinemia multiple myeloma (antibody or nonantibody
nodular lymphoma
n riJU
CLL
t, l
y)il
plasmacytoma
Figure 2.-Postulated range of B cell disorders including chronic lymphocytic leukemia (CLL).
tive, however, because the previously sensitized, circulating T cell interacts normally with its antigen and the skin macrophage. In sum, then, the leukemic B cell is an immunologically incompetent and long-lived cell, which may, by its accumulation and dilution of the normal T and B cell interactions, lead to the alterations in immunocompetence seen in patients with CLL. The cause of CLL is unknown. One might, however, postulate a defect producing a range of B cell disorders of function (see Figure 2). For example, in the acquired hypogammaglobulinemic state, a defect of release of gamma globulin has been detected, but this does not progress to neoplasia (even though the patients do have intestinal nodular hyperplasia). The same alteration (for example, an inherited defect or an environmental pathogen, or both) might lead to neoplastic transformation in B cells of different types or stages, with the observed clinical syndrome resulting from the functional capabilities of the particular cell which has been transformed. A genetic susceptibility to B cell disorders of this kind has been suggested by studies of families in whose members lymphatic leukemias or lym-
CHRONIC LYMPHOCYTIC LEUKEMIA
phomas developed at an unusually high frequency.7 In these families, those siblings in whom the leukemia or lymphoma did not develop do have abnormalities of immunoglobulin production. Furthermore, there is an increased incidence of leukemia in patients with x-linked agammaglobulinemia. The susceptibility to malignancy could be simply due to the neoplastic transformation itself, or more likely to the immunologic defect, resulting in increased susceptibility to an environmental carcinogenic agent or loss of immunologic surveillance giving rise to the establishment of neoplasia. Returning to CLL, let us now discuss some more general considerations: CLL accounts for 25 percent of all leukemias. It is more commonly reported in whites than blacks, most commonly among Jews and relatively rarely among Asiatics. The male to female ratio is 2:1. The disease is rare in persons under 40 years of age. Eighty percent of new diagnoses are made in patients over 50. My discussion of the clinical syndrome will include the following areas: infiltrative manifestations, immunologic phenomena, infections, second malignancies and causes of death. We will then discuss prognosis and therapy. Because the infiltrative manifestations are those that most commonly bring the patient to the doctor, we shall begin with them. Of these, the most common presenting symptom in all series is enlarged lymph nodes, although CLL is an accidental finding on routine complete blood counts in an equal number of patients.8 The other initial symptoms include those of anemia in 25 percent of patients and sweating and weight loss in 20 percent. Fever, complications secondary to enlarged liver or spleen, cutaneous or mucosal hemorrhage and itching each were noted in about 10 percent. Diffuse lymph node enlargement is also the most common physical finding (63 to 89 percent) on initial presentation. The nodes are often small, discrete, firm and freely -movable, increasing in size as the disease progresses. Node compression, especially in the mediastinum or retroperitoneal areas, can lead to bronchial or other obstructive symptoms or, more rarely, a superior vena cava syndrome or aphonia from recurrent laryngeal nerve compression.
Splenomegaly is present in about half of the patients, and hypersplenism, splenic infarction, subcapsular bleeding and perisplenitis can occur if the splenomegaly is massive.
The bone marrow in untreated patients is hypercellular and infiltrated by lymphocytes. At diagnosis, a lymphocyte count greater than 60 percent is found 94 percent of the time and will increase to 80 to 100 percent terminally. Bone marrow function, however, is usually good throughout most of the course, though in a significant number of cases, marrow failure, with refractory anemia and thrombocytopenia may supervene. Organ infiltration by the leukemic cells has been reported in almost every system. That in the liver, kidney, endocrine organs, esophagus and gastrointestinal tract is usually asymptomatic. That into the salivary and lacrimal glands can produce xerostomia and xerophthalmia (in contrast, note that the infiltrate in Sj"ogren syndrome is polyclonal and stains for B cells). In the skin, exfoliative erythroderma is seen along with tumors, especially of the face, and infiltrated plaques. Pleural effusions are not an infrequent finding, whereas an actual lung infiltration is rare. Central nervous system manifestations include the more common herpes zoster, along with the rare cranial nerve palsy and spinal cord compression. The bone lesion is most typically generalized osteoporosis, but steroid responsive hypercalcemia with normal parathyroids has been reported. Other rare findings include glaucoma secondary to limbic infiltration, and acropachy-that is, finger clubbing with symmetrical destruction of terminal phalanges secondary to subungual infiltration. Weight loss is seen not infrequently late in the course of disease in these patients. While it is probably not due to infiltration into the gastrointestinal tract, there may be more to it than the "hypermetabolic state." Malabsorption in patients with CLL was documented in 1960.9 In macroglobulinemia, the malabsorption has been felt to be secondary to deposition of Bence-Jones amyloid in the extracellular spaces,10 but this has not been seen and would not necessarily be expected in CLL where the paraprotein production is much less. Hypogammaglobulinemia, however, as stated above, is common in CLL. Diarrhea with malabsorption is seen in other such states and in these states is found to be secondary to giardia infestation. In the reported cases of CLL with malabsorption, giardiosis was not looked for and levels of gamma globulin were not reported. These THE WESTERN JOURNAL OF MEDICINE
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studies would seem to be the logical next step in elucidating the mechanism of the malabsorption in the CLL patients. Next, let us turn to the associated immunologic phenomena, as herein lies one of the paradoxes of this disease. As mentioned before, the leukemic cells poorly synthesize antibody and, in fact, the gamma globulin levels often fall as the disease progresses, and yet an assortment of antibody mediated complications occur.8 The CLL cell products do not seem to be responsible. An IgM spike is found in less than 10 percent of patients, and in all cases where it has been examined it is identical to that on the leukemic B cell surface. It does have anti-human IgG activity,'1 but it has never been shown to have anti-red cell, antiplatelet or anti-nuclear specificity. Furthermore, as it is an IgM, not an IgG, one would not expect it to cause the observed Coombs' positive hemolytic anemia. In fact, it probably only produces trouble as a cryoglobulin, and that rarely. Allergic phenomena are retained in CLL (for example, allergies to penicillin and other medications) but this is most likely due to the retained normal B cells. Anaphylaxis (to gamma globulin injections, for instance) also can occur, but this is a T cell and IgE mediated phenomenon and could be explained by retained low rates of IgE production. Patients also have severe reactions to mosquito bites, and, occasionally, to skin tests. Autoimmune hemolytic anemia (AIHA) is found in 25 percent of patients, and other reported associated phenomena include idiopathic thrombocytopenic purpura (ITP), systemic lupus erythematosus (SLE), pure red cell aplasia,12 bullous pemphigoid13 and thyroiditis, as well as rheumatoid arthritis, vasculitis and membranous glomerulonephritis with nephrotic syndrome.'4 The causes of the autoimmune and so-called collagen diseases are, of course, unknown, and it is very possibly folly on my part to try to find relationships between two processes, the causes of both of which are unknown. However, we can say that any theory explaining the unusual concurrent incidence of autoimmune disease and CLL will have to explain both the relative selectivity of the immune abnormalities, and also the often independent courses of the CLL and the autoimmune disease in the same patient. There may be an inherited predisposition to both diseases, or susceptibility induced by some characteristic of one disease may lead to acquisition of the others (or both). Again, as when I discussed the patho224
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IB+T
CELL
POPULATION]
X factor
X
? genetic ? pathogen
|ALTERED
IMMUNE
COMPETENCE
± CL ? pathogen A
pathogen(s) B . . . Z antigen antibody complexes cross reacting antibody
AIHA, ITP, SLE
membranous glomerulonephritis
bullous pemphigoid
rheumatoid arthritis vasculitis
AIHA=autoimmune hemolytic anemia ITP=idiopathic thrombocytopenic purpura SLE=systemic lupus erythematosus
Figure 3.-Theory of relationship between chronic lymphocytic leukemia (CLL) and frequently accompanying immunologic disorders.
genesis of CLL itself, I find myself invoking the presence of a genetic susceptibility, with or without an effect from those elusive environmental pathogens. First, let us consider genetic susceptibility to both diseases, as this possibility is suggested by a very interesting mouse model.' In inbred mice, the histocompatibility complex, H-2, includes genes that code for the transplantation antigens as well as those that determine the magnitude and immunoglobulin class of antibody produced in response to specific immunogens, the susceptibility to leukemia viruses and the intensity of cellmediated immune responses. In humans no such immune response region has yet been characterized, but in cultured lymphocytes the level of antibody production to streptococcal antigen has been shown to have a histocompatibility locus A (HL-A) association; and single HL-A loci have been associated both with allergic, and with autoimmune phenomena. In each of the family studies of CLL there was, in addition to the unusually high incidence of CLL among the siblings, frequently a sibling or daughter without CLL but with clinical rheumatoid arthritis, rheumatic fever, joint disease, atopic skin disease, anemia or thrombocytopenia. Now to explore the second theory. The top row of the diagram in Figure 3 simply represents a synthesis of the theories I mentioned regarding the cause of CLL. That is, either a creation of immune deficient state via genetic or environmental forces, or both, which then led to CLL, or vice
CHRONIC LYMPHOCYTIC LEUKEMIA B +T CELL POPULATION /
X factor
\
? genetic / - ? pathogen
\ \
ALTERED IMMUNE COMPETENCE decreased suppressor T cell function exogenous antigen increased antibody response
? pathogen A ?ptoe
(break in tolerance) antibody to endogenous
antigen increased cross reacting antibody
I AIHA, ITP, SLE, bullous pemphigoid
AIHA, ITP, SLE, bullous pemphigoid
AIHA=autoimmune hemolytic anemia ITP=idiopathic thrombocytopenic purpura SLE=systemic lupus erythematosus
Figure 4.-Theory of relationship between chronic lymphocytic leukemia (CLL) and immunologic disorders involving abnormal T cell function.
versa. In either event, altered immune competence clearly is present in CLL. All I have added, then, is some different pathogens, working in this immunologically deficient milieu, leading to the autoimmune phenomena. In patients with congenital or acquired hypogammaglobulinemia, who do not have CLL, there is an increased incidence of rheumatoid arthritis-like disease, systemic lupus erythematosus, idiopathic thrombocytopenic purpura and hemolytic anemia. Moreover, the arthritis often resolves when gamma globulin injections are given. The autoimmune hemolytic anemia then might be a deleterious by-product of an inappropriate response to an environmental pathogen. There is certainly an association noted in otherwise healthy persons of autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura following viral infection; and in other species, viruses have caused blood group-type antigens to appear on the infected cells. The immune incompetence in CLL could be simply widening the range of viruses capable of inducing such phenomena in humans. The rarely reported rheumatoid arthritis, vasculitis and membranous nephropathy may be secondary to circulating anti-
gen/antibody complexes produced by a poorly cleared viral infection. The fact that IgG therapy may reverse the arthritis in x-linked hypogammaglobulinemia patients suggests that the response is secondary to clearing of such an infection.
The T cell arm of regulation may also be out of balance in the immunodeficiency state. In Figure 4 "decreased suppressor T activity" has been added to emphasize the effects this alone might produce. The helper T cell population is felt to be normal in CLL, but there are no studies at present of the activity of the suppressor T cells in CLL. Should their activity or contact with normal B cells also be diminished through dilutional effects in the lymph nodes, spleen or other parts of the circulation, or should the leukemic B cells prove to have receptors for these T cells as well, antibody production to common antigens, exogenous or endogenous, might be excessive or inappropriate. Mice which acquire autoimmune hemolytic purpura, systemic lupus erythematosuslike renal lesions and dermatitis if thymectomized at birth, in fact, do not get them if raised in a germ free environment.'5 The autoimmune hemolytic anemia in man, then might be the product of crossreacting antibody produced in excessive amounts to some pathogen. Normal human B cells have receptors capable of reacting with antigens such as deoxyribonucleic acid (DNA) and thyroglobulin. That they usually do not suggests they ordinarily are suppressed. The systemic lupus erythematosus, thyroiditis or even autoimmune hemolytic anemia then might be due to a break in this immunologic tolerance. There is some indirect evidence that the suppressor T cells are not, in fact, functioning up to par, at least in the suppression of cell-mediated immunity, since, as you recall, in CLL patients there frequently are excessive delayed hypersensitivity responses to mosquito bites and skin tests. The reverse hypothesis (that is, that chronic stimulation of antibody production leads to CLL, such as seen in New Zealand Black mice whose lymphoreticular disorders are always preceded by multiple immune phenomena) seems not to apply. The autoimmune phenomena in CLL can precede or follow the appearance of the disease, and the courses even when simultaneous are independent. Returning to more practical considerations, consider the infections in patients with CLL. Infection is the major cause of morbidity and mortality in patients with CLL. The infectious agents are most commonly bacterial, especially those requiring antibody for optimal clearance. Pneumococci and staphylococci predominate, followed by Escherichia coli, Proteus, Pseudomonas and streptococci. Cryptococcal infection, especially of the central nervous system is increased, and toxoTHE WESTERN JOURNAL OF MEDICINE
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plasmosis and pneumocystic infection are also being reported. Herpes zoster is the most common serious viral pathogen. The best correlation with the increased susceptibility to infection in these patients is the level of gamma globulin. The exact cause of the hypogammaglobulinemia is uncertain. As in other hypogammaglobulinemic states, the half-life of the globulin is prolonged rather than shortened. Contributing factors might include those mentioned before, such as decreased antigen contact with the diluted normal B and T cells, or lessened helper T cell contact with B cells, or T cell "binding" by the leukemic B cell. Miller and Karnofsky found that a gamma globulin level of 0.7 mg per dl or less was uniformly found in those patients in whom recurrent infection was a problem. As you recall, hypogammaglobulinemia is present in most patients with disease of greater than five years' duration. The hypogammaglobulinemia is irreversible, despite improvement in other factors with therapy. It seems, however, that there must be in CLL other immune derangements contributing to the high infection rate since in patients with congenital hypogammaglobulinemia there are much lower infection rates with comparable globulin levels. Steroid therapy is not the only culprit; the patients in the series mentioned had an increased incidence of infection before steroid therapy was begun. No abnormality of the secretory immunoglobulin system or alternate complement pathway has been defined. The inflammatory exudate has also been examined, and both leukocytes and macrophages are normal in number. However, leukocytes require antibody coating of bacteria for optimal phagocytosis, and macrophages require products of activated lymphocytes for their optimal activity. The functional capabilities of both these cells may be reduced when the nonantibody producing, and nontransformable B cell of CLL dilutes the normal one. T cell function is probably normal, which explains the general lack of problems with intracellular pathogens and most viruses but leaves another mystery, that of the increased incidence of both zoster infection and dissemination. The age expected incidence of zoster infections is 1 percent, and yet it is found in 13 percent of patients with CLL. Zoster appears more frequently in sites of tumor infiltration or trauma and is significantly increased in irradiated areas.'7 There is no correlation with immunosuppressive therapy (surgical: 226
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splenectomy or thymectomy; medical: azathioprine, prednisone, actinomycin), hypogammaglobulinemia or leukopenia. A similar type of viral behavior is seen in a virus of E. coli K-12, lambda bacteriophage. Lambda bacteriophages have been shown to enter the genome of the host cell (E. coli K-12) and multiply only as the cell itself does unless exposed to ultraviolet light, x-ray or nitrogen mustard. If such an exposure occurs, induction follows with rapid multiplication of phage and subsequent host cell destruction. Studies investigating the question of herpes virus integration into the human genome are now underway. Furthermore, when a CLL patient has an attack of zoster, there is a higher chance it will disseminate. Antibody levels do not correlate with dissemination, but vesicular interferon levels do have a delayed rise in those patients who disseminate.'8 It may be true here also that the lack of products of activated lymphocytes impairs macrophage function, leading to the dissemination (there are normal macrophage numbers at the bases of the vesicles). In any event, even in CLL dissemination usually is self-limited, lasting only three to four days, and usually without serious consequences. There is an increased incidence of second malignancies in patients with CLL.8 Most of this is accounted for by an 8- to 12-fold increase in skin cancer, with only a 2-fold increase in other types of cancer. Many types of malignancy have been reported, but their incidence does not seem to match that in the general population. A lack of "immune surveillance" would not explain this peculiar skewing. Moreover, there is no significant correlation here with hypogammaglobulinemia or autoimmune phenomena, and the helper T cells are normal. Acute leukemia is a rare complication and represents, in most cases, a second malignancy. There has been one report of a lymphoblastic leukemia developing in two patients with CLL, one of whose cells were studied. The lymphoblastic leukemic cells produced the same immunoglobulin as that present on the small CLL cells, suggesting an actual blastic transformation of the CLL cell.19 In all but one of the other reported cases of superimposed acute leukemia, the patients had received radioactive phosphorus ('32p), alkylating agents or radiation therapy, or both. This association raises questions regarding safety of these therapeutic agents. To complete the clinical picture, I should mention the causes of death in CLL. Infection is by
CHRONIC LYMPHOCYTIC LEUKEMIA
far the most common, followed by "other disease," cachexia-that wasting syndrome with a hypermetabolic state that occasionally supervenes -anemia and lastly hemorrhage, the latter representing only 3 percent. Finally, we turn to considerations of therapy. In thinking about therapy for this disease, as in any other, it is essential to consider the natural course of the disease unmodified by therapy and the risks versus benefits of the therapeutic options. In CLL, this caution is especially relevant. The natural course and prognosis of this disease is difficult to state. Most past studies have been hampered by several factors: (1) Before the era of routine complete blood counts, the disease was detected only after symptoms had developed. Today, too, younger people are subject to fewer routine screening procedures than older ones. (2) More fundamentally, the nature of the cell of classic CLL has only recently been elucidated. Before this, many other morphologically similar diseases, especially chronic lymphosarcoma cell leukemia (CLSL), which may have very different natural histories, were being lumped in with CLL series and affecting the survival data. Previous studies have shown that survival best correlates with how long the disease had been present symptomatically before the diagnosis was made and how many complications were present at the time of diagnosis. Rai and co-workers have formalized this into a proposed staging scheme.20 Their data indicate that median survival in patients picked up accidentally is greater than 150 months. Survival in patients presenting with lymphocytosis and splenomegaly with anemia or thrombocytopenia, that is stage 3 and 4, is a median of only 19 months. Therapy, too, has been difficult to evaluate, since therapies were not compared in groups with comparable stages of disease.2' It seems the general conclusion is to keep in mind the philosophy of do no harm. Studies comparing patients treated infrequently or symptomatically with those treated regularly, irrespective of symptoms, showed no difference in survival rates. Indications for therapy include22 bulky lymphadenopathy, symptomatic splenomegaly, autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura, marrow "failure," that is neutropenia,
anemia, thrombocytopenia or hypermetabolic state with weight loss, sweating and the like. Allopurinol, of course, should be given before beginning any therapy. As to chemotherapy, there
is a virtual absence of good studies comparing different regimens. In the absence of hemolytic symptoms, chlorambucil can be used safely and will reduce lymphadenopathy and spleen size in 25 percent and decrease peripheral counts in 70 percent of cases. Usually the hematocrit and platelet count will not rise significantly, and the gamma globulin levels will remain depressed. Steroids should be the first line of therapy in patients with autoimmune hemolytic anemia or packed marrow states, as alkylating agents may lead to a precipitous fall in the hematocrit before the process is brought under control. As soon as possible an alkylating agent should be added and the steroid tapered. Therapy with steroids in other patients is also useful; it shrinks the spleen and lymph nodes and decreases lymphocyte counts in the marrow even though the peripheral counts may rise initially. With the "unpacking" of the marrow, the hemoglobin, neutrophil and platelet levels seem to rise. In stage 3 and 4 disease a regimen of cyclophosphamide (Cytoxan®), vincristine and prednisone has clearly been shown to increase survival over that expected. Several types of radiation therapy have been tried, but in general they are unpredictable in their effects on the blood counts in this disease and are therefore less safe. Local radiation therapy to leukemic masses may be used safely in most cases.23 Mediastinal irradiation, however, has been shown to lead to severe depression of both neutrophil and lymphocyte counts, resulting in severe and often fatal infections.8 Both splenic and low-dose total body irradiation (150 to 300 rads)23 have led to improvements in lymph node and spleen size, anemia and platelet counts, and even to complete remissionsagain for unclear reasons. Even extracorporeal irradiation through a Scribner shunt has been efficacious in patients refractory to other therapy.24 In addition to the cellular lethality of radiation and alkylator therapy, the question of their roles in the appearance of a second malignant process in CLL is an important one and may affect one's choice of therapeutic agent, especially in a young patient. The method with the best therapeutic index is leukapheresis25-simply taking off the excess lymphocytes, although this is a time consuming process for the patient. For nonhemolytic anemia in patients for whom steroid therapy or radiation has not been of benefit, androgen therapy in large doses along with glucocorticoids has been reported to be of beneTHE WESTERN JOURNAL OF MEDICINE
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fit.22 For the autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura, glucocorticoids and immunodepressants, if necessary, are obviously the first choice of therapy. In refractory cases spenectomy has been helpful and should be seriously considered. It should also be used for severe symptomatic hypersplenism. Infection deserves yet another word. Prevention of infection by the usual commonsense measures, including keeping the patient out of hospital, decreasing local obstruction produced by enlarged nodes, does seem to help. Fever in this form of leukemia is usually of infectious origin, not secondary to the disease, and a vigorous search should be made for the cause. The types of infections, again, are most commonly pneumonia and furunculosis; the bacterial pathogens are usually the Pneumococcus, Staphylococcus, E. coli, Pseudomonas and Proteus. Cryptococcal meningitis should be looked for and zoster thought of in a patient complaining of radicular pain. At present there is no role identified for a zoster immune globulin in CLL patients, even those exposed to a child with varicella.26 In a double-blind comparison with a placebo; interferon-if therapy is started early-has been shown to be useful in reducing pain and distal cutaneous spread. Adenine arabinoside for severe disseminated infection has provided some encouraging results in early trials. Some special cautions here: do not attempt to immunize these patients with live virus of any sort, as they may get severe local reactions and even generalized infections without significant antibody responses being achieved. The malabsorption problem may in fact be a giardia infestation, as proposed above.. Pending further studies of this matter, I think that malabsorption should be looked for in a patient with diarrhea or weight loss and hypogammaglobulinemia. If it is present, a search for giardia should be made, and an empiric trial of therapy for giardiosis begun if no other cause appears. In severe cases of hypogammaglobulinemia with recurrent infections gamma globulin has been of help22 but in respiratory disease large doses may be necessary. Fresh frozen plasma, a source of IgM, may be useful in addition. I have tried to provide an overview of CLL: some of the characteristic findings of the disease,
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some of the theories that try to explain these findings, and some practical management hints. I hope this information will prove of use in your understanding and treatment of patients with CLL. REFERENCES 1. Fudenberg HH: Basic and Clinical Immunology. Los Altos, Lange Medical Publications, 1976, p 653 2. Allison AC: Interaction of Ab, complement components and various cell types in immunity against viruses and pyogenic bacteria. Transplant Rev 19:3-55, 1974 3. Fudenberg HH, Wybran J, Chantler S: Isolation of normal T cells in chronic lymphocytic leukemia. Lancet 1:126-129, Jan 20, 1973 4. Harris J, Copeland D: Impaired immunoresponsiveness in tumor patients. Ann NY Acad Sci 230:56-73, Mar 1974 5. Schroer K, Briles DE, Van Boxel JA, et al: Idiotypic uniformity of cell surface immunoglobulin in chronic lymphocytic leukemia (evidence for monoclonal proliferation). J Exper Med 140:1416-1419, Aug 1974 6. Preud'homme JL, Seligmann M: Surface bound immunoglobulins as a cell marker in human lymphoproliferative disease. Blood 40:777-794, Dec 1972 7. Fraumeni J Jr, Wertelecki W, Blattner W, et al: Varied manifestations of a familial lymphoproliferative disorder. Am J Med 59:145-151, Jul 1975 8. Hansen MM: Chronic lymphocytic leukaemia-Clinic studies based on 189 cases followed for a long time. Scand J i-{ematol, Suppl #18, Copenhagen, 1973 9. Pitney WR, Joske RA, MacKinnon NL: Folic acid and other absorption tests in lymphosarcoma, chronic lymphocytic leukemia, and some related conditions. J Clin Path 13:440-447, May 1960 10. Pruzanski W, Warren RE, Goldie JH, et al: Malabsorption syndrome with infiltration of the intestinal wall by extracellular monoclonal macroglobulin. Am J Med 54:811-818, Jun 1973 11. Preud'homme JL, Seligmann M: Anti-human immunoglobulin G activity of membrane-bound monoclonal immunoglobulin M in lymphoproliferative disorders. Proc Natl Acad Sci USA 69: 2132-2135, Aug 1972 12. Abeloff MD, Waterbury L: Pure red blood cell aplasia and chronic lymphocytic leukemia. Arch Intern Med 134:721-724, Oct 1974 13. Cuni W, Grunwald H, Rosner F: Bullous pemphigoid in chronic lymphocytic leukemia with the demonstration of antibasement membrane antibodies. Am J Med 57:987-992, Dec 1974 14. Dathan JRE, Heyworth MF, Maciver AG: Nephrotic syndrome in chronic lymphocytic leukaemia. Br Med J 3:655-657, Sep 14, 1974 15. Stutman 0: Immunodeficiency and cancer, In Green I, Cohen S, McClusky R (Eds): Mechanisms of Tumor Immunity. New York, Wiley, 1977, p 27 16. Miller DG, Karnofsky DA: Immunologic factors and resistance to infection in chronic lymphocytic leukemia. Am J Med 31:748-757, Nov 1961 17. Rifkind D: The activation of varicella-zoster virus infections by immunosuppressive therapy. J Lab and Clin Med 68:463-474, Sep 1966 18. Armstrong RW, Gurwith MJ, Waddell D, et al: Cutaneous interferon production of patients with Hodgkin's disease and other cancers infected with varicella or vaccinia. N Engl J Med 283:1182-1187, Nov 1970 19. Brouet JC, Preud'homme JL, Seligmann M, et al: Blast cells with monoclonal surface immunoglobulin in two cases of acute blast crisis supervening on chronic lymphocytic leukaemia. Br Med J 4:23-24, Oct 6, 1973 20. Rai KR, Sawitsky A, Cronkite EP, et al: Clinical staging of chronic lymphocytic leukemia. Blood 46:219-234, Aug 1975 21. Silver RT: The treatment of chronic lymphocytic leukemia. Semin Hematology 11:141, 1974 22. Gunz F, Baikie AG: Leukemia, 3rd Ed. New York, Grune and Stratton, 1974, p 841 23. Sawitsky A, Rai K, Isumettin A, et al: Mediastinal irradiation for chronic lymphocytic leukemia. Am J Med 61:892-896, Dec 1976 24. Storb R, Epstein RB, Buckner CD, et al: Treatment of chronic lymphocytic leukemia by extracorporeal irradiation. Blood 31:490-502, Apr 1968 25. Curtis JE, Hersh EM, Freireich EJ, et al: Leukapheresis therapy of chronic lymphocytic leukemia. Blood 39:163-175, Feb 1972 26. Uduman S, Gershon AA, Brunell PA: Should patients with zoster receive zoster immune globulin? JAMA 234:1049-1051, Dec
8, 1975
Medical Staf Conference
Chronic Lymphocytic Leukemia These discussions are selected from the weekly staff conferences in the Department of Medicine, University of California, San Francisco. Taken from transcriptions, they are prepared by Drs. David W. Martin, Jr., Associate Professor of Medicine, and Robert C. Siegel, Associate Professor of Medicine and Orthopaedic Surgery, under the direction of Dr. Lloyd H. Smith, Jr., Professor of Medicine and Chairman of the Department of Medicine. Requests for reprints should be sent to the Department of Medicine, University of California, San Francisco, CA 94143.
DR. SMITH: * It has been our custom to ask our chief medical residents at Moffitt Hospital to discuss a topic at Medical Grand Rounds near the conclusion of their residency year. We have been privileged to have Dr. Janet Abrahm as chief resident during this past year. She will discuss the topic of chronic lymphocytic leukemia. DR. ABRAHM:t The first description of leukemia was published simultaneously in 1845 by Craigie in Edinburgh and Virchow in Berlin. In 1905 acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL) and "myelogenous" leukemias were first officially distinguished. The process of discovering and defining the different types of leukemic cell is still continuing. Before describing to you some of what we know about the leukemic cell in CLL, I would like to briefly review the characteristics and functions of normal T and B cells."2 T, or thymus derived, cells are distinguished from B, or bone marrow derived, cells by immunologic characteristics. The former make up most of the circulating lymphocyte population and are located in characteristic areas of lymph nodes and spleen. Their functions are still being *Lloyd H. Smith, Jr., MD, Professor and Chairman, DeparttJanet L. Abrahm, MD, Chief Resident.
ment of Medicine.
discovered, but it is felt, from studies in patients devoid of them, that T cells ( 1 ) are key mediators of cellular immune responses, including delayed hypersensitivity reactions, (2) may modulate B cell responses to antigens both as facilitators, so called "helper" T cells, and possibly as inhibitors, so called "suppressor" T cells. Patients without functional T cells, therefore, are prone to fungal, parasitic and intracellular bacterial infections. Their role in viral disease is still unclear, although they are clearly involved in the response to viruses that spread directly from cell to cell, such as in herpes zoster. B cells are major antigen recognizers and antibody producers. Patients who lack them are plagued by extracellular bacterial infections, as most bacteria must be coated by opsonizing antibody in order to be subject to optimal phagocytosis and clearing from the blood stream. Antibody also seems to affect the infectivity and dissemination of several viruses by inhibiting attachment, penetration or replication, especially of those that produce systemic infection. In patients with CLL there remain some functional, normal B cells and a normal T cell pool.3'4 But the leukemic B cell is the predominant cell in 98 percent of the cases of CLL. Moreover, it now seems clear that CLL is due to the proliferation of THE WESTERN JOURNAL OF MEDICINE
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NORMAL ABBREVIATIONS USED IN TEXT = ALL acute lymphocytic leukemia AIHA=autoimmune hemolytic anemia CLL=chronic lymphocytic leukemia CLSL=chronic lymphosarcoma cell leukemia DNA= deoxyribonucleic acid HL-A=histocompatibility locus A ITP = idiopathic thrombocytopenic purpura SLE=systemic lupus erythematosus
clone of cells. The surface immunoglobulin produced by the malignant cells of CLL has been shown to be monoclonal, with single antibody specificity and single idiotype (variable region).5,6 The cells of CLL are structurally and functionally abnormal in several ways (including different specificity of C3 receptors, different scanning EM morphology) but the most clinically significant abnormalities involve their immunologic responsibilities. In vitro, the cells have delayed antibody secretion and delayed, if any response, to normal mitogens. In vivo studies in patients with CLL show an inability to produce antibodies to new antigens, to remember old antigens and produce antibodies to them, and to develop a delayed hypersensitivity response to an antigen to which the organism had not previously been exposed. Significantly, the delayed hypersensitivity (skin test) response to old antigens is retained. How might we explain these in vivo findings? Figure 1 schematically illustrates what happens to the lymphocyte pools in a patient with CLL. The sizes of the normal B and T cell pools remain unchanged, but the total pool size is greatly increased by the leukemic B cells. In addition, the presence of the abnormal B cells in the lymph nodes and splenic channels may impair contact between T cells and B cells. Moreover, the leukemic B cells may have receptors for the normal T cells, and so, by competitive inhibition, interfere with normal T-B cell interaction. This functional dilution of T-B cell interaction might explain the observed inability to produce antibody to new antigens. The dilution of normal T or B cells themselves in the lymph nodes and spleen might sufficiently decrease contact with new or old, frequently occurring antigens so as to lead both to impaired ability to mount a hypersensitivity response to a new antigen and to a general decrease of antibody production. This might then explain the hypogammaglobulinemia found in the majority of patients with disease of greater than five years. The standard skin tests remain posiSEPTEMBER 1977
*
127
*
3
T
cell i
Figure 1.-Proposed dilution of normal B cell and T cell interactions by leukemic B cells of chronic lymphocytic leukemia (CLL).
one
222
leukemic B
B
B+T CELL POPULATION X factor
? genetic ? pathogen ALTERED IMMUNE COMPETENCE
ACQUIRED HYPOGAMMA
? pathogen(s)
NEOPLASTIC TRANSFORMED B CELLS etc. Waldenstrom's macroglobulinemia multiple myeloma (antibody or nonantibody
nodular lymphoma
n riJU
CLL
t, l
y)il
plasmacytoma
Figure 2.-Postulated range of B cell disorders including chronic lymphocytic leukemia (CLL).
tive, however, because the previously sensitized, circulating T cell interacts normally with its antigen and the skin macrophage. In sum, then, the leukemic B cell is an immunologically incompetent and long-lived cell, which may, by its accumulation and dilution of the normal T and B cell interactions, lead to the alterations in immunocompetence seen in patients with CLL. The cause of CLL is unknown. One might, however, postulate a defect producing a range of B cell disorders of function (see Figure 2). For example, in the acquired hypogammaglobulinemic state, a defect of release of gamma globulin has been detected, but this does not progress to neoplasia (even though the patients do have intestinal nodular hyperplasia). The same alteration (for example, an inherited defect or an environmental pathogen, or both) might lead to neoplastic transformation in B cells of different types or stages, with the observed clinical syndrome resulting from the functional capabilities of the particular cell which has been transformed. A genetic susceptibility to B cell disorders of this kind has been suggested by studies of families in whose members lymphatic leukemias or lym-
CHRONIC LYMPHOCYTIC LEUKEMIA
phomas developed at an unusually high frequency.7 In these families, those siblings in whom the leukemia or lymphoma did not develop do have abnormalities of immunoglobulin production. Furthermore, there is an increased incidence of leukemia in patients with x-linked agammaglobulinemia. The susceptibility to malignancy could be simply due to the neoplastic transformation itself, or more likely to the immunologic defect, resulting in increased susceptibility to an environmental carcinogenic agent or loss of immunologic surveillance giving rise to the establishment of neoplasia. Returning to CLL, let us now discuss some more general considerations: CLL accounts for 25 percent of all leukemias. It is more commonly reported in whites than blacks, most commonly among Jews and relatively rarely among Asiatics. The male to female ratio is 2:1. The disease is rare in persons under 40 years of age. Eighty percent of new diagnoses are made in patients over 50. My discussion of the clinical syndrome will include the following areas: infiltrative manifestations, immunologic phenomena, infections, second malignancies and causes of death. We will then discuss prognosis and therapy. Because the infiltrative manifestations are those that most commonly bring the patient to the doctor, we shall begin with them. Of these, the most common presenting symptom in all series is enlarged lymph nodes, although CLL is an accidental finding on routine complete blood counts in an equal number of patients.8 The other initial symptoms include those of anemia in 25 percent of patients and sweating and weight loss in 20 percent. Fever, complications secondary to enlarged liver or spleen, cutaneous or mucosal hemorrhage and itching each were noted in about 10 percent. Diffuse lymph node enlargement is also the most common physical finding (63 to 89 percent) on initial presentation. The nodes are often small, discrete, firm and freely -movable, increasing in size as the disease progresses. Node compression, especially in the mediastinum or retroperitoneal areas, can lead to bronchial or other obstructive symptoms or, more rarely, a superior vena cava syndrome or aphonia from recurrent laryngeal nerve compression.
Splenomegaly is present in about half of the patients, and hypersplenism, splenic infarction, subcapsular bleeding and perisplenitis can occur if the splenomegaly is massive.
The bone marrow in untreated patients is hypercellular and infiltrated by lymphocytes. At diagnosis, a lymphocyte count greater than 60 percent is found 94 percent of the time and will increase to 80 to 100 percent terminally. Bone marrow function, however, is usually good throughout most of the course, though in a significant number of cases, marrow failure, with refractory anemia and thrombocytopenia may supervene. Organ infiltration by the leukemic cells has been reported in almost every system. That in the liver, kidney, endocrine organs, esophagus and gastrointestinal tract is usually asymptomatic. That into the salivary and lacrimal glands can produce xerostomia and xerophthalmia (in contrast, note that the infiltrate in Sj"ogren syndrome is polyclonal and stains for B cells). In the skin, exfoliative erythroderma is seen along with tumors, especially of the face, and infiltrated plaques. Pleural effusions are not an infrequent finding, whereas an actual lung infiltration is rare. Central nervous system manifestations include the more common herpes zoster, along with the rare cranial nerve palsy and spinal cord compression. The bone lesion is most typically generalized osteoporosis, but steroid responsive hypercalcemia with normal parathyroids has been reported. Other rare findings include glaucoma secondary to limbic infiltration, and acropachy-that is, finger clubbing with symmetrical destruction of terminal phalanges secondary to subungual infiltration. Weight loss is seen not infrequently late in the course of disease in these patients. While it is probably not due to infiltration into the gastrointestinal tract, there may be more to it than the "hypermetabolic state." Malabsorption in patients with CLL was documented in 1960.9 In macroglobulinemia, the malabsorption has been felt to be secondary to deposition of Bence-Jones amyloid in the extracellular spaces,10 but this has not been seen and would not necessarily be expected in CLL where the paraprotein production is much less. Hypogammaglobulinemia, however, as stated above, is common in CLL. Diarrhea with malabsorption is seen in other such states and in these states is found to be secondary to giardia infestation. In the reported cases of CLL with malabsorption, giardiosis was not looked for and levels of gamma globulin were not reported. These THE WESTERN JOURNAL OF MEDICINE
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studies would seem to be the logical next step in elucidating the mechanism of the malabsorption in the CLL patients. Next, let us turn to the associated immunologic phenomena, as herein lies one of the paradoxes of this disease. As mentioned before, the leukemic cells poorly synthesize antibody and, in fact, the gamma globulin levels often fall as the disease progresses, and yet an assortment of antibody mediated complications occur.8 The CLL cell products do not seem to be responsible. An IgM spike is found in less than 10 percent of patients, and in all cases where it has been examined it is identical to that on the leukemic B cell surface. It does have anti-human IgG activity,'1 but it has never been shown to have anti-red cell, antiplatelet or anti-nuclear specificity. Furthermore, as it is an IgM, not an IgG, one would not expect it to cause the observed Coombs' positive hemolytic anemia. In fact, it probably only produces trouble as a cryoglobulin, and that rarely. Allergic phenomena are retained in CLL (for example, allergies to penicillin and other medications) but this is most likely due to the retained normal B cells. Anaphylaxis (to gamma globulin injections, for instance) also can occur, but this is a T cell and IgE mediated phenomenon and could be explained by retained low rates of IgE production. Patients also have severe reactions to mosquito bites, and, occasionally, to skin tests. Autoimmune hemolytic anemia (AIHA) is found in 25 percent of patients, and other reported associated phenomena include idiopathic thrombocytopenic purpura (ITP), systemic lupus erythematosus (SLE), pure red cell aplasia,12 bullous pemphigoid13 and thyroiditis, as well as rheumatoid arthritis, vasculitis and membranous glomerulonephritis with nephrotic syndrome.'4 The causes of the autoimmune and so-called collagen diseases are, of course, unknown, and it is very possibly folly on my part to try to find relationships between two processes, the causes of both of which are unknown. However, we can say that any theory explaining the unusual concurrent incidence of autoimmune disease and CLL will have to explain both the relative selectivity of the immune abnormalities, and also the often independent courses of the CLL and the autoimmune disease in the same patient. There may be an inherited predisposition to both diseases, or susceptibility induced by some characteristic of one disease may lead to acquisition of the others (or both). Again, as when I discussed the patho224
SEPTEMBER 1977 * 127 * 3
IB+T
CELL
POPULATION]
X factor
X
? genetic ? pathogen
|ALTERED
IMMUNE
COMPETENCE
± CL ? pathogen A
pathogen(s) B . . . Z antigen antibody complexes cross reacting antibody
AIHA, ITP, SLE
membranous glomerulonephritis
bullous pemphigoid
rheumatoid arthritis vasculitis
AIHA=autoimmune hemolytic anemia ITP=idiopathic thrombocytopenic purpura SLE=systemic lupus erythematosus
Figure 3.-Theory of relationship between chronic lymphocytic leukemia (CLL) and frequently accompanying immunologic disorders.
genesis of CLL itself, I find myself invoking the presence of a genetic susceptibility, with or without an effect from those elusive environmental pathogens. First, let us consider genetic susceptibility to both diseases, as this possibility is suggested by a very interesting mouse model.' In inbred mice, the histocompatibility complex, H-2, includes genes that code for the transplantation antigens as well as those that determine the magnitude and immunoglobulin class of antibody produced in response to specific immunogens, the susceptibility to leukemia viruses and the intensity of cellmediated immune responses. In humans no such immune response region has yet been characterized, but in cultured lymphocytes the level of antibody production to streptococcal antigen has been shown to have a histocompatibility locus A (HL-A) association; and single HL-A loci have been associated both with allergic, and with autoimmune phenomena. In each of the family studies of CLL there was, in addition to the unusually high incidence of CLL among the siblings, frequently a sibling or daughter without CLL but with clinical rheumatoid arthritis, rheumatic fever, joint disease, atopic skin disease, anemia or thrombocytopenia. Now to explore the second theory. The top row of the diagram in Figure 3 simply represents a synthesis of the theories I mentioned regarding the cause of CLL. That is, either a creation of immune deficient state via genetic or environmental forces, or both, which then led to CLL, or vice
CHRONIC LYMPHOCYTIC LEUKEMIA B +T CELL POPULATION /
X factor
\
? genetic / - ? pathogen
\ \
ALTERED IMMUNE COMPETENCE decreased suppressor T cell function exogenous antigen increased antibody response
? pathogen A ?ptoe
(break in tolerance) antibody to endogenous
antigen increased cross reacting antibody
I AIHA, ITP, SLE, bullous pemphigoid
AIHA, ITP, SLE, bullous pemphigoid
AIHA=autoimmune hemolytic anemia ITP=idiopathic thrombocytopenic purpura SLE=systemic lupus erythematosus
Figure 4.-Theory of relationship between chronic lymphocytic leukemia (CLL) and immunologic disorders involving abnormal T cell function.
versa. In either event, altered immune competence clearly is present in CLL. All I have added, then, is some different pathogens, working in this immunologically deficient milieu, leading to the autoimmune phenomena. In patients with congenital or acquired hypogammaglobulinemia, who do not have CLL, there is an increased incidence of rheumatoid arthritis-like disease, systemic lupus erythematosus, idiopathic thrombocytopenic purpura and hemolytic anemia. Moreover, the arthritis often resolves when gamma globulin injections are given. The autoimmune hemolytic anemia then might be a deleterious by-product of an inappropriate response to an environmental pathogen. There is certainly an association noted in otherwise healthy persons of autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura following viral infection; and in other species, viruses have caused blood group-type antigens to appear on the infected cells. The immune incompetence in CLL could be simply widening the range of viruses capable of inducing such phenomena in humans. The rarely reported rheumatoid arthritis, vasculitis and membranous nephropathy may be secondary to circulating anti-
gen/antibody complexes produced by a poorly cleared viral infection. The fact that IgG therapy may reverse the arthritis in x-linked hypogammaglobulinemia patients suggests that the response is secondary to clearing of such an infection.
The T cell arm of regulation may also be out of balance in the immunodeficiency state. In Figure 4 "decreased suppressor T activity" has been added to emphasize the effects this alone might produce. The helper T cell population is felt to be normal in CLL, but there are no studies at present of the activity of the suppressor T cells in CLL. Should their activity or contact with normal B cells also be diminished through dilutional effects in the lymph nodes, spleen or other parts of the circulation, or should the leukemic B cells prove to have receptors for these T cells as well, antibody production to common antigens, exogenous or endogenous, might be excessive or inappropriate. Mice which acquire autoimmune hemolytic purpura, systemic lupus erythematosuslike renal lesions and dermatitis if thymectomized at birth, in fact, do not get them if raised in a germ free environment.'5 The autoimmune hemolytic anemia in man, then might be the product of crossreacting antibody produced in excessive amounts to some pathogen. Normal human B cells have receptors capable of reacting with antigens such as deoxyribonucleic acid (DNA) and thyroglobulin. That they usually do not suggests they ordinarily are suppressed. The systemic lupus erythematosus, thyroiditis or even autoimmune hemolytic anemia then might be due to a break in this immunologic tolerance. There is some indirect evidence that the suppressor T cells are not, in fact, functioning up to par, at least in the suppression of cell-mediated immunity, since, as you recall, in CLL patients there frequently are excessive delayed hypersensitivity responses to mosquito bites and skin tests. The reverse hypothesis (that is, that chronic stimulation of antibody production leads to CLL, such as seen in New Zealand Black mice whose lymphoreticular disorders are always preceded by multiple immune phenomena) seems not to apply. The autoimmune phenomena in CLL can precede or follow the appearance of the disease, and the courses even when simultaneous are independent. Returning to more practical considerations, consider the infections in patients with CLL. Infection is the major cause of morbidity and mortality in patients with CLL. The infectious agents are most commonly bacterial, especially those requiring antibody for optimal clearance. Pneumococci and staphylococci predominate, followed by Escherichia coli, Proteus, Pseudomonas and streptococci. Cryptococcal infection, especially of the central nervous system is increased, and toxoTHE WESTERN JOURNAL OF MEDICINE
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plasmosis and pneumocystic infection are also being reported. Herpes zoster is the most common serious viral pathogen. The best correlation with the increased susceptibility to infection in these patients is the level of gamma globulin. The exact cause of the hypogammaglobulinemia is uncertain. As in other hypogammaglobulinemic states, the half-life of the globulin is prolonged rather than shortened. Contributing factors might include those mentioned before, such as decreased antigen contact with the diluted normal B and T cells, or lessened helper T cell contact with B cells, or T cell "binding" by the leukemic B cell. Miller and Karnofsky found that a gamma globulin level of 0.7 mg per dl or less was uniformly found in those patients in whom recurrent infection was a problem. As you recall, hypogammaglobulinemia is present in most patients with disease of greater than five years' duration. The hypogammaglobulinemia is irreversible, despite improvement in other factors with therapy. It seems, however, that there must be in CLL other immune derangements contributing to the high infection rate since in patients with congenital hypogammaglobulinemia there are much lower infection rates with comparable globulin levels. Steroid therapy is not the only culprit; the patients in the series mentioned had an increased incidence of infection before steroid therapy was begun. No abnormality of the secretory immunoglobulin system or alternate complement pathway has been defined. The inflammatory exudate has also been examined, and both leukocytes and macrophages are normal in number. However, leukocytes require antibody coating of bacteria for optimal phagocytosis, and macrophages require products of activated lymphocytes for their optimal activity. The functional capabilities of both these cells may be reduced when the nonantibody producing, and nontransformable B cell of CLL dilutes the normal one. T cell function is probably normal, which explains the general lack of problems with intracellular pathogens and most viruses but leaves another mystery, that of the increased incidence of both zoster infection and dissemination. The age expected incidence of zoster infections is 1 percent, and yet it is found in 13 percent of patients with CLL. Zoster appears more frequently in sites of tumor infiltration or trauma and is significantly increased in irradiated areas.'7 There is no correlation with immunosuppressive therapy (surgical: 226
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splenectomy or thymectomy; medical: azathioprine, prednisone, actinomycin), hypogammaglobulinemia or leukopenia. A similar type of viral behavior is seen in a virus of E. coli K-12, lambda bacteriophage. Lambda bacteriophages have been shown to enter the genome of the host cell (E. coli K-12) and multiply only as the cell itself does unless exposed to ultraviolet light, x-ray or nitrogen mustard. If such an exposure occurs, induction follows with rapid multiplication of phage and subsequent host cell destruction. Studies investigating the question of herpes virus integration into the human genome are now underway. Furthermore, when a CLL patient has an attack of zoster, there is a higher chance it will disseminate. Antibody levels do not correlate with dissemination, but vesicular interferon levels do have a delayed rise in those patients who disseminate.'8 It may be true here also that the lack of products of activated lymphocytes impairs macrophage function, leading to the dissemination (there are normal macrophage numbers at the bases of the vesicles). In any event, even in CLL dissemination usually is self-limited, lasting only three to four days, and usually without serious consequences. There is an increased incidence of second malignancies in patients with CLL.8 Most of this is accounted for by an 8- to 12-fold increase in skin cancer, with only a 2-fold increase in other types of cancer. Many types of malignancy have been reported, but their incidence does not seem to match that in the general population. A lack of "immune surveillance" would not explain this peculiar skewing. Moreover, there is no significant correlation here with hypogammaglobulinemia or autoimmune phenomena, and the helper T cells are normal. Acute leukemia is a rare complication and represents, in most cases, a second malignancy. There has been one report of a lymphoblastic leukemia developing in two patients with CLL, one of whose cells were studied. The lymphoblastic leukemic cells produced the same immunoglobulin as that present on the small CLL cells, suggesting an actual blastic transformation of the CLL cell.19 In all but one of the other reported cases of superimposed acute leukemia, the patients had received radioactive phosphorus ('32p), alkylating agents or radiation therapy, or both. This association raises questions regarding safety of these therapeutic agents. To complete the clinical picture, I should mention the causes of death in CLL. Infection is by
CHRONIC LYMPHOCYTIC LEUKEMIA
far the most common, followed by "other disease," cachexia-that wasting syndrome with a hypermetabolic state that occasionally supervenes -anemia and lastly hemorrhage, the latter representing only 3 percent. Finally, we turn to considerations of therapy. In thinking about therapy for this disease, as in any other, it is essential to consider the natural course of the disease unmodified by therapy and the risks versus benefits of the therapeutic options. In CLL, this caution is especially relevant. The natural course and prognosis of this disease is difficult to state. Most past studies have been hampered by several factors: (1) Before the era of routine complete blood counts, the disease was detected only after symptoms had developed. Today, too, younger people are subject to fewer routine screening procedures than older ones. (2) More fundamentally, the nature of the cell of classic CLL has only recently been elucidated. Before this, many other morphologically similar diseases, especially chronic lymphosarcoma cell leukemia (CLSL), which may have very different natural histories, were being lumped in with CLL series and affecting the survival data. Previous studies have shown that survival best correlates with how long the disease had been present symptomatically before the diagnosis was made and how many complications were present at the time of diagnosis. Rai and co-workers have formalized this into a proposed staging scheme.20 Their data indicate that median survival in patients picked up accidentally is greater than 150 months. Survival in patients presenting with lymphocytosis and splenomegaly with anemia or thrombocytopenia, that is stage 3 and 4, is a median of only 19 months. Therapy, too, has been difficult to evaluate, since therapies were not compared in groups with comparable stages of disease.2' It seems the general conclusion is to keep in mind the philosophy of do no harm. Studies comparing patients treated infrequently or symptomatically with those treated regularly, irrespective of symptoms, showed no difference in survival rates. Indications for therapy include22 bulky lymphadenopathy, symptomatic splenomegaly, autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura, marrow "failure," that is neutropenia,
anemia, thrombocytopenia or hypermetabolic state with weight loss, sweating and the like. Allopurinol, of course, should be given before beginning any therapy. As to chemotherapy, there
is a virtual absence of good studies comparing different regimens. In the absence of hemolytic symptoms, chlorambucil can be used safely and will reduce lymphadenopathy and spleen size in 25 percent and decrease peripheral counts in 70 percent of cases. Usually the hematocrit and platelet count will not rise significantly, and the gamma globulin levels will remain depressed. Steroids should be the first line of therapy in patients with autoimmune hemolytic anemia or packed marrow states, as alkylating agents may lead to a precipitous fall in the hematocrit before the process is brought under control. As soon as possible an alkylating agent should be added and the steroid tapered. Therapy with steroids in other patients is also useful; it shrinks the spleen and lymph nodes and decreases lymphocyte counts in the marrow even though the peripheral counts may rise initially. With the "unpacking" of the marrow, the hemoglobin, neutrophil and platelet levels seem to rise. In stage 3 and 4 disease a regimen of cyclophosphamide (Cytoxan®), vincristine and prednisone has clearly been shown to increase survival over that expected. Several types of radiation therapy have been tried, but in general they are unpredictable in their effects on the blood counts in this disease and are therefore less safe. Local radiation therapy to leukemic masses may be used safely in most cases.23 Mediastinal irradiation, however, has been shown to lead to severe depression of both neutrophil and lymphocyte counts, resulting in severe and often fatal infections.8 Both splenic and low-dose total body irradiation (150 to 300 rads)23 have led to improvements in lymph node and spleen size, anemia and platelet counts, and even to complete remissionsagain for unclear reasons. Even extracorporeal irradiation through a Scribner shunt has been efficacious in patients refractory to other therapy.24 In addition to the cellular lethality of radiation and alkylator therapy, the question of their roles in the appearance of a second malignant process in CLL is an important one and may affect one's choice of therapeutic agent, especially in a young patient. The method with the best therapeutic index is leukapheresis25-simply taking off the excess lymphocytes, although this is a time consuming process for the patient. For nonhemolytic anemia in patients for whom steroid therapy or radiation has not been of benefit, androgen therapy in large doses along with glucocorticoids has been reported to be of beneTHE WESTERN JOURNAL OF MEDICINE
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fit.22 For the autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura, glucocorticoids and immunodepressants, if necessary, are obviously the first choice of therapy. In refractory cases spenectomy has been helpful and should be seriously considered. It should also be used for severe symptomatic hypersplenism. Infection deserves yet another word. Prevention of infection by the usual commonsense measures, including keeping the patient out of hospital, decreasing local obstruction produced by enlarged nodes, does seem to help. Fever in this form of leukemia is usually of infectious origin, not secondary to the disease, and a vigorous search should be made for the cause. The types of infections, again, are most commonly pneumonia and furunculosis; the bacterial pathogens are usually the Pneumococcus, Staphylococcus, E. coli, Pseudomonas and Proteus. Cryptococcal meningitis should be looked for and zoster thought of in a patient complaining of radicular pain. At present there is no role identified for a zoster immune globulin in CLL patients, even those exposed to a child with varicella.26 In a double-blind comparison with a placebo; interferon-if therapy is started early-has been shown to be useful in reducing pain and distal cutaneous spread. Adenine arabinoside for severe disseminated infection has provided some encouraging results in early trials. Some special cautions here: do not attempt to immunize these patients with live virus of any sort, as they may get severe local reactions and even generalized infections without significant antibody responses being achieved. The malabsorption problem may in fact be a giardia infestation, as proposed above.. Pending further studies of this matter, I think that malabsorption should be looked for in a patient with diarrhea or weight loss and hypogammaglobulinemia. If it is present, a search for giardia should be made, and an empiric trial of therapy for giardiosis begun if no other cause appears. In severe cases of hypogammaglobulinemia with recurrent infections gamma globulin has been of help22 but in respiratory disease large doses may be necessary. Fresh frozen plasma, a source of IgM, may be useful in addition. I have tried to provide an overview of CLL: some of the characteristic findings of the disease,
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some of the theories that try to explain these findings, and some practical management hints. I hope this information will prove of use in your understanding and treatment of patients with CLL. REFERENCES 1. Fudenberg HH: Basic and Clinical Immunology. Los Altos, Lange Medical Publications, 1976, p 653 2. Allison AC: Interaction of Ab, complement components and various cell types in immunity against viruses and pyogenic bacteria. Transplant Rev 19:3-55, 1974 3. Fudenberg HH, Wybran J, Chantler S: Isolation of normal T cells in chronic lymphocytic leukemia. Lancet 1:126-129, Jan 20, 1973 4. Harris J, Copeland D: Impaired immunoresponsiveness in tumor patients. Ann NY Acad Sci 230:56-73, Mar 1974 5. Schroer K, Briles DE, Van Boxel JA, et al: Idiotypic uniformity of cell surface immunoglobulin in chronic lymphocytic leukemia (evidence for monoclonal proliferation). J Exper Med 140:1416-1419, Aug 1974 6. Preud'homme JL, Seligmann M: Surface bound immunoglobulins as a cell marker in human lymphoproliferative disease. Blood 40:777-794, Dec 1972 7. Fraumeni J Jr, Wertelecki W, Blattner W, et al: Varied manifestations of a familial lymphoproliferative disorder. Am J Med 59:145-151, Jul 1975 8. Hansen MM: Chronic lymphocytic leukaemia-Clinic studies based on 189 cases followed for a long time. Scand J i-{ematol, Suppl #18, Copenhagen, 1973 9. Pitney WR, Joske RA, MacKinnon NL: Folic acid and other absorption tests in lymphosarcoma, chronic lymphocytic leukemia, and some related conditions. J Clin Path 13:440-447, May 1960 10. Pruzanski W, Warren RE, Goldie JH, et al: Malabsorption syndrome with infiltration of the intestinal wall by extracellular monoclonal macroglobulin. Am J Med 54:811-818, Jun 1973 11. Preud'homme JL, Seligmann M: Anti-human immunoglobulin G activity of membrane-bound monoclonal immunoglobulin M in lymphoproliferative disorders. Proc Natl Acad Sci USA 69: 2132-2135, Aug 1972 12. Abeloff MD, Waterbury L: Pure red blood cell aplasia and chronic lymphocytic leukemia. Arch Intern Med 134:721-724, Oct 1974 13. Cuni W, Grunwald H, Rosner F: Bullous pemphigoid in chronic lymphocytic leukemia with the demonstration of antibasement membrane antibodies. Am J Med 57:987-992, Dec 1974 14. Dathan JRE, Heyworth MF, Maciver AG: Nephrotic syndrome in chronic lymphocytic leukaemia. Br Med J 3:655-657, Sep 14, 1974 15. Stutman 0: Immunodeficiency and cancer, In Green I, Cohen S, McClusky R (Eds): Mechanisms of Tumor Immunity. New York, Wiley, 1977, p 27 16. Miller DG, Karnofsky DA: Immunologic factors and resistance to infection in chronic lymphocytic leukemia. Am J Med 31:748-757, Nov 1961 17. Rifkind D: The activation of varicella-zoster virus infections by immunosuppressive therapy. J Lab and Clin Med 68:463-474, Sep 1966 18. Armstrong RW, Gurwith MJ, Waddell D, et al: Cutaneous interferon production of patients with Hodgkin's disease and other cancers infected with varicella or vaccinia. N Engl J Med 283:1182-1187, Nov 1970 19. Brouet JC, Preud'homme JL, Seligmann M, et al: Blast cells with monoclonal surface immunoglobulin in two cases of acute blast crisis supervening on chronic lymphocytic leukaemia. Br Med J 4:23-24, Oct 6, 1973 20. Rai KR, Sawitsky A, Cronkite EP, et al: Clinical staging of chronic lymphocytic leukemia. Blood 46:219-234, Aug 1975 21. Silver RT: The treatment of chronic lymphocytic leukemia. Semin Hematology 11:141, 1974 22. Gunz F, Baikie AG: Leukemia, 3rd Ed. New York, Grune and Stratton, 1974, p 841 23. Sawitsky A, Rai K, Isumettin A, et al: Mediastinal irradiation for chronic lymphocytic leukemia. Am J Med 61:892-896, Dec 1976 24. Storb R, Epstein RB, Buckner CD, et al: Treatment of chronic lymphocytic leukemia by extracorporeal irradiation. Blood 31:490-502, Apr 1968 25. Curtis JE, Hersh EM, Freireich EJ, et al: Leukapheresis therapy of chronic lymphocytic leukemia. Blood 39:163-175, Feb 1972 26. Uduman S, Gershon AA, Brunell PA: Should patients with zoster receive zoster immune globulin? JAMA 234:1049-1051, Dec
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