Postgraduate Medicine
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Managing chronic leukemias Murray N. Silverstein To cite this article: Murray N. Silverstein (1977) Managing chronic leukemias, Postgraduate Medicine, 61:1, 212-216, DOI: 10.1080/00325481.1977.11714522 To link to this article: http://dx.doi.org/10.1080/00325481.1977.11714522
Published online: 07 Jul 2016.
Submit your article to this journal
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipgm20 Download by: [Australian Catholic University]
Date: 08 August 2017, At: 00:49
hematology • rev1ew
Downloaded by [Australian Catholic University] at 00:49 08 August 2017
special series
• manag1ng chronic leukemias Murray N. Silverstein, MD
Mayo Clinic and Mayo Foundation Rochester, Minnesota
Chronic lymphocytic leukemia and chronic granulocytic leukemia vary considerably in their clinical features, laboratory findings, and therapy, but both generally have an ominous prognosis. Chemotherapy remains the mainstay of treatment in both disorders; with adjunctive measures to control complications such as anemia and splenomegaly. lmmunotherapy for granulocytic leukemia is still under study but appears promising.
212
• Chronic leukemias of the lymphocytic and the granulocytic types are common in general practice. Therefore, it is appropriate to review the clinical manifestations, course, modes of therapy, and complications of these disorders. Chronlc Lymphocytlc Leukemia
Chronic lymphocytic leukemia is a disease of older people. Men are affected a little more frequently than women. Most of the time, patients present as a result of organomegaly (big nodes, big spleen, big li ver) or as a resultofsymptoms related to anemia or thrombocytopenia. The outstanding laboratory abnormality is a high leukocyte count, with 75% to 90% of the cells being lymphocytes. Thrombocytopenia is seen initially in about 15% of patients and later on in about 60% to 70% of patients with active disease. Anemia may result from either a packed marrow or hemolysis. In our series at the Mayo Clinic, approximately 80% of patients who became anemie during the clinical course had the packed marrow syndrome and 20% were anemie because of hemolysis. 1 It is important to recognize the mechanism of the anemia or the thrombocytopenia because treatment varies depending on the mechanism. In chronic lymphocytic leukemia, the peripheral blood smear typically shows monotonous sheets of lymphocytes spread all through the smear. The bane marrow sections also show a fairly monotonous picture of lymphocytes spread throughout the marrow, with a marked decrease in all other marrow elements. Differentiai diagnosis- The major disorder to be differentiated from chronic lymphocytic leukemia l.s the syndrome of chronic lymphosarcoma cell leukemia. Patients with lymphosarcoma cell leukemia generally are younger than the average patient with chronic lymphocytic leukemia, have lower leukocyte counts and specifie morphologie differences, and do not survive as long. In lymphosarcoma cellleukemia, one sees large cells with cleaved nuclei and often with nucleoli. The question is, Does the patient have a solid-tissue lymphoma with bloodstream invasion or chronic lymphosarcoma cell leukemia? Without getting involved in semantics, I think that in terms of treating these patients, one must decide whether the problem is solid-tissue or liquid disease and how much marrow disease is present. Treatment is based on these features. It is
POSTGRADUATE MEDICINE
o
January 1977
o
Vol. 61
o
No. 1
Downloaded by [Australian Catholic University] at 00:49 08 August 2017
necessary to point out that perhaps a third to a half of patients with solid-tissue lymphoma, especially the well-differentiated nodular type, have a peripheral blood picture indistinguishable from that of patients with chronic lymphosarcoma cell leukemia. Immunologie features-Two types of lymphocytes are now recognized. B lymphocytes arise primarily from the bone marrow and perhaps from the lymph nodes. They are important in the manufacture of antibodies and therefore in humoral defense. T lymphocytes probably start out in the bone marrow, circulate through the thymus, and acquire certain qualities that mediate delayed hypersensitivity. . In almost every patient in our series, the cells involved in chronic lymphocytic leukemia have been B lymphocytes. We have seen four patients with classic chronic lymphocytic leukemia of T-cell origin. We suspect that this is a monoclonal proliferation. Early on, humoral irnmunity (that is, the ability to develop circulating antibodies) is impaired, but delayed hypersensitivity remains intact. Patients with chronic lymphocytic leukemia often have low serum immunoglobulin levels, and the autoimmune disorders (autoimmune hemolytic anemia and thrombocytopenia) are frequent. Treatment-In general practice, there are two types of patients with chronic lymphocytic leukemia. One type remains in extremely stable condition, requires little treatment, and can be followed up for years and years. The other type is seen at large medical centers ali too frequently. They have extremely active disease with progressively higher leukocyte counts, bone marrow failure, anemia, and thrombocytopenia and require treatment almost continuously.
Vol. 61 • No. 1 • January 1977 • POSTGRADUATE MEDICINE
In terms of general practice, treatment goals for chronic lymphocytic leukemia can be simply stated: (1) Above ali, avoid doing more harm than good, (2) relieve signs and symptoms of the disease when they occur, and (3) try to forestall complications. I think this is axiomatic. On this basis, the current therapy available for chronic lymphocytic leukemia includes alkylating agents (chlorambucil and cyclophosphamide), radiotherapy (whole-body, focal, or extracorporeal), adrenal steroids (specifie situations only), and leukopheresis. Leukopheresis therapy, which requires a cell separator, is new within the past five to six years. This method of treatment can remove a large amount of tumor from the peripheral blood, especially in patients with hyperproliferative chronic lymphocytic leukemia. Its marked advantage is that the patient is not exposed to drugs with mutagenic potential ordirectly tox-rays. We have used leukopheresis to treat both hyperproliferative and hypoproliferative disease. In comparison with chemotherapy and regular radiotherapy, however, this approach does not appear to be particularly beneficiai. At the present time, ·the mainstay for treatment of chronic lymphocytic leukemia is chemotherapy. Un til other methods have been studied in a prospective fashion, the drug of choice in general practice probably is chlorambucil (Leukeran). This drug is available as a 2-mg tablet, and the dosage is 4 to 6 mg/day. It is inexpensive, orally· administered, and weil tolerated, and the patient can be seen on an outpatient basis. The next question is, Whom do you treat? My associates and I treat those patients with chronic lymphocytic leukemia who have a high leukocyte count (> 100 x 109 /liter) or
213
ln almost every patient in our series, the cells involved ln chronlc lymphocytic leukemia have been 8 lymphocytes.
Downloaded by [Australian Catholic University] at 00:49 08 August 2017
The outstanding feature of chronic granulocytic leukemia is the presence of the Philadelphia chromosome.
who are symptomatic. Our treatment of choice, until the matter has been settled by prospective studies, is chlorarnbucil. (Severa} national groups, including the Eastern Cooperative Oncology Group, have established protocols to decide whether radiotherapy, chemotherapy, or a combination is best in terms of survival.) Typically, we start chlorarnbucil therapy at a dosage of 6 mg/ day. Serum urie acid level is checked and allopurinol (Zyloprim) therapy is started. Even in the chronic lymphoproliferative disorders, purine turnover is sufficient for urie acid nephropathy to occur. We have used chlorarnbucil as the sole agent in treating the disease when the patient has not had associated anemia or thrombocytopenia. When the patient is anemie at onset, we add prednisone. The major complication is anemia, and one must decide whether the anemia is due to the packed marrow syndrome or to hemolysis. Survival of erythrocytes is markedly decreased if the anemia is hemolytic. The marrow erythropoiesis is minimal in patients with the packed marrow syndrome but can be normal or even increased in patients with hemolytic anemia. Reticulocytosis and a positive Coombs' test suggest the presence of autoimmune hemolytic disease, as does a normal or increased platelet count. If hemolytic anemia is present, we prescribe prednisone, 60 to 80 mg/day. If the packed marrow syndrome is present, we primarily use an alkylating agent. Even with the packed marrow syndrome, the addition of prednisone to the chlorarnbucil or cyclophosphamide (Cytoxan) regimen seems to give somewhat better results than use of the alkylating agent alone. For the patient with the packed marrow syndrome who has thrombocytopenia, the use of alkylating therapy (chlorarnbucil, 4, 6, or 8 mg/day) has been effective. For ali patients with serious thrombocytopenia, especially those with prolonged bleeding times, we have elected to treat with prednisone in addition to the alkylating agent. If splenomegaly is a
214
problem, we favor the use of focal irradiation over the spleen in addition to prednisone. Adrenal steroids have had a prominent role in the treatment of chronic lymphocytic leukemia. They are lympholytic, probably because of the ir gluconeogenic effects. In our experience, patients with autoimmune hemolytic anemia have responded weil (about 78%) to prednisone alone. 1 Patients with thrombocytopenia have responded less weil (40% to 50% ). 1 Continuous therapy has little to offer over intermittent therapy unless the patient requires continuous therapy to keep the disease under control. Survival-It has been difficult to get reliable survival statistics because these are re ally sick patients. From culling the literature, I found, much to my surprise, that the median survival in patients with active chronic lymphocytic leukemia seems to be about four years. Probably 20% (at least more than 15%) live 10 to 15 more years with little or no treatment. The data from around the country and the world do not show a correlation between survival and the presence or absence of specifie constitutional symptoms, organ enlargement, or complications. I think the safest thing we can say is that our patients with lymphosarcoma cell leukemia do not do as weil as our patients with chronic lymphocytic leukemia. The Southeast Cooperative Oncology Group has suggested that patients who are asymptom atic and res pond· to treatmen t will probably survive longerthan patients who are symptomatic and do not respond to treatment. I think this is realistic. Chronic Granul9cytic Leukemia
In contrast to chronic lymphocytic leukemia, chronic granulocytic leukemia is a disease of young persons. Most patients are between 30 and 50 years old. A unique chromosomal abnormality, the Philadelphia (Ph 1) chromosome, is seen in approximately 85% of patients. 2 (No similar continuing
POSTGRADUATE MEDICINE • January 1977 • Vol. 61 • No. 1
Downloaded by [Australian Catholic University] at 00:49 08 August 2017
abnormality has been noted in patients with chronic lymphocytic leukemia.) Splenomegaly, the hallmark of ali myeloproliferative diseases, is especially prominent in chronic granulocytic leukemia. In this condition, in contrast to chronic lymphocytic leukemia, adenopathy is not frequent. In patients with chronic granulocytic leukemia, there is a correlation between the se verity of symptoms and the increase in leukocyte count. This is not the case in chronic lymphocytic leukemia. Autoimmune complications, immunoglobulin deficiencies, and opportunistic infections are common in patients with lymphoproliferative diseases but are unusual in patients with chronic granulocytic leukemia. A terminal blastic explosion (the so-called blast crisis) is typical in patients with chronic granulocytic leukemia but rarely, if ever, occurs in patients with chronic lymphocytic leukemia. Cell kinetics-The total granulocyte mass goes berserk: It is about 10 to 150 times the normal size. The leukemic granulocytes have the same cell cycle time as the nonleukemic granulocytes but have a much longer life span, which causes the trouble. Another unique feature of the leukemic granulocytes is that they wander through the extravascular space but eventually get back into the blood. Then they retum to the bone marrow, where they proliferate. Diagnosis-The presence of the Ph 1 chromosome, apparently a 22 chromosome th athas lost material from its long arm, is the outstanding feature of chronic granulocytic leukemia. In differentiai diagnosis, the major question is: Is this chronic granulocytic leukemia or a leukemoid reaction? In general, if the leukocyte count is high (> 100 x 1Q9/liter), chronic granulocytic leukemia is probably present. Basophilia also suggests chronic granulocytic leukemia. With a high sedimentation rate, toxic polymorphonuclear leukocytes, and rouleaux, a leukemoid reaction is likely. The leukocyte alkaline phosphatase
Vol. 61 • No. 1 • January 1977 • POSTGRADUATE MEDICINE
Murray N. Silverstein
Dr. Silverstein is chairman, division of hematology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota.
score is 0 or very low in the vast majority of patients with chronic granulocytic leukemia but is very high in patients with a leukemoid reaction. Marrow hypoplasia can occur in both. The presence of splenomegaly favors a diagnosis of chronic granulocytic leukemia. Several factors are associated with an ominous prognosis in chronic granulocytic leukemia, including fever, skin involvement, and lymphadenopathy. Absence of Ph 1 chromosome also is ominous. I believe that without the Ph 1 chromosome, the condition is not chronic granulocytic leukemia. These patients more closely resemble patients who have agnogenic myeloid metaplasia and cellular marrow. Nevertheless, the absence of Ph 1 chromosome, the presence of myelofibrosis, and the presence of muramidasuria signal a bad situation. Impending blast crisis, when the patient's condition is about to deteriorate, is characterized by the following features: (1) increasing basophilia, (2) increasing leukocyte alkaline phosphatase score, which previously was 0, 1+, or 2+, (3) appearance of many Ph 1 chromosomes, (4) appearance of aneuploidy or other chromosoma1 abnorma1ities, and (5) mye1ofibrosis (in about 8% of patients who go into b1ast crisis). 2 Blast crisis, the usual terminal phase, is indistinguishable from the acute form of granulocytic leukemia except that the Ph1 chromosome persists. About 3% of patients with terminal disease are resistant to ali forms oftherapy; they have not gone into blast crisis, have high leukocyte counts, are anemie, and have thrombocytopenia. 2 About 8% of our pa-
215
Downloaded by [Australian Catholic University] at 00:49 08 August 2017
tients with chronic granulocytic leukemia die with a syndrome indistinguishable from myelofibrosis. 2 Treatment-Again, the physician should avoid doing more harm than good. The need for treatment can be identified earlier in patients with chronic granulocytic leukemia than in those with chronic lymphocytic leukemia because. in chronic granulocytic leukemia, the increase in leukocyte count is directly related to the severity of symptoms. Our therapy to date has allowed the patient to live a normal life almost until the time of death, but we are not certain if survival bas been increased. lt do es appear th at chemotherapy is more effective than radiotherapy in controlling this disease and prolonging survival. The drug of choice is busulfan (My leran). lt is available as a 2-mg tablet, and we use dosages of 4 to 6 mg/day. Busulfan is inexpensive, orally administered, and well tolerated. The probability of producing complete remission is good. However, there is one important caution: Busulfan is an important cause of marrow aplasia in our practice. In addition, allopurinol must be prescribed to decrease urie acid levels. The suggested approach is to give 4 to 6 mg of busulfan per day for about two weeks. In this interval, the leukocyte count will start to decrease. When it reaches 40 x 109 / liter, we usually eut the dosage to 2 mg/day; when it bits 20 x 109/liter, we stop the treatment. Busulfan bas a half-life of at least three weeks, so its effect continues after administration is stopped. Busulfan can produce addisonian pigmentation, wasting, and hypotension (much like Addison's disease), and in rare cases, it can produce a curious interstitial pulmonary fibrosis. Survival-Again, the accumulation of hard data is difficult. Nevertheless, it does appear that chronic granulocytic leukemia is a very lethal disease. The interval from onset of symptoms to death is about 21h years. What is the role of splenectomy? At present, there is sorne controversy as to
216
whether splenectomy increases survival. A well-controlled prospective study is needed to resolve this question. There is one definite indication for splenectomy in chronic granulocytic leukemia-a big spleen and hypersplenism after chemotherapy or radiotherapy. What about the role of immunotherapy? The buffy coats of patients with chronic granulocytic leukemia have three antigens: A, B, and C. When grown in culture, cells from any patient with acute myelomonocytic leukemia make antibodies to one, two, or all three of these antigens. Therefore, at the Mayo Clinic we are giving leukemic cells from patients with acute leukemia plus BCG or MER (methanol-extractable residue of BCG) to patients with chronic granulocytic leukemia to see whether, in fact, immunotherapy plus chemotherapy will markedly increase survival. 1 can only say that this program is in the earl y stages and that the five patients we are treating are doing well. At least five to ten years of study will be needed before we can decide on the best approach. Comment
Treatment of chronic lymphocytic leukemia is aimed primarily at patients who are symptomatic. Indications for treatment include elevated white counts and development of anemia, thrombocytopenia, or both. Alkylating agents and adrenal steroids are the mainstays of therapy. 1 think the future is bright in regard to chronic granulocytic leukemia. As we push on in terms of immunotherapy, chemotherapy, and surgery, we may fin ally make progress against this disease. • Address reprint requests to Division of Publications, Scott and White Clinic, Temple, TX 76501.
References 1. Zacharski LR, Linman JW: Chronic lymphocytic leukemia versus chronic lymphosarcoma cellleukemia:Analysis of 496 cases. Am J Med 47:75-.81, 1969 2. Silverstein MN: Myeloproliferative diseases: Their shifting spectrums. Postgrad Med 43:167-171, May 1968
POSTGRADUATE MEDICINE o January 1977 o Vol. 61 o No. 1
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Managing chronic leukemias Murray N. Silverstein To cite this article: Murray N. Silverstein (1977) Managing chronic leukemias, Postgraduate Medicine, 61:1, 212-216, DOI: 10.1080/00325481.1977.11714522 To link to this article: http://dx.doi.org/10.1080/00325481.1977.11714522
Published online: 07 Jul 2016.
Submit your article to this journal
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipgm20 Download by: [Australian Catholic University]
Date: 08 August 2017, At: 00:49
hematology • rev1ew
Downloaded by [Australian Catholic University] at 00:49 08 August 2017
special series
• manag1ng chronic leukemias Murray N. Silverstein, MD
Mayo Clinic and Mayo Foundation Rochester, Minnesota
Chronic lymphocytic leukemia and chronic granulocytic leukemia vary considerably in their clinical features, laboratory findings, and therapy, but both generally have an ominous prognosis. Chemotherapy remains the mainstay of treatment in both disorders; with adjunctive measures to control complications such as anemia and splenomegaly. lmmunotherapy for granulocytic leukemia is still under study but appears promising.
212
• Chronic leukemias of the lymphocytic and the granulocytic types are common in general practice. Therefore, it is appropriate to review the clinical manifestations, course, modes of therapy, and complications of these disorders. Chronlc Lymphocytlc Leukemia
Chronic lymphocytic leukemia is a disease of older people. Men are affected a little more frequently than women. Most of the time, patients present as a result of organomegaly (big nodes, big spleen, big li ver) or as a resultofsymptoms related to anemia or thrombocytopenia. The outstanding laboratory abnormality is a high leukocyte count, with 75% to 90% of the cells being lymphocytes. Thrombocytopenia is seen initially in about 15% of patients and later on in about 60% to 70% of patients with active disease. Anemia may result from either a packed marrow or hemolysis. In our series at the Mayo Clinic, approximately 80% of patients who became anemie during the clinical course had the packed marrow syndrome and 20% were anemie because of hemolysis. 1 It is important to recognize the mechanism of the anemia or the thrombocytopenia because treatment varies depending on the mechanism. In chronic lymphocytic leukemia, the peripheral blood smear typically shows monotonous sheets of lymphocytes spread all through the smear. The bane marrow sections also show a fairly monotonous picture of lymphocytes spread throughout the marrow, with a marked decrease in all other marrow elements. Differentiai diagnosis- The major disorder to be differentiated from chronic lymphocytic leukemia l.s the syndrome of chronic lymphosarcoma cell leukemia. Patients with lymphosarcoma cell leukemia generally are younger than the average patient with chronic lymphocytic leukemia, have lower leukocyte counts and specifie morphologie differences, and do not survive as long. In lymphosarcoma cellleukemia, one sees large cells with cleaved nuclei and often with nucleoli. The question is, Does the patient have a solid-tissue lymphoma with bloodstream invasion or chronic lymphosarcoma cell leukemia? Without getting involved in semantics, I think that in terms of treating these patients, one must decide whether the problem is solid-tissue or liquid disease and how much marrow disease is present. Treatment is based on these features. It is
POSTGRADUATE MEDICINE
o
January 1977
o
Vol. 61
o
No. 1
Downloaded by [Australian Catholic University] at 00:49 08 August 2017
necessary to point out that perhaps a third to a half of patients with solid-tissue lymphoma, especially the well-differentiated nodular type, have a peripheral blood picture indistinguishable from that of patients with chronic lymphosarcoma cell leukemia. Immunologie features-Two types of lymphocytes are now recognized. B lymphocytes arise primarily from the bone marrow and perhaps from the lymph nodes. They are important in the manufacture of antibodies and therefore in humoral defense. T lymphocytes probably start out in the bone marrow, circulate through the thymus, and acquire certain qualities that mediate delayed hypersensitivity. . In almost every patient in our series, the cells involved in chronic lymphocytic leukemia have been B lymphocytes. We have seen four patients with classic chronic lymphocytic leukemia of T-cell origin. We suspect that this is a monoclonal proliferation. Early on, humoral irnmunity (that is, the ability to develop circulating antibodies) is impaired, but delayed hypersensitivity remains intact. Patients with chronic lymphocytic leukemia often have low serum immunoglobulin levels, and the autoimmune disorders (autoimmune hemolytic anemia and thrombocytopenia) are frequent. Treatment-In general practice, there are two types of patients with chronic lymphocytic leukemia. One type remains in extremely stable condition, requires little treatment, and can be followed up for years and years. The other type is seen at large medical centers ali too frequently. They have extremely active disease with progressively higher leukocyte counts, bone marrow failure, anemia, and thrombocytopenia and require treatment almost continuously.
Vol. 61 • No. 1 • January 1977 • POSTGRADUATE MEDICINE
In terms of general practice, treatment goals for chronic lymphocytic leukemia can be simply stated: (1) Above ali, avoid doing more harm than good, (2) relieve signs and symptoms of the disease when they occur, and (3) try to forestall complications. I think this is axiomatic. On this basis, the current therapy available for chronic lymphocytic leukemia includes alkylating agents (chlorambucil and cyclophosphamide), radiotherapy (whole-body, focal, or extracorporeal), adrenal steroids (specifie situations only), and leukopheresis. Leukopheresis therapy, which requires a cell separator, is new within the past five to six years. This method of treatment can remove a large amount of tumor from the peripheral blood, especially in patients with hyperproliferative chronic lymphocytic leukemia. Its marked advantage is that the patient is not exposed to drugs with mutagenic potential ordirectly tox-rays. We have used leukopheresis to treat both hyperproliferative and hypoproliferative disease. In comparison with chemotherapy and regular radiotherapy, however, this approach does not appear to be particularly beneficiai. At the present time, ·the mainstay for treatment of chronic lymphocytic leukemia is chemotherapy. Un til other methods have been studied in a prospective fashion, the drug of choice in general practice probably is chlorambucil (Leukeran). This drug is available as a 2-mg tablet, and the dosage is 4 to 6 mg/day. It is inexpensive, orally· administered, and weil tolerated, and the patient can be seen on an outpatient basis. The next question is, Whom do you treat? My associates and I treat those patients with chronic lymphocytic leukemia who have a high leukocyte count (> 100 x 109 /liter) or
213
ln almost every patient in our series, the cells involved ln chronlc lymphocytic leukemia have been 8 lymphocytes.
Downloaded by [Australian Catholic University] at 00:49 08 August 2017
The outstanding feature of chronic granulocytic leukemia is the presence of the Philadelphia chromosome.
who are symptomatic. Our treatment of choice, until the matter has been settled by prospective studies, is chlorarnbucil. (Severa} national groups, including the Eastern Cooperative Oncology Group, have established protocols to decide whether radiotherapy, chemotherapy, or a combination is best in terms of survival.) Typically, we start chlorarnbucil therapy at a dosage of 6 mg/ day. Serum urie acid level is checked and allopurinol (Zyloprim) therapy is started. Even in the chronic lymphoproliferative disorders, purine turnover is sufficient for urie acid nephropathy to occur. We have used chlorarnbucil as the sole agent in treating the disease when the patient has not had associated anemia or thrombocytopenia. When the patient is anemie at onset, we add prednisone. The major complication is anemia, and one must decide whether the anemia is due to the packed marrow syndrome or to hemolysis. Survival of erythrocytes is markedly decreased if the anemia is hemolytic. The marrow erythropoiesis is minimal in patients with the packed marrow syndrome but can be normal or even increased in patients with hemolytic anemia. Reticulocytosis and a positive Coombs' test suggest the presence of autoimmune hemolytic disease, as does a normal or increased platelet count. If hemolytic anemia is present, we prescribe prednisone, 60 to 80 mg/day. If the packed marrow syndrome is present, we primarily use an alkylating agent. Even with the packed marrow syndrome, the addition of prednisone to the chlorarnbucil or cyclophosphamide (Cytoxan) regimen seems to give somewhat better results than use of the alkylating agent alone. For the patient with the packed marrow syndrome who has thrombocytopenia, the use of alkylating therapy (chlorarnbucil, 4, 6, or 8 mg/day) has been effective. For ali patients with serious thrombocytopenia, especially those with prolonged bleeding times, we have elected to treat with prednisone in addition to the alkylating agent. If splenomegaly is a
214
problem, we favor the use of focal irradiation over the spleen in addition to prednisone. Adrenal steroids have had a prominent role in the treatment of chronic lymphocytic leukemia. They are lympholytic, probably because of the ir gluconeogenic effects. In our experience, patients with autoimmune hemolytic anemia have responded weil (about 78%) to prednisone alone. 1 Patients with thrombocytopenia have responded less weil (40% to 50% ). 1 Continuous therapy has little to offer over intermittent therapy unless the patient requires continuous therapy to keep the disease under control. Survival-It has been difficult to get reliable survival statistics because these are re ally sick patients. From culling the literature, I found, much to my surprise, that the median survival in patients with active chronic lymphocytic leukemia seems to be about four years. Probably 20% (at least more than 15%) live 10 to 15 more years with little or no treatment. The data from around the country and the world do not show a correlation between survival and the presence or absence of specifie constitutional symptoms, organ enlargement, or complications. I think the safest thing we can say is that our patients with lymphosarcoma cell leukemia do not do as weil as our patients with chronic lymphocytic leukemia. The Southeast Cooperative Oncology Group has suggested that patients who are asymptom atic and res pond· to treatmen t will probably survive longerthan patients who are symptomatic and do not respond to treatment. I think this is realistic. Chronic Granul9cytic Leukemia
In contrast to chronic lymphocytic leukemia, chronic granulocytic leukemia is a disease of young persons. Most patients are between 30 and 50 years old. A unique chromosomal abnormality, the Philadelphia (Ph 1) chromosome, is seen in approximately 85% of patients. 2 (No similar continuing
POSTGRADUATE MEDICINE • January 1977 • Vol. 61 • No. 1
Downloaded by [Australian Catholic University] at 00:49 08 August 2017
abnormality has been noted in patients with chronic lymphocytic leukemia.) Splenomegaly, the hallmark of ali myeloproliferative diseases, is especially prominent in chronic granulocytic leukemia. In this condition, in contrast to chronic lymphocytic leukemia, adenopathy is not frequent. In patients with chronic granulocytic leukemia, there is a correlation between the se verity of symptoms and the increase in leukocyte count. This is not the case in chronic lymphocytic leukemia. Autoimmune complications, immunoglobulin deficiencies, and opportunistic infections are common in patients with lymphoproliferative diseases but are unusual in patients with chronic granulocytic leukemia. A terminal blastic explosion (the so-called blast crisis) is typical in patients with chronic granulocytic leukemia but rarely, if ever, occurs in patients with chronic lymphocytic leukemia. Cell kinetics-The total granulocyte mass goes berserk: It is about 10 to 150 times the normal size. The leukemic granulocytes have the same cell cycle time as the nonleukemic granulocytes but have a much longer life span, which causes the trouble. Another unique feature of the leukemic granulocytes is that they wander through the extravascular space but eventually get back into the blood. Then they retum to the bone marrow, where they proliferate. Diagnosis-The presence of the Ph 1 chromosome, apparently a 22 chromosome th athas lost material from its long arm, is the outstanding feature of chronic granulocytic leukemia. In differentiai diagnosis, the major question is: Is this chronic granulocytic leukemia or a leukemoid reaction? In general, if the leukocyte count is high (> 100 x 1Q9/liter), chronic granulocytic leukemia is probably present. Basophilia also suggests chronic granulocytic leukemia. With a high sedimentation rate, toxic polymorphonuclear leukocytes, and rouleaux, a leukemoid reaction is likely. The leukocyte alkaline phosphatase
Vol. 61 • No. 1 • January 1977 • POSTGRADUATE MEDICINE
Murray N. Silverstein
Dr. Silverstein is chairman, division of hematology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota.
score is 0 or very low in the vast majority of patients with chronic granulocytic leukemia but is very high in patients with a leukemoid reaction. Marrow hypoplasia can occur in both. The presence of splenomegaly favors a diagnosis of chronic granulocytic leukemia. Several factors are associated with an ominous prognosis in chronic granulocytic leukemia, including fever, skin involvement, and lymphadenopathy. Absence of Ph 1 chromosome also is ominous. I believe that without the Ph 1 chromosome, the condition is not chronic granulocytic leukemia. These patients more closely resemble patients who have agnogenic myeloid metaplasia and cellular marrow. Nevertheless, the absence of Ph 1 chromosome, the presence of myelofibrosis, and the presence of muramidasuria signal a bad situation. Impending blast crisis, when the patient's condition is about to deteriorate, is characterized by the following features: (1) increasing basophilia, (2) increasing leukocyte alkaline phosphatase score, which previously was 0, 1+, or 2+, (3) appearance of many Ph 1 chromosomes, (4) appearance of aneuploidy or other chromosoma1 abnorma1ities, and (5) mye1ofibrosis (in about 8% of patients who go into b1ast crisis). 2 Blast crisis, the usual terminal phase, is indistinguishable from the acute form of granulocytic leukemia except that the Ph1 chromosome persists. About 3% of patients with terminal disease are resistant to ali forms oftherapy; they have not gone into blast crisis, have high leukocyte counts, are anemie, and have thrombocytopenia. 2 About 8% of our pa-
215
Downloaded by [Australian Catholic University] at 00:49 08 August 2017
tients with chronic granulocytic leukemia die with a syndrome indistinguishable from myelofibrosis. 2 Treatment-Again, the physician should avoid doing more harm than good. The need for treatment can be identified earlier in patients with chronic granulocytic leukemia than in those with chronic lymphocytic leukemia because. in chronic granulocytic leukemia, the increase in leukocyte count is directly related to the severity of symptoms. Our therapy to date has allowed the patient to live a normal life almost until the time of death, but we are not certain if survival bas been increased. lt do es appear th at chemotherapy is more effective than radiotherapy in controlling this disease and prolonging survival. The drug of choice is busulfan (My leran). lt is available as a 2-mg tablet, and we use dosages of 4 to 6 mg/day. Busulfan is inexpensive, orally administered, and well tolerated. The probability of producing complete remission is good. However, there is one important caution: Busulfan is an important cause of marrow aplasia in our practice. In addition, allopurinol must be prescribed to decrease urie acid levels. The suggested approach is to give 4 to 6 mg of busulfan per day for about two weeks. In this interval, the leukocyte count will start to decrease. When it reaches 40 x 109 / liter, we usually eut the dosage to 2 mg/day; when it bits 20 x 109/liter, we stop the treatment. Busulfan bas a half-life of at least three weeks, so its effect continues after administration is stopped. Busulfan can produce addisonian pigmentation, wasting, and hypotension (much like Addison's disease), and in rare cases, it can produce a curious interstitial pulmonary fibrosis. Survival-Again, the accumulation of hard data is difficult. Nevertheless, it does appear that chronic granulocytic leukemia is a very lethal disease. The interval from onset of symptoms to death is about 21h years. What is the role of splenectomy? At present, there is sorne controversy as to
216
whether splenectomy increases survival. A well-controlled prospective study is needed to resolve this question. There is one definite indication for splenectomy in chronic granulocytic leukemia-a big spleen and hypersplenism after chemotherapy or radiotherapy. What about the role of immunotherapy? The buffy coats of patients with chronic granulocytic leukemia have three antigens: A, B, and C. When grown in culture, cells from any patient with acute myelomonocytic leukemia make antibodies to one, two, or all three of these antigens. Therefore, at the Mayo Clinic we are giving leukemic cells from patients with acute leukemia plus BCG or MER (methanol-extractable residue of BCG) to patients with chronic granulocytic leukemia to see whether, in fact, immunotherapy plus chemotherapy will markedly increase survival. 1 can only say that this program is in the earl y stages and that the five patients we are treating are doing well. At least five to ten years of study will be needed before we can decide on the best approach. Comment
Treatment of chronic lymphocytic leukemia is aimed primarily at patients who are symptomatic. Indications for treatment include elevated white counts and development of anemia, thrombocytopenia, or both. Alkylating agents and adrenal steroids are the mainstays of therapy. 1 think the future is bright in regard to chronic granulocytic leukemia. As we push on in terms of immunotherapy, chemotherapy, and surgery, we may fin ally make progress against this disease. • Address reprint requests to Division of Publications, Scott and White Clinic, Temple, TX 76501.
References 1. Zacharski LR, Linman JW: Chronic lymphocytic leukemia versus chronic lymphosarcoma cellleukemia:Analysis of 496 cases. Am J Med 47:75-.81, 1969 2. Silverstein MN: Myeloproliferative diseases: Their shifting spectrums. Postgrad Med 43:167-171, May 1968
POSTGRADUATE MEDICINE o January 1977 o Vol. 61 o No. 1
