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The Management of Chronic Myeloproliferative Disorders
The Management of Chronic M yeloproliferative Disorders IRWIN H. KRAKOFF, M.D. The myeloproliferative disorders are generally chronic diseases, which can be successfully controlled for long periods by radiotherapy and chemotherapy. Dr. Krakojj discusses the manifestations of the myeloproliferative diseases, and describes recent new developments and current views on their management. The appropriate treatment of the various myeloproliferative disorders can be applied only on a background of proper classification of the disease in an individual patient. The relationships between the various manifestations of the myeloproliferative diseases have been discussed in detail by Dameshek. 2 Their complex interrelations are demonstrated in Figure 1. It is important to recognize the relation of these diseases to each other and particularly the fact that transitions between them occur, although in their typical forms each can be readily recognized and classified. There are many areas of overlap, however, and frequently patients are seen whose abnormality can be recognized only as a myeloproliferative disorder without specific classification within that group. The myeloproliferative diseases most frequently seen are chronic granulocytic leukemia, myeloid metaplasia, and polycythemia vera. Although the purpose of this paper is to discuss the management of these diseases rather than their natural histories, their principal clinical features are summarized in Table 1 as a basis for describing their proper management. The development of the leukocyte alkaline phosphatase stain13 has served in some cases to differentiate chronic granulocytic leukemia in which it is always low from myeloid metaplasia in which it may be low, normal or high. More recently, the recognition l l of the Philadelphia chromosome has proved to be a further aid in differentiating these two conditions. It has been stated 7 that the Philadelphia chromosome is absent in some cases of chronic granulocytic leukemia and that those cases are clinically somewhat atypical and respond less well to therapy than do those with the Philadelphia chromosome. It should be noted, however, that upon careful analysis of the cases described, many which are called "Ph-negative chronic granulocytic leukemia" would be From the Division of Clinical Chemotherapy, Sloan-Kettering Institute for Cancer Research and the Departments of MediCine, Memorial and James Ewing Hospitals and Cornell University Medical College, New York, N. Y. Medical Clinics of North America- Vol. 50, No. 3, May, 1966
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Figure 1. Schema of possible relationships in the myeloproliferative disorders. (Reprinted from: Gunz, F. W., The Myeloproliferative Disorders. New Zealand M. J. 57:428, 1958, by permission of the author and publishers.)
classified by some hematologists as myeloid metaplasia rather than chronic granulocytic leukemia. In general, there is a high degree of correlation between a typical clinical picture in chronic granulocytic leukemia and the presence of the Philadelphia chromosome. It is important to distinguish these two conditions, if at all possible, since the approach to therapy should be different in the two diseases. In polycythemia vera the Philadelphia chromosome is absent and the leukocyte alkaline phosphatase is characteristically high. In a large, collected series l2 of cases the median survival time in chronic granulocytic leukemia was 2.7 years, although individual cases vary widely from the median. Two individual studies l • 8 have Table 1.
Characteristics of the Chronic Myeloproliferative Disorders CHRONIC GRANULOCYTIC LEUKEMIA
White Blood Cells Platelets Hemoglobin Bone Marrow
100-300,000 Normal to High Normal Hypercellular
Spleen
Enlarged
Special Characteristics Ph chromosome Leukocyte alkaline phosphatase
MYELOID METAPLASIA
POLYCYTHEMIA VERA
25-50,000 Normal to Low Low Hypocellular and Sclerotic Enlarged
10-20,000 Very High High Hypercellular
Low to High
High
Slightly Enlarged
+ Low
THE MANAGEMENT OF CHRONIC MYELOPROLIFERATIVE DISORDERS
805
reported median survivals of 11 and 13 years in polycythemia vera. No accurate data on median survival are available for patients with myeloid metaplasia.
CHRONIC GRANULOCYTIC LEUKEMIA Ionizing Radiations Two methods of therapy with iOnIzmg radiations are in current practical use. The first, and probably more widely used, is external x-ray therapy given to the spleen. This can be administered either with conventional 250 kilovolt equipment or with supervoltage equipment of 1000 kilovolts. With the relatively small doses used in this disease there is no particular advantage to the use of supervoltage equipment. The customary dose is 400 to 600 roentgens given in increments of 100 roentgens over a period of two to three weeks. This usually results in a rapid fall in the granulocyte count, decrease in cellularity of the bone marrow, and reduction in the size of the spleen. Following such treatment, when used early in the disease, it is common for patients to remain in remission for prolonged periods of time, often exceeding one year. Eventually elevation of the leukocyte count and enlargement of the spleen recurs and the patient may respond well to a second course of treatment. In general, subsequent responses are of shorter duration than initially and ultimately x-ray therapy ceases to be effective in controlling the disease. At this time the clinical picture may have changed to one resembling acute myeloblastic leukemia with the development of anemia and thrombocytopenia and the appearance of a hypocellular bone marrow or one in which the normal elements have been replaced by primitive immature cells of the granulocytic Table 2. Agents Used in Treatment of Chronic Myeloproliferative Disorders AGENT
Alkylating Agents Busulfan
2-6 mg./day
Chlorambucil
6-12 mg./day
Cyclophosphamide 50-200 mg./day
Purine Analogues 6-Mercaptopurine 6-Thioguanine Azathioprine Allopurinol Ionizing Radiations External x-ray Phosphorus-32
INDICATION
DOSE
Leukocytosis and splenomegaly in chronic granulocytic leukemia Erythremia and thrombocythemia in polycythemia vera
1
2.5 mg./kg./day } Acute myeloblastic phase. 2.0 mg./kg./day 6 mg./kg./day 600 mg./day, divided Hyperuricemia. 400-600 r to spleen } 4-6 millicuries
Leukocytosis and splenomegaly in chronic granulocytic leukemia {Erythremia and thrombocythemia in polycythemia vera
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series. Further x-ray therapy at this stage of the disease is rarely useful in achieving further control of the disease. Ionizing radiation can also be administered in the form of the systemic administration of radioactive isotopes. The isotope which has had wide use in this condition is radioactive phosphorus (P~2). It can be given orally or intravenously in a dose of 4 to 6 millicuries and, as is the case with external radiation, may be followed by a prolonged remission in the disease. p:l2 also can be given repeatedly to control the white blood count and splenomegaly. Ultimately, as with external x-ray therapy, further p32 produces no benefit. The use of p~2 is a simple and useful way to control chronic granulocytic leukemia. However, it is no more effective than external x-ray therapy to the spleen.
Chemotherapy Chemotherapy was probably first used in chronic granulocytic leukemia 100 years ago, when Lissauer4 described the efficacy of arsenic in controlling the disease. The usefulness of this substance, in the form of potassium arsenite, was redemonstrated by Forkner and Scott5 in 1931 and was used in treating chronic granulocytic leukemia until the development, in the early 1940's, of other, more satisfactory compounds. Research during World War II on the mustard gases revealed that these substances were capable of producing bone marrow depression and had a therapeutic effect in certain lymphomas and leukemias. This information became public in 1946 and since that time extensive research on the nitrogen mustards and other polyfunctional alkylating agents has been done with the result that a number of such compounds are now available for the treatment of chronic granulocytic leukemia, as well as other neoplastic deseases. The polyfunctional alkylating agent most commonly used in this disease is busulfan (1, 4-dimethanesulfonyloxybutane; Myleran). This compound, administered orally in a dose of 2 to 6 mg. daily, is capable of producing gradual fall in the leukocyte count and decrease in splenomegaly over a period of two to six weeks. When a hematologically normal state has been achieved, it is appropriate to discontinue therapy with busulfan since the disease may remain under control for a long period of time without the need for maintenance therapy. When relapse occurs, as manifested by a rising white blood count and enlarging spleen, a patient will usually respond again to therapy with busulfan and at that time it is customary for therapy to be continued with daily small doses (2 to 4 mg.). The prolonged use of busulfan may cause hyperpigmentation, particularly in the skin creases, amenorrhea and, in rare cases, pulmonary fibrosis. Excessive dosage causes severe depression of all of the bone marrow elements. Although busulfan has not been demonstrated to produce any increase in survival time as compared with x-ray therapy, it is, in the minds of many investigators, the preferred form of treatment since its effect is achieved more gradually thus avoiding the rapid lysis of leukemic cells with consequent marked hyperuricemia that is sometimes seen with the use of x-ray therapy. In addition, the use of small daily doses of busulfan can result in a prolonged smooth course without the marked fluctuation in leukocyte count and spleen size often seen with the intermittent use of x-ray therapy. Although busulfan has come to be considered the alkylating agent of choice in the treatment of chronic granulocytic leukemia, it
THE MANAGEMENT OF CHRONIC MYELOPROLIFERATIVE DISORDERS
807
is important to note that this property is not peculiar to busulfan alone. Satisfactory results can be achieved with chlorambucil, cyclophosphamide, and with a number of other polyfunctional alkylating agents which have not achieved widespread clinical use. It is, therefore, appropriate for the occasional patient who experiences gastrointestinal discomfort from busulfan to use chlorambucil as an alternate drug in a dose of 8 to 12 mg. daily. This dose, however, as well as the recommended dose of busulfan, is merely an average and it is important during the early portion of any patient's therapy to follow the patient's leukocyte and platelet count carefully in order to establish the optimum dose for that individual. Ultimately, in patients treated with polyfunctional alkylating agents as in those treated with ionizing radiation, the disease enters a phase in which it is no longer responsive to therapy, and the marrow is either hypocellular or filled with numerous primitive blast cells. There is increasing splenomegaly, anemia, and thrombocytopenia. At this stage, although therapy with other agents should be attempted and may produce brief periods of improvement, further prolonged remission is uncommon. Another group of compounds which can produce satisfactory control of chronic granulocytic leukemia is the purine antagonists. The most commonly used member of this group is 6-mercaptopurine (Purinethol). This compound, given in a dose of 2.5 mg./kg. daily by mouth, is capable of producing a fall in white blood count and marked decrease in the splenomegaly. In contrast to the alkylating agents, it is nearly always necessary to continue maintenance therapy with 6-mercaptopurine since relapse usually occurs promptly when therapy is discontinued. When maintenance therapy is employed, it is common for 6-mercaptopurine to produce prolonged satisfactory control of the disease. It is not, however, usually considered the initial treatment of choice. The common practice is to use busulfan as the initial chemotherapeutic agent, reserving 6-mercaptopurine for the acute blastic phase in which it may, in rare instances, produce a remission. Other purine analogues, e.g., thioguanine and azathioprine, can be used as alternatives to 6mercaptopurine for the occasional patients who manifest gastrointestinal intolerance to 6-mercaptopurine. Demecolcin, an analogue of colchicine, is also capable of producing satisfactory control of chronic granulocytic leukemia. It is given orally in a dose of 5 to 8 mg./day. It appears to have no advantages over busulfan and 6-mercaptopurine and has not achieved widespread use. A number of other compounds have been used experimentally and have been shown to produce satisfactory results in chronic granulocytic leukemia but have not been used widely since they appear to possess no advantages over the better established agents. These include hydroxyurea and urethan. The latter drug has the disadvantage of producing a high incidence of nausea and vomiting and drowsiness when given in adequate doses. Other compounds under current investigation are known to be effective in chronic granulocytic leukemia although their precise role in the management of this disease has not yet been defined. It is appropriate, when this diagnosis has been made, to refer the patient to a medical center which is concerned with the evaluation of new drugs in the treatment of neoplastic diseases. The investigator may use as :the initial therapy an experimental drug which has been investigated
808
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sufficiently for a safe dose to be known since this disease is almost uniquely responsive to various chemotherapeutic agents and can provide an ideal clinical study of the possible efficacy of the new drug. Therefore, a patient to whom this has been thoroughly explained and who is willing to remain under close observation during this initial phase of his treatment, can contribute to the more rapid assessment of a new chemotherapeutic agent without undue hazard to himself and with the distinct possibility of establishing the usefulness, in his own disease, of a compound which might be helpful at a time when his disease has become unresponsive to more conventional agents.
MYELOID METAPLASIA It is essential to attempt to differentiate between chronic granulocytic leukemia and myeloid metaplasia. Although the typical case of chronic granulocytic leukemia can be expected to respond regularly to treatment, patients with myeloid metaplasia do not respond as well. The patient with a high white blood count and splenomegaly due to myeloid metaplasia may have a decrease in white blood count and perhaps a decrease in splenomegaly when treated with x-ray therapy or any of the chemotherapeutic agents described above. However, it is common for these patients when treated to become more anemic or thrombocytopenic. In occasional patients splenomegaly may be so marked that it becomes a mechanical burden and the patient is troubled by repeated splenic infarcts. In such cases, small doses of x-ray therapy to the spleen may be useful in reducing its size. However, this should be done very cautiously since anemia or thrombocytopenia may result from such treatment. In general, the response to x-ray therapy or chemotherapy in this group of patients has been so poor that it appears at present that the best therapy which can be offered is supportive and that specific attempts to treat the disease should be withheld. This disease characteristically follows a long, chronic, indolent course. In patients with myeloid metaplasia in whom there is marked anemia or thrombocytopenia testosterone has been used in an attempt to stimulate the bone marrow. Although this method of therapy has appeared to produce improvement in some cases of aplastic anemia, its usefulness in myeloid metaplasia is less well established. In both chronic granulocytic leukemia and myeloid metaplasia, splenectomy has sometimes been resorted to because of the enormous size of the spleen. This has been a technically difficult procedure and has not appeared to offer any significant benefit. Mathe l l has performed splenectomies in 12 patients with chronic granulocytic leukemia during the early portion of their disease. Although this group of patients has been followed to date for only a short time, he has stated that he does not believe that splenectomy has produced any significant changes in the evolution of the disease. It remains to be seen whether, in the absence of the spleen, greater or more rapid enlargement of the liver will occur.
POLYCYTHEMIA VERA In early cases, polycythemia vera may be confused with chronic granulocytic leukemia with which it has certain features in common.
THE MANAGEMENT OF CHRONIC MYELOPROLIFERATIVE DISORDERS
809
However, the overproduction of erythrocytes usually exceeds the granulocytic and megakaryocytic hyperplasia and the degree of splenomegaly is usually, though not always, less than that seen in chronic granulocytic leukemia. Death may occur from thromboembolic disease or cardiac failure. Late in the disease splenomegaly becomes more marked, the previously elevated hemoglobin begins to fall, the granulocyte count begins to rise with the appearance of immature granulocytes in the peripheral blood and the platelet count may fall to abnormally low levels. The bone marrow at this stage may be hypocellular, indicating that the disease has entered a phase of myeloid metaplasia with myelosclerosis. In other cases the progress may be into acute myeloblastic leukemia. Polycythemia vera can be treated with repeated phlebotomies, removing 500 cc. of whole blood on each occasion, and it is possible to manage the disease successfully for long periods of time in that way. Ionizing radiation in the form of P"2 has been widely used in the treatment of polycythemia and it is possible to maintain patients in good control with this as the sole therapeutic modality. It can be given repeatedly to control the hematocrit and splenomegaly. Dameshekl has suggested that many of the cases of acute leukemia developing in polycythemia vera may be due to the use of p:l2 rather than a natural transition of the disease and for this reason has suggested that other modalities be used. Alkylating agents, in particular busulfan, have been shown to induce control of polycythemia vera and, as in chronic granulocytic leukemia, prolonged remissions without therapy can be achieved after several weeks of busulfan in small doses (2 to 4 mg. daily). In those cases which undergo a transition into myeloid metaplasia, the management must be similar to that outlined for myeloid metaplasia not preceded by polycythemia. In those cases of polycythemia in which acute myeloblastic leukemia supervenes, patients should be treated with appropriate antimetabolite therapy in an attempt to obtain remission of the acute leukemia. The percentage of remissions occurring in this circumstance is low as is the case in primary acute myeloblastic leukemia and the prognosis is poor.
MANAGEMENT OF COMPLICATIONS One of the consistent biochemical abnormalities in the myeloproliferative diseases is the overproduction of uric acid. This results, in those patients who survive sufficiently long, in a high incidence of secondary gout. It has been estimated 14 that 5 to 9 per cent of patients with myeloproliferative disorders may develop secondary gout. The degree of overproduction of uric acid seen in these diseases exceeds that usually seen in primary gout and gout appears to be more difficult to manage in this group of patients than in those with primary gout. The management of this complication in the myeloproliferative diseases has been similar in every respect to that employed in the treatment of primary gout. Colchicine is most often used in the management of the acute arthritic attack and Probenecid is given on a long term basis to attempt to diminish the frequency of acute gouty attacks. Another important complication of the consistent overproduction of uric acid is uric acid nephropathy. This may occur as intermittent uric acid calculi or "gravel" or there may be deposition of urate through-
(Text continued on page 816.)
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813
THE MANAGEMENT OF CHRONIC MYELOPROLIFERATIVE DISORDERS
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h~nlive
Hlolsl.I,ITI.IL
814
IRWIN
H.
KRAKOFF
Figure 4. Diagram of clinical course of Case Ill, a patient with polycythemia vera. (Read across both pages, starting at top of opposite page.)
J. M. Birth Date 8/22/97 PS 90
NT 169
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Symptoms- occasionar-mild chest discomfort Hgb. 16.8-18.4 WOC 16.0-24.0 Plot. 237.7
leen
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mossive
'
Hgb. 15.9-17.1 WOC 14.5-26.0
Treatment - Nitroglycerine pm.
H!O!S!P!,!T!.!L PS 70-80 liT 167
:
~AJV., pr .'.pleen·•Bcm. 17cm
I
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• 15cm. spleen + IBem
I
I
.
$ymptoms- minimal joint pain
Hgb. 18.2-15.4 WOC 8.9-6.B Plot. 186.. 0-436.0 BUN 22.0-27.0 Uric Acid 8.3
Hgb. 15.5 WBe 6.0
Plot. 227.0 Uric Acid 8.6
Trectment - Benemid, Colchicine, - - - Myleran/ Chlorambucil Phlebotomy X 3 -
A I
Treotmenr Benemid, Colchicine
- - - Chlorambucil
L
815
THE MANAGEMENT OF CHRONIC MYELOPROLIFERATIVE DISORDERS
19S3
PS 60 wTI53
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wee 19.0
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Hgb 16.7
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wee 16.0
Het. 59%
wee 15.4
Bone marrow OSQirotion - Hyperplastic ITreatment - Subtotal gastrectomy at 0 - Peptic ulcer of duodenum
Blood and plasma transfusions
~-
Polycythemia Vera Bleeding peptic ulcer
Hlolslpl,lrl.IL PS 90 WT 169
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~nonnal
Hgb. 15.5-12.7 wee 24.0-30.5
Symptn:,- intermitten"t poin of large toes 0 th feet, weakness, "angina", SOB on exertion
Symptoms- painful jomts, diorrheo
Hgb. 12.4 wee 30.0 Plat. 317.9
Uric Acid 13.5-15.6
Cholesterol 55-24
LAP 169
Bone morl"O\lt aspiration - Hyperplastic
Hgb. 8.0-10.3 Plat.299.0-741.0
wee 44.0-16.0 BUN 20.0-40.
Stools guioe positive
Uric Acid 13.5
Treatment - Probenemid, Iron,
- - - Colchicine, Antacids Myleron
Hospitolized for three months
PS 70-80 WTI80
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I~HV"'6cm. sp leen t 20cm I Symptoms- weokness, large toe poin, occasional angina Acute smoll bowel obstruction lysis of adhesions 6/13
Hgb. 7.0-10.0 Plat. 173.0-398.0
Uric Acid 5.6-8.5
Treatment - Benemid, Colchicine - - - Chlorambucil
Phlebotomy X I
.
Treatment- Benemid, Colchicine - - - Chlorambucil
wee 4.0-6.4
BUN 17.0-30.0
Bone marrow aspirotions - Hypoplosti c Treotment - discontinue Chlorambucil - - - Allopurinol,lmferon Plasmo ond blood transfusions Hospitalized for 6 months I'tlolsl~il
rlAI!..
816
IRWIN
H.
KRAKOFF
out the finer collecting tubules, the renal pelvis and ureters with obstruction of urinary flow from uric acid crystals and ensuing oliguria or anuria. In rare instances, this may occur without therapy. However, more frequently it occurs following the administration of irradiation or a potent chemotherapeutic agent, with rapid reduction in the white blood count and in the size of the spleen. This complication has, in the past, been managed with cautious initiation of therapy, vigorous hydration of the patient in an attempt to maintain a high urine volume and attempts to alkalinize the urine with sodium bicarbonate or acetazolamide. If, in spite of these precautions, renal shutdown occurs due to uric acid nephropathy, it may be treated with extracorporeal hemodialysis with varying degrees of success. 4 A potent xanthine oxidase inhibitor, 4-hydroxypyrazolo (3, 4-d) pyrimidine (allopurinol; Zyloprim), has provided a safe and effective method of inhibiting uric acid production and thus avoiding uric acid nephropathy.6 Allopurinol is also successful in the maintenance treatment of secondary gout and appears over a long period of time to decrease the number of acute gouty attacks. 15 Even in patients who have not developed overt gout, the presence of prolonged hyperuricemia in association with one of the myeloproliferative diseases may represent an indication for the use of allopurinol to prevent the development of gout. In this connection, it should be remembered that allopurinol is capable also of blocking the degradation of 6-mercaptopurine. Therefore, in patients in whom 6-mercaptopurine is to be used in conjunction with allopurinol, it should be given in a dose approximately one quarter of that usually recommended. Bacterial infections occur commonly in the later stages of all of the myeloproliferative diseases at a time when the production of mature granulocytes is decreased due to myelosclerosis, transition to an acute leukemic form, or the effect of previous therapy. These infections should be treated vigorously and early with antibiotics, often before the identification of the offending organism is complete. The prophylactic use of antibiotics in cases of granulocytopenia is usually not advisable since it may contribute to the development of infections resistant to antibiotic therapy. Severe anemia occurs also late in the evolution of the myeloproliferative diseases. Transfusions of whole blood in order to maintain a hemoglobin of over 8 grams are useful in maintaining the patient in a satisfactorily functional state. Thrombocytopenia with bleeding also occurs commonly in the late stages of the myeloproliferative disorders. The use of transfusions of platelet concentrates has proved to be a useful measure in elevating the platelet count and in combating hemorrhagic tendencies. In particular, this supportive measure is indicated in patients whose thrombocytopenia may be due in part to the effects of chemotherapy or irradiation and in whom recovery of the bone marrow may be anticipated. Bleeding in association with surgical procedures, even minor ones, is common in patients with chronic granulocytic leukemia, even without thrombocytopenia. Therefore, careful evaluation of clotting factors should be done before surgery and the possibility of hemorrhage should be anticipated. Thromboembolic phenomena may occur in patients with polycythemia vera in whom thrombocythemia is a prominent feature. Although these should be treated by treatment of the underlying disease,
THE MANAGEMENT OF CHRONIC MYELOPROLIFERATIVE DISORDERS
817
the temporary use of anticoagulants may be indicated until the markedly elevated platelet count can be decreased with specific therapy.
CASE REPORTS CASE I. Figure 2 demonstrates the course of chronic granulocytic leukemia in a 27 year old woman who was treated initially with chlorambucil. Her unusually long course was uneventful throughout most of the 8 years of her disease. Terminally, her bone marrow revealed an increasing number of primitive early myelocytes with a decrease in mature granulocytes. She became anemic, thrombopenic, and developed a pneumonitis which was refractory to treatment with antibiotics. CASE Il. Figure 3 demonstrates a course of a man with myeloid metaplasia and myelosclerosis. His disease was characterized by marked splenomegaly, anemia, thrombocytopenia, and a moderately elevated white blood count. Several attempts at chemotherapy and radiotherapy produced no benefit. His disease ultimately entered an acute "blastic" phase with the appearance in his peripheral blood of numerous primitive blast cells. CASE Ill. Figure 4 demonstrates the prolonged course of a patient with polycythemia vera. Two episodes of anemia during his course were found to be due to a bleeding duodenal ulcer. The satisfactory treatment of his ulcer resulted in recurrence of a polycythemic picture. This was satisfactorily controlled with phlebotomies and chlorambucil for several years. He developed secondary gout. Ultimately, his bone marrow picture changed from that of panmyelosis to a sclerotic "empty" marrow. He developed anemia, leukopenia, and relative thrombocytopenia. At present he is receiving only supportive therapy.
REFERENCES 1. Calabresi, P., and Meyer, O. 0.: Polycythemia vera I and n., Ann. Intern. Med. 50: 1182, 1959. 2. Dameshek, W.: Some speculations on the myeloproliferative syndrome, Blood 6:372, 1951. 3. Dameshek, W., and Gunz, F.: Leukemia. New York, Grune & Stratton, 1964. 4. Firmat, J., Vanamee, P. Klauber, L., Krakoff, 1., and Randall, H. T.: The artificial kidney in the treatment of renal failure and hyperuricemia in patients with lymphoma and leukemia. Cancer 13:276,1960. 5. Forkner, C. E., and Scott, T. F. M.: Arsenic as a therapeutic agent in chronic myelogenous leukemia. Preliminary report. J.A.M.A. 97:3, 1931. 6. Krakoff, 1. H., and Meyer, R.: Prevention of hyperuricemia in leukemia and lymphoma: Use of allopurinol, a xanthine oxidase inhibitor. J.A.M.A. 193:1, 1965. 7. Krauss, F., Sandberg, A. A., and Sokal, J. E.: Atypical variance of chronic myelocytic leukemia. Proc. Am. A. Cancer Res. 5:37, 1964. 8. Lawrence, J. H.: Polycythemia. New York, Grune & Stratton, 1955. 9. Lissauer: Zwei Falle von Leucaemie. Ber!. klin. Wchnschr. 2:403, 1865. 10. Mathe G.: Personal communication. 11. Nowell, T. C., and Hungerford, D. A.: A minute chromosome in human chronic granulocytic leukemia. Science 132: 1497, 1960. 12. Tivey, H.: The prognosis for survival in chronic granulocytic and lymphocytic leukemia. Am. J. Roentgenol. 72:68, 1954. 13. Wachstein, M.: Alkaline phosphatase activity in normal and abnormal human blood and bone marrow cells. J. Lab. & Clin. Med. 31:1,1946. 14. Yu, T. F.: Secondary gout associated with myeloproliferative diseases. Arthritis & Rheumat. 8:765, 1965. 15. Yu, T. F., and Gutman, A. B.: Effect of allopurinol (4-hydroxy-pyrazolo[3,4-d] pyrimidine) on serum and urine uric acid in primary and secondary gout. Am. J. Med. 37:885, 1964. 444 East 68th Street New York, N.Y. 10021
803
804
IRWIN
H.
KRAKOFF
Figure 1. Schema of possible relationships in the myeloproliferative disorders. (Reprinted from: Gunz, F. W., The Myeloproliferative Disorders. New Zealand M. J. 57:428, 1958, by permission of the author and publishers.)
classified by some hematologists as myeloid metaplasia rather than chronic granulocytic leukemia. In general, there is a high degree of correlation between a typical clinical picture in chronic granulocytic leukemia and the presence of the Philadelphia chromosome. It is important to distinguish these two conditions, if at all possible, since the approach to therapy should be different in the two diseases. In polycythemia vera the Philadelphia chromosome is absent and the leukocyte alkaline phosphatase is characteristically high. In a large, collected series l2 of cases the median survival time in chronic granulocytic leukemia was 2.7 years, although individual cases vary widely from the median. Two individual studies l • 8 have Table 1.
Characteristics of the Chronic Myeloproliferative Disorders CHRONIC GRANULOCYTIC LEUKEMIA
White Blood Cells Platelets Hemoglobin Bone Marrow
100-300,000 Normal to High Normal Hypercellular
Spleen
Enlarged
Special Characteristics Ph chromosome Leukocyte alkaline phosphatase
MYELOID METAPLASIA
POLYCYTHEMIA VERA
25-50,000 Normal to Low Low Hypocellular and Sclerotic Enlarged
10-20,000 Very High High Hypercellular
Low to High
High
Slightly Enlarged
+ Low
THE MANAGEMENT OF CHRONIC MYELOPROLIFERATIVE DISORDERS
805
reported median survivals of 11 and 13 years in polycythemia vera. No accurate data on median survival are available for patients with myeloid metaplasia.
CHRONIC GRANULOCYTIC LEUKEMIA Ionizing Radiations Two methods of therapy with iOnIzmg radiations are in current practical use. The first, and probably more widely used, is external x-ray therapy given to the spleen. This can be administered either with conventional 250 kilovolt equipment or with supervoltage equipment of 1000 kilovolts. With the relatively small doses used in this disease there is no particular advantage to the use of supervoltage equipment. The customary dose is 400 to 600 roentgens given in increments of 100 roentgens over a period of two to three weeks. This usually results in a rapid fall in the granulocyte count, decrease in cellularity of the bone marrow, and reduction in the size of the spleen. Following such treatment, when used early in the disease, it is common for patients to remain in remission for prolonged periods of time, often exceeding one year. Eventually elevation of the leukocyte count and enlargement of the spleen recurs and the patient may respond well to a second course of treatment. In general, subsequent responses are of shorter duration than initially and ultimately x-ray therapy ceases to be effective in controlling the disease. At this time the clinical picture may have changed to one resembling acute myeloblastic leukemia with the development of anemia and thrombocytopenia and the appearance of a hypocellular bone marrow or one in which the normal elements have been replaced by primitive immature cells of the granulocytic Table 2. Agents Used in Treatment of Chronic Myeloproliferative Disorders AGENT
Alkylating Agents Busulfan
2-6 mg./day
Chlorambucil
6-12 mg./day
Cyclophosphamide 50-200 mg./day
Purine Analogues 6-Mercaptopurine 6-Thioguanine Azathioprine Allopurinol Ionizing Radiations External x-ray Phosphorus-32
INDICATION
DOSE
Leukocytosis and splenomegaly in chronic granulocytic leukemia Erythremia and thrombocythemia in polycythemia vera
1
2.5 mg./kg./day } Acute myeloblastic phase. 2.0 mg./kg./day 6 mg./kg./day 600 mg./day, divided Hyperuricemia. 400-600 r to spleen } 4-6 millicuries
Leukocytosis and splenomegaly in chronic granulocytic leukemia {Erythremia and thrombocythemia in polycythemia vera
806
IRWIN
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series. Further x-ray therapy at this stage of the disease is rarely useful in achieving further control of the disease. Ionizing radiation can also be administered in the form of the systemic administration of radioactive isotopes. The isotope which has had wide use in this condition is radioactive phosphorus (P~2). It can be given orally or intravenously in a dose of 4 to 6 millicuries and, as is the case with external radiation, may be followed by a prolonged remission in the disease. p:l2 also can be given repeatedly to control the white blood count and splenomegaly. Ultimately, as with external x-ray therapy, further p32 produces no benefit. The use of p~2 is a simple and useful way to control chronic granulocytic leukemia. However, it is no more effective than external x-ray therapy to the spleen.
Chemotherapy Chemotherapy was probably first used in chronic granulocytic leukemia 100 years ago, when Lissauer4 described the efficacy of arsenic in controlling the disease. The usefulness of this substance, in the form of potassium arsenite, was redemonstrated by Forkner and Scott5 in 1931 and was used in treating chronic granulocytic leukemia until the development, in the early 1940's, of other, more satisfactory compounds. Research during World War II on the mustard gases revealed that these substances were capable of producing bone marrow depression and had a therapeutic effect in certain lymphomas and leukemias. This information became public in 1946 and since that time extensive research on the nitrogen mustards and other polyfunctional alkylating agents has been done with the result that a number of such compounds are now available for the treatment of chronic granulocytic leukemia, as well as other neoplastic deseases. The polyfunctional alkylating agent most commonly used in this disease is busulfan (1, 4-dimethanesulfonyloxybutane; Myleran). This compound, administered orally in a dose of 2 to 6 mg. daily, is capable of producing gradual fall in the leukocyte count and decrease in splenomegaly over a period of two to six weeks. When a hematologically normal state has been achieved, it is appropriate to discontinue therapy with busulfan since the disease may remain under control for a long period of time without the need for maintenance therapy. When relapse occurs, as manifested by a rising white blood count and enlarging spleen, a patient will usually respond again to therapy with busulfan and at that time it is customary for therapy to be continued with daily small doses (2 to 4 mg.). The prolonged use of busulfan may cause hyperpigmentation, particularly in the skin creases, amenorrhea and, in rare cases, pulmonary fibrosis. Excessive dosage causes severe depression of all of the bone marrow elements. Although busulfan has not been demonstrated to produce any increase in survival time as compared with x-ray therapy, it is, in the minds of many investigators, the preferred form of treatment since its effect is achieved more gradually thus avoiding the rapid lysis of leukemic cells with consequent marked hyperuricemia that is sometimes seen with the use of x-ray therapy. In addition, the use of small daily doses of busulfan can result in a prolonged smooth course without the marked fluctuation in leukocyte count and spleen size often seen with the intermittent use of x-ray therapy. Although busulfan has come to be considered the alkylating agent of choice in the treatment of chronic granulocytic leukemia, it
THE MANAGEMENT OF CHRONIC MYELOPROLIFERATIVE DISORDERS
807
is important to note that this property is not peculiar to busulfan alone. Satisfactory results can be achieved with chlorambucil, cyclophosphamide, and with a number of other polyfunctional alkylating agents which have not achieved widespread clinical use. It is, therefore, appropriate for the occasional patient who experiences gastrointestinal discomfort from busulfan to use chlorambucil as an alternate drug in a dose of 8 to 12 mg. daily. This dose, however, as well as the recommended dose of busulfan, is merely an average and it is important during the early portion of any patient's therapy to follow the patient's leukocyte and platelet count carefully in order to establish the optimum dose for that individual. Ultimately, in patients treated with polyfunctional alkylating agents as in those treated with ionizing radiation, the disease enters a phase in which it is no longer responsive to therapy, and the marrow is either hypocellular or filled with numerous primitive blast cells. There is increasing splenomegaly, anemia, and thrombocytopenia. At this stage, although therapy with other agents should be attempted and may produce brief periods of improvement, further prolonged remission is uncommon. Another group of compounds which can produce satisfactory control of chronic granulocytic leukemia is the purine antagonists. The most commonly used member of this group is 6-mercaptopurine (Purinethol). This compound, given in a dose of 2.5 mg./kg. daily by mouth, is capable of producing a fall in white blood count and marked decrease in the splenomegaly. In contrast to the alkylating agents, it is nearly always necessary to continue maintenance therapy with 6-mercaptopurine since relapse usually occurs promptly when therapy is discontinued. When maintenance therapy is employed, it is common for 6-mercaptopurine to produce prolonged satisfactory control of the disease. It is not, however, usually considered the initial treatment of choice. The common practice is to use busulfan as the initial chemotherapeutic agent, reserving 6-mercaptopurine for the acute blastic phase in which it may, in rare instances, produce a remission. Other purine analogues, e.g., thioguanine and azathioprine, can be used as alternatives to 6mercaptopurine for the occasional patients who manifest gastrointestinal intolerance to 6-mercaptopurine. Demecolcin, an analogue of colchicine, is also capable of producing satisfactory control of chronic granulocytic leukemia. It is given orally in a dose of 5 to 8 mg./day. It appears to have no advantages over busulfan and 6-mercaptopurine and has not achieved widespread use. A number of other compounds have been used experimentally and have been shown to produce satisfactory results in chronic granulocytic leukemia but have not been used widely since they appear to possess no advantages over the better established agents. These include hydroxyurea and urethan. The latter drug has the disadvantage of producing a high incidence of nausea and vomiting and drowsiness when given in adequate doses. Other compounds under current investigation are known to be effective in chronic granulocytic leukemia although their precise role in the management of this disease has not yet been defined. It is appropriate, when this diagnosis has been made, to refer the patient to a medical center which is concerned with the evaluation of new drugs in the treatment of neoplastic diseases. The investigator may use as :the initial therapy an experimental drug which has been investigated
808
IRWIN
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sufficiently for a safe dose to be known since this disease is almost uniquely responsive to various chemotherapeutic agents and can provide an ideal clinical study of the possible efficacy of the new drug. Therefore, a patient to whom this has been thoroughly explained and who is willing to remain under close observation during this initial phase of his treatment, can contribute to the more rapid assessment of a new chemotherapeutic agent without undue hazard to himself and with the distinct possibility of establishing the usefulness, in his own disease, of a compound which might be helpful at a time when his disease has become unresponsive to more conventional agents.
MYELOID METAPLASIA It is essential to attempt to differentiate between chronic granulocytic leukemia and myeloid metaplasia. Although the typical case of chronic granulocytic leukemia can be expected to respond regularly to treatment, patients with myeloid metaplasia do not respond as well. The patient with a high white blood count and splenomegaly due to myeloid metaplasia may have a decrease in white blood count and perhaps a decrease in splenomegaly when treated with x-ray therapy or any of the chemotherapeutic agents described above. However, it is common for these patients when treated to become more anemic or thrombocytopenic. In occasional patients splenomegaly may be so marked that it becomes a mechanical burden and the patient is troubled by repeated splenic infarcts. In such cases, small doses of x-ray therapy to the spleen may be useful in reducing its size. However, this should be done very cautiously since anemia or thrombocytopenia may result from such treatment. In general, the response to x-ray therapy or chemotherapy in this group of patients has been so poor that it appears at present that the best therapy which can be offered is supportive and that specific attempts to treat the disease should be withheld. This disease characteristically follows a long, chronic, indolent course. In patients with myeloid metaplasia in whom there is marked anemia or thrombocytopenia testosterone has been used in an attempt to stimulate the bone marrow. Although this method of therapy has appeared to produce improvement in some cases of aplastic anemia, its usefulness in myeloid metaplasia is less well established. In both chronic granulocytic leukemia and myeloid metaplasia, splenectomy has sometimes been resorted to because of the enormous size of the spleen. This has been a technically difficult procedure and has not appeared to offer any significant benefit. Mathe l l has performed splenectomies in 12 patients with chronic granulocytic leukemia during the early portion of their disease. Although this group of patients has been followed to date for only a short time, he has stated that he does not believe that splenectomy has produced any significant changes in the evolution of the disease. It remains to be seen whether, in the absence of the spleen, greater or more rapid enlargement of the liver will occur.
POLYCYTHEMIA VERA In early cases, polycythemia vera may be confused with chronic granulocytic leukemia with which it has certain features in common.
THE MANAGEMENT OF CHRONIC MYELOPROLIFERATIVE DISORDERS
809
However, the overproduction of erythrocytes usually exceeds the granulocytic and megakaryocytic hyperplasia and the degree of splenomegaly is usually, though not always, less than that seen in chronic granulocytic leukemia. Death may occur from thromboembolic disease or cardiac failure. Late in the disease splenomegaly becomes more marked, the previously elevated hemoglobin begins to fall, the granulocyte count begins to rise with the appearance of immature granulocytes in the peripheral blood and the platelet count may fall to abnormally low levels. The bone marrow at this stage may be hypocellular, indicating that the disease has entered a phase of myeloid metaplasia with myelosclerosis. In other cases the progress may be into acute myeloblastic leukemia. Polycythemia vera can be treated with repeated phlebotomies, removing 500 cc. of whole blood on each occasion, and it is possible to manage the disease successfully for long periods of time in that way. Ionizing radiation in the form of P"2 has been widely used in the treatment of polycythemia and it is possible to maintain patients in good control with this as the sole therapeutic modality. It can be given repeatedly to control the hematocrit and splenomegaly. Dameshekl has suggested that many of the cases of acute leukemia developing in polycythemia vera may be due to the use of p:l2 rather than a natural transition of the disease and for this reason has suggested that other modalities be used. Alkylating agents, in particular busulfan, have been shown to induce control of polycythemia vera and, as in chronic granulocytic leukemia, prolonged remissions without therapy can be achieved after several weeks of busulfan in small doses (2 to 4 mg. daily). In those cases which undergo a transition into myeloid metaplasia, the management must be similar to that outlined for myeloid metaplasia not preceded by polycythemia. In those cases of polycythemia in which acute myeloblastic leukemia supervenes, patients should be treated with appropriate antimetabolite therapy in an attempt to obtain remission of the acute leukemia. The percentage of remissions occurring in this circumstance is low as is the case in primary acute myeloblastic leukemia and the prognosis is poor.
MANAGEMENT OF COMPLICATIONS One of the consistent biochemical abnormalities in the myeloproliferative diseases is the overproduction of uric acid. This results, in those patients who survive sufficiently long, in a high incidence of secondary gout. It has been estimated 14 that 5 to 9 per cent of patients with myeloproliferative disorders may develop secondary gout. The degree of overproduction of uric acid seen in these diseases exceeds that usually seen in primary gout and gout appears to be more difficult to manage in this group of patients than in those with primary gout. The management of this complication in the myeloproliferative diseases has been similar in every respect to that employed in the treatment of primary gout. Colchicine is most often used in the management of the acute arthritic attack and Probenecid is given on a long term basis to attempt to diminish the frequency of acute gouty attacks. Another important complication of the consistent overproduction of uric acid is uric acid nephropathy. This may occur as intermittent uric acid calculi or "gravel" or there may be deposition of urate through-
(Text continued on page 816.)
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"1 0 1'1'1'1'1'1'
a.;...ad
Treatment- - - Chlorambucil
wac 1<45.0-36.0
Hgb. 11.6-10.4-14. 1
gastroenteritis
()~.~.~.
f
Symptid- mild epistaxis
rnl
PS 90 WT98-107
mAY - ;TLUJ[
y
- / _ ' - uterus with infantile organs
rl-~
~ ~~llnode
Chl"'~bucil_.ad
"1 0 1'1'1.1'1.1,
I..... 2mo
Treatment -
Plot. 197.0
"-
7)\
(-~
wee 36.0-8.6
Hob. 14.1
WT
PS 100
"1 0 1'1'1'1'1'1'
---v.t:"""l-!2, Iron, liver
Treatment-
Hob. -ID. 0
Symptoms- meno..-rhogia
PS 90 WT
JULV·F/UG. "-
iJ
f
"-
qd
" I 01_' 1'1'1'1'1 '
~ChlOfambucil 4mg.
Hgb. 11.7
WBC 11.0
,.,i,'once .6c"
~l (\
f
Symptoms- rnenorrnogio
PS 90 WT 112
"1 0 1'1'1'1'1'1'
Symptoms- Menorrhagia
PS 90 WT
StPT.-OCT '-
tJ f
\
"'-
polpoble ~Ieen tip
!l
(~
~ 1_0
..... ,
ehlorombt.ocil 2mg. qd
L' J.' L' l'_1..'..l.'....
Treatment-
---
Hob. 13.3 WBC. 23.5
Symptoms-URI with $Oil! throat and mild cough
P590 WT109
ttJO)SJPJIJTJAJL
Symptoms· menorrhogi (I
PS 90 WT
#01/. -bEe
I-"
00
~
:;J
~ o
;:c
2
~
~
......
<:>
PS 100
~'spleen. 3cm.
6mg~
j
T
I
A
j L
6mg.qd
" I
I ' I • I '
Hospitalized fa Psychiatric core
I.
Treatment- Plasma IV Oi"I"OrOriiDuci I Myleran ~ 2mg.qd
I
')
\
7-1
"-
/ 96:> 0
f~
first stage
1,1
i- ,"-
Myleron I
Hlolslplljr
Tetracycline lG~
~
Treatment-
AIL
~
~~~~t~o~~.
Bone morrow aspiration
Hgb. 11.-4-12.3 WBe 8.4-3.2-11. 9
Symptoms- Qcute sinvsitis
~ST:~
"IOlsl'I'I'I'I'
Treotment---r:hlarombucil 2-4mg. qd
~i?#-~~'
Bone marrow aspiration
;,7,!;~:i:;:~1r~;~::,,:;
Hgb. 12.0-13.0 WBC 16,0-139.0 Plot 146.0-218.0
Symptoms- amenormea, acc. epigastric distress
PS 90 WTII3 "-
9 (P I
1,\
/
~-
2-4m9. qd
~
'--
I,t··,-
I
"1
0
1 5 1'1'1'1'1'
Treatment- - - Myleron 2mg. qd
Hgb. 11.4 WBC 13.8-5.5
Symptoms- tr~~~:::t "gas" and slight
PS 90 WT 102
"lolsl'I'I'I'I'
Treatment-
~orambucir
~~~~~
Bone ITIOrrow aspiration
Hgb. H.0-1-4.0 w8C 3.8-69.0 Plot. 109.0-223.0
Symptoms-omenorrhea, acc. epistaxis
PS 90-100 WTI17
1\\
"-
/9(,:<'
(.~
I 6-Bmg. qd
~
/~ /
:,~
\'
':";,-
spleen
f
10cm.
~ -'-:.~' tachycardia
left maxilla
neoplostic
~process
t--
r.tr""5":""/T"
I
"1
0
1 5 1'1'1'_
n-,
14.0-0.3
EXPiRED 12/28/64
t!l~~f~~cTh:;::;t)s3~(Qi~~at'~r~~~,,~ .
Treatment - IV fluids, transfusions,
~
wac
Bone morrow ~iratians ~fl @ mast Mono ~ ~
f±t!!
Hgb. 4.4-10.0 Plat. 0.0-18.0
Symptoms- fever, weakness, nausea, anareXIO, depression, diarrhea, hemoptysis, epistaxis
infiltrates
Chjst I~t, ......• mu t,p f-Rars. e
~; ~-o
HlojsjF'j1lrjAjL
Treahnent-IUDR aint. far herpes -----c:hrarambucil 6-Bmg. qd
Treatment - Transfusions - - - Antibiotics Myleran
2mQ.Qod
t"l
t"l
"t5:
;I>
~
rJJ
........
00
rJJ
t"l :>l
t:I
:>l
o
....
tj
t"l
<:
>-l ....
~
t"l
t-<
:;;
~
."
t-<
o
~
Z ()
~
::t:
"1 (")
>-l
Z
m:r.u ---z-u-
~
~ Z
;I>
o
'\
I-',m.
Hgb. 10.5-12.5 WBC 16.0-49.0
(
I
~ t"l
Symptams-omenarrhea, acc. epistaxis
-
8E- normal
herpes zoster buttocks
\Plee n
/_/_ 9'~3 '-----
~~~~IX"'oy (0-1
PS 90 WTI12
~~~~t~o~¥-'
Bone morrow aspiration
Hgb. 12.4-5.2-9.0 Wsc. 6.5-15.7-3.7 Plot. 105.0-164.0-9.0-29.0
_ spleen I 2cm.
~
1 r,~.".",. . _____ -
("oy!
I
~-vf:~~;i'n9
norma
Ch.,t
PS 90-60 WT 90
"IOISI'I'I'I'I'
Treotment-
~ombuci
Hgb.12.0-14.0 WBC 13.0-45.0 Plot. 245.0
Symptoms- acc. anorexia, occ. epIstaXIS, amenarrheo
PS 90 WTH7
Figure 2. Diagram of clinical course of Case I, a patient with chronic granulocytic leukemia. This chart and those in Figures 3 and 4 are representative of those in current use in the Medical Oncology Service, Memorial Hospital.
r
Ch lorambuci I 4mg.qd
~horazine and Tafranil
Treatment- Suicide precautions
wee
diarrhea and anorexia
"'-
I, "..,.,
~
Hgb.9.1-I0.6 WBC 44.0-6.4-7.6
r
~.
l
~
Hgb. 10.657.9-29.8-68.0 Plat. 224.0
(
P580 WT98
~r:~t;~S;nd::~e:e p~~~:s~i~fusion
/
Symptoms- N&V, diarrhea, weaknes~, anoreXia, epistaxis, extreme depression
~-"o'mol
~~r~:jX -Ray GI-normal
WT 105
,:.sSO
"IOlsl'I,I'I'I'
HjolsjF'jrlr/AjL
Treatment--a;lOrombucil2-4mg. qd
~ambucir 2-4mg. qd
Treotment-
Hgb.9.3-12.6 WSC 63.0-13.9 Plot. 140.0-239.0
Hgb. 13.0-10.0 WBC 30.0-17.0 Plot 199.0
1,\
"-
/73"'1
PS 90-100 f~ WTI05
Symptoms - omenorrhea
t··,",
;--"-
/9..Fj'
Symptoms- menorrhagia
WTI05
812 E. S.
IRWIN
H.
KRAKOFF
Birth Date 11/24/04 JAtJ-FcB. PS 90 wTI60
Symptoms
t(
-Increasei'~bdomlnol girth
noted by patient
mAY TUW[
mAft -Af'R PS 90 WT
r:\(
PS 90 WT
SymplOml- increaHld abdominal girth
T\(
~- incr._~bdomInal girth
Poorly controlled diabetes
~-Insulin
~Insulin
Hlolslol,lTlolL
r:
J QS1
WTI63-151 PS80
~
=. 5uNey.~ Chest .X-ftay 1
=~·III~
except skull
.'
PS 90 WT ISO
~5S0rg0d1;""ll!!.m: I..
~
..ICII9ed
l!;i;.~nd
.
Symp......- .h... "I~ to _ I , controlled diabetes Hgb. II.HI.2-1I.4 WBC 5.3-31.3 Plot. 0.0-82.5
PS 80
WTl44
I'fSq
r:~-
W;v.. .
nt~
r,~I
..Iorgod
iw
-
Hgb. 9.6-11.6 wac 4.5-30.4 PI••• 63.2-149.5
9an.
n. 25cm
:w
.&!!!e!!!!!-weakneu sugar in urine Hgb. 8.3-11.4
wac 9.3-20.3
PI••• 105.0-166.6
Treatment - Insulin, Prednisone
- - - Vitamins
!!!!!!!!!!!!-lnlUlin !!:!!!!!!!!!!-Insulin
TronsfusionsX 2
Hospitalized X 2 for diabetes
Hlolslol,ITI.IL
Hlolsl.I,ITI.IL
PS 90 WT 135
PS 70 wT137
r:
'--right
r:~
~ .
_;ve
liver and spl..n
'.w Hgb.9.9-<1.0 WBC 83.0-28.6 PI••• 131.0-33.0-100.1)082.0
~-lnlUlin
Hlolslol,ITI.IL
~k
~ ~~.::..both 1_,8f8
Spl-
-'''''
~...... - pracluc:6J.l_h, SOl,
~fever
Hgb. 9.3-7.5".4
wac 61.0-193.0-101.0
Hgb.7.1-6.2-7.8
wac 55.0-7.4
Pia•• 154. o-IZS. 0
Plot. 133. G-64. 0 !letl •• 11.2-10.0
-s
Treatment .. Antibiotics ~
lmulin
Diuril
Treatment .. 1.... lIn
- - - Dllitoxin
Dlurll
10 I, I T 1.1 L
Figure 3. Diagram of clinical course of Case 11, a patient with myeloid metaplasia and myelosclerosis. (Read across both pages.)
813
THE MANAGEMENT OF CHRONIC MYELOPROLIFERATIVE DISORDERS
--
PS 90
enlargod nodes
~
/'
NOII.-DEC.
SEPT.-OCT.
:rULY-RU&
r:~
~'i_f3FB
f::"'ln.( \)" ' .( /\
..
-1-
massive
1i.I
~-w ••
I...
'11::( "'"::.r...
11gb. 10.0-9.2-10.1
wac 18.8-24.2-5.7
wac 20.6-21.4
",b. 10.6-13.3-10.4
wac 5.7-12.7
PI ••• 74.9
Stomal bono _
- h,......lIul... reiaRve increase Of ...... Iocytic: series Treatment - 1...,lIn Radiation l\oonIpy to .1_
l!:!!!!!!!!!!-Insulin
HIOISI.I,ITI.IL
PI••• 26.6-69.2
~-Insulin
Hlolsl,l,lTlolL
Hlolsl.I,ITlolL
PS 90
PS 90
WTI29
I'''.
r:~
'_fl~_
~
_
I q .. ~
wTI36
f
~t""('
~I:'::~ ~ . en:
29~
'IW
Iu pc,n
11gb. 8.6-10.6
11gb. 9.4
Plot. 73. 0-146. 0
Plat. 43.0"220.0
S
~ -~. anklo odomo wUh
wac 6.0-33.3
11gb. 5.8-11.8
wac 5.2-15. 2
~onlargod nod..
/
wac 12.H.I.O
Plat 82.0-165.0
y..........,- ..,..dln
far pneumonia Ono unI. pocbd coli.
~WotiCl
and_I.
AoWttod to '-'tol X 2'"' .......
HIOISI,I,ITI.IL
PS'"
wT 138
r:~~~ and...-
we liver
lI!!e!!!!!! - SO'on'~on ",b. 7.5".0
wac 75.0-&7.0
riot 99. 0-t4l. 0-t09. 0
l!!!!!!!!!!!-Insulin Hlolsl,I,ITI.IL
PS 60
WT 138
_"::'='
r::~' ~. .'-ot .
"""'and._
eve liver
.-
Hlolsl.I,ITI.IL
generalized shotty
,4
PS 60-11
~nopathy
Ek:-tt~bothr.~.. ...\01.. ,... d.Nities
both ""11 R.lds
.
bases
i.,.li.,...
and spleen •
ascites
!I!!!e!!!!!-_h~w_
lI!!e!!!!!!- log poln:~k_
11gb. 7.4-6.8
wac 11.0-278.0
wac 144. 0-101. 0 PIat. 54..0-79.0
11gb. 6.8".5
PI••• 48. 0-tS. 0
M WO .. lane
mcn'GIW ~ration
11... Mono Plot Cel
35:l)-mr r
Treatment ... PKked cells SOOc.co
T _ - I... lln
- - - DI,llOIdn DlurU
HIO"""'TI.IL
T _ - I...lln - - - Digitoxin
Dfuril
HIOlsl.I,ITI.IL
5iiiiiiOftcy ...........nd ....
Devel.,-d respiratiwy dis..... , beCCIIM and unresponsive EXPIRED 11/22/63
h~nlive
Hlolsl.I,ITI.IL
814
IRWIN
H.
KRAKOFF
Figure 4. Diagram of clinical course of Case Ill, a patient with polycythemia vera. (Read across both pages, starting at top of opposite page.)
J. M. Birth Date 8/22/97 PS 90
NT 169
/ 1SIP ("
PS 90 WTI77
1.....,\
/ Cl .3-7
('
~;HV"'3cm.
'~iI;V" . 8cm. , spleen
t
'---..,
29cn
I
.
Symptoms- occasionar-mild chest discomfort Hgb. 16.8-18.4 WOC 16.0-24.0 Plot. 237.7
leen
I
mossive
'
Hgb. 15.9-17.1 WOC 14.5-26.0
Treatment - Nitroglycerine pm.
H!O!S!P!,!T!.!L PS 70-80 liT 167
:
~AJV., pr .'.pleen·•Bcm. 17cm
I
~ I;V"
• 15cm. spleen + IBem
I
I
.
$ymptoms- minimal joint pain
Hgb. 18.2-15.4 WOC 8.9-6.B Plot. 186.. 0-436.0 BUN 22.0-27.0 Uric Acid 8.3
Hgb. 15.5 WBe 6.0
Plot. 227.0 Uric Acid 8.6
Trectment - Benemid, Colchicine, - - - Myleran/ Chlorambucil Phlebotomy X 3 -
A I
Treotmenr Benemid, Colchicine
- - - Chlorambucil
L
815
THE MANAGEMENT OF CHRONIC MYELOPROLIFERATIVE DISORDERS
19S3
PS 60 wTI53
~~i~~~:;~
~
..................
PS 90 'NT 175
\
rlA ~nla,ged
process RH
GI series
"S 90
/'IT 170
~~
(l;vOl t 5FB p.SPleen t 12FB
I;ve
.~and spleen
suggests ulcer
i
;
I
~t:f::":~~g~~::~~ jrs~=f;~i:h:~~c;r:Y cough, weakness
Hgb 7.9-14.0 PI at. 143.0-467.0
wee 19.0
Uric Acid 9.0-7.9
Hgb 16.7
Hgb 16.6-18 .•
wee 16.0
Het. 59%
wee 15.4
Bone marrow OSQirotion - Hyperplastic ITreatment - Subtotal gastrectomy at 0 - Peptic ulcer of duodenum
Blood and plasma transfusions
~-
Polycythemia Vera Bleeding peptic ulcer
Hlolslpl,lrl.IL PS 90 WT 169
"560 WTI42
~e:!r-Roy BE nonnal
~nonnal
Hgb. 15.5-12.7 wee 24.0-30.5
Symptn:,- intermitten"t poin of large toes 0 th feet, weakness, "angina", SOB on exertion
Symptoms- painful jomts, diorrheo
Hgb. 12.4 wee 30.0 Plat. 317.9
Uric Acid 13.5-15.6
Cholesterol 55-24
LAP 169
Bone morl"O\lt aspiration - Hyperplastic
Hgb. 8.0-10.3 Plat.299.0-741.0
wee 44.0-16.0 BUN 20.0-40.
Stools guioe positive
Uric Acid 13.5
Treatment - Probenemid, Iron,
- - - Colchicine, Antacids Myleron
Hospitolized for three months
PS 70-80 WTI80
/ f/'3 ~ "--, r
I
){SPleen
t
~.
Hgb. 17.1
PI at. 455.0
;ve, I 5cm.
spleen. 2lcm
13cm
i wee 7.0
19/,¥
/' "---, ~IX-Ray ( ~~ ~~tD
!
Symptoms- occasiondt slight dyspneo urinory calculi
Hgb. 15.4
wee 7.6
Plat. 382.0
PS 50 'NTl25
/9 ('S / ......herpes zoster r . . . . . right chest \
I~HV"'6cm. sp leen t 20cm I Symptoms- weokness, large toe poin, occasional angina Acute smoll bowel obstruction lysis of adhesions 6/13
Hgb. 7.0-10.0 Plat. 173.0-398.0
Uric Acid 5.6-8.5
Treatment - Benemid, Colchicine - - - Chlorambucil
Phlebotomy X I
.
Treatment- Benemid, Colchicine - - - Chlorambucil
wee 4.0-6.4
BUN 17.0-30.0
Bone marrow aspirotions - Hypoplosti c Treotment - discontinue Chlorambucil - - - Allopurinol,lmferon Plasmo ond blood transfusions Hospitalized for 6 months I'tlolsl~il
rlAI!..
816
IRWIN
H.
KRAKOFF
out the finer collecting tubules, the renal pelvis and ureters with obstruction of urinary flow from uric acid crystals and ensuing oliguria or anuria. In rare instances, this may occur without therapy. However, more frequently it occurs following the administration of irradiation or a potent chemotherapeutic agent, with rapid reduction in the white blood count and in the size of the spleen. This complication has, in the past, been managed with cautious initiation of therapy, vigorous hydration of the patient in an attempt to maintain a high urine volume and attempts to alkalinize the urine with sodium bicarbonate or acetazolamide. If, in spite of these precautions, renal shutdown occurs due to uric acid nephropathy, it may be treated with extracorporeal hemodialysis with varying degrees of success. 4 A potent xanthine oxidase inhibitor, 4-hydroxypyrazolo (3, 4-d) pyrimidine (allopurinol; Zyloprim), has provided a safe and effective method of inhibiting uric acid production and thus avoiding uric acid nephropathy.6 Allopurinol is also successful in the maintenance treatment of secondary gout and appears over a long period of time to decrease the number of acute gouty attacks. 15 Even in patients who have not developed overt gout, the presence of prolonged hyperuricemia in association with one of the myeloproliferative diseases may represent an indication for the use of allopurinol to prevent the development of gout. In this connection, it should be remembered that allopurinol is capable also of blocking the degradation of 6-mercaptopurine. Therefore, in patients in whom 6-mercaptopurine is to be used in conjunction with allopurinol, it should be given in a dose approximately one quarter of that usually recommended. Bacterial infections occur commonly in the later stages of all of the myeloproliferative diseases at a time when the production of mature granulocytes is decreased due to myelosclerosis, transition to an acute leukemic form, or the effect of previous therapy. These infections should be treated vigorously and early with antibiotics, often before the identification of the offending organism is complete. The prophylactic use of antibiotics in cases of granulocytopenia is usually not advisable since it may contribute to the development of infections resistant to antibiotic therapy. Severe anemia occurs also late in the evolution of the myeloproliferative diseases. Transfusions of whole blood in order to maintain a hemoglobin of over 8 grams are useful in maintaining the patient in a satisfactorily functional state. Thrombocytopenia with bleeding also occurs commonly in the late stages of the myeloproliferative disorders. The use of transfusions of platelet concentrates has proved to be a useful measure in elevating the platelet count and in combating hemorrhagic tendencies. In particular, this supportive measure is indicated in patients whose thrombocytopenia may be due in part to the effects of chemotherapy or irradiation and in whom recovery of the bone marrow may be anticipated. Bleeding in association with surgical procedures, even minor ones, is common in patients with chronic granulocytic leukemia, even without thrombocytopenia. Therefore, careful evaluation of clotting factors should be done before surgery and the possibility of hemorrhage should be anticipated. Thromboembolic phenomena may occur in patients with polycythemia vera in whom thrombocythemia is a prominent feature. Although these should be treated by treatment of the underlying disease,
THE MANAGEMENT OF CHRONIC MYELOPROLIFERATIVE DISORDERS
817
the temporary use of anticoagulants may be indicated until the markedly elevated platelet count can be decreased with specific therapy.
CASE REPORTS CASE I. Figure 2 demonstrates the course of chronic granulocytic leukemia in a 27 year old woman who was treated initially with chlorambucil. Her unusually long course was uneventful throughout most of the 8 years of her disease. Terminally, her bone marrow revealed an increasing number of primitive early myelocytes with a decrease in mature granulocytes. She became anemic, thrombopenic, and developed a pneumonitis which was refractory to treatment with antibiotics. CASE Il. Figure 3 demonstrates a course of a man with myeloid metaplasia and myelosclerosis. His disease was characterized by marked splenomegaly, anemia, thrombocytopenia, and a moderately elevated white blood count. Several attempts at chemotherapy and radiotherapy produced no benefit. His disease ultimately entered an acute "blastic" phase with the appearance in his peripheral blood of numerous primitive blast cells. CASE Ill. Figure 4 demonstrates the prolonged course of a patient with polycythemia vera. Two episodes of anemia during his course were found to be due to a bleeding duodenal ulcer. The satisfactory treatment of his ulcer resulted in recurrence of a polycythemic picture. This was satisfactorily controlled with phlebotomies and chlorambucil for several years. He developed secondary gout. Ultimately, his bone marrow picture changed from that of panmyelosis to a sclerotic "empty" marrow. He developed anemia, leukopenia, and relative thrombocytopenia. At present he is receiving only supportive therapy.
REFERENCES 1. Calabresi, P., and Meyer, O. 0.: Polycythemia vera I and n., Ann. Intern. Med. 50: 1182, 1959. 2. Dameshek, W.: Some speculations on the myeloproliferative syndrome, Blood 6:372, 1951. 3. Dameshek, W., and Gunz, F.: Leukemia. New York, Grune & Stratton, 1964. 4. Firmat, J., Vanamee, P. Klauber, L., Krakoff, 1., and Randall, H. T.: The artificial kidney in the treatment of renal failure and hyperuricemia in patients with lymphoma and leukemia. Cancer 13:276,1960. 5. Forkner, C. E., and Scott, T. F. M.: Arsenic as a therapeutic agent in chronic myelogenous leukemia. Preliminary report. J.A.M.A. 97:3, 1931. 6. Krakoff, 1. H., and Meyer, R.: Prevention of hyperuricemia in leukemia and lymphoma: Use of allopurinol, a xanthine oxidase inhibitor. J.A.M.A. 193:1, 1965. 7. Krauss, F., Sandberg, A. A., and Sokal, J. E.: Atypical variance of chronic myelocytic leukemia. Proc. Am. A. Cancer Res. 5:37, 1964. 8. Lawrence, J. H.: Polycythemia. New York, Grune & Stratton, 1955. 9. Lissauer: Zwei Falle von Leucaemie. Ber!. klin. Wchnschr. 2:403, 1865. 10. Mathe G.: Personal communication. 11. Nowell, T. C., and Hungerford, D. A.: A minute chromosome in human chronic granulocytic leukemia. Science 132: 1497, 1960. 12. Tivey, H.: The prognosis for survival in chronic granulocytic and lymphocytic leukemia. Am. J. Roentgenol. 72:68, 1954. 13. Wachstein, M.: Alkaline phosphatase activity in normal and abnormal human blood and bone marrow cells. J. Lab. & Clin. Med. 31:1,1946. 14. Yu, T. F.: Secondary gout associated with myeloproliferative diseases. Arthritis & Rheumat. 8:765, 1965. 15. Yu, T. F., and Gutman, A. B.: Effect of allopurinol (4-hydroxy-pyrazolo[3,4-d] pyrimidine) on serum and urine uric acid in primary and secondary gout. Am. J. Med. 37:885, 1964. 444 East 68th Street New York, N.Y. 10021