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Treatment of Acute Leukemia
Symposium on Pediatric Oncology
Treatment of Acute leukemia
Donald Pinkel, M.D.*
During the past five years it has become clear that a high proportion of children with acute leukemia treated with modern methods are surviving continuously free of leukemia for 5 to 10 years.L 20, 22, 23 They may be cured of their disease. Although a welcome sequel to decades of discouraging effort this improvement has placed an additional burden on physicians. No longer can it be said that the child with leukemia "will die anyway." Now it is necessary to make certain that diagnosis is prompt, evaluation expeditious, and treatment provided where the personnel, programs, and facilities are optimal for achieving lengthy leukemia-free survival and possible cure. Recently an official of the National Cancer Institute was heard to say that treatment ofleukemia required only a good protocol and a physician who adheres to it. No more than a French cookbook makes a French chef or a map a navigator, a set of instructions does not provide expertise in care of children with leukemia. The purpose of this article is to give a current view of the treatment and prognosis of acute leukemia in children rather than to provide a map or teach navigation. The physician who wishes to treat these children must receive specialized training in a modern childhood leukemia center or work in close collaboration with such a center to be certain that his patients benefit from continuing progress. The main portion of this article is devoted to acute lymphocytic leukemia (ALL) which accounts for 78 per cent of childhood leukemia.
*Professor and Chairman, Department of Pediatrics, Milwaukee Children's Hospital, Milwaukee, Wisconsin This manuscript is derived from studies at St. Jude Children's Research Hospital supported by National Cancer Institute grants CA08480, CA07594, CA05176, CA08151, by the American Cancer Society and by ALSAC. The work of the Midwest Childhood Cancer Center is supported by National Cancer Institute grants CA17700, CA17851, CA18602, CA17997, by the American Cancer Society, and by the Faye McBeath Foundation.
Pediatric Clinics of North America-Vol. 23, No.1, February 1976
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.DONALD PINKEL
ACUTE LYMPHOCYTIC LEUKEMIA Diagnosis and Evaluation Although fever; bleeding, hepatosplenomegaly, and lymphadenomegaly usually suggest acute lymphocytic leukemia, some children present only with vague joint pains, unexplained pallor, or slowly resolving infection. Bone marrow aspiration and smear reveal replacement of normal hematopoiesis with lymphoblasts, lymphocytes, and immature unclassified "stem cells" in varying proportions. When the unclassified cells predominate some hematologists prefer to use the terms "stem cell" leukemia or simply acute leukemia. However, for purposes of patient management it is better to include all acute leukemias without clear-cut myelocytic or histiocytic (monocytic) differentiation under the rubric acute lymphocytic leukemia. Meningeal leukemia is diagnosed by study of cytocentrifuge preparations of cerebrospinal fluid, not by cell counts of the fluid. Special care must be taken to differentiate young or transformed lymphocytes and monocytes from leukemia cells. Recently, Sen and Borella have determined that there are 2 types of acute lymphocytic leukemia in children and adolescents (Table 1).19 Approximately 20 per cent of patients have thymic acute lymphocytic leukemia. Their leukemic lymphoblasts form heat-stable rosettes with sheep red blood cells and have two surface antigens characteristic of thymocytes (Fig. 1).12 Usually they are boys and they tend to be older and have high initial white blood cell counts and anterior mediastinal (thymic) masses. 13, 19 Although initially they respond to treatment they are inclined to relapse within a year. The leukemic lymphoblasts of the remaining 80 per cent of children with acute lymphocytic leukemia do not have detectable immunological markers at cell surfaces. These children with "null cell" acute lymphocytic leukemia have an equal sex ratio and tend to be younger and have low initial white blood cell counts. The majority of them remain free ofleukemia after modern treatment. Thus, thymic and "null cell" acute lymphocytic leukemia are not only different in origin and possibly in pathogenesis but also in their clinical features and prognosis.
Table 1. Types of Acute Lymphocytic Leukemia in Children* THYMIC
Median age Sex ratio Median white blood cell count at diagnosis Mediastinal mass Prognosis
"NULL"
9 years llM:1F
4 years: 1:1
53,OOO/mm3
13,OOO/mm3
Frequent Poor
Rare Good
*In thymic acute lymphocytic leukemia the leukemic lymphoblasts form heat stable rosettes with sheep red blood cells and demonstrate thymic antigens. (Data from Sen, L., and Borella, L.: Personal communication.) .
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119
Figure 1. Thymic leukemic lymphoblasts form rosettes with sheep red blood cells that remain stable at 37° C. They also possess antigens specific for thymocytes.
Induction of Complete Remission
"I
After initial diagnosis and evaluation of the patient, induction of remission is an urgent priority. This consists of sufficient eradication of leukemic cells such that normal hematopoiesis returns and no detectable evidence of the disease remains by physical examination or study of peripheral blood and bone marrow. The immediate risks of infection, bleeding, and interruption of normal physiology due to the leukemia are thus reduced. Theoretically more important, "late" leukemia, which can only be palliated by antimetabolites in the mouse (L121O) leukemia model, is converted into "early" leukemia, which is often cured by antimetabolites in the mouse model. For the past 13 years prednisone and vincristine have been the standard combination for induction of remission. Approximately 90 per cent of children with acute lymphocytic leukemia enter complete remission after four weeks of daily prednisone and weekly vincristine therapy. These drugs have several advantages. They have additive antileukemia effects without additive toxic effects, they act rapidly, and they do not produce vomiting, mucosal ulceration, or significant depression of hem atopoietic regeneration like other antileukemia agents. Drugs such as daunorubicin (daunomycin), doxorubicin (adriamycin), or L-asparaginase have been added to this combination in recent years, but there is no proof that they improve the frequency of remissions except in instances where response to prednisone and vincristine is unsatisfactory. On the
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other hand they carry additional risks of toxicity, particularly myelosuppression and immunosuppression. A major reason for their employment during or shortly after remission induction is the possibility that they might reduce leukemia cell mass further than the prednisone-vincristine combination and thus make the leukemia "earlier" and perhaps more susceptible to cure by antimetabolites. Several investigations in progress are designed to test the validity of this hypothesis. The achievement of complete remission, as demonstrated by normal appearance of bone marrow, is the first goal in treatment of acute lymphocytic leukemia.
Preventive Treatment of Meningeal Leukemia Children with acute lymphocytic leukemia who receive combination chemotherapy to continue their remissions will often develop initial relapse in the arachnoid meninges unless specific measures are taken to eradicate leukemia cells in the arachnoid early during remission. I6 The likely reason is the relatively poor diffusion of antileukemia drugs into cerebrospinal fluid. Three methods are used to specifically eliminate arachnoid leukemia cells early in remission and thus prevent arachnoid meningeal relapse: intrathecal administration of methotrexate or a combination of intrathecal methotrexate and arabinosyl cytosine, systemic administration of particularly high doses of antimetabolites in order to achieve higher levels in the cerebrospinal fluid, and irradiation of cranial or craniospinal meninges. 23 Combinations ofthese methods are also used. Thus far only the utilization of craniospinal irradiation or cranial irradiation combined with intrathecal methotrexate have been proved effective in comparative studies that have been published in detail (Table 2).20,22 Transient neurological difficulties can follow cranial irradiation but long-term observation has not yet demonstrated permanent neuropsychological impairment. 24 Careful attention to techniques ofirradiation (Fig. 2) and ofintrathecal drug administration is essential. Systenic 'nethotrexate should be o'nitted during intrathecal administration.
Table 2. Effects of Craniospinal Irradiation in Preventing Weningeal Leukemia':' CRANIOSPINAL
N umber of patients Patients with initial meningeal relapse Patients with continuous complete remission for 5 to 7 years Patients free of leukemia and off therapy 1 to 4 years
IRRADIA TION
NONE
45
49
2
33
23
7
24
18
*In this 1968 to 1970 comparative study 2400 R of .oCo irradiation was administered during the first month of complete remission. Subsequently the patients were continued on combination chemotherapy for up to three years. The results demonstrate the effectiveness of irradiation in preventing meningeal leukemia.
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MULTIMODALITY THERAPY IN PEDIATRIC NEOPLASMS
Figure 2. Cranial radiation port. Each of the lateral ports extends beyond the scalp and includes the meninges of the entire cranium and part of the upper cervical cord as indicated on this localization film. Failure to use adequate ports increases the risk of meningeal relapse.
Continuation Chemotherapy Once complete remission has been achieved so that the leukemia is undetectable and thus "early," and specific measures have been taken to eradicate leukemia cells in the arachnoid, the next goal is to eliminate residual leukemia in marrow, lymph nodes, and viscera in order to cure the "early" leukemia. Multiple drug therapy is most effective for continuing remissions. Maximal dosage is required for optimal effectiveness (Table 3).14 To achieve maximal dosage while minimizing serious toxic hazards, it is Table 3. CO'nparison of Full and Half Dosage Combination Chemotherapy * HALF DOSAGE
Number of patients Median complete remission Median hematological remission
21
FULL DOSAGE
21
6 months
15 months
16 months
33 months
*This 1965 to 1967 study utilized the combination of methotrexate, mercaptopurine, cyclophosphamide, and vincristine for continuation therapy after remission induction. Full, more toxic dosage resulted in longer remissions.
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essential that the patients be examined and their blood cells be counted weekly. Particularly important are inspection of mucous membrane and skin, and neurological evaluation. The total white blood cell count should be kept between 2000 and 3000 per cubic mm with approximately 500 to 1000 phagocytes per cubic mm and 500 to 1000 lymphocytes per cubic mm. Phagocytes include granulocytes and monocytes. In a recent comparative study the combination of methotrexate and mercaptopurine was as effective as the combination of methotrexate, mercaptopurine and cyclophosphamide or of methotrexate, mercaptopurine, cyclophosphamide and arabinosyl cytosine, and was considerably less immunosuppressive (Tables 4 and 5).7,23 In some leukemia centers up to eight drugs are being used simultaneously or in cyclic sequences with a high frequency of prolonged remissions. 4 Further study, particularly comparative investi'gations of key principles and features of the multiple drug regimens, is needed to determine how to achieve the greatest frequency of long lasting remissions and possible cure with least risk and trauma to the child. Cessation of Therapy While patients are receiving combination chemotherapy for acute leukemia they are at increased risk of serious infection, particularly with viruses of the herpes group and protozoa such as Pneumocystis carinii and Toxoplasma gondii. 9, 10 Some patients experience growth inhibition and most demonstrate progressive marrow hypoplasia. With continued methotrexate administration hepatic fibrosis can result, especially when it is prolonged past three to four years. Long-term cyclophosphamide ad ministration can lead to fibrosis of the urinary bladder. The long range carcinogenic effects of antineoplastic drugs may be significant, as
Table 4. Comparison of Four Regimens of Combination Chemotherapy * METHOTREXATE MERCAPTOPURlNE
Number of patients Number ofrelapses Number who died in remission Patients with contiDuous complete remission
METHO-
METHOTREXATE
TREXATE
MERCAPTOPURINE
PHAMIDE
METHO-
MERCAPTO-
CYCLOPHOS-
ARABINOSYL
TREXATE
PURlNE
PHAMIDE
CYTOSINE
20
64
62
62
14
10
16
8
1
0
2
4
5
54
44
50
CYCLOPHOS-
*In this 1972 to 1975 study patients were randomized after remission induction and cranial irradiation plus intrathecal methotrexate. They received maximal tolerated dosage of drugs. Randomization to the methotrexate alone group was terminated early because of frequent leukoencephalopathy. The two drug regimen is as effective as three or four drugs, thus far. (Data from Simone, J. V., and Aur, R. J. A., Personal communication.)
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MULTIMODALITY THERAPY IN PEDIATRIC NEOPLASMS
Table 5. Relative Immunosuppression during Complete Remission by Three Regimens of Chemotherapy * METHOTREXATE METHOTREXATE
MERCAPTOPURINE
METHOTREXATE
MERCAPTOPURINE
CYCLOPHOSPHAMIDE
MERCAPTOPURINE
CYCLOPHOSPHAMIDE
ARABINOSYL CYTOSINE
Normal peripheral blood B lymphocytes per cu mmmean (range)
99 (15-328)
7 (2-27)
3 (0-11)
Frequency of Pneumocystis carinii pneumonia
2/64
7/62
23/62
*The mean levels of B lymphocytes were severely reduced and risk of P. carinii pneumonia increased by use of additional drugs for continuation chemotherapy. (Data from Green, A. A., Sen, L., and Borella, L.: Personal communication.)
already demonstrated for cyclophosphamide, an apparent urinary bladder carcinogen. 25 On the other hand there is no good evidence that combination chemotherapy lowers relapse rate past three to four years, when the relapse rate levels off in patients who have received effective preventive central nervous system therapy with their combination chemotherapy (Fig. 3).1. 20. 23 For these reasons we tend to stop chemotherapy of acute lymphocytic leukemia after 3 years of continuous complete remission. Approximately 15 per cent of patients experience relapse after stopping treatment, predominantly within the first year. 1 Would this rate be reduced by chemotherapy until four or five years? Would the risk of acute or delayed fatal toxicity during the additional one or two years outweigh the possible therapeutic advantage during that period? We do not have the answers to these important questions. After stopping chemotherapy the children usually experience increased appetite and growth rate and may "catch up" for growth lost while on therapy. Hematopoiesis returns to normal in 6 to 12 months after a period of "immunological rebound" the first 3 months. The lymphocytosis and lymphoblastosis of the bone marrow which occur during the immunological rebound can be confused with early relapse of acute lymphocytic leukemia. 3
Curability Are most of the children surviving free of leukemia for four or more years cured of their disease? In Figure 3 the initial continuous complete remissions of children treated with multiple drug chemotherapy and 2400 R of cranial or craniospinal irradiation during the years 1967 to 1970 are plotted on a semilogarithmic graph. One can see that the patients had a constant risk of relapse for two years, a tendency to a reduced rate of relapse for 1 year, an increased risk for the following year (after cessation of chemotherapy), and a relatively slight risk after four years of complete
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.....Q) 0.7 Q)
0.
E 0.6 0
u
c: c: 0 :;; '0
0-
e a..
0.5 Therapy Stopped
0.4
Z 2
3
4
5
6
7
8
9
YEARS Figure 3. A semilogarithmic graph of continuous complete remission of 76 patients treated in 1967 to 1970 studies with combination chemotherapy and 2400 R craniospinal irradiation or cranial irradiation plus intrathecal methotrexate. All patients have been followed for 5% to 8 years. There was a steady relapse rate for 4 years followed by a plateau representing reduced risk of relapse. Thus, patients in continuous complete remission for 4 years and off therapy for 1 year appear to be biologically different from those who relapse while on chemotherapy or during the first year off therapy. This difference may represent cure, at least of the cellular phase of leukemia. The current objective of therapeutic innovation is to increase the height of the plateau, i.e., the proportion of patients surviving free of leukemia at low risk of relapse and thus possibly cured.
remission. This suggests that the children represented by the plateau after four years differ from those in the exponential regression curve before four years. This difference might represent eradication ofleukemia cells or cellular cure of their disease. Since a plateau for complete remission of acute lymphocytic leukemia has been established, the main objective of therapeutic m'anipulations now must be the raising of this plateau. No longer can we measure therapeutic success in terms of survival, of hematological remission duration, or of median complete remission. We need to gauge our therapeutic efforts by the proportion of children surviving continuously free ofleukemia and at minimal or no risk ofrelapse, Le., by the height of the plateau of initial complete remission on a semilogarithmic graph.
Toxic Effects of Treatment All patients with acute lymphocytic leukemia who receive adequate therapy suffer toxic effects. This is inevitable. The physician's task is to minimize these effects without compromising treatment any more than necessary. Again, frequent examinations, sensitivity to the subtleties of the patient, awareness of all possible toxic effects, and readiness to adjust drug dosage are essential to good patient care. Every child needs his own physician who provides unified, continuous comprehensive care, who is "tuned in" on the child and his family as well as on the disease and its treatment. When remission induction therapy is initiated, three immediate risks
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are metabolic disorder, infection, and bleeding. The most frequent metabolic disorder is hyperuricemia due to rapid destruction ofleukemia cells and subsequent oxidation of released purines. Administration of allopurinol reduces formation of uric acid but not the total purine load to be excreted, so that generous hydration and alkalinization with sodium bicarbonate may also be required to prevent crystallization of xanthine, hypoxanthine, or uric acid in renal tubules. This is particularly true when the patient has large masses of leukemic tissue in the mediastinum, spleen, kidneys, or peripheral blood. Renal infiltration with leukemia can contribute to the metabolic difficulty in the first days of remission induction. Azotemia, hyperkalemia, and hyperphosphatemia are also encountered in these patients. The antileukemia drugs are immunosuppressive so that susceptibility to infection is increased during their administration. Not infrequently the patient who harbors Staphylococcus aureus or Hemophilus influenzae at diagnosis will develop virulent infection with bacteremia shortly after chemotherapy is initiated. The use of broad spectrum antibiotic therapy may lead to serious infections with Escherichia coli, Klebsiella species, Pseudomonas aeruginosa, or Candida albicans. 9 • 11 Although broad spectrum antibiotic therapy may be required for suspected but undiagnosed sepsis, it should not be prolonged. When the organism causing a virulent infection is identified, specific antibiotic therapy should be utilized. Again, the duration of antibiotic therapy needs to be limited. Often it is better to take a relatively small risk of recurrence of infection due to a sensitive organism rather than a greater risk of superinfection with antibiotic-resistant organisms such as Candida or Aspergillus. During complete remission of leukemia, streptococcal and pneumococcal infections are unusual, perhaps because of the antibacterial activity of the antileukemia drugs. There is a high risk of infection due to Hemophilus influenzae, Staphylococcus aureus, coliform bacteria, and fungi. However, the most serious infectious threats are with the large deoxyribonucleic acid viruses such as varicella-zoster and cytomegalovirus, and with protozoa such as Pneumocystis carinii and Toxoplasma gondii. 5 • 9. 10 Prompt cessation of chemotherapy and prophylactic administration of zoster immune plasma (ZIP) or zoster immune globulin (ZIG) will usually minimize the morbidity of varicella. 5 There is no treatment of proven value for these virus infections. Patients with Pneumocystis carinii pneumonia present with fever, cough, chest pain, and tachypnea and have no abnormal auscultatory findings in their chests.1° Roentgenography may be normal initially or demonstrate alveolitis. Typically, capillary or arterial p02levels are low and pC0 2levels normal. Diagnosis is made by methenamine silver nitrate stains of drops of transcutaneous pulmonary aspirate. These patients can be treated with trimethoprim and sulfamethoxazole or with pentamidine isethionate. The use of continuous negative external thoracic pressure appears to improve oxygenation when simple administration of oxygen by mask does not result in improved arterial or capillary p02levels.17 Bleeding in patients with newly diagnosed acute lymphocytic leukemia usually stops after prednisone therapy is initiated. Platelet transfusions are helpful for temporary control of thrombocytopenic bleeding at any time during the course.
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DONALD PINKEL
In addition to immunosuppression, the antileukemia drugs have numerous other toxic effects. Prednisone causes hypertension, sodium retention with edema, hyperglycemia, hypokalemic alkalosis, muscle atrophy, acne, and osteoporosis. Courses of prednisone should be limited to four weeks. Vincristine causes peripheral neuropathy, ineffective erythropoiesis, hypertension, convulsions, ileus, and inappropriate antidiuretic hormone secretion. L-asparaginase causes anaphylactoid reactions, pancreatitis, hepatic dysfunction, hyperglycemia, and coagulopathy. Doxorubicin (adriamycin) and daunorubicin (daunomycin) cause vomiting, diarrhea, mucositis with ulcerations-particularly of the uvula and pharynxhematosuppression, and cardiomyopathy. Methotrexate causes vomiting, diarrhea, mucosal ulceration, megaloblastosis, hepatic damage sometimes leading to hepatic fibrosis, and hematosuppression. More recently it has been recognized that young children receiving large doses of methotrexate intravenously or intrathecally can develop leukoencephalopathy leading to permanent diffuse brain damage. 15 • 22 Mercaptopurine primarily causes hematosuppression and gastrointestinal disorders. The alkylating agents cause vomiting, diarrhea, mucosal ulcerations, and hematosuppression. Cyclophosphamide, in addition, causes urinary bladder hemorrhage and occasionally bladder fibrosis and carcinoma years later. 25 Arabinosyl cytosine (cytarabin e) causes severe emesis, diarrhea, mucosal ulcers, and hematosuppression. Antileukemia therapy is hazardous and difficult on the child, his family, and his nurses and physicians. Only through cautious, gentle, well organized and planned administration by a skilled and spirited team with their own inpatient and outpatient facilities can it be both tolerable and optimally effective.
Prevention of Infection Several relatively simple measures are used to reduce the risks of serious infection in children with acute lymphocytic leukemia. Most important, hospitalization is minimized, not only because of 'the pathogenic organisms in a hospital environment but because of the nonpathogenic but unfamiliar flora in a hospital which can cause virulent infections in these patients. When hospitalization is required, the child is placed in a private room, preferably one with rapid exchange of filtered air and positive air pressure. Strict handwashing by all personnel touching the patient is essential. Intramuscular injections are avoided and skin punctures are preceded by both iodine and alcohol preparations. Intravenous sites-are changed every 24 hours when feasible. Mist tents and other sources of air-borne infection are not used. Visiting is limited and both the child and the room are kept clean. In the clinic it is better to admit the child directly to a clean, well equipped examining room without a sojourn in a waiting room. Again, handwashing is essential before touching the patient. At home, good hygiene and good nutrition are important. Public swimming pools and close contact with animals are avoided. Children
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can attend school if they feel well enough but should be kept out during epidemics of infectious disease, particularly varicella. Live virus vaccines are not administered to children with leukemia until at least one year after being removed from therapy. As mentioned previously, the total white blood cell count is kept above 2000 per cubic mm during complete remission (not during remission induction) with greater than 500 phagocytes per cubic mm and greater than 500 lymphocytes per cubic mm. Unnecessary and prolonged antibiotic therapy is avoided. For household exposure to varicella the susceptible child is given zoster immune plasma or zoster immune globulin and the chemotherapy is discontinued for three weeks or until all pox lesions are dry.4 It is important to regard fever during leukemia as evidence of infection, not a manifestation of leukemia, and to be aware that cerebrospinal fluid pleocytosis may reflect bacterial, viral, fungal, or protozoal meningitis rather than meningeal relapse. Based on animal experimentation and clinical investigation, granulocyte transfusions are being administered to patients with granulocytopenia and infections in many centers. 8 , 18 However, the efficacy of this procedure remains questionable. Expensive, elaborate "life island" methods to protect hospitalized patients from infection are advocated in some centers.2 There is no evidence that these methods are more effective than pre-antibiotic era type room isolation, handwashing, ventilation, and sanitation.
Emotional Support Children with acute lymphocytic leukemia and their families need to feel confident in the physicians and nurses looking after them. A well organized, smoothly operating team consisting of the primary physician and the multidisciplined group at a childhood cancer center is the first essential. Ideally, the primary physician should retain his role in the week to week care of the child in his own community. This provides ready availability of medical care in time of need, reduces disruption of family routine, and gives the child a trusted and familiar advocate in his relationship with his family, neighborhood, and school. The childhood cancer center is required to provide continuing, up-to-date expertise in initial and periodic evaluation, planning and prescription of treatment, consultation to the primary physician, and care of the child during critical periods such as remission induction, radiotherapy, diagnosis and treatment of serious infections, and solving of specific metabolic, toxic, or psychological problems. Even at the center each child needs to be assigned to a specific staff physician who can become familiar with the child, the family, and the primary physician in the community. Children should be told their diagnosis by their parents or by the physician in the presence of their parents. Their questions need to be answered honestly but with gentleness and tact. Not just the mother but the father and siblings need to participate in the management ofthe child with leukemia. Some families require specialized attention for their psychological, spiritual, and social needs. The physician must select carefully the professional personnel who attend to these needs. I
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If it becomes apparent that the child in relapse will not regain remission status it is important to formulate with the family plans for terminal care. For many families the death of the child is better conducted at home or in a community hospital. Most families and patients accept death courageously if they have had ample opportunity to discuss their feelings with each other and with a trusted physician throughout the course of the disease. Financial burdens can add unnecessary distress to families of children with acute lymphocytic leukemia. Childhood cancer centers and primary physicians caring for the children should not request compensation from their families beyond that provided by third party payers or granting agencies. The payers and agencies, on the other hand, should support the centers and the physicians adequately so that they can provide optimal services. A nation that supports Las Vegas and the Department of Defense can certainly afford it.
TREATMENT OF ACUTE MYELOCYTIC, ACUTE MYELOMONOCYTIC, AND ACUTE HISTIOCYTIC (MONOCYTIC) LEUKEMIA With present methods it is possible to induce complete remission in 65 to 70 per cent of children with acute nonlymphocytic leukemia. 6 Some methods combine two or more hematosuppressive and antimucosal drugs such as mercaptopurine or its analog thioguanine, arabinosyl cytosine (cytarabine), cyclophosphamide, daunorubicin (daunomycin), or doxorubicin (adriamycin).4 Prednisone is often added for its nonspecific hemostatic effect and vincristine for whatever antileukemia effect it may offer. Combined hematosuppressive and antimucosal chemotherapy in patients who already have deficiencies in platelets and normal granulocytes often results in severe neutropenia, lymphopenia, thrombocytopenia, and mucositis. Life threatening infection, bleeding, and severe emesis and diarrhea often ensue during the remission induction procedures. Some patients are lost before they have the opportunity to benefit from the medications by regeneration of normal hematopoiesis and achievement of complete remission. Hospitalization is often required throughout the four to eight weeks of remission induction and intensive supportive care is needed for infection and bleeding. A relatively gentle method of inducing remission is used by some leukemia therapists. This consists of daily intravenous administration of 6-Azauridine, an antimetabolite that does not damage normal hematopoiesis and mucous membrane, for 10 days.6 Accompanying this the patients receive weekly vincristine and daily mercaptopurine in moderate dosage for four to six weeks. The remission induction rate in children is approximately the same as for the more toxic methods but the morbidity and mortality from treatment are less. Patients with acute myelocytic and myelomonocytic leukemia and acute histiocytic or monocytic leukemia do not usually develop hyperuricemia after therapy although some may present with it. How-
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TREATMENT OF ACUTE LEUKEMIA
ever, they do experience complications not seen in patients with acute lymphocytic leukemia. For example, children with acute myelocytic or myelomonocytic leukemia sometimes bleed because of coagulopathies not related to platelet deficiency. Patients with acute histiocytic or monocytic leukemia often suffer from hypoalbuminemia, edema, and hemolytic anemia. Continuation of remission is much less successful with acute myelocytic and acute histiocytic leukemia than with acute lymphocytic leukemia. Combinations of two or more drugs are used in sequential or simultaneous treatment schemes. Arabinosyl cytosine, mercaptopurine or thioguanine, and daunorubicin or doxorubicin are the most frequently used. The combination of cyclophosphamide and doxorubicin appears especially effective in histiocytic neoplasms. The same basic principles for prevention and treatment of infection , control of toxicity, and supportive care are used as in care of patients with acute lymphocytic leukemia. Meningeal relapse often terminates complete remission in children with acute myelocytic leukemia. 6 As with acute lymphocytic leukemia, it appears that the longer patients remain in complete remission the higher is the frequency of cerebrospinal fluid leukemia. Intrathecal methotrexate, arabinosyl cytosine, or both are used in treatment of meningeal acute myelocytic leukemia but improvement is temporary. Data from studies in progress suggest that meningeal relapse of acute myelocytic and myelomonocytic leukemia can be prevented by craniospinal irradiation early in remission. 21 Only 5 per cent or less of patients with acute nonlymphocytic leukemia remain in continuous complete remission more than three years. Experimental approaches to acute myelocytic leukemia include marrow transplantation from tissue-matched donors and immunological stimulation with BCG vaccine. Neither is of established value.
COMMENT Basic and clinical research are required to identify the causes and mechanisms of acute leukemia so that it can be prevented or treated with more specific agents. In the meantime we need to continue exploratory and comparative studies of leukemia therapy with currently available measures. Approximately one half of children with acute lymphocytic leukemia are experiencing long-term, leukemia-free survival and possible cure with best present methods oftreatment in skilled hands. Every child with acute lymphocytic leukemia should have the opportunity for cure. REFERENCES 1. Aur, R. J. A., Simone, J. V., Hustu, H. 0., et aI.: Cessation of therapy during complete remission of childhood acute lymphocytic leukemia. New Engl. J. Med., 291 : 1230-1234, 1974. 2. Bodey, G. R.: Isolation for the compromised host. J.A.M.A., 233:543-545, 1975.
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3. Borella, L., Green, A. A., and Webster, R. G.: Immunologic rebound after cessation oflongterm chemotherapy in acute leukemia. Blood,40:42, 1972. 4. Clarkson, B. D., Dowling, M. D., Gee, T. S., et al.: Treatment of acute leukemia in adults. Cancer, 36:775-795, 1975. 5. Feldman, S., Hughes, W. T., and Daniel, C. B.: Varicella in children with cancer: Seventyseven cases. Pediatrics, 56:388-397, 1975. 6. Fleming, I., Simone, J., Jackson, R., et al.: Splenectomy and chemotherapy in acute myelocytic leukemia of childhood. Cancer, 33:427-434, 1974. 7. Green, A. A., Sen, L., and Borella, L.: Immunologic aspects of acute lymphocytic leukemia (ALL): Is ALL a disease of lymphoid cells? In Sinks, L. F., and Godden, J. O. (eds.): Conflicts in Childhood Cancer. New York, Alan R. Liss, Inc., 1975, pp. 56-65. 8. Higby, D. J., Yates, J. W., Henderson, E. S., etal.: Filtration leukapheresis for granulocyte transfusion therapy. Clinical and laboratory studies. New Engl. J. Med., 292:761-766, 1975. 9. Hughes, W. T.: Fatal infections in childhood leukemia. Am. J. Dis. Child., 122:283,1971. 10. Hughes, W. T., Price, R. A., Kim, H. K., et al.: Pneumocystis carinii pneumonitis in children with malignancies. J. Pediat., 82:404, 1973. 11. Hughes, W. T., and Smith, D. R.: Infection during induction of remission in acute lymphocytic leukemia. Cancer, 31 : 1008, 1973. 12. Mills, B., Sen, L., and Borella, L.: Reactivity of anti-human thymocyte serum with acute leukemic blasts. J. Immunol., 115:1038-1044, 1975. 13. Murphy, S. B., Borella, L., Sen, L., et al.: Lack of correlation oflymphoblast cell size with presence ofT-cell markers or with outcome in childhood acute lymphoblastic leukaemia. Brit. J. Haematol., 31 :95-101, 1975. 14. Pinkel, D., Hernandez, K., Borella, L., et al.: Drug dosage and remission duration in childhood lymphocytic leukemia. Cancer, 27:247-256, 1971. 15. Price, R. A., and Jamieson, P. A.: The central nervous system in childhood leukemia. II. Subacute leukoencephalopathy. Cancer, 35 :306-318, 1975. 16. Price, R. A., and Johnson, W. W.: The central nervous system in childhood lymphocytic leukemia. I. The arachnoid. Cancer, 31 :520, 1973. 17. Sanyal, S. K., MacGaw, D., and Hughes, W. T.: Continuous negative chest-wall pressure as therapy for severe respiratory distress in an older child: Preliminary observations. J. Pediat., 85:230-232, 1974. 18. Schiffer, C. A., Buchholz, D. H., Aisner, J., et al.: Clinical experience with transfusion of granulocytes obtained by continuous flow filtration leukophoresis. Am. J. Med., 58 :373381,1975. 19. Sen, L., and Borella, L.: Clinical importance oflymphoblasts with T markers in childhood acute leukemia. New Engl. J. Med., 292:828-832, 1975. 20. Simone, J.: Acute lymphocytic leukemia in childhood. Sem. Hematol., 11 :25-39, 1974. 21. Simone, J.: Personal communication. 22. Simone, J. V., Aur, R. J. A., Hustu, H. 0., et al.: Acute lymphocytic leukemia in children. Cancer, 36:770-774, 1975. 23. Simone, J. V., Aur, R. J. A., Hustu, H. 0., et al.: Combined modality therapy of acute lymphocytic leukemia. Cancer, 35 :25-35, 1975. 24. Soni, S. S., Marten, G. W., Pitner, S. E., etal.: Effects of central-nervous-system irradiation on neuropsychologic functioning of children with acute lymphocytic leukemia. New Engl. J. Med., 292:113-118, 1975. 25. Wall, R. L., and Clausen, K. P.: Carcinoma of the urinary bladder in patients receiving cyclophosphamide. New Engl. J. Med., 293:271-273, 1975. Department of Pediatrics Milwaukee Children's Hospital 1700 West Wisconsin Avenue Milwaukee, Wisconsin 53233
Treatment of Acute leukemia
Donald Pinkel, M.D.*
During the past five years it has become clear that a high proportion of children with acute leukemia treated with modern methods are surviving continuously free of leukemia for 5 to 10 years.L 20, 22, 23 They may be cured of their disease. Although a welcome sequel to decades of discouraging effort this improvement has placed an additional burden on physicians. No longer can it be said that the child with leukemia "will die anyway." Now it is necessary to make certain that diagnosis is prompt, evaluation expeditious, and treatment provided where the personnel, programs, and facilities are optimal for achieving lengthy leukemia-free survival and possible cure. Recently an official of the National Cancer Institute was heard to say that treatment ofleukemia required only a good protocol and a physician who adheres to it. No more than a French cookbook makes a French chef or a map a navigator, a set of instructions does not provide expertise in care of children with leukemia. The purpose of this article is to give a current view of the treatment and prognosis of acute leukemia in children rather than to provide a map or teach navigation. The physician who wishes to treat these children must receive specialized training in a modern childhood leukemia center or work in close collaboration with such a center to be certain that his patients benefit from continuing progress. The main portion of this article is devoted to acute lymphocytic leukemia (ALL) which accounts for 78 per cent of childhood leukemia.
*Professor and Chairman, Department of Pediatrics, Milwaukee Children's Hospital, Milwaukee, Wisconsin This manuscript is derived from studies at St. Jude Children's Research Hospital supported by National Cancer Institute grants CA08480, CA07594, CA05176, CA08151, by the American Cancer Society and by ALSAC. The work of the Midwest Childhood Cancer Center is supported by National Cancer Institute grants CA17700, CA17851, CA18602, CA17997, by the American Cancer Society, and by the Faye McBeath Foundation.
Pediatric Clinics of North America-Vol. 23, No.1, February 1976
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.DONALD PINKEL
ACUTE LYMPHOCYTIC LEUKEMIA Diagnosis and Evaluation Although fever; bleeding, hepatosplenomegaly, and lymphadenomegaly usually suggest acute lymphocytic leukemia, some children present only with vague joint pains, unexplained pallor, or slowly resolving infection. Bone marrow aspiration and smear reveal replacement of normal hematopoiesis with lymphoblasts, lymphocytes, and immature unclassified "stem cells" in varying proportions. When the unclassified cells predominate some hematologists prefer to use the terms "stem cell" leukemia or simply acute leukemia. However, for purposes of patient management it is better to include all acute leukemias without clear-cut myelocytic or histiocytic (monocytic) differentiation under the rubric acute lymphocytic leukemia. Meningeal leukemia is diagnosed by study of cytocentrifuge preparations of cerebrospinal fluid, not by cell counts of the fluid. Special care must be taken to differentiate young or transformed lymphocytes and monocytes from leukemia cells. Recently, Sen and Borella have determined that there are 2 types of acute lymphocytic leukemia in children and adolescents (Table 1).19 Approximately 20 per cent of patients have thymic acute lymphocytic leukemia. Their leukemic lymphoblasts form heat-stable rosettes with sheep red blood cells and have two surface antigens characteristic of thymocytes (Fig. 1).12 Usually they are boys and they tend to be older and have high initial white blood cell counts and anterior mediastinal (thymic) masses. 13, 19 Although initially they respond to treatment they are inclined to relapse within a year. The leukemic lymphoblasts of the remaining 80 per cent of children with acute lymphocytic leukemia do not have detectable immunological markers at cell surfaces. These children with "null cell" acute lymphocytic leukemia have an equal sex ratio and tend to be younger and have low initial white blood cell counts. The majority of them remain free ofleukemia after modern treatment. Thus, thymic and "null cell" acute lymphocytic leukemia are not only different in origin and possibly in pathogenesis but also in their clinical features and prognosis.
Table 1. Types of Acute Lymphocytic Leukemia in Children* THYMIC
Median age Sex ratio Median white blood cell count at diagnosis Mediastinal mass Prognosis
"NULL"
9 years llM:1F
4 years: 1:1
53,OOO/mm3
13,OOO/mm3
Frequent Poor
Rare Good
*In thymic acute lymphocytic leukemia the leukemic lymphoblasts form heat stable rosettes with sheep red blood cells and demonstrate thymic antigens. (Data from Sen, L., and Borella, L.: Personal communication.) .
TREATMENT OF ACUTE LEUKEMIA
119
Figure 1. Thymic leukemic lymphoblasts form rosettes with sheep red blood cells that remain stable at 37° C. They also possess antigens specific for thymocytes.
Induction of Complete Remission
"I
After initial diagnosis and evaluation of the patient, induction of remission is an urgent priority. This consists of sufficient eradication of leukemic cells such that normal hematopoiesis returns and no detectable evidence of the disease remains by physical examination or study of peripheral blood and bone marrow. The immediate risks of infection, bleeding, and interruption of normal physiology due to the leukemia are thus reduced. Theoretically more important, "late" leukemia, which can only be palliated by antimetabolites in the mouse (L121O) leukemia model, is converted into "early" leukemia, which is often cured by antimetabolites in the mouse model. For the past 13 years prednisone and vincristine have been the standard combination for induction of remission. Approximately 90 per cent of children with acute lymphocytic leukemia enter complete remission after four weeks of daily prednisone and weekly vincristine therapy. These drugs have several advantages. They have additive antileukemia effects without additive toxic effects, they act rapidly, and they do not produce vomiting, mucosal ulceration, or significant depression of hem atopoietic regeneration like other antileukemia agents. Drugs such as daunorubicin (daunomycin), doxorubicin (adriamycin), or L-asparaginase have been added to this combination in recent years, but there is no proof that they improve the frequency of remissions except in instances where response to prednisone and vincristine is unsatisfactory. On the
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other hand they carry additional risks of toxicity, particularly myelosuppression and immunosuppression. A major reason for their employment during or shortly after remission induction is the possibility that they might reduce leukemia cell mass further than the prednisone-vincristine combination and thus make the leukemia "earlier" and perhaps more susceptible to cure by antimetabolites. Several investigations in progress are designed to test the validity of this hypothesis. The achievement of complete remission, as demonstrated by normal appearance of bone marrow, is the first goal in treatment of acute lymphocytic leukemia.
Preventive Treatment of Meningeal Leukemia Children with acute lymphocytic leukemia who receive combination chemotherapy to continue their remissions will often develop initial relapse in the arachnoid meninges unless specific measures are taken to eradicate leukemia cells in the arachnoid early during remission. I6 The likely reason is the relatively poor diffusion of antileukemia drugs into cerebrospinal fluid. Three methods are used to specifically eliminate arachnoid leukemia cells early in remission and thus prevent arachnoid meningeal relapse: intrathecal administration of methotrexate or a combination of intrathecal methotrexate and arabinosyl cytosine, systemic administration of particularly high doses of antimetabolites in order to achieve higher levels in the cerebrospinal fluid, and irradiation of cranial or craniospinal meninges. 23 Combinations ofthese methods are also used. Thus far only the utilization of craniospinal irradiation or cranial irradiation combined with intrathecal methotrexate have been proved effective in comparative studies that have been published in detail (Table 2).20,22 Transient neurological difficulties can follow cranial irradiation but long-term observation has not yet demonstrated permanent neuropsychological impairment. 24 Careful attention to techniques ofirradiation (Fig. 2) and ofintrathecal drug administration is essential. Systenic 'nethotrexate should be o'nitted during intrathecal administration.
Table 2. Effects of Craniospinal Irradiation in Preventing Weningeal Leukemia':' CRANIOSPINAL
N umber of patients Patients with initial meningeal relapse Patients with continuous complete remission for 5 to 7 years Patients free of leukemia and off therapy 1 to 4 years
IRRADIA TION
NONE
45
49
2
33
23
7
24
18
*In this 1968 to 1970 comparative study 2400 R of .oCo irradiation was administered during the first month of complete remission. Subsequently the patients were continued on combination chemotherapy for up to three years. The results demonstrate the effectiveness of irradiation in preventing meningeal leukemia.
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MULTIMODALITY THERAPY IN PEDIATRIC NEOPLASMS
Figure 2. Cranial radiation port. Each of the lateral ports extends beyond the scalp and includes the meninges of the entire cranium and part of the upper cervical cord as indicated on this localization film. Failure to use adequate ports increases the risk of meningeal relapse.
Continuation Chemotherapy Once complete remission has been achieved so that the leukemia is undetectable and thus "early," and specific measures have been taken to eradicate leukemia cells in the arachnoid, the next goal is to eliminate residual leukemia in marrow, lymph nodes, and viscera in order to cure the "early" leukemia. Multiple drug therapy is most effective for continuing remissions. Maximal dosage is required for optimal effectiveness (Table 3).14 To achieve maximal dosage while minimizing serious toxic hazards, it is Table 3. CO'nparison of Full and Half Dosage Combination Chemotherapy * HALF DOSAGE
Number of patients Median complete remission Median hematological remission
21
FULL DOSAGE
21
6 months
15 months
16 months
33 months
*This 1965 to 1967 study utilized the combination of methotrexate, mercaptopurine, cyclophosphamide, and vincristine for continuation therapy after remission induction. Full, more toxic dosage resulted in longer remissions.
122 I
I
DONALD PINKEL
essential that the patients be examined and their blood cells be counted weekly. Particularly important are inspection of mucous membrane and skin, and neurological evaluation. The total white blood cell count should be kept between 2000 and 3000 per cubic mm with approximately 500 to 1000 phagocytes per cubic mm and 500 to 1000 lymphocytes per cubic mm. Phagocytes include granulocytes and monocytes. In a recent comparative study the combination of methotrexate and mercaptopurine was as effective as the combination of methotrexate, mercaptopurine and cyclophosphamide or of methotrexate, mercaptopurine, cyclophosphamide and arabinosyl cytosine, and was considerably less immunosuppressive (Tables 4 and 5).7,23 In some leukemia centers up to eight drugs are being used simultaneously or in cyclic sequences with a high frequency of prolonged remissions. 4 Further study, particularly comparative investi'gations of key principles and features of the multiple drug regimens, is needed to determine how to achieve the greatest frequency of long lasting remissions and possible cure with least risk and trauma to the child. Cessation of Therapy While patients are receiving combination chemotherapy for acute leukemia they are at increased risk of serious infection, particularly with viruses of the herpes group and protozoa such as Pneumocystis carinii and Toxoplasma gondii. 9, 10 Some patients experience growth inhibition and most demonstrate progressive marrow hypoplasia. With continued methotrexate administration hepatic fibrosis can result, especially when it is prolonged past three to four years. Long-term cyclophosphamide ad ministration can lead to fibrosis of the urinary bladder. The long range carcinogenic effects of antineoplastic drugs may be significant, as
Table 4. Comparison of Four Regimens of Combination Chemotherapy * METHOTREXATE MERCAPTOPURlNE
Number of patients Number ofrelapses Number who died in remission Patients with contiDuous complete remission
METHO-
METHOTREXATE
TREXATE
MERCAPTOPURINE
PHAMIDE
METHO-
MERCAPTO-
CYCLOPHOS-
ARABINOSYL
TREXATE
PURlNE
PHAMIDE
CYTOSINE
20
64
62
62
14
10
16
8
1
0
2
4
5
54
44
50
CYCLOPHOS-
*In this 1972 to 1975 study patients were randomized after remission induction and cranial irradiation plus intrathecal methotrexate. They received maximal tolerated dosage of drugs. Randomization to the methotrexate alone group was terminated early because of frequent leukoencephalopathy. The two drug regimen is as effective as three or four drugs, thus far. (Data from Simone, J. V., and Aur, R. J. A., Personal communication.)
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MULTIMODALITY THERAPY IN PEDIATRIC NEOPLASMS
Table 5. Relative Immunosuppression during Complete Remission by Three Regimens of Chemotherapy * METHOTREXATE METHOTREXATE
MERCAPTOPURINE
METHOTREXATE
MERCAPTOPURINE
CYCLOPHOSPHAMIDE
MERCAPTOPURINE
CYCLOPHOSPHAMIDE
ARABINOSYL CYTOSINE
Normal peripheral blood B lymphocytes per cu mmmean (range)
99 (15-328)
7 (2-27)
3 (0-11)
Frequency of Pneumocystis carinii pneumonia
2/64
7/62
23/62
*The mean levels of B lymphocytes were severely reduced and risk of P. carinii pneumonia increased by use of additional drugs for continuation chemotherapy. (Data from Green, A. A., Sen, L., and Borella, L.: Personal communication.)
already demonstrated for cyclophosphamide, an apparent urinary bladder carcinogen. 25 On the other hand there is no good evidence that combination chemotherapy lowers relapse rate past three to four years, when the relapse rate levels off in patients who have received effective preventive central nervous system therapy with their combination chemotherapy (Fig. 3).1. 20. 23 For these reasons we tend to stop chemotherapy of acute lymphocytic leukemia after 3 years of continuous complete remission. Approximately 15 per cent of patients experience relapse after stopping treatment, predominantly within the first year. 1 Would this rate be reduced by chemotherapy until four or five years? Would the risk of acute or delayed fatal toxicity during the additional one or two years outweigh the possible therapeutic advantage during that period? We do not have the answers to these important questions. After stopping chemotherapy the children usually experience increased appetite and growth rate and may "catch up" for growth lost while on therapy. Hematopoiesis returns to normal in 6 to 12 months after a period of "immunological rebound" the first 3 months. The lymphocytosis and lymphoblastosis of the bone marrow which occur during the immunological rebound can be confused with early relapse of acute lymphocytic leukemia. 3
Curability Are most of the children surviving free of leukemia for four or more years cured of their disease? In Figure 3 the initial continuous complete remissions of children treated with multiple drug chemotherapy and 2400 R of cranial or craniospinal irradiation during the years 1967 to 1970 are plotted on a semilogarithmic graph. One can see that the patients had a constant risk of relapse for two years, a tendency to a reduced rate of relapse for 1 year, an increased risk for the following year (after cessation of chemotherapy), and a relatively slight risk after four years of complete
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DONALD PINKEL
c: 0 'iii
Ul
1.0 0.9
E 0.8 Q) 0::
.....Q) 0.7 Q)
0.
E 0.6 0
u
c: c: 0 :;; '0
0-
e a..
0.5 Therapy Stopped
0.4
Z 2
3
4
5
6
7
8
9
YEARS Figure 3. A semilogarithmic graph of continuous complete remission of 76 patients treated in 1967 to 1970 studies with combination chemotherapy and 2400 R craniospinal irradiation or cranial irradiation plus intrathecal methotrexate. All patients have been followed for 5% to 8 years. There was a steady relapse rate for 4 years followed by a plateau representing reduced risk of relapse. Thus, patients in continuous complete remission for 4 years and off therapy for 1 year appear to be biologically different from those who relapse while on chemotherapy or during the first year off therapy. This difference may represent cure, at least of the cellular phase of leukemia. The current objective of therapeutic innovation is to increase the height of the plateau, i.e., the proportion of patients surviving free of leukemia at low risk of relapse and thus possibly cured.
remission. This suggests that the children represented by the plateau after four years differ from those in the exponential regression curve before four years. This difference might represent eradication ofleukemia cells or cellular cure of their disease. Since a plateau for complete remission of acute lymphocytic leukemia has been established, the main objective of therapeutic m'anipulations now must be the raising of this plateau. No longer can we measure therapeutic success in terms of survival, of hematological remission duration, or of median complete remission. We need to gauge our therapeutic efforts by the proportion of children surviving continuously free ofleukemia and at minimal or no risk ofrelapse, Le., by the height of the plateau of initial complete remission on a semilogarithmic graph.
Toxic Effects of Treatment All patients with acute lymphocytic leukemia who receive adequate therapy suffer toxic effects. This is inevitable. The physician's task is to minimize these effects without compromising treatment any more than necessary. Again, frequent examinations, sensitivity to the subtleties of the patient, awareness of all possible toxic effects, and readiness to adjust drug dosage are essential to good patient care. Every child needs his own physician who provides unified, continuous comprehensive care, who is "tuned in" on the child and his family as well as on the disease and its treatment. When remission induction therapy is initiated, three immediate risks
TREATMENT OF ACUTE LEUKEMIA
125
are metabolic disorder, infection, and bleeding. The most frequent metabolic disorder is hyperuricemia due to rapid destruction ofleukemia cells and subsequent oxidation of released purines. Administration of allopurinol reduces formation of uric acid but not the total purine load to be excreted, so that generous hydration and alkalinization with sodium bicarbonate may also be required to prevent crystallization of xanthine, hypoxanthine, or uric acid in renal tubules. This is particularly true when the patient has large masses of leukemic tissue in the mediastinum, spleen, kidneys, or peripheral blood. Renal infiltration with leukemia can contribute to the metabolic difficulty in the first days of remission induction. Azotemia, hyperkalemia, and hyperphosphatemia are also encountered in these patients. The antileukemia drugs are immunosuppressive so that susceptibility to infection is increased during their administration. Not infrequently the patient who harbors Staphylococcus aureus or Hemophilus influenzae at diagnosis will develop virulent infection with bacteremia shortly after chemotherapy is initiated. The use of broad spectrum antibiotic therapy may lead to serious infections with Escherichia coli, Klebsiella species, Pseudomonas aeruginosa, or Candida albicans. 9 • 11 Although broad spectrum antibiotic therapy may be required for suspected but undiagnosed sepsis, it should not be prolonged. When the organism causing a virulent infection is identified, specific antibiotic therapy should be utilized. Again, the duration of antibiotic therapy needs to be limited. Often it is better to take a relatively small risk of recurrence of infection due to a sensitive organism rather than a greater risk of superinfection with antibiotic-resistant organisms such as Candida or Aspergillus. During complete remission of leukemia, streptococcal and pneumococcal infections are unusual, perhaps because of the antibacterial activity of the antileukemia drugs. There is a high risk of infection due to Hemophilus influenzae, Staphylococcus aureus, coliform bacteria, and fungi. However, the most serious infectious threats are with the large deoxyribonucleic acid viruses such as varicella-zoster and cytomegalovirus, and with protozoa such as Pneumocystis carinii and Toxoplasma gondii. 5 • 9. 10 Prompt cessation of chemotherapy and prophylactic administration of zoster immune plasma (ZIP) or zoster immune globulin (ZIG) will usually minimize the morbidity of varicella. 5 There is no treatment of proven value for these virus infections. Patients with Pneumocystis carinii pneumonia present with fever, cough, chest pain, and tachypnea and have no abnormal auscultatory findings in their chests.1° Roentgenography may be normal initially or demonstrate alveolitis. Typically, capillary or arterial p02levels are low and pC0 2levels normal. Diagnosis is made by methenamine silver nitrate stains of drops of transcutaneous pulmonary aspirate. These patients can be treated with trimethoprim and sulfamethoxazole or with pentamidine isethionate. The use of continuous negative external thoracic pressure appears to improve oxygenation when simple administration of oxygen by mask does not result in improved arterial or capillary p02levels.17 Bleeding in patients with newly diagnosed acute lymphocytic leukemia usually stops after prednisone therapy is initiated. Platelet transfusions are helpful for temporary control of thrombocytopenic bleeding at any time during the course.
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DONALD PINKEL
In addition to immunosuppression, the antileukemia drugs have numerous other toxic effects. Prednisone causes hypertension, sodium retention with edema, hyperglycemia, hypokalemic alkalosis, muscle atrophy, acne, and osteoporosis. Courses of prednisone should be limited to four weeks. Vincristine causes peripheral neuropathy, ineffective erythropoiesis, hypertension, convulsions, ileus, and inappropriate antidiuretic hormone secretion. L-asparaginase causes anaphylactoid reactions, pancreatitis, hepatic dysfunction, hyperglycemia, and coagulopathy. Doxorubicin (adriamycin) and daunorubicin (daunomycin) cause vomiting, diarrhea, mucositis with ulcerations-particularly of the uvula and pharynxhematosuppression, and cardiomyopathy. Methotrexate causes vomiting, diarrhea, mucosal ulceration, megaloblastosis, hepatic damage sometimes leading to hepatic fibrosis, and hematosuppression. More recently it has been recognized that young children receiving large doses of methotrexate intravenously or intrathecally can develop leukoencephalopathy leading to permanent diffuse brain damage. 15 • 22 Mercaptopurine primarily causes hematosuppression and gastrointestinal disorders. The alkylating agents cause vomiting, diarrhea, mucosal ulcerations, and hematosuppression. Cyclophosphamide, in addition, causes urinary bladder hemorrhage and occasionally bladder fibrosis and carcinoma years later. 25 Arabinosyl cytosine (cytarabin e) causes severe emesis, diarrhea, mucosal ulcers, and hematosuppression. Antileukemia therapy is hazardous and difficult on the child, his family, and his nurses and physicians. Only through cautious, gentle, well organized and planned administration by a skilled and spirited team with their own inpatient and outpatient facilities can it be both tolerable and optimally effective.
Prevention of Infection Several relatively simple measures are used to reduce the risks of serious infection in children with acute lymphocytic leukemia. Most important, hospitalization is minimized, not only because of 'the pathogenic organisms in a hospital environment but because of the nonpathogenic but unfamiliar flora in a hospital which can cause virulent infections in these patients. When hospitalization is required, the child is placed in a private room, preferably one with rapid exchange of filtered air and positive air pressure. Strict handwashing by all personnel touching the patient is essential. Intramuscular injections are avoided and skin punctures are preceded by both iodine and alcohol preparations. Intravenous sites-are changed every 24 hours when feasible. Mist tents and other sources of air-borne infection are not used. Visiting is limited and both the child and the room are kept clean. In the clinic it is better to admit the child directly to a clean, well equipped examining room without a sojourn in a waiting room. Again, handwashing is essential before touching the patient. At home, good hygiene and good nutrition are important. Public swimming pools and close contact with animals are avoided. Children
-TREATMENT OF ACUTE LEUKEMIA
127
can attend school if they feel well enough but should be kept out during epidemics of infectious disease, particularly varicella. Live virus vaccines are not administered to children with leukemia until at least one year after being removed from therapy. As mentioned previously, the total white blood cell count is kept above 2000 per cubic mm during complete remission (not during remission induction) with greater than 500 phagocytes per cubic mm and greater than 500 lymphocytes per cubic mm. Unnecessary and prolonged antibiotic therapy is avoided. For household exposure to varicella the susceptible child is given zoster immune plasma or zoster immune globulin and the chemotherapy is discontinued for three weeks or until all pox lesions are dry.4 It is important to regard fever during leukemia as evidence of infection, not a manifestation of leukemia, and to be aware that cerebrospinal fluid pleocytosis may reflect bacterial, viral, fungal, or protozoal meningitis rather than meningeal relapse. Based on animal experimentation and clinical investigation, granulocyte transfusions are being administered to patients with granulocytopenia and infections in many centers. 8 , 18 However, the efficacy of this procedure remains questionable. Expensive, elaborate "life island" methods to protect hospitalized patients from infection are advocated in some centers.2 There is no evidence that these methods are more effective than pre-antibiotic era type room isolation, handwashing, ventilation, and sanitation.
Emotional Support Children with acute lymphocytic leukemia and their families need to feel confident in the physicians and nurses looking after them. A well organized, smoothly operating team consisting of the primary physician and the multidisciplined group at a childhood cancer center is the first essential. Ideally, the primary physician should retain his role in the week to week care of the child in his own community. This provides ready availability of medical care in time of need, reduces disruption of family routine, and gives the child a trusted and familiar advocate in his relationship with his family, neighborhood, and school. The childhood cancer center is required to provide continuing, up-to-date expertise in initial and periodic evaluation, planning and prescription of treatment, consultation to the primary physician, and care of the child during critical periods such as remission induction, radiotherapy, diagnosis and treatment of serious infections, and solving of specific metabolic, toxic, or psychological problems. Even at the center each child needs to be assigned to a specific staff physician who can become familiar with the child, the family, and the primary physician in the community. Children should be told their diagnosis by their parents or by the physician in the presence of their parents. Their questions need to be answered honestly but with gentleness and tact. Not just the mother but the father and siblings need to participate in the management ofthe child with leukemia. Some families require specialized attention for their psychological, spiritual, and social needs. The physician must select carefully the professional personnel who attend to these needs. I
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DONALD PINKEL
If it becomes apparent that the child in relapse will not regain remission status it is important to formulate with the family plans for terminal care. For many families the death of the child is better conducted at home or in a community hospital. Most families and patients accept death courageously if they have had ample opportunity to discuss their feelings with each other and with a trusted physician throughout the course of the disease. Financial burdens can add unnecessary distress to families of children with acute lymphocytic leukemia. Childhood cancer centers and primary physicians caring for the children should not request compensation from their families beyond that provided by third party payers or granting agencies. The payers and agencies, on the other hand, should support the centers and the physicians adequately so that they can provide optimal services. A nation that supports Las Vegas and the Department of Defense can certainly afford it.
TREATMENT OF ACUTE MYELOCYTIC, ACUTE MYELOMONOCYTIC, AND ACUTE HISTIOCYTIC (MONOCYTIC) LEUKEMIA With present methods it is possible to induce complete remission in 65 to 70 per cent of children with acute nonlymphocytic leukemia. 6 Some methods combine two or more hematosuppressive and antimucosal drugs such as mercaptopurine or its analog thioguanine, arabinosyl cytosine (cytarabine), cyclophosphamide, daunorubicin (daunomycin), or doxorubicin (adriamycin).4 Prednisone is often added for its nonspecific hemostatic effect and vincristine for whatever antileukemia effect it may offer. Combined hematosuppressive and antimucosal chemotherapy in patients who already have deficiencies in platelets and normal granulocytes often results in severe neutropenia, lymphopenia, thrombocytopenia, and mucositis. Life threatening infection, bleeding, and severe emesis and diarrhea often ensue during the remission induction procedures. Some patients are lost before they have the opportunity to benefit from the medications by regeneration of normal hematopoiesis and achievement of complete remission. Hospitalization is often required throughout the four to eight weeks of remission induction and intensive supportive care is needed for infection and bleeding. A relatively gentle method of inducing remission is used by some leukemia therapists. This consists of daily intravenous administration of 6-Azauridine, an antimetabolite that does not damage normal hematopoiesis and mucous membrane, for 10 days.6 Accompanying this the patients receive weekly vincristine and daily mercaptopurine in moderate dosage for four to six weeks. The remission induction rate in children is approximately the same as for the more toxic methods but the morbidity and mortality from treatment are less. Patients with acute myelocytic and myelomonocytic leukemia and acute histiocytic or monocytic leukemia do not usually develop hyperuricemia after therapy although some may present with it. How-
129
TREATMENT OF ACUTE LEUKEMIA
ever, they do experience complications not seen in patients with acute lymphocytic leukemia. For example, children with acute myelocytic or myelomonocytic leukemia sometimes bleed because of coagulopathies not related to platelet deficiency. Patients with acute histiocytic or monocytic leukemia often suffer from hypoalbuminemia, edema, and hemolytic anemia. Continuation of remission is much less successful with acute myelocytic and acute histiocytic leukemia than with acute lymphocytic leukemia. Combinations of two or more drugs are used in sequential or simultaneous treatment schemes. Arabinosyl cytosine, mercaptopurine or thioguanine, and daunorubicin or doxorubicin are the most frequently used. The combination of cyclophosphamide and doxorubicin appears especially effective in histiocytic neoplasms. The same basic principles for prevention and treatment of infection , control of toxicity, and supportive care are used as in care of patients with acute lymphocytic leukemia. Meningeal relapse often terminates complete remission in children with acute myelocytic leukemia. 6 As with acute lymphocytic leukemia, it appears that the longer patients remain in complete remission the higher is the frequency of cerebrospinal fluid leukemia. Intrathecal methotrexate, arabinosyl cytosine, or both are used in treatment of meningeal acute myelocytic leukemia but improvement is temporary. Data from studies in progress suggest that meningeal relapse of acute myelocytic and myelomonocytic leukemia can be prevented by craniospinal irradiation early in remission. 21 Only 5 per cent or less of patients with acute nonlymphocytic leukemia remain in continuous complete remission more than three years. Experimental approaches to acute myelocytic leukemia include marrow transplantation from tissue-matched donors and immunological stimulation with BCG vaccine. Neither is of established value.
COMMENT Basic and clinical research are required to identify the causes and mechanisms of acute leukemia so that it can be prevented or treated with more specific agents. In the meantime we need to continue exploratory and comparative studies of leukemia therapy with currently available measures. Approximately one half of children with acute lymphocytic leukemia are experiencing long-term, leukemia-free survival and possible cure with best present methods oftreatment in skilled hands. Every child with acute lymphocytic leukemia should have the opportunity for cure. REFERENCES 1. Aur, R. J. A., Simone, J. V., Hustu, H. 0., et aI.: Cessation of therapy during complete remission of childhood acute lymphocytic leukemia. New Engl. J. Med., 291 : 1230-1234, 1974. 2. Bodey, G. R.: Isolation for the compromised host. J.A.M.A., 233:543-545, 1975.
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3. Borella, L., Green, A. A., and Webster, R. G.: Immunologic rebound after cessation oflongterm chemotherapy in acute leukemia. Blood,40:42, 1972. 4. Clarkson, B. D., Dowling, M. D., Gee, T. S., et al.: Treatment of acute leukemia in adults. Cancer, 36:775-795, 1975. 5. Feldman, S., Hughes, W. T., and Daniel, C. B.: Varicella in children with cancer: Seventyseven cases. Pediatrics, 56:388-397, 1975. 6. Fleming, I., Simone, J., Jackson, R., et al.: Splenectomy and chemotherapy in acute myelocytic leukemia of childhood. Cancer, 33:427-434, 1974. 7. Green, A. A., Sen, L., and Borella, L.: Immunologic aspects of acute lymphocytic leukemia (ALL): Is ALL a disease of lymphoid cells? In Sinks, L. F., and Godden, J. O. (eds.): Conflicts in Childhood Cancer. New York, Alan R. Liss, Inc., 1975, pp. 56-65. 8. Higby, D. J., Yates, J. W., Henderson, E. S., etal.: Filtration leukapheresis for granulocyte transfusion therapy. Clinical and laboratory studies. New Engl. J. Med., 292:761-766, 1975. 9. Hughes, W. T.: Fatal infections in childhood leukemia. Am. J. Dis. Child., 122:283,1971. 10. Hughes, W. T., Price, R. A., Kim, H. K., et al.: Pneumocystis carinii pneumonitis in children with malignancies. J. Pediat., 82:404, 1973. 11. Hughes, W. T., and Smith, D. R.: Infection during induction of remission in acute lymphocytic leukemia. Cancer, 31 : 1008, 1973. 12. Mills, B., Sen, L., and Borella, L.: Reactivity of anti-human thymocyte serum with acute leukemic blasts. J. Immunol., 115:1038-1044, 1975. 13. Murphy, S. B., Borella, L., Sen, L., et al.: Lack of correlation oflymphoblast cell size with presence ofT-cell markers or with outcome in childhood acute lymphoblastic leukaemia. Brit. J. Haematol., 31 :95-101, 1975. 14. Pinkel, D., Hernandez, K., Borella, L., et al.: Drug dosage and remission duration in childhood lymphocytic leukemia. Cancer, 27:247-256, 1971. 15. Price, R. A., and Jamieson, P. A.: The central nervous system in childhood leukemia. II. Subacute leukoencephalopathy. Cancer, 35 :306-318, 1975. 16. Price, R. A., and Johnson, W. W.: The central nervous system in childhood lymphocytic leukemia. I. The arachnoid. Cancer, 31 :520, 1973. 17. Sanyal, S. K., MacGaw, D., and Hughes, W. T.: Continuous negative chest-wall pressure as therapy for severe respiratory distress in an older child: Preliminary observations. J. Pediat., 85:230-232, 1974. 18. Schiffer, C. A., Buchholz, D. H., Aisner, J., et al.: Clinical experience with transfusion of granulocytes obtained by continuous flow filtration leukophoresis. Am. J. Med., 58 :373381,1975. 19. Sen, L., and Borella, L.: Clinical importance oflymphoblasts with T markers in childhood acute leukemia. New Engl. J. Med., 292:828-832, 1975. 20. Simone, J.: Acute lymphocytic leukemia in childhood. Sem. Hematol., 11 :25-39, 1974. 21. Simone, J.: Personal communication. 22. Simone, J. V., Aur, R. J. A., Hustu, H. 0., et al.: Acute lymphocytic leukemia in children. Cancer, 36:770-774, 1975. 23. Simone, J. V., Aur, R. J. A., Hustu, H. 0., et al.: Combined modality therapy of acute lymphocytic leukemia. Cancer, 35 :25-35, 1975. 24. Soni, S. S., Marten, G. W., Pitner, S. E., etal.: Effects of central-nervous-system irradiation on neuropsychologic functioning of children with acute lymphocytic leukemia. New Engl. J. Med., 292:113-118, 1975. 25. Wall, R. L., and Clausen, K. P.: Carcinoma of the urinary bladder in patients receiving cyclophosphamide. New Engl. J. Med., 293:271-273, 1975. Department of Pediatrics Milwaukee Children's Hospital 1700 West Wisconsin Avenue Milwaukee, Wisconsin 53233