The Acute Leukemias

CURRENT THERAPEUTIC CONCEPTS

The Acute Leukemias

By Douglas G. Christian, William A. Camelis and Clarence L. Fortner

T

he leukemias are a group of related malignant diseases character-· ized by (1) quantitative and morpho-. logic alterations in the peripheral blood white cells and in the precursors of the affected white cell series in the bone marrow and by (2) secondary anemia, granulocytopenia and thrombocytopenia due to leukemic cell infiltration of the bone marrow and crowding out of normal myeloid elements. Untreated, the patient ultimately succumbs to progression of the disease, infection and! or hemorrhage. The approximate incidence of leukemia is 6.5 cases per 100,000 population; approximately 40 percent of the total in-· cidence are acute varieties of leukemia. Leukemias will be responsible for an estimated 15,000 deaths this year with 2,000 victims being children under 15 years of age. There is generally an acute and a chronic form of leukemia for each main type of white cell, and the varying histories and clinical courses of these diseases allow that each may have a different pathogenesis. Although theories of the etiology of leukemias and scattered case reports describe infective (viral) agents, genetic factors and chemical (or environmental) inducers, the fact remains that no etiology other than high-dose radiation exposure has been proven for any of the human leukemias. Anyone of the above agents could, however, alter genetic structure, and predisposition to the disease by this means is feasible. Acute and chronic forms of leukemia are defined by expected length of survival after diagnosis, which is

closely related to the morphology of the predominating white cell. Immature cells in the peripheral blood exhibit less than optimal normal, activity for their type, and leukemic cells, by virtue of structural and biologic er-· rors in development, are even less effective. It is not surprising, therefore, that prognosis of the various types of leukemias depends on the stage of white cell maturation at which the malignancy has centered. In general, the less mature the predominating cell type, the worse the prognosis. Acute leukemias are detected by a high percentage of very immature forms of the white cell series involved, in the peripheral blood and bone marrow. The prognosis for untreated acute leukemias is a lifespan of two to three months or less. Chronic leukemias, in contrast, would be expected to permit a lifespan of two to five years uno. treated, and the predominating white cell would be a more mature form. Classification

Besides the general division of leukemias into "acute" and "chronic" categories, it is necessary to subclassify the disease in terms of white blood cell morphology, as each type responds differently to treatment. Acute lymphocytic leukemia, for instance, responds to therapy with a much greater degree of success than acute myelocytic leukemia. There are five series of white blood cells and each follows a similar pathway of maturation, deriving from a "blast" cell (itself arising from a fixed-·

tissue reticulum cell) and progressing through histologically defined stages to the mature form, which is then released into the bloodstream (Figure 1, page 475). The normal percentage distribution of the white cell types in peripheral blood is described in Table I (page 476). In circumstances of physiologic stress, it is not uncommon for the less mature leukocyte forms to appear in the peripheral blood. The very primitive blastic stage of white cell, however, should not be present in the pe-· ripheral blood, and its appearance in-· troduces clinical suspicion of leukemia. The diagnostic process necessarily includes complete history, physical examination, peripheral blood studies and bone marrow sampling to differentiate leukemias from other possible The purpose of Current Therapeutic Concepts is to present to the practicing pharmacist up-to-date information 'on the treatment of commonly encountelred disease states. Some background on the pathology, etiology and diagnosis of these diseases is also presented so that therapeutic concepts discussed can be placed into a clinical perspective. These articles are not intended to be reviews of current literature but rather as a source of continuing education for the pharmacist. The series was originally initiated and is currently coordinated by Eric T. Herfindal, PharmD, and Joseph L. Hirschman, PharmD, assistant clinical professors of pharmacy at the University of California school of pharmacy at San Francisco.

Vol_ NS12, No_ 9, September 1972

473

The Baltimore Cancer R esearch Center (BCRC) is a fifty-bed chemotherapy research branch of the National Cancer In titute. Located in .. Public Health Service Hosthe pital, Baltimore, Maryland, BCRC contracts for many of the supportive ser ices of the hospital but has its own staff of research clinicians and maintains its own specialty services including outpatient clinic, intensive care unit, platelet and granulocyte transfusion service labs, microbiology laboratories, pharmacology laboratories, and clinical pharmacy and nursing services. Th e Patient Care Pharmacy Service (P PS) provides unit-of-use dispensing and intravenous admixture programs, preparation of all investigational drug doses, computerized medication profiles and the spectrum of consultative and surveillance services needed to assure accurate and efficacious use of potent drugs required 'in this clinical research institution. Studies currently underway at BCRC involve treatment of various solid tumors, brain tumors, testicular and ovarian carcinomas, lymphomas includin g Hodgkins disease, and leukemias.

causes of peripheral leukocytosis and occurrences of atypical white blood cell. Some of these causes include toxic bone marrow stimulation by chemical (eg, lead), aplastic anemias, certain viral diseases including infectiou mononucleosis, tissue destruction and the normal granulocytic response to infectio n. At diagnosis , the actual white cell count may be within normal limit, depre ed or elevated. If sec-· ondary anemia is present, it may be of the normocytic, normochromic type or macrocytic, normochromic type. Acute lymphocytic leukemia (ALL), a hown in Figure 1, is defined by proliferation within the lymphocytic erie. This disease, especially in children aged two to 19 years, has begun to yield to therapeutic advances. Several drugs , in specified dosage ranges and treatment regimens to be di cu sed, can be expected to prolong the life of 20 percent of childhood ALL patients for five or more yeClJrs. Acute myelocytic leukemia (AML) involves the precursors of the granulocytes or polymorphonuclear leukocytes. Relative to discussion, therapeutic considerations and prognosis, AML is often grouped with acute monocytic leukemia (AMOL) and acute myelomonocytic leukemia (AMML). The three entities together are referred to as acute nonlymphocytic leukemia (ANLL). ANLL has responded much less dramatically to therapeutic attempts than has ALL, with median survival for all treated 474

Douglas G. Christian is deputy chief, Patient Care Pharmacy Service, National Cancer Institute (NCI), Baltimore Cancer Research Center (BCRC), USPHS Hospital, Baltimore, Maryland, and is a commissioned officer of the U.S. Public Health Service. He earned the BS in pharmacy degree from University of the Pacific at Stockton, California, in 1968. Christian is a member of the American Pharmaceutical Association, American Society of Hospital Pharma. cists, Kappa Psi and Rho Chi.

William A. Cornelis is a staff pharmacist, Patient Care Pharmacy Service, NCI, BCRC, USPHS Hospital, Baltimore, Maryland, and is a commissioned officer of the U.S. Public Health Service. He received his BS in pharmacy from Wayne State University in 1970. Cornelis is a member of the American Pharmaceutical Association, American Society of Hospital PharmaCists and Rho Chi.

Clarence L. Fortner is chief, Patient Care Pharmacy Service, NCI, BCRC, USPHS Hospital, Baltimore, Maryland, and a commissioned officer of the U.S. Public Health Service. He is a clinical assistant professor at the University of Maryland school of pharmacy. Fortner received his BS in pharmacy at the University of Tennessee college of pharmacy and MS in pharmacology at ur School Medical Sciences. His memberships include the American Pharmaceutical Association, American Society of Hospital Pharmacists and Maryland Society of Hospital Pharmacists.

ANLL patients about six months. Nonresponders survive an average of 2.5 months and those whQ respond to treatment may expect an average twelve-month survival. Clinical Course

The presenting symptomatology of patients with acute leukemia varies greatly but usually can be referred to the underlying disorders of the disease. D isplacement of normal elements from the bone marrow by neoplastic cells leads to anemia, thrombocytopenia and granulocytopenia. Symptoms referrable to these conditions would include the possibilities listed in Table II (page 476). Fever and weight loss can be ascribed to increased metabolic activity of the bone marrow tissue. Many signs of organ infiltration are absent in the acute forms of leukemia, but lymphadenopathy and splenomegaly are not uncommon. These clinical findings are vague at best, and diagnosis must always be based as mentioned on complete evaluations, including bone marrow studies. Because the patient can often relate these symptoms to more benign disorders he has previously experienced, tentative diagnosis of leukemia is often made upon blood studies drawn for less specific purposes. Whichever cell type is prevalent, there are many factors which will in-, fluence the clinical course of a patient with an acute leukemia. At diagnosis,

Journal of the AMERICAN PHARMACEUTICAL ASSOCIATION

these factors include the age and general condition of the patient (presence or absence of other underlying conditions such as diabetes, cardiovascular disease or impaired renal or hepatic function) and the interval from onset of symptoms to diagnosis and treatment. Occurrence of septicemia while the patient's immune response is compromised and toxicity of the vigorous treatment regimen will greatly affect the progress of treatment. The greatest factor in successful therapy, however, is achievement of the state of "complete remission" (CR), wherein all symptoms of the disease including peripheral blood and bone marrow ap-· pearance are normalized. The treatment leading to remission status from clinical disease is termed "induction." Although undetectable by current methods, leukemia stem cells undoubtedly linger even when the patient is in complete remission. Treatment which is given during remission in an attempt to destroy newly activating leukemic oells is termed "maintenance." "Reinduction" courses will be necessary to treat each successive relapse, or return of active disease, which is recognized by return of symptoms and of "blasts" in the bone mar·, row. Complete remission status infers functional as well as morphologic normalization, and the patient in remission is no longer subject to abnormal hemorrhagic r,isk or the greatly lowered resistanoe to infection. It is established that increased survival for a re-

FIGURE

1

White Blood Cell Series Maturation Sequence (The names of malignant proliferative diseases which can be associated with each cell type are indicated in parenthesis and italics.) Tissue Reticulum Cell (Reticulum Cell Sarcoma)

1

"Hematopoietic Stem Cell"

?""''''''~

Plasmablast

Myeloblast (Acute Myelogenous "Granulocytic" Leukemia)

Lymphoblast (Acute Lymphocytic Leukemia)

Proplasmacyte (Myeloma)

Promyelocyte (Acute Progranulocytic

Prolymphocyte (Subacute Lymphocytic Leukemia)

/U"k.ml")~ Eosinophilic Myelocyte

Neutrophilic Myelocyte (Chronic Myelogenous Leukemia)

Monoblast (Acute Monocytic Leukemia)

Megakaryoblast

Megakaryocyte

Basophilic Myelocyte

Mature Plasma Cell (Myeloma)

=======Metamyelocyte Eosinophilic =

Neutrophilic = Metamyelocyte

Basophilic Metamyelocyte

Eosinophilic Band Cell

Neutrophilic Band Cell

Basophilic Band Cell

Eosinophilic Segmented Granulocyte

Neutrophilic Segmented Granulocyte

Basophilic Segmented Granulocyte

Mature Lymphocyte (Chronic Lymphocytic Leukemia)

Monocyte

Thrombocyte "platelet"

NOTE-The Double Horizontal Line represents the marrow/blood barrier, and cell types listed below it would be found in the normal peripheral blood. (See Table I for normal percentage distributions)

mitting patient is very comparable to the total time spent in complete remission. Thus, therapy of acute leukemia has been aimed at (1) achievement and maintenance of remission (s), and (2) supportive therapy during granu-· locytopenic and thrombocytopenic phases before remission can be induced. One reason that acute nonlymphocytic leukemias have responded less to therapeutic efforts than the acute

lymphocytic variety may be that inducing remission in ANLL requires a more lengthy and profound marrow aplasia before new, normalized myeloid elements reappear. Therefore, morbidity due to infection and bleeding during the induction period is higher in ANLL than ALL. The granulocytopenia seen in ALL is only secondary to marrow-crowding and competition for nutrients by the abnormal lymphoid elements. Chemo-

therapy directed against lymphocytic precursors allows relatively rapid recovery of the granulocytic (myelocytic) precursors remaining after treatment. In ANLL, the malignant myeloid precursors are the target of chemotherapy, so suppression of that series of WBCs is more profound. Survival during this compromised period may reflect, again, on the age and general condition of the patient as lymphoblastic malignancy occurs Vol. NS12, No.9, September 1972

475

~

TABLE I

TABLE II

The Normal Differential White Blood Cell Count

Clinical Symptoms From Leukemic Replacement of Normal Bone Marrow Elements

Total neutrophils Segmented neutrophils (polys) Band cells Metamyelocytes Lymphocytes Monocytes Eosinophils Basophils Blasts (of any type)

50-70% 50-70% 3-5% 0-1% 2(}-40%

0-7% 0-5% 0-1% 0-0% Total white cell count is in the range of 5000 to 10,OOO/cubic millimeter, with considerable normal variation. Of this number, the above percentage distribution of cell types is normal in the peripheral blood.

largely in a very young (i.e., more immunologically resilient) patient population. This does not adequately account for the large disparity between achievement of successful first complete remission inductions in acute lymphocytic leukemia (currently 9095 percent in some series of children) and in acute nonlymphocytic leukemia (favorable reports list complete remission rates of 50 to 65 percent). Chemotherapy seems to exhibit less activity against ANLL than ALL. In both diseases, duration of each succeeding remission tends to be pro-· gressively shorter, though exceptions are noted. Present figures for median survival amongst childhood ALL patients achieving at least one complete remission averages 36 months. Among adult ALL patients, survival averages 18 months. Comparable data for ANLL patients in a series from the Baltimore Cancer Research Center lists median survival at 11.5 months. Leukemic cell infiltration of many organs and tissues of the body (bowel, liver, spleen, lymph nodes, kidneys, bone marrow and subcutaneous lesions) presents little morbidity in acute varieties of leukemia if the leukemic cell line is responsive to therapy. Central nervous system (CNS) involvement, however, is a serious and not uncommon development. Ultimately but not acutely life-threatening is the fact that the CNS can be a reservoir for leukemic cells (not reached by therapeutic agents which cannot cross the blood-brain barrier) and may give rise to systemic relapse. Another CNS leukemic involvement of concern is development of meningeal leukemia. This CNS leukemic proliferation can occur independently of bone marrow condition and indeed may arise and progress while the patient is in bone marrow and peripheral blood remission. This complication has become more prevalent in all varieties of leu476

Anemia

Thrombocytopenia

Granulocytopenia

Fatigue Pallor Shortness of breath Headache Tachycardia

Conjunctival and fundal hemorrhages Gingival hemorrhages Gastrointestinal bleeding (emesis or melena) Renal hemorrhages (blood in urine) Petechiae; ecchymosis Purpura Subarachnoid hemorrhages

Infection (fever and/or chills) "Flu" symptoms; frequent or prolonged colds

kemia as their respective survival times have lengthened. Meningeal leukemia can be treated with varying degrees of success by intrathecal administration of methotrexate or cytosine arabinoside and! or external irradiation of the spinal column and brain. Neurologic manifestations of CNS leukemia may be minimal or flagrant but symptoms of increased intracranial pressure and cranial nerve palsies are reason for concern. Leukemic cells which have infiltrated or proliferated in the CNS can be identified by lumbar puncture and cerebrospinal fluid (CSF) sampling, followed by Cytocentrifuging® and examining a preparation of the resultant material. CSF samples as well as bone marrow and peripheral blood samples become important in moni-· toring progression of the disease as well as success of treatment, especially in the later stages. Leukemic cell infiltration of intracerebral alveolar structures (rather than the meninges and subarachnoid space) may occur, especially when peripheral white cell counts exceed 200,000 cells/mm. s Intracerebral intravascular plugging, with increased local pressure on vessel walls, is a critical situation predisposing to intracranial hemorrhage and must be treated vigorously. At pres-· ent, effective means of lowering the very high peripheral white cell levels are available in the form of hydroxyurea. Available Modalities of Treatment In all malignant conditions, therapy may utilize one or more of the follow-· ing agents-surgery, ionizing irradiation, immunotherapy or chemotherapy. In leukemias, surgical excision of the tumor tissue is impossible, which relegates this modality to a minor supportive role. Irradiation also has a supportive role in antileukemic therapy, particu-. larly in reducing the size of an infit.tra-

Journal of the AMERICAN PHARMACEUTICAL ASSOCIATION

tive leukemic mass. This is useful when functional impairment of some organ or vessel has occurred, or when pain is the result of marrow hyperactivity (ie, sternal tenderness) or leukemic infiltration in an area such as a joint. Irradiation is also used to de .. crease numbers of proliferating leukemic cells when they occur in the CNS. Immunotherapy has received some attention in recent years with the demonstration of specific tumor antigenic sites in two cancerous states, Burkitt's lymphoma and choriocarci.. noma. BCG vaccine is being investigated clinically as a means of rallying the body's total immune response (after a patient has achieved remission). Specific active immunotherapeutic response may be feasible if a viral agent is proven as the etiology of the disorder or if specific "foreign tissue" antigenic sites are described for other tumors and responsive antibody stimulation can be developed. To date, successful treatment of the acute leukemias has rested almost entirely on chemotherapy. Briefly, the history of antileukemic chemotherapy began with demonstration of the lympholytic properties of adrenocortical steroids in 1947 and extrapolation of this activity of prednisone and prednisolone to acute leukemia in 1949. Development of antineoplastic drugs has been steady since that time. Attrition has left us with fewer than ten drugs presently in common use against acute leukemias. Many of the basic pharmacologic and pharmacokinetic! pharmacodynamic characteristics of these are still being investigated, while clinical use of the agents has produced therapeutic advances. We have mentioned that science has pot yet elucidated the e~ternal agent or biologic errors which cause leukemias. Because of this, many theories, pro· posals and models of antileukemic

Glossary Anemia-reduction below normal of the number of erythrocytes in the blood Aplasia-lack of development of a tissue; also complete suppression or failure of development Aplastic-pertaining to or characterized by aplasia; having no tendency to develop new tissue Granulocyte-any cell containing granules, especially a leukocyte containing neutrophilic, basophilic or eosinophilic granules in its cytoplasm Leukemia-neoplastic disease of the white cell forming tissue of the bone marrow Lymphocytic Leukemia-associated with bone marrow hyperplasia and overactivity within the lymphocytic series Acute Lymphocytic Leukemia-predominant leukocytes are Iymphoblasts; synonyms-ALL, (acute) lymphoblastic leukemia Myelocytic Leukemia-associated with bone marrow hyperplasia and overactivity within the myeloid series (also known as the granulocytic series) Acute Myelocytic Leukemia-predominant leukocytes are myeloblasts, usually of the neutrophilic series; synonyms-AML, (acute) myeloblastic leUkemia, acute granulocytic leukemia Lymphoid-pertaining to lymphatic tissue; for purposes of this paper, the lymphocytic series of leukocyte Myeloid-pertaining to, derived from, resembling bone marrow; especially the myelocytic series of leukocyte -Osis-suffix denoting an abnormal increase in the number of the type of cell named in the root word; examples-leukocytosis, thrombocytosis -Penia-suffix from the Greek indicating "poverty"; a relative decrease in the number of the type of cell named in the root word; examples-leukopenia, thrombocytopenia Thrombocyte-blood platelet

chemotherapy were developed in an empiric manner. Progress to date represents refined extrapolation of the original principles, plus a tremendous effort to demonstrate in well-controlled clinical trials the added benefit or toxicity of each proposed improvement, whether in drug moiety or schedule of drug administration.

Concepts Relative to Chemotherapy Understanding antineoplastic chemotherapy requires exposure to the concepts of cytotoxicity in general, as modified by the principle of selective toxicity when antineoplastic agents are used in a tumor-bearing human. In addition, supportive therapy is important in all malignant conditions but has even greater significance for the course and prognosis of a patient with acute leukemia. Modern growth-kinetic studies have disproved the concept of the leukemic cell population as a runaway prolific body. Analogous to growth of a bacterialcolony, as the leukemic cell pop-' ulation expands and nutrient supplies dwindle, rate of growth seems to "plateau." Henderson has thus described leukemic cell populations as "self-renewal systems which, though they march to a different drummer, depend , upon external stimuli and internal mechanisms similar to other living tissues." It is worthwhile to review the cell

cycle as it is depicted by Figure 2, (page 478). This description applies to both normal and malignant cells. The portion of the cycle labeled "D" represents cellular division (mitosis). "G 1 " (which is also referred to as "Go" in chemotherapy literature) is a resting phase, until recently considered to be relatively quiescent. The "S" phase is that of active DNA synthesis, which is followed by "G2 ," another resting phase. The S, G 2 , and D phases are relatively fixed periods of time for a given cell population, and if rate of division (length of the average cell cycle) varies, it is usually the G 1 phase which accommodates. When cells stop proliferating and come to rest, they do so in the G 1 phase and when proliferative activity is high the G 1 may become very short. Certain aspects of RNA production are known to occur during the G 1 phase, but it is not known how a cell receives the bio-, logic message to proceed to DNA synthesis. In a malignant body of cells, the immediately premitotic event of spindle formation and the cell division, as well as the S-phase of DNA replication necessary for r!!production of the cell line, have been the specific targets of antineoplastic chemotherapy. Drugs which act at these or some other defined phase of cell life are called cyclespecific. Drugs, for which no phase specificity has been demonstrated are also effective and are designated cyclenonspecific. The classification is rela-,

tive rather than absolute. Antileukemic chemotherapeutic approaches must take advantage of very subtle differences in rate of growth and cellular metabolism between the leukemic cell population and the patient's normal tissues. Both irradiation and chemotherapeutic drugs are basically toxic or injurious to all cells, and selectivity of response depends on the vulnera:bility of malignant vs. normal cells. Cycle-specific drugs tend to be more effective in 1 apidly proliferating t~s­ sues, where their incorporation into disruptive cytotoxic events will kill maximal tumor cells with minimal ef-, fect on normal cells. Predictably, toxic manifestations of most antineoplastic drugs are borne by normal tissues (i.e., the bone marrow, gastrointestinal mucosa, skin and hair fol, licles) in which the rate of cell division approaches or exceeds that of the malignant tissue under treatment. In antileukemic chemotherapy, toxicity to certain elements of the bone marrow is the object of treatment, but the need for careful titration of dosage is obvious. Recalling the mechanisms of drug activity above, remission induction involves lysis of the many immature leukocytes present in their peripheral circulation and bone marrow. Maintenance phases are designed to suppress only those newly-proliferating leukemic stem cells (in an otherwise normal hematologic state) before they cause relapse to clinical disease. Though exceptions exist, cell cycle-specific drugs are generally used in induction, while cycle-nonspecific drugs are most effective in maintenance. The timing of sequential doses of chemotherapeutic agents to catch larger numbers of neoplastic cells in their susceptible phase is of clinical importance. Like normal tissues, leukemic cell lines do not exhibit synchronized division. That is, at a given moment, different cells within the leukemic cell population are in different phases of their individual cycle. As such, only a percentage will be vulnerable to the effects of a cycle-specific drug while that drug is present in an active form in the body. The experience to date has shown that combinations of agents which produce qualitatively different toxicities can produce additive and perhaps synergistic increases in remission induction rate and remission duration. The 'ldministration of combinations of antineoplastic drugs in some cancers has two cytotoxic objectives. The first is to combine drugs which act at different points of the cell cycle and thus expose a larger percentage of the cancerous cells to the drug when they are in a susceptible state. Secondly (analVol. NS12, No.9, September 1972

477

ogous in many respects to theories of antimicrobial therapy) is to expose u ceptible cancer cell to toxic effects by many mechanism as possible to uppr elective emergence of cell train which are re i tant to further th rapy. With the addition of each drug in a propo ed combination regimen everal consideration must be made- 1) I the tumo~ type unif rmly nd reliably usceptible to one drug or doe resistance to repeated ther py occur? (2) Does the propo ed combination produce additive t xicity t particular normal tissues, or re the combined expected toxicities pread t different organs of the body? (3) I n effective dose of one drug r all drug ) in the combination influ nced by concomitant or subsequent admini tration of the other drugs? (4) I the effective do age schedule of nc drug (or all drugs) in the combination altered qy administration of the ther drug? As can be seen, complexity f the variables involved in combination antineopla tic chemotherapy dictate that this approach b'e undertaken by physicians with the backgr und and ufficieI1t laboratory and

supportive facilities to monitor results of drug administration. ntileukemic Drugs In Use The two drugs of choice when used ingularly in acute lymphocytic leukemia are prednisone (Pred) and vincristine sulfate (VCR). The average successful complete remission (CR) rates with either approach is 50 percent. Other age~ts can produce the following CR rates when used in ALL: L-Asparaginase (L-ASP; investigational) 45 percent, daunorubicin (daunomycin DMN; investigational) 40 percent, 6-mercaptopurine ( 6-MP) 36 percent, methotrexate (MTX) 31~100 percent (the latter on a schedule of intermittant massive infusion). Methotrexate administered daily, cyclophosphamide (CTX) and cytarabine (arabinosyl cytosine ARA-C) are less effective but do demonstrate some activity when used alone against ALL. Several 2-, 3-, and 4-drug combinations are in current use against acut~ lymphocytic leukemia. Prednisone and vincristine together produce CR rates near 88 percent. It can be seen

FIGURE 2

The Mitotic Cell Cyc'e

M ITOSIS D

/ .......... -

-

--:--

S

DNA PRODUCTION

478

J o urn~1 of the AMERICAN PHA RM ACE UT ICA L ASSO CI ATIQN

",.

./

/

I G..:

that this figure is better than for either agent used alone, but is not equal to or greater than the additive CR rates of the two drugs used alone. Other 2drug combinations and their respecti ve expected CR rates are as followsPred and 6-MP, 78 percent; Pred and DMN, 65 percent; Pred and CTX, 52 percent. Many others have been tried which do not exhibit better CR rates than the constituent drugs when used alone. A 3-qrug combination of Pred, VCR and DMN has produced CR rates above 95 percent, and in a specific dose schedule py Mathe and coworkers (Lancet, 2, 380, 1967) a CR rate of 100 perce.n t was reported. This combination is not in widespread use because daunorubicin is still investigational, and because the drug has a very narrow therapeutic margin. The doses and schedule for administration of the 4-drug combination known as "POMP" (for prednisone, On'covin or vincristine, methotrexate, and Purinethol or 6-mercaptopurine) is in common use acro~s the nation and produc~s CR rates approaching 95 percent. In acute nonlymphocytic leukemia the results are less gratify,ing, though progress has been mad~. Prednisone, so effective as a single agent against ALL, produces complete remissions in only 15 percent of AML cases. Daunorubicin, however, will produce CR rates of up to 50 percent. Arabinosyl cytosine produces CR rates varying from 20 to 45 percent (or higher) depending on dose, schedule of administration and th~age of the patient. Expe~ted CRs with other agents when used alone in AML are-VCR, 36 per-, cent (one study; patients, mostly children); 6-MP, 11 percent; MTX, 10 percent. CTX and L-:ASP are active but less effective. ' . Compared to success of single-drug chemotherapy against AML, some of the combination regimens
TABLE III

Drugs in Current Use Against Acute Leukemias Drug Name

Pharmacologic Category

CycleSpecificity

Mechanism of Action

Outstanding toxitities and Side Effects

AppHcati!ln in Acute Leukemias

L-Asparaginase (investigational)

Enzyme

Unknown

Depletion of endogenous extracellular asparagine

Multiple defects in protein synthesis; clotting abnormalities, hypoalbuminemia Hepatic and pancreatic toxicities Allergic response

ALL remission induction. Intrathecal use in eNS leukemic infiltration

Cyclophosphamide

Polyfunctional alkylating agent

?Nonspecific

Requires in viVO' activation; believed to act by crosslinking macromolecules including DNA

Nausea and vomiting Myelosuppression Chemically-induced sterile hemorrhagic cystitis Alopecia

ALL remission induction

Cytarabine Pyrimidine analog (Ara binosyl cytosine; cytosine arabinoside)

Specific

Nausea and vomiting Interferes with conversion of cytidylic to deoxycytidylic Myelosuppression acid; inhibits DNA synthesis Hepatic dysfunction Esophagitis

AML and ALL remission induction and maintenance Intrathecal use in CNS leukemic infiltration

Daunorubicin (Daunomycin; rubidomycin) (investigational)

Antibiotic

Unknown

Inhibition of RNA and DNA synthesis

Nausea and vomiting Myelosuppression Cardio toxicity

AML and ALL remission induction only

6-Mercaptopurine

Purine analog

Specific

Inhibition of purine synthesis; inhibition of DNA synthesis

Nausea and vomiting Myelosuppression Hepatic dysfunction Stomatitis Diarrhea

ALL remission induction and maintenance

Methotrexate

Folic acid antagonist Specific

Inhibits activity of enzyme dehydrofolate reductase; interferes with synthesis of tetra hydrofolic acid, a coenzyme necessary in metabolic translormations in the production of DNA

Myelosuppression Oral and gastrointestinal ulceration Hepatic dysfunction Alopeda Dermatitis

AML and ALL remission induction and mairltenance Intrathecal use in CNS leukemic infiltration

Prednisone, Prednisolone

Adrenocortical steroids

?N onspecific

Direct lysis of lymphoid tissue. Psychoses ALL remission induction Acute hypertension, peptic ? inhibition of DNA synthesis ulcer, fluid retention, immunosuppression, etc. Osteoporosis

6-Thioguanine

Purine analog

Specific

Inhibition of purine synthesis; inhibition of DNA synthesis

Nausea and vomiting Myelosuppression Hepatic dysfunction Stomatitis Diarrhea ..

ALL remission induction and maintenance

Vincristine S04

Vinca alkaloid

Specific

Disruption of mitotic spindle formation. Inhibition of RNA and DNA synthesis

Peripheral neurop,.athies Paralytic ileus Alopecia

ALL remission inductio n

Pharmacologic mechanisms, como, manly encountered toxicities and the clinical applications of current antileukemic drugs are Listed briefly in Table III (see above). Further information can be obtained from selected references listed at the conclusion of this paper. One exception to those drugs which act by some interference with cell division is that of L-asparaginase, which will be discussed briefly because of its historic interest. Development of this agent followed discovery that some leukemic cells did not have the capacity to synthesize thei'r own require·, ments of the amino acid, L-asparagine. These cells utilized circulating aspar-

agine produced by other cells. It was postulated that sensitive leukemic cells could be starved out if endogenous asparagine was eliminated, and it was shown that the enzyme asparaginase from bacteria (especially E. Coli) inhibits replication of susceptible leukemiccells in vitro and in vivo. This is an apparent effect of catalyzing hy.. drolysis of L-asparagine in the blood and extracellular fluid. Asparaginase thus exploits a difference in metabolic requirements between leukemic and normal cells. Theoretically, L-asparaginase should be the most specific cytotoxic drug available to date, less toxic to normal tissues, especially those of the hematopoeitic system. Because

of this potential for relative marrowsparing specificity, it was investigated in combination chemotherapy with myelotoxic drugs. . Unfortunately, the specificity of the drug does not appear as great as postulated. Evidetice has accumulated to suggest that some leukemic cells can produce sufficient asparagine for survival and that normal tissue may in contrast be damaged. Hepatic toxicity is of particular concern at present. Allergic responses have also been frequent. The drug has proven more effective in ALL than AML and those complete remissions inuuced by L~ asparaginase have been of relatively short duration. Although the experiVol. NS12, No.9, September 1972

479

ence to date with L-asparaginase has been disappointing, the approach is promising and future developments along similar lines may evolve clinically effective agents.

Supportive Therapy As has been stressed, terminal pathology of the acute leukemias has been associated in many cases with two morbid states, infection and hemorrhage. Hyperuricemia and resultant urate nephropathy was formerly a third complication which may now be largely circumvented. As recently as 1959, hemorrhages were responsible for nearly 67 percent of deaths from acute leukemias. Many of these were generalized hemorrhages, although the greatest percentage were pulmonary hemorrhages associated with pneumonias. Other difficulties included bleeding into the subarachnoid space and into the gastrointestinal tract. Complex coagula-· tion problems exist in these patients, but the greatest cause of secondary hemorrhage is an insufficient quantity of platelets due to leukemic crowding of platelet precursors (megakaryocytes) or myelosuppression by chemotherapy. Freshly collected platelets obtained from whole blood or plasmapheresis techniques are able to maintain effective levels of circulating platelets when given by transfusion. Since this procedure became available in 1961, the percentage of hemorrhagic deaths in acute leukemias has dropped from 66.8 percent to 37.2 percent, as discussed by Hersh et al. (see Recommended Readings). The category most greatly affected has been that of generalized (systemic) hemorrhage. Half-life of transfused platelets is approximately 24 to 48 hours in the thrombocytopenic recipient. Repeated infusions are thus necessary as dictated by circulating platelet levels, until the patient's marrow regains the ability to sustain platelet counts above a hemostatic level. This requires adequate blood banking facilities with relatively great platelet sources. Infections in the granulocytopenic patient continue to be a serious prob-, lem. The number of leukemic deaths precipitated by infection has remained at 70 percent. Since deaths due to hemorrhage have been reduced in proportion to the total over the past few years, it is reasonable that figures for infections may have been inflated in spite of the numerous advances in antibacterial chemotherapy during the same period. Due to effective suppression of some species, the pattern of infective organisms involved has been altered quite drastically. With 480

the use of penicillinase-resistant antibiotics, incidence of fatal staphylococcal infection has dropped from 23.5 percent to 3.1 percent of those deaths due to infection. Decrease in prevalence of this organism has been supplanted in turn by Pseudomonas aerugenosa, Escherichia coli and Klebsiella sp. In an attempt to reduce morbidity due to these three species of bacteria, the Baltimore Cancer Research Center currently employs a "triple-antibiotic" regimen consisting of intravenous carbenicillin disodium, gentamicin sulfate and cephalothin sodium. Because progression of a septicemia or pneumonia is so rapid in the immunologically compromised patient, our protocol states that the above drugs shall be started at the first sign of systemic infection in granulocytopenic patients. Cultures of suspected sites of origin plus blood, urine, stool, nose, gingiva and axilla are taken at the time the antibiotics are begun. Once the cultures from a patient become available, drugs can be altered to suit the sensitivities as determined by disc and tube-dilution methods. With relative success of this and similar antibacterial regimens, Enterobacter sp., Klebsiella sp., group D streptococcus and Candida sp. (moni-, Iia) appear on the upswing. Treatment of infections in the acute leukemic patient promises to continue as a therapeutic challenge. Effective prophylaxis against infection would provide more reasonable therapeutics than treating infections when they occur. Current investigation along this line is evaluating reo. verse isolation (isolating the patient from contact with bacteria from exogenous sources) in programs at several institutions with the aim of protecting the patient from nosocomial microorganisms as well as protecting him prophylactically from opportunis-, tic invasion by his own normal flora. The latter frequently occurs with gastrointestinal lesions, including hemorrhoids, as the portal of entry. In very stringent approaches, "life island" and laminar air flow (LAF) rooms place the patient in a virtually sterile environment. Supplies are sterilized before being passed to patients confined in these units, uncooked foods are avoided and contamination from all sources (including drug prod-· ucts) must be considered. In addition, topical flora of the patient's body is suppressed by rigid hygienic efforts, and flora of the gastrointestinal tract by administration of oral, non absorbable antibiotics (nystatin, gentamicin and vancomycin). BCRC is conducting a controlled study utilizing laminar-,air flow rooms in conjunction with the oral nonabsorbable antibiotics. The group of patients treated on this

Journal of the AMERICAN PHARMACEUTICAL ASSOCIATION

program will be compared against those with the same disease (ANLL) maintained in the usual hospital environment, with and without the oral antibiotics. Another rational prophylactic measure and means of supportive treatment against infection in granulocytopenic patients would seem to be the transfusion of granulocytes from donors. This approach has not been investigated on a controlled basis because until recently the procedure presented several technical problems. Elaborate selective centrifuging techniques have been unsuccessful in yielding great enough numbers of granulocytes to effectively transfuse, Red cells and platelets can be obtained in pure fractions for transfusion be·· cause their specific gravities and other physical characteristics allow successful filtration, sedimentation and centrifugation procedures. Leukocytes are relatively few in number in the prospective donor (red cells: platelets: 500: 20: 1) and are interleukocytes mediate in size and specific gravity. Thus, collected leukocytes have gen .. erally been contaminated with the other two formed elements. A new plastic wool filtering device (Leukopak, Baxter Laboratories) is currently under investigation and hopefully will yield much higher numbers of viable cells, It should be emphasized that efficacy of LAF protection, the oral nonabsorbable antibiotic regimen and granulocyte transfusion has not been determined though controlled studies are now in progress for this purpose, There may well be major toxic reactions to orally-administered gentamicin, vancomycin and nystatin (ie, acquisition and infection with Pseudomonas sp. after discontinuing these drugs) or the Leukopak (ie, shaking chills and liver function abnormalities in the donor after return of blood), As with all experimental trials, these and other reactions as yet undetected may eventually lead to abandonment of the described procedures. Anemia, as a result of leukemic crowding of red cell precursors in the marrow, chemotherapeutically-induced aplasia or hemorrhage can be treated by transfusion of packed red cells or whole blood. Hyperuricemia and resultant obstructive urate nephropathy can result from the increased nucleoprotein production of large numbers of neoplastic cells. The problem is compounded when chemotherapy produces lysis of large numbers of tumor cells and release of their contents. Degradation of the purine byproducts of these nucleoproteins to the final metabolite, uric acid, is mediated by the enzyme xanthine oxidase, Administration of

=

L

the xanthine oxidase inhibitor allopurinol interferes with the process at this point, leaving purine degradation products in the form of xanthines, which are more soluble metabolic precursors of uric acid. Prevention of hyperuricemia, a nearly inevitable consequence of the leukemia and its treatment, is much more satisfactory than treating urate nephropathy once it occurs. Additional measures utilized in prevention and treatment of hyperuricemia, with differing degrees of success, include adequate hydration of the patient, and alkalinization of the urine with sodium bicarbonate or acetazolamide to favor solubility of uric acid. Routine use of allopurinol, recognizing its possible untoward effects, can circumvent the problem in most cases. Clinical Monitoring of Chemotherapy Having noted the clinical course of acute leukemias, the concepts relative to antineoplastic chemotherapy and supportive therapy, it is obvious that this patient population requires intensive surveillance efforts by all health professionals concerned with their care. The drug therapy each patient receives lis the specific end result of diagnostic procedures, clinical evalua·, tions and efforts to minimize toxicities, side effects and complicating secondary problems. The pharmacist, utilizing support of current medication profiles and accurate dispensing records (including intravenous drugs and fluids), is in an excellent position to review all aspects of the patient's status. Surveillance efforts relative to chemotherapy are directed at the emergence of toxic effects, side reactions and drug interactions of clinical sig-' nificance and adherence to rational utilization of antineoplastic drugs. "Rational utilization" is a relative term in this instance, since the optimal doses, dosage schedules and the complete indications for most of the antineoplastic drugs are not yet fully known. Effective doses for these agents in a given disease state may in fact be much different from the dosage range expressed in the product literature. Balanced against this is the fact that the drugs are not completely selective for neoplastic cells and exhibit a narrow therapeutic margin. The effectiveness of many antineoplastics is measured by appearance of their toxic effects,and the doses prescribed are often titrated against "tolerable" levels of adverse effects, especially against hematopoietic tissues. With respect to drug interactions, this delicate balance assumes special significance. If the biologic availability of antineoplastic agents is

enhanced, or their metabolism or excretion inhibited the danger of increased toxicity should be readily apparent. To date, few reported drug interactions involving cancer chemother-, apeutic agents have been well documented. A working understanding of the pharmacology of the drugs involved and the mechanisms which are plausible for a suspected potential interaction is invaluable to the pharma-, cist, who should expect to do some reasonable extrapolation from those principles. The pharmacist who is interested in monitoring effects of these drugs in patients will have to be familiar also with laboratory indices, especially those concerning bone mar-, row function, peripheral blood counts and coagulation parameters. Additionally, hepatic and renal function can be reviewed. With respect to renal function ,in leukemic patients it should be remembered that as systemic infection occurs, several antibiotics (including all those of the aminoglycoside class) might be needed and can themselves produce acute tubular necrosis. When decreased renal function is noted, doses of gentamicin sulfate may be adjusted on the basis of serum creatinine values. Evaluation of the dinical situation might suggest similar alterations for other drugs the patient is taking which are normally excreted in active forms in the urine. Electrolytes and acid-base balance can be monitored as indicated. In addition to their leukemia, these patients present a normal cross-section of other medical problems, including hypertension, diabetes, congestive heart failure, etc. Treatment for these conditions must continue, but the pa-, tient should be observed carefully for adverse response in the face of chemo-, therapy. Steroids used to lyse neoplastic lymphoid tissue, for example, may aggravate or precipitate a diabetic condition. Drugs used for treating underlying problems will have their contraindications and toxicities and adequate monitoring can avoid additive complications of these and the antineoplastic drugs.

Conclusion The acute leukemias are malignancies of the white blood cell-forming tissue of bone marrow. Chemotherapy, administered in sequential or concomitant doses of combinations of toxic drugs may prolong the useful life of the victim if complete, though temporary, remission of the disease is achieved. Side effects of the treatment regimens and complications of the disease are severe, and success in

achieving remission status is variable. Nearly 95 percent of children with ALL and approximately 50-60 percent of adults with ANLL will achieve complete remission, extending their useful life up to five years and one year or more respectively. Thus, significant progress has been noted and hopeful avenues of research have been opened to investigation. More selective cytotoxic agents, improved techniques to limit infection as a complication of treatment, and approaches utilizing specific active immunotherapy will be goals of future development. It is anticipated that for several years to come, effective induction therapy of acute nonlymphocytic leukemias will of necessity be restricted to specialized treatment centers where supportive facilities can adequately serve the needs of the patient. Wellevaluated therapeutic regimens and more completely elucidated apprecia-, tion for possible complications allows the successful chemotherapy of acute lymphocytic leukemia in children in conventional medical facilities. Through multifaceted surveillance efforts, assurance of an accurate and well-documented drug delivery system and constant involvement in the clinical area with patients, physicians and nurses, the pharmacist can serve a vital function in direct care of those pa-, tients being treated for acute leukemias . •

Recommended Reading 1. Goodman, L.S., and Gilman,

A.,

editors,

The Pharmacologic Basis of Therapeutics, 4th ed"

MacMillan Company, New York, 1344

(1970) W., editor, Drugs of Choice 19722. Modell, 1973, C.V. Mosby Company, St. Louis, 556 (1972) 3. Bernard, J,; Jacquillat, C.; Wei!, M., "Treatment of the Acute Leukemias," Seminars in Hematology, 9, 2, 181 (April 1972) 4. Goldin, A.; Sandberg, J.S.; Henderson, E.S.; Newman, J.W.; Frei, E.; Holland, J,F., "The Chemotherapy of Human and Animal Acute Leukemia," Cancer Chemotherapy Reports Part I, 55, 4, 309 (November 1971) 5, Henderson, E., "Treatment of Acute Leukemia," Seminars in Hematology, 6, 3, 271 (July 1969) • 6. Hersh, E.M.; Bodey, G.P,; Nies, B.A., and Frei
Acknowledgments The authors would like to express their gratitude to Dr. Peter H. Wiernik, chief, Medical Oncology, Baltimore Cancer Research Center, National Cancer IMtitute, National IMtiMes of Health, and Dr. Stephen Schimpf!, acting assistant chief, Medical Oncology, BCRC, NCI, NIH, for their thoughtful comments in reviewing the manuscript.

Vol. NS12, No.9, September 1972

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