CURE AS THE AIM IN THERAPY FOR THE ACUTE LEUKÆMIAS

473

Occasional

Survey

CURE AS THE AIM IN THERAPY FOR THE ACUTE LEUKÆMIAS A. S. D. SPIERS Medical Research Council Leukæmia Unit, Royal Postgraduate Medical School, London W.12

Until quite recently the objective of chemotherapeutic regimens in the acute leukæmias was to achieve remission. The purpose of this review is to suggest that by using aggressive cyclic chemotherapeutic regimens allied with prophylaxis to avoid central-nervous-system involvement it is now possible to aim at cures, or at least at remissions for 5 years or more after treatment is stopped. Sum ary

indefinite remission maintenance. Skipper and his colleagues 18 demonstrated a cytokinetic basis for the chemo-

therapeutic curability of a transplanted murine leukaemia, whereby the progress of the untreated disease could be expressed in terms of the total-body burden of tumour cells, and the effect of each dose of antileukxmic agent in terms of the absolute number-of cells destroyed. Cue implied the destruction of every tumour cell. Although the cytokinetics of human leukaemias almost certainly differ in detail, therapeutic approaches based on the Skipper model have been successful in terms of extended survival. The main innovation of this fourth therapeutic era in acute leukamia is one of outlook: instead of skilful palliation, aimed at prolonging comfortable survival but accepting relapse and death as inevitable, therapy is planned from the outset with the aim of total disease eradication. Attempts are being made to destroy all the leukasmic cells by aggressive chemotherapy with curative intent. 11 Another approach, as yet unproved, is the attempted elimination of residual leukxmic cells by immunological means.19 PRESENT STATUS OF TREATMENT

FOR THE ACUTE LEUKaeMIAS

INTRODUCTION

four partially overlapping in the therapy of the acute leukxmias:

HISTORICALLY, there eras

are

Before Introduction of Specific Antileukaemic Chemotherapy Despite supportive therapy with blood-transfusion and antimicrobial agents, the median survival from diagnosis about 2-2 months for children and adults.1 Rar( spontaneous" remissions occurred, 2, but could not b( deliberately induce.4,5 was "

Induction of Disease Remission This was first achieved in 1948 with the folate antagonist aminopterin.6 Remission was associated with significant lengthening of survival in both children and adults and in lymphoblastic and acute myeloid leukaemias.7-10 Late! more drugs were developed and treatment schedules were improved for inducing leukaemic remission in an everincreasing proportion of patients. Today, a first remission is obtained in about a half of adults with acute myeloid leukaemias and in 94% of children with lymphoblastic

leukaemia.ll,12z

Improved Techniques for Remission Maintenance Maintenance chemotherapy prolonged remission,?, 13, 14 and increased duration of remission was shown to be with longer survival in lymphoblastic leukxmia.12 The association was also evident in acute Maintenance therapy has myeloid leukxmias, 3,10,12 become accepted, and has evolved from single drugs administered sequentially, or in predetermined cycles, to the use of drug combinations. Its intensity has increased from the use of maintenance doses smaller than those given to induce remission, to full dosages, to the practice of highdose maintenance treatment, sometimes called " consolidation " or " cytoreduction " therapy. Comparison of programmes for remission maintenance requires large numbers of patients and lengthy follow-up. Although an optimal " maintenance therapy cannot be specified, undoubted progress has been made,"’,12,115 and median survivals of 33 months in childhood lymphoblastic leukaemia 16 and 6 months in adults with acute myeloid

strongly associated

"

leukaemias 17 are now commonplace. The disappointingly small improvement for adults is attributable to persistently high death-rates in the first few weeks from diagnosis, and to the brief duration of remissions despite maintenance

therapy. Attempts at Cure Although the cause of acute leukxmia remains unknown, therapeutic progress has prompted attempts at cure as a logical extension of the earlier phase, where the aim was

Therapeutic

progress has been

unequal

in the

leukaemias. Acute myeloid leukxmia, comprising myeloblastic, myelomonocytic, monocytic, and erythroleukasmic subvarieties, and principally affecting adults, remains a refractory group with a low remission-rate and short survival-time. Therapeutic effort is aimed at increasing the remission-rate and achieving more effective remission maintenance. Childhood lymphoblastic leukaemia, on the other hand, is now in the third and fourth phases of therapeutic development-attempts at indefinite remission maintenance or outright cure. Already there are indications that attempts at cure are achieving limited success: deliberate cures in acute leukaemia, though still uncommon, are much more frequent than the chance different

cures

acute

of former years.

MEANING OF CURE IN ACUTE LEUKaeMIA

Cures not Attributable to Special Efficacy of Therapy In 1968, Burchenal 20 collected 157 cases of long survival with acute leukaemia, many of the patients had had no treatment for years and seemed to be cured. No common factor such as age, cytological type of leukxmia, or therapeutic approach was discernible. Many of the widely varying treatments were inadequate by present standards-e.g., a single brief The patients course of cortisone or corticotrophin. were apparently a minute fraction of those surveyed, and hundreds receiving similar treatments have relapsed and died. Evidently such cures are chance events, attributable to the nature of the disease in particular patients and not to any special feature of the treatment. Cures of this type are so rare that their occurrence has not altered median survival or prognosis in acute leukaemia. There is no evidence that these chance cures are becoming more common, and, unfortunately, their study has not suggested how other patients might be cured. However, the study showed that patients in remission 5 years after diagnosis had a 50% chance of not relapsing, and that after 10 years the chance of relapsing was negligible. It is not known whether patients kept in remission for 5 years by intensive therapy have the same chance of not relapsing as the inadequately treated long-term survivors.

474

Deliberate Therapeutic Cure No definition of therapeutic cure in acute leuksemia has been generally accepted, but disease-free survival for 5 years after treatment stops could be prima-facie evidence of cure. A regimen producing this result in as few as 5% of a large series of patients would seem to have curative capabilities, since the incidence of chance cures is certainly less than 1%. Late recurrences of disease after 5 years off therapy are difficult to interpret-are these relapses or inductions of a second leuksemia in a susceptible individual ? Followup of patients remaining disease-free for 5 years without maintenance therapy should disclose whether they are indeed " cured " or merely experiencing exceptionally long remissions. EVIDENCE OF CURE IN CHILDHOOD LYMPHOBLASTIC LEUKAEMIA

Krivit and his colleagues 21 followed up 229 children treated with moderately intensive chemotherapy in a cooperative trial begun in 1963. 15 children (6-5%) had experienced continuous remission for 30-40 months when maintenance chemotherapy was discontinued in 8 and continued in 7. In the next two years, bone-marrow relapse occurred in 1 patient from each group, and 1 patient in the no-therapy group developed leukasmic infiltration of one testis. 12 patients were still in remission 54-64 months from diagnosis. The similar relapse-rate in each group suggests that in many children maintenance therapy is unnecessary after lengthy continuous remissions. Eradication of the leukaemia would best explain this

finding. Pinkel and his group at Memphis have obtained striking results in several series of children with lymphoblastic leukxmia.22-24 In 31 children remission was induced with vincristine and prednisone, and a short course of high-dosage methotrexate, mercaptopurine, and cyclophosphamide in sequence was followed by craniospinal irradiation to 1200 rad. Thereafter continuous maintenance therapy with methotrexate, mercaptopurine, cyclophosphamide, and vincristine was given.22 Therapy was stopped after 24-33 months of continuous " complete " remission (i.e., haematological and other systems apparently clear of disease). Follow-up 23 showed a median survival of 35 months. More important, 5 of the 31 patients had been free of all manifestations of leukaemia for 66 to 76 months, having had no treatment for 42-43 months. No patient had relapsed after treatment was withdrawn. This remarkable result-a 16% 5-year cure-was unaltered at further follow-up 6 months later.24 Thus, some patients are in remission 6 years from diagnosis, though none has yet had 5 years off therapy. Since the craniospinal irradiation did

affect the incidence of central-nervous-system (c.N.s.) leukxmia in this study, more effective prophylaxis should further improve results, because c.N.s. leukaemia terminated " complete " remission in over half the patients in a median time of 11 months.25 The development of overt c.N.s. leukaemia, even though not

bone-marrow remission persists, probably means that a patient is no longer curable. In a further series,25 cranial irradiation (2400 rad) plus intrathecal methotrexate (five doses of 12 mg. per sq.m.) substantially

reduced the incidence of c.N.s. leukaemia, and median " complete " remission duration lengthened from 15 months 23 to more than 25 months.25 Because of the reduced incidence of c.N.s. leukaemia, if the haematological remission pattern in this series follows that of earlier series 23 a 50% leukaemia-free 5-year survival is to be expected.26 Although these results are encouraging, irradiation and intrathecal drug therapy have significant side-

effects, including possible c.N.s. damage. 27 Prolonged aggressive systemic chemotherapy has risks: deaths from infection during complete remission are disturbing,23.25 and some patients cannot complete the full programme of irradiation and chemotherapy. The excellent results in terms of 5-year " cures " have some bias, since patients eligible for evaluation are already a selected group by virtue of having completed the entire treatment protocol. Whilst admitting the hazards of long-continued combination chemotherapy, less aggressive regimens are significantly inferior in the long term,28 and, despite more intensive chemotherapy, analysis has not shown a significant secular increase in needs for supportive therapy with blood products. 29 Prophylactic c.N.s. irradiation seems essential, since doses which are effective prophylaxis have been shown to be inadequate for the eradication of established c.N.s. leukaemia.26 INDICATIONS FROM PRESENT EVIDENCE

Precise interpretation of evidence from small numbers of cases is not possible, but tentative conclusions may be drawn:

(1) A 5-year " cure " can be achieved in at least onesixth of children with lymphoblastic leukaemia: recent developments suggest that the figure may be one-half. (2) This cure-rate seems certain to be due to therapy, unlike the isolated cures of the past. (3) Maintenance of an initial, continuous, " complete " (haematological plus C.N.S.) remission for 2-3 years is necessary. Exactly how long maintenance therapy is required is uncertain. (4) Long-term aggressive combination chemotherapy seems the best means of achieving this objective. (5) Effective prophylaxis of c.N.S. leukaemia will increase the proportion of patients achieving 3-year complete remissions. Absolute proof of cure is not yet available, but this

only because the more intensive therapeutic regimens are of relatively recent advent.30 Unfortunately, present evidence permits no conclusions about possible cure of acute myeloid leukaemias in children, nor about cure of any type of leukaemia in adults. With current therapy, 3-year complete remis-

may be

sions

are rare

in these diseases and there has been little

to test the possibility. Nevertheless, it is to plan and to carry out therapeutic trials in

opportunity

reasonable these diseases

on the assumption that the same principles apply, and the main therapeutic effort in this unit is directed toward the acute myeloid leukaemias. We are treating a group of children with lymphoblastic leukaemia according to the programme summarised in the figure and reviewed in detail elsewhere.ll Three drug combinations are used: cyclophosphamide / vincristine / cytarabine / prednisolone (C.O.A.P.),3 prednisolone / vincristine / methotrexate mercaptopurine CP.O.M.P.),15 and cytarabine / aspara-

475

Ommaya reservoir

A.L.L. programme

At the time when the

at

Hammersmith Hospital.

Ommaya reservoir is inserted 90%

ginase / daunorubicin / thioguanine (C.A.R. T .).11 These combinations exploit known synergies between various antileukxmic drugs, avoid excessive overlap of drug toxicities, and ensure the early and repeated exhibition of every first-line drug. No drug is reserved to treat relapse; the programme is cure-oriented, not relapseoriented. Treatment is given in 5-day pulses with 9-day treatment-free intervals, so for nearly twothirds of the time the patient receives no drugs. The side-effects of vincristine and corticosteroids are mild with this regimen. Most children are admitted to hospital for only the first one or two courses of C.O.A.P. therapy; once in remission a fortnightly outpatient visit is sufficient. Since intramuscular injections

(cytarabine, methotrexate, asparaginase) are given at home by the family doctor, district nurse, or parents, patients living at a distance can be managed. During remission, the doses of antileukxmic drugs can usually be increased well beyond those tolerated initially. Despite this aggressive chemotherapy, continued for 36 months from the induction of remission, the children attend school full-time and some are at the head of their classes. After remission induction, an Ommaya subcutaneous cerebrospinal fluid (c.s.F.) reservoir is inserted via an occipital burr hole.32, sDrugs injected into the reservoir pass into the lateral cerebral ventricle, allowing intrathecal therapy without lumbar puncture. Fortnightly injections, methotrexate alternating with cytarabine, are given for 120 weeks 34; such treatment would be difficult without the c.s.. reservoir. Since drugs intrathecally administered cannot reach leukxmic cells within the cerebral substance or in less accessible parts of the subarachnoid space, C.N.S. prophylaxis includes the administration of 2400 rad (linear accelerator) to the intracranial contents and 1200 rad to the spinal cord. The high incidence, serious manifestations, and high relapse-rate of established C.N.S. leukaemia fully justify this aggressive approach to clinically undetectable C.N.S. involvement. COMMENT

The early part of this programme is exacting, involving two hospital admissions, a neurosurgical operation, and radiotherapy producing severe but reversible alopecia. Subsequent treatment is not distressing to the patient or parents; only twenty-six hospital visits are made each year, and interference with normal life is minimised. Neither unacceptable

of

patients

are

in remission.

nor parental distress has necessitated withdrawal of any of our present small series of patients from the programme. Because this study only began in 1970, no patient has yet had 36 months’ continuous complete remission, at which stage therapy will be discontinued. Although no patient has developed meningeal leukasmia or bonemarrow relapse, 1 child has infiltration of the optic chiasm, requiring further radiotherapy. It will require several years to evaluate results properly in these patients, but evidence from other sources 22-26 suggests that they will be significantly better than those obtained with older, palliative therapeutic approaches.

morbidity

Radiation therapy in our patients is supervised by Dr. L. Szur. The Ommaya reservoirs were inserted by Mr. J. L. Firth, Institute of Neurology, London. REFERENCES 1. Tivey, H. Ann. N.Y. Acad. Sci. 1954, 60, 322. 2. Southam, C. M., Craver, L. F., Dargeon, H. W., Burchenal, J. H.

32. 33.

Cancer, 1951, 4, 39. Freireich, E. J., et al. J. chron. Dis. 1961, 14, 593. Bierman, H. R., Cohen, P., McClelland, J. N., Shimkin, M. B. J. Pediat. 1950, 37, 455. Wetherley-Mein, G., Cottom, M. Br. J. Hæmat. 1956, 2, 25. Farber, S., Diamond, L. K., Mercer, R. D., et al. New Engl. J. Med. 1948, 238, 787. Freireich, E. J., Gehan, E., Frei, E., et al. Blood, 1963, 21, 699. Karon, M., Freireich, E. J., Frei, E., et al. Clin. Pharmac. Ther. 1966, 7, 332. Wolff, J. A., Brubaker, C. A., Murphy, M. L., et al. J. Pediat. 1967, 70, 626. Ellison, R. R., Holland, J. F., Weil, M., et al. Blood, 1968, 32, 507. Spiers, A. S. D. Clins Hæmat., 1972, 1, 127. Henderson, E. S. Sem. Hemat. 1969, 6, 271. Selawry, O. J. Am. med. Ass. 1965, 194, 75. Colebatch, J. H., Baikie, A. G., Lee, C. W. G., Clark, A. C. L., Lewis, I. C., Jones, D. L., Newman, N. M. Lancet, 1968 ii, 869. Frei, E., Freireich, E. J. Adv. Chemother. 1965, 2, 269. Henderson, E. S., Samaha, R. J. Cancer Res. 1969, 29, 2272. Henderson, E. S. Ann. intern. Med. 1968, 69, 628 Skipper, H. E., Schabel, F. M., Wilcox, W. S. Cancer Chemother. Rep. 1964, 35, 1. Mathé, G Clins Hæmat. 1972, 1, 165. Burchenal, J. H. Cancer, 1968, 21, 595. Krivit, W., Gilchrist, G., Beatty, E. C. J. Pediat. 1970, 76, 138. George, P., Hernandez, K., Hustu, O., et al. ibid. 1968, 72, 399. Pinkel, D. J. Am. med. Ass. 1971, 216, 648. Pinkel, D. Personal communication. Aur, R. J. A., Simone, J., Hustu, H. O., et al. Blood, 1971, 37, 272. Aur, R. J. A., Simone, J., Hustu, H. O., Verzosa, M. S. Cancer, 1972, 29, 381. Lancet, 1972, i, 297. Pinkel, D., Hernandez, K., Borella, L., et al. Cancer, 1971, 27, 247. Simone, J. V. ibid. 1971, 28, 562. Clarkson, B. D., Fried, J. Med. Clins N. Am. 1971, 55, 561. Whitecar, J. P., Bodey, G. P., Freireich, E. J. Proc. Am. Ass. Cancer Res. 1970, 11, 83. Ommaya, A. K. Lancet, 1963, ii, 983. Ratcheson, R. A., Ommaya, A. K. New Engl. J. Med. 1968, 279,

34.

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1025. A. S.

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