1980 55: 199-204   

 GA Omura, S Moffitt, WR Vogler and MM Salter randomized central nervous system prophylaxisCombination chemotherapy of adult acute lymphoblastic leukemia with

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Blood, Vol. 55, No. 2 (February), 1980 199

Combination Chemotherapy of Adult Acute Lymphoblastic LeukemiaWith Randomized Central Nervous System Prophylaxis

By George A. Omura, Steven Moffitt, W. Ralph Vogler, and Merle M. Salter (Writing Committee

for the Southeastern Cancer Study Group)

Although major progress has been made in the treatment of childhood leukemia. the optimal chemotherapy of acutelymphoblastic leukemia (ALL) in adults has been unclear. In addition. the value of central nervous system prophylaxis(CNS-P) in adults has been assumed. but not established in a systematic fashion. The Southeastern Cancer Study Grouphas completed a prospective study in which the use of vincristine plus low-dose methotrexate and high-dose prednisone in

adult acute Iymphoblastic leukemia has produced an 80% (79/99) complete remission rate in patients age 1 5 yr and over.

Younger patients had a significantly higher remission rate but no increase in remission duration. This induction regimenwas associated with minimal toxicity. Random assignment to CNS-P or to no prophylaxis. after a multidrug consolidationregimen. has demonstrated a significant prolongation of CNS relapse-free interval (p=.O.008) in favor of CNS-P. CNS-P did

not improve hematologic remission duration or survival. All complete remitters were maintained on mercaptopurine.

methotrexate, and cyclophosphamide with pulses of prednisone and vincristine; the median time from remission to eitherhematologic or CNS relapse was 19.3 mo after CNS-P. and survival for these patients was 26.1 mo. We conclude that ourcurrent induction regimen is highly effective in adult ALL and that CNS prophylaxis is indicated in such patients.

A MINORITY ofadults with acute leukemia have

morphological and other features of their disease

consistent with childhood lymphoblastic leukemia.

However, the response rate to “induction” chemother-

apy has been lower and the response duration has been

considerably shorter in adults.’ Although prophylaxis

against central nervous system (CNS) leukemia has

been a major advance in the management of childhood

leukemia, its value in adults has been unclear. In view

of multiple complications of CNS prophylaxis that

have been reported2 � and uncertainty about the

frequency of CNS leukemia in adults, the Southeast-

em Cancer Study Group began a controlled trial in

1972. We sought to confirm the promising results of

an earlier Group study that induced remissions with

vincristine plus low-dose methotrexate and high-dose

prednisone.6 A maintenance drug schedule, based on a

regimen used successfully in children,7 was to be

preceded by a multidrug consolidation regimen. In

anticipation of slow case accrual in this uncommon

disease, we chose to study only one question in a

prospective randomized fashion, namely, is cranial

radiation plus intrathecal methotrexate of value in

preventing leukemic meningitis in adults?

MATERIALS AND METHODS

Untreated patients age 15 yr and over with a diagnosis of ALL

were eligible after written informed consent. The morphological

diagnosis was made by the individual investigator using the follow-

ing criteria: Auer rods must not be present; megaloblastic erythro-

poiesis and cytoplasmic granules must be minimal: leukemic cells

must have no more than a moderate amount of cytoplasm; the

degree of marrow infiltration and the uniformity of leukemic cells

must be fairly high.

Eighty-eight of the cases evaluable for induction had slides

reviewed by the senior author, who agreed with each investigator

about the diagnosis; the other I I evaluable cases did not have slides

available for this review. Special histochemical stains were encour-

aged but not required: immunologic and other special studies were

not routinely done. No attempt was made to subclassify the ALL

cases morphologically.

From the Departments of Medicine and Radiation Oncology.

University of Alabama in Birmingham. and the Departments of

Medicine and Biometri’. Lmort’ University, and other institutions

of the Southeastern (‘ancer Studt Group.

Supported in part h3’ LLSPHS grants from the National (ancer

Institute. NIH.

Submitted April 18. 1979; accepted October 3. 1979.

The fdlowing members of the Southeastern Cancer Studt

Group participated in and the fi/lowing USPHS grants supported

this study; R. Burson. M. (‘amphell. J. (‘arpenter, J. Durant, R.

Gams, D. Lineberry. G. Omura, M. Poon, and J. Prchal (Universitt

ofA/abama in Birmingham. (‘A-030/3. (‘A /9657 and (‘A 24456);

H. Si/berman (Duke Universit�, CA-03/77); H. Cohen (Durham

V.A. Hospital. CA-05634); J. Butts, C. (‘orlet. L. Hefiner. (‘.

Huguley, H. Kann. J. Keller, M. Robertson, W. Vogler. and F.

Winton (Emory Universiti-. (‘A 03227 and (‘A 1/263); G. Faguet

and C. Wright (Medical College ofGeorgia. CA 06807); Y. Ahn. H.

Lessner and M. Troner (Universitt’ of Miami, (‘A 05641); S.

Fischer. R. Joseph. R. Smalley. and R. Wright (Temple University,

(‘A 0796/); V. Loeb (Washington University. (‘A 03376); N.

Ma/donado, F. Robert, and F. Vele:-Garcia (University of Puerto

Rico, CA /2223); S. Gregory and W. Knospe (Rush MedicalCollege, (A /2840); 5. Krauss and T. Sonoda (University of

Tennessee, Knoxville. (‘A /3237); K. Tornt’os (New Orlean.c V.A.

Hospital. (‘A /3249); W. Forman. R. Kellermever. A. Lubin. and A.

Rassiga (Case Western Reserve University, (‘A /5584); W. Arrow-

smith (Oschner Clinic. (‘A /5578); (‘. Nee/t (University of Tenne.c-

see, Memphis, (‘A /7027); G. Broun and P. Petruska (St. Lt.ui.c

University, (‘A 1 7214); P. De Simone and J. Gockerman (Ulniversit3-

ofKentucky. (‘A 20255); 0. Martelo (University of Cincinnati); W.

Hanson (Radiological Physics Center. M. D. Anderson Hospital.

Houston, Texas).

Presented in part to the American Society of (‘linical Oncology,

April 4. /978, Washington. D.C.

Address reprint requests to George A. Omura, M.D.. 638 Zeigler

Building. University Station. Birmingham. Ala. 35294.

© I 980 by Grune & Stratton, Inc.

0006-497//80/5502-00/6$01 .00/0

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200 OMURA ET AL.

Treatment Program Induction

The induction treatment was given in 20-day cycles, using a single

daily dose of prednisone, 350 mg/sq m orally for 10 days, then 70

mg/sq m every other day through day 20. Vincristine, I mg/sq m

intravenously once weekly, and methotrexate, 2 mg/sq m orally

every 6 hr for 4 doses repeated twice weekly, were started on day I.

The entire cycle was to be repeated as long as progressive improve-

ment continued. Allopurinol, hydration, blood products, and anti-

biotics were given as needed. A complete remission was diagnosed

when the marrow was normocellular with 0%-5% blasts, erythroid

activity at least 1 5%, granulocytic elements at least 25%, the blood

had more than 10 g/dl hemoglobin concentration, more than 2000

granulocytes and more than 100,000 platelets, and there were no

relevant physical findings. Spinal fluid examination was not

required to diagnose complete remission.

Consolidation

Once a complete remission (CR) was confirmed, ‘�consolidation”

treatment was given: arabinosyl cytosine (ARA-C), 100 mg/sq m

intravenously, plus 6-thioguanine, 100 mg/sq m orally, every 12 hr

times 10 doses; approximately 9 days later, asparaginase, 500 lU/sq

m, was given intravenously daily times 5, plus vincristine, I mg/sq

m on days I and 5, and prednisone, 50 mg/sq m daily times 5, as a

second consolidation.

At the end of the consolidation phase, a repeat bone marrow

examination was done to confirm continuing marrow remission. In

addition, a lumbar puncture was done with cytocentifugation of the

spinal fluid. If the lumbar puncture showed 10 or more mononuclear

cells or any definite blast cells, cranial radiation and intrathecal

methotrexate were given on a nonrandomized basis.

CNS Prophylaxis

If the spinal fluid was normal and the bone marrow normal,

patients were randomly assigned to 3 wk of systemic mercaptopu-

rine, 50 mg/sq m/day, plus cyclophosphamide, 200 mg/sq m

weekly, with or without intrathecal methotrexate and cranial radia-

tion, 2400 rad in 12 fractions over 2.5 wk through opposing lateral

ports to the head, with each field being treated each day. A shaped

port was used to include the extensions of the meninges. The

treatment portals were to include the whole brain, excluding the

ocular globes, which were to be adequately shielded. The anterior

superior and posterior boundaries of the field were to extend at least

to the external table of the bones of the calvarium and to the

posterior wall of the orbit. Inferiorly, the line was to extend to the

auditory canal, including the entire middle fossa (temporal lobes),

and from here to follow the clivus, extending posteriorly to the level

of C-2.

Shielding materials were to have at least five half-value layers for

megavoltage energies. Localization films on the treatment machine

were to be obtained on every patient. A supervoltage source was

required with the treatment distance being at least 70 cm to the skin

or to the isocenter. Preservative-free intrathecal methotrexate, 10

mg/sq m (no maximum dose), was given twice weekly for 5 doses

using Elliott’s B solution as diluent.

Maintenance

Nonrandomized maintenance therapy for 24 mo included 6-

mercaptopurine, 50 mg/sq m orally daily, cyclophosphamide, 200

mg/sq m orally or intravenously weekly, and methotrexate, 20

mg/sq m orally, intramuscularly, or intravenously weekly. “Inducer

dosing” with vincristine, I .5 mg/sq m intravenously weekly times 3,

plus prednisone 50 mg/sq m daily times 14, was repeated every 8

wk, after a follow-up bone marrow examination to confirm the

remission.

At the end of 24 mo maintenance, bone marrow examination and

lumbar puncture were repeated; if normal, no further treatment was

given as long as remission persisted, but monthly blood counts and

every 2 mo bone marrows were to be done thereafter. No additional

spinal taps were done except on clinical indication. Documentation

of a bone marrow relapse marked the end of the remission. If CNS

relapse occurred while still in hematologic remission, CNS therapy

was given as described above and the patient remained on study. All

patients were followed for the duration of remission and survival.

Dose Adjustment

Induction. Vincristine could be discontinued for disabling

paresthesias or weakness.

Consolidation. Asparaginase could be discontinued for anaphy-

laxis, abdominal pain, or an increased serum amylase.

CNS phase. If the granulocyte count was less than 2000 or

platelet count less than IOO,000/pl, the 6-MP and cyclophospha-

mide were omitted; if the granulocyte count was less than I 500 or

the platelet count less than 75,000/pl, the intrathecal methotrexate

was delayed until blood counts improved.

Maintenance phase. The doses of 6-MP, cyclophosphamide,

and methotrexate were to be titrated up or down proportionately to

maintain the white count at 3000-4000. Cyclophosphamide was to

be discontinued if hemorrhagic cystitis occurred. Hematologic

toxicity was graded according to SEG criteria.8 A granulocyte

toxicity score of I + equals fall from normal to 0.75-1 .5 x l09/liter

orfrom 1.5-3.0 x l09/litertoO.20-O.75 x 109/Iiter;2+ indicatesa

fall from normal to the range of 0.20-0.75 x 109/Iiter or from the

range of I .5-3.0 x I 09/liter to <0.20 x I 0’/liter. A platelet toxicity

score of I + equals fall from more than 130 x 109/liter to 50-100 x

lO’/liter or from 100-130 x 109/liter to 10-50 x 109/liter; 2+

indicates a fall from <130 x 10’/liter to the range of 10-50 x

109/liter or from the range of 100-130 x 109/liter to <10 x

lOt/liter. A score of 3 + toxicity indicates life-threatening infection

or bleeding associated with blood count depression.

Statistical Methods

Survival and remission curves were plotted according to the

technique of Kaplan and Meier.9 The curves were statistically

compared by the generalized Wilcoxon technique of Gehan.’#{176}

Table 1 . Pretreatment Characteristics

Age range 15-70 yr (median age, 23)

Sex: 53 male, 46 female

Race: 80 white, 1 9 black

Spleen: 54 palpable, 45 not palpable

Mediastinal mass: 3 present, 96 absent

Adenopathy: 30 present, 69 absent

WBC: �100,000, 75; �100,000, 24

Platelet < 1 00,000, 84; � 100,000, 15

Ta ble 2. Response

Percent

Eval CR PR NC Worse Dead CR

Induction 99 79 7 3 2 8 80%

Consolidation 77 7 1 5 1 92%

CNS-P + Chemo 28 27 1 96%

Chemo only 34 33 1 97%

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TREATMENT OF ADULT ALL 201

Granulocytes Platelets

1�- 2+ 3+1� 21 3+

Induction

Consolidation

Maintenance

(99evaluable)

(77 evaluable)

(54 evaluable)

17(17%)

1 3 ( 1 7%)

1 7 (3 1 %)

16(16%)

32 (42%)

1 1 (20%)

1 (1%)

2 (3%)

11 (11%)

22 (29%)

8 (1 5%)

4(4%)

19 (25%)

1 (2%)

2(2%)

For grading of toxic) ty see Materials and Met hods section.

Response rates were compared using a x2 test on proportions.

Prognostic factors were assessed for association with duration of

remission using a step-wise version of Cox’s regression analysis’ ‘ and

for association with achievement of remission using a logistic

regression analysis.’2

RESULTS

One-hundred-fourteen (I 14) patients were entered

from August 1972 through June 1978 and have had

their review completed. Nine were not eligible (prior

therapy, 3; acute myelogenous leukemia, 3, blastic

phase of chronic myelogenous leukemia, I � prior

lymphoma, 2), 3 had major protocol violations during

the induction phase, and 3 refused to continue therapy.

Thus, 99 were evaluable for induction. Their pretreat-

ment characteristics are shown in Table I.

Table 2 shows the outcome of induction, consolida-

tion, and the randomized treatment phase (chemo-

therapy plus or minus CNS prophylaxis). Seventy-

nine patients (80%) achieved complete remission, 27

within 4 wk; 30 took 4-6 wk, and 22 required more

than 6 wk of treatment. The induction regimen was

generally well tolerated. However, two patients died of

pneumocystis infection in complete remission after

requiring multiple cycles of induction therapy. One

patient developed urate nephropathy despite the use of

allopurinol. Two patients developed a transient steroid

psychosis, and five patients developed hyperglycemia

during induction. One patient had acute pancreatitis

attributed to asparaginase. One patient had transient

paraplegia after intrathecal methotrexate. During the

CNS phase, I 8% of patients receiving prophylaxis had

headaches; 30% had nausea compared with I 5� of

those receiving chemotherapy only. No late sequelae

of the cranial radiation have been noted to date on the

semiannual follow-up forms, although no specific

neurologic testing is called for in the protocol. One

patient developed hemorrhagic cystitis requiring

cessation ofcyclophosphamide. Several patients devel-

Table 4. Nonhem atologic Toxicity

Stomatitis

Nausea

�

Vomiting

Pares-

thesias

Induction

Consolidation

Maintenance

(99 evaluable)

(77 evaluable)

(54 evaluable)

14 (14%)

3 (4%)

8 (15%)

20 (20%)

1 1 (14%)

18 (33%)

21 (21%)

6 (7%)

14 (26%)

oped transient liver function abnormalities, but none

had drug toxicity established as the cause. Other

aspects of toxicity are shown in Tables 3 and 4.

Table 5 shows response by age for induction; in the

age group I 5-23, the complete remission rate was

90%; of the 5 failures, 3 achieved normal marrow and

blood counts, but 2 of them had persistent spleno-

megaly and the other had residual adenopathy. In

those aged 24 and older, the complete remission rate

was 67%, which is significantly lower (p = 0.01). If

one chooses age 20 as a break point, the CR rate was

92% (33/36) for those aged 15-20, and 73% (46/63)

for those aged 21 and over (p = 0.03).

Of 71 patients remaining in CR at the end of

consolidation, 2 were not randomized to the CNS

phase because of overt CNS leukemia; after CNS

therapy, one has had a CNS relapse and the other a

hematologic relapse. Of 69 who were randomized, 2

refused CNS prophylaxis and were lost to follow-up.

Two others who were randomized to no prophylaxis

were considered inevaluable because of poor com-

pliance and major medication errors early in this

phase of treatment; one subsequently had a CNS

relapse and the other a hematologic relapse. Two

patients had incomplete records. One other patient

was taken off protocol because of what was thought to

be intercurrent illness shortly after completing the

CNS prophylaxis but died in hematologic relapse.

Thus, there were 62 patients evaluable for the

randomized phase of the study.

Eleven of 34 evaluable patients in the no-prophy-

laxis group have had a CNS relapse. Of 28 evaluable

patients receiving cranial radiation and intrathecal

methotrexate as prophylaxis, 3 had a CNS relapse.

The difference between the two groups is significant at

the p = 0.03 level (x2 = 4.93). Since this calculation

does not take into account the time at risk for CNS

Table 5. Rasp onse by Age (lnducti on)

Number of Patients

15-23’ 24-30 31-40 41-50 51-60 60+

<CR

CR

Total

5

45

50

7

7

14

4

12

16

1

8

9

2

4

6

2

2

4

Age in years.

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1.

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

C0

00.00.

Total Fail In Rem Median

34 18 16 24.7 0NoCNSP28 16 12 21.2 ‘�s CNS P

0 ts V5 0�ts P=0.757

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

Total3428

C0

00.0

0.Fail Censrd11 23 oNoCNSP3 25 �CNSP

OE�iV5O�1� P=0.008

6 12 18 24 30 36 42 480

Total Fail Censrd Median34 14 20 32.2 0NoCNSP28 14 14 30.5 ACNS P

O� VSOeAPO.9890.9

0.8

0.7

.� 0.6

�. 0.50

0. 0.4

0.2

0.1

0.00 7 14 21 28 35 42 49 56

Months

Survival from Date on Study for PatientsEvaluable for CNS Phase

202 OMURA ET AL.

Fig. 3. Survival from date on study for patients evaluable forCNS phase.

Months

CNS Relapse Free Interval for EvaluablePatients According to Treatment

(CNS-P CNS Prophylaxis; No CNSPNoCNS Prophylaxis)

Fig. 1 . CNS relapse-free interval for evaluable patients

according to treatment (CNS-P. CNS prophylaxis; No CNS-P, NoCNS prophylaxis).

relapse, the CNS relapse-free interval for both groups

was plotted from the end of the CNS prophylaxis

phase; this parameter is also significantly different

(p = 0.008) in favor ofCNS prophylaxis (Fig. I). The

median time has not been reached for either group, but

for those who have had a CNS relapse, the median

time from the end of the prophylaxis phase to this

event is 1 3 mo for the treated group and 7 mo for the

controls. The estimated CNS relapse rate is 7% versus

2% at 6 mo, 42% versus 69� at 1 2 mo, and 42� versus

19% at 24 mo for the no-prophylaxis group and the

CNS prophylaxis group, respectively. However, hema-

tologic remission duration (Fig. 2) and survival (Fig.

3) are not significantly different for the two groups.

Not shown in these figures are the median remission

duration ( I 6.9 mo) for all complete remitters ( I 4.7 mo

for ages I 5-20 versus 20.4 mo for older patients, p -

0.671) and the median survival (24.2 mo) for all

patients evaluable for induction (21.5 mo for ages

1 5-20 versus 24.9 mo for age 2 1 plus, p = 0.348). Age

was not a significant factor (p = 0.3 1 ) in relation to

CNS relapse-free interval after accounting for CNS

prophylaxis (p = 0.04).

Twenty-five patients receiving cranial radiation as

part of their CNS prophylaxis had this aspect of their

treatment reviewed in detail. Fourteen had the dose

0.2

0.1

0.00 7 14 21 28 35 42 49 56

Months

Remission from Onset for PatientsEvaluable for CNS Phase

Fig. 2. Remission from onset for patients evaluable for CNSphase.

verified by the Radiological Physics Center, Houston,

Texas, to within ±5% of protocol requirements; two

had a low dose. In another eight cases, the institution

had not been visited by the Radiological Physics

Center staff, and in one case, the equipment had been

removed. The port films were available for review in

I 9 of 25 cases; 7 of these were judged not acceptable in

regard to treatment volume. The treatment program

itself met protocol requirements in I 3 cases, was

acceptable with minor variations in another 9, and was

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TREATMENT OF ADULT ALL 203

not acceptable in 3. In regard to the 3 patients who

had a CNS relapse in spite of CNS prophylaxis, the

port film in one showed an inadequate treatment

volume; the second had a low dose (2200 rad instead of

2400) and neither the dose nor the treatment volume

could be verified in the third. It should be noted that

all of these patients received intrathecal methotrexate

as well, so the relative importance of these protocol

deviations is unclear.

Of 54 evaluable patients in the maintenance phase,

16 completed 2 yr of maintenance treatment; of these,

5 have had a marrow relapse and I I remain in hema-

tologic remission from I to 27 mo posttreatment.

Thirty-eight have not completed the maintenance

phase, 25 because of relapse; I 3 remain in remission in

the maintenance phase. Of the 16 who completed

maintenance, 8 had received CNS prophylaxis with 2

marrow relapses (at I .5 and 6 mo); of the others, 3 had

a marrow relapse (at I , 1 .5, and 4 mo after completing

treatment). There have been no late CNS relapses in

either group.

Potential prognostic variables (age, sex, hemoglobin

level, platelet count, white count, splenomegaly, hepa-

tomegaly, mediastinal or other adenopathy) were

examined in multivariate fashion, but none were

predictive of remission rate or duration except age

versus remission rate (p = 0.01, x2 test of signifi-

cance).

DISCUSSION

In any large series of adults with ALL, prednisone

plus vincristine produces approximately a 509� remis-

sion rate,’ compared with over 90% in children.7

Several reports have indicated an improved remission

rate in adults by the addition of anthracyclines or

asparaginase. Woodruff’ has tabulated the results of

such trials, showing adult remission rates ofabout 759�.

for prednisone plus vincristine plus an anthracycline in

some recent studies, with median remission durations

ranging from 7.5 to 25 mo. In general, teenagers have

had a higher remission rate.

One of the larger trials was reported by Lister et

al.’3 in which 71% (36/51) of adults achieved CR

using prednisone plus vincristine plus adriamycin plus

asparaginase; the remission rate was 79% ( 1 5/ 1 9) in

those aged 15-20 and 66% (21/32) in older patients,

but there was no correlation between age and remis-

sion duration, as in the present report. The predicted

median remission duration was 18.5 mo and the

survival 27 mo. All patients in that trial were to

receive CNS prophylaxis; 3 of 30 who received it had

their initial relapse in the central nervous system.

Henderson and Glidewell’4 reported a study of pred-

nisone plus vincristine plus asparaginase in ALL

patients aged 20 and older, adding daunorubicin in

those not in remission by 4 wk. The CR rate was 72%

and median remission duration I 5 mo. Dowling et al.’5

used prednisone, vincristine, and adriamycin for

induction in 25 adults aged I 5 plus; 4 were considered

not evaluable; 20 achieved CR. Remission duration

after a multiple drug consolidation and maintenance

program appeared to be longer than with their

previous protocol. All patients in those studies received

CNS prophylaxis.

The present study indicates that the addition of

low-dose methotrexate to vincristine plus high-dose

prednisone can produce a high complete remission rate

(80%), especially in those aged 15-20 (92%), with

minimal toxicity. When this teenage group is

excluded, the median remission duration is actually a

bit longer, 20.4 mo, and the remission rate (73%) is

not inferior to the general experience cited by Wood-

ruff.’ It has been assumed that the benefits of CNS

prophylaxis in children would apply to adults, but this

has not been previously evaluated in a systematic

manner. The present study establishes that CNS

prophylaxis is of value in decreasing the occurrence of

CNS relapse in adults with lymphoblastic leukemia.

Although there is currently no advantage regarding

hematologic remission duration or survival, it is of

interest that the effect of CNS prophylaxis on hemato-

logic remission duration in children is not seen during

the first 24 mo of remission.7 It is likely that the full

impact of CNS prophylaxis on adult lymphoblastic

leukemia will not become apparent until better

systemic therapy is developed.

The relative importance of the consolidation

program and of the specific maintenance program that

we used cannot be stated. Further improvements are

clearly needed, especially in regard to remission induc-

tion in older adults, reduction in the CNS relapse rate

after CNS prophylaxis, and increased hematologic

remission duration. Identification of other poor-risk

factors, such as T-cell ALL, Burkitt-type leukemia,

blastic CML presenting as ALL, extreme leukocyto-

sis, or extensive tissue infiltration,’ may help to iden-

tify subcategories in which new approaches will be

required.

ACKNOWLEDGMENT

L-Asparaginase, preservative-free methotrexate for intrathecal

administration, and Elliot’s B solution were supplied by the Division

ofCancer Treatment, National Cancer Institute. The human inves-

tigations described herein were performed after approval by the

Human Investigations Committee of each participating institution

and in accord with assurances filed with and approved by the

Department of Health, Education and Welfare.

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204

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