Influence of Intensive Asparaginase in the Treatment of Childhood Non-T-Cell Acute Lymphoblastic Leukemia1

(CANCER RESEARCH 43, 5601-5607, November 1983]

Stephen E. Sallan,2 Suzanne Hitchcock-Bryan, Richard Gelber, J. Robert Cassady, Emil Frei III, and David G. Nathan

Departments of Pediatrie Oncology [S. E. S., S. H-B., E. F. Ill, D. G. N.J and Biostatistics [R. G.], Dana-Farber Cancer Institute; the Division of Hematology/Oncology [S. E. S, D. G. A/yand the Department of Radiation Therapy [J. R. C.Â¡of the Children's Hospital; the Joint Center for Radiation Therapy [J. R. C.]; and the Department of Pediatrics [S. E. S., D. G. N.], Medicine [E. F. Ill], and Radiation Therapy [J. R. C.Â¡,Harvard Medical School and the Harvard School of Public Health Â¡R.G.], Boston, Massachusetts 02115

ABSTRACT remission induction regimen, a short consolidation period, CNS prophylaxis, a randomized intensification, and continuation ther Between June 1977 and December 1979, 72 Ã©valuablepa apy to complete 30 months in continuous complete remission. tients with childhood non-T-cell acute lymphoblastic leukemia Based upon our successful experience with high-dose aspara were induced into complete remission using vincristine, predni- ginase in children with relapsed leukemia, as well as a prior sone, and doxorubicin. All received asparaginase consolidation demonstration of improved disease-free survival in patients re and central nervous system prophylaxis with cranial irradiation ceiving a consolidating course of asparaginase (14), we initiated and intrathecal methotrexate. All patients then received pro the randomized trial which featured prolonged intensification longed intensification with vincristine, prednisone, and doxorub using vincristine, prednisone, and doxorubicin or those 3 drugs icin, and half of them were randomized to receive weekly high- plus weekly asparaginase. dose asparaginase. Continuation therapy was with vincristine, This report describes the treatment program and its results as prednisone, methotrexate, and 6-mercaptopurine. of July 1983 after a median follow-up time of 57 months. After a median follow-up of 57 months, there were four remis sion deaths and 25 relapses. Central nervous system relapse MATERIALS AND METHODS was the first event in 4% of patients. There were fewer treatment failures in the asparaginase-treated group [2-sided, p = 0.04 The diagnosis of ALL was established by 2 or more experienced (0.07 controlling for standard and high-risk groups)]. Asparagi morphologists. Patients with acute undifferentiated leukemia, defined as nase toxicity occurred in six patients (8%) and was self-limited, having lymphoblasts with L2 morphology (3) and both periodic acid- but it precluded further use of the drug in those patients. The Schiff and myeloperoxidase negativity, were included in the treatment major toxicity of this treatment program was drug-induced car- program. Children with lymphoma-like disease were included if the bone marrow contained greater than 25% lymphoblasts at the time of diag diomyopathy which occurred in 10 patients (14%) and was fatal nosis. Thus, previously untreated patients with the diagnosis of ALL or in three of them. acute undifferentiated leukemia and whose immunological cell surface In summary, we conclude that the intensive use of high-dose markers were non-T-cell (27) were eligible for entry into the protocol. asparaginase has an important role in the treatment of children Cell preparation for immunological testing has been reported previously with acute lymphoblastic leukemia. The morbidity of multiple (27). doses of doxorubicin outweighed its antileukemic advantage in Seventy-four consecutive children less than 20 years old who pre standard-risk patients. sented to the Dana-Farber Cancer Institute and the Children's Hospital between June 1, 1977, and December 31, 1979, were entered in the treatment program. Informed consent was obtained before therapy was INTRODUCTION begun. As of July 1983, the median follow-up for this treatment program was 57 months. One patient failed to enter remission, and another The effective use of systemic and intrathecal chemotherapy, with or without CNS3 irradiation, has resulted in long-term dis patient was withdrawn from the program immediately after entering remission and prior to consolidation. The presenting clinical characteris ease-free survival for 35 to 50% of children with ALL (2,11, 12, tics of 72 Ã©valuable patients who entered complete remission and 18, 27). Various clinical and laboratory measures at the time of received intensification therapy are listed in Table 1. diagnosis have proven to be of predictive value for relapse. Disease-free survival was measured from the time of complete remis Adverse prognostic factors at the time of diagnosis include sion to relapse or death, whichever occurred first. Curves for disease- elevated WBC count, age, presence of a thymic mass, CNS free survival were estimated using the method of Kaplan and Meier (15). leukemia, or T-cell markers on the lymphoblasts (5, 12, 18, 27, All p values were computed using a 2-sided log rank test (22) or by fitting Cox proportional hazard regression models (6). 29). Treatment Regimens. The treatment protocol is depicted in Chart 1. In an attempt to improve treatment results, we designed a protocol for patients with non-T-cell ALL. The treatment program, Remission induction consisted of vincristine (1.5 mg/sq m/week i.V.; maximum dose, 2 mg), prednisone (40 mg/sq m/day in divided p.o. begun in June 1977 and called Protocol 77-01, used a 3-drug doses), and doxorubicin (45 mg/sq m i.v. on the first day of therapy). 1Supported in part by Grants CA 19589, CA 22719, and CA 06516, National Asparaginase was used to affect early consolidation. Escherichia coli Cancer Institute, NIH; and by a grant from the Dyson Foundation. asparaginase at 50,000 ILJ/sq m/dose i.v. was given to children less than 2To whom requests for reprints should be addressed, at 44 Binney Street, 6 years old, and 25,000 ID/sq m/dose i.v. was given to patients greater Boston, Mass. 02115. than or equal to 6 years old, based upon our previous experience which 3 The abbreviations used are: CNS, central nervous system; ALL, acute lym suggested that older children were relatively less tolerant of the higher phoblastic leukemia; VPD, vincristine, prednisone, and doxorubicin; VPDA, vincris tine, prednisone. doxorubicin, and asparaginase; CALLA, common ALL antigen. dose (9). During consolidation, the drug was given every other day for a Received March 9,1983; accepted August 3,1983. total of 5 doses. CNS prophylaxis consisted of whole brain irradiation

NOVEMBER 1983 5601

using a linear accelerator to 2400 rads (13 fractions over 17 days) and 5 doses of intrathecal methotrexate given during the same time span. The intrathecal methotrexate dosage was based upon the patient's age (4): 12 mg for patients age 3 years or older; 10 mg for those 2 to 3 years; 8 mg for those 1 to 2 years; and 6 mg for those less than 1 year. Intrathecal methotrexate doses were reduced by 50% during severe myelosuppression (granulocyte counts <500//il), and the drug was ad ministered every 18 weeks following CMS irradiation until the completion of all chemotherapy. Intensification treatment consisted of either VPD or VPDA. The drug dosages were: vincristine (2 mg/sq m i.v.; maximum, 2 mg) on Day 1; prednisone (120 mg/sq m/day in divided p.o doses) on Days 1 to 5; doxorubicin (45 mg/sq m i.v.) on Day 1; and asparaginase in the same i.v. doses as described above given on a weekly schedule. Intensification cycles were repeated every 3 weeks until patients completed a total cumulative doxorubicin dose. Continuation therapy consisted of vincristine and prednisone in the dosage and schedule used during intensification. In addition, patients received 6-mercaptopurine (250 mg/sq m/day in divided p.o. doses) on Days 1 to 5 and methotrexate (8 mg/sq m/day on Days 1 to 5, i.v. on Day 1 and i.m. on Days 2 to 5). During continuation therapy, 6-mercap topurine and methotrexate dosages were adjusted to attain granulocyte atâ€” O> moi nadirs of 750 to 1200/^1. Continuation therapy cycles were repeated every 3 weeks. Treatment was electively discontinued after 30 months in continuous complete remission. The selection of intensification regimen was made by random assign ment for the first 64 patients who entered complete remission. When treatment differences became apparent (October 1979), direct assign ment to VPDA was done for the last 8 patients (2 standard-risk and 6 high-risk (see below)] entered into the study. When we initiated the protocol, patients received doxorubicin 60 mg/ sq m/dose every 3 weeks. The doxorubicin dosage was reduced to 45 mg/sq m/dose after the occurrence of a single episode of fatal drug- I related cardiotoxicity (see below), as well as an inordinate number of episodes of prolonged and severe myelosuppression and fever (including

O) O) CO a single remission death from infection). Thus, the first 10 patients on Â»- *- CO protocol were treated with doxorubicin 60 mg/sq m, the next 14 had some doses at 60 mg/sq m and some doses at 45 mg/sq m, and from January 1978, the last 48 patients were treated with 45 mg/sq m/dose. I* Reduction in doxorubicin dosage occurred comparably within the ran A domized treatment groups (VPD or VPDA). The cumulative doxorubicin dosage for the first 56 patients who completed doxorubicin was 440 mg/sq m. Four failures occurred before completion of doxorubicin (3 relapses and one remission death). In October 1979, the total cumulative doxorubicin dosage for the remaining patients (the last 12 still receiving doxorubicin) was reduced to 400 mg/sq m.

RESULTS

The status of the study as of July 1983 is shown in Table 2 and Chart 2. Seventy-four patients entered the protocol, 73 of whom (98%) entered complete remission. The only induction failure occurred in a 9-month-old black female who had acute undifferentiated leukemia. She was one of 2 black children on C\J C^ 5 the protocol. One patient was withdrawn in remission at one month, left the country, and was not evaluated. One of the 72 Ã©valuablepatients discontinued treatment after 8 months in complete remission because her parents refused further therapy. Of the 72 Ã©valuablepatients who entered complete remission, 4 died while in clinical and hematological remission. One death occurred after 5 months in remission from viral pneumonia, and 3 others occurred after 5, 7, and 9 months in remission from drug-induced cardiomyopathy. As shown in Table 2, 25 patients relapsed: 18, in the bone marrow; 3, in the CNS; 3, simultaneously in the bone marrow

5602 CANCER RESEARCH VOL. 43

Chart 1. Chemotherapy schema. Vincristine (V): 1.5 mg/sq m i.v. (maximum, 2 mg) weekly during induction, then 2 mg/sq m i.v. every 3 InductionWeeks0 weeks (q 3 wk); prednisone (P): 40 mg/sq m/ day p.o. during induction, then 120 mg/sq m P.O.every 3 weeks; doxorubicin (0): 45 mg/sq 1 2 3 4 5 6 7 8 9 1.0 1 1SCHEMAIntensificationMonthsContinuation m i.v. every 3 weeks until cumulative dose of 440 mg/sq m; asparaginase (ASP): <6 years old, 50,000 lU/sq m i.V.; ^6 years old, 25,000 Vincristine VVVV V Weekly ID/sq m; intrathecal(IT)methotrexate (MTX):Â»3 Prednisone P years old. 12 mg/dose; 2 to 3 years old, 10 mg/ Asparaginase dose; 1 to 2 years old, 8 mg/dose; <1 year old, Doxorubicin D q 3 wk until 6 mg/dose; methotrexate (MTX): 8 mg/sq m/ cumulative Asparaginase Doxorubicin day i.v. or i.m. Days 1 to 5, repeated every 3 No weeks; 6-mercaptopurine (6 MP): 250 mg/sq Methotrexate IT q18wk Asparaginase m/day p.o. Days 1 to 5, repeated every 3 Cranial Rads weeks.

treatment actually received (36 VPD and 36 VPDA). Two of the VPD patients were randomized to VPDA but never received weekly "intensification" asparaginase due to adverse reactions to asparaginase during "consolidation"; 8 of the VPDA patients were directly assigned. When the appropriate statistical analysis comparing disease-free survival by randomized groups was per formed (34 VPD and 30 VPDA), the result was very close to that reported previously (p = 0.07). Standard versus High-Risk Groups. In addition to the differ 1.0 2.0 3.0 4.0 5.0 6.0 ences between the VPD and VPDA treatment groups, we also Years assessed differences in disease-free survival between standard and high-risk patients. Standard-risk criteria included WBC OCR Fail Total count, <20,000/nl; age, >2 and <9 years; L1 morphology; 43 29 72 absence of CNS leukemia; and absence of a mediastinal mass. 7/83 All other patients were considered in the high-risk group. Only Chart 2. Disease-free survival for 72 Ã©valuablepatients who entered remission. one child was evaluated in the high-risk group solely because of CCR, continuous complete remission. Bar, 95% confidence limits. undifferentiated (L2) morphology. He was in continuous remis and CMS; and one, in the testes. Bone marrow relapses occurred sion at 71 + months. between 3 and 42 months; CMS relapses were at 13, 14, and As shown in Chart 4, standard-risk patients had much better 17 months; and the combined relapses were at 2, 5, and 16 disease-free survival than did high-risk children (p = 0.02). Of months. Of the 6 patients with CNS involvement at the time of the standard-risk patients, those who received weekly aspara relapse, 5 were less than 2 years old, and 3 of those were less ginase had the best disease-free survival (86%). Similarly, high- than one year old at the time of diagnosis. (One of these patients risk children who received asparaginase also fared better (64%). had congenital leukemia.) All of the patients with CNS relapse A WBC >20,000//J and age <2 or >9 years were found to be originally presented with elevated WBC ranging from 50,000 to individually adverse factors for this patient population (p = 270,000/Ail. Characteristics of all patients who relapsed are 0.0008 and 0.03, respectively). This finding differed from our presented in Table 3. previous study wherein neither WBC nor age alone was of As of July 1983, 46 patients had completed therapy after 30 prognostic significance in non-T-cell patients (27). months in continuous complete remission and had been followed This protocol had a high number of patients less than 2 years from 44+ to 72+ months. In this group, there have been 4 old at the time of diagnosis (13 of 74 or 18%). One of the 13 relapses: 3 in the bone marrow and the other in the testes at 42, infants failed to enter remission, and another discontinued treat 39, 34, and 32 months, respectively. ment after 8 months of VPDA therapy (but is known to continue VPD versus VPDA. As shown in Chart 1, patients received in remission at 6+ years). Six of the remaining 11 patients either VPD or VPDA beginning at Week 12. Table 2 and Chart 3 relapsed. Four of the relapses were in the VPD group; the 2 show the results of the 72 patients analyzed by the treatment VPDA group relapses were both extramedullary. There were 2 received: VPD or VPDA. The difference between the disease- remission deaths in under 2-year-old patients, one each in the free survival curves was statistically significant at the p = 0.04 VPD and VPDA arms. level (2-sided log rank test). Of the 19 failures in the VPD group, CALLA. We have reported previously that the presence of the one was a remission death from infection; one, a CNS relapse; CALLA on lymphoblast surfaces may be of prognostic impor 14, bone marrow relapses; and 3, simultaneous bone marrow tance (27). In this study, the presence of CALLA was Ã©valuable and CNS relapses. Of the 10 failures in the VPDA group, 3 were in 59 patients. However, the assignment of treatment was not remission deaths from drug-related cardiomyopathy; 2, CNS balanced within the CALLA+ and CALLA- subgroups (Table 1). relapses; 4, bone marrow relapses; and one was a testicular Thus, although the CALLA+ patients had statistically significantly relapse that occurred after elective cessation of therapy. Three better disease-free survival than did CALLA- patients (p = 0.03; of the 4 VPDA patients who relapsed in the bone marrow had corrected for risk group), it was not possible to determine the received 5 or fewer doses of "intensification" asparaginase. extent to which treatment differences influenced this result. To The aforementioned results compare groups of patients by ensure that the overall observed treatment differences were not

NOVEMBER 1983 5603

1.0

"""-4 WttHI-HÂ»-H-HHH

I Mill I III lililÃ

1.0 2.0 3.0 4.0 5.0 6.0 Years

RX CCR Fail Total VPD I7 I9 36 VPDA 26 10 36

7/83 Charts. Disease-free survival according to treatment received. Bars, 95% confidence limits; p = 0.04 (0.07 corrected for risk group). RX. treatment; CCR, continuous complete remission.

due to the CALLA imbalance, we evaluated treatment effects co i- co within the subgroup of 46 CALLA+ patients. Similar to the total study results, VPDA was superior to VPD within the CALLA+ subgroup (p = 0.05; corrected for risk groups). Three-Agent Remission Induction. Because we (25) and others (17, 18) had previously shown that the time to enter complete remission may influence disease-free survival, we in vestigated the time to enter complete remission as a prognostic CM 'SÃ® variable in this study. Patients were evaluated in 2 groups: those who entered complete remission within 30 days or between 31 I! and 60 days. Only 4 of 72 patients required more than 30 days to enter complete remission. Two of the 4 relapsed compared to 23 of 68 relapses among those who achieved complete ! remission within 30 days. VI, CNA Prophylaxis. Four children had evidence of CNS leuke mia at the time of diagnosis (or prior to CNS prophylaxis). One of them was an infant with congenital ALL, and was the only patient in this study who did not receive cranial irradiation. She subsequently relapsed in the bone marrow and CNS at 2 months. Another of the 4 relapsed in the bone marrow at 3 months. The 2 remaining patients were treated with intrathecal drugs until the cerebrospinal fluid was cleared of lymphoblasts, and then re ceived a boost of radiation therapy to 2800 rad, in addition to 5 concurrent doses of intrathecal methotrexate. They remained in continuous complete remission at 53+ and 57+ months. There were 3 primary CNS relapses and 2 additional simulta neous bone marrow and CNS relapses. The 3 primary relapses occurred in boys aged 8 months, 19 months, and 2 years at diagnosis, who had WBC of 105,000, 120,000, and 129,000/^1, respectively. Two of them received VPDA. The remaining 2 children with CNS involvement as a combined site of relapse were girls aged 1 and 7 years at diagnosis, who had WBC counts of 52,000 and 50,000/^1 respectively; both were in the VPD group. Complications. The major complications of this program were related to doxorubicin and asparaginase (Tables 4 and 5). Ten patients developed clinically evident congestive heart failure. Their ages at diagnosis ranged from 1 to 5 years; 7 of them were treated with VPDA, all developed clinical manifestations of heart failure between 6 and 10 months from the time of diagnosis,

5604 CANCER RESEARCH VOL. 43

Table 3 RelapsesPatient12345678910111213141516171819202122232425Site(s)BM"/CNSBMBMBMBMCNSBM/CNSBMBMBMBM/CNSBMBMBMBMBMBMBMBMBMBMBMCNSTesticleCNSNo. diagnosisAge of mo. to to com- relapse515517251716610324112942341739751620143213At(yr)114131638 CALLAremission+ pÃete 22+ 23+ 2220+

2121+ (mo.)711461 222029423022+

(mo.)533142931010171219

29+ 22+ 22+ 22-1- 22+ 21+ 225029+

22+ (mo.)21 27+ (mo.)2WBC(X1000/>.I)5211147503510550190411727010021555811342234621120152129Days21+ 21IntensificationVPDVPDVPDVPDVPDVPDVPDVPDVPDVPDVPDVPDVPDVPDVPDVPDVPDVPDVPDA6VPDA6VPDA6VPDA6VPDAVPDAVPDA(3)cW(5)(13) BM, bone marrow. 0 Randomized to asparaginase but could not tolerate all protocol doses because of toxicity. c Numbers in parentheses, number of asparaginase doses received.

Table 4 ~Â«JOOQ.1.08.6.4.2"\L_sHâ€”,NMMmH4tt44*MMi<8H>HI- Congestive heart failure to clinical conges tive heart failure from first tive doxo- doxorubi-cin cin dos rubicindosage(mg/sq dose(mo.)67997881098OutcomeDeathA&W3A&Wage(mg/sqm)60804545454545454545Cumula PatientABCDEFGH1JAge(yr)4551422232GroupVPDAVPDVPDAVPDAVPDAVPDVPDVPDAVPDAVPDATimem)465469440440444440412441440400 1.0 2.0 3.0 4.0 5.0 6.0 Years withDIGA&W withDIGDeathA&W Risk Group CCR Fail Total withDIGA&WA&WA&WDeathDoxorubi- â€” StandardHigh I8 5 23 25 24 49

7/83 Chart 4. Disease-free survival according to risk group (see text for definition), a A&W, alive and well; DIG, digoxin. ears, 95% confidence limits; p = 0.02. CCfl, continuous complete response.

TableÃ³ Asparaginase toxicity and 3 died from drug-induced cardiomyopathy. All cases of No. of intensification congestive heart failure occurred during or within 3 months after Patient3Problem9 doses of asparaginase completing doxorubicin therapy. Of the 7 who survived acute relapse episodes of congestive heart failure, all became clinically well, 17 t>3 Pancreatitis BM relapse echocardiograms reverted to normal in 2, but 3 require mainte 19 Pancreatitis BM relapse 20 45 Hypersensitivity BM relapse nance digoxin. All 7 had normal activity and exercise tolerance 21 Hepatitis BM relapse with follow-up from 41+ to 64+ months from the time of their 22b 13Pancreatitis HepatitisOutcomeBM1 BM relapse initial clinical cardiac symptomatology. a Patient numbers correspond to those in Table 3. 6 Toxicity occurred during "consolidation" therapy; therefore, patients never Other major toxicity was related to asparaginase. Six patients received "intensification" asparaginase. developed toxicity secondary to asparaginase and subsequently c BM, bone marrow. required a change in therapy. The details of these patients are shown on Table 5. Three patients developed reversible pancrea DISCUSSION titis; 2, reversible hepatitis; and one, hypersensitivity to both E. coli and Erwinia species. None of these patients received further Asparaginase is an active antileukemic agent and can induce asparaginase, and all subsequently relapsed. complete remissions in 40 to 50% of patients with refractory

NOVEMBER 1983 5605

ALL (23, 28). The optimal dosage and schedule of asparaginase consistent with the report of Legha ef al. (16) who found that are unknown. A study of 413 children with relapsed ALL sug cardiac toxicity may be related to peak drug levels. gested that the proportion of remissions increased with increas It has been suggested that 3 induction agents may be superior ing dosages of asparaginase (8). The rationale for the use of to 2 induction agents (7). In our study, it was difficult to evaluate high doses of asparaginase administered on a weekly schedule the relative efficacy of a 3-agent induction regimen. Indirect was based upon our experience with relapsed patients with ALL. evidence for the utility of the 3-agent induction used here may In a group of such children who were in their second or subse be obtained from a comparison of these data with data from our quent remissions, we found that high-dose asparaginase given preceding program, Protocol 73-01. Using only vincristine and weekly resulted in prolonged durations of second remissions (1). prednisone for remission induction therapy in 89 non-T-cell ALL What was the relative contribution of asparaginase? Its addi patients in the latter program, we found that 38 of 73 early tion resulted in superior antileukemic efficacy in all patients remitters (<30 days) eventually relapsed compared to 12 of 16 irrespective of risk group. Of 32 patients who tolerated weekly late remitters (31 to 60 days; p = 0.06) (25). We previously asparaginase, none had a bone marrow relapse and, among reported the early results of a randomized trial of 2- versus 3- standard-risk patients, there were also no extramedullary re agent remission induction therapy (26). Long-term follow-up lapses (Table 3). However, the 2 drug-induced mortalities were (median of 8 years) for patients treated on Protocol 73-01 reveals unacceptable. Therefore, we no longer use doxorubicin intensi a Kaplan-Meier disease-free survival of 64% for patients treated fication for standard-risk patients. with vincristine, prednisone, and an anthracyline compared to The influence, if any, of systemically administered asparagi 39% for those treated with only vincristine and prednisone (p = nase in CMS prophylaxis was difficult to assess. All patients on 0.03). The addition of doxorubicin to vincristine and prednisone Protocol 77-01, as well as its predecessor Protocol 73-01, re in Protocol 77-01 resulted in all but four of the 72 patients ceived cranial irradiation and intrathecal methotrexate. The latter entering complete remission within 30 days. Thus, the time to patients had the lowest incidence of primary CNS relapse of any enter remission could not be evaluated for its prognostic signifi reported childhood ALL study (13). Using the identical CNS cance. This is an example of how a treatment regimen can alter treatment regimen in Protocol 77-01, we experienced CNS in the influence of individual prognostic factors. volvement as a sole site of relapse in 3 patients and as a Another potential problem with the comparison of treatment combined site (in addition to the bone marrow) in 3 other patients programs pertains to variations in patient populations and in risk for an overall CNS relapse incidence of 8%. The slight increase group definitions. For example, in Protocol 77-01, 13 of 74 in CNS failures in Protocol 77-01 compared to Protocol 73-01 patients (18%) were less than 2 years old at diagnosis compared may be related to the increased number of under 2-year-old to 8 of 126 (6%) non-T-cell patients in Protocol 73-01. As described in "Results," patients under 2 years old had an adverse patients in the former program (see below). Riccardi ef al. (24) have shown that, in monkeys, single dose prognosis. Therefore, series of patients with disproportionately of i.v. asparaginase depleted cerebrospinal fluid and plasma high numbers of infants may understate the efficacy of a treat asparagine levels for at least 5 days and, in humans, i.m. aspar ment regimen for older children. As an example, in a large study of CNS prophylaxis conducted by the Children's Cancer Study aginase 6000 ID/sq m given 3 times/week depleted cerebrospinal fluid asparagine for about 1 week (or at least as long as plasma Group, infants under 18 months of age were treated differently asparagine was depleted). We hypothesized that asparaginase and excluded from analysis (20). In our patient population (Table as used in Protocol 77-01 would cause prolonged depletion of 3), the exclusion of patients 2 years old or less would remove 4 both cerebrospinal fluid and plasma asparagine. Assuming that of 6 CNS relapses. Thus, the exclusion of this young population the antileukemic effect of asparaginase is, at least in part, related who may be at increased risk for CNS leukemia could markedly to asparagine depletion (21), we anticipated an increased efficacy alter treatment results. in the prevention of CNS leukemia. We are unable to explain the The major advantage of this treatment program was improved 2 CNS relapses in the VPDA-treated group. However, we have disease-free survival at 3 years for children treated with the noted that, in all of our protocols, CNS relapses occurred only in VPDA combination (86% for standard-risk and 64% for high-risk patients with WBC counts >50,000//zl at diagnosis (13). patients). No relapses occurred in standard-risk patients who Did the VPDA combination result in excessive cardiac toxicity received the VPDA combination. However, of the 36 patients compared to VPD or to previous studies? Between 1973 and treated with VPDA, 3 died of therapy-related causes. Therefore, 1977, we treated 129 consecutive patients with ALL and expe if adjustments in drug dosage, schedule, and route of adminis rienced only a single episode of doxorubicin-induced cardiotox- tration could result in reduced toxicity without diminished effi icity (10). The maximum cumulative doxorubicin dose was 450 cacy, this program would provide a good foundation for subse mg/sq m, and the dosage rate was 30 mg/sq m/dose or less quent antileukemic protocols. (because doxorubicin doses were adjusted for myelosuppres- Since the close of Protocol 77-01, we have made modifications sion, whereas this was not routinely done in Protocol 77-01). in the dosage and cumulative dose of doxorubicin (now 30 mg/ The incidence of drug-induced cardiomyopathy in Protocol 77- sq m/dose to a total dose of 345 mg/sq m) as well as in the 01 was 3 of 36 in the VPD group and 7 of 36 in the VPDA group. route of administration of asparaginase (now given i.m. in order This suggested that children who received weekly high-dose to diminish toxicity) (19). Preliminaryevaluation of 67 consecutive asparaginase in addition to pulses of doxorubicin may have been high-risk patients (including those with T-cell ALL) treated be at increased risk for cardiomyopathy, at least when the total tween June 1981 and July 1983 showed 4 relapses and no cumulative anthracycline dose was 450 mg/sq m, and/or when evidence of cardiac toxicity. We have continued to use weekly the dosage rate was 45 to 60 mg/sq m. Adjustments in dosage high doses of asparaginase (in addition to maintenance therapy rate and cumulative doxorubicin dose have subsequently re with methotrexate and 6-mercaptopurine) in 44 consecutive sulted in markedly reduced cardiac toxicity (see below). This is standard-risk patients, and there have been no relapses.

5606 CANCER RESEARCH VOL. 43

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Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 1983 American Association for Cancer Research. Influence of Intensive Asparaginase in the Treatment of Childhood Non-T-Cell Acute Lymphoblastic Leukemia

Stephen E. Sallan, Suzanne Hitchcock-Bryan, Richard Gelber, et al.

Cancer Res 1983;43:5601-5607.

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