Indian J Pediatr 1988; 55:789-795

Evaluation of different induction regimens in children with acute lymphocytic leukemia

V. P. Choudhry and L. S. Arya

Hematology Div&ion, D~7)atltnent o f PediaOics, Al l hldia htstitute o f Medical Sciences, New Delhi

Four h~duction regimens-plednisolone and 6-melraptoptoine (group I), plednisolone and vhlclisthw (group II), prednisolone, vhwlisthw & I-asparaginase (group 111) and prednisolone, vinctisthw and adliamyehl followed by cyclophosphamide and l-asparaginase (group 1V)-have been evahtated . Successfid induction remission was achieved h~ 16 (69.6%) hi group L 23 (92.0%) hi group II, 36 (94. 7%) in group II[, 31 (96.8%) h~ group IV.. Relapses wele seen hi 10 (62.5%), 10 (73.8%), 25 (69..1%) and 9 (29.0%) h~ the fottr grottps respectively. Relapses seen h~ group IV were infi'equent as compared to children of group I, H & III. Advoxe risk factolx n,ere similar hl all the Jbttr groups. Ninety four children (61.3%) Itad one or mote poor prognostic factolx at diagnosis. Tluve of 4.3(7%) chihh'en with no poor prognostic factotx died &tting hzduction therapy as compared to 18 of 94 (19.1%) children associated, with poor prognostic factotx at diagnosis. Iligher mortality was seen under two yeatx of age.

Key words: Induction regimen; Acute lymphocytic leukemia

With the advent of newer chemo- therapeutic agents, efforts have been made to achieve induction remission in maximum number of children. Combination of vin- cristine and prednisolonc in thc 'Seventees rcsuhed in complcte remission in 85-90% of children with acute lymphocytic leu- kemia (A.L.L)J 3 Addition of a third drug like adriamycin, daunomycin, cyclophos- phamide improved the induclion rcmission rates marginally but the relapse rates were significantly reduced, zs Further intensi-

Reprint requests: Dr V.P. Choudhry, Associate Professor, Department of Pediatrics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110 029.

fication of induction therapy and con- solidation treatment with multiple agents has significantly prolonged the event free survival rates. 6-8

In the present report results of various induction remission regimens have been evaluated in Indian children with A.L.L.

Materials and Methods

Between January 1 9 7 2 through December 1985, 137 children with A.L.L. fulfilling the following criteria were studied: (1) had not received any chemotherapeutic agents, (2) absence of CNS involvement, (3) absence of massive

789

790 TIlE INDIAN JOURNAL OF PEDIATRICS Vol. 55, No. 5

mediastinal lymphadenopathy, and (4) willing to undergo complete chemotherapy. The investigations done in these children to determine the extent of the disease were hemoglobin, total differential leucocyte counts, platelet counts, peripheral blood and bone marrow morphology and cytochemistry (negative Sudan black and peroxidase stains), total and differential proteins and bilirubin, transaminases, creatinine, BUN, serum uric acid, CSF cytology and biochemistry, skiagram of chest and skeletal survey. Effort were made to isolate the microorganisms by cultures of blood, urine, throat swab, and pus points and serological tests for salmonella and brucellosis, etc. At follow-up, cultures of blood, urine, stool, and CSF were done if the patient presented with fever. Febrile episodes were treated initially with ampicillin and gentamycin. However the antibiotics therapy was changed depending upon their availability and sensitivity pattern of the offending agent.

Four different induction regimens were used. Prednisolone (60 mg/M 2) was given for first 28 days in all regimens. In group I (1972-1977) children received 6 mercapto- purine (60 mg/M 2) daily orally for 28 days. In group II (1977-1980) children received vincristine (1.5 mg/M 2 I.V. once a week) on days 1, 7, 14 and 21, while in group III (1980-1982) children received l- asparaginase (10,000 units/M 2 I.V.) on days 2, 8, 15 and 22nd in addition. In group IV (1983-i985) children received vincristine (1.5 mg/M 2 I.V.) on days 1, 7, 14, 21 and 28th along with adriamycin (30 mg/M 2 I.V.) on 1, 2, 14, 15, 28 and 29th day.

Bone marrow aspiration was repeated at the end of induction therapy. If the blast count was more than 5 percent the induction regimen was continued for additional 2 weeks in the same schedule. If the repeat bone marrow at the end of 6 weeks of induction therapy still showed blast count of more than 5 percent, the patient was considered as failure to induction therapy. In group IV, children after their successful induction treatment received consolidation therapy consisting of cyclophosphamide (1000 mg/M 2 I.V.) on day 1, 14, 28th and L-asparaginase (10,000 U/M 2) I.V. on days 1, 5, 10, 15, 20 and 25th day.

On achieving complete remission, CNS prophylaxis was administered with intra- thecal methotrexate (15 mg/M 2) in 6 doses over 2 or 3 week either alone or with radiotherapy (2000-2400 R) in 3 week. Maintenance therapy consisted of 6- mercaptopurine (60 mg/M2/day orally) and methotrexate (15 mg/M2/week orally). The doses of these agents were increased or decreased proportionately to maintain the leucocyte counts between 2500 to 3500/ cu mm.

Duration of complete remission was the period between complete remission and occurrence of clinical, hematological, CNS or testicular relapse. Clinical relapse was considered on appearance of signs and the presence of the blast cells in blood or blast count of more than 10 per cent in the bone marrow. CNS relapse was considered in the presence of blast cells in CSF with or without evidence of clinical symptoms. Enlargement of testes with histological evidence of leukemia was diagnosed as

CIIOUDtlRY AND ARYA : INDUCTION REGIMENS IN A.L.L. 791

testicular relapse. Blast cells of over 10 per cent in the bone marrow and/or in the peripheral blood in the absence of clinical picture of leukemia was considered as

hematological relapse.

Results

Of 137 children (101 boys and 36 girls, age range 5 months to 13 years), who were

treated with different regimens, 11 were below 2 years, 109 between 2-10 years and 17 above 10 years of age. Boys pre- dominated in all the groups.

Successful remission rates were calculated in children who underwent full

induction therapy. Those who failed to complete the course, or who died were ex- cluded. Complete remission was obtained in 16 of 23 (69%) in group I, in 23 of 25 (92.0%) in group II, in 36 of 38 (94.7%) in

group III, and in 31 of 32 (96.8%) in group

IV children (Table I). Successful induction

remission rates were, significantly higher in children of group II, III and IV when compared with group I (p < 0.01). The overall mortality during the induction

period was 13.6 percent. None of the patients in group I died during induction therapy while mortality was 20 percent in group IV children. Overall mortality during induction remission was maximum in children below 2 years as 6 of 11 (54.5%)

children died, while 4 of 17 (23.5%) children over 10 years of age died (Table Ii).

Relapsc rates in differcnt groups I, II, III and IV wcrc 62.5, 73.8, 69.4 and 29.0% rcspectively (Table III). Three patients of group II did not relapse for 46, 120 and 120 months; while none of the patients in any other group were in remission for that long. However, nine children in group IV

enjoyed event-free survival period between 18 to 24 (mean 23.4) months; and were still

on maintenance therapy.

Table I. Successful remission rates in different groups

Groups No. of Mortality Failure to Successful (drug combi- cases during achieve remission nation) induction remission

remission No. %

I (P + 6MP) 23 0 7 16 69.6

II (P +VCR) 29 4 2 23 92.0

III (P + VCR + 45 7 2 36 94.7 L--ASP)

IV (P+VCR+ 40 8 1 31 96.8 Adria)

P = Prednisolone; 6-MP = 6-mercaptopurine; VCR = Vincristine; Adria = Adriamycin; xx 2 = 13.21; p<0.01; L-ASP = L-Asparaginase

792 TIIE INDIAN JOURNAL OF PEDIATRICS Vol. 55, No. 5

Table II. Relationship of age with mortality

Age No. of No. Deaths (years) children (%)

< 2 11 6 54.5

2-10 109 9 ~ 10.3

. J > 10 17 4

X~ 2 = 13.1; p<O.01

The effect of bad prognostic factors like age below 2 or above 10 years, total leucocyte count greater than 50,000/#1 massive lymphadenopathy, hepatomegally and splenomegaly of over 5 cm were given equal weightage with a score of one each. Final score of each patient was computed by adding them all. Distribution of children with bad prognostic scores was identical in all the four groups (Table IV). Ninety four children (61.3%) had presence of one or more poor prognostic factors at diagnosis. Three of 43 (7%) children with absence of poor prognostic factors at diagnosis died during induction remission, compared with 18 of 94 (19.1%) children who had one or more poor prognostic factors.

Discussion

Complete remission with prednisolone and vincristine was achieved in 92 percent of children compared to 85-90 percent in other studies. TM Addition of L-asparaginase (group III) and adriamycin (group IV) during the induction therapy in the present series did not improve the induction remission rates significantly. Similar

observations have been documented by others. 3,9 Overall higher mortality rate (13.9%) during induction therapy could be attributed to poor nutritional status of these children, inadequate supportive therapy (platelet concentrates, antibiotics, isolation etc.) and higher proportion of children with poor prognostic factors at diagnosis. Nearly 61 percent of children had one or more of the adverse clinical prognostic factors at diagnosis as compared to 20-30 percent of children in western series. 9"1~ Addition of L- asparaginase to induction therapy did not reduce relapses in the present series,' in contrast to western studies. 11 However, Jones and his colleagues observed prolonged remission in children when L- asparaginase was administered on completion of prednisolone and vincristine therapy and not along with it. 12 Similarly, incorporation of more therapeutic agents in the induction phase has also resulted in poor initial remission rates and early relapses compared to combination of prednisolone and vincristine. 13'14 Thus it appears that administration of chemo- therapeutic agents in a time sequence is more important for optimal results. Addition of adriamycin in the induction phase and consolidation therapy in group IV children resulted in improving the survival rates as relapses were seen in only 29 percent of children while nine children in this group were having event-free survival between 18-24 months. Thus the early intensification of induction chemo- therapy and addition of consoli-dation therapy along with CNS chemoprophylaxis by methotrexate and radiotherapy have

CI I O U D I I RY A N D A R Y A : I N D U C T I O N R E G I M E N S IN A.L.L. 793

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Table IV. Distribution of bad prognostic factors in different induction regimens

Group I Group II Group III Group IV

Clinical Pred + 6MP Pred + VCR Pred + VCR + Pred + VCR + score n = 23 n = 29 L-Asp n = 45 Adria n = 40

No. % No. % No. % No. %

0 10 43.5 10 34.5 18 40 15 37.5

1 6 26.1 8 27.6 11 24.4 13 32.5

2 4 17.4 7 24.1 10 22.2 7 17.5

3 or more 3 13.0 4 13.8 6 -- 5 --

Children with poor score 84 (61.3%)

improved the results.

In the absence of other large studies from this country and observat ion of

overall poor results in the present series, it is suggested that studies with intensive chemotherapy with a larger number of chemotherapeutic agents during induction phase along with consolidation therapy,

should be conducted to improve the overall

survivals. Better supportive facilities should

be made available to decrease the mortality

during inducfion phase. Pulse therapy

consisting of agents either used during

induction therapy or with different chemo-

therapeutic agents may be employed to

prevent the relapses during the main- tenance phase as in other studies. 7,15'16 Poor

compliance has been responsible for

increased number of relapses in developing countries. 17 Feasible protocols need to be

designed in such a way that all children are

able to continue the chemotherapy. Such

studies should preferably be conducted as a

part of regional multicenteric trials or at national institutes with good supportive and investigative facilities.

References

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4. Simone JV. Childhood leukemia as a model for cancer research. The Richard & Hinda Rosenthal Foundation Award Lecture. CancerRes 1979; 39:4301-4307

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CIIOUDItRY AND ARYA : INDUCTION REGIMENS IN A.L.L 795

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