American Journal of Hematology 1:201-209 (1976)
CHEMOTHERAPY OF ACUTE LYMPHOBLASTIC LEUKEMIA IN CHILDREN Mahroo Haghbin, M.D. Memorial Sloan-Kettering Cancer Center, New York, New York
Between 1969-1973,75 consecutive children under the age of 15 years with acute lymphoblastic leukemia were treated with a multiple-drug regimen (L-2). Prophylaxis for meningeal leukemia was limited to the repeated intrathecal injections of methotrexate. Seventy-four patients achieved remission; the duration of remissions could be evaluated only for 70. Relapse terminated complete remission within 1-54 months in 2 1 children. Four of these relapses were confined to the central nervous system. Forty-nine patients continue in complete remission from 2 3 to 63 months. Chemotherapy has been discontinued in 29 children, and 25 of these remain without evidence of recurrence for 2-27 months posttreatment. Key words: acute leukemia, chemotherapy, lymphoblastic leukemia
INTRODUCTION
The opportunity for long-term disease-free survival in children with acute lymphoblastic leukemia has improved greatly within the past decade, but still one-half of the patients fail to reach a 5-year continuous complete remission mark (1). In order to improve upon what had already been accomplished, an intensive multiple-drug protocol was designed in 1969. The treatment program which is termed “L-2”was intended to increase the number of complete remissions as well as to lengthen their duration. MATERIALS AND METHODS
The outline of the protocol, which is composed of 3 phases: induction, consolidation and maintenance, is presented in Table I. The concepts leading to the formulation of this regimen and the details of drug administration have been reported before ( 2 , 3). In the induction regimen, the addition of daunorubicin to the conventional combination of prednisone and vincristine is aimed at achieving a higher remission rate. Following induction, the 2 subsequent phases of the protocol, consolidation and maintenance, are designed to prevent relapse through the elimination of the remaining leukemic cells (2). It is presumed that after induction, the growth fraction of the remaining leukemic cells will increase and the combination of arabinosyl cytosine and 6-thioguanine will be cytocidal to this proliferating population. L-asparaginase and 1-3 bis (2-chloroethyl)-l-nitrosourea (BCNU) are expected to cause further cytoreduction (2). It is hoped that by prolonged therapy with several drugs in the maintenance phase, the problem of persisting residual leukemic cells will be overcome. Address reprint requests t o M. Haghbin, M. D., 1275 York Avenue, New York, NY 10021.
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@ 1976 Alan R. Liss, Inc., 150 Fifth Avenue, New York, N.Y. 10011
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Haghbin
TABLE I. Outline of L-2 Protocol INDUCTION: Prednisone Vincristine Daunorubicin CONSOLIDATION: Arabinosyl cytosine 6-Thioguanine L-asparaginase 1-3-bis-(2-chtoroe thy1)1-nitrosourea (BCNU)
60 mg/m2 orally daily for 4 weeks 1.5-2 mg/mz intravenously weekly for 4 weeks 60 mg/m2 intravenously for 2 consecutive days 1 week rest
150 mg/m2 intravenously daily 75 mg/m2 orally daily both as S d a y courses for 4 courses with 2 days rest between courses 60,000 IU/m2 intravenously on alternate days for 1 2 doses following above
60 mg/m2 intravenously a single dose following above 2 weeks rest
MAINTENANCE: 300 mg/m2 orally daily for 4 days 6-Thioguanine 600 mg/mz intravenously on day 5 Cyclophosphamide 2,400 mg/m2 orally daily for 4 days Hydroxyurea Daunorubicin 45 mg/m2 intravenously on day 5 10 mg/m2 orally daily f o c 4 days Methotrexate BCNU 60 mg/ma intravenously on day 5 Arabinosyl cytosine 150 mg/m2 intravenously for 4 days Vincristine 2 mg/mz intravenously on day 5 I week rest between each 5 d a y course; new rotation starts with 6-Thioguanine after the rest from last course CNS PROPHYLAXIS: Intrathecal methotrexate 6.25 mg/m2 1 dose, day 4th of induction, 2 doses before, and 1 at the end of consolidation, 2 doses at the end of each rotation on maintenance, every 2 months.
Repetitive, intermittent administration of intrathecal methotrexate throughout the treatment course is the only method that was employed for the prevention of meningeal leukemia. In the initial design of the protocol, no provision for intrathecal methotrexate beyond the consolidation phase was made; an amendment was added in 1970 providing for continued intrathecal therapy during the maintenance. Between 1969-1973,75 consecutive children under 15 years of age with acute lymphoblastic leukemia who had no prior therapy or minimal therapy were entered on the L 2 protocol. The presenting features of these children are shown in Tables I1 and 111. The diagnosis was based on the examination of bone marrow smears stained with WrightGiemsa or Tetrachrome stain. The lymphoblasts are defined as cells measuring 12-20 l.t in diameter with a high nuclear to cytoplasmic ratio, agranular cytoplasm, and round or oval nucleus which contains 1-2 ill defined nucleoli. The nuclear chromatin is slightly, but visibly clumped. A minute or deep cleft of the nucleus is often seen. Bone marrow aspirations were performed at the end of induction, monthly through the consolidation phase, and every 2 months during the maintenance. Cerebrospinal fluid was examined at the time of each intrathecal injection, i.e., at the beginning of induction, prior to, and at the end of consolidation, and every 2 months thereafter. All cerebrospinal fluid samples were examined for their chemical (sugar and protein) and cellular contents. The diagnosis of meningeal leukemia was based on the morphology of the cells and not on pleocytosis alone. The morphology of the cells was studied on the centrifuged material
203
L y m p h o b l a s t i c Leukemia
TABLE 11. Presenting Features at the Time of Diagnosis in 75 Children Entered Into L-2 Protocol: Age, Sex, and Hematologic Values Age No. of Years patients
CHEMOTHERAPY OF ACUTE LYMPHOBLASTIC LEUKEMIA IN CHILDREN Mahroo Haghbin, M.D. Memorial Sloan-Kettering Cancer Center, New York, New York
Between 1969-1973,75 consecutive children under the age of 15 years with acute lymphoblastic leukemia were treated with a multiple-drug regimen (L-2). Prophylaxis for meningeal leukemia was limited to the repeated intrathecal injections of methotrexate. Seventy-four patients achieved remission; the duration of remissions could be evaluated only for 70. Relapse terminated complete remission within 1-54 months in 2 1 children. Four of these relapses were confined to the central nervous system. Forty-nine patients continue in complete remission from 2 3 to 63 months. Chemotherapy has been discontinued in 29 children, and 25 of these remain without evidence of recurrence for 2-27 months posttreatment. Key words: acute leukemia, chemotherapy, lymphoblastic leukemia
INTRODUCTION
The opportunity for long-term disease-free survival in children with acute lymphoblastic leukemia has improved greatly within the past decade, but still one-half of the patients fail to reach a 5-year continuous complete remission mark (1). In order to improve upon what had already been accomplished, an intensive multiple-drug protocol was designed in 1969. The treatment program which is termed “L-2”was intended to increase the number of complete remissions as well as to lengthen their duration. MATERIALS AND METHODS
The outline of the protocol, which is composed of 3 phases: induction, consolidation and maintenance, is presented in Table I. The concepts leading to the formulation of this regimen and the details of drug administration have been reported before ( 2 , 3). In the induction regimen, the addition of daunorubicin to the conventional combination of prednisone and vincristine is aimed at achieving a higher remission rate. Following induction, the 2 subsequent phases of the protocol, consolidation and maintenance, are designed to prevent relapse through the elimination of the remaining leukemic cells (2). It is presumed that after induction, the growth fraction of the remaining leukemic cells will increase and the combination of arabinosyl cytosine and 6-thioguanine will be cytocidal to this proliferating population. L-asparaginase and 1-3 bis (2-chloroethyl)-l-nitrosourea (BCNU) are expected to cause further cytoreduction (2). It is hoped that by prolonged therapy with several drugs in the maintenance phase, the problem of persisting residual leukemic cells will be overcome. Address reprint requests t o M. Haghbin, M. D., 1275 York Avenue, New York, NY 10021.
20 1
@ 1976 Alan R. Liss, Inc., 150 Fifth Avenue, New York, N.Y. 10011
202
Haghbin
TABLE I. Outline of L-2 Protocol INDUCTION: Prednisone Vincristine Daunorubicin CONSOLIDATION: Arabinosyl cytosine 6-Thioguanine L-asparaginase 1-3-bis-(2-chtoroe thy1)1-nitrosourea (BCNU)
60 mg/m2 orally daily for 4 weeks 1.5-2 mg/mz intravenously weekly for 4 weeks 60 mg/m2 intravenously for 2 consecutive days 1 week rest
150 mg/m2 intravenously daily 75 mg/m2 orally daily both as S d a y courses for 4 courses with 2 days rest between courses 60,000 IU/m2 intravenously on alternate days for 1 2 doses following above
60 mg/m2 intravenously a single dose following above 2 weeks rest
MAINTENANCE: 300 mg/m2 orally daily for 4 days 6-Thioguanine 600 mg/mz intravenously on day 5 Cyclophosphamide 2,400 mg/m2 orally daily for 4 days Hydroxyurea Daunorubicin 45 mg/m2 intravenously on day 5 10 mg/m2 orally daily f o c 4 days Methotrexate BCNU 60 mg/ma intravenously on day 5 Arabinosyl cytosine 150 mg/m2 intravenously for 4 days Vincristine 2 mg/mz intravenously on day 5 I week rest between each 5 d a y course; new rotation starts with 6-Thioguanine after the rest from last course CNS PROPHYLAXIS: Intrathecal methotrexate 6.25 mg/m2 1 dose, day 4th of induction, 2 doses before, and 1 at the end of consolidation, 2 doses at the end of each rotation on maintenance, every 2 months.
Repetitive, intermittent administration of intrathecal methotrexate throughout the treatment course is the only method that was employed for the prevention of meningeal leukemia. In the initial design of the protocol, no provision for intrathecal methotrexate beyond the consolidation phase was made; an amendment was added in 1970 providing for continued intrathecal therapy during the maintenance. Between 1969-1973,75 consecutive children under 15 years of age with acute lymphoblastic leukemia who had no prior therapy or minimal therapy were entered on the L 2 protocol. The presenting features of these children are shown in Tables I1 and 111. The diagnosis was based on the examination of bone marrow smears stained with WrightGiemsa or Tetrachrome stain. The lymphoblasts are defined as cells measuring 12-20 l.t in diameter with a high nuclear to cytoplasmic ratio, agranular cytoplasm, and round or oval nucleus which contains 1-2 ill defined nucleoli. The nuclear chromatin is slightly, but visibly clumped. A minute or deep cleft of the nucleus is often seen. Bone marrow aspirations were performed at the end of induction, monthly through the consolidation phase, and every 2 months during the maintenance. Cerebrospinal fluid was examined at the time of each intrathecal injection, i.e., at the beginning of induction, prior to, and at the end of consolidation, and every 2 months thereafter. All cerebrospinal fluid samples were examined for their chemical (sugar and protein) and cellular contents. The diagnosis of meningeal leukemia was based on the morphology of the cells and not on pleocytosis alone. The morphology of the cells was studied on the centrifuged material
203
L y m p h o b l a s t i c Leukemia
TABLE 11. Presenting Features at the Time of Diagnosis in 75 Children Entered Into L-2 Protocol: Age, Sex, and Hematologic Values Age No. of Years patients
