Therapeutic Considerations in Acute Lymphocytic Leukemia James F. Holland, MD
Evidence that the first human neoplasm systematically explored with chemotherapeutic treatments has apparently been cured in a palpable segment of affected patients evolves optimism for other types of cancer. The application of similar effort, similar logic, and quantitative experimental therapeutic approaches to the common cancers augurs well for cancer research and clinical medicine. (Am J Pathol 90:521-528, 1978)
IT IS NO ACCIDENT that acute lymphocytic leukemia is the crucible in which chemotherapy and immunotherapy have both first been launched. Twenty years of research in acute lymphocytic leukemia by the Cancer and Leukemia Group B, involving 2000 patients, is shown in Text-figure 1. The plateaus, at 8 to 10 years, give some intimation of cures of this disease. This is more easily seen when plotted on a semi-logarithmic graph (Text-figure 2). The slopes, which might be called the death functions, show progressive decreases. All patients are not receiving the same treatment. They are stratified and randomized to several comparison arms within each study. Each curve contains both worse and better regimens. The best regimens of the Cancer and Leukemia Group B from 1963 on are shown in Text-figure 3. Some plateaus are now up to 10 years. There is little likelihood that patients will die of the disease after several years of a plateau in the entire population. A clinical translation of the contribution of Skipper and Schabel and their colleagues concerning induction, intensive treatment, and other concepts of cell kinetics relating to the potential for killing cells and for quantifying the number killed was made in 1963 and is shown in Textfigure 4. Patients remained untreated after intensive therapy. We tried to estimate the number of leukemic cells remaining in the marrow, spleen, nodes, liver, and blood based on simplistic extrapolations from calculated data. We calculated that 237 leukemic cells were present at diagnosis in children with acute lymphocytic leukemia. The effect of chemotherapy was to decrease the population "by extrapolated reasoning" by approxiFrom the Department of Neoplastic Diseases, Mount Sinai School of Medicine, New York, New York. Supported in part by Grants CA-04457 and 2R10-CA 16118-03 from the National Cancer Institute. Presented at the Sixty-first Annual Meeting of the Federation of American Societies for Experimental Biology, Chicago, Illinois, April 6, 1977. Address reprint requests to Dr. James F. Holland, Department of Neoplastic Diseases, Mount Sinai School of Medicine, New York, NY 10029.
521
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YEARS FROM PROTOCOL -
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MED- 6 MIOS f1EDO 6 11OS MED213 MOS MED-22 MOS 1EDzl7 MOS MIEDO28 M10S llED-32 fiOS
HEOD'9 OS NO MED
LD
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TEXT-FIGURE 1 (top )-Results of 20 years (1956-1976)
in C-)-
of research involving patients with lymphocytic leuTEXT-FIGURE 2 kemia.
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Vol. 90, No. 2 February 1978
523
THERAPEUTIC CONSIDERATIONS
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65/68 57/60 38/56 11/36 13/71
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mately two thirds in exponential terms. If we had extended the treatment for 120 days, and if killing had continued at the same rate, it might have led to complete cell killing. Since we are often 100% wrong, we extended the next program to 240 days. Induction was followed by intensive treatment for 8 months, sometimes with pulsed reinforcement; then at random some patients were left untreated (Text-figure 5). The duration of complete remissions from the time of last chemotherapy is plotted in Text-figure 6. Patients were observed without further treatment after either 8 months or 3 months of methotrexate courses. Those treated with three courses of treatment had a steep relapse curve.
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TEXT-FIGURE 4-Model of leukemic cell kinetics.
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524
American Journal of Pathology
HOLLAND
TEXT-FIGURE 5-Study design for protocol ALB No. 6601.
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10
TEXT-FIGURE 6-Duration of unmaintained complete remission in children with
acute
lymphocytic
leukemia. Remission was induced with vincristine and prednisone. Subsequent 5-day courses of methotrexate were given approximately every 2 weeks for 3 courses (1 month) or for 8 months. One group also received vincristine and prednisone reinforcement of the methotrexate.
Vol. 90, No. 2 February 1978
525
THERAPEUTIC CONSIDERATIONS
Except one child without relapse at 7 years, no patient stayed in remission more than 1½/2 years. The group of children who received 8 months of courses of methotrexate are in unmaintained remission 7 and 8 years later without treatment; those who received 8 months of courses of methotrexate plus vincristine and prednisone reinforced treatments show the highest proportion of survivors without disease in the 7- to 9-year period after cessation of treatment. It therefore appears possible to cure acute lymphocytic leukemia with chemotherapy in approximately 20 to 30% of patients, using the best arm of this protocol. We have tried to improve this result many times by using intensive continued courses of methotrexate and of 6-mercaptopurine. The studies have not gone on for enough years to allow us to say that we have improved it. We have embarked on other studies, too, which are continuous maintenance programs instead of intensive treatments. In a continuous maintenance program of 6-mercaptopurine, conducted many years ago, vincristine and prednisone used during the course of the remission prolonged the duration of remission from maintenance chemotherapy, a phenomenon we call reinforcement (Text-figure 7). I nn_ lu
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TEXT-FIGURE 7-Duration of remissions maintained by daily oral 6-mercaptopurine alone or in addition to monthly inducer (reinforcement) doses of vincristine and prednisone.
American Journal of Pathology
HOLLAND
526
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TEXT-FIGURE 9-Duration of complete remission in children in program 6801 of the Cancer and Leukemia Group B. The dotted line represents children who received intrathecal methotrexate during their remission induction, did not receive daunorubicin, and were maintained on a combination of 6mercaptopurine and methotrexate. The solid line represents patients receiving identical chemotherapy, randomized not to receive the intrathecal methotrexate. The difference is significant.
Vol. 90, No. 2 February 1978
THERAPEUTIC CONSIDERATIONS
527
In 1968 a protocol was initiated with five randomizations, 26, for 32 arms. Patients up to 21 years of age did or did not receive asparaginase, received vincristine and prednisone with or without daunorubicin, did or did not receive intrathecal methotrexate, received methotrexate alone or in combination with 6-mercaptopurine, and received reinforcement doses of vincristine and prednisone or of vincristine, prednisone, and daunorubicin (Text-figure 8). The outcome of this study was that certain of these randomizations conveyed specific and particular advantage and others did not. In the best of the arms, 60% of those children who reached remission remained in remission for 5 years and more (Text-figure 9). At 5 years the treatment was discontinued in one half the patients at random. We do not know the proper time to stop treatment. We do not think that it is at 3 years as others have advocated, because relapses are still occurring. The long plateau is of considerable importance, suggesting the possibility that the disease can be eradicated by maintenance treatments. The difference between the two arms is the net effect of giving intrathecal methotrexate.
528
HOLLAND
American Journal of Pathology
[End of Article]
Evidence that the first human neoplasm systematically explored with chemotherapeutic treatments has apparently been cured in a palpable segment of affected patients evolves optimism for other types of cancer. The application of similar effort, similar logic, and quantitative experimental therapeutic approaches to the common cancers augurs well for cancer research and clinical medicine. (Am J Pathol 90:521-528, 1978)
IT IS NO ACCIDENT that acute lymphocytic leukemia is the crucible in which chemotherapy and immunotherapy have both first been launched. Twenty years of research in acute lymphocytic leukemia by the Cancer and Leukemia Group B, involving 2000 patients, is shown in Text-figure 1. The plateaus, at 8 to 10 years, give some intimation of cures of this disease. This is more easily seen when plotted on a semi-logarithmic graph (Text-figure 2). The slopes, which might be called the death functions, show progressive decreases. All patients are not receiving the same treatment. They are stratified and randomized to several comparison arms within each study. Each curve contains both worse and better regimens. The best regimens of the Cancer and Leukemia Group B from 1963 on are shown in Text-figure 3. Some plateaus are now up to 10 years. There is little likelihood that patients will die of the disease after several years of a plateau in the entire population. A clinical translation of the contribution of Skipper and Schabel and their colleagues concerning induction, intensive treatment, and other concepts of cell kinetics relating to the potential for killing cells and for quantifying the number killed was made in 1963 and is shown in Textfigure 4. Patients remained untreated after intensive therapy. We tried to estimate the number of leukemic cells remaining in the marrow, spleen, nodes, liver, and blood based on simplistic extrapolations from calculated data. We calculated that 237 leukemic cells were present at diagnosis in children with acute lymphocytic leukemia. The effect of chemotherapy was to decrease the population "by extrapolated reasoning" by approxiFrom the Department of Neoplastic Diseases, Mount Sinai School of Medicine, New York, New York. Supported in part by Grants CA-04457 and 2R10-CA 16118-03 from the National Cancer Institute. Presented at the Sixty-first Annual Meeting of the Federation of American Societies for Experimental Biology, Chicago, Illinois, April 6, 1977. Address reprint requests to Dr. James F. Holland, Department of Neoplastic Diseases, Mount Sinai School of Medicine, New York, NY 10029.
521
z
V0-4 (I) z
LLJ
0LI
0
YEARS FROM PROTOCOL -
39/39 299/301 l117/151 6307-6311 91/95 177/183 6313 6601 22i/285 6801 317/459 7111 271/646 37/30q 7411
5631 5702 6005
MED- 6 MIOS f1EDO 6 11OS MED213 MOS MED-22 MOS 1EDzl7 MOS MIEDO28 M10S llED-32 fiOS
HEOD'9 OS NO MED
LD
I-1
TEXT-FIGURE 1 (top )-Results of 20 years (1956-1976)
in C-)-
of research involving patients with lymphocytic leuTEXT-FIGURE 2 kemia.
0z llJ
(L
(bottom)-Semilogarithmic graph of data in Textfigure 1. 0
YERRS FROM PROTOCOL 5601 ....... ...
*.
*............. -
-
-
@ " -@ @
-
-
-
5702 6005
39/39 MEDO 6 MOS 299/301
*6307-6311 91/95 6313 177/163 6601 224/285 317/459 6601 7111 271/646
7411
MEOr
'
1147/151 MEO=13
37/30q
MED'22 MED=17 NED=28 MED-32 MED=49
MOS MOS
NOS MOS NOS NOS NOS
NO MED
Vol. 90, No. 2 February 1978
523
THERAPEUTIC CONSIDERATIONS
X
'
b-I
~~~
h~I*
o 23z
H H
'm
:D
a
tn
6
TEXT-FIGURE 3-Best regimens of Cancer and Leukemia Group B (1963-1974).
14
6-
2E
I
x
2
1
3
a
5
6
7
8
9
10
YEARS FROM PROTOCOL ---
-------
.........
*
.
I
-
6307-6311 MTX BIV MfIfNT 6313 6M CYT MTX(I COURSE).UNMNT 6601 MTX/VP (8 MOS COURSES).UNMNT 68601 6MP MTX VP IT MTX.Mfi]NT 7111 6MP MIX VP IT MTXX.M"INT
65/68 57/60 38/56 11/36 13/71
MED=2q MOS MEOt23 MGS MEDOAS MOS NO MED MED-47 MOS
mately two thirds in exponential terms. If we had extended the treatment for 120 days, and if killing had continued at the same rate, it might have led to complete cell killing. Since we are often 100% wrong, we extended the next program to 240 days. Induction was followed by intensive treatment for 8 months, sometimes with pulsed reinforcement; then at random some patients were left untreated (Text-figure 5). The duration of complete remissions from the time of last chemotherapy is plotted in Text-figure 6. Patients were observed without further treatment after either 8 months or 3 months of methotrexate courses. Those treated with three courses of treatment had a steep relapse curve.
It it
TEXT-FIGURE 4-Model of leukemic cell kinetics.
hi
hi a hi -J a
I-,
nL
DAYS ON STUDY
524
American Journal of Pathology
HOLLAND
TEXT-FIGURE 5-Study design for protocol ALB No. 6601.
z C)
Ur) X:
e IrLJ LU :-
0
In
Om Om~~ =
z I-
a:
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C) Lii
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YEARS FROM LAST CHEMOTHERAPY A
@ a0O.0
0
35/37 ONE MONTH FTX COURSES 27/33 EIGHT mO'S MTX COURSES EIGHT MO'S MTX COURSES. VCR+PRI 25/33 P-
10
TEXT-FIGURE 6-Duration of unmaintained complete remission in children with
acute
lymphocytic
leukemia. Remission was induced with vincristine and prednisone. Subsequent 5-day courses of methotrexate were given approximately every 2 weeks for 3 courses (1 month) or for 8 months. One group also received vincristine and prednisone reinforcement of the methotrexate.
Vol. 90, No. 2 February 1978
525
THERAPEUTIC CONSIDERATIONS
Except one child without relapse at 7 years, no patient stayed in remission more than 1½/2 years. The group of children who received 8 months of courses of methotrexate are in unmaintained remission 7 and 8 years later without treatment; those who received 8 months of courses of methotrexate plus vincristine and prednisone reinforced treatments show the highest proportion of survivors without disease in the 7- to 9-year period after cessation of treatment. It therefore appears possible to cure acute lymphocytic leukemia with chemotherapy in approximately 20 to 30% of patients, using the best arm of this protocol. We have tried to improve this result many times by using intensive continued courses of methotrexate and of 6-mercaptopurine. The studies have not gone on for enough years to allow us to say that we have improved it. We have embarked on other studies, too, which are continuous maintenance programs instead of intensive treatments. In a continuous maintenance program of 6-mercaptopurine, conducted many years ago, vincristine and prednisone used during the course of the remission prolonged the duration of remission from maintenance chemotherapy, a phenomenon we call reinforcement (Text-figure 7). I nn_ lu
q, sC;
_
>0
%.0-0
P.O. Group (N
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-
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TEXT-FIGURE 7-Duration of remissions maintained by daily oral 6-mercaptopurine alone or in addition to monthly inducer (reinforcement) doses of vincristine and prednisone.
American Journal of Pathology
HOLLAND
526
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TEXT-FIGURE 9-Duration of complete remission in children in program 6801 of the Cancer and Leukemia Group B. The dotted line represents children who received intrathecal methotrexate during their remission induction, did not receive daunorubicin, and were maintained on a combination of 6mercaptopurine and methotrexate. The solid line represents patients receiving identical chemotherapy, randomized not to receive the intrathecal methotrexate. The difference is significant.
Vol. 90, No. 2 February 1978
THERAPEUTIC CONSIDERATIONS
527
In 1968 a protocol was initiated with five randomizations, 26, for 32 arms. Patients up to 21 years of age did or did not receive asparaginase, received vincristine and prednisone with or without daunorubicin, did or did not receive intrathecal methotrexate, received methotrexate alone or in combination with 6-mercaptopurine, and received reinforcement doses of vincristine and prednisone or of vincristine, prednisone, and daunorubicin (Text-figure 8). The outcome of this study was that certain of these randomizations conveyed specific and particular advantage and others did not. In the best of the arms, 60% of those children who reached remission remained in remission for 5 years and more (Text-figure 9). At 5 years the treatment was discontinued in one half the patients at random. We do not know the proper time to stop treatment. We do not think that it is at 3 years as others have advocated, because relapses are still occurring. The long plateau is of considerable importance, suggesting the possibility that the disease can be eradicated by maintenance treatments. The difference between the two arms is the net effect of giving intrathecal methotrexate.
528
HOLLAND
American Journal of Pathology
[End of Article]
