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seven are in second remission for 6 to 23 +
months and two have been reinduced into new
remissions after a second relapse off therapy.
The durations of their third hematologie remissions
are 7 + and 18 + months. Of the eight
patients who had treatment stopped for a second
time, one completed therapy only recently
and six are in unmaintained second remissions
for 12 + to 51 + months. Another child
who also developed a second relapse off
therapy attained a third remission and is now
off treatment a third time for 6 + months.
Among the 17 survivors, 14 have had
long-term leukemia-free remissions. Their
median survival since diagnosis is 9 years
(range 5-14 years), with a median of 33 +
months (range 19+ to 76+ mo) of continuous
complete remission since their last relapse.
F. Discussion
These results demonstrate that prolonged second
remissions are attainable in about onethird
of the patients who develop a marrow
relapse after elective cessation of initial cureoriented
therapy. Most importantly, in a certain
proportion of children therapy may be
stopped altogether for a second time. Although
it is still not possible to prediet the
likelihood of relapse in individual patients
after cessation ot treatment (Sirnone et al.
1978), statistical analysis of patient variables
at the time of relapse can provide a reliable
estimate of prognosis. Patients whose first
complete remission lasts Ion ger than 3 years,
whose first relapse occurs more than 6 months
after cessation of therapy, and whose si te of
relapse is exclusively hematologic have a significantly
better chance to attain a extended
second remission.
Other large series of patients are not available
for comparison. Instances of extended
se co nd remissions have been reported, but
only in patients who relapsed after unmaintained
remissions following short-term initial
therapy, i.e., 3-13 months (Leventhal et al.
1975).
When first diagnosed with ALL, none of the
children in these studies had clinical or biologie
features that are today regarded as carrying
a "high risk" for early treatment failure. The
most plausible explanation for their variable
therapeutic responsiveness is that subpopulations
of leukemic cells not eradicated by initial
treatment have different growth potentials,
which would account for the wide range in
duration of second remissions (3 to 78 +
months). For the few patients who remain free
of leukemia after completing a second course
of therapy, one could speculate that there
relapses stemmed from the emergence of
a new (and hence more drug-sensitive) clone
of leukemic cells. Evidence for the emergence
of different clones of leukemic cells in previously
treated patients is supported by several
re cent reports (Fisher et al. 1977; Merteksmann
et al. 1978; Spector et al. 1979).
The treatment results presented here were
obtained by administering a second program of
thera y :omparable to that originally given to
these children. The only notable exception was
that CNS prophylaxis was not repeated in
about one-half of the subjects, because at the
onset of the study the need for such additional
treatment was unknown. Repeating a treatment
that has be co me ineffective would not be
recommended today. It should be stressed,
however, that even in this circumstance about
onethird of our patients responded weIl to
therapy, an outcome that compares favorably
to results for initially treated childhood ALL.
Ultimately, the prospects for obtaining larger
proportions of long-term remissions following
relapse will depend on the development of
more effective chemotherapy, preferably with
agents not used earlier, to suppress the emergen
ce of drug-resistant disease. A new protocol
study to test the value of cyclie combination
chemotherapy for maintenance of second remissions
is underway at this center.
We conclude that children with ALL who
develop marrow relapses during unmaintained
remissions should be retreated just as aggressively
as newly diagnosed patients.
Acknowledgments
I thank J.R. Gilbert for criticisms and editorial
suggestions throughout preparation of this paper.
References
Aur RJA, Simone JV, Verzosa MS, Hustu HO,
Barker LS, Pinkel DP, Rivera G, Dahl GV, Wood A,
Stagner S, Mason C (1978) Childhood acute lymphocytic
leukemia. Study VIII. Cancer
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