German Multicenter Trial for Adult ALL/ AUL, FRG.
Supported by the Bundesministerium für Forschung und Technologie.
Contract No.01 ZW 450
The German Multicenter Trial for Adult Acute Lymphoblastic (ALL)
and Acute Undifferentiated (AUL) Leukemia was undertaken to improve
remission duration by using a modified form of an intensified induction
regimen successful in childhood ALL (Riehm et al. 1980). The results
from the pilot study, with a total of 162 patients and a median
observation time of 41/2 years, now allow some conclusions regarding
prognostic factors which influence the achievement of complete remission
or the length of remission.
The concept of this therapeutic trial was to eradicate as much
as possible of the initial tumor cell load by an eight-drug induction
therapy and a similarly intensive early consolidation therapy after
3 months, whereas the maintenance therapy is conventional with 6-mercaptopurine
and methotrexate. The 8-week induction regimen consists of two phases:
In the first 4 weeks prednisone 60 mg/m² PO daily, vincristine 1.5
mg/m² IV once weekly, daunorubicin 25 mg/m² IV once weekly, and
l-asparaginase 5000 units/m² IV on days 1-14; and in the second
4 weeks cyclophosphamide 650 mg/m² IV 3 doses at 2-week intervals,
cytosine arabinoside 75 mg/m² IV on 4 days per week for 4 weeks,
and 6-mercaptopurine 60 mg/m² PO daily for 4 weeks. CNS prophylaxis
consists in methotrexate 10 mg/m² intrathecally each week and CNS
irradiation with 24 Gy. A 6-week reinduction course is given after
3 months and is similar to the induction regimen, adriamycin being
substituted for daunorubicin, dexamethasone for prednisone, and
thioguanine for 6-mercaptopurine; L-asparaginase is omitted. Maintenance
therapy with 6-mercaptopurine 60 mg/m² PO daily and methotrexate
20 mg/m² PO or IV once weekly is continued for 2 years. Further
details of the therapy and of the diagnostic procedure have been
described previously (Hoelzer et al. 1984).
From October 1978 to June 1981 a total of 162 adult patients from
25 hospitals entered the study, and 126 (77.8%) achieved complete
remission. At the evaluation date, 30 November 1983, the median
survival time for all patients was 23.4 months and that for complete
remitters was 34 months. Median remission duration was 20.5 months.
The probability of being in complete remission at 4 1/2 years is
0.397. Cell marker analysis identified c-ALL in 56.4%, null-AL (defined
as being non-B-ALL, non-T-ALL, cALLA-) in 25.6%, T-ALL in 15.4%,
B-ALL in 0%, and mixed leukemia in 2.6%.The best results were achieved
in patients with T -ALL for whom the probability of being in continuous
complete remission at 4 1/2 years is 0.636.
Table 1. Prognostic factors for remission
duration: Pilot study
D.Prognostic Factors and Risk Groups
Regarding the complete remission rate. none of the initial laboratory
or clinical features, such as age, leukocyte count, hepatosplenomegaly,
mediastinal tumor, CNS involvement, or other organ infiltration,
had an unfavorable influence on the achievement of complete remission.
The adverse effect of older age, high initial leukocyte count, and
hepatosplenomegaly, which have been shown in other studies to have
an unfavorable influence on the achievement of complete remission,
could not be confirmed in the large number of patients in this study
(Hoelzer et al. 1984).
Prognostic factors for remission duration (Table I) were time req
uired to achieve remission, initial leukocyte count, immunological
subtype, and age.
The difference in remission duration for patients above and below
35 years of age was evident. In earlier studies (Hoelzer 1984) higher
age was also found to exert an unfavorable influence on the survival
time and remission duration. This multicenter ALL/ AUL study has
proved that results for older patients who did not require any essential
omissions or reductions in the therapy program were similar to those
for younger patients. The main problem is that for many of the older
patients it is not possible to carry out the complete therapy schedule.
In this therapy study, as in other ALL studies in adults (Schauer
et al. 1983) or children, a high initialleukocyte count was found
to be unfavorable for a long remission.
The best prognosis in this study was for the subtype T-ALL, for
which the median remission duration has not yet been reached. This
finding is remarkable, since up to now patients with T-ALL, who
frequently have a high initial leukocyte count, a mediastinal tumor,
or CNS involvement, have had a poor prognosis. The worst prognosis,
in keeping with findings from another study (Lister et al. 1979),
was for patients with null-AL, who had a median remission duration
of 13 months. Of the patients with c-ALL, 44% were disease-free
at the evaluation date.
Time Required to Achieve Complete Remission.
The length of treatment required to achieve complete remission had
the strongest influence on remission duration. Late response to
therapy probably reflects a primarily more resistant population
of leukemic cells. Other adult ALL therapy studies have also shown
that of a total of 70% remission patients, only 50% achieved remission
within 4 weeks (Hoelzer 1984). In childhood ALL the proportion of
patients who reach complete remission after prolonged treatment
is very low ( < 5% ). For them, it is also true that late response
to therapy is correlated with a very poor prognosis (Frei and Sallan
II. Definition of Risk Groups
On the basis of these factors found to have prognostic significance
for remission duration in the pilot study, it was possible to define
groups of patients exposed to different degrees of risk. Those defined
as low-risk patients are the ones who have none of the four risk
factors, in comparison to high-risk patients who have one or more
of the four risk factors. At the last evaluation date of 30 November
1983, 79% of the low-risk patients were still in first remission,
whereas only 20% of the high-risk patients were still free of disease.
E. Risk-Adapted Therapy Protocol
The study group has developed anew riskadapted therapy protocol
based on the results of the pilot study, which was activated on
I July 1983. According to this, in addition to the intensive induction
therapy and consolidation therapy, high-risk patients will receive
further cycles of consolidation therapy with VM-26 and cytosine
arabinoside, to improve results in this group. In addition, the
high-risk patients are to be considered for allogeneic bone marrow
transplantation in first remission if a suitable donor is available.
After establishment of the method, autologous bone marrow transplantation
also appears to be useful for these patients. The low-risk patients
will be treated according to the present protocol with no essential
changes. It is to be expected that in this group, even with chemotherapy
alone, more than 50% will reach the 5-year limit without disease
and might thereby be considered as cured.
Frei E, Sallan SE (1978) Acute lymphoblastic leukemia. treatment.
Hoelzer D (1984) Current status of ALL/ AUL therapy in adults. In.
Thiel E, Thierfelder S (eds) Leukemia. Springer, Berlin Heidelberg
New York Tokyo, pp 182-203 (Recent results in cancer research, vol
Hoelzer D, Thiel E, Lamer H, Bodenstein H, Plaumann L, Büchner T,
Urbanitz D, Koch P, Heimpel H, Engelhardt R, Müller U, Wendt FC,
Sodomann H, Rühl H, Herrmann F, Kaboth W, Dietzfelbinger H, Pralle
H, Lunscken C, Hellriegel K-P, Spors S, Nowrousian RM, Fischer l,
Fülle H, Mitrou PS, Pfreundschuh M, Garg C, Emmerich B, Queisser
W, Meyer P, Labedzki L, Essers U, Kanig H, Mainzer K, Herrmann R,
Messerer D, Zwingers T ( 1984) Intensified therapy in acute lymphoblastic
and acute undifferentiated leukemia in adults. Blood 64:38-46
Lister TA, Roberts MM, Brearly RL, Woodruff RK, Greaves MF (1979)
Prognostic significance of cell surface phenotype in adult acute
lymphoblastic leukaemia. Cancer Immunol Immunother 6:227-230
Riehm H, Gadner H, Henze a, Langermann H-l, Odenwald E ( 1980) The
Berlin childhood acute lymphoblastic leukemia therapy study, 1970-1976.
Am 1 Pediatr Hematol Oncol 2:299-306
Schauer P, Arlin ZA, Mertelsmann R, Cirrincione C, Friedman A, Gee
TS, Dowling M, Kempin S, Straus Dl, Koziner B, McKenzie S, Thaler
HT, Dufour P, Little C, Dellaquila C, Ellis S, Clarkson B (1983)
Treatment of acute lymphoblastic leukemia in adults. Results of
the L-IO and L-I0M protocols. 1 Clin Oncol I :462-470