6 Therapy of B-cell acute lymphoblastic leukaemia in childhood: The BFM experience

6 Therapy of B-cell acute lymphoblastic leukaemia in childhood: The BFM experience ALFRED REITER

To Prof. Dr Hansj6rg Riehm who initiated the treatment strategy describedin this chapter, dedicated to his 60th anniversary. B-ceU acute lymphoblastic leukaemia (B-ALL) was recognized in the late 1970s as a rare sub-type of childhood ALL (Flandrin et al, 1975; Wolff et al, 1976). The most striking features are the frequent presence of gross lymphomatous tumours, and a poor response to therapy protocols which proved otherwise very successful in childhood ALL. The leukaemic cells are characterized by surface expression of monoclonal irnmunoglobulins and an L3 morphology according to the French-American-British (FAB) classification (Flandrin et al, 1975; Bennett et al, 1976; Greaves et al, 1981; Crist et al, 1985). The relationship of B-ALL to Burkitt's lymphoma was recognized early, and it was hypothesized that both represent different manifestations of Burkitt's lymphoma rather than different diseases (Magrath and Ziegler, 1979). The relationship was confirmed by the detection of three non-random chromosomal translocations t(8;14)(q24;q32), t(2;8)(p12;q24), and t(8;22)(q24;q11) in both Burkitt's lymphoma and B-ALL cells (Berger and Bernheim 1982; First MIC Cooperative Study Group, 1986). The pattern of treatment failure in both B-ALL and Burkitt's lymphoma is characterized by initial non-response or a very early relapse (Flandrin et al, 1975; Ziegler, 1977; Mtiller-Weihrich et al, 1982; Lemerle, 1985). The rapid fatal course of the disease corresponds to the high proliferation rate and the short cell cycle time of the malignant cells with an estimated cell generation time of 25 h (Iversen et al, 1974; Murphy et al, 1979). Different study groups have developed therapy strategies especially designed for these B-cell neoplasms which have some principles in common (Miiller-Weihrich et al, 1984; Murphy et al, 1986; Patte et al, 1986). The treatment protocols include cyclophosphamide, and methotrexate (MTX), which has been proven effective in Burkitt's lymphoma (Djerassi and Kim, 1976; Ziegler, 1977; Ramirez et al, 1979). The schedules are characterized by continuous infusion, and fractionation of drugs. The rationale is to maintain cytotoxic serum drug concentrations over 3-5 days. Ideally, this would give every malignant cell the chance to enter the cell cycle (Murphy et al, 1985). This type of therapy course results in a high-dose intensity in order Baillibre's ClinicaIHaernatotogy--

Vol. 7, No. 2, June 1994 ISBN0-7020-1825-2

321 Copyright© 1994,by Bailli6reTindall All rights of reproductionin any form reserved

322

A. REITER

to reach a maximal cell kilt with each course. A severe post-chemotherapeutic bone marrow hypoplasia is accepted. The therapy courses are administered with a short interval in between to minimize the chance of leukaemic cell regrowth. With this kind of highly intensive, short-pulse therapy delivered within a few weeks after diagnosis the event-free survival (EFS) of children suffering from B - A L L could be improved to more than 70% (Patte et al, 1991; Reiter et al, 1992). In this chapter the therapy strategy, its evolution, and the therapy results for B - A L L patients of three consecutive multi-centre studies of the Berlin-Frankfurt-Miinster (BFM) G r o u p are presented. The three studies ALL-BFM-81, ALL-BFM-83, A L L - B F M - 8 6 will be referred to as studies 81, 83, 86.

PATIENTS AND PATIENT C H A R A C T E R I S T I C S From April 1981 to March 1990 a total of 87 B - A L L patients was enrolled in the three studies 81, 83, and 86 after informed consent. All patients who were -< 18 years of age, and had been newly diagnosed as suffering from

Table 1. Patient characteristics. ALL-BFM-81 (Apr 1981Sept 1983) Patients Male:female Age (years) Median Range Peripheral blood blasts (per IM) Median Range BM blasts (%) 25-50 51-89 ___90 CNS involvement (patients) Organ involvement (patients) Hepatomegaly >_4 cm* Splenomegaly _>4 cm* Kidney(s) Skeleton Testes Ovaries Lymphomatous tumours Karyotype t(8;14) t(8;22) del 8q24 Normal Not available * Below costal margin.

ALL-BFM-83 (Oct 1983Sept 1986)

ALL-BFM-86 (Oct 1986Mar 1990)

22 16:6

24 19:5

41 35:6

10.7 3.0-15.75

7.6 2.25-18.0

8.0 0.9-16.5

1328 64-33,856

808 0-17,958

831 0-106,600

6 8 8 8

3 14 7 7

6 19 16 0

10 4 12 5 1 1 13

7 4 8 5 1 2 19

16 12 13 9 1 1 30

1 0 0 0 21

6 1 0 2 15

14 0 1 7 19

323

THERAPY OF B-ALL IN CHILDHOOD

B-ALL were eligible for these studies. B-ALL was diagnosed when 25% or more FAB L3 lymphoblasts were present in the bone marrow (BM). The presence of surface immonoglobulin (SIg) was determined in 62 patients (71%) using standard techniques as described elsewhere (Ludwig et al, 1988). In 25 patients, the diagnosis of B-ALL was based on L3 morphology only, because immunophenotyping was not available. The details of immunophenotyping, and chromosome analyses have been described elsewhere (Reiter et al, 1992). Patient characteristics are summarized in Table 1. The study populations were comparable with respect to age, sex, the number of peripheral blasts, the extent of BM replacement, organ involvement, and the presence of banphomatous tumours. However, in contrast to studies 81 and 83 no patient in study 86 had overt central nervous system (CNS) disease at the time of diagnosis. Sixty-two of the 87 cases (71%) had gross lymphomatous tumours at the time of diagnosis. Of the remaining 25 'ALL-type' patients, ten had kidney and/or skeletal involvement, but 15 had no detectable localized infiltrates. In six of the nine patients with a normal diploid karyotype of the blasts, the presence of SIg was determined, and light chain restriction K or X found in four of them.

T H E R A P Y S T R A T E G Y A N D RESULTS

The general treatment strategy and its development is shown in Figure 1. All patients received a 5 day pre-phase (V) (prednisone 30 mg/m 2 per day orally (p.o.) combined with cyclophosphamide 200mg/m 2 per day intravenously (i.v.)) for careful reduction of the leukaemic cell mass in order to prevent an acute cell lysis syndrome. The first therapy course followed immediately thereafter. ALL-BFM

THERAPY

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Figure 1. Treatment strategy for B-ALL in studies ALL-BFM-81, ALL-BFM-83, and ALLBFM-86. V, cytoreductive pre-phase: prednisone 30mg/m z orally x 5 days and cyclophosphamide 200mg/m z i.v. x 5 days; PRED, prednisone 60mg/m 2 per day. B1 and B2, therapy courses in study ALL-BFM-81. B1, B2, Blz, B2z, therapy courses in study ALL-BFM-83. AA and BB, therapy courses in study ALL-BFM-86. RX, CNS irradiation. *, in the first year of study ALL-BFM-81, RX was performed after completion of chemotherapy in CNS-negative patients, but earlier in CNS-positive patients. Later on, RX was applied after the first two therapy courses in all patients. (Reproduced with permission of W.B. Saunders Co.)

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methotrexate; CP, cyclophosphamide; DOX, doxorubicin; DEXA, dexamethasone; VCR, vincristine; IFO, ifosfamide; PRED-S prednisolone; i.v., intravenously; INF, infusion; i.t., intrathecally; i.ventr., intraventricularly; p.o., orally; h, hour. In study ALL-BFM-83, courses B1 and B2 (Figure 1) were identical to courses B1 and B2 of study ALL-BFM-81 but supplemented with DEXA. (Reproduced with permission of W.B. Saunders Co.)

Figure 2. Therapy courses in studies ALL-BFM-81, ALL-BFM-83, and ALL-BFM-86. VM26, teniposide; ARA-C, ara-C (cytarabine); MTX,

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325

THERAPY OF B-ALL IN CtIILDHOOD

Study ALL-BFM 81

Therapy Two different chemotherapy courses were given up to a total of eight courses. The therapy courses B 1 and B2 were composed of an intermediatedose (ID)-MTX, fractionated cyclophosphamide, and teniposide (VM26)/ ara-C (cytarabine) i.v. (course B1) or doxorubicin (course B2). The details are given in Figure 2. Ten percent of the ID-MTX was given i.v. as a loading dose over 30 rain. Ninety percent of the dose were administered in the form of a 23.5 h continuous i.v. infusion. Intrathecal (i.t.) MTX was given at hour 2. Citrovorum factor (CF) rescue (12 mg/m2) was administered at hours 48 and 54, intramuscularly (i.m.). Conditions to start a course of therapy were: platelets > 50 000/txl, white blood cell count (WBC) > 1000/~1, neutrophils > 200/~1 for courses, 2, 3, 4; W B C > 2000/~xl and neutrophils > 500/p.1 for the following courses. Cranial irradiation (RX) was incorporated. The dosage was 24 Gy for CNS-negative patients. CNS-positive patients received 30Gy, plus additional spinal irradiation up to 24 Gy. Doses were reduced for children < 2 years of age.

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Figure 3. Probability of duration of EFS (pEFS) for B-ALL patients in study ALL-BFM-81, ALL-BFM-83, ALL-BFM-86; p(study 81: study 86) = 0.014; p(study 83: study 86) = 0.025;/, indicates last patient entering each study, pEFS was calculated using the Kaplan and Meier method (1958) with differences compared by the log-rank test (Mantel, 1966). Failure to achieve CR (non-response, early death) or termination of first remission (relapse, death in CCR, second malignancy) were evaluated as events.

326

A. REITER

Local therapy. S e c o n d

l o o k s u r g e r y was p r o j e c t e d for p a t i e n t s w i t h a b d o m i nal d i s e a s e w h o h a d r e s i d u a l t u m o u r s a f t e r t w o t h e r a p y c o u r s e s . L o c a l r a d i o t h e r a p y at a d o s e o f 2 5 - 3 0 G y was r e s t r i c t e d to p a t i e n t s with r e s i d u a l u n r e s e c t a b l e disease.

R~u~ T h e m o s t i m p o r t a n t e x p e r i e n c e s f r o m s t u d y 81 w e r e as follows. T h e historically p o o r o u t c o m e of B - A L L p a t i e n t s i m p r o v e d to a 2 y e a r d u r a t i o n of E F S o f a b o u t 4 5 % ( F i g u r e 3); t h e r e m a i n i n g r e l a p s e s o c c u r r e d while o n t h e r a p y o r s h o r t l y a f t e r t e r m i n a t i o n o f t h e r a p y ; t h e C N S w a s t h e p r e d o m i n a n t site o f t h e r a p y f a i l u r e ( T a b l e 2).

Study ALL-BFM 83

Therapy T w o m a i n c h a n g e s as c o m p a r e d with s t u d y 81 w e r e m a d e . F i r s t , t h e r a p y d u r a t i o n was r e d u c e d f r o m e i g h t to six c o u r s e s ( F i g u r e 1). S e c o n d l y , C N S c h e m o t h e r a p y was intensified. M T X i.t. was g i v e n on d a y 1 o f t h e cytor e d u c t i v e p r e - p h a s e . D e x a m e t h a s o n e was i n c o r p o r a t e d i n t o e a c h c o u r s e . A f t e r t h e first c o u r s e B1, a s u b c u t a n e o u s r e s e r v o i r was i m p l a n t e d f o r i n t r a v e n t r i c u l a r d e l i v e r y o f M T X a n d a r a - C in c o u r s e s 2 - 5 ( c o u r s e s B l z a n d B2z) ( F i g u r e s 1 a n d 2). T h e d o s a g e s of R X r e m a i n e d u n c h a n g e d b u t spinal i r r a d i a t i o n was o m i t t e d .

Table 2. Treatment results. Patients CR achieved Early death Death in CCR Remission failure Relapses Site of failuret CNS CNS/BM BM BM/local Local Second malignancy Lost to follow-up CCR Follow-up, range (years)

ALL-BFM-81

ALL-BFM-83

ALL-BFM-86

Total

22 20 0 1 2 9

24 22 1 0 1 10

41 38 2 1 1 5

87 80 3 2* 4 24

65 2 2 1 0 1 2 7 9.5-11.8

0 3 8 0 0 0 1 11 6.5-9.4

1 0 0 2 3 0 0 32 3.0-6.4

7:~ 5 10 3 3 1 3§ 50 11.8-3.0

* One patient due to multi-organ dysfunction after two therapy courses, and one after four therapy courses with disseminated alveolar infiltrations. In both cases no micro-organisms and no other reasons for death were found upon autopsy. t Remission failure or relapse. $ One patient had additional skin involvement at relapse. § After 18 months, 5.8 and 9.5 years of observation.

THERAPY OF B - A L L IN C H I L D H O O D

327

Results The overall outcome of patients in study 83 was comparable to the outcome of patients in study 81 despite the shortened therapy duration (Figure 3). Therapy failure in the CNS compartment could be reduced (Table 2). BM was now the predominant site of failure.

Study ALL-BFM 86

Therapy The main goal was to reduce systemic relapses. The following changes in the therapy regimen as compared with study 83 were made (Figures 1 and 2): ID-MTX was replaced by high-dose (HD)-MTX (5 g/m2), and vincristine was added to each course. In course AA, cyclophosphamide was replaced by ifosfamide and the dosages of VM26 and ara-C were increased and fractionated. The schedule of HD-MTX administration was identical with that of ID-MTX in studies 81 and 83 but the CF rescue was started at hour 36 with 75mg/m 2 i.v., followed by five doses of 15mg/m 2 i.v./p.o, every 3h and additional four doses every 6 h. In 10/1988 the CF rescue was reduced to six doses of 15mg/m2 every 6h. MTX/ara-C/prednisolone i.t. in two fractionated dosages per course was introduced for local CNS therapy. The intraventricular route of drug administration was no longer used. CNS irradiation was omitted.

Results The estimate for a 5 year duration of EFS (pEFS) for the patients in study 86 is 78 + 6% (Figure 3). No isolated BM relapse and only one CNS relapse occurred. In that study abdominal tumours were involved in four of the five relapses (Table 2). The therapy results of all three studies are summarized in Table 2. Overall, 80 of the 87 patients (92%) achieved complete remission (CR). Three patients died before CR was achieved, one due to overwhelming disease at day 2, and two patients died an early toxic death. Two patients suffered from toxic death in continuous CR (CCR). Four patients failed to achieve a CR and died. Only two of the 24 patients who suffered from relapse survived, 4.9 years and 2.3 years after allogeneic and autologous BM transplantation, respectively. Fifty patients from the total group are still in their first CCR with a minimal follow-up of 3 years.

Therapy realization and morbidity. The median time for completing chemotherapy was 6 months in study 81, and 4 months in studies 83 and 86. Impaired renal functions due to hyperuricaemia or/and kidney infiltration, requiring haemodialysis and a reduction of the chemotherapy were observed in two, two and four patients of studies 81, 83 and 86, respectively. Severe neutropenia < 500/lxl was observed in all patients after most of the therapy courses. The most frequent morbidity was oro-intestinal mucositis.

328

A. REITER

Local therapy. Second look surgery was performed in ten patients. Only one patient had a vital residual tumour (study 86), and received local radiotherapy for it. However, the tumour rapidly progressed during therapy. DISCUSSION AND CONCLUSIONS The impact of different therapy intensity on outcome

The probability of EFS (pEFS) at 5 years for the 41 patients in study 86 is 78% which is significantly higher when compared with pEFS for the patients in study 81 (P<0.02) and 83 (P<0.03) (Figure 3). The evaluation of the effect of the intensified therapy approach on the improved outcome in study 86 is limited by the lack of CNS-positive patients in that study. The probability of EFS for the patients in study 86 still appears to be higher when the comparison is restricted to the CNS-negative patients in studies 81 (n=14, pEFS=57_+13%, p=0.13), and 83 (n=17, p E F S = 5 3 + 1 2 % , p = 0.067). The difference is statistically not significant, but the numbers of CNS-negative patients in studies 81 and 83 are critically small. We attribute the favourable outcome in study 86 mainly to the introduction of HD-MTX. The high proliferation rate of B-ALL blasts (Iversen et al, 1974; Murphy et al, 1979) may make the cells especially vulnerable to the cytotoxic action of HD-MTX (Hryniuk et at, 1969). MTX is incorporated in most successful therapy regimens for B-ALL and B-cell lymphomas (Hann et al, 1990; Patte et al, 1991; Schwenn et al, 1991; Bowman et al, 1992). Our HD-MTX schedule in study 86 differed from that of other groups in that either a higher dose of 5 g/m 2 was given, the infusion time was extended to 24 h, or the beginning of the CF rescue was not started until hour 36. This schedule is sensitive to cytotoxic properties of MTX. Serum concentrations of MTX above 20 txmol/l are achieved and allow intracellular MTX uptake by passive diffusion in addition to the active transmembrane transport (Warren et al, 1978; Milano et al, 1990). The prolonged exposure favours the time-dependant intracellular MTX-polyglutamate synthesis (Schilsky et al, 1980) and the cytotoxic action of MTX (O'Keefe et al, 1982). Furthermore, cytotoxic MTX concentrations _>lp.mol/l are achieved in the cerebrospinal fluid (CSF) (Hryniuk and Bertino, 1969; Milano et al, 1990), and are boosted by i.t. MTX application 2 h after the start of MTX infusion. CNS therapy

Initial CNS disease has previously been considered a poor prognostic indicator in B-ALL (Murphy et al, 1986; Patte et al, 1986). Intriguing preliminary results from CNS-positive patients were recently reported from the French study LMB 86 (Patte et al, 1990). In this therapy strategy HD-ara-C, HD-etoposide, HD-MTX 8 g/m 2 (4-h infusion), and CNS irradiation were incorporated. For 23 CNS-positive B-ALL and stage IV B-cell non 1 Hodgkin's lymphoma (NHL) patients, an EFS of 75% was achieved. The benefit of CNS irradiation may be uncertain even for CNS-positive patients.

24 0 0.5x8 8/0 0/0 0 14 5 1 2

30 24 0.5x8 8/0 0/0 0 8 6 4 1

CNS positive 24 0 0.5x6 3/16 0/4 0 17 7 0 1

CNS negative 30 0 0.5x6 3/16 0/4 0 7 4 0 2

CNS positive

ALL-BFM-83

* Dosages for i.t, and intraventricularly (i,vent.) administration as given in Figure 2. t Remission failure or relapse.

Cranial RT (Gy) Spinal RT (Gy) MTX (g/m2 x n) MTX (i.tJi.vent,* x n) Ara-C (i.t Ji.vent. * x n) Prednisolone (i.t.* x n) Number of patients Number of failurest CNS alone CNS combined

CNS negative

ALL-BFM-81

Table 3. CNS therapy and results.

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330

A. REITER

The CNS therapy modalities in the three BFM studies 81, 83, 86 and the results are summarized in Table 3. In our study 81, one CNS-positive patient suffered from progress of the CNS while on radiotherapy. Four CNSpositive patients suffered from a CNS relapse during or shortly after complete neuroaxis irradiation. We attribute the improved CNS protection in study 83 to the intensified local CNS chemotherapy. MTX and ara-C were applied intraventricutarly, in order to achieve a better distribution within the CSF (Shapiro et al, 1975). MTX was fractionated to achieve a higher concentration over time (Bleyer et al, 1978). Since there were no CNSpositive B-ALL patients in study 86 we could not test the efficacy of HD-MTX in combination with i.t. triple drug therapy for overt CNS disease. We would like to argue that in addition to systemic HD-MTX and HD-ara-C therapies, intraventricularly applied chemotherapy will be beneficial for CNS-positive patients. In our ongoing study we are examining this hypothesis. For B-ALL patients without overt CNS disease at diagnosis, RX can safely be omitted in therapy regimens including combined HD-MTX and i.t. therapy. In our study 86 only one CNS relapse occurred among 41 patients (Table 3). This is in agreement with the findings of the French group (Patte et al, 1986, 1991).

Therapy duration In our studies 83 and 86 chemotherapy was completed within a median time of only 4 months. Of the 24 relapses across all three studies, seven were diagnosed while on therapy, 12 shortly after termination of therapy, and an additional three between 6 and 12 months after achieving CR. Two relapses occurred unexpectedly late, 20 and 23 months after CR. This time pattern at which failure occurred suggests that relapse was due to early development of resistance to treatment rather than escape of sensitive cells. We conclude that prolonged therapy is of no benefit in this disease. Furthermore in the French trial LMB 84 no difference in EFS was observed in either of the two therapy groups with nine and with six courses of therapy (Patte et al, 1991). Schwenn et al (1991) reported an even shorter therapy strategy of only 2 months duration. The numbers of B-ALL patients enrolled, however, are still small.

Prognostic parameter Due to the still small number of patients, the analysis of prognostic variables must be interpreted with caution. No single diagnostic parameter could be identified which was consistently correlated with the risk of therapy failure in all three studies including cytogenetic findings (Table 4). When all patients in the three studies were examined as a group the only prognostic factor for therapy failure was the presence of residual manifestations after two therapy courses which were residual local tumours in the majority of cases. The question arises how improved local tumour control can be achieved.

331

THERAPY OF B-ALL IN CHILDHOOD

Table 4. Association of pre-treatment and response parameters on the risk of non-response and relapse.* Study

ALL-BFM-81 P

PB blasts> 1000/~1 BM blasts ->90% Liver -->4 cm Spleen ->4 cm CNS disease NHL-type Head/neck Abdomen Skeletal involvement Kidney involvement No CR after two courses t(8;14)

ALL-BFM-83 ALL-BFM-86 Total P P P

0.12" 0.08* 0.15" 0.17" 0.13" 0.002* 0.20*

0.07* 0.10" 0.08

0.055 0.18

* For analysisin individual studies Fisher's exact test was used. For analysisin the total group of patients, the log linear model (Bishop et al, 1975) was used. Only P values --<0.2are shown. Patients who died due to therapy-related complications and patients lost to follow-up were excluded from analysis.

Local therapy T h e determination of the role of local therapy modalities in the treatment of B - A L L is limited by the small n u m b e r of patients. A residual t u m o u r after the first two therapy courses m a y not necessarily herald subsequent progressive disease. In the majority of cases these residuals consist of necrotic fibrous tissue. Only those patients with vital residual turnouts after two or three courses of c h e m o t h e r a p y have a p o o r prognosis. These patients usually present disseminated abdominal disease at diagnosis. In those patients, local therapy modalities such as second look surgery, and local radiotherapy are limited in application and, as a consequence, in efficacy. This is the conclusion from the analysis of 177 patients with abdominal B-cell N H L treated according to a similar c h e m o t h e r a p y protocol (Reiter et al, 1994). Mega-dose c h e m o t h e r a p y with B M rescue may be an option for patients with persistent active disease after the initial c h e m o t h e r a p y (Philip et al, 1988).

CURRENT APPROACH T h e therapy regimen for B - A L L patients in the ongoing study N H L - B F M 90 is depicted in Figure 4. The general treatment plan remained unchanged. H o w e v e r , fractionated intraventricularly applied c h e m o t h e r a p y was reintroduced for patients with overt CNS disease at diagnosis (therapy courses A A z , BBz; Figures 4 and 5). Patients with incomplete response after two therapy courses receive an intensification course CC (Figure 5). Patients with vital residual manifestations after the conventional intensification

332

A. REITER

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Vital Tumor

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4. Therapy strategy for B-ALL patients in study NHL-BFM-90. V, AA, BB as in Figures 1 and 2, except for replacement of teniposide (VM26) by etoposide (VP16) in course AA. AAz, BBz, therapy courses for patients with overt CNS disease; CC, intensification course CC for patients with incomplete response after two therapy courses; ABMT, autologous BM transplantation for patients with vital residual manifestations after the intensification course CC. Figure

receive mega-dose chemotherapy (busulfan, etoposide, and cyclophosphamide) with autologous BM rescue. In patients with overt CNS disease at diagnosis, cyclophosphamide is replaced by thiotepa (Ebell et al, 1992). The results of an interim analysis are encouraging. At least the favourable outcome of B-ALL patients in study 86 can be confirmed although 25% of the evaluable B-ALL patients in study NHL-BFM-90 presented overt CNS disease. SUMMARY

In 1981 the BFM group introduced a new treatment strategy for B-ALL based on two alternating 5-day courses of chemotherapy delivered in short intervals up to a total of eight. The therapy courses were composed of fractionated cyclophosphamide, MTX 0.5 g/m2 (24-h infusion), i.t. MTX therapy, and ara-C/VM26 alternating with doxorubicin. The development of the therapy strategies during the subsequent two studies was characterized by shortening treatment duration from eight to six courses, and intensification of CNS chemotherapy in study ALL-BFM-83, and the introduction of HD-MTX (5 g/m2, 24-h infusion) in study ALL-BFM-86. In study ALL-BFM-81, CNS therapy consisted of ID-MTX in combination with i.t. MTX, and RX. CNS-positive patients received complete neuroaxis irradiation. In study ALL-BFM-83, CNS chemotherapy was intensified by adding dexamethasone, while MTX/ara-C were administered intraventricularly. Spinal irradiation for CNS-positive patients was omitted. In study ALLBFM-86, i.t. MTX/ara-C/prednisolone therapy was introduced in combination with HD-MTX but the intraventricular route of drug administration was no longer used. Radiotherapy was omitted completely. In all, 87 patients were enrolled, 22 (eight CNS positive) in study ALL-BFM-81, 24

333

THERAPY OF B-ALL IN CHILDHOOD

AAz VP-16

J t

I

I

I

t

I

1 MTX 1,5 2 2,5 3

(lh)100mg/m2/d

ARA-C

p.i.

(1h)150mg/m = x 4

VCR

i.v.

1,5mg/m =

MTX / PRED i.vent.

I I

p.i.

2

3

ARA-C

i.vent.

HD-MTX

p.i.

IFO

p.i.

DEXA

p.o.

(24h)

5g/m 2

(lh)800mg/m=/d 10mg/m2/d

5

PRED 1 1,5 2 2,5

ARA-C 16 20 26 30

i.vent. mg at age < 1 year mg at age ~ 1 u, < 2y. mg a t a g e ~ 2 u . < 3y. mg at age ~ 3 years

CC I I

VP-16

p.i.

HD-ARA-C

p.i.(3h)

(1 h ) 1 5 0 m g / m 2 / d 2

g/m2/12h

MTX / ARA-C / PRED i,th.

F-1 MTX 6 8 10 12

2

3 PRED 16 20 26 30

4

VDS

i.v,

DEXA

p.o.

3mg/m 2 20 m g / m ~ / d

5 ARA-C 4 6 8 10

i,th. mg mg mg mg

at at at at

age age age age

< 1 year z 1 u. < 2y. ~ 2 u. < 3y. ~ 3 years

Figure 5. Above: Therapy course AAz for CNS positive patients, i.vent., intraventricularly; VP-16, etoposide; all other abbreviations as in Figure 2. Course BBz, same but VP-16 and ara-C are replaced by doxorubicin as in course BB (Figure 2). Below: Intensification course CC. VP16, etoposide; HD-ara-C, high-dose ara-C; MTX, methotrexate; VDS, vindesine; DEXA, dexamethasone; PRED, prednisolone; p.i., intravenous infusion; i.t., intrathecatly; i.v., intravenously; p.o., orally.

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(seven CNS positive) in study ALL-BFM-83, and 41 (none CNS positive) in study ALL-BFM-86. The estimated 5-year duration of EFS was 40% in study ALL-BFM-81, 50% in study ALL-BFM-83, and 78% in study ALLBFM-86 (minimal follow-up 36 months). Nineteen of 24 relapses occurred while on therapy or shortly thereafter. In study ALL-BFM-81, the CNS was the most frequent site of failure. In ALL-BFM-83 there were no isolated CNS relapses but more BM relapses occurred. In ALL-BFM-86 localized manifestations were the predominant site of failure, no isolated BM relapses occurred, and only one CNS relapse was diagnosed. No single parameter exerted a consistent influence on outcome with one exception. The presence of residual disease after the first two courses was correlated with an increased risk of therapy failure. Our conclusions from the three studies are listed below. • An intensive, short-pulse therapy delivered within a 4 month period is highly effective in the treatment of B-ALL. • Prolonged therapy duration is of no value. • In addition to fractionated cyclophosphamide-ifosfamide, a 24-h infusion of HD-MTX 5 g/m 2 in conjunction with an i.t. therapy is a very important component for prevention of both systemic and CNS relapses. CNS irradiation is not needed for CNS-negative patients. • Fractionated intraventricularly administered chemotherapy may be beneficial for patients with overt CNS disease. • With reduced systemic relapses local tumour control may become crucial for patients with lymphomatous tumours. But even in patients with local failure megadose chemotherapy with BM rescue may be a more promising alternative to local approaches such as surgery and/or radiotherapy. In the ongoing study NHL-BFM-90 the following adaptations of the therapy regimen for B-ALL patients have been made. Fractionated intraventriculady applied chemotherapy are reintroduced for CNS-positive patients; patients with incomplete response after two therapy courses receive intensification with HD-ara-C, etoposide, and vindesine; patients with vital residual manifestations receive mega-dose chemotherapy with autologous BM rescue.

Acknowledgements This article is based on the work of many physicians and scientists who contributed to the development of B-ALL therapy within the BFM group. The author wishes to thank the contributing members for excellent collaboration: G. Henze (Berlin); U. Bode (Bonn); H.-J. Spaar (Bremen); J.-D. Thaben (Coburg); W. Andler (Datteln); H. Breu (Dortmund); U. Goebel (Dtisseldorf); J.D. Beck (Erlangen); W. Havers (Essen); B. Kornhuber, V. Gerein (Frankfurt); C.M. Niemeyer, S. Sauter (Freiburg); F. Lampert (Giefien); M. Lakomek (G6ttingen); C. Urban (Graz); N. Graf (Homburg); G. Nessler (Karlsruhe); H. Wehinger (Kassel); R. Schneppenheim (Kiel); F. Berthold (K61n); W. Sternschulte (K61n); C. Eschenbach (Marburg); St. Mtiller-Weihrich (Miinchen); P. Klose (Munich); C. Bender-G6tze (Miinchen); G. Schellong, J. Ritter, H. J/irgens (Mtinster); A. Jobkc (Ntirnberg); H. Grienberger (Salzburg); J. Treuner (Stuttgart); D. Niethammer (Ttibingen); E. Kleihauer (Ulm); H. Gadner (Wien); and J. Ktihl (Wiirzburg). Immunophenotyping: W.-D. Ludwig, E. Thiel (Berlin); U. Koeller,

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W. Knapp (Vienna); R. Kabisch (Hamburg). Chromosome analyses: J. Harbott, F. Lampert (Giessen); O. Hass (Wien). Statistics: A. Brandt and M. Zimmermann (Hannover). Supported in parts by the Hans Meinecke Foundation, Hannover; the Elternverein zur F0rderung der Behandlung krebskranker Kinder, Hannover eV; and the Deutsche Krebshilfe eV, Bonn.

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