Journal of Neuro-Oncology 38: 167–180, 1998. 1998 Kluwer Academic Publishers. Printed in the Netherlands.
Meningeosis leukaemica in adult acute lymphoblastic leukaemia Nicola Go¨kbuget and Dieter Hoelzer Medizinische Klinik III, Universita¨tsklinikum Frankfurt, Frankfurt, Germany
Key words: meningeosis leukaemica, CNS, ALL, therapy, trials, prophylaxis, relapse Summary This review addresses diagnosis of CNS involvement, incidence and treatment of CNS disease at time of diagnosis, prophylaxis and treatment of CNS relapse and risk factors for meningeal recurrence in adult acute lymphoblastic leukaemia (ALL). At the time of diagnosis meningeosis leukaemica is present in about 6% (1–10%) of the adult ALL patients with a higher incidence in ALL subgroups T-ALL (8%) and B-ALL (13%). With the invention of early additional CNS directed therapy it no longer represents an unfavourable prognostic factor. In the absence of prophylaxis meningeal relapses occur in approximately one third of adults with ALL. A literature review including more than 4000 adult ALL patients showed for the different prophylactic treatment approaches the following CNS relapse rates: intrathecal therapy alone 13% (8–19%), intrathecal therapy and CNS irradiation 15% (6–22%), high dose chemotherapy 14% (10–16%), high dose chemotherapy and intrathecal therapy 8% (2–16%) and high dose chemotherapy, intrathecal therapy together with CNS irradiation 5% (1–12%). It became obvious that the early onset of intrathecal therapy and CNS irradiation and the continuation of intrathecal administrations throughout maintenance are essential. The most favourable results where achieved with high dose chemotherapy combined with intrathecal therapy and/or CNS irradiation. The majority of treatment regimens in adult ALL already include high dose chemotherapy in order to reduce the risk of bone marrow relapse. The outcome of patients with CNS relapse is still poor. Although a remission can be induced in the majority of patients (> 60%) it is usually followed by a bone marrow relapse and the survival is poor (< 5–10%). Bone marrow transplantation might be in adults at present the only curative approach.
Introduction Substantial progress has been achieved in the treatment of adult acute lymphoblastic leukaemia (ALL) in the recent 20 years. Current treatment approaches include induction therapy followed by several consolidation cycles and maintenance treatment for 2–2.5 years. With such intensive combination chemotherapy regimens a complete remission is achieved in 70–80% of the patients and approximately 30% of the patients can be cured [37, 36]. With the advent of effective control of systemic disease the importance of CNS as a site of relapse be-
came evident. By the introduction of specific CNS directed treatment modalities the rate of CNS relapses could be reduced substantially. The following review will address diagnosis of CNS involvement in ALL, incidence and treatment of CNS disease at time of first diagnosis, prophylaxis and treatment of CNS relapse and risk factors for meningeal recurrence in adult ALL.
Diagnosis of meningeosis leukaemica in ALL The most common form of CNS involvement in
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168 ALL is meningeosis leukaemica. According to the recommendations of the Rome workshop diagnosis requires the morphologic identification of leukaemic blasts in a cytocentrifuge preparation of the cerebrospinal fluid (CSF) together with the finding of more than 5 cells/µl [60]. Although it is the most commonly used method with morphology alone it can be difficult in some cases to distinguish blast cells from reactive lymphocytes, which may be present in leukaemia for several reasons, e.g. prior intrathecal therapy [29] or irradiation, infections etc. If morphology is not clear a surface marker analysis can add specificity. It allows the identification of B- and T-lineage specific markers and further subgroups as it is standard for the classification of blast cells in bone marrow and peripheral blood. Several other immune parameters have been investigated but no convincing marker for the differentiation of meningeosis from autoimmune or inflammatory conditions could be identified [87]. Future investigations may reveal additional reliable markers such as CD27 which showed in one study a good specificity and sensitivity in ALL patients with suspected CNS involvement and also correlated with remission and relapse in a longitudinal observation [50]. Diagnostic problems may also occur in patients with CSF cell counts below 5/µl and definite blast cells in the CSF. At the time of diagnosis this situation was present in 6% of 1544 childhood ALL patients [30]. During maintenance therapy of childhood ALL the incidence was only 0.7% [84]. In a retrospective study no difference in terms of CNS relapse rate or survival was detected between childhood ALL patients without blast cells and patients with detectable blasts and cell counts below 5/µl at the time of diagnosis or during maintenance therapy [30, 84]. These results have been questioned by other investigators reporting that the presence of blast cells in the CSF independent of the cell count increases the risk of CNS relapse [65, 56]. These contradictory findings may be attributed to differences in patient characteristics and intensity of CNS prophylaxis since in the latter trial CNS irradiation was scheduled after one year of therapy and all risk groups were included [56].
For adult ALL no similar investigations have been published. Since the diagnosis of CNS leukaemia has important implications for the subsequent therapy it may be a practical conclusion to treat all patients with detectable CSF blasts with intensive prophylaxis as tailored for other groups at high risk of CNS relapse e.g. patients with initial CNS involvement and to perform frequent control examinations.
Meningeosis leukaemica at time of diagnosis At the time of diagnosis extramedullary involvement is a common finding in de novo ALL and the CNS is one of the most frequent sites. For the incidence of this manifestation a weighted mean of 6% was reported for 2008 patients from 10 trials in adult ALL (Table 1). Initial CNS involvement is usually diagnosed during a routine diagnostic examination of the CSF. In few patients unequivocal symptoms such as cranial nerve palsies or signs in CT or MRT examination contribute to the diagnosis. The frequency of initial CNS involvement ranges between 1 and 10%. The variability can be attributed in part to the fact that not in all trials a routine CSF examination has been performed at the time of diagnosis. In some studies the diagnosis has therefore been solely based on the presence of typical CNS symptoms which leads to an underestimation. Table 1. Incidence of initial CNS involvement in adult ALL Author
Year
Stryckmans [77] Hoelzer [39] Kantarjian [48] Ellison [21] Linker [53] Cuttner [16] Fiere [24] Todeschini [83] Thomas [81] Larson [51] Thiebaut [80]
1987 1988 1990 1991 1991 1991 1993 1994 1995 1995 1996
Weighted mean
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N
Incidence
100 368 105 277 109 164 550 86 52 197 37
6% 6% 5% 8% 6% 10% 7% 3% 10% 1% 6%
2008
6%
169 In addition the incidence of initial CNS involvement depends on the immunologic subtype. It ranges from 3% in B-precursor ALL up to 8% and 13% in T-Lineage and mature B-ALL respectively [38]. In lymphoblastic lymphoma characterised by convoluted tumor masses even a rate of 18% has been reported [55]. The exclusion of patient subsets such as B-ALL patients from clinical trials thereby influences the incidence of initial CNS involvement. The necessity of CSF examination at the time of diagnosis has been questioned by some investigators particularly since the CSF might be contaminated with leukocytes and blast cells during lumbar puncture. The risk is increased in patients with high white blood count and blast cells in peripheral blood. In addition in 30% of the ALL patients thrombocytopenia below 25000/µl is present and a lumbar puncture is associated with the risk of bleeding. In all other patients an examination of the CSF at time of diagnosis is important since there is a general consent that CNS positive patients require additional CNS directed treatment. A common regimen is the application of intrathecal methotrexate 2 times weekly continued for 3–4 doses after the clearance of blast cells from the CSF followed by cranial irradiation after achievement of CR and monthly intrathecal maintenance therapy [21, 16, 53, 58]. It is known that spinal irradiation adds efficacy but may contribute to increased toxicity in terms of prolonged haematologic suppression with delays in subsequent systemic chemotherapy and the risk of cardiac or pulmonal damages. The beneficial effect of additional CNS directed treatment in patients with initial CNS involvement is apparent since in adequately treated patients it seems to be no longer an adverse prognostic factor for leukaemia free survival [74, 39, 53, 80]. Some authors found a tendency towards a lower CR rate in patients with initial CNS involvement [48, 39]. Only one group reported a significantly lower remission duration for CNS positive patients. This was probably influenced by the fact that two of the four CNS positive patients suffered from B-ALL, which was formerly associated with an inferior prognosis [48].
Prophylaxis of meningeal recurrence The successful development of CNS prophylaxis in childhood ALL has been reviewed in detail elsewhere [7, 69]. In adult ALL the issue of CNS prophylaxis has not been investigated in prospective trials since the major problem is still the achievement of a durable bone marrow remission. Nevertheless with improved efficacy of systemic chemotherapy it became evident that the risk of CNS relapse is high in adult ALL as well since the systemically administered drugs do not reach cytotoxic levels in the CSF. Without specific CNS directed prophylaxis approximately 31% (30–32%) [15, 67] of adult ALL patients develop a meningeal recurrence. If only patients surviving more than 12 months were analysed the rate of CNS recurrence even reached 50% [52]. Table 2 summarises CNS directed treatment in therapy trials for adult ALL. The CNS relapse rate includes isolated CNS relapses and combined relapses in CNS and bone marrow. If the results are compared it has to be considered that they are not only influenced by the applied treatment modalities but also by other factors such as exclusion criteria e.g. initial CNS involvement, B-ALL, the overall intensity of systemic therapy and the number of CSF control punctures during maintenance therapy. In some publications it is not clear whether combined CNS and bone marrow relapses have been included it the CNS relapse rate. The only randomised trial in adult ALL addressing the question of CNS prophylaxis revealed that the application of CNS irradiation together with intrathecal methotrexate leads to a significantly reduced CNS relapse rate of 11% compared to 32% without prophylaxis [67].
Intrathecal chemotherapy Intrathecal chemotherapy is the backbone of CNS prophylaxis in adult ALL. Cytotoxic drug levels in the CSF with minimal systemic toxicity can thereby be achieved. Methotrexate at the dose level of 12 mg [8] has been widely used for this purpose. In some trials it has been combined with cytarabine or
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34 73
Please indicate author’s corrections in blue, setting errors in red
159834 NEON ART.NO KRA-12 (777) ORD.NO 234777.Z 164 89 247 57 79 114 92 358 1200
Weighted mean
− − − − − − − −
− −
24 D 24 24 24 D 24 HR 24 24 24 24 24D
− − −
− −
CNS irrad. (Gy)
Weighted mean
602
Cranial irradiation, high dose chemotherapy and intrathecal chemotherapy Stryckmans 1987 100 18 Durrant 1992 266 18 D Willemze 1995 26 24 Elonen 1992 51 24 (HR) Linker 1991 109 18 Chiu 1994 50 18
167
112 55
High dose chemotherapy and intrathecal therapy Cuttner 1991 Cassileth 1992 Cassileth 1992 Bassan 1992 Evensen 1994 Cortes 1995 Cortes 1995 Mandelli 1996
1995 1993
Weighted mean
High dose chemotherapy alone Cortes Wiernik
1597
149 28 368 277 145 212 86 61 74 197
Intrathecal therapy and cranial irradiation Henderson 1979 Omura 1980 Hoelzer 1984 Ellison 1991 Lluesma-G [54] 1992 Bassan 1992 Todeschini 1994 Scherrer 1994 Bosco 1995 Larson 1995
Weighted mean
440
135 168 137
107
N
Weighted mean
Intrathecal therapy alone Clarkson Hussein Lluesma-G. 1984 1989 1991
1980 1995
No CNS prophylaxis Omura Cortes
Weighted mean
Year
First author
MTX × 6 − MTX × 1 MTX − −
− − − MTX MTX − MTX + AC MTX + PRED × 5
− −
MTX × 3 − MTX × 4 MTX × 1 MTX × DEX × 8 MTX × 1 MTX × 6 MTX × 4 MTX × 1 −
MTX MTX × 6 MTX + DEX × 6
− −
Induction
Intrathecal therapy
MTX × 6 MTX × 4 MTX × 1 MTX × 15 MTX × 6 MTX × 18
MTX × 3 MTX × 8 MTX × 6 MTX MTX × 10 AC × 22 HR MTX + AC ×4–16 MTX + PREC × 12
− −
MTX × 6 MTX − MTX × 5 MTX + DEX × > 10 MTX × 8 MTX − MTX × 4 MTX × 7
MTX × >6 MTX × 8 MTX + DEX × > 10
− −
Postinduction
Table 2. Prophylaxic treatment of the central nervous system and isolated and combined CNS relapse rates in adult ALL
± HDAC ± HDMTX HDAC ± BMT HDMTX IDMTX HDMTX
IDMTX HDAC HDAC HDAC HDMTX HDAC, IDMTX HDMTX, HDAC IDMTX
HDAC, IDMTX HDMTX
− − − − − − − − − −
− − −
− −
High dose chemotherapy
5%
1% (1/0) 8% 4% (1/0) 12% (3/2) 1% (0/1) 5% (0/2)
8%
11% (12/0) 4% 4% 11% 2/2) 11% (7/0) 16% (6/6) 2% (0/2) 9% (25/0)
14%
16% (11/4) 10% (2/2)
15%
12% 11% 8% 26% 8% (8/1) 23% (14/20) 7% (2/3) 10% (4/1) 6% (2/1) 19% (25/7)
13%
8% 11% (8/5) 19% (15/6)
31%
32% 30%
Relapse rate1 in CNS ± BM (CNS/BM)
170
171 corticosteroids such as prednisone, hydrocortisone or dexamethasone. Intrathecal combination therapy was designed in order to increase antileukaemic efficacy. Corticosteroids in addition may reduce the chemical arachnoiditis induced by methotrexate and cytarabine [78, 25, 26]. It remains however open whether the combination of two or three drugs provides an advantage compared to methotrexate as a single drug [79]. With intrathecal therapy alone a weighted mean of 13% (8–19%) was reported for the CNS relapse rate in 440 patients (Table 2).
CNS irradiation In the majority of adult ALL trials additional prophylactic CNS irradiation was included. Standard treatment is fractionated irradiation of the skull with 24 Gy given in fractions of 1.8–2 Gy 5 times weekly after achievement of CR. In some trials a dose of 18 Gy has been applied [77, 20, 53, 13]. Comparative studies have not been done however. Neurologic side effects of cranial irradiation are limited in adult ALL. The major problem is bone marrow suppression, since in the majority of trials cranial irradiation is applied parallel to induction chemotherapy. It also may compromise subsequent high dose chemotherapy due to the risk of leukencephalopathy particularly if intravenous methotrexate is administered following CNS irradiation [7]. It has therefore been attempted to give cranial irradiation delayed during consolidation therapy. This approach resulted in a tendency towards a higher CNS relapse rate however [40]. For trials with delayed irradiation the weighted mean of CNS relapse rate was 20% (12–26%) [34, 21, 51] compared to 11% (7–23%) in studies with early CNS irradiation [67, 3, 83, 72, 10, 54, 36a].
Intrathecal chemotherapy and CNS irradiation A combination of intrathecal therapy and CNS irradiation probably yields increased efficacy. In 1597 patients treated with cranial irradiation together with intrathecal therapy the CNS relapse rates
ranged between 6 and 26%. The weighted mean was 15% (Table 2). The intrathecal administration of methotrexate and dexamethasone early during induction and for more than 10 doses during maintenance therapy resulted in a CNS relapse rate of 19% in one study. In the subsequent trial with additional cranial irradiation only 8% of the patients showed a recurrence in the CNS. This improvement was however also influenced by a more intensive systemic chemotherapy, particularly by the introduction of asparaginase [54]. Commonly 3–4 doses of methotrexate are administered parallel to irradiation followed by intermittent applications during consolidation and maintenance treatment. The early onset of both intrathecal therapy and CNS irradiation seems to be essential. In a non randomised comparison a CNS relapse rate of 18% was reported in patients treated with delayed CNS irradiation and concomitant intrathecal methotrexate. The same regimen with additional methotrexate during induction yielded a relapse rate of 8% [34]. In another trial the high CNS relapse rate of approximately 19% was apparently due to the late onset of CNS prophylaxis. Patients received one intrathecal application of methotrexate during induction. CNS prophylaxis with additional intrathecal methotrexate parallel to cranial irradiation with 24 Gy was stipulated for day 141 of the protocol. Eight percent CNS relapses occurred before onset of CNS prophylaxis and additional 11% after CNS prophylaxis which accounts for a total of 19% CNS relapses. In the subsequent trial intrathecal prophylaxis was therefore scheduled earlier after achievement of CR [21]. Similarly in a trial with delayed cranial irradiation and intrathecal therapy the high CNS relapse rate of 19% led to a protocol amendment with earlier onset of intrathecal treatment [51]. The intermittent application of intrathecal methotrexate continued during maintenance therapy appears to increase efficacy of CNS prophylaxis. Six to eight intrathecal doses of methotrexate were insufficient in a trial reported by Clarkson et al. The CNS relapse rate was 23% compared to 4% in the subsequent trial with intermittent intrathecal methotrexate applications during the whole course of
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172 maintenance therapy of 3 years in addition to intensified consolidation treatment [14]. The efficacy of intrathecal therapy is limited by the fact that adequate distribution and cytotoxic drug levels can not always be achieved. In case of overt leukaemia CSF flow may be disturbed. Technical precautions during application and the maintenance of a horizontal body position after administration may influence the ventricular drug level. In patients with involvement of brain tissue such as cranial nerves cytotoxic levels are not achieved [6, 1, 4].
for neurologic toxicity are avoided. This regimen proved to be effective in remission induction of overt meningeal leukaemia [61]. It is questionable however whether high dose chemotherapy alone is sufficient for effective prevention of CNS relapse since the relapse rate in 167 patients ranged between 10 and 16% (weighted mean 14%) (Table 2). This may be partly attributed to the late onset of high dose chemotherapy in the reported trials.
High dose chemotherapy combined with intrathecal therapy High dose chemotherapy This problem can to some extent be circumvented by the administration of high dose systemic chemotherapy. Methotrexate represents an ideal substance for this purpose since after intravenous administration of high doses systemic toxicity can be limited by the application of a delayed rescue with folinic acid. Dose levels of 1.5–3 g/m2 yield therapeutic CSF levels. The dose efficacy can be improved by prolonged 24 hour infusion after an initial loading dose. Compared to intrathecal application of methotrexate continuous cytotoxic CSF levels over a prolonged period can be achieved. In addition the sequential administration of intrathecal and intravenous methotrexate yields a considerable increase of methotrexate concentrations in the CSF compared with high dose methotrexate alone [reviewed in 32, 4]. In patients with overt CNS leukaemia increased CSF drug concentrations during intravenous methotrexate therapy are observed [62]. High dose cytarabine shows a better penetration to the CSF compared to methotrexate [4] causes however a higher systemic toxicity. A further pharmacological advantage of cytarabine is the fact that the CSF half life is 8 times higher than plasma half life due to low CSF levels of the inactivating enzyme cytidine deaminase [35, 73]. High dose cytarabine applied as intravenous infusion over 3 hours every 12 hours at a dose level of 3 g/m2 provides continuous cytotoxic CSF levels. In addition by continuous infusion excessive peak levels which account
The most effective approach in terms of CNS relapse rate and control of systemic disease is apparently the combination of CNS specific and intensive systemic chemotherapy. The administration of intrathecal therapy together with high dose chemotherapy resulted in CNS relapse rates ranging between 2 and 16%. The weighted mean in 1200 patients was 8%. The question whether cranial irradiation adds efficacy to this setting cannot be answered on the basis of this literature review and has not been investigated in comparative trials. The combination of high dose chemotherapy, intrathecal therapy and cranial irradiation yielded a weighted mean for CNS relapse rate of 5% (1–12%) in 602 patients. In two studies the authors concluded that the CNS prophylactic regimen appeared to be suboptimal. In one of them the CNS relapse rate of 16% was attributed to the late onset of intrathecal therapy which was in addition only scheduled for high risk patients [15]. In one further trial with a CNS relapse rate of 13% the authors reasoned that the high dose methotrexate regimen probably was not optimal due to the fact that infusions were administered over 3 hours which might not yield sufficient cytotoxic drug levels in the CSF. In addition CNS irradiation was only applied to high risk patients [22]. The continuous intensification of CNS prophylaxis is reflected in a recent retrospective analysis of four consecutive studies conducted at the MD Anderson Cancer Center. The CNS relapse rate could
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173 be reduced from 29% in the first trial without CNS prophylaxis to 16% in the second trial by the introduction of high dose chemotherapy and 15% in the third trial with additional intrathecal therapy for high risk patients. The most favourable results with a CNS relapse rate of 2% were achieved in the last trial incorporating early high dose chemotherapy and intrathecal therapy for all patients [15].
Conventional systemic chemotherapy These results demonstrate the efficacy of a combined CNS directed treatment approach. In addition pharmacological investigations revealed that at least some of the conventional drugs used in systemic leukaemia treatment exert a cytotoxic effect in the CSF. Dexamethasone compared to prednisone reaches higher drug levels in the CSF after systemic administration [2, 44]. Consequently in childhood ALL the use of dexamethasone instead of prednisone has been associated with a better prevention of CNS relapse and improved event free survival [45, 86]. Asparaginase leads to a depletion of asparagine in the CSF following intramuscular administration [18] and thereby may inhibit leukemic cell growth. Etoposide yields cytotoxic CSF levels as well and even higher CSF concentrations are achieved in children with overt CNS leukaemia [70]. The use of these agents can therefore contribute to a reduction of CNS relapse risk.
Risk factors for CNS relapse In the treatment of adult leukaemia a trend towards risk adapted treatment strategies is apparent. This approach is also reasonable for the scheduling of CNS prophylaxis since various risk factors for the development of CNS relapse have been defined (Table 3). The most important risk factor is whether CNS prophylaxis has been done or not [66]. Beside that in a retrospective analysis it became evident that high serum LDH levels and a high proliferative index (more than 14% cells in S and G2M compartment) were the strongest predictive factors for CNS relapse. The incidence of CNS relapse in patients without any of these features was 4% compared to 13–29% for patients with one feature and 56% for patients with both features. It has to be considered however that patients in that trial received either no CNS prophylaxis or high dose chemotherapy as sole CNS prophylaxis [49]. In addition the proliferative index is not a parameter available in the majority of patients. Nevertheless these and additional risk factors such as elevated initial white blood cell count, L3 morphology, mediastinal involvement/T-ALL, extramedullary disease, the presence of Ph-chromosome and elevated alkaline phosphatase have also been reported by others [22, 51, 76]. It is evident that the risk of CNS recurrence depends on the bulk of disease present at diagnosis indicated by factors
Table 3. Risk factors for CNS relapse in adult ALL Risk factors
Elonen et al. [22]
WBC LDH Mediastinal tumor Extramedullary disease Immunologic subtype Morphology Ph chromosome Alkaline phosphatase Ohter
> 35.000/µl > 600 U/l + +
Kantarjian [49]
Larson et al. [51]
Stewart et al. [76]
> 30.000/µl
> 25.000/µl > 600 U/l
> 600 U/l
+ L3 + > 80 U/l Hb > 10 g/l Creatinine > 1.4 mg% Fibrinogen > 400 mg/dl, high proliferative index
T-ALL L3 +
Abbreviations: WBC – white blood cell count; LDH – lactate dehydrogenase; Ph – Philadelphia.
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AUL > 85 U/l BM cellularity > 95% Age < 20 years
174 like LDH and WBC. In addition it is influenced by biologic properties of the disease and is more common in subsets of leukaemia characterised by an aggressive disease process and the propensity of blast cells to invade extramedullary tissues as present in B-ALL/L3 morphology and T-ALL. Factors like high creatinine and alkaline phosphatase may also indicate a subclinical involvement of extramedullary organs such as liver or kidney and CNS. It has been attempted to define additional independent risk factors for the development of CNS relapse such as elevated serum levels of beta-2 microglobulin [47, 33] or CSF levels of thymidine kinase [63]. Confirmation in further trials is required however.
Meningeosis leukaemica as a site of relapse Meningeal recurrence not only adds considerable morbidity for the individual patient but also frequently precedes a subsequent bone marrow relapse with dismal outcome. CNS relapse usually occurs in patients under therapy and is detected by routine surveillance punctures. Thus Mandelli et al. reported that CNS relapse was mainly detected between 10th and 24th month of treatment [57]. The therapeutic armentarium available for the treatment of CNS relapse is roughly the same as for CNS prophylaxis.
Treatment and outcome of CNS relapse A remission of CNS disease can be obtained in the majority of the patients with intrathecal therapy, high dose therapy with cytarabine or methotrexate and cranial irradiation as single or combined modalities. The remission duration after CNS relapse is however short. In a trial reported by the Cancer and Leukemia Group B 25 patients suffered a CNS relapse. In 18 of them it was followed by bone marrow relapse 1–19 months later. Eventually all but 3 patients died from recurrent leukaemia [51]. In three further trials all of 27 and 12 patients with CNS re-
lapse died [21, 20] and all out of 3 patients with CNS relapse achieved a second CR but none survived [22]. Recent PCR analyses provided additional evidence that CNS relapse heralds a recurrence of systemic disease. It could be demonstrated that in 4 of 6 patients with T-ALL in morphologic remission and overt CNS leukaemia minimal residual disease in bone marrow was present. In the remaining patients MRD in bone marrow became evident after treatment and CR of CNS disease [64]. In all 5 patients with CNS-relapse studied in another trial minimal disease in bone marrow was detected simultaneously [71]. Although the investigated patient numbers are small CNS relapse should no longer be considered as an isolated event and clearly has to be treated with intensive systemic chemotherapy. In childhood ALL in recent trials with intensive retreatment schedules including intrathecal therapy, high dose chemotherapy and cranial irradiation leukaemia free survival appeared to be improved and ranged between 10–83% (reviewed in 69, 71). In one trial reporting an overall survival of 83% the followup time was however only 2 years and only patients having completed 6 months of chemotherapy and radiation have been included [69]. For the interpretation of the results it is also important to assure that similar definitions for the diagnosis of CNS relapse are used [75]. Treatment results in adult patients with isolated or combined CNS relapse are still poor. Twenty of 25 patients with CNS relapse were retreated with intensive both systemic and CNS oriented therapy and 65% achieved a second CR. Only 4 of them survived [57]. With high dose cytarabine alone a CR rate of 68% could be achieved in 25 adult ALL patients with overt CNS recurrence. In patients with isolated CNS relapse the CR rate was even 100%. Finally however only 2 of 25 patients survived disease free. The great majority of patients relapsed in bone marrow some additional in CNS. Solely patients treated with bone marrow transplantation (BMT) after consolidation with high dose cytarabine became long term survivors [61].
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175 Bone marrow transplantation in the treatment of CNS relapse Bone marrow transplantation is the most effective treatment of relapse in adult ALL. However, it is primarily designed to control bone marrow disease and additional CNS directed therapy may be required in patients with previous CNS involvement. In one trial 98 patients with ALL or high grade Non-Hodgkin’s lymphoma were treated with allogeneic or autologous BMT including total body irradiation (TBI). The overall probability of CNS relapse was 11%, with a significant difference between patients with (27%) or without (5%) previous CNS involvement [28]. Similar results were reported in 198 patients treated with allogeneic BMT. All of them received TBI. The probability of CNS relapse was 13%. It was significantly higher in patients with the history of CNS disease. The administration of intrathecal methotrexate after transplantation appeared to be beneficial in these patients. In patients with previous CNS involvement the probability of CNS relapse was 52% without intrathecal prophylaxis compared to 17% in those with posttransplant intrathecal methotrexate. At the same time however the risk of leukencephalopathy was increased in patients treated with CNS irradiation and intrathecal methotrexate before and after transplantation [82].
Intraventricular chemotherapy In adults intraventricular therapy is rarely attempted. This approach should be re-evaluated in patients with CNS relapse since it leads to a more complete distribution of the inoculated drug throughout the ventricular space, less variability and higher local drug concentrations [4]. In a small series of adult patients with CNS relapse intraventricular therapy proved to be more effective than intrathecal therapy. It yielded significantly higher CR rates (88% vs 33%), a lower incidence of second CNS relapse (none vs 50%) and a longer overall survival. Although 22% device-related complications were reported the beneficial effects of intraventricular therapy deserve further evaluation [43].
Future directions The development of new alternative therapies with less neurological and systemic toxicity but equal effectivity is required. New cytotoxic drugs for intrathecal administration are under investigation e.g. diaziquone, 6-mercaptopurine, mafosfamide and topotecan [4, 5]. New approaches developed for the treatment of brain tumours may provide alternatives. One of them is the rescue after high dose administration of etoposide with ICRF187 since the latter does not cross blood brain barrier and therefore antagonises the cytotoxic action of etoposide predominantly in normal tissues [41]. The distribution of drugs to the CNS should be considered when a conditioning regimen for BMT is selected. Thus before autologous BMT in brain tumours high dose busulfane and thiotepa have been used since they yield a good penetration to the CNS [46].
Side effects of CNS directed treatment In childhood ALL with a high rate of long-term survivors the side effects of CNS directed treatment have been investigated extensively and range from subclinical neurological sequelae to encephalopathy, neuropsychologic and growth impairment, endocrine dysregulation and brain tumours. In adult ALL the neurologic side effects particularly of cranial irradiation appear to be far less pronounced. In one trial cranial irradiation combined with intrathecal methotrexate commonly caused malaise and lethargy but no significant toxicity. Twenty percent of the patients developed symptoms of arachnoiditis such as headache, nausea and vomiting. Delayed toxicity in terms of a somnolence syndrome occurred in 10% of the patients [53]. A trial focusing on quality of life after bone marrow transplantation failed to demonstrate significant differences between patients before and after TBI [68]. To our knowledge only one study addressed the long term side effects of CNS prophylaxis. Ten years after 5 applications of intrathecal methotrexate and cranial irradiation in 17 longterm survivors of ALL only subclinical neurological
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176 sequelae were detected. Neurological symptoms and moderate brain atrophy were more pronounced in patients older than 30 years. Nevertheless all patients have been fully rehabilitated and returned to their normal occupational activities [85]. The most severe side effect is probably leukencephalopathy. In childhood ALL the risk is correlated with the overall intensity of CNS effective treatment. Toxicity of intrathecal treatment apparently depends on the presence of leukemic involvement, methotrexate concentrations in the CSF and MTX diluent. Particularly in patients with pre-existing leukemic meningitis increased toxicity may be related to delayed clearance of methotrexate from the CSF [29]. Although leukencephalopathy occurs in single cases of patients treated with only one treatment modality e.g. with high dose methotrexate [12, 27] and high dose cytarabine [19] alone it seems to be more frequent in patients treated with irradiation and intrathecal methotrexate followed by intravenous methotrexate [9, 31]. In patients with pretransplant CNS directed therapy and posttransplant intrathecal methotrexate the incidence reached 7% and the risk increased with the number of intrathecal instillations [82].
Conclusions Initial CNS involvement 1. Initial involvement, which was formerly a risk factor for CNS relapse seems to have no longer adverse prognostic consequences if it is treated with additional CNS directed treatment modalities. CNS prophylaxis 2. Standard treatment of adult ALL includes combinations of intrathecal therapy, cranial irradiation and high dose chemotherapy with cytarabine or methotrexate. 3. With the introduction of specific CNS directed treatment elements the incidence of CNS re-
4.
5.
6.
7.
8.
lapse in adult ALL could be reduced to less than 5–10% in recent trials. Intrathecal therapy has to be started early during induction treatment and continued intermittent applications during maintenance therapy increase efficacy. High dose chemotherapy is included in most of the recent trials in order to reduce the rate of bone marrow relapses and also yields an improved efficacy of CNS prophylaxis. It is currently attempted to omit CNS irradiation in order to avoid treatment delays after parallel application of induction therapy and CNS irradiation. The delayed administration of CNS irradiation, which is another approach to reduce toxicity of induction treatment leads to an increased incidence of CNS relapse. Risk factors for CNS relapse are known but they are mostly overlapping with risk factors for bone marrow relapse since they are markers for an aggressive disease process. They can therefore be easily included in risk adapted treatment approaches for biologic subgroups of ALL.
CNS relapse 9. The survival after CNS relapse is poor. Although a CR can be induced in the majority of patients it is usually followed by a bone marrow or second CNS relapse. 10. CNS relapse has to be treated not only with CNS directed treatment modalities but with intensive systemic retreatment since it apparently represents an early stage of systemic recurrence. 11. Increased toxicity particularly leukencephalopathy is observed in case that treatment elements already administered during first line treatment such as high dose methotrexate, CNS irradiation are repeated at the time of CNS recurrence. 12. Bone marrow transplantation at present appears to be the only curative approach. Thus far the largest experience exists with allogeneic BMT. Experience from treatment of bone mar-
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177 row relapses shows however that any kind of BMT – also autologous and matched unrelated BMT – is superior to the treatment with chemotherapy. 13. Patients with CNS involvement at relapse are still at increased risk for CNS relapse after BMT. Intrathecal maintenance therapy after BMT may be beneficial.
13.
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References 1. Balis FM: Pharmacologic considerations in the treatment of acute lymphoblastic leukemia. Ped Clin North Am 35: 835, 1988 2. Balis FM, Lester CM, Chrousos GP, Heiemann RL, Poplack DG: Differences in cerebrospinal fluid penetration of corticosteroids: possible relationship to prevention of meningeal leukemia. J Clin Oncol 5: 202, 1987 3. Bassan R, Battista R, Rohatiner AZS, Love S, Carter M, Buelli M, Viero P, D’Emilio A, MacCallum P, Amess J, Dini E, Barbui T, Lister TA: Treatment of adult acute lymphoblastic leukaemia (ALL) over a 16 year period. Leukemia 6 (Suppl 2): 186, 1992 4. Blaney SM, Balis FM, Poplack DG: Current pharmacological treatment approaches to central nervous system leukemia. Drugs 41: 702, 1991 5. Blaney SM, Cole DE, Godwin K, Sung C, Poplack DG, Balis FM: Intrathecal administration of topotecan in nonhuman primates. Cancer Chemother Pharmacol 36: 121, 1995 6. Blaney SM, Poplack D, Godwin K, McCully SL, Murphy R, Balis FM: Effect of body position on ventricular CSF methotrexate concentration following intralumbar administration. J Clin Oncol 13: 177, 1999 7. Bleyer WA: Central nervous system leukemia. In: Lister TA, Henderson ES (eds) Leukemia. W.B. Saunders, Philadelphia 733–768, 1991 8. Bleyer WA, Coccia PF, Sather HN et al.: Reduction in central nervous system leukemia with a pharmacokinetically derived intrathecal methotrexate dosage regimen. J Clin Oncol 1: 317, 1983 9. Bleyer WA, Poplack DG: Prophylaxis and treatment of leukemia in the central nervous system and other sanctuaries. Semin Oncol 12: 131, 1985 10. Bosco J, Teh A: Outcome of treatment in adult acute lymphoblastic leukaemia in an Asian population: comparison with previous multicentre German study. Leukemia 9: 951, 1995 11. Cassileth PA, Andersen JW, Bennett JM, Hagland HC, Mazza JJ, O’Connell MC, Paietta E, Wiernik P: Adult acute lymphocytic leukemia: the Eastern Cooperative Oncology Group experience. Leukemia 6 (Suppl 2P): 178, 1992 12. Chessels JM: Central nervous system directed therapy in
16.
17.
18.
19.
20.
21.
22.
23.
24.
acute lymphoblastic leukaemia. Bailliere’s Clinical Haematology 7: 349, 1994 Chiu EKW, Chan LC, Liang R, Lie A, Kwong YL, Todd D, Chan TK: Poor outcome of intensive chemotherapy for adult acute lymphoblastic leukemia: A possible dose effect. Leukemia 8: 1469, 1994 Clarkson B, Ellis S, Little C, Gee T, Arlin Z, Mertelsmann R, Andreeff M, Kempin S, Koziner B, Chaganti R, Ihanwar S, McKenzie S, Cirricincione C, Gaynor J: Acute lymphoblastic leukemia in adults. Sem Oncol 12: 160, 1984 Cortes J, O’Brien SM, Pierce S, Keating MJ, Freireich EJ, Kantarjian GM: The value of high-dose systemic chemotherapy and intrathecal therapy for central nervous system prophylaxis in different risk groups of adult acute lymphoblastic leukemia. Blood 86: 2091, 1995 Cuttner J, Mick R, Budman DR, Mayer RJ, Lee EJ, Henderson ES, Weiss RB, Paciucci PA et al.: Phase III trial of brief intensive treatment of adult acute lymphocytic leukemia comparing daunorubicin and mitoxantrone: A CALGB study. Leukemia 5 (5): 425, 1991 Dekker AW, van ’t Veer MB, Sizoo W, Haak HL, van der Lelie J, Ossenkoppele G, Huijgens PC, Schouten HC, Sonneveld P, Willemze R, Verdonck LF, van Putten WLJ, Lo¨wenberg B, for the Dutch Hemato-Oncology Research Group: Intensive postremission chemotherapy without maintenance therapy in adults with acute lymphoblastic leukemia. J Clin Oncol 15: 476, 1997 Dibenedetto SP, Di Cataldo A, Ragusa R, Meli C, Lo Nigro L: Levels of L-asparagine in CSF after intramuscular administration of asparaginase from Erwinia in children with acute lymphoblastic leukemia. J Clin Oncol 13: 339, 1995 Dunton SF, Nitsche R, Spruce WE et al.: Progressive ascending paralysis following administration of intrathecal and intravenous cytosine arabinoside. Cancer 57: 1083, 1986 Durrant IJ, Richards SM: Results of Medical Research Council trial UKALL IX in acute lymphoblastic leukaemia in adults: report from the Medical Research Council Working Party on Adult Leukaemia. Br J Haematol 85: 84, 1993 Ellison RR, Mick R, Cuttner J, Schiffer CA, Silver RT, Henderson ES, Woliver T, Royston I, Davey FR, Glicksman AS, Bloomfield CD, Holland JF: The effects of postinduction intensification treatment with cytarabine and daunorubicin in adult acute lymphocytic leukemia: a prospective randomized clinical trial by Cancer and Leukemia Group B. J Clin Oncol 9: 2002, 1991 Elonen E, Almqvist A, Ha¨nninen A, Jansson S-E, Ja¨rventie G, Koistinen P, Koivunen E, Lahtinen M: Intensive treatment of acute lymphatic leukaemia in adults: ALL86 protocol. Haematologica 76 (Suppl 4): 133, 1991 Evensen SA, Brinch L, Tjonnefjord G, Stavem P, Wisloff F: Estimated 8-year survival of more than 40% in a populationbased study of 79 adult patients with acute lymphoblastic leukaemia. Br J Hematol 88: 88, 1994 Fiere D, Lepage E, Sebban C, Boucheix C, Gisselbrecht C, Vernant JP, Varet B et al.: Adult acute lymphoblastic leukemia: A multicentric randomized trial testing bone marrow
Please indicate author’s corrections in blue, setting errors in red 159834 NEON ART.NO KRA-12 (777) ORD.NO 234777.Z
178 transplantation as postremission therapy. J Clin Oncol 11 (10): 1990, 1993 25. Fujimoto T, Goya G, Makagawa K, Yamashita F, Ito M, Asano K, Furusho K: Comparison of high dose infusion of methotrexate (MTX) vs sequential-complementary method for maintenance of remission in acute childhood leukemia. A cooperative study. Proc 11th Ann Meeting ASCO 16: 65, 1975 26. Fujimoto T, Goya G, Nakagawa K, Yamashita F, Fuji Y, Asano K, Furusho K: Chemotherapy of acute childhood leukemia I: Comparison of high dose infusion of MTX vs sequential-complementary method for maintenance of remission. Jpn J Clin Hematol 15: 1106, 1974 27. Gagliano RG, Constanzi JJ: Paraplegia following intrathecal methotrexate: report of a case and review of the literature. Cancer 37: 1663, 1976 28. Ganem G, Kuentz M, Bernaudin F et al.: Central nervous system relapses after bone marrow transplantation for acute lymphoblastic leukemia in remission. Cancer 64: 1796, 1989 29. Geiser CF, Bishop Y, Jaffe N et al.: Adverse effects of intrathecal methotrexate in children with acute leukemia in remission. Blood 45: 189, 1975 30. Gilchrist GS, Tubergen DG, Sather H, Coccia PF, O’Brien RT, Waskerwitz MJ, Hammond D: Low numbers of CSF blasts at diagnosis do not predict for the development of CNS leukemia in children with intermediate-risk acute lymphoblastic leukemia: a Childrens Cancer Group report. J Clin Oncol 12: 2594, 1994 31. Glass JP, Lee YY, Bruner J, Fields WS: Treatment related leukoencephalopathy. A study of three cases and literature review. Medicine 65: 154, 1986 32. Go¨kbuget N, Hoelzer D: High-dose methotrexate in the treatment of adult acute lymphoblastic leukemia. Ann Hematol 72: 194, 1996 33. Hansen PB, Kjeldsen L, Dalhoff K, Olesen B: Cerebrospinal fluid beta-2-microglobulin in adult patients with acute leukemia or lymphoma: a useful marker in early diagnosis and monitoring of CNS-involvement. Acta Neurol Scand 85: 224, 1992 34. Henderson ES, Scharlau C, Cooper MR, Haurani FI, Silver RT, Brunner K, Carey RW, Falkson G, Blom J, Nawabi IV, Levine AS, Bank A, Cuttner J, Cornwell GG, 3d, Henry P, Nissen NI, Wiernik PH, Leone L, Wohl H, Rai K, James GW, Weinberg V, Glidewell O, Holland JF: Combination chemotherapy and radiotherapy for acute lymphocytic leukemia in adults: results of CALGB protocol 7113. Leuk Res 3: 395, 1979 35. Ho DHW, Frei E: Clinical pharmacology of 1-beta-D-arabinofuranosyl cytosine. Clin Pharmacol Ther 12: 944, 1971 36a. Hoelzer D, Thiel E, Löffler 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 KP, Spors S, Nowrousian RM, Fischer J, Fülle HH, Mitrou PS, Pfreundschuh M, Görg C, Emmerich B, Queisser W, Meyer P, Labedzki L, Essers U, König H, Mainzer K,
36.
37. 38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
Herrmann R, Messerer D, Zwingers T: Intensified therapy in acute lymphoblastic and acute undifferentiated leukemia in adults. Blood 64: 38, 1984 Hoelzer D: Therapy of the newly diagnosed adult with acute lymphoblastic leukemia. Hemat/Oncol Clin North Am 7 (1): 139, 1993 Hoelzer D: Acute lymphoblastic leukemia – progress in children, less in adults. N Engl J Med 329: 1343, 1993 Hoelzer D, Go¨kbuget N, Arnold R, Bu¨chner T, Freund M, Gassmann W, Heil G, Hiddemann W. Lo¨ffler H, Lipp T, Ludwig WD, Maschmeyer G, Thiel E, Messerer D: Akute lymphatische Leuka¨mie des Erwachsenen. Diagnostik, Risikogruppen und Therapie. Internist 37: 994, 1996 Hoelzer D, Thiel E, Lo¨ffler H, Bu¨chner T, Ganser A, Heil G, Koch P, Freund M, Diedrich H, Ru¨hl H, Maschmeyer G, Lipp T, Nowrousian MR, Burkert M, Gerecke D, Pralle H, Mu¨ller U, Lunscken C, Fu¨lle H, Ho AD, Ku¨chler R, Busch FW, Schneider W, Go¨rg C, Emmerich B, Braumann D, Vaupel HA, Paleske A, Bartels H, Neiss A, Messerer D: Prognostic factors in a multicenter study for treatment of acute lymphoblastic leukemia in adults. Blood 71: 123, 1988 Hoelzer D, Thiel E, Ludwig WD, Lo¨ffler H, Bu¨chner T, Freund M, Heil G, Hiddemann W, Maschmeyer G, Vo¨lkers ¨ , for the German ALL Study Group: The GerB, Aydemir U man multicenter trials for treatment of acute lymphoblastic leukemia. Leukemia 6: 175, 1992 Holm B, Jensen PB, Sehested M: ICRF-187 rescue in etoposide treatment in vivo. A model targeting high-dose topoisomerase II poisons to CNS tumors. Cancer Chemother Pharmacol 38: 203, 1996 Hussein KK, Dahlberg S, Head D, Waddell CC, Dabich L, Weick JK, Morrison F et al.: Treatment of acute lymphoblastic leukemia in adults with intensive induction, consolidation and maintenance chemotherapy. Blood 73 (1): 57, 1989 Iacoangeli M, Roselli R, Pagano L, Leone G, Marra R, Pompucci A, Trignani R, Scerrati M: Intrathecal chemotherapy for treatment of overt meningeal leukemia: comparison between intraventricular and traditional intralumbar route. Ann Oncol 6: 377, 1995 Ito C, Evans WE, McNinch L, Coustan-Smith E, Mahmoud HH, Pui CH, Campana D: Comparative cytotoxicity of dexamethasone and prednisolone in childhood acute lymphoblastic leukemia. J Clin Oncol 14: 2370, 1996 Jones B, Freeman A, Shuster JJ et al.: Lower incidence of meningeal leukemia when prednisone is replaced by dexamethasone in the treatment of acute lymphocytic leukemia. Med Pediatr Oncol 19: 269, 1991 Kalifa C, Hartmann O, Demeocq F, Vassal G, Couanet D, Terrier-Lacombe MJ, Valteau D, Brugieres L, Lemerle J: High-dose busulfan and thiotepa with autologous bone marrow transplantation in childhood malignant brain tumors: a phase II study. Bone Marrow Transplant 9: 227, 1992 Kantarjian HM, Smith T, Estey E, Polyzos A, O’Brien S, Pierce S, Beran M, Feldman E, Keating MJ: Prognostic significance of elevated serum beta 2-microglobulin levels in
Please indicate author’s corrections in blue, setting errors in red 159834 NEON ART.NO KRA-12 (777) ORD.NO 234777.Z
179
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
adult acute lymphocytic leukemia [see comments]. Am J Med 93: 599, 1992 Kantarjian HM, Walters RS, Keating MJ, Smith TL, O’Brien S, Estey EH, Huh YO, Spinolo J et al.: Results of vincristine, doxorubicin, and dexamethasone regimen in adults with standard- and high-risk acute lymphocytic leukemia. J Clin Oncol 8: 994, 1990 Kantarjian HM, Walters RS, Smith TL, Keating MJ, Barlogie B, McCredie KB, Freireich EJ: Identification of risk groups for development of central nervous system leukemia in adults with acute lymphocytic leukemia. Blood 72: 1784, 1988 Kersten MJ, Evers LM, Dellemijn PL, Portegies P, Hintzen RQ, van Lier RA, von dem Borne AE, van Oers RH: Elevation of cerebrospinal fluid soluble CD27 levels in patients with meningeal localization of lymphoid malignancies. Blood 87: 1985, 1996 Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR, Hooberman AL, Westbrook CA, Arthur DC, George SL, Bloomfield CD, Schiffer CA: Five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: Cancer and Leukemia Group B Study 8811. Blood 85: 2025, 1995 Law IP, Blom J: Adult acute leukemia. Frequency of central nervous system involvement in long term survivors. Cancer 40: 1304, 1977 Linker CA, Levitt LJ, O’Donnell M, Forman SJ, Ries CA: Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood 78: 2814, 1991 Lluesma-Gonalons M, Pavlovsky S, Santarelli MT, Eppinger-Helf M, Dorticos Bavea E, Corrado C, Carnot J, and members of GATLA-GLATHEIM: improved results of an intensified therapy in adult acute lymphocytic leukemia. Ann Oncol 2: 33, 1991 MacKintosh FR, Colby TV, Podolsky WJ, Burke JS, Hoppe RT, Rosenfelt FP, Rosenberg SA, Kaplan HS: Central nervous system involvement in non-Hodgkin’s lymphoma: an analysis of 105 cases. Cancer 49: 586, 1982 Mahmoud HH, B M, Ch B, Rivera GK, Hancock ML, Krance RA, Kun LE, Behm FG, Ribeiro RC, Sandlund JT, Crist WM, Pui CH: Low leukocyte counts with blast cells in cerebrospinal fluid of children with newly diagnosed acute lymphoblastic leukemia. N Engl J Med 329: 314, 1993 Mandelli F, Annino L, Rotoli B, for the GIMEMA Cooperative Group I: The GIMEMA ALL 0183 trial: analysis of 10-year follow-up. Br J Hematol 92: 665, 1996 Mandelli F, Annino L, Vegna ML, Camera A, Ciolli S, Deplano W, Fabiano F, Ferrara F, Ladogana S, Muti G, Peta A, Recchia A, Sica S, Stasi R, Tabilio A, Visani G, Baccarani M: GIMEMA ALL 0288: a multicentric study on adult acute lymphoblastic leukemia. Preliminary results. Leukemia 6 (Suppl 2): 182, 1992 Mandelli F, Annino L, Vegna ML, Ferrari A, Ciolli S, Chierichini A, Del Poeta G, Fabbiano F, Falda M, Ferrara F, In-
60.
61.
62.
63.
64.
65.
66.
67.
68.
69. 70.
71.
72.
vernizzi R, Ladogna S, Recchia A, Montillo M, Sica S, Specchia G, Tabilio A, Zagonel V, Baccarani M: Adult acute lymphoblastic leukemia (ALL): Results of the Gimema ALL 0288 trial. Br J Hematol 144: 551, 1996 Mastrangelo R, Poplack D, Bleyer A, Riccardi R, Sather H, D’Angio G: Report and recommendations of the Rome workshop concerning poor-prognosis acute lymphoblastic leukemia in children: Biologic bases for staging, stratification and treatment. Med Pediatr Oncol 14: 191, 1986 Morra E, Lazzarino M, Brusamolinio E, Pagnucco G, Castagnola C, Bernasconi P, Orlandi E, Corso A, Santagostino A, Bernasconi C: The role of systemic high-dose cytarabine in the treatment of central nervous system leukemia. Cancer 72: 439, 1993 Morse M, Savitch J, Balis F, Miser J, Feusner J, Reaman G, Poplack D, Bleyer A: Altered central nervous system pharmacology of methotrexate in childhood leukemia: another sign of meningeal relapse. J Clin Oncol 3: 19, 1985 Musto P, Modoni S, Ladogana S, Salcuni G, Fusilli S, Carotenuto M: Increased risk of neurological relapse in acute lymphoblastic leukemias with high levels of cerebrospinal fluid thymidine kinase at diagnosis. Leuk Lymphoma 9: 121, 1993 Neale GA, Pui CH, Mahmoud HH, Mirro J Jr, Crist WM, Rivera GK, Goorha RM: Molecular evidence for minimal residual bone marrow disease in children with ‘isolated’ extra-medullary relapse of T-cell acute lymphoblastic leukemia. Leukemia 8: 768, 1994 Odom L, Wilson H, Cullen J et al.: Significance of blasts in low-cell-count cerebrospinal fluid specimens from children with acute lymphoblastic leukemia. Cancer 66: 1748, 1990 Omura GA, Bass D: Prognostic factor analysis of central nervous system relapse in adult acute lymphoblastic leukemia. A Southeaster Cancer Study Group report. Am J Clin Oncol 17: 93, 1994 Omura GA, Moffitt S, Vogler WR, Salter MM: Combination chemotherapy of adult acute lymphoblastic leukemia with randomized central nervous prophylaxis. Blood 55: 199, 1980 Peper M, Schraube P, Kimming B, Wagensommer C, Wannenmacher M, Haas R: Long-term cerebral side-effects of total body irradiation and quality of life. Recent Res Cancer Res 130: 219, 1993 Pinkel D, Woo S: Prevention and treatment of meningeal leukemia in children. Blood 84: 355, 1994 Relling MV, Mahmoud HH, Pui CH, Sandlund JT, Rivera GK, Ribeiro RC, Crist WM, Evans WE: Etoposide achieves potentially cytotoxic concentrations in CSF of children with acute lymphoblastic leukemia. J Clin Oncol 14: 399, 1996 Ribeiro RC, Rivera GK, Hudson M, Mulhern RK, Hancock ML, Kun L, Mahmoud H, Sandlund JT, Crist WM, Pui CH: An intensive re-treatment protocol for children with an isolated CNS relapse of acute lymphoblastic leukemia. J Clin Oncol 13: 333, 1995 Scherrer R, Betterheim P, Geissler K, Ja¨ger U, Kno¨bl P, Kyrle PA, Laczika K, Mitterbauer G, Neumann E, Schneider B, Schwarzinger I, Lechner K: High efficacy of the German
Please indicate author’s corrections in blue, setting errors in red 159834 NEON ART.NO KRA-12 (777) ORD.NO 234777.Z
180
73.
74.
75. 76.
77.
78.
79.
80.
81.
82.
multicenter ALL (GMALL) protocol for the treatment of adult acute lymphoblastic leukemia (ALL) – a single-institution study. Ann Hematol 69: 181, 1994 Slevin ML, Piall EM, Aherne GW, Harvey VJ, Johnston A, Lister TA: Effect of dose and schedule on pharmacokinetics of high-dose cytosine arabinsoide in plasma and cerebrospinal fluid. J Clin Oncol 1: 546, 1983 Smedmyr B, Simonsson B, Sundstro¨m C, for the Swedish ALL-group: Acute lymphoblastic leukaemia in adults in Sweden 1877–84: A retrospective analysis. Eur J Haematol 43: 167, 1989 Steinherz PG: CNS leukemia: problem of diagnosis, treatment and outcome. J Clin Oncol 13: 310, 1995 Stewart DJ, Keating MJ, McCredie KB, Smith TL, Youness E, Murphy SG, Bodey GP, Freireich EJ: Natural history of central nervous system acute leukemia in adults. Cancer 47: 184, 1981 Stryckmans P, Marie JP, Suciu S, Solbu G, Debuscher L, Bury J, Peetermans M, Andrien JM, Fiere D, Cauchie C, van Camp B, Zittoun R: Therapy for adolescent and adult acute lymphoblastic leukemia: randomisation of induction and consolidation therapies (preliminary results of EORTC study 58791). In: Bu¨chner, Schellong, Hiddemann, Urbanitz, Ritter (Eds) Haematology and Blood Transfusion: Acute Leukemias. Springer, Berlin, Heidelberg, 1987, p 130 Sullivan MP, Humphrey GB, Vietti T, Komp D: Combination intrathecal (IT) therapy for meningeal leukemia: Two vs three drugs. Proceedings of the 11th Annual Meeting of ASCO 16: 85, 1975 Sullivan MP, Moon TE, Trueworthy R, Vietti TH, Humphrey GB, Komp D (A Southwest Oncology Group Study): Combination intrathecal therapy for menigeal leukemia: Two versus three drugs. Blood 50: 471, 1977 Thiebaut A, Sebban C, Vernant JP, Thomas X, Fiere D: Initial central nervous sytem (CNS) involvement in adult acute lymphoblastic leukemia (ALL): Characteristics and longterm outcome. Blood ASH 1996: 1996 Thomas X, Danaila C, Bach QK, Dufour E, Fiere D: Sequential induction chemotherapy with vincristine, daunorubicin, cyclosphosphamide, and prednisone in adult acute lymphoblastic leukemia. Ann Hematol 70: 65, 1995 Thompson CB, Sanders JE, Flournoy N, Buckner CD, Tho-
83.
84.
85.
86.
87.
88.
89.
90.
mas ED: The risks of central nervous system relapse and leukoencephalopathy in patients receiviing marrow transplants for acute leukemia. Blood 67: 195, 1986 Todeschini G, Meneghini V, Pizzolo G, Cassibba V, Ambrosetti A, Veneri D, Nadali G, Zanotti R, Tecchio C, Perona G:: Relationship between daunorubicin dosage delivered during induction therapy and outcome in adult acute lymphoblastic leukemia. Leukemia 8: 376, 1994 Tubergen DG, Cullen J, Boyett JM, Gilchrist GS, O’Brien RT, Coccia PF, Waskerwitz MJ: Blasts in CSF with a normal cell count do not justify alteration of therapy for acute lymphoblastic leukemia in remission: A Childrens Cancer Group Study. J Clin Oncol 12: 273, 1994 Tucker J, Prior PF, Green CR, Ede GMV, Stevenson JF, Gawler J, Amal GA, Charlesworth M, Thakkar CM, Patel P, Lister TA: Mimimal neuropsychological sequelae following prophylactic treatment of the central nervous system in adult leukaemia and lymphoma. Br J Cancer 60: 775, 1989 Veerman AJ, Hahlen K, Kamps WA: Results of the ALL-VI protocol for non-high risk childhood acute lymphoblastic leukemia from the Dutch Childhood Leukemia Study Group. Haematologica 76: 105: 1991 Weller M, Stevens A, Sommer N, Schbet M, Wietholter H: Tumor cell dissemination triggers an intrathecal immune response in neoplastic meningitis. Cancer 69: 1475, 1992 Wiernik PH, Dutcher JP, Paietta E, Gucalp R, Markus S, Weinberg V, Azar C, Garl S, Benson L: Long-term follow-up of treatment and potential cure of adult acute lymphocytic leukemia with MOAD: a non-anthracycline containing regimen. Leukemia 7: 1236, 1993 Willemze R, Zijlmans JM, den Ottolander GJ, Kluin-Nelemans JC, Falkenburg JHF, Starrenburg CWJ, van der Burgh JF, Fibbe WE: High-dose Ara-C for remission induction and consolidation of previously untreated adults with ALL or lymphoblastic lymphoma. Ann Hematol 70: 71, 1995 Wolk RW, Mase SR, Conklin R et al.: The incidence of central nervous system leukemia in adults with acute leukemia. Cancer 33: 863, 1974
Address for offprints: D. Hoelzer, Universita¨tsklinikum, Medizinische Klinik III, Theodor Stern Kai 7, 60590 Frankfurt, Germany
Please indicate author’s corrections in blue, setting errors in red 159834 NEON ART.NO KRA-12 (777) ORD.NO 234777.Z