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PubMed1994

Therapy of B-cell acute lymphoblastic leukaemia in childhood: the BFM experience.

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 ALL-BFM-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 (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 ALL-BFM-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-MTX5 g/m2 in conjunction with an i.t. therapy is a very important component for prevention of both systemic and CNS relapses.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1994

Central nervous system directed therapy in acute lymphoblastic leukaemia.

CNS-directed treatment is an essential component of therapy for both children and adults with acute lymphoblastic leukaemia. The choice between combinations of i.t. drugs, radiotherapy and high-dose systemic chemotherapy is not a clear one and will depend on the age of the patient, the type of leukaemia and indeed the available treatment facilities. A plea is made for any prospective trials of CNS-directed therapy to incorporate formal assessment of neuropsychological performance, and in the young child, of growth and pubertal progression.

Adrenal Cortex Hormones↗
PubMed1994

Long-term sequelae of therapy for childhood acute lymphoblastic leukaemia.

Childhood ALL has provided the model for basic therapeutic principles in the past and now provides the model for late effects studies. Common threads which run throughout the literature in this area of clinical research are the importance of young age with increased vulnerability to long-term treatment induced sequelae and the relatively large contribution of radiation as compared with chemotherapy in the pathogenesis of adverse sequelae. Previous retrospective studies of long-term childhood ALL survivors focused on neuropsychologic changes and anatomic changes in the CNS after cranial irradiation. More recent retrospective studies have made the following new observations: (i) the high frequency of significant short adult stature in those less than 6 years of age at diagnosis who received 24 Gy cranial irradiation; (ii) actuarial risk of 2.5% of developing a second malignancy with approximately one-half of secondary malignancies occurring in the CNS in children 5 years of age or less who received cranial irradiation; (iii) the association of secondary ANLL with epipodophyllo-toxin use, and (iv) delayed cardiac toxicity despite anthracycline dosage reduction. Current therapy regimens, especially in high-risk patients, are both more successful and more intensive than those used in the past. While it will be another decade before many of the long-term sequelae begin to emerge, one can anticipate, based on current experience, some of the problems that will occur.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Intrathecal chemotherapy.

An unforeseen consequence of improved disease-free survival in many hematologic and solid tumor malignancies has been an increase in the incidence of disease recurrence in the leptomeninges. The recognition of the central nervous system (CNS) as a unique 'sanctuary' site has resulted in the development of therapeutic strategies specifically directed at the leptomeninges. Although therapeutic strategies have been successful in the prevention and treatment of CNS leukemia, there are still a paucity of therapeutic options for patients with neoplastic meningitis due to solid tumors or recurrent CNS leukemia. This article provides an overview of the pharmacology and toxicity of intrathecal agents that are commonly employed in the treatment and prevention of leptomeningeal disease, and describes new agents that are in the early stages of clinical development.

Antineoplastic Agents↗
PubMed2001

Allosterically controllable maxizyme-mediated suppression of progression of leukemia in mice.

Chronic myelogenous leukemia (CML) is a hematopoietic malignant disease associated with expression of a chimeric BCR-ABL gene. We recently succeeded in designing a novel allosterically controllable ribozyme, the maxizyme (Tanabe et al. Biomacromolecules 2000, 1, 108-117; Kuwabara et al. Biomacromolecules 2001, 2, 788-799), that not only specifically cleaves BCR-ABL mRNA and induces apoptosis in cultured CML cells but also shows significant inhibition against the growth of an established BV173 cell line in a mouse model (Tanabe et al. Nature 2000, 406, 473-474). As an extension of our studies, we tested the maxizyme against primary CML cells in the same mouse model. The maxizyme under the control of a tRNA(Val) promoter showed significant inhibition against the growth of the primary bone marrow cells from a Japanese patient with CML. Specifically, to examine the applicability of the maxizyme in the treatment of CML, we assessed the antitumor effect of the maxizyme in murine models of CML. Fourteen weeks after the injection of primary CML cells into a NOD-SCID mouse, the bone marrow of the mouse was filled with primary CML cells as a result of diffuse leukemia. In marked contrast, when maxizyme-expressing primary CML cells were injected, the mouse remained disease-free. These results further strengthen our earlier suggestion that the maxizyme technology might provide a useful approach to the treatment of CML.

Allosteric Regulation↗
PubMedDate not supplied

Prophylaxis and treatment of neoplastic meningeosis in childhood acute lymphoblastic leukemia.

The introduction of cranial radiotherapy (CRT) has provided efficient control of overt or subclinical meningeosis in acute leukemia. Especially due to the long-term toxicity of CRT, reduction or elimination of radiotherapy appeared mandatory after cure rates of more than 70% had been achieved in acute lymphoblastic leukemia (ALL). Several large clinical trials of the Berlin-Frankfurt-Münster (BFM) Study Group with more than 3500 patients since 1981 have demonstrated that intensive systemic and intrathecal chemotherapy without or with limited CRT can efficiently prevent central nervous system (CNS) relapses in a large percentage of patients. However, only in low-risk patients prophylactic radiotherapy can be completely and safely replaced by conventional doses of methotrexate. In addition, reduction of chemotherapy in low-risk ALL increased the rate of relapses with CNS involvement. Thus, only a combination of multidrug induction, high-dose methotrexate (HD-MTX) consolidation, and reintensification allowed safe elimination of CRT in low-risk ALL. This approach combined with CRT with 12Gy and 18 Gy in medium and high risk ALL, respectively, reduced the incidence of relapses with CNS involvement to less than 5% (trial ALL-BFM 86). Patients with inadequate response to therapy, or with T-cell ALL, or with overt CNS disease are at particularly high risk for relapse with CNS involvement, and require more systemic and intrathecal chemotherapy combined with cranial irradiation. In B-cell ALL, short intensive chemotherapy pulses including HD-MTX could completely replace radiotherapy. In AML, post-consolidation CRT appears to be advantageous with regard to control of extramedullary as well as systemic relapses.

Antimetabolites, Antineoplastic↗
PubMedDate not supplied

In situ hybridization: a possible diagnostic aid in leptomeningeal metastasis.

In this review we discuss the clinical features and pathophysiology of leptomeningeal metastasis (LM), and elaborate on diagnostic tools for the detection of this serious complication of cancer. Because of the low sensitivity of the cytologic examination, new diagnostic approaches have been developed. The in situ hybridization technique may prove to be a reliable and early test for the detection of LM.

Adenocarcinoma↗
PubMedDate not supplied

Animal models of leptomeningeal metastasis.

Animal models of leptomeningeal metastasis (LM) should give insight into pathophysiological mechanisms and allow to evaluate new treatments including their neurotoxicity. Syngeneic models use tumor cells of mouse, rat, rabbit or guinea pig origin. Allogeneic models usually rely on human tumor cells injected into nude mice or rats. A review of the literature revealed 2 (4) different glioma, 3 medulloblastoma, 3 (3) carcinoma, 3 (1) melanoma, 1 rhabdomyosarcoma, 2 (8) leukemia and 2 (2) non-Hodgkin's lymphoma allogeneic (syngeneic) models of LM. These models have been used to study the evolution of LM and to evaluate systemic or intrathecal chemotherapy, intrathecal immunotherapy (interleukin-2, interferon-beta, uncoupled, toxin- or radionuclide-conjugated antibodies), and recently gene therapeutic approaches. On the whole, pathophysiological, therapeutic and neurotoxic findings have been well transferable to the clinical situation. Therefore, it seems rational to preclinically test new treatments in an appropriate animal model of LM before using them in patients.

Animals↗
PubMedDate not supplied

Meningeosis leukaemica in adult acute lymphoblastic leukaemia.

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.

Adult↗
PubMedDate not supplied

Cytology of neoplastic meningosis.

Where a leptomeningeal carcinomatosis is clinically diagnosed, evidence should be provided of tumor cells in the CSF. Not necessarily in the first specimen, but in the course of the illness. The staining of the cells with the Pappenheim method generally provides sufficient information about the cells. The identification of cells in metastases of epithelial tumours is not difficult for anyone with some experience. Identifying cells from primary brain tumours - which however only rarely cause meningosis - can sometimes be more difficult. Attention should be paid to whether the cells occur in clusters or singly. However, extreme caution is called for. The cytological monitoring of the CSF is an essential part of chemotherapy or radiation treatment.

Brain Neoplasms↗
PubMedDate not supplied

Treatment of neoplastic meningitis by targeted radiation using (131)I-radiolabelled monoclonal antibodies. Results of responses and long term follow-up in 40 patients.

Between 1984 and 1993, monoclonal antibodies (MAbs) radiolabelled with (131)I were administered into the CSF of 52 patients with neoplastic meningitis (meningosis) with progressive disease despite active conventional therapy. Selection of MAbs was based on immunoreactivity with patients' tumour and lack of binding to normal central nervous system (CNS) tissue. Following full clinical assessment and neuro-imaging which included isotope flow study of CSF pathways, (131)I-MAb was administered via a ventricular access device, lumbar catheter or both. Radioisotope activity varied from 25 mCi to 160 mCi in adults. Dose escalation was carried out and some patients received multiple doses. Distribution of (131)I-MAb and clearance kinetics were derived from serial scintigraphy and CSF/blood sampling. Evidence of localisation to tumour was frequently observed. Toxicity was minimal and easily treated, although one death occurred, possibly due to a seizure. The best results were obtained in primitive neuroectodermal tumour (n=22), where 53% of evaluable cases had responses and 11% had stable disease, adults responding better than children. Three exceptional survivals have been recorded; one patient leads a normal life at 10 years 11 months, one case is alive and normal at 3 years, 2 months. A third case survived in good condition for 8 years. The mean survival of responders was 39 months and non-responders 4 months. In the total series, 50% of patients survived for at least one year with 2 long term survivors. CSF therapy with (131)I-MAb appears to be valuable as a single agent or when used in combination with other modalities. Results of treating leukaemia and carcinoma cases suggest that re-seeding into the CSF compartment from active systemic disease may account for early relapse in the CNS. One carcinoma case with no apparent systemic disease made a remarkable response and survival for 4 years following a single treatment. Neoplastic meningitis generally carries a dismal prognosis. The results obtained in this initial trial are sufficiently encouraging to stimulate further attempts at CSF therapy with (131)I-MAbs.

Adolescent↗
PubMedDate not supplied

Leptomeningeal metastases: rationale for systemic chemotherapy or what is the role of intra-CSF-chemotherapy?

Malignant subarachnoid deposits complicate both primary central nervous system (CNS) tumors and systemic neoplasms. Although the pathophysiology of symptoms and signs can not be separated by the category of primary tumors that seeds the leptomeninges, the approach to therapy is not similar in primary CNS tumors and in systemic neoplasms. Standard therapy for subarachnoid seeding in primary CNS tumors include conventional or high doses of systemic chemotherapy with various combinations of radiotherapy given either to limited fields or to the whole neuroaxis. Direct administration of chemotherapy to the CSF is not being used. In contrast, whenever a systemic tumor seeds the subarachnoid space the standard approach includes intensive intra-CSF chemotherapy, radiotherapy to limited or extended CNS fields and various combinations of systemic chemotherapy. The published experience with the conventional therapy is reviewed and is critically analyzed. Evidence indicating that high dose systemic chemotherapy can replace intra-CSF treatment in some subgroups are also reviewed and the rationale for this approach is specified. Recent experience in which intra-CSF therapy was prospectively eliminated from the treatment protocol of leptomeningeal metastases of solid tumors reveals that the response rate and survival are similar to those obtained by protocols that differed only by the inclusion of intra-CSF chemotherapy. Patients who were treated by radiotherapy alone combined with systemic chemotherapy but without the intra-CSF therapy were spared the high rate of early and delayed complications directly related to intra-CSF therapy. Still, treatment outcome did not differ. Therefore, future research efforts and prospective clinical trials should investigate the best chemotherapeutic schedules and their sequencing with radiotherapy or with more intensive complementary systemic chemotherapy schemes. Newly designed drugs with long circulation time and improved CNS penetration may serve for this purpose.

Antimetabolites, Antineoplastic↗