Prevention and treatment of meningeal leukemia in children

The prevention of meningeal leukemia has long been a keystone in its cure. The need was recognized when it became apparent in the 1950s and 1960s that meningeal relapse heralded hematologic relapse and a fatal course and that its incidence increased as systemic chemotherapy became more effective in controlling hematologic and visceral leukemia. Evasion of a biologic safety net, the blood-CSF barrier, is required to prevent meningeal leukemia. Three methods are used: meningeal radiotherapy, intrathecal administration of antileukemia drugs, and high-dosage intravenous antileukemia drugs. Recent and current clinical studies reflect a continuing dialogue about which methods are preferable and under what circumstances. For prevention of meningeal leukemia, extended intrathecal therapy and intensive systemic chemotherapy appear to be as effective as radiotherapy for most patients. For treatment of overt meningeal leukemia, meningeal radiotherapy may be necessary. However, its administration compromises subsequent systemic chemotherapy so that delay may be advisable to allow intensive systemic chemotherapy for control of concurrent hematologic and visceral leukemia, whether clinically evident or not. For patients with meningeal leukemia at diagnosis, cranial irradiation may be delayed or possibly omitted if evidence of disease is minimal and intrathecal and systemic chemotherapy are intensive. For those who develop meningeal leukemia while on therapy or after its completion, cranial or craniospinal irradiation is probably required as well as intensive intrathecal and systemic chemotherapy. Hopefully, current and future studies will dispel the uncertainties and better quantitate risks and benefits of alternative methods. Whatever method is used, careful attention to technical details is required to assure optimal efficacy at the least possible expense in immediate toxicity and late sequelae.     

Experiences with the ommaya reservoir for prophylaxis and treatment of the central nervous system in adult acute myelocytic leukemia

Summary Intraventricular chemotherapy was administered to adult AML patients via an Ommaya reservoir. Twenty-eight patients received central nervous system (CNS) prophylaxis and seven patients were treated for meningeal leukemia (ML). A treatment course lasted at least 6 months. Asymptomatic ML developed in two patients (7%) of the prophylaxis group concomitantly with bone marrow relapse. One of these patients had not completed the standard course. CNS remission could be obtained in all evaluable patients with ML. The easy entrance to the cerebrospinal fluid (CSF) offers the advantage of frequent investigations of the CSF, early diagnosis and treatment of CNS relapses without radiotherapy, and caused little patient discomfort. CNS prophylaxis in this small study seemed to prolong first remission duration slightly. In M4 and M5 subtypes CNS prophylaxis can be valuable.     

Central nervous system involvement at first relapse in patients with acute myeloid leukemia

The risk factors for and incidence of central nervous system involvement at first relapse in adult patients with acute myeloid leukemia have not been established. This single-center study analyzed the prognostic factors for and cumulative incidence of meningeal relapse in 458 adult patients achieving complete remission. Before 1990, patients received old chemotherapy approaches without stem cell transplantation that often included prophylactic intrathecal chemotherapy. Since 1990, modern protocols included stem cell transplantation without intrathecal prophylaxis. Meningeal relapse occurred in 6 patients (overall 5-year cumulative incidence 1.3%). The 5-year cumulative incidence of meningeal relapse in patients treated with old and modern protocols were 3.9% and 0.3%, respectively. Univariate and multivariate analyses showed that the chemotherapy approach was the main prognostic factor for central nervous system relapse (P=0.02). This study shows an extremely low incidence of meningeal relapse in adult patients with acute myeloid leukemia treated with modern protocols including stem cell transplantation without intrathecal prophylaxis.     

Activity of all-trans-retinoic acid in a case of central nervous system extramedullary relapse of acute promyelocytic leukemia

We describe a patient with an acute promyelocytic leukemia (APL) previously treated with two courses of cytarabin, idarubicin and all-trans retinoic acid (ATRA), who presented a medullary and meningeal relapse after 8 months of complete remission. A diagnosis of central nervous system (CNS) involvement was based on the appearance of APL blasts in the cerebrospinal fluid (CSF); magnetic resonance (MR) imaging was negative. The neurological symptoms were not evident at the time of recognition of the medullary recurrence, but appeared a few days later, when the patient had already received a reinduction treatment. When the CSF was first examined, showing atypical promyelocytes, there was no excess of blasts on bone-marrow examination. The patient was treated with ATRA and intrathecal administrations of cytoxic drugs, achieving a complete long-lasting CNS remission. The appearance of mature myeloid cells in the CSF during this treatment suggested a possible differentiating effect of ATRA towards extramedullary relapse.     

High incidence of meningeal leukemia in lymphoid blast crisis of chronic myelogenous leukemia

Fifteen patients with lymphoid blast crisis of chronic myelogenous leukemia (LyBC-CML) and five patients with acute lymphoblastic leukemia converting to Philadelphia-positive (Ph+) chronic myeloid leukemia (ALL Ph + CML) were followed. Seven of 15 (46.7%) LyBC-CML patients developed meningeal leukemia within a median period of 6 months (range 2–11 months), while there was no medullary relapse. Five of these responded well to triple intrathecal therapy. In the ALL Ph + CML patients, in spite of central nervous system (CNS) prophylaxis with IT MTX and 18 Gy cranial radiation, two of five patients (40%) experienced meningeal leukemia, one isolated and the other with medullary relapse. The data confirm that LyBC-CML patients experience a high incidence of meningeal leukemia. The role of CNS prophylaxis is not very clear, but its use may delay development and reduce morbidity due to CNS disease.     

Central Nervous System Involvement of Previously Undiagnosed Chronic Lymphocytic Leukemia in a Patient with Neuroborreliosis

Leukemic involvement of the central nervous system (CNS) in previously undiagnosed chronic lymphocytic leukemia (CLL) is very rare. We report the case of a 62-year-old man with neuroborreliosis in which cytologic, immunocytochemical, and flow cytometry analyses revealed the presence of clonal B-lymphocytes in the cerebrospinal fluid (CSF). After the patient received antimicrobial therapy, his meningeal symptoms cleared up, and the number of cells in the CSF decreased. Monoclonal lymphocytes were still detectable at the same percentage, however, despite systemic chlorambucil therapy. The application of intrathecal dexamethasone therapy led to the disappearance of B-cell CLL (B-CLL) cells in the CSF. We presumed that the neuroborreliosis enabled the transmigration of leukocytes, including B-CLL cells, across the blood-brain barrier via activation of matrix metalloproteinase 9, an enzyme known to open the blood-brain barrier.     

Leukemia in the Central Nervous System

ABSTRACT The frequency of central nervous system (CNS) leukemia was studied in patients aged 15–59 with acute leukemia, who had received induction treatment in the years 1971–1986. Twelve out of 103 patients with acute lymphoblastic leukemia (ALL) developed CNS leukemia in spite of prophylaxis consisting of intrathecal methotrexate. Ten out of 217 patients with acute myelogenous leukemia (AML) developed CNS leukemia. None had been given preventive treatment. Leukemic blasts with either M4 or M5 morphology appeared to increase the risk of CNS relapse. Treatment was adjusted to the clinical problem of each patient, but always included intrathecal methotrexate. Median survival after a diagnosis of CNS leukemia was 8 and 6 months in ALL and AML respectively, with bone marrow failure due to hematologic relapse as the leading cause of death. CNS leukemia, if properly treated, does probably not shorten survival. An active approach to diagnosis and treatment is therefore mandatory.     

Acute myelogenous leukemia with recurrence of the meningeal, spinal cord and the optic nerve infiltration with remission induction by Co therapy and maintained by intrathecal chemotherapy with Ommaya reservoir

A 42-year-old woman was diagnosed as having acute myelogenous leukemia (M 2 of FAB classification) in May, 1985. Complete remission was achieved with the BHAC-DP therapy (BHAC, daunomycin and prednisolone). Whole skull irradiation and intra thecal chemotherapy were performed by way of prevention. In 1986, she developed her visual disturbance and paraplegia. Myelography and metrizamide CT indicate intraspinal and meningeal infiltration of leukemic cells in the upper thoracic spine. Leukemic cells were found in the cerebrospinal fluid but not in the bone marrow. Complete remission was obtained by irradiation and intrathecal chemotherapy. In Dec. 1986, Ommaya tubing was repeated. Hematological and neurological examinations showed no evidence of malignancy for 3 years. In Oct. 1988, she admitted to our hospital for the maintenance of the remission state, and died of sepsis. The result of autopsy revealed no leukemic cells in her CNS. It is said the intraspinal infiltration of leukemic cells is rather rare. As it is said the intrathecal injection of anti-leukemic agents is not effective for the intraspinal infiltration, irradiation should be needed. Therefore it is very important to critically differentiated intraspinal from meningeal infiltration. Furthermore, Ommaya tubing is effective in order to maintain remission in a patient with CNS leukemia.     

Intensive treatment of AIDS-related non-Hodgkin's lymphomas with the MACOP-B protocol

Abstract: The usefulness of intensive chemotherapy with the MACOP-B protocol was evaluated in 8 patients with AIDS-related non-Hodgkin's lymphoma (NHL). Four patients had a prior AIDS diagnosis. The median CD4+ lymphocyte count was 0.079 cells × 10⁹/1 (range 0.016–0.330). All patients responded to treatment. Four patients finished chemotherapy, all with complete remission, while another 3 patients deteriorated prior to finishing treatment and died. The median survival was 4 months (range 1 to 86 months). Major causes of the poor outcome were AIDS-related opportunistic infections and meningeal CNS involvement by NHL developing during or after chemotherapy. Patients with AIDS-related NHL usually do not appear to benefit from treatment with MACOP-B protocol. Advanced immunodeficiency is associated with poor tolerance to treatment and inability to finish this chemotherapy protocol. MACOP-B chemotherapy does not prevent meningeal spread of lymphoma in spite of using repeatedly systemic methotrexate crossing the blood-brain barrier. CNS prophylaxis with repeated application of intrathecal methotrexate may lower the risk of meningeal spread of lymphoma, which developed in 1 of 5 patients given CNS prophylaxis as compared to 2 of 3 patients without CNS prophylaxis.     

Improved outcome for children with acute lymphoblastic leukemia: results of Total Therapy Study XIIIB at St Jude Children's Research Hospital

St Jude Total Therapy Study XIIIB for childhood acute lymphoblastic leukemia (ALL) incorporated more stringent risk classification, early intensification of intrathecal chemotherapy, reinduction treatment, and the addition of dexamethasone to postremission therapy to increase the proportion of event-free survivors without jeopardizing their quality of life. Cranial irradiation was reserved for the 12% of patients who had T-cell ALL and a presenting leukocyte count of 100 x 10(9)/L or more, or CNS-3 (5 or more leukocytes/microL with identifiable blast cells in an atraumatic sample or the presence of cranial nerve palsy) status. Among the 247 consecutive patients enrolled in the study, 117 were classified as having lower-risk leukemia and received mainly antimetabolite-based continuation therapy; the 130 cases with higher-risk leukemia received more intensive continuation chemotherapy with multiple drug pairs administered in weekly rotation. The 5-year event-free survival estimate was 80.8% +/- 2.6% (SE); the 8-year rate was 78.6% +/- 5.8%. The 5-year cumulative risk of an isolated central nervous system (CNS) relapse was 1.7% +/- 0.8%, and that of isolated plus combined CNS relapse was 3.0% +/- 1.1%. The 5-year cumulative risks of etoposide-related myeloid malignancies were 1.8% +/- 1.3% in the lower-risk patients who received a cumulative dose of 1.2 g/m(2) and 5.0% +/- 2.0% in the higher-risk patients who received a cumulative dose of up to 14.4 g/m(2) (P = .18). Independent adverse prognostic features included the presence of MLL-AF4 or BCR-ABL fusion gene and minimal residual leukemia of 0.01% or more at the end of the 6-week remission induction phase. Our results suggest the efficacy of early intensification of intrathecal chemotherapy and provide the basis for studies omitting cranial irradiation altogether.     

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急性白血病(AL)中枢神经系统受累,称中枢神经系统白血病(CNSL),发生在AL任何时期,以急性淋巴细胞白血病(ALL)居高。初发时高白细胞计数、有明显髓外侵润、某些类型如M4、M5a、T细胞型、成熟Burkitt型、复发M3及有t(4;11)、Ph+遗传学特征都是CNSL高危发病因素。脑脊液(CSF)涂片中找到白血病细胞最具诊断意义。CSF白细胞>5个/μL,伴有CNS异常表现即可诊断CNSL。对CSF进一步分类有助于ALL分层治疗。CNSL治疗重在预防,常用的防治方法有鞘内化疗、全身系统治疗以及放射治疗。现代治疗模式不再强调放疗的作用,中大剂量化疗药物的早期使用可有效防治CNSL。     

Malignancy: Meningeal Myeloma: A Case Report and Review of Literature

Purpose: Report and review of an uncommon complication of multiple myeloma. Methods: We report a case of leptomeningeal myeloma and using Medline, review previously reported cases. Results: We found 35 previously reported cases of meningeal myeloma. Of the 36 cases, including the present case, the male to female ratio was 2:1 with a median age of 58 years (range, 31 to 83 years). Forty five percent of the patients had circulating plasma cells and 90.9% had plasma cells in the cerebrospinal fluid. All but 4 cases were diagnosed antemortem. Thirty patients had a pre-existing diagnosis of multiple myeloma, while leptomeningeal disease was the presenting feature in six. Management included a combination of intrathecal chemotherapy and radiation therapy, radiation therapy alone or intrathecal chemotherapy alone in 14, 3, and 3 patients respectively. Thirteen patients also received systemic chemotherapy in addition to some form of local therapy. The median survival for the entire group was 8 weeks (range 4 days to 18 months). Even those who initially responded to local therapy relapsed in the central nervous system (CNS) or succumbed to systemic disease. Five of six patients in whom CNS disease was the presenting feature survived 4 weeks or less. Conclusions: Leptomeningeal involvement is a rare and fatal complication of multiple myeloma with a short survival despite aggressive intrathecal and systemic chemotherapy and radiation therapy.     

Remission Maintenance Therapy for Meningeal Leukaemia: Intrathecal Methotrexate and Dexamethasone versus Intrathecal Craniospinal Irradiation with a Radiocolloid

Thirty-two patients with meningeal leukaemia who achieved meningeal remission with intrathecal methotrexate (MTX) plus dexamethasone (DMT) were entered in a randomized study of two maintenance treatments: (a) I6 patients received intermittent intrathecal doses of MTX plus DMT, and (b) I6 patients received intermittent intrathecal doses of radioactive chromic phosphate (CROP). The population and clinical characteristics of the cases assigned to each maintenance regimen were similar. The duration of meningeal remission was 55-600 + d (median 550 d) for the MTX and DMT group and 56-555 d (median 360 d) for the CROP group. There was no statistical difference (P greater than 0.05) between the curves of the two groups. Intrathecal CROP seems to be as effective as intrathecal MTX plus DMT as maintenance treatment for intrathecal MTX plus DMT induced meningeal remission. Further uses of this compound should be explored but it seems to be dangerous to administer it by lumbar puncture.     

Importance of effective central nervous system therapy in isolated bone marrow relapse of childhood acute lymphoblastic leukemia. BFM (Berlin- Frankfurt-Munster) Relapse Study Group

Presymptomatic central nervous system (CNS) treatment in children with a late isolated first bone marrow (BM) relapse of acute lymphoblastic leukemia (ALL) was based on intermediate-dose systemic and intrathecal (IT) methotrexate (MTX) in the multicenter trial, ALL-REZ BFM 85. Because this was associated with an excess of overt second CNS relapses, cranial radiotherapy (cRT) plus prolonged triple IT therapy with MTX, cytarabine, and prednisone was instituted during the course of the subsequent trial, ALL-REZ BFM 87. Results of children with or without cRT, but otherwise identical chemotherapy, are presented here. Between April 1985 and March 1990, 93 children with their first late isolated BM relapse of ALL were entered on protocols ALL-REZ BFM 85M and ALL-REZ BFM 87. An intensive 6-month phase of multiagent chemotherapy that included 8 courses of systemic MTX (1 g/m2) plus IT MTX was followed by 2 years of conventional maintenance therapy with daily 6-thioguanine and biweekly MTX. Children with bone marrow transplantation excluded, 73 were in complete remission at the end of intensive polychemotherapy, 40 of whom received fractionated cRT plus triple IT therapy during the following 6 months; 11 did not receive cRT but prolonged triple IT; 22 received neither cRT nor prolonged triple IT. Except for a higher percentage of children who had received cRT in front-line protocols (29 of 33 v 20 of 40), the patient groups without or with salvage cRT were comparable. Of 33 children without salvage cRT, 26 relapsed, compared with 21 of 40 who had received cRT (P < .05). The difference was solely attributable to second relapses with CNS involvement (10 of 33 v 1 of 40; P < .01). Estimated 6-year event- free survival rates were .18 for children without cRT and .46 for children with cRT (P < .01). In patients without cRT, no impact of prolonged IT therapy could be shown. The data suggest that second CNS prophylaxis with cRT and prolonged triple IT therapy in children with late isolated BM relapse of ALL is effective in preventing CNS relapses, in reducing the overall relapse rate, and in increasing the overall survival rate.     

Compassionate use of intrathecal depot liposomal cytarabine as treatment of central nervous system involvement in acute leukemia: report of 6 cases

The depot formulation of liposomal cytarabine (DepoCyte) has proven to be useful as intrathecal (IT) treatment of neoplastic and lymphomatous meningitis. We report the results of compassionate use of DepoCyte in 6 patients diagnosed with acute leukemia (AL) and CNS involvement. Two patients had CNS involvement at diagnosis and the remaining 4 had CNS relapse. Three patients received DepoCyte as adjuvant therapy and achieved complete response whereas 2 out of the remaining 3 cases treated with DepoCyte as the only drug showed sustained response. The side effects were mild and manageable in all patients. These findings justify the development of clinical trials to evaluate the efficacy and safety of IT depot cytarabine in meningeal involvement of AL.     

Venetoclax + hypomethylating agents combined with dose-adjusted HAG for relapsed/refractory acute myeloid leukemia: Two case reports

Rationale:Some acute myeloid leukemia (AML) patients are unresponsive to treatment or have remission followed by worsening of disease (known as relapsed/refractory AML [R/RAML]) after standardized treatment. The CAG/HAG regimen is not often used clinically because heterogenous patient responses, resistance, and hematopoietic bone marrow dysfunction have been reported with its use. We present 2 cases of R/RAML treated with a new combined therapy (venetoclax+ hypomethylating agents [HMAs]) in which the HAG dose was adjusted and effective in the first course of treatment.Patient characteristics:Case 1 involved a 23-year-old man who had suffered from AML for >4 years, and his FLT3 mutation status was positive at the initial diagnosis. After the first course of treatment with the standard-dose “Da” plan, the patient experienced complete remission. During the subsequent courses of treatment, the patient experienced 6 recurrences and was treated with the “ID Ara-C + MIT + sidaaniline” and “CAG + sidaaniline” regimens. However, the disease did not respond. Case 2 involved a 26-year-old man who received chemotherapy with the “Da,” “ID Ara-C,” “decitabine + half-dose CAG,” and “HAE” regimens. In this patients, remission could not be achieved. Reintroduction of the “ia” scheme also failed after treatment in our hospital.Diagnosis:Two patients were diagnosed with R/RAML.Interventions:The patient in case 2 received chemotherapy interventions, whereas the patient in case 1 refused to receive medical services at our hospital.Outcomes:The patient in case 1 was discharged after complete response treatment due to economic reasons and relapsed 2 months later. The patient ultimately died of infection and heart failure. The patient in case 2 is receiving a second cycle of chemotherapy.Lessons:We recommend the “venetoclax + HMAs combined with dose-adjusted CAH/HAG” regimen as an effective treatment for adult R/RAML.     

Randomized trial of radiation-free central nervous system prophylaxis comparing intrathecal triple therapy with liposomal cytarabine in acute lymphoblastic leukemia

Developing optimal radiation-free central nervous system prophylaxis is a desirable goal in acute lymphoblastic leukemia, to avoid the long-term toxicity associated with cranial irradiation. In a randomized, phase II trial enrolling 145 adult patients, we compared intrathecal liposomal cytarabine (50 mg: 6/8 injections in B-/T-cell subsets, respectively) with intrathecal triple therapy (methotrexate/cytarabine/prednisone: 12 injections). Systemic therapy included methotrexate plus cytarabine or L-asparaginase courses, with methotrexate augmented to 2.5 and 5 g/m² in Philadelphia-negative B- and T-cell disease, respectively. The primary study objective was the comparative assessment of the risk/benefit ratio, combining the analysis of feasibility, toxicity and efficacy. In the liposomal cytarabine arm 17/71 patients (24%) developed grade 3–4 neurotoxicity compared to 2/74 (3%) in the triple therapy arm (P=0.0002), the median number of episodes of neurotoxicity of any grade was one per patient compared to zero, respectively (P=0.0001), and even though no permanent disabilities or deaths were registered, four patients (6%) discontinued intrathecal prophylaxis on account of these toxic side effects (P=0.06). Neurotoxicity worsened with liposomal cytarabine every 14 days (T-cell disease), and was improved by the adjunct of intrathecal dexamethasone. Two patients in the liposomal cytarabine arm suffered from a meningeal relapse (none with T-cell disease, only one after high-dose chemotherapy) compared to four in the triple therapy arm (1 with T-cell disease). While intrathecal liposomal cytarabine could contribute to improved, radiation-free central nervous system prophylaxis, the toxicity reported in this trial does not support its use at 50 mg and prompts the investigation of a lower dosage. (clinicaltrials.gov identifier: NCT-00795756).     

鞘内注射甲氨蝶呤和地塞米松治疗狼疮性脑病的临床观察

目的 探讨鞘内联合注射甲氨蝶呤（MTX）和地塞米松（DXM）治疗狼疮性脑病（CNS－SLE）的疗效。方法 选择住院的系统性红斑狼疮（SLE）患者14例，临床上具有精神和神经异常表现，脑脊液（CSF）检查、头颅CT异常表现的狼疮性脑病，在常规剂量糖皮质激素治疗狼疮性脑病不能缓解的情况下鞘内注射MTX和DXM。结果 14例患者都得到了不同程度的缓解。结论 鞘内注射MTX和DXM是治疗狼疮性脑病的一种安全而有效的方法。     

Neurologic complications associated with intrathecal liposomal cytarabine given prophylactically in combination with high-dose methotrexate and cytarabine to patients with acute lymphocytic leukemia

Central nervous system (CNS) prophylaxis has led to a significant improvement in the outcome of patients with acute lymphocytic leukemia (ALL). Liposomal cytarabine (Enzon Pharmaceuticals, Piscataway, NJ; Skye Pharma, San Diego, CA), an intrathecal (IT) preparation of cytarabine with a prolonged half-life, has been shown to be safe and effective in the treatment of neoplastic meningitis. Liposomal cytarabine was given for CNS prophylaxis to 31 patients with newly diagnosed ALL. All patients were treated concurrently with hyper-CVAD chemotherapy (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) including high-dose methotrexate (MTX) and cytarabine on alternating courses. Liposomal cytarabine 50 mg was given intrathecally on days 2 and 15 of hyper-CVAD and day 10 of high-dose MTX and cytarabine courses until completion of either 3, 6, or 10 IT treatments, depending on risk for CNS disease. Five patients (16%) experienced serious unexpected neurotoxicity, including seizures, papilledema, cauda equina syndrome (n = 2), and encephalitis after a median of 4 IT administrations of liposomal cytarabine. Toxicities usually manifested after the MTX and cytarabine courses. One patient died with progressive encephalitis. After a median follow-up of 7 months, no isolated CNS relapses have been observed. Liposomal cytarabine given via intrathecal route concomitantly with systemic chemotherapy that crosses the blood-brain barrier such as high-dose MTX and cytarabine can result in significant neurotoxicity.     

Central nervous system leukemia in children with acute nonlymphoblastic leukemia

Factors contributing to the development of central nervous system (CNS) leukemia, and the impact of leukemic involvement of this site on subsequent remission length, were determined in 184 children with acute nonlymphoblastic leukemia who had been treated in two successive clinical trials. Preventive CNS therapy in both studies consisted of intrathecal methotrexate (12 mg/m2) given monthly during the first six months of therapy and then every three months until all treatment was stopped. Children with CNS leukemia at diagnosis or relapse were given intrathecal chemotherapy weekly for four weeks and then monthly throughout the remainder of the treatment course. Those continuing in complete remission received 2,400 rad cranial irradiation plus five doses of intrathecal methotrexate before cessation of therapy. The 38 children (20.7%) with CNS leukemia at diagnosis were more likely to have an initial leukocyte count greater than or equal to 25 X 10(9)/L (P = .01) and age less than 2 years (P = .03). The presence of CNS leukemia at diagnosis did not adversely affect the remission induction rate (P = .13) or the length of complete remissions (P = .73). CNS relapse ended initial remissions in 11 patients only and did not preclude subsequent long-term survival, as four of these children are off therapy and in second complete remission for 33+ to 78+ months. Three features at diagnosis were predictive of CNS relapse: monocytic or myelomonocytic leukemia (P = .002); age less than 2 years (P = .0001); and leukocyte count greater than or equal to 25 X 10(9)/L (P = .012). By stepwise Cox regression analysis, each factor was found to have independent predictive value. Despite the apparent effectiveness of intrathecal methotrexate as preventive CNS treatment, our findings indicate that more effective prophylaxis is needed for patients with features predisposing to CNS relapse.