Prevention and treatment of meningeal leukemia in children

zy zyxwvuts zyxwvut zyxwvutsr zyxw The Journalof The American Society of Hematology BLOOD VOL 84, NO 2 JULY 15,1994 REVIEW ARTICLE Prevention and Treatment of Meningeal Leukemia in Children By Donald Pinkel and Shiao Woo HE STORY OF meningeal leukemia illustrates three lessons in medical therapeutics: how a biologic safety net can obstruct success, how the safety net can be evaded, and how its evasion can result in unexpected benefits. Early studies of the pharmacokinetics of methotrexate (Mtx) and 6-mercaptopurine (6MP) demonstrated their poor diffusion from plasma into cerebrospinal fluid (CSF) through the protective biologic blood-CSF barrier.'.' The barrier was soon evaded by direct intrathecal injection of Mtx and later by intravenous administration of high doses of Mtx that yielded therapeutic levels in the CSF.'*3Meanwhile, it was shown that prevention of meningeal leukemia by an additional method of evasion, cranial radiation, when combined with multiple drug systemic chemotherapy, resulted in a 50% cure rate of acute lymphoid leukemia (ALL).4 Unexpected benefits of high-dosage M& were a 10-fold reduction of isolated testicular relapse and a probability that it also decreased the risk of hematologic Thus, much of the progress in curing ALL resulted from a biologic safety net that required evasion. The purpose of this communication is to briefly reviewthe nature of meningeal leukemia, to summarize recent studies of its prevention and treatment, and to suggest guidelines for its management. PATHOLOGY Meningeal leukemia arises from neoplastic lymphocytes or myelocytes in cranial arachnoid The proliferating cells originate in walls of superficial veins and extend through the superficial arachnoid into the arachnoid surrounding arteries, veins, arterioles, and venules as they course into and through the brain. With increasing mass, the leukemia cells reduce the caliber of these vessels, producing cerebral hypoperfusion. Eventually, they can burst out of the arachnoid trabeculae into the CSF, ,resulting in leukemic meningitis that leads to symptoms of morning headache, vomiting, meningismus, and papilledema? With further increase in mass, the leukemia cells can pass through the piaglial barrier into brain parenchyma, producing further cerebral dysfunction.' In some cases, such as B-cell ALL and acute myelomonocytic leukemia with eosinophilia and chromosomal inversion 16, actual tumor masses are formed with symptoms of discrete brain tumors. Because cranial nerves pass through the leptomeninges, they and their vasculature Blood, V01 84, No 2 (July 15). 1994 pp 355-366 can be compressed and damaged by leukemic infiltrates, resulting in clinical neuropathy, including leukemic optic neuritis and consequent optic atrophy.'.'' Hypothalamic and pituitary invasion can result in endocrine disturbances, including accelerated growth, Cushing's syndrome, and diabetes insipidus. Spinal leptomeningeal leukemia can extend to dorsal nerve roots, producing tabetic symptoms, or to the cauda equina, causing paraparesis. CLINICAL DIAGNOSIS OF MENINGEALLEUKEMIA Although most children and many adults probably have some degree of asymptomatic meningeal leukemia at diagnosis, the clinical diagnosis of meningeal leukemia in the patient without neurologic symptoms or signs is not always clear. One definition commonly used requires a cell count of 5 or more per microliter of CSF and the presence of unequivocal leukemic blast cells on a cytospin preparation." However, this definition is challenged by reports that the presence of blasts in the CSF at diagnosis or during therapy increases the risk of meningeal relapse regardless of cell co~nt.'~-'~ Another problem is differentiation of leukemic from normal lymphocytes in the CSF. Patients with leukemia frequently develop CSF lymphocytosis for various reasons, oftenwith transformed normal lymphocytes. Staining for terminal deoxynucleotidyl transferase (TdT) is helpful in the distinction between leukemic and normal lymphocyte^.'^"' Unequivocal identification of leukemia cells in the CSF, regardless of cell count, signifies clinical meningeal leukemia. When uncertain, CSF examination is repeated in 1 to 2 weeks. FACTORS IN MENINGEALLEUKEMIA Downloaded from http://ashpublications.org/blood/article-pdf/84/2/355/614961/355.pdf by guest on 09 April 2024 T zy zyxwvu In addition to the blood-CSF barrier, several other factors figure in the development of meningeal leukemia. Age is From the University of Texas M.D. Anderson CancerCenter, Houston; and the Baylor College of Medicine, Houston, Ix. Submitted August 26. 1993; accepted April 5, 1994. Address reprint requests to Donald Pinkel, MD,University of Texas M.D. Anderson Cancer Center,1515 Holcombe Blvd,Box 87, Houston, Ix 77030. 0 1994 by The American Society of Hematology. oooS-4971/94/8402-0036$3.00/0 355 356 zyxwvutsrqponm zy zyxwvutsrqpo zyxwvutsrqp PINKEL AND WOO Table 1. Historical Outcome of Treatment of Isolated Meningeal Relapse of ALL in 107 Children From 1967 to 1979 (George et ala and Ochs et ala) With intrathecal chemotherapy there is the question of using Mtx alone; Mtx and cytarabine (Ara-C); or Mtx, AraC, and a soluble corticosteroid, notably hydrocortisone or methylprednisolone. Another question is how soon, how ofLeukemia outcome ten, and how long should they be administered and whether Hematologic relapse 42% an Ommaya reservoir should be used. Perhaps most imSecond meningeal relapse 26% Other failure 15% portant is whether cranial meningeal irradiation needs to be Survivors, 5 t o 17 yr 17% added to intrathecal therapy, especially in those deemed to Neurologic sequelae be at higher risk of meningeal leukemia. Although parapare42% Seizures sis and encephalopathy have been reported after intrathecal changes Anatomical 78% medication, with proper preparation and administration mordisabilitymotor Major 10% bidity is I O W . ~ ‘ ~ ~ ~ nerve Cranial loss 6% The diffusion of drugs into perivascular leptomeninges is CNS infection 6% dependent on the ebb and flow of cerebrospinal fluid from tumor Intracranial 2% the subarachnoid space, which is distant from arterioles and Lowered average intelligence venules deep in the brain.’ For this reason, radiation therapy early in remission was introduced for prevention of meningeal leukemia? Although effective, cranial irradiation can result in several adverse sequelae, including fever and somimportant. Infants and preschool children are more susceptinolence 6 to 8 weeks later; neuropsychologic impairment; ble than adolescents and adults, possibly because a higher proportion of their vasculature isin the 1ept0meninges.l~ growth disturbances, both local and pituitary-mediated; leukoencephalopathy; cerebral microangiopathy; and brain tuBiologic features of the leukemia are also important. High mors.33-50 Preschool children experience more growth inhibiinitial peripheral blood leukemia cell counts, male sex, leution and neuropsychologic sequelae than older children and kemia cells in the CSF, T-cell or B-cell immunophenotype, girls more than boys.464xWhen radiation is extended to the the presence of the Philadelphia chromosome, French-Amerspine, it impairs spinal growth, increases risk of cardiac ican-British (FAB) M5 morphology, and FAB M4 morpholdysfunction, and impedes future administration of systemic ogywith eosinophilia and chromosomal inversion 16 are associated with higher risk of meningeal l e ~ k e r n i a . ” . ’ ~ - ~ ~ hematosuppressive ~ h e m o t h e r a p y . ~ ~ . ~ ~ , ” The choice of radiation modality, volume, and dose varies Systemic chemotherapy is another factor. Full-dosage from one study to another but, when used, cranial radiation continuation chemotherapy carries a lower risk of meningeal is generally preferred for prevention and craniospinal for leukemia than half-d~sage.~’ Asparaginase depletes CSF asTo be remembered is that portals need to be paragine and dexamethasone diffuses into CSF more readily sufficient to encompass all leptomeningeal tissue, including than prednisone, so that use of these agents may contribute that within the optic nerve and cauda equina. to reduction of meningeal The roles of highThe third and mostrecent method of preventing and treatdosage antimetabolites and intrathecal therapy are discussed ing meningeal leukemia is high-dosage antimetabolite therlater. apy. By administering high-dosage Mtx by continuous intraWhen meningeal leukemia develops, both the frequency venous infusion over 24 hours, CSF levels in the therapeutic of survival and quality of survival are considerably reduced. range may be The ratio of CSF to plasma conTable 1 summarizes the historical outcome of children who centration of Mtxis increased in the presence of overt meninhad initial clinically isolated meningeal relapse of ALL begeal leukemia.53Delayed leucovorin rescue prolongs expotween 1967 and 1979 and were treated with systemic chemosure, increasing the opportunity for Mtx uptake and storage therapy and central nervous system (CNS) radiotherapy with by leukemia cells in the exposed arachnoid. In a similar or without intrathecal c h e r n ~ t h e r a p y . Only ~~.~~ 17% of the way, intravenous 6MP (1,200 mg/m* over 24 hours) achieves children survived and their survival was marked by a high continuous plasma concentrations in the 6 pmol/L range and frequency of significant neurologic disorders. Prevention of maintains cytotoxic CSF concentrations of approximately 1 meningeal leukemia is essential to cure of children with pmol/L, about 20% of plasma c0ncentration.5~Finally, CSF ALL. levels of Ara-C approximate 20% to 40% of plasma levels and the drug is more slowly converted to its degradation METHODS OF PREVENTION ANDTREATMENT OF product, Ara-U, in CSF than in plasma.55High-dosage intraMENINGEALLEUKEMIA venous Ara-C is demonstrated to be effective in meningeal Three methods are useful for prevention of meningeal le~kemia.’~ leukemia: intrathecal injection of antileukemia antimetaboThe toxicity of high-dosage intravenous antimetabolite adlites with or without corticosteroids, high-dosage intravenous ministration is well described and affects the central nervous administration of the antimetabolites sufficient to achieve system as well as hematopoiesis, epithelium, liver, kidneys, and lungs.34Although most of these effects are reversible, therapeutic levels in the CSF, and meningeal radiation therchildren who have received prior cranial radiation are espeapy. After three decades of clinical trials, their relative valcially susceptible to permanent leukoencephalopathy and ceues, indications, and riskhenefit ratios are still subjects of rebral microangiopathy after parenteral M ~ x . ~ ’ . ~ ’ controversy. Downloaded from http://ashpublications.org/blood/article-pdf/84/2/355/614961/355.pdf by guest on 09 April 2024 zyxwvutsrqpo zyxwvutsrq 357 MENINGEAL LEUKEMIA zyxwvu zyx ceived multiple systemic drugs in standard dosage and extended intrathecal Mtx therapy. For the patients with initial Table 2 summarizes the results of more recent published white blood cell ( W C ) counts of 5O,OOO/pL or higher, the studies that use the three methods described for prevention 5-year actuarial CNS relapse rates were significantly differof meningeal leukemia in patients with ALL.57-68 Earlier reent: 9%for those who received cranial radiotherapy and 27% sults are tabulated in a previous review.69Interpretation of for those who did not. There was no significant difference these results is confounded by differences in patient selecin rate for those with initial WBC counts less than 50,000/ tion, in systemic chemotherapy, in technical factors, in length pL. This suggests that cranial irradiation is needed in patients of follow-up, and in data analysis. with lymphomatous presentation or T-cell ALL with initial However, the predominance of tabulated data support the WBC counts of 50,0OO/pLor greater. However, it is possible conclusion that extended intrathecal therapy is highly effective that the use of high-dosage intravenous and three-drug infor preventingmeningealleukemiainpatientswith"lowtrathecal therapy might obviate this need. risk" and B-precursor ALL.5s,63,67 When combined with intenBoth intravenous Mtx or Ara-C therapy and cranial irradisive systemic chemotherapy, it is also effective in "intermediation can produce neurologic and neuropsychologic disorate-risk" ALL.68The combination of intrathecal therapy with ders,34-36.77However, cranial irradiation results in growth disintermediate-dose Mtx (1 g/m2/24 h) and intermediate-dose turbances and, more ominously, cranial tumors later in life, Ara-C (1 g/m2/24 h) or high-dose 6MP (1 g/m2/8h) (intratheespecially in preschool ~ h i l d r e nThe . ~majority ~ ~ ~ of ~ chil~ ~ ~ ~ cal and intravenous drugs administered separately to reduce dren with ALL are cured and appear destined to normal life neurotoxicity) appears to be effective in prevention of meninspans and the risk of radiation induced cranial solid tumors geal relapse in "high-risk" B-precursor ALL as This appears to be continuous throughout life. This appears to be conclusion is further supported by the resultsof a 1986-1991 the prime reason why cranial radiotherapy should be avoided Pediatric Oncology Group (POG) study based on the Krance in the face of equivalent efficacy of intensive intrathecal and et al study@ (Vita Land,personalcommunication,August intravenous antimetabolite therapy. 1993). Of 415 children with high-risk and standard-risk BTo summarize, the data available lead to the conclusion precursor ALL receiving similar treatment with intravenous that extended intrathecal chemotherapy and systemic chemoMtx, Ara-C, and three-drug intrathecal therapy, only 18(4%) therapy appropriate to the biologic species and/or risk group have developed isolated meningeal relapse. A weakness of is as effective as radiation-containing regimens for preventhese studies is lackof information about theCSF concentration of meningeal ALL, and preferable, in children with Btions of antimetabolites achieved by intermediate- and highprecursor ALL, low- and intermediate-risk ALL, B-cell dosage intravenous infusions. ALL, and T-cell or lymphomatous ALL with initial WBC The question remains whether three-drug intrathecal thercounts less than 50,00O/pL. Whether the administration of apy is superior to Mtx therapy alone. Historically, combinahigh-dosage intravenous chemotherapy and three-drug intion antimetabolite therapy has beenmore effective than trathecal therapy will also eliminate the need for preventive single agents in ALL. One might expect Mtx and Ara-C to cranial irradiation in patients with T-cell ALL or lymphomaaffect different leukemia cells as well as to act synergistically tous presentation with W C counts above 50,00O/pL rein others, although, with regard to hydrocortisone, one report mains to be seen. suggests that it protects myeloid leukemia cells from AraRecently, the POG felt compelled to revert to threePREVENTION OF MENINGEALAML drug intrathecal therapy in a studywhentheuse of Mtx Less study has been made of the prevention of meningeal alone appeared to be resulting in more meningeal relapses leukemia in AML. One reason is that systemic treatment than expected. regimens are less effective than in ALL so that hematologic As noted in Table 2, very high doses of intravenous Mtx relapse most often pre-empts initial meningeal relapse. An combined with extended intrathecal chemotherapy were reearly report of preventive cranial radiation and intrathecal ported to be effective in preventing meningeal relapse in methotrexate in children with AML indicated that it served patients at exceptionally high risk of relapse and in infants its purpose but did not alter survival.'8 Table 3 summarizes less than 1 year of age.60*6' experience with various methods used to prevent meningeal Patients with B-cell ALL and T-cell ALL have a high risk relapse in A M L . ~ ~Again, , ~ ~interpretation ~ ~ ~ - ~ is~ confounded of early meningeal l e ~ k e m i a . ~With ~ . ~ 'regard to B-cell ALL, by the heterogeneity of the patients, their leukemia phenorecent reports indicate that intensive intrathecal and hightypes, and the selection, dosage, schedule, and duration of dosage intravenous chemotherapy are effective in its preventheir chemotherapy. However, the general consensus is that tion and possibly for Currently, cranial irrarepeated administration of intermediate to high dosage of diation is excluded entirely in some treatment protocols and Ara-C and intrathecal Ara-C with or without intrathecal Mtx is administered only for overt meningeal leukemia in others. are probably adequate measures. With regard to T-cell ALL, a recent Childrens Cancer Recently, it was suggested on the basis of a nonrandom Group (CCG) report describes the outcome of children with comparison that preventive cranial radiotherapy reduced the lymphomatous presentation or T-cell immunophenotype frequency of hematologic relapse in children with AML and ALL who were randomized to receive or not receive prevenled to higher cure rates.84This concept fits an hypothesis of tive cranial radiotherapy early during remission.?6All reearly studies of preventive meningeal therapy." The hypothePREVENTION OF MENINGEAL ALL Downloaded from http://ashpublications.org/blood/article-pdf/84/2/355/614961/355.pdf by guest on 09 April 2024 zyxwvuts zyxwv 358 zyxwvutsrqpo zy PINKEL AND WOO Table 2. Prevention of Meningeal Relapse of ALL Isolated Meningeal Relapse Method Reference Steinherz et aI5' (1986) Littman a)*% et (1987) Abromowitch et al' (1988) Poplack et alM)(1989) Reaman et aI6' (1989) Camitta et aI6' (1989) Rivera et ale3(1991) Krance et a164(1991) Camitta et a165(1992) Gelber et a('' (1993) Pullen et al" (1993) Tubergen et altB8(1993) Tubergen et alt6' (1993) 89 high risk % 5 7 Overall Outcome % 4 yr EFS 69 11 250 low risk 4.5 yr EFS 66 6 10 4 yr DFS 67 IT Mtx, extended IV Mtx g/m2/24 1 h IT Mtx, extended 254 low risk 154 B-precursot 15 15 Cranial RT 18 Gy IT Mtx, extended Cranial RT 24 Gy IT Mtx, Early IV Mtx 33 g/m2124 h IV cytarabine IT Mtx + Ara-C, extended IV M t x 33 g/m2/24 h IT Mtx Ara-C, extended IV Mtx 1 g/m2/24 h IV 6MP 1 g/m2/8 h IT Mtx, extended IT Mtx, Ara-C, HC, extended 155 B-precursor 6 4 4 yr DFS 56 408 B-precursol 33 8 8 yr EFS 44 zyxw 1 2 yr EFS 69 5 3 yr EFS 48 9 3 high risk 1 100 < l yr age 5 59 low risk 0 108 low risk 4 4 4 yr EFS 81 IT Mtx, Ara-C, HC, extended Cranial RT. 18 Gy, after 1 yr IV Mtx 1 g/m2124 h IV Ara-C 1 g/m2/24 h IT Mtx, Ara-C, HC, extended IT Mtx, Ara-C, HC, extended IV Mtx 1 g/m2/24 h IV 6MP 1 g/m% h Cranial RT 18-28 Gy IT Mtx, extended IT Mtx, Ara-C, HC, extended IV Mtx 1 g/m2/1 h Cranial RT 18 Gy IT Mtx, early 233 high risk 14 6 4 yr EFS 69 45 high risk B-precursor 54 low risk B-precursor 2 1 4 2 4 yr EFS 53 4 yr EFS 71 83 high risk 7 9 4 yr EFS 75 518 20 4 7 yr EFS 62 577 B-precursor 575 B-precursor 697 intermediate risk 21 48 42 8.3 7 7 yr EFS 68 IT Mtx, extended Cranial RT 18 Gy IT Mtx, early Standard chemotherapy 691 intermediate risk 131 intermediate risk age 1-9 yr 51 10 9 7.6 7 yr EFS 64 7 yr EFS 71 IT Mtx, extended Standard chemotherapy 128 intermediate risk age 1-9 yr 23 Cranial RT 18 Gy IT Mtx, early Intensive chemotherapy 384 intermediate risk age 1-9 yr 19 4.9 7 yr EFS 78 IT Mtx. extended Intensive chemotherapy 374 intermediate risk age 1-9 yr 16 4.2 7 yr EFS 79 + Downloaded from http://ashpublications.org/blood/article-pdf/84/2/355/614961/355.pdf by guest on 09 April 2024 Van Eys et aI5' (1989) + IT M t x Ara-C, extended Cranial RT 18 Gy Intensive chemotherapy Cranial RT 18 Gy Early IT Mtx No. 4 yr EFS 94 18 5 yr DFS 61 7 yr EFS 63 zyxwvut Abbreviations: IT, intrathecal; W, intravenous; HC, hydrocortisone; RT. radiation therapy; EFS. event-free survival; DFS, disease-free survival. * Additional data provided by Harland Sather (August 1993). t Data derived from same study. MENINGEAL LEUKEMIA 359 Method Patients IT Mtx, extended Cranial RT 24 Gy at completion of therapy Cranial RT 18 Gy IT Mtx, early IT Mtx and/or Ara-C, extended 138 zyxwvu zyxwv 119 1 Table 3. Prevention of Meningeal Relapse in Acute Myeloid Leukemia Isolated Meningeal Relapse Reference (1985) Pui et al*“ Creutzig et al” (1985) Chessells et alsD(1986) Grier et al’’ (1987) Amadori et ala’ (1987) Ravindranath et aIm (1991) 66 5 % 115 8 Overall Outcome % yr CCR 37 1 yr EFS 41 zyxwvu zyxwvu 5 8 45 457 107 8 3 0 18 170 2 4 1 yr CCR 34 9 3 4 yr EFS 33 238 EFS 12% survival 5 yr DFS 45 yr DFS 41 3 yr 33 Abbreviations: SC, subcutaneous; CCR, continuous complete remission. * Thirty-five of 184 patients had CSF leukemia cells at diagnosis; no adverse effect on outcome. Downloaded from http://ashpublications.org/blood/article-pdf/84/2/355/614961/355.pdf by guest on 09 April 2024 Steuber et ala’ (1991) None IT Ara-C, extended IT Ara-C, extended SC or IV Ara-C, 150 mglm’ q 8 h x 3 d 300 mglm’/d x 3 d Cranial RT (24 Gy) IT Mtx, early IT Ara-C, early IV Ara-C, 3 g/m2 q 12 hr x 4 5 No. zyxwvu zyxwvuts sis was that exposure to suboptimal concentrations of antileukemic drugs in the CSF promoted development of drug resistance by leukemic cells in the arachnoid. These drugresistant cells then were the nidus of systemic relapse with resistant leukemia. However, historical comparison of two FQG studies of childhood A M L , one using cranial radiation and the other not, fail to show a significant difference in event-free survival (Table 3).8’*83 TREATMENT OF MENINGEAL LEUKEMIA The significance of a few leukemia cells in the CSF at diagnosis without symptoms and of their appearance in the CSF, with or without symptoms, during or after completion of systemic chemotherapy, may differ. Meningeal leukemia at diagnosis is usually sensitive to chemotherapy, whereas meningeal leukemia that occurs during adequate systemic and intrathecal chemotherapy is more likely resistant or relatively resistant to chemotherapy. Meningeal leukemia developing after cessation of chemotherapy might be the result of inadequacy of intrathecal and systemic chemotherapy or drug resistance. The distinction is not clear but there is currently a trend to use cranial or craniospinal radiotherapy and intensive intrathecal therapy for isolated meningeal relapse but to rely on intensive intrathecal therapy and intermediate to high-dosage systemic therapy for the patient who at diagnosis has less than 5 leukemia cellslyl and no clinical evidence of meningeal leukemia.” One reason is the problem of administering intermediate- to high-dosage antimetabolites, specifically Mtx, once therapeutic radiation has been delivered to the cranium or craniospinal axis. This consideration led POG to delete cranial irradiation in children with B-cell ALL who presented with meningeal le~kemia.’~ Although the cure rate is lower for such children than for those without meningeal leukemia at diagnosis, it is not caused by meningeal relapse. Table 4 summarizes the results of treatment of clinically isolated meningeal relapse with various method^.^*^^-*' Although hematologic relapse and death caused by refractory leukemia often follows isolated meningeal relapse, outcome has improved in recent years with extended intrathecal chemotherapy and meningeal irradiation accompanied by adequate systemic chemotherapy. An important question is whether the irradiation needs to be cranial and spinal or whether cranial irradiation alone is sufficient. Its importance derives from the additional serious sequelae observed when spinal irradiation is administered. Considerable hematopoietic tissue is reached by irradiation when spinal ports are used, resulting in lengthy hematosuppression and poor hematologic tolerance of subsequent hematosuppressive chemotherapy.33Secondly, spinal growth is inhibited, leading to reduced stature and possibly lordosis as the abdominal viscera enlarge with age.50 Thirdly, the spinal radiation fields increase considerably the number of organs and volume of tissue at increased risk of radiation injury and carcinogenesis. The practice of administering craniospinal irradiation for meningeal relapse was originally based on experience with medulloblastoma, where the presence of neoplastic cells in the cerebrospinal fluid necessitated spinal irradiation to avoid spinal rec~rrence.’~ This practice was supported by a British study that randomly compared cranial versus craniospinal irradiation for treatment of overt meningeal relapse of ALL.” All eight patients in first meningeal relapse who received cranial radiotherapy developed a second meningeal relapse in a median period of 15 weeks. In contrast, 4 of 9 receiving craniospinal radiotherapy were alive and without meningeal leukemia 2.5 to 4 years later. However, the patients received only six intrathecal doses of a single drug at body surface area rather than age-related dosage before irradiation, and no intrathecal therapy after irradiation. Perhaps more importantly, they received low-dosage systemic chemotherapy zyxwvu zyxwvutsrqponmlk PINKEL AND WOO zyxwvu that would not be expected to influence the course of menintemic chemotherapy to prevent it once cranial or craniospinal geal leukemia. radiotherapy has been administered, have led to further studA POG comparative studyx5suggested that cranial and ies in which radiotherapy is delayed. This allows intensive craniospinal irradiation were equally effective in preventing treatment with intrathecal drugs and with intravenous chesecond meningeal relapse (Table 4). The poor overall outcome motherapy in sufficient dosage to establish therapeutic levels in the cranial radiotherapy group was attributable to relapse in the CSF. The outcome of two such pilot studies, one by at other sites.However,theequivalentresults in thetwo Mandell et aig6and the other by are summarized in groups for preventionof second meningeal relapse might have Table 4. The POG protocol consisted of remission induction been caused by the extended use of intrathecal drug therapy with dexamethasone, vincristine, daunorubicin, and threedrug intrathecal therapy; 6 weeks of consolidation with highin the children who received cranial irradiation but not in those who received craniospinal irradiation, rather than therapeutic dosage Ara-C and L-asparaginase; and 12 weeks of intensiequivalence of the two methods of irradiation. ficationwith etoposide, cyclophosphamide, intermediate Three other studies support the use of cranial irradiation high-dose intravenous Mtx, and high-dose intravenous 6MP, followed by craniospinal irradiation (24 Gy/15 Cy). Subsewithout spinal irradiation for treatment of isolated meningeal relapse: a POG study** that also used extended three-drug quently, the patients received conventional dosage of Mtx intrathecal therapy, a German study” that included high-dose and 6MP and vincristine and cyclophosphamide for 18 intravenous Mtx as well as extended three-drug intrathecal months. With 62 patients registered in the studyand45 therapy, and an unpublished retrospective comparison of St having completed the first 6 months of chemotherapy and Jude data (Judith Ochs, personal communication, January the radiation therapy, the 2-year event-free survival estimate 1994). In the St Jude comparison, 15 children received 18 is 83% (?lo%). Only 1 patient had a second isolated meninto 24 Gy of cranial radiotherapy after a median 17 months geal relapse and only 1 patient experienced relapse before irradiation. These early results are superior to pastPOG of intrathecal chemotherapy and 14 children, comparable experience with treatment of isolated meningeal relapse, but with regard to initial WBC and duration of first remission, received 24 Gy of cranial radiotherapy and 12 to 24 Gy of further follow-up is required. Several experimental approaches are being made to treatspinal irradiation after a median 15 months of intrathecal ment of meningeal leukemia. Among them are intrathecal chemotherapy. Ten of each group are alive andwell 10 6MP, intrathecal diaziquone, high-dosage intravenous 6MP, years or more since radiation therapy. This suggests that and high-dosage intravenous ~ ~ ~ o - T E P A The . ~ ~ antileu,~’.~~ craniospinal irradiation has no therapeutic advantage over kemic drug, cladribine, was reported to clear leukemia cells cranial irradiation when preceded by extended intrathecal from CSF in 2 of 3 patients when administered by continuous drug therapy. intravenous infusion for 5 days.95Total body irradiation with The high riskof hematologic relapse after isolated menina craniospinal “boost,” combined with myeloablative chegeal relapse, and the problem of delivering intensive sys- Downloaded from http://ashpublications.org/blood/article-pdf/84/2/355/614961/355.pdf by guest on 09 April 2024 e 360 zyxwv zy Table 4. Treatment of Isolated Meningeal Relapse in ALL Second Isolated Meningeal Hematologic Patients Other Method Reference et Land aIE5 Cranial (1985) (%) RT 24 Gy IT Mtx, Ara-C, HC, extended Craniospinal RT 24/14 Gy IT Mtx, Ara-C, HC, early I V Mtx, Ara-C Mandell et aIE6(1490) IT or T Intensive chemotherapy Delayed 14-21 mo cranial and spinal RT 18/12 Gy Henze et aI8’ (1991) 1Cranial 8 RT 24 Gy IT Mtx, Ara-C, HC, extended IV M t x 1 g/m2/36 h Winicket alee(1993)Cranial RT 24 Gy IT Mtx, Ara-C, HC, extended Gelberet alB8(1993)ITMtx, Ara-C, 17 patients BMT, 3 patients Ritchey et ala’ (1993) IT Mtx, Ara-C, HC, extended Intensive chemotherapy High-dose IV Mtx, Ara-C, 6MP Delayed 6 mo cranial and spinal RT 24/15 Gy 29 20 9 2 * 4 DFS 14% yr 4 DFS 70% zyxwvu 120 20 yr 1 1 * 0 0 2yrs follow-up Median 3 1 yr 0 13 35 12 8 9 1 5 5 EFS 72% 4 yr EFS 46% 5 yr EFS 10% zyxwvutsrqp 45 1 2 yr EFS 83% Abbreviation: ITV, intraventricular. x Data not reported. Remissions terminated in a totalof 16 patients treated with cranial radiotherapy and 5 treated with craniospinal radiotherapy. 361 MENINGEAL LEUKEMIA DOSAGE AND TECHNIQUE OF INTRATHECALTHERAPY the drugs are essential. They need to be free of preservative and freshly dissolved in preservative-free buffered saline or balanced salt solution. The solution is brought to room temperature, millipore-filtered, and injected slowly without aspiration after allowing approximately one-half the injection volume to flow freely from an atraumatic lumbar puncture. The injection is performed with the patient in the lateral recumbent position to reduce caudal drug concentration. Immediately after injection the patient is placed in the ventral Trendelenburg position to reduce lumbar hydrostatic pressure and promote cephalad diffusion of the drugs, as demonstrated in primates.99 The use of Ommaya reservoirs is questionable because the ventricles lack leptomeningeal tissue, ventriculitis is more serious than meningitis, foreign bodies in the brain are hazardous, and rarely are reservoirs needed for technical reasons. zyxwv DOSE AND TECHNIQUE OF RADIATIONTHERAPY For ALL, early attempts at CNS prophylaxis using 5 and 12 Gy (1 Gy = 100 rad) of craniospinal irradiation were unsuccessful." When the radiation dose was increased to 24 Gy, the isolated CNS relapse rate decreased to less than 10%. Twenty-four gray became the standard prophylactic dose for cranial irradiation in combination with intrathecal methotrexate! In recent years, it was found that a dose of 18 Gy was equally efficacious. It is still uncertain whether the incidence andor severity of any neuropsychologic effect attributed to cranial irradiation are less after 18 Gy of cranial irradiation than after 24 Gy. Nonetheless, in children with ALL, 18 Gy is now the standard dose when cranial irradiation is administered for preventive meningeal ther- Downloaded from http://ashpublications.org/blood/article-pdf/84/2/355/614961/355.pdf by guest on 09 April 2024 motherapy and allogeneic or autologous marrow transplantation, has been suggested for treatment of isolated meningeal relapse." Adding the severe immediate and late toxicity of such measures appears unacceptable when approximately one-half of children are surviving isolated meningeal relapse with current treatment and there is no convincing evidence of a therapeutic advantage of marrow transplant procedures in ALL.96 It seems advisable that patients with meningeal relapse of ALL, either isolated or combined with other sites, be registered on institutional or collaborative studies designed to answer questions about the optimal method of management with regard to both cure rate and quality of survival. The present trials of intensive intrathecal and high-dose intravenous antimetabolite chemotherapy followed by meningeal irradiation appear to be a reasonable approach. Randomized comparative study is needed to determine whether craniospinal irradiation is more effective than cranial irradiation in the context of modem chemotherapy. If it is not advantageous, the next question might be whether any irradiation is necessary for optimal cure rate. Scant data is available about treatment of isolated meningeal relapse in AML because it is usually followed quickly by hematologic relapse and death. However, the methods used for meningeal relapse of ALL, intensive intrathecal and systemic chemotherapy and possibly radiation therapy, would appear reasonable. zy zyxwvut Because the brain develops and matures before other organs, the volume of CSF is more closely related to brain size than weight or body surface area.97Although brain size aPY,6,57,58,63,68 is best reflected by head circumference, it is also related to age of the patient. It is now customary to use age to deterFor the treatment of established meningeal leukemia, mine intrathecal drug doses, as indicated in Table 5. In using some evidence in the literature suggests that craniospinal irradiation is the preferred treatment.51.91 When craniospinal age-related dosage of intrathecal Mtx, caution must be exercised in infants. Intrathecal Mtx slowly infuses from the CSF irradiation is used for established meningeal leukemia, the into plasma so that it behaves like a prolonged intravenous radiation doses range from 24 to 30 Gy for the cranium and from 15 to 24 Gy for the spine. The spinal axis is usually infusion. When dosage is age-related, the plasma Mtx levels can be expected to be considerably higher in infants than in treated to a lower dose mainly because of the belief that older children and adults, resulting in systemic Mtx toxicity. chemotherapeutic agents administered intrathecally are disThe same can occur in patients with renal d y s f u n c t i ~ n . ~ ~tributed better over the spinal meninges than over the cranial Some ALL protocols specify administration of one dose of meninges. leucovorin 24 hours after intrathecal Mtx to "rescue" the For cranial irradiation, the patient is simulated for opposed patient from excessive systemic Mtx toxicity. lateral treatment fields and the entire cranial meningeal surCareful formulation, preparation, and administration of face is covered. Special attention is given to the posterior retina (which may harbor leukemic cells), the posterior globe (as the meningeal reflection along the optic nerve comes very close to the posterior aspect of the globe), the cribriform Table 5. Age-Related Dosage of Triple Intrathecal Drugs plate, and the middle cranial fossa. The treatment fields are shaped using cerrobend. An attempt is made to shield the 1 yr 2 yr 3 to 8 yr 9 yr and Older roots of the maxillary teeth in children. Cobalt-60, 4 MV, Mtx 8 or 6 MV photons are suitable. A dose of 1.5 to 2 Gy per 10 12 15 8 10 12 15 treatment fraction is usually prescribed to the midplane. HyHydrocortisone Ara-C 16 20 24 30 perfractionated cranial irradiation has been performed in a Volume 5.3 mL 6.7 mL 8 mL 10 mL limited fashion and theoretically has a potential advantage Drugs are preservative-free and dissolved in preservative-free Elof decreasing late morbidity.'00 However, it has notbeen liott's B, Ringer's lactate, or buffered saline solution. rigorously studied in large numbers of patients. It is interest- zyxwvutsrqpon zyxwvu zyxwvutsrqpon PINKEL AND WOO 362 zy sion results in CSF concentrations approximately 20% to 40% of plasma concentrations, partly because of longer persistence of Ara-C in CSF than in plasma.55,'0"'04The CSF to plasma ratio of Ara-C concentrations tends to be lower with increasing dosages of intravenous Ara-C. If a l pmol/ L CSF concentration is considered adequate, a continuous intravenous infusion of 2,000 mg/m2 over 24 hours should sufficeto achieve it. Repeated injections of 3,000 mg/m2 over 2 hours every 12 hours or 3,500 mg/mz by continuous 24-hour infusion maintain CSF concentrations in the 3 pmoV L range. For 6MP, continuous infusion of 1,000 to 1,200 mg/m' over 24 hours achieves CSF concentrations of approximately 1 pmoVL, which is considered t h e r a p e ~ t i cHowever, .~~ unlike Mtx and Ara-C, high-dosage intravenous 6MP has not been demonstrated to produce remissions of overt meningeal leukemia. As with Mtx, precautions are required with regard to renal and hepatic function and hydration. In summary, high-dosage intravenous antimetabolite chemotherapy achieves therapeutic levels in the CSF that can serve to prevent meningeal relapse, and, with Mtx and AraC, to treat meningeal relapse. Optimal dosages and schedules need to be determined. SUMMARY DOSAGE AND TECHNIQUE OF INTRAVENOUS CHEMOTHERAPY The prevention of meningeal leukemia has long been a keystone in its cure. The need was recognized when it beThe optimal methods for using intravenous chemotherapy came apparent in the 1950s and 1960s that meningeal relapse to prevent or treat meningeal leukemia are ~ndetermined.'~.~' heralded hematologic relapse and a fatal course and that its Drug dosages and schedules vary considerably in published incidence increased as systemic chemotherapy became more studies and often lack correlative evaluation of plasma and effective in controlling hematologic and visceral leukemia? CSF concentrations. Drugs tend to clear more slowly from Evasion of a biologic safety net, the blood-CSF barrier, is required to prevent meningeal leukemia. Three methods CSF than plasma, increasing exposure time and raising conare used: meningeal radiotherapy, intrathecal administration centration X time values. CSF concentrations tend to reach of antileukemia drugs, and high-dosage intravenous antileumaximum levels at the end of continuous infusions. Perhaps kemia drugs. Recent and current clinical studies reflect a most importantly, the low number of cells in the CSF precontinuing dialogue about which methods are preferable and vents measurement of incorporation of the drugs into cell under what circumstances. For prevention of meningeal leumetabolism. This is particularly important with the antileukemia, extended intrathecal therapy and intensive systemic kemic antimetabolites since their effectiveness depends on chemotherapy appear to be as effective as radiotherapy for enzymatic conversion within cells: Mtx to Mtx polyglutamost patients. For treatment of overt meningeal leukemia, mate, Ara-C to Ara-C triphosphate, and 6MP to thioguanine meningeal radiotherapy may be necessary. However, its adnucleotides. ministration compromises subsequent systemic chemotherFor methotrexate, CSF concentrations reach levels apapy so that delay may be advisable to allow intensive sysproximately 3% of steady-state plasma level^.^*'^^^^ Protemic chemotherapy for control of concurrent hematologic longed 24- to 36-hour infusions and delayed leucovorin resand visceral leukemia, whether clinically evident or not. For cue at 48 hours increase exposure time. an If Mtx patients with meningeal leukemia at diagnosis, cranial irradiconcentration of 1 pmol/L is considered therapeutically adeation may be delayed or possibly omitted if evidence of quate, an Mtx steady-state plasma concentration of 35 to 50 disease is minimal and intrathecal and systemic chemotherpmol/L is probably sufficient. This can be expected with a apy are intensive. For those who develop meningeal leukecontinuous infusion of approximately 3,000 mg/m* over 24 mia while on therapy or after its completion, cranial or crahours after an initial bolus of 10% of the dose. Higher niospinal irradiation is probably required as well as intensive CSF:plasma ratios are reported in the presence of overt intrathecal and systemic chemotherapy. Hopefully, current meningeal leukemia.53 Considerable precaution mustbe and future studies will dispel the uncertainties and better taken with regard to renal and hepatic function, hydration, quantitate risks and benefits of alternative methods. alkalinization, and avoiding drugs that can reduce clearance Whatever method is used, careful attention to technical of Mtx. Leucovorin dosage and duration are based on plasma details is required to assure optimal efficacy at the least Mtx concentrations. possible expense in immediate toxicity and late sequelae. For Ara-C, either bolus administration or continuous infu- Downloaded from http://ashpublications.org/blood/article-pdf/84/2/355/614961/355.pdf by guest on 09 April 2024 ingto note that, in a recent CCG study, patients whose prophylactic cranial fields did or did not encompass the entire meningeal surface had equivalent CNS relapse rates.76 Nevertheless, it should be emphasized that meticulous radiotherapy technique in cranial irradiation remains a sound policy. For craniospinal irradiation, the patient is simulated in the prone position, usually with positioning devices such as the alpha cradle and a special head positioning device (either one commercially available or custom-made from plaster of paris). For young children who cannot cooperate by holding still, sedation or general anesthesia is needed. The spinal axis is usually treated down to the bottom of the thecal sac. Although the thecal sac usually ends at about the second or third sacral vertebral body, a magnetic resonance image scan of the lumbosacral spine provides an accurate position. In a few institutions, electrons have been used to substitute for photons for the spinal irradiation of young children. It is important to emphasize that craniospinal irradiation is a technically difficult and tedious procedure that requires careful attention to many details. For this reason, it needs to be performed in institutions where there has been sufficient experience by the radiation oncologist, physicist, dosimetrist, and technologist. zy zyxwvutsrqp zyxwvutsrqp zyxwvutsrqp zyxwvuts zyxwvutsrqp MENINGEALLEUKEMIA 363 REFERENCES 17. 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