Central Nervous System Prophylaxis in Adults With Acute Lymphoblastic Leukemia

Central Nervous System Prophylaxis in Adults With Acute Lymphoblastic Leukemia Current and Emerging Therapies Elias Jabbour, MD; Deborah Thomas, MD; Jorge Cortes, MD; Hagop M. Kantarjian, MD; and Susan O Brien, MD, BA Central nervous system (CNS) recurrence continues to be a significant complication in the treatment of adult patients with acute lymphoblastic leukemia (ALL). Preventing CNS recurrence has been a therapeutic challenge and has not been addressed critically in many clinical trials. Adult studies modeled on childhood ALL studies have used multiple treatment modalities, including radiation therapy, systemic therapy, intrathecal therapy, and combinations thereof. Cranial irradiation is effective but is offset by substantial toxicity, including neurologic sequelae. Systemic chemotherapy, especially with cytarabine (AraC) and methotrexate, has demonstrated promise in decreasing CNS recurrence, but therapeutic levels of drugs in the cerebrospinal fluid (CSF) are not maintained. Intrathecal chemotherapy with or without high-dose systemic therapy is the most common approach to CNS prophylaxis. Liposomal AraC recently has become available and confers prolonged levels of free AraC in the CSF, a critical requirement for CNS prophylactic therapy. This review discusses the various modalities used for CNS prophylaxis in patients with ALL and the emerging trends, with specific emphasis on the outcome in terms of event-free survival and toxicity. Cancer 2010;116:2290 300. VC 2010 American Cancer Society. KEYWORDS: acute lymphoblastic leukemia, central nervous system prophylaxis, intrathecal chemotherapy, methotrexate, cytarabine, liposomal cytarabine. Acute lymphoblastic leukemia (ALL) refers to a group of lymphoid disorders resulting from monoclonal proliferation and expansion of lymphoid blasts in the bone marrow, blood, and other organs. ALL occurs at a rate of approximately 1 to 1.5 per 100,000 individuals and exhibits a bimodal distribution with an early peak in children ages 4 to 5 years (4 to 5 per 100,000 individuals) followed by a second peak at approximately age 50 years (2 per 100,000 individuals). 1 ALL is relatively uncommon in late childhood, adolescence, and young adulthood. 2 The etiology of the disease is not yet well known. Chromosomal translocations that occur in utero during fetal hematopoiesis have been suggested as the primary cause for pediatric ALL, and postnatal genetic events have been suggested as secondary contributors. 3 Associations between human T-cell lymphotrophic virus type 1 and adult T-cell leukemia/lymphoma, as well as human immunodeficiency virus and lymphoproliferative disorders, also have been established. 4,5 Age remains an important determinant of prognosis and outcome. 6,7 Before the use of central nervous system (CNS) prophylaxis, the CNS was the most frequently reported site of initial recurrence in children with ALL, accounting for up to 75% of cases. 8,9 However, with therapies that incorporate CNS prophylaxis, 5-year event-free survival rates of approximately 80% have been achieved in pediatric ALL. 10 Still, CNS recurrence remains a major limitation to achieving complete cure, accounting for 30% to 40% of recurrences in some pediatric clinical trials. 11,12 Although the cure rate in children with ALL has reached approximately 80%, cure rates in adults with ALL remain at only 30% to 40%. 7,13 Several reasons exist for the discrepancy between adult and child outcomes. Childhood ALL protocols typically involve more dose-intense regimens, whereas adults typically receive less intensive protocols because of their poorer tolerance of chemotherapeutics like asparaginase and methotrexate (MTX). 14 It has been demonstrated that increasing the intensity of chemotherapy, as opposed to increasing its duration, improves ALL survival rates. 15 Thus, the adaptation of protocols from childhood ALL has improved survival rates greatly for adults with ALL. However, because systemic control remains Corresponding author: Elias Jabbour, MD, Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 0428, Houston, TX 77030; Fax: (713) 794-4297; ejabbour@mdanderson.com Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, Texas DOI: 10.1002/cncr.25008, Received: March 18, 2009; Revised: August 17, 2009; Accepted: September 1, 2009, Published online March 5, 2010 in Wiley Inter- Science (www.interscience.wiley.com) 2290 Cancer May 15, 2010

CNS Prophylaxis in Adults With ALL/Jabbour et al Table 1. Signs and Symptoms of Neoplastic Meningitis According to Primary Central Nervous System Domain a CNS Domain/Symptoms Signs Cerebral Headache Alteration of mentation Difficulty walking Nausea and vomiting Loss of consciousness Cranial nerves Diplopia Hearing loss Visual loss Facial numbness Dysphagia Spinal Focal weakness Paresthesias Back pain Radicular pain Bladder and bowel dysfunction Cognitive deficits Seizures Gait disturbances Sensory disturbances Papilloedema Oculomotor paresis III, IV, VI Acoustin neuropathy VIII Optic neuropathy II Facial paresis VII Hypoglossal neuropathy XII; trigeminal neuropathy V; diminished gag reflex IX, X Reflex asymmetry Sensory loss Upper motor neuron weakness Lower motor neuron weakness Decreased rectal tone, straight leg raising, nuchal rigidity CNS indicates central nervous system. a Reprinted from Gleissner B, Chamberlain MC. Neoplastic meningitis. Lancet Neurol. 2006;5:443-452 24 with permission from Elsevier. Figure 1. Long-term survival of adults who had acute lymphoblastic leukemia with or without central nervous system disease at diagnosis is shown. The Wilcoxon rank-sum test was used to determine statistical significance. Obs./exp. indicates observed/expected. This research originally was published in Blood. Lazarus HM, Richards SM, Chopra R et al; Medical Research Council (MRC)/National Cancer Research Institute (NCRI) Adult Leukemia Working Party of the United Kingdom and the Eastern Cooperative Oncology Group. Central nervous system involvement in adult acute lymphoblastic leukemia at diagnosis: results from the international ALL trial MRC UKALL-XII/ECOG E2993. Blood. 2006;108:465-472. 16 Copyright VC 2006 by The American Society of Hematology. problematic in adults, CNS recurrence in this patient population has not been addressed as thoroughly. 13 Consequently, the benefit of CNS prophylaxis in adults is less well established. In this review, we examine the value of CNS prophylactic therapy in this difficult-to-treat population. The prevalence and outcome of CNS recurrence in adult patients with ALL are considered, and the available CNS prophylactic therapies and important considerations when deciding on CNS prophylaxis therapies are discussed. Adult ALL and CNS Involvement CNS involvement at the time of presentation is uncommon in adults with ALL; it has been reported in as few as 5% to 7% of patients. 16,17 This may be an underestimate, however, because much of the data are derived from patient characteristics at clinical trial enrollment in which patients with suspected CNS involvement were excluded. 16 The use of cerebrospinal fluid (CSF) cytology or CSF flow cytometry to evaluate patients affects the frequency with which occult CNS involvement is detected (with flow cytometry the more sensitive tool). 18 Without prophylaxis, CNS recurrence occurs in approximately 30% of adult patients in complete response. 19 CNS recurrence can occur in 3 settings: isolated CNS recurrence, concomitant bone marrow and CNS recurrence, or postbone marrow recurrence, and the clinical manifestations can be devastating. 20 CNS involvement may manifest as lymphomatous or leukemic meningitis, both forms of neoplastic meningitis (NM) that occur in approximately 5% to 15% of patients with leukemia or lymphoma and in 5% of all cancer patients overall. 21-23 NM has multiple signs and symptoms, can progress rapidly, and can result in profound morbidity and mortality (Table 1). 24 The survival of patients with untreated NM is estimated to be only 4 to 6 weeks. 21 Patients with ALL also can present with parenchymal metastases. Clinical manifestations may vary and depend on the size and number of metastases. Lazarus and colleagues reported a significantly lower rate of survival in adults with ALL and CNS involvement at diagnosis who were treated on the United Kingdom Medical Research Council (MRC) ALL/Eastern Cooperative Oncology Group (ECOG) protocol compared with patients who had no (or unknown) CNS involvement (Fig. 1). 16 Indeed, of the patients who developed disease recurrence on that regimen, 4% developed disease recurrence in the CNS, and the 5-year overall survival rate was 0% for those patients. 25 Cancer May 15, 2010 2291

Surapaneni and colleagues demonstrated that, among patients who had an isolated CNS recurrence (n ¼ 17 of 439 patients), 88% (n ¼ 15) subsequently developed disease recurrence in the bone marrow, which contributed to the continued poor outcome in this patient population. 20 Moreover, Sancho and colleagues reported that adults with ALL and CNS recurrence had a poor prognosis similar to that for patients who developed only bone marrow recurrence. 26 These findings demonstrate that, whether isolated or concomitant with bone marrow recurrence, CNS recurrence is associated with poor outcomes. Therefore, effective CNS prophylaxis in adult patients with ALL remains the best approach to address CNS recurrence. 20,27 Risk Factors for CNS Involvement in Patients With ALL Because the incidence of CNS recurrence in hematologic malignancies is variable, certain risk factors help identify the patients most at risk of CNS involvement. An increased risk of CNS involvement has been observed in patients who exhibit elevated serum lactate dehydrogenase levels, a high leukemic cell proliferation index, and/or the mature B-cell subtype of ALL (B-ALL). 28,29 A retrospective analysis by Bassan and colleagues indicated that adult patients with mature B-ALL had an 18% incidence of CNS involvement at presentation compared with an overall incidence of 4.5%, suggesting that there is an increased risk of CNS involvement in this subgroup. 30 In contrast, in an analysis from the United Kingdom MRC trial, the investigators reported a higher incidence of CNS involvement at diagnosis associated with the T-cell immunophenotype. 16 Associations with increased leukocyte counts and the presence of a mediastinal mass also were reported in that trial. Other clinical characteristics associated with CNS leukemia include elevated hemoglobin, creatinine, alkaline phosphatase, and fibrinogen levels; the Philadelphia (Ph) chromosome-positive karyotype; and a high proliferative index. 9,31 Other chromosomal abnormalities also are associated with worse outcomes in adult ALL. Moorman et al demonstrated that, in addition to Ph-positive karyotype, patients with chromosomal translocations t(4;11), t(8;14), a complex karyotype that involves >5 chromosomal abnormalities, or low hypodiploidy/near triploidy had significantly lower 5-year event-free and overall survival than patients with the Ph-negative karyotype; and the latter 3 variables were independent of sex, age, white blood cell count, and T-cell status. 32 It was suggested recently that children with high hyperdiploid ALL have a higher disposition for developing recurrences to the CNS and testes. 33 On the basis of the association between white blood cells (WBCs) in the CSF and the frequency of CNS recurrence, CNS risk stratification for patients with ALL was developed. Patients at risk were stratified as follows: CNS1 status, no leukemic blasts in the CSF; CNS2 status, <5 WBCs/lL in CSF with blasts; and CNS3 status, 5 WBCs/lL in CSF with blasts. 10,34 Evaluating risk status can help determine the most appropriate CNS prophylactic modality while avoiding the possible over treatment of patients who are not at high risk of CNS recurrence. 10,34,35 CNS Prophylaxis: Therapeutic Modalities To reduce the incidence of CNS involvement, effective CNS prophylaxis regimens have been developed based on pediatric ALL protocols. Standard prophylaxis for CNS malignancy can involve radiation therapy (RT), systemic chemotherapy, intrathecal (IT) chemotherapy, or a combination thereof. Radiation Therapy Cranial and/or craniospinal irradiation (CSI) are the oldest CNS prophylaxis therapies considered for both pediatric and adult patients with ALL. 36 In most patients, RT is combined with either systemic or IT chemotherapy to achieve prolonged event-free survival. 37,38 Simone et al observed a benefit when using cranial irradiation or CSI with or without IT MTX in pediatric patients with ALL. 39 This was confirmed later in a study by Pui et al in which a combination of cranial irradiation with IT MTX also produced a benefit. 40 Very few studies have systematically recorded the use of RT as CNS prophylaxis in adult ALL. Sanders et al reported the effectiveness of CSI in preventing CNS recurrence in adults with ALL who already had achieved remission of their primary cancer. 41 However, although CSI with or without IT chemotherapy eliminated CNS recurrence in the spine, it did not prevent extraneural recurrences. Radiation can be an effective form of CNS-directed therapy in ALL but often is associated with late adverse effects, such as secondary neoplasms, endocrinopathy, neurocognitive dysfunction, and neurotoxicity. 42 Quality-of-life studies in long-term young adult survivors of ALL indicate lower marital rates than adult controls; these correlate with the side effects of RT that affect growth, ie, those related to neuroendocrine deficits 43 and learning 2292 Cancer May 15, 2010

CNS Prophylaxis in Adults With ALL/Jabbour et al defects. 44 The side effects caused by cranial irradiation are fewer and less pronounced in adult patients with ALL than in children, although patients aged >60 years appear to be more susceptible than younger adults to cognitive impairment after RT. 45,46 Efforts to omit cranial irradiation in patients with ALL have been tested in both pediatric and adult ALL trials. Without RT, the observed CNS recurrence rate (including combined CNS and hematologic recurrence) was between 6% and 8.3% in 2 pediatric trials. 47,48 However, the overall 5-year event-free survival rate was only 60.7% and 68.4%, respectively. The investigators suggested that inadequate systemic chemotherapy for the primary cancer was the main factor. In this context, Annino et al observed that, in adults, the addition of high-dose dexamethasone to systemic treatment reduced the CNS recurrence rate to 2%. 49 Kantarjian et al also reported that the addition of intensive systemic and IT MTX and cytarabine (AraC) reduced the CNS recurrence rate in adults to 4%. 50 Furthermore, when effective systemic chemotherapy was administered, the radiation dose was reduced without increasing the risk of CNS recurrence. 51 In a CNS prophylaxis study of adults with ALL who received IT and systemic therapy but not cranial irradiation, the frequency of CNS recurrence was similar to that observed in protocols that included cranial irradiation. 26 The Berlin-Frankfurt-Munster (BFM) Study Group also has demonstrated that high-risk patients (defined in their study as those with >1000 leukemic blasts per llin peripheral blood on Day 8 of the ALL BFM 90 protocol, or <1000 leukemic blasts per ll but 5% more bone marrow blasts on Day 33 of the protocol, or Ph-positive ALL) could receive a lower dose of radiation (12 grays) without increasing the risk of CNS recurrence. 51 A retrospective analysis of intermediate or high-risk adult patients with ALL (aged >30 years, >30,000 WBCs/lL, adverse cytogenetics, and/or residual leukemia on a Day-28 bone marrow biopsy after induction) who were treated on normal BFM protocols or on augmented BFM protocols (which included prophylactic radiation; 1800 centigrays over first 2 weeks of consolidation) experienced a 7% CNS recurrence rate. It is noteworthy that, in that trial, patients who received the augmented BFM protocol (n ¼ 13) experienced a 0% rate of CNS recurrence. 52 Furthermore, the augmented BFM protocol included higher doses of systemic vincristine, asparaginase, MTX, and dexamethasone. The United Kingdom MRC ALL/ECOG 2993 protocol, as described above, included high-dose systemic MTX and RT and resulted in a 4% recurrence rate. Thus, the prevention of CNS recurrence can depend on an effective systemic therapy regimen. In the past 2 decades, therapeutic approaches have concentrated on circumventing cranial irradiation for multiple reasons, including ease of administration and cost. 9 Currently, it is widely believed that, in the low-risk groups, CNS irradiation can be replaced with systemic, high-dose MTX or IT-MTX. 53 Pui concluded that a combination of early, intensive, systemic and IT chemotherapy could lower the CNS recurrence rate in patients with ALL, providing the opportunity to omit prophylactic cranial irradiation. 13 Systemic chemotherapy Success in treating and preventing CNS recurrence with chemotherapy depends primarily on maintaining cytotoxic drug concentrations within the CNS. Systemic chemotherapy is affected by factors like the agent s ability to cross the blood-brain barrier (BBB), the active transportation of the agent out of the CNS, and the distribution of the drug within the brain parenchyma. 54 The ability of high-dose AraC (1-7.5 g/m 2 ) and high-dose MTX (5-8 g/m 2 ) to penetrate the BBB make them useful agents for CNS prophylaxis in ALL. 55-58 Cortes et al demonstrated the utility of high-dose MTX, AraC, and IT AraC to prevent CNS recurrence in adults with ALL (Fig. 2). 28 Using combined vincristine, doxorubicin, and dexamethasone (VAD), the authors compared a regimen with no CNS prophylaxis (pre-vad) with a series of modified VAD regimens that included different prophylactic modalities in 391 adult patients with ALL who were on 4 consecutive protocols (Fig, 2). Overall, the CNS recurrence rate fell from 31% among patients who did not receive any CNS prophylaxis (pre-vad) to 18%, 17%, and 3% among patients who subsequently received VAD, modified VAD, and hyperfractionated cyclophosphamide plus VAD (hyper-cvad) prophylactic modalities, respectively. 28 Those authors also concluded that early IT chemotherapy was necessary to reduce the CNS recurrence rate in high-risk patients who had elevated lactate dehydrogenase levels and a high proliferative index. Corticosteroids have been an integral part of systemic CNS prophylaxis in patients with ALL. Prednisolone is used systematically to induce remission and in maintenance therapy. 59 Dexamethasone may offer greater CNS protection than prednisone because of its superior penetration and longer half-life in the CSF. 60-63 The effect of systemic dexamethasone in decreasing the risk of CNS recurrence in all risk groups of pediatric and Cancer May 15, 2010 2293

efficacy of systemic therapy and radiation while circumventing their limitations. Figure 2. The 5-year central nervous system (CNS) recurrence rate in adults with acute lymphoblastic leukemia is shown according to the type of CNS-directed prophylaxis with vincristine, doxorubicin, and dexamethasone (VAD)-containing regimens. Pre-VAD indicates no CNS prophylaxis; VAD, highdose cytarabine (3 g/m 2 ) and 0.4 to 1.6 g/m 2 of methotrexate; modified VAD, high-dose cytarabine (3 g/m 2 ) and 0.4 to 1.6 g/m 2 of methotrexate plus 1 mg of intrathecal (IT) cytarabine administered weekly after a complete response in highrisk patients. Hyper-CVAD indicates hyperfractionated cyclophosphamide plus VAD with high-dose cytarabine, high-dose methotrexate, and early IT methotrexate at a dose of 12 mg; the cytarabine dose was 100 mg for all patients. Data Source: Cortes J, O Brien SM, Pierce S, Keating MJ, Freireich EJ, Kantarjian HM. 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. 1995;86:2091-2097. 28 adolescent patients with ALL has been demonstrated; however, toxicity, including behavioral problems, myopathy, osteopenia, and excessive weight gain, were major limitations to the use of systemic steroids for CNS prophylaxis in patients with ALL. 63 Systemic chemotherapy alone is not adequate for CNS prophylaxis; it is difficult to maintain prolonged therapeutic concentrations of drug in the CSF. Furthermore, systemic therapy is associated with widespread toxicities. High-dose AraC is associated with liver dysfunction, cerebellar dysfunction, mucositis, diarrhea, rash, and fever. 64 High-dose MTX is associated with renal dysfunction, transient hepatitis, mucositis, and (rarely) neurotoxicity. 53 Poor penetration of the BBB, difficulty in achieving and maintaining cytotoxic levels of systemic therapy in the CSF, and adverse events after cranial radiation have led to the need for alternative therapeutic strategies for CNS prophylaxis in ALL. The objective of including IT therapy in CNS prophylaxis protocols is to improve the Intrathecal chemotherapy IT chemotherapy has been used widely in the last decade to treat CNS lymphoma and leukemia, because it allows direct intra-csf treatment and potentially sustained therapeutic drug concentration in the CSF. 28,65 Commonly used IT therapies include MTX, AraC, liposomal AraC, and N,N 0 N 0 -triethylenethiophosphoramide. IT chemotherapy in combination with systemic chemotherapy has produced successful results and can eliminate the need for radiation. 13 Modified regimens involve repeated administration either of IT MTX or AraC alone or of IT chemotherapy with a combination of systemic MTX, AraC, and corticosteroids. 9 The combination of IT MTX with systemic high-dose MTX has been regarded as a superior option for CNS-directed prophylactic therapy compared with IT MTX alone. 66 In the absence of IT therapy, isolated CNS recurrence can account for 10% to 16% of recurrences, 53 warranting the inclusion of IT chemotherapy in CNS prophylactic regimens. Pui et al demonstrated that early intensification of IT chemotherapy, consisting of simultaneous administration of MTX, AraC, and hydrocortisone (triple IT), resulted in a 5-year cumulative risk of an isolated CNS recurrence of only 1.2% and a cumulative risk of any CNS recurrence of 3.2% in children with ALL. 67 A multicenter phase 2 trial of adults with ALL suggested that high-dose AraC in combination with IT MTX was effective for CNS prophylaxis, with a reported CNS recurrence rate of only 3%. 68 Triple IT therapy also was used recently in the Dana Farber Cancer Institute 91-01 protocol in adults with ALL who presented with positive CSF cytology (16%). 69 Patients received high-dose, systemic MTX during induction and received triple IT therapy during induction, intensification, and maintenance. Cranial radiation also was given during induction. The CSF cleared in all previously positive patients, and prophylaxis was tolerated relatively well. The hyper-cvad regimen also has been adapted to incorporate CNS prophylaxis: Investigators alternated 4 cycles of hyper-cvad with 4 cycles of highdose MTX and high-dose AraC therapy accompanied by IT MTX and AraC in adults with ALL. They reported complete remission in 91% of patients, and the incidence of CNS recurrence was only 4%. 50 Other pediatric regimens that have been adapted for use in adolescent and young adult patients with ALL are compared in Table 2. 50,70 It is interesting to note that the BFM protocols 2294 Cancer May 15, 2010

CNS Prophylaxis in Adults With ALL/Jabbour et al Table 2. Central Nervous System Recurrence Rate in Adult Acute Lymphoblastic Leukemia Protocols a Protocol CNS Recurrence Rate, % CNS Prophylaxis Hyper-CVAD 4 IT MTX 12 mg (6 mg Ommaya) on D2, IT AraC 100 mg on D8 for each cycle for a total of 16 IT treatments BFM b 1 Induction: IT AraC on D0, IT MTX on D14; consolidation: IT MTX (12 mg) on D1, D8, D15, and D22 plus RT 1800 cgy; delayed intensification: IT MTX (12 mg) on D29 and D36; long-term maintenance: IT MTX (12 mg) on D0 Augmented BFM 1 Same as BFM, with the addition of IT MTX (12 mg) on D0, D20, and D40 of interim maintenance and an additional IT MTX (12 mg) on day 0 of long-term maintenance CALGB 8811 11 Maintenance: RT (2400 cgy) on D1-D12, IT MTX (15 mg) on D1, D8, D15, D22, and D29 CNS indicates central nervous system; Hyper-CVAD, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone; IT, intrathecal; MTX, methotrexate; BFM, Berlin-Frankfurt-Munster; AraC, cytarabine; RT, radiation therapy; CALGB, Cancer and Leukemia Group B; cgy, centigrays. a See Kantarjian 2000 50 and Stock 2008. 70 b Adapted by the Children s Cancer Study Group. provided earlier and more intense CNS prophylaxis compared with the Cancer and Leukemia Group B protocol and resulted in a lower CNS recurrence rate. Liposomal AraC, a relatively new agent, is a sustained-release formulation of aqueous AraC that is encapsulated in spherical, multivesicular particles known as DepoFoam. 71 This agent is administered only intrathecally. The liposomal preparation provides a prolonged exposure of free AraC in the cerebrospinal compartment. Exposure for an extended period is particularly important because of the proliferation kinetics of leukemic cells in the CNS. 54,72 Earlier phase 1/2 studies established that the administration of liposomal AraC resulted in the maintenance of elevated AraC levels in the CSF for 14 days, requiring fewer lumbar punctures or intraventricular administrations compared with conventional IT therapies like MTX and AraC. 73,74 Side effects commonly associated with liposomal AraC include headache, arachnoiditis, and confusion. 71 Patients who receive liposomal AraC should be given dexamethasone to mitigate the occurrence of arachnoiditis. 71 IT therapy often is given by lumbar puncture or by direct intraventricular administration using an implantable device, such as an Ommaya reservoir. Both routes are associated with complications. Lumbar puncture may be time-consuming, can lead to suboptimal drug distribution throughout the neuraxis, and, in the case of traumatic lumbar puncture, inadvertent introduction of drug into the epidural or subdural space. 35,75 Indeed, at our institution, we routinely administer IT chemotherapy by lumbar puncture, because the procedure can be performed by physicians or trained nurses and does not require any neurology referral. Intraventricular administration is used only in exceptional cases, such as when lumbar punctures are contraindicated. Contraindication to Ommaya reservoir implantation include tumor presence at the intended burr hole site, 76 and patients with thrombocytopenia and the risk of intravascular coagulation or clotting should be evaluated preoperatively. 77 Before device implantation, patients should be evaluated for CSF flow obstructions with an 111 In-diethylenetriamine penta-acetic acid flow study. 78 Focal irradiation of the obstructed area can restore normal flow; however, if flow is still abnormal, then IT therapy should be avoided. The risks associated with intraventricular administration involve surgical complications, including intracranial hemorrhage and catheter complications, leading to infection and localized necrotizing leukoencephalopathy; however, it affords painless and rapid administration compared with lumbar puncture. 79 Infections can be prevented by the prophylactic use of antibiotics before surgical catheter placement. 78 Catheter misplacement and its consequent effect on parenchymal toxicity can be minimized by the intraoperative confirmation of catheter position with fluoroscopic guidance or endoscopy. 78 Maximizing the Use of Effective CNS Prophylaxis Modalities The most appropriate systemic chemotherapy to control primary disease combined with systemic and IT CNS prophylaxis have contributed to greatly reduced CNS recurrence rates. To this end, studies have focused on therapeutic regimens that can achieve greater efficacy and improved survival rates with reduced CNS recurrence. Immunotherapy with rituximab, in conjunction with hyper-cvad and IT MTX and AraC, was proposed for the treatment of adults with B-ALL. The results demonstrated a 3-year overall survival rate of 89%, an event-free survival rate of 80%, and a disease-free survival rate of 88% with no isolated CNS recurrence. 80 It should be Cancer May 15, 2010 2295

noted that 2 patients had evidence of CNS or leptomeningeal disease at presentation. The therapeutic benefits and the reduced dosing frequency offered by liposomal AraC make it a promising option as a CNS prophylactic treatment for adults with ALL. It is believed that a lower dose intensity of liposomal AraC may be effective and well tolerated in combination with high-dose AraC and/or MTX. However, recent experience combining IT liposomal AraC with systemic chemotherapies to prevent CNS recurrence has been associated with several unexpected toxicities. Jabbour and colleagues investigated the use of liposomal AraC for CNS prophylaxis in 31 adults with ALL. 81 The treatment regimen involved concomitant administration of 50 mg of liposomal AraC on Days 2 and 15 of the hyper-cvad regimen, which also included systemic high-dose MTX and high-dose AraC on alternating courses. Liposomal AraC was administered by lumbar puncture on Day 10 of the high-dose MTX and AraC course. After a median of 4 IT administrations of liposomal AraC, neurologic complications occurred in 5 patients (16%) and included seizures, papilledema, cauda equina syndrome, and encephalitis. Toxic events, such as seizures, were extremely uncommon with hyper-cvad treatment and standard IT AraC; therefore, the neurotoxicity could be attributed in part to the long half-life of liposomal AraC in the CSF. 82 Traumatic lumbar puncture during the administration of liposomal AraC also has been suggested as a possible contributor to the observed neurotoxic effects. 83 In contrast, in a retrospective analysis, McClune and colleagues reported a more manageable safety profile when using liposomal AraC for CNS prophylaxis in adults with ALL. 84 Liposomal AraC 50 mg was administered to patients (N ¼ 14) through an Ommaya reservoir only once per cycle of the hyper-cvad regimen. After the occurrence of hyponatremia and somnolence in 1 patient, the dose of liposomal AraC was reduced to 25 mg for all patients. After an 18-month follow-up, no CNS recurrences were reported, and no patients discontinued treatment because of the side effects associated with liposomal AraC. The investigators suggested that, when using liposomal AraC prophylactically, the concomitant administration of local or systemic neurotoxic medications should be avoided. Indeed, depending on the cycle in which liposomal AraC is given, exposure to high-dose AraC and high-dose MTX could prime the nervous system to any additional IT AraC, compounding the adverse effects observed with liposomal AraC. Systemic high-dose AraC has been associated with neurologic complications, such as seizures, cerebral dysfunction, and cerebellar syndrome, with an incidence of 14%. 85 To further illustrate the importance of evaluating the preconditioning of the CNS to adverse events with liposomal AraC, Hilgendorf and colleagues administered 50 mg of liposomal AraC by lumbar puncture as CNS prophylaxis to 6 patients with hematologic malignancies after hematopoietic stem cell transplantation (HSCT) (n ¼ 4 patients with ALL, n ¼ 1 patient with acute myelogenous leukemia, n ¼ 1 patient with Burkitt lymphoma). 86 Two patients developed signs of sacral radiculopathy, 1 of whom also developed irreversible cauda equina. Both patients had a history of spinal cord surgery or subarachnoid hemorrhage that may have disrupted CSF flow. Uninterrupted CSF flow, as highlighted above, is an essential precondition for successful IT therapy, as is careful evaluation of any preexisting CNS toxicities. It is suggested that liposomal AraC not be administered before or concomitant with high-dose, systemic chemotherapy but, rather, after such systemic treatment. 87 Thus, the optimal interval between the administration of systemic chemotherapy that penetrates the BBB and IT chemotherapy remains to be determined. Clearly, additional studies controlling for these factors are necessary to maximize the efficacy of available CNS prophylactic therapies while avoiding serious toxicities. Those patients who do develop recurrent disease are afforded treatment options similar in method to CNS prophylaxis. Systemic therapies like high-dose MTX and/ or AraC are able to treat both leptomeningeal and parenchymal metastases but necessarily are associated with higher systemic toxicities. IT administration of these agents also is a viable treatment option. In a subanalysis of the international United Kingdom MRC ALL/ECOG 2993 trial, the outcome of adults with ALL who had CNS involvement at diagnosis was analyzed. 16 Patients were treated on protocol in addition to IT or intraventricular MTX (12.5 mg) 3 times per week with the option of providing cranial irradiation at the physicians discretion. After induction and intensification, patients received either consolidation/maintenance or HSCT. Both chemotherapy and HSCT resulted in a 29% 5-year overall survival rate compared with 38% in patients without CNS involvement at diagnosis, and patients with Ph-negative ALL could achieve a relatively long-term disease-free survival. Ph-positive ALL is more common in adults than in children with ALL and is relatively treatment-resistant. 88,89 Allogenic transplantation remains the standard 2296 Cancer May 15, 2010

CNS Prophylaxis in Adults With ALL/Jabbour et al of treatment for these patients. 90 The tyrosine kinase inhibitor imatinib also is accepted treatment but fails to penetrate the BBB to the CSF, resulting in a 20% CNS recurrence rate. 91 More recently, it was demonstrated that another tyrosine kinase inhibitor, dasatinib, penetrated the CSF, making it a promising candidate for the treatment of CNS leukemia. 92 This supports both conventional and targeted chemotherapy and HSCT as viable treatment options for patients with CNS metastases. Most important to effective treatment outcome of CNS metastases is the early diagnosis of disease. However, the difficulties associated with early diagnosis, including possible traumatic lumbar punctures to assess CSF cytology and unfamiliarity with the early signs and symptoms of NM, make prophylaxis the best first-line option in managing CNS metastases from ALL. Conclusions Clinical trials that involve pediatric or adult patients with ALL consistently have highlighted the need for more effective strategies to prevent CNS involvement to achieve longer event-free survival and cure rates. Currently, early and frequent IT therapy combined with systemic chemotherapy is the most effective approach for reducing CNS recurrence. Because of the toxicity associated with CNS prophylactic therapies, it is important to carefully evaluate and identify the appropriate patient groups that will benefit from the different prophylactic modalities. Newer agents that can maintain a prolonged therapeutic level in the CSF will be beneficial candidates for CNS prophylaxis. Further study and monitoring of the therapeutic regimens are needed to establish the most effective agents and regimens to prevent CNS recurrence in adults with ALL. 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