Central nervous system prophylaxis in adults with acute lymphoblastic leukemia

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. © 2010 American Cancer Society.     

Central nervous system morbidity following an initial isolated central nervous system relapse and its subsequent therapy in childhood acute lymphoblastic leukemia

The frequency and types of major CNS toxicity and morbidity were analyzed in 107 children with acute lymphoblastic leukemia (ALL) following an isolated primary CNS relapse. Seventy-nine (73%) have had multiple subsequent marrow or CNS relapses requiring intensive and prolonged therapy to the CNS. Median survival time is two years. Of these 79 patients, two thirds have had one or more types of major CNS toxicity, including epileptiform seizures (35), moderate to severe structural abnormalities (24 of 27 evaluated), major motor disabilities (9), blindness (2), CNS infection (6), cranial nerve palsies (2), and intracranial lymphoma (2). The remaining 28 patients (26%) have had no or one additional CNS relapse and have received therapy for a median of eight years. One half of this surviving group of patients have had major CNS toxicity, including seizures (9), major motor disability (2), and intracranial calcifications (12/19). When neuropsychologic evaluations were compared between the 28 survivors and 50 of their contemporaries who had been in initial continuous complete remission, the CNS survivors had significantly lower Full Scale IQ scores (83 +/- 16 v 99 +/- 14, P = less than .001) with similarly lower measures of academic performance. The relative contributions of meningeal leukemia itself and intrathecal or radiation therapy to these effects cannot be determined. Since major CNS sequelae occurred in the majority of patients who had a primary isolated CNS relapse, and the frequency of CNS relapse is dependent on the efficacy of the method of CNS prophylaxis, the best method of avoiding major CNS sequelae is the most effective form of CNS prophylaxis.     

The importance of an isolated central nervous system relapse in children with acute lymphoblastic leukemia

We assessed the influence of an initial isolated meningeal relapse on treatment outcome in 839 children with acute lymphoblastic leukemia (ALL) who were admitted to St Jude Children's Research Hospital (Memphis) from mid-1967 through mid-1979. The patients were entered in a series of five clinical trials (Total Therapy Studies V through IX), each designed to test one or more modifications of treatment for ALL. Two groups were compared: 699 children who received CNS prophylaxis (2,400-rad craniospinal irradiation or 2,400-rad cranial irradiation plus intrathecal methotrexate) v 56 who did not. Our results, obtained with a time-dependent covariate model and a matching technique, indicate a 2 to 3.5-fold increase in the risk of hematologic relapse or death among patients who experienced an isolated CNS relapse compared with similar patients (matched for leukocyte count and length of complete remission) who remained free of CNS involvement. Of the 107 children with an initial isolated CNS relapse, 89 (83%) have died or have had a subsequent relapse. There was no detectable difference in the rate of hematologic relapse or death after a CNS relapse between patients who had received preventive therapy and those who had not. We conclude that CNS prophylaxis is important both for the prevention of initial CNS leukemia and for reducing the risk of hematologic relapse or death subsequent to a CNS relapse.     

Central nervous system relapse after bone marrow transplantation for acute myeloid leukemia

Central nervous system (CNS) relapse with meningeal leukaemia occurred 6 months after allogeneic bone marrow transplantation (BMT) for acute myeloid leukaemia, without systemic relapse. Despite intrathecal chemotherapy a severe progressive proprioceptive impairment of the lower limbs developed. Autopsy revealed selective ascending tract degeneration of the gracile fasciculi of the posterior columns of the spinal cord and residual endoneurial deposits were found in lumbosacral dorsal nerve roots and ganglia. While CNS relapse may occur in acute leukaemia after chemotherapy, it has rarely been reported following BMT.     

The significance of an isolated central nervous system relapse, occurring as first relapse in children with acute lymphoblastic leukemia

In a retrospective study, which comprised the whole Dutch childhood population of approximately 3 million children, the authors assessed the influence of an isolated meningeal relapse, occurring as first relapse, together with some patient and treatment characteristics on prognosis in 142 children with acute lymphoblastic leukemia (ALL). Until their first relapse, patients were initially treated according to standard protocols, whereas the treatment for relapse was heterogeneous. Concerning the probability of achieving a second complete remission (CR) it appears that the duration of the first CR is the single most important prognostic factor. The duration of the first CR is also the most important factor with regard to the duration of the second CR, upon which also age and sex have a significant influence. Concerning the survival from the time of central nervous system (CNS) relapse, again the duration of the first CR appears to be the most important prognostic factor, followed by age and the institution of systemic reinduction treatment. Other factors, such as initial leukocyte count, attainment of first CR within 48 days, type of reinduction treatment, and the cerebral spinal fluid (CSF) blast count at the time of relapse, have a less important, but nevertheless significant influence on survival. The median survival from the time of CNS relapse is 25 months, the 5-year survival is 25%, whereas the ultimate survival will be less than 20%. From 90 patients who developed second or subsequent relapses, 75% experienced a bone marrow relapse during the follow-up period. From this study the authors conclude that CNS relapse in children with ALL carries a grave prognosis, which requires the institution of intensive retreatment programs.     

Central nervous system radiotherapy in acute leukemia

From Dec. 1976 through June 1986, 474 patients with acute leukemia were treated with central nervous system (CNS) irradiation for the purpose of preventing relapse of CNS leukemia. Of the whole series, whole cranial irradiation at a dosage of 24 Gy and 4–5 intrathecal instillations of methotrexate (MTX) were given in 149 patients, simple intrathecal instillation of MTX in 44 patients and high dose intravenous MTX in 5 patients; the CNS relapse rates were 4.0%, 20.5% and 40.0% respectively. It was proved by our experience that whole cranial irradiation plus intrathecal MTX is the best approach to prevention of CNS leukemia relapses.     

Central nervous system relapses after bone marrow transplantation for acute lymphoblastic leukemia in remission

This study defines the risk of central nervous system (CNS) relapse in patients undergoing bone marrow transplantation (BMT) for acute lymphoblastic leukemia (ALL) in remission, with no posttransplant prophylactic CNS therapy. Ninety-two consecutive patients in complete remission received BMT for ALL (n = 82) or high-grade non-Hodgkin's lymphoma with poor prognostic factors at diagnosis (n = 10). Sixty-six patients received allogeneic BMT (Allo-BMT) and 26 patients, without an identical sibling, underwent autologous BMT (Auto-BMT). Fifteen patients had CNS involvement at diagnosis and underwent BMT in first remission. Eight patients experienced CNS relapse after BMT, corresponding to a probability of 11% at 3 years. Apart from a history of prior CNS involvement, no patient characteristic evaluated statistically influenced CNS relapse after BMT. The probability of CNS relapse was 5.5% for the 70 patients without history of CNS involvement and 27.5% for the 22 patients with prior CNS involvement. However, subgroup analysis showed that the increased risk of CNS relapse is mainly observed in Auto-BMT patients with history of prior CNS involvement, particularly in patients undergoing BMT in first remission (three of five Auto-BMT versus one of ten Allo-BMT). Taking into account the multiple factors which influence the occurrence and the treatment of CNS leukemia, the results on this retrospective study suggests that (1) for patients without CNS involvement at diagnosis and for whom BMT is performed in first remission, cranial irradiation before BMT and posttransplant prophylactic CNS therapy can be omitted because of the low probability of CNS relapse after BMT (3.4%), when total-body irradiation (TBI) is included in the conditioning regimen; and (2) the difference observed between Allo-BMT and Auto-BMT patients with previous CNS involvement and undergoing BMT in first remission could indicate that graft-versus-host leukemia acts even in the CNS in Allo-BMT patients.     

Second central nervous system prophylaxis in children with acute lymphoblastic leukemia who relapse after elective cessation of therapy

A treatment plan to achieve better disease control in patients with acute lymphoblastic leukemia (ALL) who relapse after elective cessation of therapy was assessed. The principal modifications were (1) a second preventive treatment of the central nervous system (CNS) at relapse and every six weeks throughout therapy, using intrathecal methotrexate with cytosine arabinoside, and (2) a four-week course of systemic chemotherapy given immediately before therapy was stopped a second time. Twenty-four patients were studied. There have been no meningeal relapses, in contrast to seven among 16 similar patients who were retreated without CNS prophylaxis. Although the median length of second hematologic remission was not significantly different from the outcome in the comparison group, a much higher proportion of patients (eight of 24 versus zero of 17) remain in prolonged reinduced complete remission (48-79 months). Children whose first relapse occurred later than six months after cessation of therapy had significantly longer subsequent remissions. These end results establish the value of intrathecal CNS prophylaxis in relapsed ALL and suggest that a late intensive phase of therapy will extend remissions in a substantial proportion of patients.     

Central nervous system involvement in adult acute leukemia

Central nervous system (CNS) involvement was present in 16 of 59 (27%) adults with leukemia, i.e. in 13 of 40 (33%) with AML, of 3 (33%) with AMoL, and 2 of 8 (25%) with ALL. CNS leukemia was found at the time of diagnosis in 2 patients, during induction therapy in 2 patients, early in remission in 2 patients, during remission in patients, and at relapse in 4 patients. Fifteen of the 16 patients responded to intrathecal methotrexate, cytosine arabinoside or cranial irradiation. Only patients developed CNS relapse. CNS leukemia had no effect on survival. In 3 of 5 patients without CNS prophylaxis, the onset of neurologic manifestations was observed within one year of remission, whereas it was delayed for more than one year in all patients who had received prophylactic intrathecal methotrexate.     

Concurrent hypopituitarism and leukemic retinopathy in a child with B-precursor acute lymphoblastic leukemia and isolated central nervous system relapse

Hypopituitarism in leukemia is very rare. In addition, central nervous system (cns) relapse and leukemic retinopathy in childhood acute lymphoblastic leukemia (all) have declined with the use of modern systemic chemotherapy that includes cns prophylaxis. Here, we report the case of a 4-year-old girl who received chemotherapy and intrathecal therapy without cns radiation after a diagnosis of B-precursor all without cns involvement. Three months after chemotherapy completion, she presented with lower-extremity weakness and was diagnosed with an isolated cns relapse. Concurrent hypopituitarism and leukemic retinopathy were also found. After receiving craniospinal radiotherapy and systemic chemotherapy, her retinopathy and vision improved. She is now in complete remission, and she is still on chemotherapy according to the guideline from the Pediatric Oncology Group. Although rare, hypopituitarism and leukemic retinopathy should be taken into consideration in patients with cns involvement by leukemia.     

Central nervous system involvement in adult acute lymphoblastic leukemia at diagnosis and/or at first relapse: results from the GET-LALA group

Outcome of adult acute lymphoblastic leukemia (ALL) with central nervous system (CNS) involvement is not clearly defined. We studied 104 patients presenting with CNS involvement at diagnosis among 1493 patients (7%) included into the LALA trials, and 109 patients presenting CNS disease at the time of first relapse among the 709 relapsing patients (15%). Eighty-seven patients (84%) with CNS leukemia at diagnosis achieved complete remission (CR). Fifty-three patients underwent stem cell transplantation (SCT): 25 allogeneic SCT, 28 autologous SCT, while 34 continued with chemotherapy alone. Seven-year overall survival (OS) and disease-free survival (DFS) were 34% and 35%, respectively. There were no significant differences in terms of CR, OS and DFS among patients with CNS involvement at diagnosis and those without CNS disease. There were also no differences among the two groups regarding T lineage ALL, B lineage ALL, and among those who underwent SCT. After a first relapse, 38 patients with CNS recurrence (35%) achieved a second CR. The median OS was 6.3 months. Outcome was similar to that of relapsing patients without CNS disease. CNS leukemia in adult ALL is uncommon at diagnosis as well as at the time of first relapse. With intensification therapy, patients with CNS leukemia at diagnosis have a similar outcome than those who did not present with CNS involvement. CNS leukemia at first relapse remains of similar poor prognosis than all other adult ALL in first relapse.     

Central nervous system (CNS) prophylaxis in children with low risk acute lymphoblastic leukemia (ALL)

Five hundred four children with low risk acute lymphocytic leukemia (previously untreated, age 3 to 6 years with white blood counts less than 10,000/mm3 at diagnosis) were randomized into two different central nervous system prophylaxis regimens. One regimen (250 patients) consisted of cranial radiation and intrathecal methotrexate (IT MTX). The second regimen (254 patients) consisted of IT MTX only. Median follow-up time for surviving patients is currently 54 months from randomization. Life table analysis of central nervous relapse, marrow relapse, disease-free survival, and survival shows very similar outcome for both treatment groups. The results indicate that maintenance IT MTX as described in this report can be substituted for cranial radiation in children with low risk ALL.     

成人急性淋巴细胞白血病治疗进展

【指示性摘要】尽管应用各种不同的诱导缓解方案,80％-95％的成人急性淋巴细胞白血病（ALL）可获得形态学上的完全缓解,但大部分病人很快复发。能否获得免疫学或分子水平的微小残留病（MRD）状态及达到MRD的速度极为重要。缓解后治疗是病人长期生存的关键。接受异基因移植的病人复发率明显降低。但在年龄35—40岁以上的移植患者中,较高的移植相关死亡率抵消了异基因移植的生存优势。相配无关供体移植的应用日益广泛,可用于所有高危病人。降低强度的移植可能增加老年患者的生存率。伊马替尼甲磺酸的应用彻底改变了ph阳性ALL的治疗方法,特别是该型老年患者。诊断时有CNS累及的患者,只要给予及时治疗,对预后无明显不利影响。     

Immunologic monitoring in adults with acute lymphoblastic leukemia

Investigation of minimal residual disease (MRD) by immunophenotyping and molecular techniques has proven to be a powerful approach for disease monitoring in patients with acute leukemia. Multiparameter flow cytometry, through the use of triple or quadruple marker combinations, identifies aberrant or uncommon phenotypic profiles in more than 90% of adult patients with acute lymphoblastic leukemia (ALL) at diagnosis. These profiles allow identification of residual leukemic cells in bone marrow or peripheral blood once morphologic complete remission is achieved. Until now, most immunophenotypic MRD studies in ALL have focused on children. In contrast, information on the value of MRD in adults with ALL is scanty and usually restricted to polymerase chain reaction studies. In this review, we focus on technical aspects of MRD detection by flow cytometry and on the clinical data concerning the value of immunologic MRD studies as a tool for relapse prediction in adult ALL. Although prospective studies are needed, we assert that immunophenotypic MRD studies are clinically useful. Such studies should be incorporated into the routine management of adult ALL patients for identification of those at high risk of relapse, who could benefit from new alternative therapeutic approaches, and to distinguish these patients from others who could be cured with more conventional approaches.     

Isolated central nervous system relapse in lymphoid blast crisis chronic myeloid leukemia and acute lymphoblastic leukemia in patients on imatinib therapy

Philadelphia chromosome positive ALL and CML have shown remarkable responses to imatinib (Gleevec, STI571) in phase I, II and III studies. However, imatinib has very poor penetration of the blood brain barrier resulting in subtherapeutic levels in the CNS. We present 2 cases of patients treated with imatinib that achieved complete cytogenetic remission within 3 months who subsequently developed CNS relapses while remaining in complete cytogenetic remission on bone marrow examination. Both patients went on to achieve CNS remission following treatment with intrathecal methotrexate and cytarabine.     

成人急性淋巴细胞白血病治疗进展

尽管应用各种不同的诱导缓解方案,80%-95%的成人急性淋巴细胞白血病(ALL)可获得形态学上的完全缓解,但大部分病人很快复发.能否获得免疫学或分子水平的微小残留病(MRD)状态及达到MRD的速度极为重要.缓解后治疗是病人长期生存的关键.接受异基因移植的病人复发率明显降低.但在年龄35-40岁以上的移植患者中,较高的移植相关死亡率抵消了异基因移植的生存优势.相配无关供体移植的应用日益广泛,可用于所有高危病人.降低强度的移植可能增加老年患者的生存率.伊马替尼甲磺酸的应用彻底改变了ph阳性ALL的治疗方法,特别是该型老年患者.诊断时有CNS累及的患者,只要给予及时治疗,对预后无明显不利影响.     

Central nervous system involvement in adult acute lymphocytic leukemia

With effective CNS prophylaxis, most adults with ALL may remain free of CNS leukemia. Several combinations of IT chemotherapy, high-dose systemic chemotherapy, and cranial irradiation have been used with varying results. Excellent prophylaxis can be achieved without cranial irradiation, and in view of the potential acute and long-term toxicity of radiation, these methods may be preferable. A prophylactic approach tailored to the risk of CNS leukemia was shown to be valuable in childhood ALL and in at least one adult study. Further studies should focus on defining risk groups for CNS leukemia and designing effective prophylaxis for each group. More research is needed to define the intensity and duration of treatment and the role of cranial irradiation in the treatment of isolated CNS relapses.