The following institutions and clinicians participated in the study: Hospital Universitari Germans Trias i Pujol, Badalona (J. M. Ribera, J. M. Sancho, A. Oriol, and E. Feliu); Hospital Carlos Haya, Malaga (C. Bethencourt); Hospital Virgen del Rocio, Sevilla (R. Parody); Hospital Virgen de la Victoria, Malaga (M. J. Moreno and M. J. Queipo de Llano); Hospital Clinico Universitario, Salamanca (J. M. Hernandez-Rivas); Hospital Clinico San Carlos, Madrid (E. del Potro); Hospital General, Alicante (C. Rivas and P. Fernandez-Abellan); Hospital Clinico Universitario, Valencia (M. Tormo and M. J. Terol); Hospital Son Dureta, Palma de Mallorca (J. Besalduch and A. Novo); Hospital Universitario La Fe, Valencia (M. A. Sanz and F. Moscardo); Hospital Xeral, Lugo (J. Arias); Hospital Morales Meseguer, Murcia (J. M. Moraleda and I. Heras); Hospital Vall d'Hebron, Barcelona (J. Bueno and J. J. Ortega); Hospital Clinico, Valladolid (J. Fernandez-Calvo and D. Borrego); Hospital Puerta del Mar, Cadiz (V. Martin-Reina); Hospital Juan Canalejo, A Coruna (G. Deben); Hospital General, Valencia (F. Carbonell and M. Orts); Centro Medico Teknon, Barcelona (P. Vivancos); Hospital Doce de Octubre, Madrid (C. Grande); Hospital Clinico Universitario, Santiago de Compostela (J. L. Bello); Hospital General, Segovia (J. A. Queizan); Hospital Txagorritxu, Vitoria-Gasteitz (J. Guinea); Hospital de Sant Pau, Barcelona (S. Brunet); Hospital de San Pedro de Alcantara, Caceres (J. L. Bergua); Hospital Reina Sofia, Cordoba (A. Rodriguez-Villa); Hospital de Galdakao, Bilbao (K. Atutxa); Hospital General de Guadalajara (G. Diaz-Morfa); Hospital General Universitario, La Laguna (L. Hernandez-Nieto); Hospital General de Especialidades, Jaen (F. Gamez); Hospital Joan XXIII, Tarragona (A. Llorente); Hospital Rio Carrion, Palencia (F. Ortega-Rivas); Hospital Rio Hortega, Valladolid (M. D. Penarrubia); Hospital Xeral-Cies, Vigo (C. Poderos); Hospital Mutua de Terrassa, Barcelona (J. M. Marti); and Hospital Josep Trueta, Girona (S. Gardella).
The presence of blast cells in the cerebrospinal fluid (CSF) is a feature that appears in approximately 5% of adult patients who are diagnosed with acute lymphoblastic leukemia (ALL). Leukemic meningitis is associated with a greater probability of central nervous system (CNS) recurrence and a reduction in survival. In the absence of CNS prophylaxis, leukemia recurs in approximately 30% of adult patients with ALL.1 Cranial or craniospinal radiotherapy and intrathecal (IT) administration of antimetabolites, in addition to high-dose systemic chemotherapy with drugs that pass through the blood-brain barrier, are effective methods to prevent CNS recurrence in patients with acute leukemia.2
The predictive factors for initial involvement and recurrence in CNS and the strategies of prophylaxis and treatment of recurrences are well established in childhood ALL.2–9 The same approach has been applied to adult populations with ALL. However, to our knowledge, few studies specifically have analyzed leukemic meningeosis in adults with ALL either at diagnosis or at recurrence.1, 10–16 Moreover, the results from some of those studies cannot be compared because of the absence of homogeneity in the schedules of CNS prophylaxis, specially with regard to the administration of cranial irradiation. The objective of the current study was to analyze the frequency, predictive factors, and prognosis of CNS involvement and recurrence in adult patients with ALL who were treated on 4 protocols of the Spanish Programa para el Estudio y Tratamiento de Hemopatias Malignas (PETHEMA) Group that did not include cranial irradiation for CNS prophylaxis.
MATERIALS AND METHODS
From June 1989 to December 2003, 467 adult patients (age ≥15 years) who were diagnosed with de novo ALL in 22 Spanish hospitals were included in 1 of 4 protocols of the PETHEMA Group: ALL-89 (standard-risk and high-risk ALL; n = 108 patients [23%]), ALL-93 (high-risk ALL; n = 222 patients [47.5%]), ALL-96 (standard-risk ALL; n = 84 patients [18%]), and ALL3-97 (Burkitt leukemia; n = 53 patients [11%]). Diagnoses of ALL were established by using morphologic,17 immunologic,18 and cytogenetic criteria. In these protocols, high-risk ALL was defined as ALL in patients who fulfilled ≥1 of the following criteria: ages 30 years to 50 years; a white blood cell (WBC) count ≥25 × 109/L; and the presence of t(9;22) rearrangement, t(4;11) or other 11q23 rearrangements, and t(1;19). The remaining patients with non-Burkitt ALL were categorized with standard-risk ALL. Descriptions of the protocols and their results have been published elsewhere.19–22
In all protocols, CNS prophylaxis included systemic, high-dose methotrexate (MTX) and cytarabine (Ara-C) during the intensification phase in addition to the administration of triple-IT therapy (TIT) with MTX, Ara-C, and hydrocortisone (Table 1). No patients received cranial or craniospinal radiotherapy. Patients who were treated according to the ALL-89 protocol19 received 12 courses of TIT over the first of the 2 years of therapy. In the ALL-93 protocol,20 patients who were randomized to the chemotherapy arm received 12 courses of TIT over the first of the 2 years, and patients who were randomized to undergo autologous or allogeneic stem cell transplantation (SCT) received 13 courses. Patients who were included in the ALL-96 protocol21 received 14 courses over the first of the 2 years of therapy. Finally, in the ALL3-97 protocol,22 CNS prophylaxis consisted of 12 courses of TIT over 18 weeks of treatment.
Table 1. Central Nervous System Prophylaxis in Patients Included in the Programa para el Estudio y Tratamiento de Hemopatias Malignas Group Protocols
PETHEMA: Programa para el Estudio y Tratamiento de Hemopatias Malignas Group; ALL: acute lymphoblastic leukemia; MTX: methotrexate; Ara-C: cytarabine; TIT: triple intrathecal therapy.
The dose was 1.5 g/m2 for patients age >50 years.
For patients who were randomized to undergo stem cell transplantation.
For patients who were randomized to receive chemotherapy.
For patients who were randomized to receive delayed intensification.
CNS leukemia either at diagnosis or at recurrence was defined by the presence of ≥5 leukemic blasts per μL with the assurance that there was no sample contamination by peripheral blood. Patients who had CNS leukemia at diagnosis received TIT twice weekly until the findings disappeared on 2 consecutive CSF examinations for a minimum of 5 TIT administrations. Treatment thereafter was administered according to the protocol schedule.
In each patient, the following variables were collected: age, gender, morphologic17 and immunologic18 ALL subtype, the presence of mediastinal mass or testicular involvement (investigated by physical examination and confirmed by ultrasonography), WBC and platelet counts, hemoglobin, lactate dehydrogenase (LDH) and albumin levels, and liver function tests. The type of treatment and response also were evaluated. With regard to recurrences, 3 groups were defined: 1) patients with isolated CNS recurrence (defined by the presence of blast cells in a sample of CSF with a normal bone marrow [BM] study), 2) patients with combined (CNS plus BM) recurrence (defined by BM recurrence simultaneously or within 1 week after the detection of CNS recurrence), and 3) patients with recurrence that did not involve the CNS (BM and others). In all patients who had BM recurrence, a lumbar puncture was performed to determine the presence of CNS involvement.
A comparison of patients with and without CNS involvement at diagnosis and patients with and without isolated or combined CNS recurrence was performed by using Student t tests or chi-square tests, as appropriate. For the multivariate analysis of risk factors for CNS leukemia at diagnosis or at recurrence, stepwise Cox logistic regression was employed. Actuarial curves for disease-free survival (DFS) and overall survival (OS) were plotted according to the method of Kaplan and Meier23 and were compared by the log-rank test.24 A P value <.05 was used to determine statistical significance. Analyses were performed with the Statistical Package for Social Sciences (version 12; SPSS Inc., Chicago, IL).
The mean (± standard deviation) age of the 467 patients was 33 years (± 16 years; range, 15-77 years), and 272 patients (58%) were males. The type of ALL according to the French–American–British classification was L1 in 130 patients (28%), L2 in 284 patients (61%), and L3 in 53 patients (11%). With regard to immunologic subtype, 66 patients (14%) had an early pre-B phenotype, 205 patients (44%) had a common phenotype, 24 patients (5.1%) had a pre-B phenotype, 53 patients (11.3%) had a mature B phenotype, and 109 patients (23.3%) had a T phenotype. The immunologic phenotype was not specified in 10 patients (2.1%). One hundred sixty-two patients (34.7%) had WBC counts >25 × 109/L, and 53 patients (11.3%) had WBC counts >100 × 109/L. A mediastinal mass was present in 45 patients (9.6%), and testicular involvement was detected in 9 of 272 males (3.3%). Blast cells were detected in CSF from 18 patients (3.9%) at the time they were diagnosed with ALL (2 patients on the ALL-89 protocol, 7 patients on the ALL-93 protocol, 3 patients on the ALL-96 protocol, and 6 patients on the in ALL3-97 protocol). The variables mediastinal mass (P = .008), testicular involvement (P = .04), mature B ALL (P<.0001), and mature T ALL (P = .007) were associated significantly with a greater risk of CNS involvement in the univariate analysis (Table 2). When these variables were included in a multivariate model, only mature B ALL and testicular involvement were found to be associated significantly with a greater risk of CNS involvement at diagnosis, whereas patients with T ALL demonstrated a trend toward a high incidence of CNS involvement (Table 3).
Table 2. Prognostic Factors for CNS Involvement at the Time of Diagnosis in Patients with ALL: Univariate Analysis
No. of Patients (%)
CNS Involvement at Diagnosis (n = 18)
No CNS Involvement at Diagnosis (n = 449)
CNS: central nervous system; ALL: acute lymphoblastic leukemia; NS: not significant; LDH: lactate dehydrogenase; FAB: French–American–British classification.
No differences were observed between patients with or without CNS involvement at diagnosis when these were analyzed as continuous variables.
Overall, complete remission (CR) was obtained in 381 of 467 patients (81%), including 159 patients (42%) who developed recurrences: BM recurrence was present in 137 patients (36%), and CNS recurrence was present in 22 patients (5.8%); there were 14 isolated recurrences and 8 combined recurrences (CNS and BM in all). Distribution of CNS recurrence by protocol was 9 in ALL-89 (7 isolated and 2 combined recurrences), 8 in ALL-93 (5 isolated and 3 combined recurrences), 2 (2%) in ALL-96 (1 isolated and 1 combined recurrence), and 3 in ALL3-97 (1 isolated and 2 combined recurrences). The risk factors for recurrence of any type were L3 subtype (P = .008), the presence of myeloid markers (P = .048), and the absence of standard response to induction chemotherapy (blast cells in BM≥10% on Day 14) (P = .03). With regard to CNS recurrence, only LDH levels >1000 U/L were associated significantly with a greater risk in the univariate and multivariate analyses (odds ratio [OR], 5.7; 95% confidence interval [95% CI], 1.8-17.8 [P = .003]) (Tables 3 and 4). The lack of a correlation between CNS involvement at diagnosis and CNS recurrence was noteworthy.
Table 4. Prognostic Factors for CNS Recurrence (Isolated or Combined) in Patients with ALL: Univariate Analysis
Isolated or Combined CNS Recurrence (n = 22)
BM Recurrence (n = 137)
CNS: central nervous system; ALL: acute lymphoblastic leukemia BM: bone marrow; NS: not significant; LDH: lactate dehydrogenase; FAB: French–American–British classification.
No differences were observed when the comparison was based on continuous variables.
At a median follow-up of 4.2 years (range, 0.7-11 years) for the entire series, the median CR duration before recurrence was 1.06 years (95%CI, 0.11-2.01 years) for patients who had isolated CNS recurrence, 0.6 years (95% CI, 0.30-0.89 years) for patients who had combined recurrences, and 0.93 years (95%CI, 0.78-1.07 years) for patients who had BM recurrence (P = .76) (Fig. 1). No differences were observed when patients who had CNS recurrence (isolated plus combined) were compared with patients who had BM recurrence (median, 0.81 years [95% CI, 0.04-1.57 years] vs. 0.93 years [95% CI, 0.78-1.07 years]; P = .51).
Treatment of CNS recurrence consisted of systemic chemotherapy and TIT in 22 patients, and cranial radiotherapy was added for 1 patient. A CR was achieved by 7 of those patients (32%), including the patient who received cranial irradiation. Four patients underwent SCT (allogeneic SCT in 3 patients and autologous SCT in 1 patient), but 2 patients died because of SCT-related complications (interstitial pneumonia and graft-versus-host disease). The other 2 patients remained in remission 65 months and 122 months after CNS recurrence. The 3 patients who did not undergo SCT developed a second CNS recurrence and died. The median OS after ALL recurrence was 0.7 years (95% CI, 0.06-1.31 years) for patients who had isolated CNS recurrences, 0.13 years (95% CI, 0.09-0.17 years) for patients who had combined recurrences, and 0.41 years (95% CI, 0.33-0.49 years) for patients who had BM recurrences (P = .11) (Fig. 2). Again, no differences were observed in OS between patients who had CNS recurrences (isolated plus combined) and patients who had BM recurrences (median, 0.25 years [95% CI, 0-0.69 years] vs. 0.41 years [95% CI, 0.33-0.49 years]; P = .48).
The inclusion of systematic CNS prophylaxis for leukemia in the schedules of treatment for ALL has led to a considerable reduction in CNS recurrence to ≤5%.1–2 However, to our knowledge, the majority of the published studies are based on the results obtained in childhood ALL,3–9 and few studies have evaluated the effect of CNS prophylaxis on the frequency of neuromeningeal recurrences in adult patients with ALL, their predictive factors, and the response to therapy.10–16
The usual schedules of CNS prophylaxis for leukemia include the administration of IT chemotherapy and cranial radiotherapy. However, the use of high-dose systemic chemotherapy with drugs that can pass the blood-brain barrier (e.g., MTX and Ara-C) has led some groups to eliminate cranial irradiation from the therapeutic regimens for ALL, particularly in childhood ALL.5, 8, 25, 26 Conversely, in adult ALL, little information exists regarding the frequency of CNS recurrence in patients who received only high-dose systemic chemotherapy and IT chemotherapy.1, 11–13
For the current study, we analyzed a large series of adult patients with ALL who were treated on several risk-adapted protocols in which CNS prophylaxis was performed homogenously, including high-dose systemic chemotherapy and IT chemotherapy. The frequency (3.9%) and predictive factors of CNS involvement at diagnosis of ALL (mature B-cell phenotype and testicular involvement) that were identified in this series were similar to those described by others.1, 2, 12, 13, 27 The main result of the current study consisted of a similar frequency (5.8%) of CNS recurrence (isolated or combined) compared with other studies in which CNS prophylaxis included cranial radiotherapy. A recent study27 that included 687 adults with ALL achieved a 5% rate of CNS recurrence with prophylactic schedules that included either cranial radiotherapy and IT chemotherapy with 1 or 3 drugs or cranial radiotherapy and high-dose systemic chemotherapy (MTX and Ara-C). Nevertheless, in that study, the frequency of CNS recurrence in the group that did not receive cranial radiotherapy as prophylaxis was greater (13%) than what we observed in the current series. In another study by the German Multicenter Acute Lymphoblastic Leukemia Study Group1 that included >4000 adults with ALL and employed different regimens of CNS prophylaxis, the frequency of CNS recurrence in patients who received high-dose systemic chemotherapy, IT chemotherapy, and cranial irradiation was 5%, compared with almost 15% for patients who received either high-dose systemic chemotherapy or IT chemotherapy. In the study by Omura and Bass,14 3 of 28 adult patients (11%) with ALL who received prophylaxis with cranial radiotherapy and IT MTX (without concomitant high-dose systemic chemotherapy) had CNS recurrence. To our knowledge, few studies to date have analyzed CNS recurrence in adults with ALL who did not received radiotherapy as prophylaxis, and their results were very similar to ours. Surapanemi et al.11 reported a 7% rate of CNS recurrence in 527 adults with ALL who received prophylaxis with systemic chemotherapy with or without IT chemotherapy. In the series reported by Annino et al.,28 an 8% rate of CNS recurrence was observed (only isolated CNS recurrences were included) with a schedule that included systemic high-dose MTX and 16 courses of IT MTX plus prednisone. Even lower frequencies have been observed in other recent studies that employed high-dose systemic therapy together with IT therapy as CNS prophylasis. In the study by Linker et al.,12 the frequency of CNS recurrence was 3%, whereas Kantarjian et al.13 reported a frequency of 4%. Therefore, the differences observed in the frequency of CNS recurrence may be related to the total dose of systemic Ara-C received by the patients. Therefore, in the study by Annino et al.,28 no high-dose systemic Ara-C was given (although the total estimated dose of Ara-C given throughout the study was 6 g/m2), whereas in the study by Linker et al.,12 patients received a total dose of 16 g/m2 during the first year of therapy and, in the study by Kantarjian et al.,13 the total dose was 12 g/m2 for 4 cycles. It should be pointed out that in the ALL-89 protocol, in which the frequency of CNS recurrence was 8%, the dose of systemic Ara-C was lower than the doses that were used in the other protocols (Table 1).
Another possible reason for differences in the frequency of CNS recurrence observed in the different studies may be the schedule of IT prophylaxis. In our study, TIT was employed (MTX at a dose of 12 mg or 15 mg, Ara-C at a dose of 30 mg, and hydrocortisone at a dose of 20 mg); whereas, in the study by Annino et al.,28 double-IT therapy was used (MTX at a dose of 12 mg and methylprednisolone at a dose of 40 mg). In the study by Linker et al.,12 only MTX (at a dose of 12 mg) was administered, and Kantarjian et al.13 used double IT (MTX at a dose of 12 mg and Ara-C at a dose of 100 mg).
To our knowledge, predictive factors for CNS recurrence of adult ALL rarely have been analyzed. In addition to the absence of CNS prophylaxis, in the study by Omura and Bass,14 ethnic origin (nonwhite) and splenomegaly were predictive factors for CNS recurrence of leukemia, but the reasons for this association were not explained in their published report. Mature B-cell and T-immunologic subtypes were the main predictive factors for CNS recurrence in the study by Bassan et al.27 Once again, the studies performed in childhood ALL have analyzed this issue more extensively. In those studies, CNS involvement at diagnosis of ALL,29 prophylactic schedule (slight superiority for cranial radiotherapy over IT MTX in children age >10 years7 or over systemic chemotherapy5; lower CNS recurrence with intensification of IT chemotherapy8), and the intensity of systemic chemotherapy7 were the main factors found to be associated with the probability of CNS recurrence of leukemia. In our series, the only predictive factor for CNS recurrence was an LDH level >1000 U/L, a feature that also was observed in another, similar study.30 The absence of any correlation between CNS involvement at diagnosis and the risk of CNS recurrence is noteworthy and differs from what has been observed in some studies of childhood ALL.29
The prognosis for patients who developed CNS recurrence in our series was very poor, as described previously.1, 2, 4, 11 The main reasons were the low frequency of remissions and the increased frequency of early recurrences, despite the addition of systemic chemotherapy to the CNS-directed therapy in all patients. In our study, only approximately 33% of patients achieved a second CR, and their survival was very poor, similar to that described in previous reports. Only 2 patients who underwent SCT (allogeneic in 1 patient and autologous in the other patient) remained in CR, a finding that is in accordance with the data from other studies in which durable remissions were obtained mainly in a minority of patients who underwent SCT.16, 31, 32
Despite the retrospective nature of the current study, the frequency of CNS recurrence was similar to the frequency described for protocols that included cranial radiotherapy. Following the trend observed in some current studies in childhood ALL, it is possible that CNS-directed radiotherapy also may be omitted in CNS prophylaxis for adult patients with ALL if IT chemotherapy is used together with high-dose. systemic chemotherapy.