Long-term follow-up of Dutch Childhood Leukemia Study Group (DCLSG) protocols for children with acute lymphoblastic leukemia, 1984-1991.

Here we report the long-term results of the DCLSG protocols ALL-6 and -7 with special emphasis on the incidence of CNS relapse after treatment without cranial irradiation. In DCLSG protocol ALL-6 (1984-1988), designed for patients with ALL non-high risk (ALL-NHR) (WBC <50 x 10(9)/l, no mediastinal mass, no B cell phenotype and no CNS involvement at diagnosis, comprising 71% of all ALL patients), CNS prophylaxis consisted of a combination of three methods of chemotherapeutic CNS prophylaxis (the use of dexamethasone during induction and maintenance therapy, i.v. medium dose methotrexate and prolonged administration of intrathecal triple therapy). Total duration of treatment: 116 weeks. 190 patients were enrolled in the study. At 10 years, the EFS rate for all patients is 81.5 +/- 2.8%, the survival rate 84.8 +/- 2.7%, and the cumulative incidence of isolated CNS relapse 1.1 +/- 0.8%. The 10-year survival rate for the 139/190 (73.1%) patients with standard risk non-T lineage ALL according to the NCI risk criteria is 80.5 +/- 3.4%. DCLSG protocol-7 was identical to the intensive ALL-BFM-86 protocol, but cranial irradiation was restricted to patients with initial CNS involvement. Patients were stratified into three risk groups (SRG, RG and EG). Treatment duration was 18 months. 218 patients were enrolled in the study. At 10 years, the EFS rate for all patients is 63.4 +/- 3.3%, the survival rate 76.4 +/- 3.0%, the 5-year cumulative incidence of isolated CNS relapse 5.7 +/- 1.8%. The EFS rate at 10 years of the 127/218 (58.3%) patients with standard risk non-T-lineage ALL according to the NCI risk criteria was 67.9 +/- 4.3%, which is not significantly different from the results achieved in this category of patients with the moderately intensive treatment according to protocol ALL-6 (logrank P = 0.17). These DCLSG studies indicate that omission of cranial irradiation does not jeopardize the overall good results.     

Treatment of childhood acute lymphoblastic leukemia: results of Dana-Farber ALL Consortium Protocol 87-01.

PURPOSE: To improve efficacy and reduce toxicity of treatment for children with acute lymphoblastic leukemia. PATIENTS AND METHODS: Patients from all risk groups, including infants and those with T-cell disease, were treated between 1987 and 1991. Standard-risk (SR) patients did not receive cranial irradiation, whereas high-risk (HR) and very high-risk (VHR) patients participated in a randomized comparison of 18 Gy of cranial irradiation conventionally fractionated versus two fractions per day (hyperfractionated). RESULTS: At a median follow-up of 9.2 years, the 9-year event-free survival (EFS +/- SE) was 75% +/- 2% for all 369 patients, 77% +/- 4% for the 142 SR patients, and 73% +/- 3% for the 227 HR/VHR patients (P =.37 comparing SR and HR/VHR). The CNS, with or without concomitant bone marrow involvement, was the first site of relapse in 19 (13%) of the 142 SR patients: 16 (20%) of 79 SR boys and three (5%) of 63 SR girls. This high incidence of relapses necessitated a recall of SR boys for additional therapy. CNS relapse occurred in only two (1%) of 227 HR and VHR patients. There were no outcome differences found among randomized treatment groups. Nine-year overall survival was 84% +/- 2% for the entire population, 93% +/- 2% for SR children, and 79% +/- 3% for HR and VHR children (P <.01 comparing SR and HR/VHR). CONCLUSION: A high overall survival outcome was obtained for SR patients despite the high risk of CNS relapse for SR boys, which was presumed to be associated with eliminating cranial radiation without intensifying systemic or intrathecal chemotherapy. For HR/VHR patients, inability to salvage after relapse (nearly all of which were in the bone marrow) remains a significant clinical problem.     

Long-term results of two consecutive trials in childhood acute lymphoblastic leukaemia performed by the Spanish Cooperative Group for Childhood Acute Lymphoblastic Leukemia Group (SHOP) from 1989 to 1998

INTRODUCTION: The first multi-centric protocol for childhood acute lymphoblastic leukaemia (ALL) treatment in Spain started in 1989 and was conducted by the Spanish Pediatric Hematology and Oncology Societies. MATERIALS AND METHODS: A total of 673 patients were included in two consecutive trials, SHOP-89 (1989-1993) and SHOP- 94 (1994-1998). Approximately 67% of the children diagnosed with ALL in Spain during this period were enrolled in these trials. The 250 eligible patients enrolled in the SHOP- 89 study were stratified to either a standard or a high-risk group. Therapy schedule was based on the central nervous system (CNS) therapy designed by St Jude CRH and the Children's Cancer Group, and the post-induction intensification developed by the BFM group. In the SHOP-94 study, a further high-risk group was included in the stratification of the 423 enrolled patients. The therapeutic protocol was characterised by intensification of systemic chemotherapy and the administration of cranial radiotherapy only to patients at high risk of relapse or with CNS involvement at diagnosis. RESULTS: Event-free survival (EFS) increased from 0.57+/- 0.03 at 15 years in SHOP-89, to 0.68+/-0.03 at 11 years in SHOP-94 (p=0.01). Relapse rate decreased from SHOP-89 to SHOP-94: 0.38 vs. 0.25 (p=0.01). CNS relapse rate was 9.1% in SHOP-89 and 4.6% in SHOP-94 (p=0.001). EFS in patients with T-immunophenotype was 0.40+/-0.08 in SHOP-89 and 0.44+/-0.06 in SHOP-94 (p=ns). CONCLUSIONS: Our therapeutic results evidence a significant improvement in EFS and systemic and CNS relapse rates among the two consecutive trials after modification of patient stratification and intensification of systemic chemotherapy.     

Results of Dana-Farber Cancer Institute Consortium protocols for children with newly diagnosed acute lymphoblastic leukemia (1981-1995).

The Dana-Farber Cancer Institute (DFCI) ALL consortium has been conducting clinical trials in childhood acute lymphoblastic leukemia (ALL) since 1981. The treatment backbone has included intensive, multi-agent remission induction, early intensification with weekly, high-dose asparaginase, cranial radiation for the majority of patients, frequent vincristine/ corticosteroid pulses during post-remission therapy, and for high-risk patients, doxorubicin during intensification. Between 1981 and 1995, 1,255 children with newly diagnosed ALL were evaluated on four consecutive protocols: 81-01 (1981-1985), 85-01 (1985-1987), 87-01 (1987-1991) and 91-01 (1991-1995). The 5-year event-free survival (EFS) rates (+/- standard error) for all patients by protocol were as follows: 74 +/- 3% (81-01), 78 +/- 3% (85-01), 77 +/- 2% (87-01) and 83 +/- 2% (91-01). The 5-year EFS rates ranged from 78 to 85% for patients with B-progenitor phenotype retrospectively classified as NCI standard-risk, 63-82% for NCI high-risk B-progenitor patients, and 70-79% for patients with T cell phenotype. Results of randomized studies revealed that neither high-dose methotrexate during induction (protocol 87-01) nor high-dose 6-mercaptopurine during intensification (protocol 91-01) were associated with improvement in EFS compared with standard doses. Current studies continue to focus on improving efficacy while minimizing acute and late toxicities.     

Improved survival of children with isolated CNS relapse of acute lymphoblastic leukemia: a pediatric oncology group study .

PURPOSE: Isolated meningeal relapse in children with acute lymphoblastic leukemia (ALL) usually has been followed by bone marrow relapse and limited survival. The purpose of this study was to prevent marrow relapse by administering intensive therapy before delayed craniospinal radiation. PATIENTS AND METHODS: Eighty-three patients with ALL in first bone marrow remission with an isolated CNS relapse were treated with systemic chemotherapy known to enter into the CSF and intrathecal chemotherapy for 6 months. Craniospinal irradiation (24 Gy cranial/15 Gy spinal) was then administered, followed by 1.5 years of maintenance chemotherapy. RESULTS: All 83 patients achieved a second remission. The 4-year event-free survival (EFS) rate was 71.1% +/- 5.3%. There was a fourfold increased risk of relapse for children whose initial remission was less than 18 months. The 4-year EFS rate for patients with a first complete remission >/= 18 months was 83.3% +/- 5.3%, and for those with a first complete remission less than 18 months, it was 46.2% +/- 10.2% (P =.0002.) There was a low incidence of neurologic toxicity and an unexpectedly high rate of allergic reactions to L-asparaginase. Five patients developed secondary malignancies: two with acute nonlymphoblastic leukemia during therapy, one with myelodysplasia after therapy, and two with brain tumors 1.5 to 2 years after cessation of therapy. CONCLUSION: For children with ALL and an isolated CNS relapse, treatment that delays definitive craniospinal irradiation by 6 months to allow for more intensive systemic and intrathecal chemotherapy results in better EFS than has been previously reported. Using this approach, the long-term prognosis for children with first complete remission >/= 18 months is comparable to that at the time of original diagnosis of ALL.     

Pilot studies of species-specific chemotherapy of childhood acute lymphoblastic leukemia using genotype and immunophenotype.

Genotype and immunophenotype can be used to define biological species of acute lymphoblastic leukemia (ALL). The purpose of these two pilot studies, conducted between 1986 and 1994, was to explore the feasibility and acceptability of classifying ALL in this manner for selection of treatment rather than using conventional risk for failure factors such as age and initial white blood cell count. The possibility that conventional risk factors would be overcome and survival improved by this approach was also considered. Flow cytometry and chromosome analysis were used to classify the ALL of 150 children into one of five biologic categories as defined by cell surface antigens, DNA index and chromosome number and arrangement. Chemotherapy regimens depended on the assigned category. There was no provision for cranial irradiation and use of alkylating agents, anthracyclines and epipodophyllotoxins was restricted in order to reduce risk of late adverse sequelae. All patients are included in the analysis regardless of presenting condition or adherence to protocol. The majority of patients were Mexican-American or African-American. Eight-year event-free survival (EFS) is 60.7% (+/-4%) and 8-year overall survival (OAS) 72.6% (+/-3.7%). EFS and OAS varied significantly among the biologic categories despite differences in chemotherapy regimens. When the patients with B-precursor ALL were retrospectively classified by current Pediatric Oncology Group (POG) criteria, 8-year EFS was 82% (+/-7.3%) for the good risk group, 68.9% (+/-5.9%) for the standard risk and 48.8% (+/-7.6%) for the poor risk, all significant differences. However, when retrospectively classified according to the Rome/NCI prognostic criteria the 8-year EFS for standard risk patients was 69.1% (+/-5.1%) and for high risk 58.8% (+/-6.9%), not a statistically significant difference. Numbers of T cell and B cell patients are too few for comparison. Gender and ethnicity influenced survival as in treatment based on prognostic factors. Initial central nervous system (CNS) relapse occurred in five patients (3%) and combined CNS and hematological relapse in six (3%). Factors significantly associated with CNS and combined relapse were leukemic pleocytosis in the initial CSF sample, pro-B immunophenotype and DNA index <1.16, but not initial white blood cell count. Only three survivors appear to have serious late adverse sequelae, the only neurologic the result of asparaginase-induced cortical vein thrombosis. The results suggest that use of biologic species as defined by immunophenotype and genotype to select therapy of ALL is feasible and acceptable but under the conditions of these studies offered no apparent therapeutic advantage over conventional risk grouping. However, the introduction of molecular genotyping and novel gene targeted therapeutic agents justify further exploration of this approach.     

Long-term results of three randomized trials (58831, 58832, 58881) in childhood acute lymphoblastic leukemia: a CLCG-EORTC report. Children Leukemia Cooperative Group.

We present here the long-term results of three randomized clinical trials conducted on children with newly diagnosed acute lymphoblastic leukemia (ALL) between 1983 and 1998 by the Children Leukemia Cooperative Group (CLCG) from EORTC. In study 58831/32, the overall event-free survival (EFS) rates (+/- s.e.) at 6 and 10 years were 66% +/- 1.8% and 65% +/- 1.8%, respectively, and the risk of isolated central nervous system (CNS) relapse was 6% +/- 1% and 7% +/- 1%, respectively. In patients with a standard risk of relapse the omission of cyclophosphamide had no adverse effect on disease-free survival rates at 10 years (trial 58831). In medium- and high-risk patients the omission of radiotherapy did not increase the risk of CNS or systemic relapse (trial 58832). In study 58881 (1989-1998) the overall EFS rate at 8 years was 68.4% +/- 1.2% and the risk of isolated CNS relapse was 4.2%+/-0.5%. In this trial which adressed three randomized questions, the following results were obtained: the combination of cytarabine at high doses with methotrexate at high doses during interval therapy did not improve prognosis. The addition of 6-mercaptopurine iv during maintenance increased the risk of late relapse. E. coli asparaginase was more toxic and has a higher efficacy than Erwinia asparaginase. Leukocyte counts >100 x 10(9)/l, specific genetic abnormalities, a poor initial response to steroids or a high level of minimal residual disease at early time points were consistently associated with an adverse prognosis in the 58881 trial.     

Childhood T-cell acute lymphoblastic leukemia: the Dana-Farber Cancer Institute acute lymphoblastic leukemia consortium experience.

PURPOSE: T-cell acute lymphoblastic leukemia (T-ALL) accounts for 10% to 15% of newly diagnosed cases of childhood acute lymphoblastic leukemia (ALL). Historically, T-ALL patients have had a worse prognosis than other ALL patients. PATIENTS AND METHODS: We reviewed the outcomes of 125 patients with T-ALL treated on Dana-Farber Cancer Institute (DFCI) ALL Consortium trials between 1981 and 1995. Therapy included four- or five-agent remission induction; consolidation therapy with doxorubicin, vincristine, corticosteroid, mercaptopurine, and weekly high-dose asparaginase; and cranial radiation. T-ALL patients were treated the same as high-risk B-progenitor ALL patients. Fifteen patients with T-cell lymphoblastic lymphoma were also treated with the same high-risk regimen between 1981 and 2000. RESULTS: The 5-year event-free survival (EFS) rate for T-ALL patients was 75% +/- 4%. Fourteen of 15 patients with T-cell lymphoblastic lymphoma were long-term survivors. There was no significant difference in EFS comparing patients with T-ALL and B-progenitor ALL (P =.56), although T-ALL patients had significantly higher rates of induction failure (P <.0001), and central nervous system (CNS) relapse (P =.02). The median time to relapse in T-ALL patients was 1.2 years versus 2.5 years in B-progenitor ALL patients (P =.001). There were no pretreatment characteristics associated with worse prognosis in patients with T-ALL. CONCLUSION: T-ALL patients fared as well as B-progenitor patients on DFCI ALL Consortium protocols. Patients with T-ALL remain at increased risk for induction failure, early relapse, and isolated CNS relapse. Future studies should focus on the identification of and treatment for T-ALL patients at high risk for treatment failure.     

Long-term outcome in children with relapsed ALL by risk-stratified salvage therapy: results of trial acute lymphoblastic leukemia-relapse study of the Berlin-Frankfurt-Münster Group 87.

PURPOSE: Approximately 20% of children with acute lymphoblastic leukemia (ALL) suffer a relapse, and their prognosis is unfavorable. Between 1987 and 1990, the multicenter trial Acute Lymphoblastic Leukemia-Relapse Study of the Berlin-Frankfurt-Münster Group (ALL-REZ BFM) 87 was conducted to establish a uniform treatment for these children in Germany and Austria. PATIENTS AND METHODS: Of 207 registered patients, 183 patients were stratified into three groups according to the protocol: A, early bone marrow (BM) relapse (n = 56); B, late BM relapse (n = 101); C, isolated extramedullary relapse (n = 26). Treatment consisted of risk-adapted alternating short-course multiagent systemic and intrathecal chemotherapy, cranial irradiation, if indicated, and conventional maintenance therapy. Additionally, 24 patients with an exceptionally poor prognosis (early BM or any relapse of T-cell ALL) were treated with individual regimens. In 35 patients, stem-cell transplantation was performed. RESULTS: The probability of event-free survival (EFS) and overall survival of all registered patients at 15 years was 0.30 +/- 0.03 and 0.37 +/- 0.03, respectively, with significant differences between the strategic groups (A, 0.18 +/- 0.05 and 0.20 +/- 0.05; B, 0.44 +/- 0.05 and 0.52 +/- 0.05; C, 0.35 +/- 0.09 and 0.42 +/- 0.10). Despite risk-adapted treatment, an early time point of relapse and T-lineage immunophenotype were significant predictors of inferior EFS in uni- and multivariate analyses. CONCLUSION: With the ALL-REZ BFM 87 protocol, more than one-third of patients may be regarded as cured from recurrent ALL with second complete remissions lasting more than 10 years. Immunophenotype and time point of relapse are important prognostic factors that allow us to adapt more precisely treatment intensity to individual prognosis in future trials.     

Effective preventive central nervous system therapy with extended triple intrathecal therapy and the modified ALL-BFM 86 chemotherapy program in an enlarged non-high risk group of children and adolescents with non-B-cell acute lymphoblastic leukemia: the Israel National Study report

BACKGROUND: Preventive cranial radiotherapy (CRT) in childhood acute lymphoblastic leukemia (ALL), although effective, may be associated with neurologic sequelae and second malignancies. Attempts to replace CRT with intensified intrathecal therapy (IT) have shown promise in lower risk subgroups. In the Israel National Study (INS) 89 trial, the efficacy of extended triple IT (TIT) alone for cranial prophylaxis in an enlarged non-high risk group (Non-HRG) was assessed in the context of a modified ALL-Berlin-Frankfurt-Munster (BFM) systemic chemotherapy program. METHODS: Non-HRG patients included the standard-risk group (SRG) and the risk group (RG), as defined in ALL-BFM 86. In the INS 89 protocol, all Non-HRG patients were treated with extended TIT x 18 times and systemic therapy based on the BFM 86 protocol, with the addition of etoposide x 4 times. The HRG patients, classified according to BFM 86 criteria, were treated with the BFM 90 HRG protocol including CRT. RESULTS: A total of 250 patients were enrolled. At a median follow-up of 58 months (range, 2-8.5 years), the overall 5-year event free survival (EFS) was 73.5% +/- 3% (standard error ?SE), and the cumulative central nervous system (CNS) recurrence rate was 4.3% +/- 1.4% (SE) (isolated, 2.3%; combined, 2%). Of the 220 eligible children, 189 (86%) were in the Non-HRG group, and their 5-year EFS was 77.8% +/- 3% (SE). The cumulative CNS recurrence rate for patients without CNS disease at presentation was 3.1% +/- 1% (SE) (isolated, 1.7%; combined, 1.4%). Within the risk subsets defined by the BFM 86 of the Non-HRG, the 5-year EFS rates of the RG (148 patients) and the SRG (41 patients) were 74.8% +/- 4% (SE) and 89.5% +/- 5% (SE), respectively, and the rates of CNS recurrence (isolated and combined) were 4% and 0%, respectively. For the HRG (31 patients), the 5-year EFS and CNS recurrence rates were 47.9% +/- 9% (SE) and 8. 5% +/- 6% (SE), respectively. CONCLUSIONS: Early extended TIT therapy in the context of modified BFM 86 systemic chemotherapy was found to provide adequate CNS protection and systemic leukemia control in patients with non-high risk ALL. However, no benefit for etoposide could be proven in this study.     

Six months of maintenance chemotherapy after intensified treatment for acute lymphoblastic leukemia of childhood.

PURPOSE: We postulated that intensification of chemotherapy immediately after remission induction might reduce the leukemic cell burden sufficiently to allow an abbreviated period of antimetabolite therapy. PATIENTS AND METHODS: Three hundred forty-seven children (ages 1 to 15 years) with previously untreated acute lymphoblastic leukemia (ALL) were enrolled onto the Tokyo L92-13 study, which excluded patients with mature B-cell ALL and patients less than 1 year old. One hundred twenty-four patients were classified as standard risk, 122 as high risk, and 101 as extremely high risk, according to age, peripheral-blood leukocyte count, selected genetic abnormalities, and immunophenotype. All subjects received four drugs for remission induction, followed by a risk-directed multidrug intensification phase and therapy for presymptomatic leukemia in the CNS. Maintenance chemotherapy with oral mercaptopurine and methotrexate was administered for 6 months, with all treatment stopped by 1 year after diagnosis. RESULTS: The mean (+/- SD) event-free survival (EFS) and overall survival rates for all patients were 59.5% +/- 3.4% and 81.5% +/- 2.2%, respectively, at 5. 5 years after diagnosis. EFS rates by risk category were similar (60. 2% +/- 6.0% for standard risk, 57.7% +/- 5.6% for high risk, and 62. 5% +/- 5.7% for extremely high risk), whereas overall survival rates differed significantly (91.2% +/- 2.7%, 80.0% +/- 4.1%, and 72.1% +/- 4.5%, respectively, P <.0001 by the log-rank test). There were 107 relapses. Eighty-five (79.4%) of these 107 patients achieved second complete remissions, with subsequent EFS rates of 61.5% +/- 7. 9% (standard risk), 42.6% +/- 8.1% (high risk), and 9.6% +/- 6.4% (extremely high risk). Of the five risk factors analyzed, only the response to prednisolone monotherapy among extremely high-risk patients proved important. CONCLUSION: Early treatment intensification did not compensate for a truncated phase of maintenance chemotherapy in children with standard- or high-risk ALL. However, 6 months of antimetabolite treatment seemed adequate for extremely high-risk patients who were good responders to prednisolone and received intensified chemotherapy that included high-dose cytarabine early in the clinical course.     

Management of advanced acute lymphoblastic leukemia in children and adults: results of the ALL R-87 protocol. AIEOP and GIMEMA Cooperative Groups

Fifty-seven patients aged < 55 years with acute lymphoblastic leukemia (ALL) in second or third bone marrow (BM) relapse or refractory to first-line therapy were enrolled in an Italian cooperative study. The ALL R-87 protocol included idarubicin (IDA) plus intermediate dose cytarabine (IDARA-C) and Prednisone (PDN) as induction, followed by a consolidation phase and BMT. Complete remission (CR) was achieved in 41/57 patients (72%). The CR rate was significantly higher in patients aged < 15 years at diagnosis and at time of treatment compared to those aged > or = 15 (84% vs 50%, p=0.01 and 85% vs 54%, p = 0.02, respectively). Nineteen of 41 responders (46.3%) underwent bone marrow transplant (BMT) (10 autologous and 9 allogeneic). The estimated probabilities of event free survival (EFS +/- SE) and survival +/- SE at 6 years were 0.13 +/- 0.05 and 0.20 +/- 0.06, respectively, for all enrolled patients. Univariate analysis showed that children had a better EFS rate compared to adults (0.16 +/- 0.07 vs 0.08 +/- 0.07, p = 0.014). The estimated probability of disease free survival (DFS +/- SE) at 6 years was 0.18 +/- 0.07 for all responders. No differences in DFS were observed between patients submitted to allogeneic or autologous BMT (0.33 +/- 0.16 vs 0.25 +/- 0.15). Among patients treated in second or third relapse, a first CR length > or = 48 months favorably influenced both DFS (p = 0.014) and EFS (p = 0.018). Our results show the efficacy of the intermediate dose ARA-C plus IDA schedule for high risk adult and childhood ALL patients. No differences in disease outcome were observed between allogeneic and autologous BMT.     

Treatment of acute lymphoblastic leukemia in Hong Kong children: HKALL 93 study

A population-based multicentre study for childhood acute lymphoblastic leukemia (ALL) was conducted in Hong Kong from 1993 to 1997. One hundred and forty-five newly diagnosed ALL patients were treated by the HKALL 93 protocol. Patients were stratified into three risk groups according to age, presenting white cell count, immunophenotyping and cytogenetic study. The patients received the same induction and early and late intensification at week 5 and week 20. Fifty-eight standard risk (SR) patients received regular intrathecal methotrexate as CNS preventive therapy, while 49 intermediate risk (IR) patients received high dose intravenous methotrexate and regular intrathecal methotrexate. Thirty-eight high risk (HR) patients were treated with prophylactic cranial irradiation and an additional intensification block at week 35. The induction remission rate was 97.2% with 2% induction death. Two patients died during first complete remission. Relapse occurred in 20.7, 42.9 and 42.1% of SR, IR and HR patients respectively. By multivariate logistic regression, age> or =10 years and white cell count> or =100 x 10(9)/l were the two significant variables accounting for mortality. The 5-year overall and event-free survival of the whole group was 81.3 and 62.6% respectively. According to risk groups, the event-free survival was 79, 49 and 61% for SR, IR and HR patients respectively, while the overall survival was 96, 73 and 68% for SR, IR and HR patients respectively. In conclusion, the treatment protocol had low treatment-related mortality but was associated with a rather high relapse rate, especially in IR patients. Salvage therapy achieved sustained second remission in some patients. More intensive treatment especially a late intensification is required to improve the outcome.     

Resultados del tratamiento a largo plazo de 209 niños con leucemia linfoblástica aguda: experiencia de un grupo multicéntrico en Venezuela

Introduction

We present the results of the treatment of 209 children suffering from acute lymphoblastic leukaemia (ALL) using th 87-01 treatment protocol from the Dana Farber Cancer Institute (DFCI), modified by the Instituto Venezolano de los Seguros Sociales Cooperative Group (IVSS-CG). Protocol 87-01 IVSS-CG is a prospective multi-centred trial for the treatment of children with newly-diagnosed ALL. Our goals were to compare event-free survival (EVS) in a group treated with doxorubicin (dox) at 30 mg/m² versus a group treated with epirubicin (epi) at 40 mg/m² and to evaluate the use of radiotherapy (XRT) of 18 Gy + met-hotrexate (mtx) intrathecal (IT) administered and IT cytarabine (IT-Ara-C). The original protocol recommended using 24 Gy + IT mtx.

Materials and methods

Between 1989 and 1998, 209 patients were treated. They were classified into three groups of standard risk (SR), high risk (HR) and very high risk (VHR) according to the DFCI ALL protocol. Induction treatment phase: all groups received asparaginase (asp), vincristine (vcr), prednisone (pred), epirubicin (epi) or doxorubicin (dox) and IT Ara-C. The SR patients received mtx 40 mg/m² and the HR and the VHR groups received high dose mtx of 4 g/m². The CNS prophy-laxis in SR was mtx IT and 18 Gy irradiation of the cranium, while the HR and VHR groups received mtx + Ara-c IT + 18 Gy. Intensification treatment phase: SR group received vcr; pred, 6-mercatopurine (6-MP) every 3 weeks plus mtx and asp weekly for 20 weeks. The HR and VHR groups received asp weekly up to the cumulative toxic doses of dox or epi. The VHR group received an initial phase of intensification with high dose mtx and Ara-C. The maintenance in all groups was with POMP until 24 months of continuous complete remission.

Results

There were 80 patients (38%) classified as SR, 102 (49%) as HR and 27 (13%) as VHR. With a median follow-up of 8 years, the 8-year disease-free survival (DFS) was 68% ± 4% (DFS ± SE) for all patients, 72% ± 4% of the 80 SR patients, 62% ± 4% for the 102 HR patients and 63% ± 11% for the 27 VHR patients. Comparison of DFS between groups (SR vs. HR vs. VHR) indicated a Chi² of 3.35 which was not statistically significant (p=0.18). The DFS was 62% for the 72 patients who received dox and which was similar to that of the 57 patients who received epi.

Conclusions

There were no statistically significant differences in results between the patients receiving dox and those receiving epi (p=0.79). Radiation at 18 Gy was as effective as 24 Gy in preventing CNS involvement.     

Long-term results of Total Therapy studies 11, 12 and 13A for childhood acute lymphoblastic leukemia at St Jude Children's Research Hospital.

We present the long-term results of three consecutive clinical trials (Total Therapy studies 11, 12 and 13A) conducted for children with newly diagnosed acute lymphoblastic leukemia (ALL) between 1984 and 1994. In study 11 (1984-1988), the overall event-free survival rates (+/-1 s.e.) were 71.8 +/- 2.4% and 69.3 +/- 2.4%, and the cumulative risks of isolated central nervous system (CNS) relapse 5.6 +/- 1.2% and 5.9 +/- 1.3%, at 5 and 10 years, respectively. In study 12 (1988-1991), event-free survival rates were 67.6 +/- 3.4% and 61.5+/- 9.0%, and isolated CNS relapse rates were 10.4 +/- 2.3% and 10.4 +/- 2.3%, respectively. Early intensive intrathecal therapy in study 13A (1991-1994) has yielded a very low 5-year isolated CNS relapse rate of 1.2 +/- 0.9%, boosting the 5-year event-free survival rate to 76.9 +/- 3.3%. Factors consistently associated with an adverse prognosis included male sex, infant or adolescent age group, leukocyte count >100 x 10(9)/l, nonhyperdiploidy karyotype and poor early response to treatment. Risk classification based on age and leukocyte count had prognostic significance in B-lineage but not T-lineage ALL. Early therapeutic interventions or modifications for patients with specific genetic abnormalities or persistent minimal residual leukemia may further improve long-term results.     

Delay of the diagnostic lumbar puncture and intrathecal chemotherapy in children with acute lymphoblastic leukemia who undergo routine corticosteroid testing: Tokyo Children's Cancer Study Group study L89-12.

PURPOSE: To determine the effects of eliminating initial lumbar punctures in 418 consecutively treated children with acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Patients were enrolled onto a trial conducted in central Japan between 1989 and 1992. Treatment consisted of standard four-drug induction therapy followed by a risk-based intensification phase, reinduction therapy, late intensification, and remission maintenance therapy (total of 104 weeks). The initial lumbar puncture, with an intrathecal injection of chemotherapy, was performed after 1 week of prednisolone sensitivity testing (day 8). End points included response to prednisolone, CNS status at the time of the day 8 lumbar puncture, subsequent adverse events in CNS and bone marrow, and event-free survival (EFS). RESULTS: The remission induction rate was 93.1% with a 6-year EFS rate (+/- SE) of 68.7% +/- 2.4%, which is similar to historical results for patients who received their diagnostic lumbar puncture and first instillation of intrathecal chemotherapy on day 0. Overall, 84.5% of the patients had good responses to prednisolone, whereas 15.5% had poor responses. Clinical outcome was strikingly better for the good responders (6-year EFS, 74.1% +/- 2.5% compared with 40.1% +/- 6.4% for patients with poor responses), suggesting that omission of intrathecal chemotherapy did not alter the predictive value of drug sensitivity testing. Eighteen patients experienced CNS relapse as their first adverse event (cumulative risk, 5.1%; 95% confidence interval, 2.7% to 7.4%), coincident with reports from groups using conventional strategies of CNS clinical management. Bleeding into the CSF at the time of the day 8 lumbar puncture was apparent in 29 cases (8.1%), but leukemic blasts were identified in only two. CONCLUSION: Delay of the initial lumbar puncture and intrathecal injection of chemotherapy seems to be feasible in children with ALL. Further controlled evaluations are needed to establish the validity of this conclusion.     

儿童急性淋巴细胞白血病在德国的治疗--COALL-92方案521例临床及疗效分析

目的：总结分析德国应用ＣＯＡＬＬ－９２方案（Ｃooperative mrlticenter treatment strdy for childhood with acute lymphoblastic leukemia of the German Pediatric Oncology and Hematology Society ＣＯＡＬＬ－９２－Ｓtudy/ＧＰＯＨ）治疗儿童急性淋巴细胞白血病的临床疗效。方法：１９９２～１９９７年间在德国１９所儿童 肿瘤治疗中心人同合作采用统一的诊断标准及治疗方案（ＣＯＡＬＬ－９２－ＳＴＵＤＹ/ＧＰＯＨ）治     

Patient stratification based on prednisolone-vincristine-asparaginase resistance profiles in children with acute lymphoblastic leukemia.

PURPOSE: To confirm the prognostic value of a drug resistance profile combining prednisolone, vincristine, and l-asparaginase (PVA) cytotoxicity in an independent group of children with acute lymphoblastic leukemia (ALL) treated with a different protocol and analyzed at longer follow-up compared with our previous study of patients treated according to the Dutch Childhood Leukemia Study Group (DCLSG) ALL VII/VIII protocol. PATIENTS AND METHODS: Drug resistance profiles were determined in 202 children (aged 1 to 18 years) with newly diagnosed ALL who were treated according to the German Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia (COALL)-92 protocol. RESULTS: At a median follow-up of 6.2 years (range, 4.1 to 9.3 years), the 5-year disease-free survival probability (pDFS) rate +/- SE was 69% +/- 7.0%, 83% +/- 4.4%, and 84% +/- 6.8% for patients with resistant (PVA score 7 to 9), intermediate-sensitive (PVA score 5 to 6), and sensitive (SPVA score 3 to 4) profiles, respectively (sensitive and intermediate-sensitive v resistant, P 相似文献   

A classification based on T cell selection-related phenotypes identifies a subgroup of childhood T-ALL with favorable outcome in the COALL studies.

During T cell selection in the thymic cortex more than 90% of the thymocytes are eliminated by apoptosis. Based on this biology, we propose to define blasts of T cell acute lymphoblastic leukemia (ALL) with the phenotype of cortical thymocytes (CD1+ and/or CD4+ 8+) as selection-related (SR) and all other T-ALL immunophenotypes as non-selection-related (NSR). The COALL cooperative treatment studies for childhood ALL offer a tool to study the outcome in T-ALL subgroups as children with T-ALL are allocated uniformly to the high risk arm of the protocol. In the COALL-85, -89 and -92 protocols, 39/83 cases presented as SR and 44/83 cases as NSR. Five-year event-free survival of SR phenotype is significantly better compared to the NSR group (0.87 +/- 0.06 vs 0.66 +/- 0.07, log rank test, P = 0.01). T-ALL with SR phenotype is a distinct subgroup of leukemia with excellent prognosis under a high risk treatment protocol.     

Bone marrow leukemic progenitor cell content in pediatric T-lineage acute lymphoblastic leukemia patients with an isolated extramedullary first relapse.

Isolated extramedullary relapse in childhood acute lymphoblastic leukemia (ALL) is associated frequently with the T-lineage immunophenotype and may be accompanied by occult bone marrow disease. We employed highly sensitive multiparameter flow cytometry and blast colony assays to quantify the leukemic progenitor cell (LPC) burden in the pretreatment bone marrows of 15 pediatric T-lineage ALL patients with an isolated extramedullary first relapse. Sites of extramedullary relapse were CNS (11 patients), testes (3 patients), and both CNS and testes (1 patient). Bone marrow LPC were detectable in 8 patients (53%) and undetectable in 7 patients (47%) at day 0 of post-relapse induction therapy, with LPC counts ranging from 0/10(6) mononuclear cells (MNC) to 518/10(6) MNC (mean +/- SEM, 50+/-34/10(6) MNC). Five of 9 patients with an early relapse (< 18 months after achieving a first complete remission [CR1]) and 3 of 6 patients with a late relapse (> or = 18 months from CR1) had detectable bone marrow LPC at day 0. Five of 8 patients with NCI-defined poor risk ALL and 3 of 7 patients with NCI-defined standard risk ALL had detectable LPC at day 0. Following post-relapse induction chemotherapy. LPC counts were detectable in bone marrows of 4 of 6 evaluated patients. Thus, approximately half of the extramedullary relapse T-lineage ALL patients studied had substantial occult involvement of the bone marrow. These findings may partly explain the previously observed poor prognosis of T-lineage patients following a CNS relapse.