Methotrexate polyglutamation may lack prognostic significance in children with B-cell precursor acute lymphoblastic leukemia treated with intensive oral methotrexate

BACKGROUND: The purpose of this study was to determine if a correlation exists between clinical outcome and accumulation and polyglutamation of methotrexate by lymphoblasts in vitro in children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). PATIENTS AND METHODS: The amount of accumulated methotrexate and of long-chain methotrexate polyglutamates (MTXPG(3-7)) by lymphoblasts was determined in 52 children newly diagnosed with BCP-ALL after incubation with 1 micromol/L [(3)H]MTX for 24 hours in vitro. All patients then received intensive multiagent chemotherapy that used divided-dose oral methotrexate during consolidation and intensive continuation and standard oral weekly methotrexate during maintenance. RESULTS: Eight patients had a bone marrow relapse at a median of 40.4 months (range 18.5-48.3 months) after diagnosis. The median follow-up for the remaining 44 patients is 69.0 months (range 22-92.8 months). There was no significant difference in the amount of accumulated methotrexate (1450.0 +/- 896.3 vs. 640 +/- 472.5 pmol/10 cells) or of accumulated MTXPG (1450.0 +/- 919.4 vs. 617.4 +/- 482.7 pmol/10(9) cells) (median +/- semi-interquartile ranges) between patients who relapsed and those who remained in continuous complete remission. The estimated 5-year event-free survival rate for patients whose lymphoblasts accumulated more than 500 pmol MTXPG(3-7)/10(9) cells was 80.0% +/- 7.3% versus 90.5% +/- 6.4% for those whose lymphoblasts accumulated less than 500 pmol MTXPG(3-7)/10(9) cells. CONCLUSIONS: In the context of effective prolonged divided-dose oral methotrexate-based therapy in the treatment of BCP-ALL, methotrexate accumulation and polyglutamation no longer seem to have prognostic significance.     

Monitoring of inosine monophosphate dehydrogenase activity in mononuclear cells of children with acute lymphoblastic leukemia: enzymological and clinical aspects

BACKGROUND: Inosine 5'-monophosphate dehydrogenase (IMPDH; EC1.1.1.205) catalyzes the rate-limiting step in guanine nucleotide biosynthesis, and may play an important role in treatment of patients with antipurines. METHODS: We used an HPLC method to measure the IMPDH activity in peripheral blood and bone marrow mononuclear cells (MNC). IMPDH activities were determined in children who were diagnosed with and treated for acute lymphoblastic leukemia (ALL), and in a group of control children. RESULTS: The median IMPDH activity for control children was 350 pmol/10(6) pMNC/hr (range 97-896; n = 47). No gender or age differences were observed. IMPDH activity at diagnosis of ALL was correlated with the percentage of peripheral blood lymphoblasts (r = 0.474; P < 0.001; n = 71). The median IMPDH activity at diagnosis was 410 pmol/10(6) pMNC/hr (range 40-2009; n = 76), significantly higher than for controls (P = 0.012). IMPDH activity significantly decreased after induction treatment, and during treatment with methotrexate (MTX) infusions (median 174 pmol/10(6) pMNC/hr; range 52-516; n = 21). The activity remained low during maintenance treatment with 6-mercaptopurine (6MP) and MTX, at a significantly lower level than for controls (P < 0.004). One year after cessation of treatment IMPDH activity returned to normal values. CONCLUSION: The decrease of IMPDH activity at remission of ALL seems to be at least partly due to the eradication of lymphoblasts with the type 2 isoform of the enzyme.     

Morphologic changes in blast cells of children with acute lymphoblastic leukemia in relapse

Relapse in children with acute lymphoblastic leukemia (ALL) on therapy may be due to development of a resistant clone of blast cells. Seven children who presented initially with the "common"-type, L1 lymphoblast relapsed with a morphologically different and more undifferentiated blast cell. All were male, with a median age of 12 years at initial presentation. One child who relapsed while off therapy was successfully reinduced and remains in hematologic remission on therapy. The remaining 6 children died within 10 months of relapse. Selection of a resistant clone of lymphoblasts by chemotherapy may be responsible for relapse in children with ALL and should be studied in hopes of controlling the disease.     

Plasma methotrexate, red blood cell methotrexate, and red blood cell folate values and outcome in children with precursor B-acute lymphoblastic leukemia: a report from the Children's Oncology Group

Plasma steady state methotrexate (MTX) level and red blood cell (RBC) MTX and folate concentrations were evaluated in 1124 children with newly diagnosed acute lymphoblastic leukemia enrolled in the Pediatric Oncology Group studies 9005 (lower risk; Regimens A and C) and 9006 (higher risk; Regimen A). These regimens included intermediate-dose MTX (1 g/m) given as a 24 hours infusion every other week for 12 doses during intensification. Plasma MTX level was evaluated at the end of MTX infusions. RBC MTX and folate concentrations were measured at the end of intensification. The 5 year continuous complete remission was 76±1.4% versus 85±3.0% for those patients with steady state MTX levels less than or equal to and greater than 14 μM, respectively (P=0.0125). Hispanic children had significantly reduced median steady state MTX levels, 8.7 μM, compared with non-Hispanic children, 9.95 μM (P=0.0015), but this did not correlate with a difference in outcome. Neither RBC MTX, RBC folate, nor the RBC MTX:folate ratio identified children at increased risk of failure.     

Impact of TCF3 Rearrangement on CNS Relapse in Egyptian Pediatric Acute Lymphoblastic Leukemia

Background: TCF3 rearrangement mostly t(1;19) (q23;p13)/ TCF3-PBX1 gene is associated with favorable outcome in acute lymphoblastic leukemia (ALL) upon treatment with intensification protocols; however, it is associated with higher incidence of central nervous system (CNS) relapse which may affect outcome of patients. Objectives: We aimed to assess TCF3 rearrangement in newly diagnosed pediatric ALL patients in relation to clinical and laboratory parameters, CNS relapse, and clinical outcome. Patients and Methods: Eighty newly diagnosed pediatric ALL patients following at Pediatric Hematology Oncology Clinic, Ain Shams University Hospitals were included in this study. Their ages ranged from 0.75 to 16 years. Seventy six (95%) patients had B-lineage ALL and four (5%) had T-lineage ALL. Data recorded included; age, sex, extramedullary manifestations, CNS, and testes infiltrations, risk stratification, response to treatment, and CBC and BM findings. TCF3 rearrangement was assessed by FISH technique using dual color break-apart probe. Results: TCF3 rearrangement [t(1;19) (q23;p13)] was detected in 16 (20%) out of the 80 studied patients, and it was significantly associated with splenomegaly, lymphadenopathy, CNS infiltration at presentation, high total leucocytic count, low platelet count, high-risk group, and isolated CNS relapse. These results identify a group of high-risk ALL patients with high incidence of CNS relapse and poor response to standard therapeutic regimen. Conclusion: Analysis of TCF3 rearrangement [t(1;19) (q23;p13)] at diagnosis may provide a valuable target for modified and intensified CNS-directed chemotherapeutic protocol aiming to improve the patients’ outcome.     

Biopterin and neurotransmitter amine metabolism in children with acute lymphoblastic leukemia receiving methotrexate therapy

To test the hypothesis that some of the neurologic sequelae of treatment for acute lymphoblastic leukemia (ALL) might be related to abnormalities in biopterin metabolism associated with methotrexate (MTX) therapy, total biopterin levels in cerebrospinal fluid (CSF) and plasma, and homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5HIAA) were measured in a cross-sectional study of 80 children with ALL. For comparison, biopterins were also measured in a group of children of similar age undergoing investigation for neurologic disease. In children with ALL studied before therapy, no significant difference was found between the means of plasma biopterin or CSF biopterin concentrations and the means in the control group. In children receiving MTX, plasma biopterin values were higher in the group given maintenance therapy than in children observed before treatment. CSF levels were significantly increased only in those patients who had completed 2 years of maintenance therapy. CSF concentrations of HVA and 5HIAA in patients with ALL who had received no treatment (median values 52 and 18 ng/ml, respectively) showed a wide scatter and were inversely related to age. In patients receiving MTX, concentrations of these metabolites were higher than in the untreated group, again reaching a peak in patients just completing 2 years of treatment (median HVA 110 ng/ml, 5HIAA 34 ng/ml). These results provide no support for the idea that neurotransmitter amine deficiency occurs in children with ALL receiving MTX, and indicate, rather, that amine and biopterin synthesis increases in such patients.     

High-dose methotrexate improves clinical outcome in children with acute lymphoblastic leukemia: St. Jude Total Therapy Study X

High-dose methotrexate (HDMTX, 1,000 mg/m2) and cranial irradiation/sequential chemotherapy (RTSC) were compared for ability to extend complete remission durations in children with acute lymphoblastic leukemia (ALL). Three hundred thirty patients were enrolled in the study, according to our criteria for standard-risk ALL: a leukocyte count less than 100 X 10(9)/L, no mediastinal mass, no leukemic involvement of the central nervous system (CNS), and blast cells lacking sheep erythrocyte receptors and surface immunoglobulin. Prednisone-vincristine-asparaginase induced complete remissions in 95% of the patients, who were then randomized to receive either HDMTX (n = 154) or RTSC (n = 155). HDMTX was administered with intrathecal MTX for the first 3 weeks following remission induction, and then every 6 weeks with daily mercaptopurine (MP) and weekly oral MTX for a total of 18 months. The RTSC regimen consisted of 1,800 cGy cranial irradiation and intrathecal MTX for 3 weeks, followed by MP/MTX, cyclophosphamide/doxorubicin, and teniposide/cytarabine administered sequentially over 18 months. The final 12 months of treatment for both groups was MP and oral MTX; all patients received intrathecal MTX every 12 weeks. With a median follow-up of 5 years, complete remission durations have been significantly longer among children treated with HDMTX, compared with RTSC (P = .049) or historical institutional control regimens (P = .002). Approximately 67% of the patients receiving HDMTX and 56% of those receiving RTSC are expected to be in continuous complete remission at 4 years. Overall, isolated CNS relapse rates were similar (P = .17) in the two treatment groups, although by newer risk criteria cranial irradiation could be expected to provide better protection in patients with an unfavorable prognosis. These findings indicate that addition of intermittent HDMTX infusions to conventional chemotherapy is an effective method for extending complete remissions in children with ALL.     

伴有t(12;21)易位的儿童急性淋巴细胞白血病的临床和实验研究

目的　研究我国儿童急性淋巴细胞白血病 (ALL)中伴有t(12 ;2 1)易位者的发生率及其临床、免疫学和预后的特征。方法　采用套式逆转录聚合酶链反应 (RT PCR)技术检测TEL AML1融合基因转录本 ,联合染色体R带核型分析和流式细胞仪免疫表型分析等方法。结果　在 5 5例儿童ALL(B系ALL 40例 ,T系ALL 13例 ,T、B系双表达ALL 2例 )中共发现 8例 (2 0 % )B系ALL有TEL AML1融合基因转录本 ,证实有t(12 ;2 1)易位存在。治疗后 8例均获完全缓解 (CR) ,随访至 1999年 5月 ,均在CR中 ,无一例复发。结论　t(12 ;2 1)B系ALL是儿童ALL中最多见且预后较好的一种亚型。RT PCR检测TEL AML1融合基因转录本是诊断t(12 ;2 1)ALL和监测其微小残留病最敏感有效的方法。     

Randomized comparison of moderate-dose methotrexate infusions to oral methotrexate in children with intermediate risk acute lymphoblastic leukemia: A Childrens Cancer Group study

Methotrexate (MTX) infusions of 500–1,000 mg/m² over 24 hours may improve survival and prevent relapse in children with acute lymphoblastic leukemia (ALL). Childrens Cancer Group (CCG) Study 139 compared weekly oral methotrexate 20 mg/m²/week (oral MTX) to MTX 500 mg/m² infused over 24 hours (IV MTX) three times during consolidation and every 6 weeks during maintenance in 164 children with intermediate-risk ALL, i.e., those patients over age 1 year with white blood cell count 10,000 to 49,999/ml and no bulky extramedullary disease. Median follow-up for CCG-139 exceeded 75 months. Thirty-four events occurred among 80 patients receiving IV and oral MTX and 36 events among 84 patients receiving oral MTX. Two children died during induction and one did not enter remission. Remission induction rate is 98%. There have been 26 marrow relapses, 11 combined marrow and extramedullary relapses, 24 CNS relapses, and five testicular or other relapses. The frequency and distribution of relapses does not differ between the two regimens. For the entire group, overall event-free survival (EFS) at 6 years is 57.9% (standard deviation = 4.0%) and actuarial survival is 80.0% (standard deviation = 3.3%). Of the 29 patients with isolated extramedullary relapse, 18 survive free of a second event, a median of 42 months from relapse. In contrast to other trials, this trial does not show that IV MTX in this dose and schedule offers an advantage over standard therapy for this group of children. © 1996 Wiley-Liss, Inc.     

Folic acid supplements in vitamin tablets: a determinant of hematological drug tolerance in maintenance therapy of childhood acute lymphoblastic leukemia

Methotrexate (MTX) is an antifolate that inhibits cell division by reducing intracellular amounts of reduced tetrahydrofolates. Of 53 children with acute lymphoblastic leukemia (ALL) in maintenance treatment with MTX and 6-mercaptopurine (6-MP), 25 had received daily folic acid supplements in vitamin tablets containing 75-200 micrograms folic acid for at least the preceding 3-month period. Experimental data have shown that increased folate concentrations intracellularly inhibit MTX metabolism and toxicity. Therefore we found it relevant to investigate the extent to which folic acid supplements affect hematological tolerance to MTX and 6-MP in children during maintenance therapy for ALL. The erythrocyte folate (ery-folate) concentration was significantly higher in children who received extra folic acid than in those who did not (p less than 0.001). The ery-folate in MTX-treated children was only marginally reduced compared with the controls. The erythrocyte methotrexate (ery-MTX) concentration correlated with the weekly dose of MTX but not with any of the investigated hematological parameters. Children who received vitamin tablets containing folic acid had higher thrombocyte counts (p = 0.0056), higher leukocyte counts (p = 0.06), higher neutrophil counts (p = 0.05), and lower erythrocyte mean cell volumes (p = 0.05) than children who received no folic acid. We conclude that folic acid supplements of 75-200 micrograms/day affect the proliferative capacity of the bone marrow. Since none of the children was folate deficient as judged by the ery-folate, we recommend that vitamins given to children in maintenance treatment with MTX and 6-MP for ALL should not contain folic acid.(ABSTRACT TRUNCATED AT 250 WORDS)     

The prognostic value of measuring cell size in acute childhood leukemia (author's transl)]

Prior to treatment we studied leukemia cell diameters in bone marrows of 89 children with acute lymphoblastic leukemia (ALL) and 26 children with myeloblastic leukemia (AML). Patients were treated according to the West-Berlin protocol. The median cell diameter (+/- S) in ALL measures 11,3 (+/- 1,1)mu, in AML 15,3 (+/- 1,1)mu. Both forms of leukemia show some overlapping of cell diameters in the range of 13,8--14,3 mu. with ALL, no difference is shown in the cell diameters of those who remained in complete remission or went into relapse. Likewise, there is no significant difference in cell-diameter, when correlating them to the following parameters: initial peripheral leucocyte count, acid phosphatase- and PAS-reaction, T-cellmarkers. The risk of relapse is the same in patients with more than 20% macrolymphoblasts (diameter greater than 12mu) and in those less than 20% macrolymphoblasts. In 11 patients with ALL cellmeasuring was performed during the first hematological relapse. The median cell-diameter in 10 of these cases is higher than in the initial bone marrow.     

Delayed craniospinal irradiation for a first isolated central nervous relapse of acute lymphoblastic leukemia: report on 14 cases

BACKGROUND: Children developing an isolated central nervous system (CNS) relapse as first recurrence of their acute lymphoblastic leukemia (ALL) are considered to have a systemic relapse as well. They are mostly treated with intensive chemotherapy and craniospinal irradiation. In most treatment schedules, irradiation is given early after induction treatment. Because craniospinal irradiation affects a large portion of hematopoietic bone marrow systemically, treatment is often delayed owing to aplasias. Also, dose reductions are frequently needed. Children receiving simultaneously irradiation and chemotherapy are prone to (often severe) neurotoxicity. This study reports on children with a first isolated CNS relapse of their ALL receiving chemotherapy for 40 weeks. Treatment ends with the administration of irradiation given after cessation of chemotherapy. PROCEDURE: Fourteen children, with blasts and >5 cells/mm(3) in two consecutive samples of cerebrospinal fluid and a blast percentage <5% in their bone marrow were treated according to an intensive systemic and site-specific chemotherapy. Craniospinal irradiation was administered after cessation chemotherapy. RESULTS: Event-free-survival was 57% (confidence interval 35-89%), freedom from relapse was 61.5%; follow-up ranges from 2.0 to 15.1 years (median 11.7 years). One child died from septicemia during induction. Five children experienced a second relapse and died from their malignancy. Two children [with a t(9;22) or a rearranged MLL gene] relapsed prior to radiotherapy. Outcome was related to duration of first remission, age at relapse, and identification as a high-risk patient at initial diagnosis. No neurologic complications were noted during and after treatment. CONCLUSIONS: Delayed irradiation for isolated CNS relapse in children with ALL gives favorable survival rates, without significant toxicity. Neurotoxicity was absent.     

Receptors for sheep erythrocytes (E) and erythrocyte-antibody-complement complexes (EAC) on the lymphoblasts of childhood acute lymphocyblastic leukemia.

Two cell-surface markers, rosette formation with sheep erythrocytes (E-rosette) as a T-cell marker and rosette formation with bovine erythrocyte-antibody-complement complex (EAC-rosette) as a B-cell marker were determined on peripheral blood lymphocytes and lymphoblasts from normal and 89 children with acute lymphoblastic leukemia (ALL). In the majority of the patients (12/15 untreated patients and 6/11 patients in relapse), lymphoblasts exhibited neither E- nor EAC-rosette formation. Lymphoblasts from one untreated patient with mediastinal mass displayed E-(50%) and EAC-rosette formation (15%). In 3 of 11 patients in relapse, lymphoblasts displayed an increase in EAC-rosette formation with progressive disease. In the remaining patients with active disease, a small and variable proportion of lymphoblasts expressed E and/or EAC-rosette formation. In 63 patients in remission, percentages of E- and/or EAC-rosette were similar (p greater than 0.05) to those of control. The results indicate a wide heterogeniety with respect to expression of lymphocyte membrane markers in lymphoblasts and in normal lymphocytes in patients with active ALL.     

The Munich study on the treatment of acute lymphoblastic leukemia in childhood (ALL 77-02)

149 children with acute lymphocytic leukemia (ALL) were admitted to a prospective therapeutic regime. Remission induction was achieved by vincristine, daunorubicine, L-asparaginase and prednisone. During consolidation the patients received three intermediate dose methotrexate (MTX) infusions over 24 hours combined with intrathecal MTX, followed by L-asparaginase. High-risk patients were treated in addition with high dose cyclophosphamide and ARA-C over 3 weeks. Standard risk patients received cranial irradiation with 18 Gy, high-risk patients with 24 Gy. Maintenance therapy was performed with 6-mercaptopurine and MTX orally. Immunologic phaenotyping revealed: c-ALL 73%, pre-T or T-ALL 15%, c/T-ALL 4% and undifferentiated leukemia (AUL) 8%. Only 1 patient was nonresponder, 7 patients died during induction therapy, 5 patients during continuous complete remission (CCR). 18 relapses occurred, 12 of which were systemic, 8 CNS and 2 testicular relapses. In the total group the 54 months probability of CCR is 0,68 +/- 0,05 (life-table-analysis), for the reduced group 0,75 +/- 0,05. In the reduced group the probability of CCR at 54 months for standard risk patients is 0,86 +/- 0,06; for high-risk patients 0,60 +/- 0,09; for patients with c-ALL 0,73 +/- 0,08; for patients with c/T-ALL 1,0 +/- 0,0; for patients with pre-T or T-ALL 0,58 +/- 0,2 and for patients with AUL 0,45 +/- 0,25. For the reduced group the CCR probability at 54 months in relation to the leukocytes (WBC) at diagnosis is in patients with WBC less than 25 X 10(3)/mm3: 0,80 +/- 0,06; for patients with WBC greater than 25 X 10(3)/mm3: 0,63 +/- 0,11.     

Receptors for sheep erythrocytes (E) and erythrocyte-antibody-complement complexes (EAC) on the lymphoblasts of childhood acute lymphoblastic leukemia

Two cell-surface markers, rosette formation with sheep erythrocytes (E-rosette) as a T-cell marker and rosette formation with bovine erythrocyte-antibody-complement complex (EAC-rosette) as a B-cell marker were determined on peripheral blood lymphocytes and lymphoblasts from normal and 89 children with acute lymphoblastic leukemia (ALL). In the majority of the patients (12/15 untreated patients and 6/11 patients in relapse), lymphoblasts exhibited neither E- nor EAC-rosette formation. Lymphoblasts from one untreated patient with mediastinal mass displayed E-(50%) and EAC-rosette formation (15%). In 3 of 11 patients in relapse, lymphoblasts displayed an increase in EAC-rosette formation with progressive disease. In the remaining patients with active disease, a small and variable proportion of lymphoblasts expressed E and/or EAC-rosette formation. In 63 patients in remission, percentages of E- and/or EAC-rosette were similar (p > 0.05) to those of control. The results indicate a wide heterogeneity with respect to expression of lymphocyte membrane markers in lymphoblasts and in normal lymphocytes in patients with active ALL.     

New aspects of the determination of blood methotrexate levels in leukemic children

Serum and CSF concentrations after medium dosage of methotrexate (MTX; 500 mg/m2 - 1,000 mg/m2) have been determined by an enzymatic assay during 142 infusions in children with ALL. If the dose of MTX was 500 mg/m2 MTX concentrations in CSF were under 10(-6) M/l in 40% of the treatments but only in 22%, when the dose was increased to 1,000 mg/m2. The systemic clearance of MTX was found to be increased significantly by the 2nd MTX treatment in children who relapsed thereafter. Such a phenomenon was not observed in children who continued in remission. The relapse free survival of children, whose MTX-clearance remained constant by the 2nd MTX treatment was significantly longer. No serious MTX toxicity has been observed in our patients.     

Hematopoietic stem cell transplantation after first marrow relapse of non-T, non-B acute lymphoblastic leukemia: a pediatric oncology group pilot feasibility study

BACKGROUND: Relapsed acute lymphoblastic leukemia (ALL) in children is associated with a poor outcome, especially for those patients whose relapse occurs during the first 36 months after diagnosis. The best therapy for these patients is not known. This study was designed to evaluate the feasibility of enrolling children with recurrent ALL in a standardized treatment protocol that included receipt of a hematopoietic stem cell transplant (HSCT). PROCEDURE: Eligible patients with a bone marrow relapse of non-T, non-B ALL underwent a common induction and consolidation followed by receipt of either an allogeneic HSCT from a human leukocyte antigen (HLA)-identical sibling or an autologous HSCT purged with B-4 blocked ricin. A common conditioning regimen was used for all patients. RESULTS: Twenty-eight patients from eight institutions were enrolled. Fourteen patients did not receive a transplant during the study, because of toxicity (4), relapse (1), inadequate purging (1), and parental or physician preference for an alternative donor transplant (8). Six patients received allogeneic HSCTs. Five of them have remained in remission for a median of 78 months. Eight patients received autologous HSCTs purged with B4-blocked ricin. Four have remained in remission for a median of 94 months. Of the nine patients who received alternative donor transplants, only two remain in remission. CONCLUSION: We conclude that well designed and controlled prospective studies are necessary to define the role of HSCTs in children with recurrent ALL. In order to be successful, such studies must have the full support of participating centers. Autologous HSC transplantation may have a role in the treatment of relapsed ALL, but further studies are needed.     

Prognostic significance of methotrexate and 6-mercaptopurine dosage during maintenance chemotherapy for childhood acute lymphoblastic leukemia.

Tolerance of full-dose methotrexate/6-mercaptopurine (MTX/6MP) maintenance therapy for childhood acute lymphoblastic leukemia (ALL) without side effects could reflect insufficient systemic drug exposure, and drug withdrawals due to toxicity might reduce the chance of cure. The present study included 122 children with non-B cell acute lymphoblastic leukemia with a median follow-up of 84 months. Leukopenia and hepatotoxicity were calculated as weighted means of all white cell counts and all serum aminotransferase measurements, respectively, registered for each patient. Forty-five patients relapsed (30 in bone marrow). Patients tolerating an average dose of MTX of more than 75% of the recommended protocol doses and having cumulated drug withdrawals of less than 1% of the period of maintenance therapy had an increased risk of hematological relapse (p = 0.008) as well as of any relapse (p = 0.03) when compared to the remaining patients. Patients with a cumulative withdrawal of MTX or of 6MP for greater than 10% of the maintenance therapy period had an increased risk of hematological relapse (MTX: p = 0.009, 6MP: p less than 0.0001) and of any relapse (MTX: p = 0.16, 6MP: p = 0.0002). Liver toxicity was the main reason for cumulative long-term drug withdrawals. However, patients with a mean aminotransferase level above the upper normal limit (40 IU/l) who were kept on therapy (cumulative withdrawals of neither drug for more than 5% of their maintenance therapy period) had a significantly lower risk of hematological relapse (p = 0.02) as well as of any relapse (p = 0.06) than the remaining children. The concept of treating to toxicity seems warranted for maintenance therapy of childhood lymphoblastic leukemia.     

Minimal requirements for the diagnosis, classification, and evaluation of the treatment of childhood acute lymphoblastic leukemia (ALL) in the "BFM Family" Cooperative Group.

Minimal requirements and their rationale for the diagnosis and the response to treatment in childhood acute lymphoblastic leukemia (ALL) were defined in the recently instituted "BFM-Family"-Group, in which the German, Austrian, Dutch, Italian, Belgian, French and Hungarian childhood leukemia study groups cooperate. ALL is defined as > or = 25% lymphoblasts in the bone marrow; for confirmation of the diagnosis and classification the criteria of the French-American-British (FAB) criteria are retained. For determination of the extent of the disease at diagnosis or relapse the criteria by the Rome Workshop [1986] are recommended: An obligatory panel of monoclonal antibodies for immunophenotyping was defined, as well as criteria for precursor B-ALL and T-ALL. Cytogenetic studies may support the diagnosis and subtyping, and are essential to identify certain patients with a high risk of treatment failure (f.i. t(9;22), t(4;11)). The role of molecular genetics for the diagnosis and the characterization of leukemia and the value of its clinical application needs further elucidation. Relapse was defined as recurrence of evident leukemia in the blood, bone marrow (> or = 25% lymphoblasts) or at any other site (to be confirmed by histological examination). Bone marrow involvement combined with extramedullary relapse was defined as > or = 5% lymphoblasts in the bone marrow.     

Minimal requirements for the diagnosis,classification, and evaluation of the treatment of childhood acute lymphoblastic leukemia (ALL) in the “BFM family” cooperative group

Minimal requirements and their rationale for the diagnosis and the response to treatment in childhood acute lymphoblastic leukemia (ALL) were defined in the recently instituted “BFM-Family”-Group, in which the German, Austrian, Dutch, Italian, Belgian, French and Hungarian childhood leukemia study groups cooperate. ALL is defined as ≥ 25% lymphoblasts in the bone marrow; for confirmation of the diagnosis and classification the criteria of the French-American-British (FAB) criteria are retained. For determination of the extent of the disease at diagnosis or relapse the criteria by the Rome Workshop [1986] are recommended: An obligatory panel of monoclonal antibodies for immunophenotyping was defined, as well as criteria for precursor B-ALL and T-ALL. Cytogenetic studies may support the diagnosis and subtyping, and are essential to identify certain patients with a high risk of treatment failure (f.i. t(9;22), t(4;11)). The role of molecular genetics for the diagnosis and the characterization of leukemia and the value of its clinical application needs further elucidation. Relapse was defined as recurrence of evident leukemia in the blood, bone marrow (≥ 25% lymphoblasts) or at any other site (to be confirmed by histological examination). Bone marrow involvement combined with extramedullary relapse was defined as ≥ 5% lymphoblasts in the bone marrow. © 1992 Wiley-Liss, Inc.