Prediction of outcome by early response in childhood acute lymphoblastic leukemia.

BACKGROUND: In the ALL-BFM studies for treatment of acute lymphoblastic leukemia, reduction of leukemic blasts in peripheral blood after a one-week prednisone pre-phase - the so-called prednisone response - has been used for risk stratification since the 1980s and has been one of the most relevant factors for identification of high-risk patients. In the trial ALL-BFM 95, early cytomorphological marrow response on day 15 of induction therapy was prospectively evaluated and its prognostic value was analyzed in comparison to the prednisone response and other established prognostic factors. RESULTS: Compared to prednisone response, day 15 marrow response was superior in outcome prediction - yet with differential effect depending on blast lineage. Outcome was poor in T cell leukemia patients with prednisone poor-response independent of day 15 marrow response, whereas among patients with prednisone good-response different risk groups could be identified by day 15 marrow response. In contrast, prednisone response lost prognostic significance in precursor B cell leukemia when stratified by day 15 marrow response. CONCLUSIONS: Selective addition of day 15 marrow response to conventional stratification criteria applied on ALL-BFM 95 may significantly improve risk-adapted treatment delivery. Even though cutting-edge trial risk stratification is meanwhile dominated by minimal residual disease evaluation, an improved conventional risk assessment, as presented here, could be of great importance to countries lacking the technical and/or financial resources associated with the application of minimal residual disease analysis.

Long-term results of four consecutive trials in childhood ALL performed by the ALL-BFM study group from 1981 to 1995. Berlin-Frankfurt-Münster.

Four thousand, four hundred and forty eligible children of up to 18 years of age were treated in four consecutive trials between 1981 and 1995 with the treatment protocols of the Berlin-Frankfurt-Münster (BFM) study group for childhood acute lymphoblastic leukemia (ALL). The probability for event-free survival (pEFS) at 8 years improved from 65.8% in study ALL-BFM 81 to 75.9% in study ALL-BFM 90. The cumulative incidence of recurrences with CNS involvement was 10.1% and 9.3% in studies ALL-BFM 81 and 83, but was reduced to less than 5% in study ALL-BFM 90 (for isolated CNS relapses from 5.3% in study ALL-BFM 81 to 1.1% in study ALL-BFM 90). Four major findings were derived from this series of trials performed by 37 to 96 centers in Germany, Austria, and Switzerland: (1) Reintensification is a crucial part of treatment, even in low risk patients; (2) presymptomatic cranial radiotherapy can be safely reduced to 12 Gy, or even be eliminated if it is replaced by early intensive systemic and intrathecal methotrexate applied; (3) maintenance therapy given a total of 24 months from diagnosis provides a lower rate of systemic relapses than treatment for 18 months; (4) inadequate response to an initial 7-day prednisone window (combined with one intrathecal injection of methotrexate on day 1) defines about 10% of the patients with a very high risk of relapse. For patients with adequate early response (90% of all) an 8-year pEFS of 80% has been achieved in the most recent trial ALL-BFM 90. While it has proven so far to be impossible to improve the outcome for the small group of high risk patients, the number of recurrences could be effectively reduced for the large group of patients responding adequately to the prednisone in vivo sensitivity test. Apart from inadequate prednisone response, patients with hyperleukocytosis, age <1 year, or the presence of the Philadelphia-chromosome (Ph+ ALL) are at a particularly high risk of failure.

Long-term results of five consecutive trials in childhood acute lymphoblastic leukemia performed by the ALL-BFM study group from 1981 to 2000.

Between 1981 and 2000, 6609 children (<18 years of age) were treated in five consecutive trials of the Berlin-Frankfurt-Münster (BFM) study group for childhood acute lymphoblastic leukemia (ALL). Patients were treated in up to 82 centers in Germany, Austria and Switzerland. Probability of 10-year event-free survival (EFS) (survival) improved from 65% (77%) in study ALL-BFM 81 to 78% (85%) in ALL-BFM 95. In parallel to relapse reduction, major efforts focused on reducing acute and late toxicity through advanced risk adaptation of treatment. The major findings derived from these ALL-BFM trials were as follows: (1) preventive cranial radiotherapy could be safely reduced to 12 Gy in T-ALL and high-risk (HR) ALL patients, and eliminated in non- HR non-T-ALL patients, if it was replaced by high-dose and intrathecal (IT) MTX; (2) omission of delayed re-intensification severely impaired outcome of low-risk patients; (3) 6-month-less maintenance therapy caused an increase in systemic relapses; (4) slow response to an initial 7-day prednisone window was identified as adverse prognostic factor; (5) condensed induction therapy resulted in significant improvement of outcome; (6) the daunorubicin dose in induction could be safely reduced in low-risk patients and (7) intensification of consolidation/re-intensification treatment led to considerable improvement of outcome in HR patients.

Prognostic impact of age in children and adolescents with acute lymphoblastic leukemia: data from the trials ALL-BFM 86, 90, and 95.

Large progress has been made in the treatment of acute lymphoblastic leukemia (ALL) of childhood and adolescence over the past 30 years. Eighty percent of the patients can be cured, but clinical subgroups with a dismal outcome can still be identified. In this study, we investigated the association of age with prognosis in 5 181 patients with ALL under 18 years (y) of age enrolled in the three consecutive treatment trials ALL-BFM 86, 90 and 95 in more than 80 centers. Event-free survival (pEFS) of the total group was significantly associated with age. The most unfavorable outcome was found in infancy and the best results were achieved at toddler and pre-school age. Beyond 5 y of age, survival probability decreased (pEFS at 8 y: < 1 y = 0.45; 1-5 y = 0.82; 6-9 y = 0.75; 10-14 y = 0.63; > or = 15 y = 0.59). The proportion of T-ALL as compared to precursor B-cell ALL (pB-ALL) was lower in younger children, due to an incidence peak of pB-ALL in toddlers and at pre-school age compared to a constant incidence of T-ALL. Within the T-ALL group, no correlation of age with sex, initial white blood cell count, CNS disease, or early treatment response was found. Children under 10 y of age had a slightly lower relapse rate compared to older patients. Within pB-ALL patients, the proportion as well as the absolute incidence of TEL/AML1 rearrangement and DNA index of > or = 1.16 was higher in the younger children. A lower proportion of BCR/ABL-positive ALL was observed in the age group of < 6 y when compared to patients aged > or = 6 y, but the absolute incidence was constant across the age groups after the first year of life. More than half of the infants had a CD10-negative pB-ALL. The incidence was constant after a peak in the first year of life, yet the percentage of CD10 negativity increased with rising age in this subgroup. Adolescents with pB-ALL had a significantly higher proportion of prednisone poor-responders. Accordingly, outcome was worse in older patients. This pattern was also evident in the biologically heterogeneous group of patients with a DNA index of > or = 1.16. In contrast, no significant age-related outcome differences could be shown within TEL/AML1- or BCR/ABL-positive patients, as well as within CD10-negative pB-ALL beyond infant age. Analysis of the pB-ALL group in a Cox's regression model including age and the above-listed biological factors revealed age < 1 year and > or = 10 years as independent risk factors. This is in line with the poorer prognosis of these age groups in the pB-ALL subgroup without specific biological characteristics. This subgroup also had an incidence peak at toddler age, presumably containing other favorable biological subsets. An independent prognostic impact of age in pediatric ALL cannot be excluded by this study. However, our analyses show that the age-associated different prognosis in childhood ALL is at least partly related to the different distribution of relevant prognostic subgroups between the age groups.

[Alteration of platelet function during intensive replacement therapy in haemophilia A (author's transl)]. / Thrombozytenfunktionsstörung während der hochdosierten Substitutionstherapie bei Hämophilie A.

This report describes two patients with haemophilia A who developed a transient thrombocytopathy with haemorrhagic diathesis during post-operative high-dose replacement therapy with antihaemophilic globulin. At the time of the bleeding the factor VIII-activity was in the normal range in both patients. The fibrinogen level, however, was elevated to 1700 mg-% and the factor VIII-associated antigen rose to more than 6-fold. At no time of replacement therapy with antihaemophilic globulin could either fibrinogen split products or fragments of the factor VIII-protein be detected by the usual methods. In view of the results of the thrombocyte aggregation experiments the authors postulate a disturbance of platelet function at the level of the membrane surface due to an overload of increased amounts of circulating proteins. Both the possible interference of dialysable factor VIII-components and the role of immunpathologic phenomena are discussed.

Use of monoclonal antibodies as a diagnostic tool in human leukemia. I. Acute myeloid leukemia and acute phase of chronic myeloid leukemia.

Various monoclonal antibodies (mAbs) detecting certain different epitopes on myeloid cells (VIMD5, D5 D6, OKM1, Leu-M3, VIEG4, OKIa 1) have been used in combination with conventional markers (antihuman myeloid hetero-antiserum, FcIgG-receptors, C3d-receptors) to further define the phenotypic heterogeneity of myeloid leukemia. Subsequent leukemic samples from previously untreated patients with acute myeloid leukemia (AML) (51 adults, 24 children) and from nine adult patients in the acute phase of chronic myeloid leukemia (CML-BC) were studied. It was possible to demonstrate quantitative differences in the expression of antigens on the various leukemia subtypes which could be exploited for diagnosis. Furthermore our results revealed that there is a very close correlation between the different surface phenotypes and the types morphologically assessed according to FAB-criteria.

Electronic platelet counting with capillary blood samples--experiences in a paediatric clinic.

For several reasons, electronic platelet counts have not been generally adopted in paediatric routine laboratories. A method of platelet counting in capillary blood samples using an electronic counter is described. This is based on brief centrifugation of the blood sample after the addition of a diluent containing heparin/dextran and with a density of 1.050. The thrombocytes are uniformly suspended in the supernatant after 5 min of centrifugation at 250 g, so that the counting procedure in the electric unit can follow immediately. This simplified, dependable and reproducible method is also suitable for venous blood, and as a result of several years of successful trial, it can be recommended for routine use, especially in clinics with paediatric patients.

Differential effects of granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor in children with severe congenital neutropenia.

Severe congenital neutropenia (SCN) is a disorder of myelopoiesis characterized by severe neutropenia secondary to a maturational arrest at the level of promyelocytes. We treated five patients with SCN with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) for 42 days and subsequently, between 1 and 3 months later, with rhG-CSF for 142 days. The objective was to evaluate the safety and ability of these factors to elicit a neutrophil response. rhGM-CSF was administered at a dose of 3 to 30 micrograms/kg/d (30 to 60 minutes, intravenously). In all patients, a specific, dose-dependent increase in the absolute granulocyte counts was observed. However, in four patients this increase was due to an increase in eosinophils, and in only one patient it was due to an increase in the absolute neutrophil counts (ANC). Subsequently, all patients received rhG-CSF at a dose of 3 to 15 micrograms/kg/d subcutaneously. In contrast to rhGM-CSF treatment, all five patients responded to rhG-CSF during the first 6 weeks of treatment with an increase in the ANC to above 1,000/microL. The level of ANC could be maintained during maintenance treatment. In one patient, the increase in ANC was associated with an improvement of a severe pneumonitis caused by Peptostreptococcus and resistant to antibiotic treatment. No severe bacterial infections occurred in any of the patients during CSF treatment. All patients tolerated rhGM-CSF and rhG-CSF treatment without severe side effects. These results demonstrate the beneficial effect of rhG-CSF in SCN patients.

[Childhood B-cell lymphomas and leukemias. Improvement of prognosis by a therapy developed for B-neoplasms by the BFM study group]. / Kindliche B-Zell-Lymphome und -Leukämien. Verbesserung der Prognose durch eine für B-Neoplasien konzipierte Therapie der BFM-Studiengruppe.

In two consecutive therapy studies, the BFM multicenter study group treated 55 children with B-NHL from 1975 until 1981 and another 55 children with B-NHL and 22 with B-ALL since 1981. In the 1975/81 study, a therapeutic regimen which produced excellent results in non-B-NHL and -ALL, emerged to be much less effective in disseminated B-NHL. With this regimen the probability of continuous complete remission (CCR) in advanced disease was 34% only after 7 years. Since 1981, a new therapeutic regimen of higher specificity for B-neoplasias improved the probability of CCR at the present time to 100% in localised B-NHL, to 63% in disseminated B-NHL and even in B-ALL to 49%.

Myelodysplastic syndromes in childhood. Report of 21 patients from Italy and West Germany.

Nine Italian and 12 German children fulfilled the criteria of myelodysplastic syndromes (MDS), according to the French-American-British (FAB) classification. All patients belonged to the more aggressive subtypes of myelodysplastic syndromes. Four presented with refractory anemia with excess of blasts (RAEB), 16 presented with refractory anemia with excess of blasts in transformation (RAEB-T), and 1 had chronic myelomonocytic leukemia (CMML). Dyserythropoiesis and dysgranulopoiesis were seen in all patients, and dysmegakaryopoiesis was seen in most patients. Cytogenetic studies in 13 of the 21 children showed karyotype abnormalities in 8; 5 had monosomy 7. Eleven patients were treated with intensive chemotherapy soon after diagnosis; 6 achieved complete remission (CR), and 2 of them are alive and still in complete remission after 48 and 69 months. Low-dose cytosine arabinoside (Ara-C) was given in six children without improvement. Bone marrow transplantation after progression of the disease has produced complete remission lasting 28 + months now in one of two patients. Four patients received only symptomatic treatment. The rate of 5-year survival for the total group was 20% (SD 9%). We conclude that children with MDS may benefit from more aggressive treatment, but that in general the survival rate is poor and similar to that observed in adults with the same subtypes of this disease.

[Incidence, clinical markers and prognostic significance of immunologic subtypes of acute lymphoblastic leukemia (ALL) in children: experiences of the ALL-BFM 83 and 86 studies]. / Inzidenz, klinische Merkmale und prognostische Bedeutung immunologischer Subtypen der akuten lymphoblastischen Leukämie (ALL) im Kindesalter: Erfahrungen der Therapiestudien ALL-BFM 83 und 86.

In the therapy studies ALL-BFM 83 and 86, immunophenotyping of ALL by monoclonal antibodies was performed in a total of 1162 protocol patients (ALL-BFM 83 n = 578; ALL-BFM 86 n = 584). Both studies yielded similar results with respect to the incidence of immunological subtypes: CD10-negative pre-pre-B ALL (ALL-BFM 83: 3.6%; ALL-BFM 86: 5.3%), common ALL (80.1%; 77.9%), B-ALL (1.9%; 2.8%), pre-T/T-ALL (13.9%; 13.5%). Leukemic cells of 3 patients in the ALL-BFM 83 study lacked lymphoid and myeloid antigens (acute unclassifiable leukemia, 0.5%), and 3 patients in the ALL-BFM 86 study exhibited different blast populations with expression of either myeloid or lymphoid features (acute mixed-lineage leukemia, 0.5%). Coexpression of myeloid antigens (CD13 and/or CD33 and/or CDw65) on lymphoblasts (My-positive ALL) was identified in 35 of the 570 (6.1%) protocol patients prospectively analyzed in the ALL-BFM 86 study. The following associations were observed between the immunological subtype and the clinical risk factors: median age (years)-pre-pre-B 3.0, common 4.3, B- 7.9, pre-T/T-ALL 8.5 (pre-pre-B, common vs. pre-T/T-ALL p = 0.05); median leukocyte counts (x 10(9)/l)-pre-pre-B 80, common 9.1, B- 12.3, pre-T/T-ALL 68.1 (common, B- vs. pre-pre-B, pre-T/T-ALL p less than 0.05). The prognostic relevance of the immunophenotype was evaluated on the basis of the therapeutic results obtained in the ALL-BFM 83 study. A significant difference in the remission rate was only recognizable between patients with common ALL (99.1%) and those with pre-T/T-ALL (93.7%, p less than 0.001). After a median follow-up of 54 months, the probability of event-free survival is 71% for pre-pre-B ALL, 67% for common ALL, 56% for pre-T/T-ALL and 27% for B-ALL (common vs. B-, pre-T/T-ALL p less than 0.001), the prognosis in patients with pre-pre-B and common ALL being markedly influenced by the initial leukocyte counts and the age.

[NHL-BFM 90 therapy study in treatment of malignant non-Hodgkin's lymphomas in children and adolescents. Part 1: Classification and allocation to strategic therapy groups. BIF study group]. / Therapiestudie NHL-BFM 90 zur Behandlung maligner Non-Hodgkin-Lymphome bei Kindern und Jugendlichen. Teil 1: Klassifikation und Einteilung in strategische Therapiegruppen. BIF Studiengruppe.

One of the goals of the study NHL-BFM 90 was to investigate the distribution and prognosis of the different subtypes of Non-Hodgkin's Lymphoma (NHL) in children and adolescents according to histological, cytomorphological and immunological characteristics. From 4/1990 to 12/1992, 346 patients (pts) (84 females, 262 males) were enrolled (median age: 9.1 years; range: 0.8-17.9 years). Histology was available from 290 pts (84%), cytomorphology from 155 (44%), and immunophenotyping from 245 (70%). Cases with L1 oder L2 cytomorphology according to the French-American-British Classification were classified as lymphoblastic lymphoma and those with L3 cytomorphology as Burkitt-Type lymphoma or acute B-cell leukemia (B-ALL) if a histological classification was not available. By means of the combined analysis of all three diagnostic criterias the classification of the NHL according to the updated Kiel-classification was possible in 312 cases: 49% were classified as Burkitt-type-lymphoma (incl. B-ALL), 22% als lymphoblastic lymphoma, 10% as large cell anaplastic lymphoma (LCAL), 6% as centroblastic lymphoma, only few cases were classified as NHL of other subtypes, 3 pts (1%) suffered from low grade malignant lymphomas, and in 34 pts (10%) the NHL was not further classified. Patients were stratified according to NHL-subentities in 3 branches (Non-B-NHL, B-NHL, LCAL) of different treatment modalities. The estimated probability of a 3-year event free survival (pEFS) was 88 +/- 2% for the whole group (follow up 7 to 40 months, median 23 months) while pEFS of different subtypes was: lymphoblastic lymphoma: 91 +/- 4%; Burkitt-type-lymphoma/B-ALL: 90 +/- 2%; centroblastic lymphoma: 94 +/- 6%, LCAL: 88 +/- 6%. We conclude that the stratification of treatment modalities in study NHL-BFM 90 according to biological entities provided patients of different NHL-subtypes an equal chance to survive event free. The efficacy of the treatment strategy for rare subtypes, however, is not evaluable yet.