Rüdiger Fengler

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.

Pain in pediatric oncology — children's and parents' perspectives

There is a lack of valid epidemiological data on malignancy‐associated pain in modern pediatric oncology. Pediatric oncology patients (self‐assessment) and their parents from 28 hospitals were questioned using age‐adapted, structured interviews and validated pain assessment tools. Pain intensity was measured by the NRS and Bieri faces scale. We conducted 363 interviews with patients and their parents, and 46 with the parents alone (if patients <2.5 years). Pain was reported at the time of the interview or within the last 24 h, 7 d, or 4 weeks in 15%, 28%, 50% and 58% of cases, respectively. The proportion of patients suffering severe to maximal pain (NRS > 3; Bieri > 2) increased significantly (p = 0.001, χ2 test). The median pain intensity for the most severe pain episode within the last 4 weeks was 6.7 (NRS 0–10). Adverse effects of anti‐tumor therapy were the most frequent cause of pain. Multivariate analyses depicted general physical condition either “severely reduced” (ASA status 3) (OR 4.0, 95% CI 1.1‐14.7, p = 0.037) or “moderately reduced” (ASA status 2) (OR 1.8, 95% CI 1.1‐2.9, p = 0.018), “in‐patient status” (OR 1.8, 95% CI 1.2‐2.9, p = 0.010), and “co‐morbidity present” (OR 3.5, 95% CI 1.1‐10.7, p = 0.030) as risk factors for severe to maximal pain. General anesthesia was the only factor significantly (OR 0.14, 95% CI 0.05‐0.39, p < 0.01) associated with a reduction in the proportion of patients suffering severe to maximal pain during bone marrow aspiration. Our data emphasize both the importance of in‐house acute pain control and the need for general anesthesia during painful procedures in pediatric oncology.

Randomized comparison of 36-hour intermediate-dose versus 4-hour high-dose methotrexate infusions for remission induction in relapsed childhood acute lymphoblastic leukemia.

PURPOSE Pharmacokinetics, toxicity, and therapeutic efficacy of two different methotrexate (MTX) infusions for remission induction of relapsed childhood acute lymphoblastic leukemia (ALL) were investigated in a randomized multicenter trial. PATIENTS AND METHODS Sixty patients with early bone marrow relapse received a polychemotherapy induction protocol starting with either 12 g/m2 MTX as a 4-hour infusion (high-dose [HDM]) or 1 g/m2 as a 36-hour infusion (intermediate-dose [IDM]). In HDM, leucovorin (LCV) was administered orally (12 times, 15 mg/m2 every 6 hours), beginning at hour 24. In IDM, only two doses were administered at hours 48 and 54. RESULTS Median serum MTX concentrations during infusion were 716 mumol/L in HDM and 7.2 mumol/L in IDM. In HDM, MTX serum levels at hour 24 (median, 2.8 mumol/L) were significantly less than steady-state levels of IDM. Concentrations greater than 1 mumol/L were maintained for 36 hours with HDM and 45 hours with IDM. General tolerance to treatment was better in the HDM group. Mucosal lesions occurred significantly more often and were more severe after IDM treatment. A median treatment delay of 3 days was required in the IDM group but not in the HDM group. At day 15, complete remission (CR) was documented in 45% of IDM- and 48% of HDM-treated patients. Persistent blasts (> 5%) appeared more frequently in HDM than in IDM (35% v 19% of patients; P = NS). After completion of induction therapy, 28 of 30 patients in each group achieved CR. CONCLUSION Both regimens produced the same remission rates. The tendency to better antileukemic activity of IDM was accompanied by more severe side effects as a consequence of long-lasting cytotoxic MTX levels. Hence, long-term infusion of IDM followed by low-dose LCV is an effective treatment for recurrent ALL.

Peripheral blast counts at diagnosis of late isolated bone marrow relapse of childhood acute lymphoblastic leukemia predict response to salvage chemotherapy and outcome. Berlin-Frankfurt-Münster Relapse Study Group.

PURPOSE In newly diagnosed childhood acute lymphoblastic leukemia (ALL), a high tumor burden indicates a poor prognosis, while no such link has been established yet after relapse. The impact of the absolute peripheral blast count (PBC) at the time of relapse on the response to salvage chemotherapy after a late isolated bone marrow (BM) relapse is the subject of this prospective analysis. PATIENTS AND METHODS Since 1983, 260 children with a first isolated BM relapse of ALL that occurred 6 months or later after elective cessation of front-line therapy were enrolled onto four consecutive multicenter trials of the Berlin-Frankfurt-Münster (BFM) Relapse Study Group. All patients received intensive multiagent induction and consolidation chemotherapy for 6 months, followed by maintenance therapy with methotrexate (MTX) and thioguanine for 2 years. Treatment of subclinical meningeal leukemia consisted of high-dose intravenous MTX and intrathecally administered cytostatic drugs, which was augmented by cranial irradiation since 1988. RESULTS At the time relapse was diagnosed, PBC varied considerably among patients (median, 1,060/microL; range, 0 to 106,800/microL). Achievement of a second complete remission (CR) was not significantly different in children without detectable circulating blasts at relapse (37 of 38) and those with moderate (1 to 9,999/microL) PBC (165 of 171). In contrast, only 42 of 51 children with high PBC (> or = 10,000/microL) achieved a second CR (P = .0015). At a median follow-up time of 40 months, the 10-year event-free survival (EFS) probability was significantly (P = .0001) higher in children without circulating blasts (.64) than in children with moderate PBC (.32) or high PBC (.10). There was a preponderance of boys in the group without detectable circulating blasts, while the three PBC-defined groups did not differ with respect to frontline treatment, age at initial diagnosis, age at relapse, time off therapy, or salvage treatment protocol. On sequential univariate and multivariate analysis, only duration of first remission > or = 48 months was an additional independent indicator of adverse prognosis, while preventive cranial irradiation improved outcome independently of PBC. CONCLUSION The absence of blasts on peripheral-blood smears at the time of a first late isolated BM relapse of childhood ALL is associated with a favorable response and prognosis in chemotherapy-treated children, who should be regarded as ineligible for bone marrow transplantation (BMT) unless a second round of chemotherapy has failed to produce a response.

Chemotherapy for Relapsed Childhood Acute Lymphoblastic Leukemia: Results of the BFM Study Group

In recent years front-line therapy for acute lymphoblastic leukemia (ALL) in childhood has been intensified in most international trials [1, 2, 3]. In Germany, intensive induction/consolidation and reinduction regimens have been applied since the mid seventies [4, 5, 6]. With these types of front-line therapy cure rates have now approached 70–75%. However, increasing success with more aggressive front-line protocols has led to challenges for effective salvage regimens for the 25% of children in whom the first treatment attempt has failed. Systematic trials for relapsed ALL have been carried out in the BFM study group since 1983.

Intermediate dose methotrexate is as effective as high dose methotrexate in preventing isolated testicular relapse in childhood acute lymphoblastic leukemia

Purpose: We evaluated the influence of three different dosages of methotrexate (MTX) during consolidation on the incidence of testicular relapse in children with acute lymphoblastic leukemia (ALL). Patients and Methods: One thousand one hundred forty-four boys with newly diagnosed ALL, enrolled in three consecutive trials of the Berlin-Frankfurt-Müinster group (ALL-BFM 81, 83. 86), were retrospectively evaluated for the influence of MTX on testicular relapse-free interval. The basic treatment design was similar in all trials. No intravenous MTX was used in trial ALL-BFM 81 in the group who received cranial irradiation (CRT) except for a part of standard risk patients. Four courses of intermediate dose MTX (IDM) (0.5 g/m2) were introduced for all patients in trial ALL-BFM 83 (IDM group), which were replaced by high dose MTX (HDM) (5 g/m2) in trial ALL-BFM 86 (HDM group). The median observation time was > 9 years. Results: The cumulative incidence of isolated testicular relapses was significantly higher in the CRT group as compared to the IDM and HDM groups (6.7% versus 2.5% and 2.3%. p = 0.02 and 0.01). HDM decreased neither the incidence nor the rate of isolated testicular relapses any further. Event-free survival (EFS) for boys was similar between trial ALL-BFM 81 and 86 (64% versus 69%, p = 0.35). but differed significantly between trials ALL-BFM 83 and 86 (61% versus 69%. p = 0.0078). Conclusion: The introduction of IDM reduced the incidence of isolated testicular relapses significantly by a factor two. but had no significant influence on overall survival. HDM did not result in a more effective prevention of testicular relapses, but resulted in better systemic control and hence better survival than IDM.

Similar Outcome in Boys with Isolated and Combined Testicular Acute Lymphoblastic Leukemia Relapse After Stratified BFM Salvage Therapy

Despite modern intensive treatment, relapses occur in about 25% children with acute lymphoblastic leukemia (ALL). After the central nervous system (CNS), the testes are the second most frequent site of an extramedullary relapse [1]. The incidence of testicular relapses has been decreased by intensification of front-line regimens, mainly by the introduction of intermediate-dose or high-dose methotrexate (MTX) [2–6]. When salvage therapy of an isolated relapse consisted of local treatment, alone or in combination with mild chemotherapy, a subsequent bone marrow relapse occurred in a high percentage of boys [3, 7–9]. Therefore, intensive systemic salvage therapy is necessary to achieve favorable results in boys with isolated as well as combined testicular relapse [10–13]. The aim of this study was to evaluate the efficacy of tumor load-adapated chemotherapy in boys with first overt testicular relapse, treated according to four consecutive Berlin-Frankfurt-Munster (BFM) relapse protocols.

Erythroblastopenia in two patients after splenectomy and polychemotherapy.

Acquired erythroblastopenia is a rare disorder of the hematopoietic system associated with viral infections, autoimmune diseases, and drugs. We report on two patients who became anemic due to maturation-arrest at the proerythroblast level, without alterations of white blood cell or platelet counts. Both patients had been splenectomized and had undergone chemotherapy for nephroblastoma or Hodgkins disease, respectively, at the same pediatric oncology unit. Erythropoietin levels were elevated in both patients. Antibodies against specific viruses, particularly parvovirus B 19, could not be detected in patient sera. Both patients responded to infusions of 7 S immunoglobulin with a rapid increase of the reticulocyte counts. In both cases, complete clinical remission was observed after a duration of 5 months. Heat-inactivated serum obtained during the acute phase and after remission as well was found to be inhibitory for normal bone marrow granulocyte and erythrocyte progenitor growth in vitro. The simultaneous appearance of this rare disorder in two otherwise unrelated patients treated at the same unit prompts speculations about a viral etiology.