Karsten Stahnke

Pharmacokinetics of native Escherichia coli asparaginase (Asparaginase medac) and hypersensitivity reactions in ALL‐BFM 95 reinduction treatment

Repeated asparaginase treatment has been associated with hypersensitivity reactions against the bacterial macromolecule in a considerable number of patients. Immunological reactions may range from anaphylaxis without impairment of serum asparaginase activity to a very fast decline in enzyme activity without any clinical symptoms. Previous investigations on a limited number of patients have shown high interindividual variability of asparaginase activity time courses and hypersensitivity reactions in about 30% of patients during reinduction treatment. Therefore, monitoring of reinduction treatment was performed prospectively in 76 children with newly diagnosed acute lymphoblastic leukaemia (ALL). According to the ALL‐Berlin–Frankfurt–Münster (BFM) 95 protocol, 10u2003000u2003U/m2 body surface area of native Escherichia coli asparaginase (Asparaginase medac) was given on du20038, 11, 15 and 18. In 45/76 children, trough and peak activities were determined with every dose, and also on du20034 and du200311 after the last administration. Data on asparaginase activity were not available from the remaining 31 patients, but information with regard to hypersensitivity reactions only was given. Eighteen out of 76 patients (24%) suffered a clinical hypersensitivity reaction; however, no silent inactivation was observed. Activity in the therapeutic range of greater than 100u2003U/l for at least 14u2003d was determined in 43 of the 45 patients who were analysed for enzyme activity.

Early Relapse in ALL Is Identified by Time to Leukemia in NOD/SCID Mice and Is Characterized by a Gene Signature Involving Survival Pathways

We investigated the engraftment properties and impact on patient outcome of 50 pediatric acute lymphoblastic leukemia (ALL) samples transplanted into NOD/SCID mice. Time to leukemia (TTL) was determined for each patient sample engrafted as weeks from transplant to overt leukemia. Short TTL was strongly associated with high risk for early relapse, identifying an independent prognostic factor. This high-risk phenotype is reflected by a gene signature that upon validation in an independent patient cohort (nxa0= 197) identified a high-risk cluster of patients with early relapse. Furthermore, the signature points to independent pathways, including mTOR, involved in cell growth and apoptosis. The pathways identified can directly be targeted, thereby offering additional treatment approaches for these high-risk patients.

Therapy of childhood acute myelogenous leukemias

Acute myelogenous leukemia (AML) accounts for approximately 20% of acute leukemias in children. Although AML is more resistant to chemotherapy than acute lymphoblastic leukemia (ALL), significant progress in improving outcome for AML patients has been achieved over the past 15 years. This can be attributed to intensification of chemotherapy, increased use of bone marrow transplantation, and improved supportive care. Thus 30–50% of children with AML achieve long-term event-free survival with current treatment strategies [61, 66, 85, 96]. This review gives an overview about the evolution of and rationale for current pediatric treatment protocols, with special emphasis on the German Berlin-Frankfurt-Münster (BFM) studies, and discusses new directions for the future.

Coincidence of Recurrent Hemiparesis and Detection of ALL in a 4-Year-Old Girl: One or Two Diseases?

Stroke like symptoms in children such as hemiparesis are often associated with infection, cranial trauma, cardiac anomalies or sickle cell disease. In childhood leukemia, stroke like symptoms at presentation are rare and normally caused by cerebral bleedings. Here we report a patient who presented with classical stroke symptoms and hemiparesis prior to the diagnosis of acute lymphoblastic leukemia without proven CNS infiltration by leukemic cells. In general, acute leukemia or cerebral lymphoma do not lead to extensive defects of brain tissue. This unusual case suggests that acute lymphoblastic leukemia may present with stroke like CNS symptoms including hemiparesis.

Mitoxantrone-Etoposide or HD-ARA-C/Mitoxantrone for Remission Induction in Children with First Relapse of AML

One third of children with AML, initially responding to chemotherapy encounter recurrence of their disease. An effective chemotherapeutic regimen with tolerable toxicity is needed for this group of heavily pretreated children. In the past AML-BFM protocols did not specify for a salvage therapy. Reinduction chemotherapy with High Dose Ara-C/Mitoxantrone (HAM) or Mitoxantrone/Etoposide (Mitox/VP) was proposed. We performed a retrospective analysis among patients with first relapse previously treated with the AML-BFM 87 protocol with respect to initial response rates, toxicity and long term survival comparing the different reinduction regimen.

Second Remission in Relapsed Childhood Acute Myelogenous Leukemia After Pretreatment with the AML-BFM 83 Protocol

In Germany more than 80% of newly diagnosed children with acute myelogenous leukemia are treated within the cooperative Berlin-Frankfurt-Munster (BFM) studies. Complete remissions (CR) of 80% are achieved with these protocols but one-third of patients relapse within the first 3 years [1]. There are only a few studies on the treatment of relapsed childhood AML; these aim at evaluating new antileukemic drugs for frontline therapy. Most of the studies enrolled either patients with relapsed AML or patients with leukemia refractory to frontline treatment. With various therapeutic regimens complete remission rates of 45%–49% were achieved [2–5]. Except for patients with allogenic bone marrow transplantation, reports on long-time survival are lacking.