•Infection:

–Due to reduced humoral and cellular immune response

–High risk of infection during induction treatment and during episodes of severe neutropenia with absolute neutrophil count (ANC) less than 0.5 × 109/l

–Symptoms of infection may be atypical during phases of neutropenia

–Procedure during fever and neutropenia (ANC less than 0.5 × 109/l): blood culture analysis and immediate start of broad-spectrum antibiotics

–In infection with Pseudomonas, E. coli, opportunistic organisms (i.e., Pneumocystis carinii), virus, or fungal infection, treatment should be according to antibiotic resistance analysis of the causative microbe

–In viral infections, antiviral agents, often in combination with addition of intravenous immunoglobulins, in cases of low serum IgG level

–When signs of interstitial pneumonia occur: high-dose trimethoprim– sulfamethoxazole: 20 mg trimethoprim/kg body weight

2.11Relapse

Fifteen percent of ALL in systemic or extramedullary (CNS, testicular, others) form(s)

•Usually the same phenoand genotype of ALL as at initial diagnosis

•Rarely another cell lineage of leukemia (a lineage switch), especially in patients with initial bilineage or biphenotypic leukemia. Differential diagnosis: secondary leukemia, which can occur quite early, i.e., within a year or two of stopping treatment for the first leukemia

•Intensive treatment necessary. Hematological stem cell transplantation may be considered in special situations. Exceptions are: isolated CNS or dedicated relapse, late hematologic relapse

•Incidence of second remission after intensive reinduction treatment: 90%

•CNS leukemia prophylaxis with chemotherapy and/or CNS irradiation needed in relapse

•Poor prognosis: early relapse during treatment or within the first 6 months after cessation of treatment

•Favorable or unfavorable diagnosis in cases of late relapse more than 6 months after cessation of first treatment, depending on type of leukemia

•Event-free survival: after early relapse, 10–30%; after late relapse, 40–50%

•In children at high risk of relapse, stem cell transplantation probably appears to provide a higher rate of event-free survival (EFS) than chemotherapy alone

2.12Special Forms

2.12.1 CNS Leukemia

•CNS leukemia occurs in less than 10% of children, mostly diagnosed subclinically in the initial analysis of cerebrospinal fluid, or during maintenance treatment, or as late relapse. It occurs more frequently in children with T ALL or mature B ALL

•Definition of CNS leukemia: more than 5 leukemic cells/ml, with leukemic blasts present

•CNS relapse can be isolated to the CNS or in combination with bone marrow and/or testicular relapse

•Treatment: initially intrathecal chemotherapy until CNS remission, in parallel with systemic induction chemotherapy, followed by CNS and spinal irradiation in some cases (not always necessary), and continuation of systematic chemotherapy

•Dose-dependent side effects of irradiation: intellectual deficiency (especially deficiency in concentration), growth deficits

•Prognosis: 90% achieve initial remission; if relapse occurs less than 18 months from diagnosis, EFS is approx. 45% compared with those relapsing more than 18 months from diagnosis who have an approx. 80% EFS at 4 years with aggressive therapy

2.12.2 Testicular Leukemia

•Frequency is less than 2% of relapsed cases

•Biopsy of testes for occult testicular infiltration is not indicated because of side effects of biopsy; systemic treatment is usually effective at eradicating occult testicular leukemia

•Isolated testicular relapse is often followed by systemic relapse; therefore, intensive systemic chemotherapy is necessary in parallel with local irradiation of both testes

•Side effects: sterility and sometimes reduced testicular hormonal function; in the latter case, hormonal substitution may be necessary

•Patients with early relapse have an approximately 40% EFS, and patients with late relapse have an approximately 85% EFS at 3 years.