Chemotherapy in 998 unselected childhood acute lymphoblastic leukemia patients. Results and conclusions of the multicenter trial ALL-BFM 86

Abstract

In trial ALL-BFM 86, the largest multicenter trial of the Berlin- Frankfurt-Munster (BFM) study group for childhood acute lymphoblastic leukemia (ALL), treatment response was used as an overriding stratification factor for the first time. In the previous trial ALL-BFM 83, the in vivo response to initial prednisone treatment was evaluated prospectively. A blast cell count of > or = 1,000/microL peripheral blood after a 7-day exposure to prednisone and one intrathecal dose of methotrexate (MTX) identified 10% of the patients as having a significantly worse prognosis. In trial ALL-BFM 86 patients with > or = 1,000/microL blood blasts on day 8 were included in an experimental branch EG. Patients with < 1,000/microL blood blasts on day 8 were stratified by their leukemic cell burden into two branches, Standard Risk Group (SRG) and Risk Group (RG). SRG patients received an eight- drug induction followed by consolidation protocol M (6-mercaptopurine, high-dose [HD] MTX 4 x 5 g/m2) and maintenance. RG patients were treated with an additional eight-drug reinduction element. For EG patients protocol M was replaced by protocol E (prednisone, HD-MTX, HD- cytarabine, ifosfamide, mitoxantrone). All patients received intrathecal MTX therapy; only those of branches RG and EG received cranial irradiation. In branch RG, patients were randomized to receive or not to receive late intensification (prednisone, vindesine, teniposide, ifosfamide, HD-cytarabine) in the 13th month. During the trial reinduction therapy was introduced in branch SRG, because in the follow-up of trial ALL-BFM 83 the randomized low-risk patients receiving reinduction did significantly better. Nine hundred ninety- eight evaluable patients were enrolled, 28.6% in SRG, 61.1% in RG, 10.3% in EG. At a median follow-up of 5.0 (range 3.4 to 6.9) years, the estimated 6-year event-free survival was 72% +/- 2% for the study population, 58% +/- 5% in branch SRG for the first 110 patients without reinduction therapy, 87% +/- 3% for the next 175 patients with reinduction therapy, 75% +/- 2% in branch RG, and 48% +/- 5% in branch EG. Late intensification did not significantly affect treatment outcome of RG patients; however, only 23% of the eligible patients were randomized. Prednisone poor response remained a negative prognostic parameter despite intensified therapy. The results confirmed the benefit of intensive reinduction therapy even for low-risk patients. The strategy of induction, consolidation, and intensive reinduction may offer roughly 75% of unselected childhood ALL patients the chance for an event-free survival.

Induction failure in acute lymphoblastic leukemia of childhood

“…Many research protocols have defined induction failure as the presence of persistent leukemia after two cycles (or 2 months) of induction therapy 1, 2, 5, 6. Our data suggest that a more conservative definition of induction failure should be used.…”

“…Ochs and colleagues19 reported that 12 of 27 (44%) patients achieved CR after one or two cycles with teniposide and cytosine arabinoside. The Berlin‐Frankfurt‐Munster (BFM) group2 reported that 9 of 20 (45%) children who were refractory to the first month of induction therapy achieved CR after treatment with cyclophosphamide, cytosine arabinoside, and 6‐mercaptopurine. In a study that included both adults and children, Giona and colleagues20 found that 7 of 13 (54%) patients who received idarubicin, cytosine arabinoside, and prednisone achieved CR.…”

“…With intensive, multiagent therapy, the vast majority (>95%) of children with acute lymphoblastic leukemia (ALL) achieve complete remission (CR) 1–3. Although it is widely accepted that failure to achieve CR after induction therapy portends a poor prognosis, there is variability among investigators regarding the precise definition of induction failure in childhood ALL.…”

“…Although it is widely accepted that failure to achieve CR after induction therapy portends a poor prognosis, there is variability among investigators regarding the precise definition of induction failure in childhood ALL. Some investigators define induction failure as persistent leukemia at the end of 1 month of therapy,4 whereas others use a 2‐month cut‐off (i.e., persistent leukemia after two cycles of induction therapy) 2, 5, 6. Some groups have differentiated patients by the percentage of bone marrow blasts at the end of 1 month, reserving the term induction failure for children with an M3 bone marrow (defined as >25% blasts) after 1 month of therapy, allowing patients with an M2 bone marrow (6–25% blasts) extra time to achieve CR (with additional chemotherapy) before removing them from study 7.…”

Identification of PML as novel PAX5 fusion partner in childhood acute lymphoblastic leukaemia

“…Immunophenotyping revealed a B‐II‐ALL positive for CD19, CD10, CD22, TdT and HLA‐DR. Treatment was performed according to the ALL‐BFM 86 protocol (Reiter et al , 1994) and the patient achieved remisson after 40 d, but relapsed 2 years and 3 months after diagnosis. At relapse biopsy of the testis showed infiltration with ALL blast cells and in the BM 45% of lymphoblasts were detected.…”