Therapy For Childhood Acute Lymphoblastic Leukemia Research Articles

Minimal residual disease analysis for the prediction of relapse in children with standard‐risk acute lymphoblastic leukaemia

We report a largely retrospective analysis of minimal residual disease (MRD) in a cohort of 66 children suffering from acute lymphoblastic leukaemia (ALL). All patients lacked high-risk features at diagnosis, i.e. the presenting white cell count was <50 x 10(9)/l, age 1-16 years and translocations t(9;22) and t(4;11) were not present. All were treated according to either the MRC protocols UKALL X or XI. PCR of IgH, TCRdelta and TCRgamma gene rearrangements and allele-specific oligoprobing were employed for the detection of MRD. Sensitivity was at least 10(-4) in 78/82 (93%) probes examined. A total of 33 patients relapsed (seven on therapy and 26 off) and 33 remain in continuing complete remission (CCR) (median follow-up 69 months from diagnosis). Of those who remain in CCR, MRD was present in the bone marrow in 32%, 10% and 0% at 1, 3 and 5 months into therapy respectively. This is in marked contrast to the presence of MRD at these times in 82%, 60% and 41% of patients who relapsed (P<0.001, P<0.005 and P<0.005). These results provide further evidence of a strong correlation between clearance of MRD early in therapy and clinical outcome in childhood ALL.

Treatment of children with epipodophyllotoxin-induced secondary acute myeloid leukemia.

Secondary acute myeloid leukemia (AML) after treatment with epipodophyllotoxins is being observed with increased frequency. Therapeutic options are limited for patients with secondary AML and the role of bone marrow transplantation is unclear. The authors report the treatment outcome of a cohort of 17 children who developed epipodophyllotoxin-induced secondary AML after therapy for childhood acute lymphoblastic leukemia (ALL) that included etoposide but no irradiation or alkylating agents. Thirteen patients (76%) had 11q23 chromosomal abnormalities that were not present at the initial diagnosis of ALL. Remission induction was attempted in 16 children, with 13 (81%) achieving a complete remission. After consolidation, 9 of these 13 patients received a bone marrow transplant (BMT): 2 with 4-hydroperoxycyclophosphamide-purged autologous marrow, 4 from a human leukocyte antigen (HLA)-identical sibling, 1 from a mismatched parental donor, and 2 from a matched unrelated donor. One additional child underwent allogeneic BMT without an attempt at reinduction. Of the 10 patients who received transplants, 2 were alive and well 27+ and 36+ months, respectively, after BMT. Of the 7 patients who did not receive a transplant, at last follow-up 1 had survived off therapy for 8 months for recurrent ALL whereas 6 died of AML. These data confirm the poor prognosis of secondary AML after epipodophyllotoxin treatment for childhood ALL. Although patients with secondary AML can achieve a remission, it is usually of brief duration. Allogeneic BMT may offer the possibility of long term remission in some of these patients. More information is needed to better define the risks and benefits of epipodophyllotoxin therapy for childhood ALL.

Epipodophyllotoxins in the treatment of childhood cancer.

We reported marked biologic activity with the epipodophyllotoxins in phase I/II studies of childhood cancer conducted in the 1970s. We have since extensively used the combination of teniposide and ara-C in the treatment of acute lymphoblastic leukemia (ALL). Initially we treated patients with refractory disease and found that the combination lacked clinical cross-resistance with standard antileukemic drugs. This formed a rationale to move teniposide and/or etoposide to front-line therapy of childhood ALL. The superior results projected for our last trial, an overall cure rate of about 75%, are attributable in part to early use of epipodophyllotoxins. This class of agents is also used extensively in the treatment of newly diagnosed childhood solid tumors, including neuroblastoma, medulloblastoma, rhabdomyosarcoma, and germ-cell tumors. Secondary leukemias following treatment with epipodophyllotoxins have been reported in a small subset of patients. Current data show that the most important risk factor is the schedule of drug delivery, which has led to appropriate protocol modifications.

Low-dose versus high-dose methotrexate during remission induction in childhood acute lymphoblastic leukemia (Protocol 81-01 update)

We evaluated event-free survival (EFS) and leukemia-free interval (LFI) of children treated for acute lymphoblastic leukemia (ALL). Patients were randomized to receive either a low dose or high dose of methotrexate (MTX) as a single agent at the time of diagnosis. Five days later, multidrug therapy was begun. We assessed the early antileukemic efficacy of the two doses of MTX, as well as toxicity and long-term efficacy. An increase in cell kill, as indicated by a larger decrease in the percentage of viable cells in the bone marrow between days 0 and 5, was observed for the high-dose MTX group when compared with the low-dose MTX group (P = .04). At 7.1 years of median follow- up, the 38 children randomized to receive high-dose MTX had a better EFS and LFI compared with the 39 patients randomized to receive low- dose MTX. The 7-year percentages (+/- SE) for EFS were 82% +/- 6% for high-dose MTX and 69% +/- 7% for low-dose MTX (P = .13). The 7-year percentages for LFI were 91% +/- 5% and 69% +/- 7%, respectively (P = .01). We recommend that high-dose MTX be considered as an effective addition to induction therapy in childhood ALL.

Low-Dose Versus High-Dose Methotrexate During Remission Induction in Childhood Acute Lymphoblastic Leukemia (Protocol 81-01 Update)

AbstractWe evaluated event-free survival (EFS) and leukemia-free interval (LFI) of children treated for acute lymphoblastic leukemia (ALL). Patients were randomized to receive either a low dose or high dose of methotrexate (MTX) as a single agent at the time of diagnosis. Five days later, multidrug therapy was begun. We assessed the early antileukemic efficacy of the two doses of MTX, as well as toxicity and long-term efficacy. An increase in cell kill, as indicated by a larger decrease in the percentage of viable cells in the bone marrow between days 0 and 5, was observed for the high-dose MTX group when compared with the low-dose MTX group (P = .04). At 7.1 years of median follow-up, the 38 children randomized to receive high-dose MTX had a better EFS and LFI compared with the 39 patients randomized to receive low-dose MTX. The 7-year percentages (±SE) for EFS were 82% ± 6% for high-dose MTX and 69% ± 7% for low-dose MTX (P = .13). The 7-year percentages for LFI were 91% ± 5% and 69% ± 7%, respectively (P =.01). We recommend that high-dose MTX be considered as an effective addition to induction therapy in childhood ALL.

Combination chemotherapy for bone marrow relapse in childhood lymphoblastic leukaemia (all)

Thirty-four children with acute lymphoblastic leukaemia (ALL) in relapse or resistant to initial induction received combination chemotherapy with prednisolone, vincristine, l-asparaginase, and daunorubicin. L-asparaginase was given subcutaneously on alternate days for four weeks and was well tolerated. A complete remission was achieved in 96% of children in relapse and in five out of six children resistant to induction. Remission was achieved without hospitalisation in over 60% of patients. The median duration of subsequent remission was only 13 weeks, but six out of eight children receiving a second course of the drug combination achieved a further remission. We conclude that prolonged l-asparaginase therapy in combination with an anthracycline might well be used in initial or consolidation therapy for childhood ALL.