Gaston K. Rivera

Acute Myeloid Leukemia in Children Treated with Epipodophyllotoxins for Acute Lymphoblastic Leukemia

BACKGROUND AND METHODS Treatment of cancer with the epipodophyllotoxins (etoposide and teniposide) has been linked to the development of acute myeloid leukemia (AML) in children and adults, but the factors that might influence the risk of this complication of therapy are poorly defined. We therefore assessed the importance of potential risk factors for secondary AML in 734 consecutive children with acute lymphoblastic leukemia who attained complete remission and received continuation (maintenance) treatment according to different schedules of epipodophyllotoxin administration. RESULTS Secondary AML was diagnosed in 21 of the 734 patients, in 17 of whom this complication was the initial adverse event. Prolonged administration of epipodophyllotoxin (teniposide with or without etoposide) twice weekly or weekly was independently associated with the development of secondary AML (P less than 0.01 by Cox regression analysis). The overall cumulative risk of AML at six years was 3.8 percent (95 percent confidence interval, 2.3 percent to 6.1 percent); but within the subgroups treated twice weekly or weekly, the risks were 12.3 percent (95 percent confidence interval, 5.7 percent to 25.4 percent) and 12.4 percent (95 percent confidence interval, 6.1 percent to 24.4 percent), respectively. In the subgroups not treated with epipodophyllotoxins or treated with them only during remission induction or every two weeks during continuation treatment, the highest cumulative risk was 1.6 percent (95 percent confidence interval, 0.4 percent to 6.1 percent). After adjustment for treatment frequency, there was no apparent relation between the total dose of epipodophyllotoxins and the development of secondary AML. The relative hazard of etoposide as compared with teniposide could not be determined. CONCLUSIONS The risk of epipodophyllotoxin-related AML depends largely on the schedule of drug administration. Other factors, including the cumulative dose of epipodophyllotoxin, radiotherapy, and the initial biologic features of the leukemic blast cells, do not appear to have critical roles.

Immunological detection of minimal residual disease in children with acute lymphoblastic leukaemia

BACKGROUND The clinical significance of submicroscopic levels of leukaemic cells in bone-marrow aspirates from children with acute lymphoblastic leukaemia (ALL) remains controversial. We prospectively determined the frequency and prognostic importance of minimal residual disease detected by a rapid immunological assay in bone-marrow aspirates of children with ALL. METHODS 158 children with newly diagnosed ALL received 6 weeks of remission-induction chemotherapy. Once complete clinical remission was attained the patients received 2 weeks of consolidation therapy followed by continuation therapy. Bone-marrow aspirates were collected after induction therapy and during weeks 14, 32, and 56 of continuation therapy, and then at 120 weeks (end of therapy). Cells with leukaemia-associated immunophenotypes were investigated by multiparameter flowcytometry capable of detecting one leukaemic cell among 10,000 normal cells. FINDINGS The proportion of patients with detectable leukaemic cells was 23% at remission induction and 17% at week 14 of continuation therapy, decreasing to 5% and 4% at weeks 32 and 56. None of the 65 samples examined at completion of therapy (week 120) showed evidence of disease. Detectable residual disease at the end of remission induction correlated with adverse genetic abnormalities--the Philadelphia chromosome and MLL gene rearrangements--but not with other presenting features. Detectable leukaemia was associated with subsequent relapse regardless of the time at which bone-marrow samples were examined (p < 0.002 for all comparisons). For example, 3-year cumulative incidence (SE) of relapse in patients with and without detectable leukaemia at remission induction was 32.5% (10.6) and 7.5% (4.0), respectively (p < 0.001); for tests done at week 14, it was 42.1% (14.6) and 6.6% (3.5), p < 0.001. These correlations remained significant after adjusting for adverse presenting features. A higher degree of marrow infiltration by leukaemic cells (> or = 0.1%) in week 14 samples identified a subset of patients with an especially poor prognosis. INTERPRETATION Immunological detection of residual leukaemic cells at any point in the treatment course is a powerful predictor of relapse in children with ALL. Alternative treatment should be considered for cases with persistent disease beyond the first 3 months of continuation therapy.

Secondary Acute Myeloid Leukemia in Children Treated for Acute Lymphoid Leukemia

We studied the risk of the development of acute myeloid leukemia (AML) during initial remission in 733 consecutive children with acute lymphoid leukemia (ALL) who were treated with intensive chemotherapy. This complication was identified according to standard morphologic and cytochemical criteria in 13 patients 1.2 to 6 years (median, 3.0) after the diagnosis of ALL. At three years of follow-up, the cumulative risk of secondary AML during the first bone marrow remission was 1.6 percent (95 percent confidence limits, 0.7 and 3.5 percent); at six years, it was 4.7 percent (2 and 10 percent). The development of secondary AML was much more likely among patients with a T-cell than a non-T-cell immunophenotype (cumulative risk, 19.1 percent [6 and 47 percent] at six years). Sequential cytogenetic studies in 10 patients revealed entirely different karyotypes in 9, suggesting the induction of a second neoplasm. In eight of these patients, the blast cells had abnormalities of the 11q23 chromosomal region, which has been associated with malignant transformation of a pluripotential stem cell. There was no evidence of loss of DNA from chromosome 5 or 7, a karyotypic change commonly observed in cases of AML secondary to treatment with alkylating agents, irradiation, or both. We conclude that there is a substantial risk of AML in patients who receive intensive treatment for ALL, especially in those with a T-cell immunophenotype, and that 11q23 chromosomal abnormalities may be important in the pathogenesis of this complication.

Improved outcome in childhood acute lymphoblastic leukaemia with reinforced early treatment and rotational combination chemotherapy

To improve outcome in childhood acute lymphoblastic leukaemia (ALL), a stratified, randomised study of extended intensified chemotherapy was done. 358 evaluable patients received remission reinforcement therapy (teniposide, cytarabine, high-dose methotrexate) added to a four-drug induction regimen. Those achieving complete remission were randomised on the basis of risk group assignment to conventional continuation treatment or to four pairs of drugs rotated weekly or every 6 weeks. All patients received intrathecal chemotherapy; higher-risk patients also received 1800 cGy cranial irradiation after 1 year of remission. Complete remission was induced in 96% of the patients. At median follow-up of 40 (range 19-73) months, 4-year event-free survival (SE) was 73 (4)% overall, 81 (6)% in the lower-risk group (n = 110), and 69 (5)% in the higher-risk group (n = 248). Outcome within risk groups was not significantly affected by the speed of rotation of drug pairs during continuation treatment. Various high-risk subgroups had apparently improved responses to this treatment. This intensified chemotherapy may cure 69-77% of children with ALL.

High incidence of secondary brain tumours after radiotherapy and antimetabolites

BACKGROUND Brain tumours rarely occur in survivors of childhood acute lymphoblastic leukaemia after cranial radiotherapy. An unusually high frequency of brain tumours seen among children enrolled in one of our leukaemia treatment protocols, Total Therapy Study XII, prompted us to identify the potential causes of this complication. METHODS We assessed clinical, biological, and pharmacokinetic features in all 52 children who received prophylactic cranial radiotherapy. We compared the cumulative incidence of brain tumours between subgroups, and with that of 421 children who received radiotherapy in previous studies. FINDINGS The incidence of brain tumours among irradiated children (six of 52, 12.8% [SE 5.0]) was high compared with patients in the same study who did not receive radiotherapy (none of 101; p=0.0008) and with other protocols that included cranial radiotherapy (p<0.0001). Of the six children, four had erythrocyte concentrations of thioguanine nucleotide metabolites higher than the 70th percentile for the entire cohort, and three had a genetic defect in thiopurine catabolism. The 8-year cumulative incidence of brain tumour among children with defective versus wild-type thiopurine methyltransferase phenotype was 42.9% (SE 20.6) versus 8.3% (4.7; p=0.0077). This protocol differed from previous protocols, in that more intensive systemic antimetabolite therapy was given before and during radiotherapy. INTERPRETATION These data support the elimination of prophylactic radiotherapy for acute lymphoblastic leukaemia except in patients at high risk of central-nervous-system relapse. Underlying genetic characteristics and treatment variables may be associated with an increased risk of radiation-associated brain tumours.

Successful Intermittent Chemoprophylaxis for Pneumocystis carinii Pneumonitis

We conducted a prospective, randomized clinical trial over a two-year period in patients with acute lymphocytic leukemia to assess the effectiveness of trimethoprim-sulfamethoxazole given on three consecutive days each week as compared with daily in the prevention of Pneumocystis carinii pneumonitis. P. carinii pneumonitis did not develop in any of 92 patients receiving the drug daily (30,602 patient-days) or in any of 74 who received it three consecutive days a week (27,329 patient-days), whereas the incidence of the infection expected without prophylaxis is 21 percent. One patient, excluded from both groups because of an adverse reaction to sulfonamides in the past, acquired P. carinii pneumonitis. Especially noteworthy was a difference in the occurrence of systemic mycoses, with 10 cases in the daily-treatment group and only 1 case in the three-days-a-week group (P = 0.024). No differences were observed in the rates of other infections or adverse effects associated with the drug. We conclude that trimethoprim-sulfamethoxazole is as effective given three days a week as it is given daily in the prevention of P. carinii pneumonitis and that the intermittent schedule has the advantages of less frequent fungal infections and lower cost. Intermittent chemoprophylaxis may be especially beneficial to certain patients who are unable to tolerate the daily doses.

Results of treatment of advanced-stage Burkitt's lymphoma and B cell (SIg+) acute lymphoblastic leukemia with high-dose fractionated cyclophosphamide and coordinated high-dose methotrexate and cytarabine.

To address the problem of historically poor results in the treatment of children with advanced-stage Burkitts lymphoma and B cell (SIg+) acute lymphoblastic leukemia (ALL), an intensive chemotherapy regimen was devised using the most effective single agents in high-dose short courses. Treatment commenced with a fractionated schedule of intravenous (IV) cyclophosphamide (300 mg/m2 every 12 hours for six doses) followed immediately by Adriamycin (50 mg/m2) and vincristine (1.5 mg/m2) with combined intrathecal (IT) methotrexate and cytarabine. Predictably, this treatment produced virtually complete disappearance of all tumor and profound myelosuppression. Immediately on hematologic recovery, IV high-dose methotrexate (1,000 mg/m2 over 24 hours) followed by IV cytarabine (400 mg/m2 over the next 48 hours) was administered with leucovorin rescue and repeated IT treatments. The treatment sequence described above is repeated four times, with the dose of cytarabine doubled in succeeding courses, up to 3,200 mg/m2. The entire planned therapy required approximately 24 weeks. Since 1981, we treated a total of 29 children with this approach, 19 of whom had massive unresectable intraabdominal tumor. According to initial extent of disease, 17 were classified as stage III, four as stage IV non-Hodgkins lymphoma (NHL), and eight as B cell ALL. Eight of the 12 patients with stage IV NHL or B cell ALL had initial involvement of the CNS. Twenty-seven of 29 patients (93%) attained a complete remission. Fourteen of 17 stage III NHL patients remain disease free, for periods ranging from 3+ months to 4 1/2+ years. The actuarial estimate of the proportion of stage III patients remaining disease free at 2 years is 81%. Results in patients with initial involvement of the CNS and/or marrow are much less favorable, with only two of ten patients who attained remission apparently being cured. In addition to stage, the initial serum lactic dehydrogenase (LDH) level emerged as a prognostic indicator, higher levels (over 1,000 IU/L) being associated with the worst prognosis (P less than .05). Major toxicity consisted of severe hematopoietic suppression and febrile episodes associated with neutropenia. We conclude that this treatment is highly effective for advanced-stage Burkitts tumors in children free of initial CNS involvement.

Secondary brain tumors in children treated for acute lymphoblastic leukemia at St Jude Children's Research Hospital.

PURPOSE To evaluate the incidence of and potential risk factors for second malignant neoplasms of the brain following treatment for childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS The study population consisted of 1,612 consecutively enrolled protocol patients treated on sequential institutional protocols for newly diagnosed ALL at St Jude Childrens Research Hospital (SJCRH) between 1967 and 1988. The median follow-up duration is 15.9 years (range, 5.5 to 29.9 y). RESULTS The cumulative incidence of brain tumors at 20 years is 1.39% (95% confidence interval [CI], 0.63% to 2.15%). Twenty-two brain tumors (10 high-grade gliomas, one low-grade glioma, and 11 meningiomas) were diagnosed among 21 patients after a median latency of 12.6 years (high-grade gliomas, 9.1 years; meningiomas, 19 years). Tumor type was linked to outcome, with patients who developed high-grade tumors doing poorly and those who developed low-grade tumors doing well. Risk factors for developing any secondary brain tumor included the presence of CNS leukemia at diagnosis, treatment on Total X therapy, and the use of cranial irradiation, which was dose-dependent. Age less than 6 years was associated with an increased risk of developing a high-grade glioma. CONCLUSION This single-institution study, with a high rate of long-term data capture, demonstrated that brain tumors are a rare, late complication of therapy for ALL. We report many more low-grade tumors than others probably because of exhaustive long-term follow-up evaluation. The importance of limiting cranial radiation is underscored by the dose-dependent tumorigenic effect of radiation therapy seen in this study.

Long-term results of Total Therapy studies 11, 12 and 13A for childhood acute lymphoblastic leukemia at St Jude Children's Research Hospital

We present the long-term results of three consecutive clinical trials (total therapy studies 11, 12 and 13a) conducted for children with newly diagnosed acute lymphoblastic leukemia (all) between 1984 and 1994. in study 11 (1984–1988), the overall event-free survival rates (±1 s.e.) were 71.8 ± 2.4% and 69.3 ± 2.4%, and the cumulative risks of isolated central nervous system (cns) relapse 5.6 ± 1.2% and 5.9 ± 1.3%, at 5 and 10 years, respectively. in study 12 (1988–1991), event-free survival rates were 67.6 ± 3.4% and 61.5± 9.0%, and isolated cns relapse rates were 10.4 ± 2.3% and 10.4 ± 2.3%, respectively. early intensive intrathecal therapy in study 13a (1991–1994) has yielded a very low 5-year isolated cns relapse rate of 1.2 ± 0.9%, boosting the 5-year event-free survival rate to 76.9 ± 3.3%. factors consistently associated with an adverse prognosis included male sex, infant or adolescent age group, leukocyte count >100 × 109/l, nonhyperdiploidy karyotype and poor early response to treatment. Risk classification based on age and leukocyte count had prognostic significance in B-lineage but not T-lineage ALL. Early therapeutic interventions or modifications for patients with specific genetic abnormalities or persistent minimal residual leukemia may further improve long-term results.

TEL gene rearrangement in acute lymphoblastic leukemia: a new genetic marker with prognostic significance.

PURPOSE TEL gene rearrangements due to the 12;21 chromosomal translocation are the most common molecular genetic abnormality in childhood acute lymphoblastic leukemia (ALL), occurring in approximately 25% of cases with a B-precursor immunophenotype. The limited number of clinically useful genetic markers in this leukemia subtype prompted us to assess TEL status as a predictor of treatment outcome. PATIENTS AND METHODS We determined the status of the TEL gene (rearranged or germline) in 188 cases of B-precursor acute leukemia using Southern blot analysis and related the findings to event-free survival. All comparisons of outcome were stratified by treatment regimen, risk classification, age, and leukocyte count. RESULTS Forty-eight patients (26%) had a rearranged TEL gene. At 5 years of follow-up, an estimated 91% +/- 5% (SE) of this group were event-free survivors, compared with only 65% +/- 5% of the group with germline TEL (stratified log-rank P = .011). For nonhyperdiploid patients, the odds ratio of an adverse event in the germline TEL group to that for the rearranged TEL group was 4.06 (95% confidence interval, 1.86 to 8.84). The relationship of TEL rearrangement to a favorable prognosis was independent of recognized good-risk features in B-precursor leukemia, including age, initial leukocyte count, and hyperdiploidy. CONCLUSION Rearrangement of the TEL gene distinguishes a large subset of children with favorable-prognosis B-precursor leukemia who cannot be identified by standard prognostic features. It may be possible to treat these patients less aggressively without loss of therapeutic efficacy.