Low-dose oral etoposide-based induction regimen for children with acute lymphoblastic leukemia in first bone marrow relapse

Hijiya, Nobuko; Gajjar, Amar; Zhang, Z.; Sandlund, John T.; Ribeiro, Raul C.; Rubnitz, Jeffrey E.; Jeha, Sima; Liu, W.; Chen, Cheng; Raimondi, Susana C.; Behm, Frederick G.; Rivera, Gaston K.; Relling, Mary V.; Pui, Ching‐Hon

doi:10.1038/sj.leu.2403467

Cited by 23 publications

(9 citation statements)

References 28 publications

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“…To be eligible for this current study, adult survivors must have serum UA measured within 5 to 10 years post-diagnosis, as well as during their current follow-up visit. Eligible adult survivors were previously treated with various protocols for ALL,[1, 2, 27–29] with a vast majority of them receiving the Total Therapy chemotherapy regimens (Supplementary Table S1). …”

Section: Methodsmentioning

confidence: 99%

Uric Acid and Neurocognitive Function in Survivors of Childhood Acute Lymphoblastic Leukemia Treated with Chemotherapy Only

Cheung

Edelmann

Mulrooney

et al. 2016

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background Hyperuricemia is implicated in cardiovascular and cerebrovascular diseases. This study evaluated associations between uric acid (UA), cardiovascular health and neurocognitive function in adolescent and adult survivors of childhood acute lymphoblastic leukemia treated with chemotherapy only. Methods 126 adolescent (mean[SD] age 14.6[5.0]; 7.8[1.7] years post-diagnosis) and 226 adult survivors (age 25.4[4.2] years; 18.1[4.4] years post-diagnosis) completed comprehensive neurocognitive testing. Concurrent UA measurements were conducted for both groups. For adult survivors, cardiovascular risk factors were assessed; and UA measurements during adolescence (12.3[4.0] years before neurocognitive testing) were also collected. UA levels were categorized into quartiles for age- and gender-based ranking, and associations with neurocognitive outcomes were examined. Results Survivors demonstrated worse attention, processing speed and executive functions than population norms (p's<0.05). Adolescent survivors with elevated UA had poorer attention (p=0.04), visual-processing speed (p=0.03) and cognitive flexibility (p=0.02). UA was not associated with neurocognitive outcomes in adult survivors. Adult survivors developed dyslipidemia (46%), hypertension (32%) and abdominal obesity (26%), and high UA during adolescence was associated with these cardiovascular risk factors as adults (all p's<0.01). Fine-motor processing speed was slower in adult survivors with dyslipidemia (p=0.04) and abdominal obesity (p=0.04). Poorer attention was marginally associated with hypertension (p=0.06). Conclusions Elevated UA is associated with neurocognitive performance in adolescent survivors. In adult survivors, relative elevation of UA during adolescence was predictive of cardiovascular health, which was associated with poorer neurocognitive outcomes. Impact Future studies should evaluate the mediating role of chronic cardiovascular health conditions between elevated UA and subsequent neurocognitive impairment in survivors.

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Section: Methodsmentioning

confidence: 99%

Uric Acid and Neurocognitive Function in Survivors of Childhood Acute Lymphoblastic Leukemia Treated with Chemotherapy Only

Cheung

Edelmann

Mulrooney

et al. 2016

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…(24;27) Regimens for relapsed tumors and for palliative care often call for continuous administration of low-dose etoposide. (28;29) Although the limited survival of this patient population obscures the true incidence of s-AML, this approach appears to confer a low risk of s-AML. (29) Consistent with this observation are the results of in vitro studies showing a greater ratio of cytotoxicity to genetic recombination after prolonged exposure to etoposide than after brief exposure.…”

Section: Aml As a Secondary Malignancymentioning

confidence: 99%

Acute leukemia as a secondary malignancy in children and adolescents: Current findings and issues

Hijiya

Ness

Ribeiro

et al. 2008

Cancer

105

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Secondary acute leukemia is a devastating complication in children and adolescents who have been treated for cancer. Secondary acute lymphoblastic leukemia (s-ALL) was rarely reported previously but can be distinguished today from recurrent primary ALL by comparison of immunoglobulin and T-cell receptor rearrangement. Secondary acute myeloid leukemia (s-AML) is much more common, and some cases actually may be second primary cancers. Treatment-related and host-related characteristics and their interactions have been identified as risk factors for s-AML. The most widely recognized treatment-related risk factors are alkylating agents and topoisomerase II inhibitors (epipodophyllotoxins and anthracyclines). The magnitude of the risk associated with these factors depends on several variables, including the administration schedule, concomitant medications, and host factors. A high cumulative dose of alkylating agents is well known to predispose to s-AML. The prevalence of alkylator-associated s-AML has diminished among pediatric oncology patients with the reduction of cumulative alkylator dose and limited use of the more leukemogenic alkylators. The best-documented topoisomerase II inhibitor-associated s-AML is s-AML associated with epipodophyllotoxins. The risk of s-AML in these cases is influenced by the schedule of drug administration and by interaction with other antineoplastic agents but is not consistently found to be related to cumulative dose. The unpredictable risk of s-AML after epipodophyllotoxin therapy may discourage the use of these agents, even in patients at a high risk of disease recurrence, although the benefit of recurrence prevention may outweigh the risk of s-AML. Studies in survivors of adult cancers suggest that, contrary to previous beliefs, the outcome of s-AML is not necessarily worse than that of de novo AML when adjusted for cytogenetic features. More studies are needed to confirm this finding in the pediatric patient population.

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“…In previously reported studies, the complete remission (CR) rate was >90% for late bone marrow relapse and from 75% to 85% for early bone marrow relapse. 3,4 Increased intensity of contemporary frontline therapy may make salvage therapy more difficult, because leukemic blast cells may become more resistant to chemotherapy than they do in patients who are treated less intensively. 3 A new agent that has a novel mechanism of cytotoxicity and preferably less crossresistance is needed to improve outcome.…”

mentioning

confidence: 99%

“…3 Although from 40% to 50% of patients with late first bone marrow relapse may survive, <20% of patients are long-term survivors after early relapse. [2][3][4][5] Induction of remission is the first crucial stage for successful retrieval treatment. In previously reported studies, the complete remission (CR) rate was >90% for late bone marrow relapse and from 75% to 85% for early bone marrow relapse.…”

mentioning

confidence: 99%

Phase II study of topotecan in combination with dexamethasone, asparaginase, and vincristine in pediatric patients with acute lymphoblastic leukemia in first relapse

Hijiya

Stewart

Zhou

et al. 2008

Cancer

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BACKGROUND. The authors evaluated the response rate, toxicity, and pharmacokinetics of topotecan given before standard induction therapy for childhood acute lymphoblastic leukemia (ALL) in first relapse. METHODS. Patients received topotecan (2.4 mg/m2 daily as a 30‐minute infusion) for 5 days before induction therapy with dexamethasone, vincristine, and asparaginase (native or pegylated Escherichia coli). The pharmacokinetics of topotecan were measured with the first dose of treatment in 23 patients. RESULTS. Twenty‐eight of 31 patients with circulating blast cells were evaluable for response to topotecan. Twenty‐five patients (89.3%) had a response (>25% decrease in circulating blast cells). The leukocyte count (P = .0001) and blast cell count (P = .0009) declined significantly during topotecan therapy. The median (range) topotecan lactone area under the concentration‐time curve after the first dose was 85.4 L/hour/m2 (range, 38.7–229.3 L/hour/m2). At the end of induction, 23 patients (74.2%) had a complete response, 1 patient (3.2%) had a partial response, 5 patients (16.1%) had no response, and 2 patients had died of infection. Six of the 17 patients who were studied for minimal residual disease (MRD) achieved MRD‐negative status at the end of induction. The main toxicities were hematologic, gastrointestinal, and hepatic. The estimated 5‐year survival rate, event‐free survival rate, and cumulative incidence of second relapse were 24.1% ± 7.9%, 18.2% ± 7.4%, and 22.8% ± 8.7%, respectively, in the 29 patients who had a hematologic first relapse. CONCLUSIONS. A regimen comprising single‐agent topotecan given with a standard 3‐drug combination was effective in inducing remission in pediatric patients with relapsed ALL and was tolerated well. Cancer 2008. © 2008 American Cancer Society.

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Low-dose oral etoposide-based induction regimen for children with acute lymphoblastic leukemia in first bone marrow relapse

Cited by 23 publications

References 28 publications

Uric Acid and Neurocognitive Function in Survivors of Childhood Acute Lymphoblastic Leukemia Treated with Chemotherapy Only

Uric Acid and Neurocognitive Function in Survivors of Childhood Acute Lymphoblastic Leukemia Treated with Chemotherapy Only

Acute leukemia as a secondary malignancy in children and adolescents: Current findings and issues

Phase II study of topotecan in combination with dexamethasone, asparaginase, and vincristine in pediatric patients with acute lymphoblastic leukemia in first relapse

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