Early response to therapy and outcome in childhood acute lymphoblastic leukemia

Gaynon, Paul S.; Desai, Anish; Bostrom, Bruce; Hutchinson, Raymond J.; Lange, Beverly J.; Nachman, James B.; Reaman, Gregory H.; Sather, Harland N.; Steinherz, Peter G.; Trigg, Michael E.; Tubergen, David G.; Uckun, Fatih M.

doi:10.1002/(sici)1097-0142(19971101)80:9<1717::aid-cncr4>3.0.co;2-b

Cited by 203 publications

(123 citation statements)

References 37 publications

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“…45,46 This observation indicates the importance of early differences in chemosensitivity. We hypothesized that the rapidity and structure of the apoptotic response within the first 24-48 h may also predict relapse-free survival.…”

Section: Discussionmentioning

confidence: 82%

Diversity of the apoptotic response to chemotherapy in childhood leukemia

et al. 2002

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Apoptosis is the primary mechanism through which most chemotherapeutic agents induce tumor cell death. The purpose of this study was to determine the extent to which blasts from children with leukemia undergo a uniform apoptotic death pathway in vivo. The expression of pro-and anti-apoptotic proteins p53, p21, MDM-2, BCL-2, BCL-X L , BCL-X S , and BAX, and caspase-3 activity was determined in circulating blasts collected from the peripheral blood of children with leukemia prior to, and at serial time points following chemotherapy. Culturing blasts ex vivo for 12 h assessed spontaneous apoptosis and the increment induced by chemotherapy. Baseline apoptosis varied between 3% and 29%. Twenty-four hours following chemotherapy the increase in the percentage of cells undergoing apoptosis ranged from Ͻ1% to 38%. Eleven of 20 patients who received initial treatment with a p53-dependent drug showed an increase in p53 expression. In these patients, the levels of p53 target genes were also increased. A uniform pattern of BCL-2 family protein expression was not observed and only a minority of samples showed a change that would favor apoptosis. We conclude that that the initial apoptotic response to chemotherapy in children with leukemia is variable involving both p53-dependent and p53-independent pathways.

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Section: Discussionmentioning

confidence: 82%

Diversity of the apoptotic response to chemotherapy in childhood leukemia

et al. 2002

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“…10,[14][15][16]21,23,25,26,30,51,52 The day 7 and day 14 marrow response to therapy has been a consistent prognostic factor. [53][54][55] Improved systemic therapy has allowed restriction of brain irradiation to fewer than 15% of patients. The cumulative incidence of second malignant neoplasm remains Ͻ2%.…”

Section: Discussionmentioning

confidence: 99%

Children's Cancer Group trials in childhood acute lymphoblastic leukemia: 1983–1995

et al. 2000

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Since 1968, the Children's Cancer Group (CCG) has treated more than 16 000 children with acute lymphoblastic leukemia (ALL). Herein, we report improvements obtained in CCG trials during two successive series of studies (1983-1988 and 1989-1995). Overall, 10-year EFS was 62% ± 10% for the 1983-1988 series and 72% ± 1% for the 1988-1995 series (P Ͻ 0.0001). Five-year cumulative rates of isolated CNS relapses were 5.9% and 4.4%. Therapy based on the Berlin-Frankfurt-Mü nster 76/79 study improved outcomes for intermediate and higher risk patients in the first series. For intermediate risk patients, delayed intensification (DI) was most crucial for improved outcome and cranial irradiation was safely replaced with maintenance intrathecal methotrexate, providing patients received intensified systemic therapy. In the second series, randomized trials showed better outcome with one vs no DI phase for lower risk patients, with two vs one DI phase for intermediate risk patients, and with the CCG 'augmented regimen' for higher risk patients with a slow day 7 marrow response. Cranial irradiation was safely replaced with additional intrathecal methotrexate for higher risk patients with a rapid day 7 marrow response. In a subsequent study, substitution of dexamethasone in place of prednisone in induction and maintenance improved outcome for standard risk patients. All patients received dexamethasone in DI. These successful treatment strategies form the basis for our current ALL trials. Leukemia (2000) 14, 2223-2233.

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“…Early treatment response is one of the most important prognostic factors in children with ALL. Most investigators assess this variable by morphologic examination of bone marrow or peripheral blood after 7 or 14 days of remission induction therapy, [24][25][26] as was done in our studies 11 and 12. 3,27 Recently, we and others have extended the evaluation of early treatment response to the measurement of minimal residual leukemia, using immunologic detection of blast cells with flow cytometry or polymerase chain reaction amplification of clone-specific immunoglobulin and T cell receptor gene rearrangements.…”

Section: Featurementioning

confidence: 99%

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

et al. 2000

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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)(1985)(1986)(1987)(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 Ͼ100 ؋ 10 9 /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. Leukemia (2000) 14, 2286-2294.

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Early response to therapy and outcome in childhood acute lymphoblastic leukemia

Cited by 203 publications

References 37 publications

Diversity of the apoptotic response to chemotherapy in childhood leukemia

Diversity of the apoptotic response to chemotherapy in childhood leukemia

Children's Cancer Group trials in childhood acute lymphoblastic leukemia: 1983–1995

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

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