Pediatric Oncology Group (POG) studies of acute myeloid leukemia (AML): a review of four consecutive childhood AML trials conducted between 1981 and 2000

Abstract

From 1981 to 2000, a total of 1823 children with acute myeloid leukemia (AML) enrolled on four consecutive Pediatric Oncology Group (POG) clinical trials. POG 8101 demonstrated that the induction rate associated with the 3 þ 7 þ 7 combination of daunorubicin, Ara-C, and 6-thioguanine (DAT) was greater than that associated with an induction regimen used to treat acute lymphoblastic leukemia (82 vs 61%; P ¼ 0.02). Designed as a pilot study to determine the feasibility of administration of noncross-resistant drug pairs and later modified to assess the effect of dose intensification of Ara-C during the second induction course, POG 8498 confirmed the high initial rate of response to DAT (84.2%) and showed that dose intensification of Ara-C during the second induction course resulted in a trend toward higher event-free survival (EFS) estimates than did standard-dose DAT (2 þ 5) during the second induction course (5 year EFS estimates, 22 vs 27%; P ¼ 0.33). Age o2 years and leukocyte count o100 000/mm 3 emerged as significantly good prognostic factors. The most significant observation made in the POG 8498 study was the markedly superior outcome of children with Down's syndrome who were treated on the high-dose Ara-C regimen. POG 8821 compared the efficacy of autologous bone marrow transplantation (BMT) with that of intensive consolidation chemotherapy. Intent-to-treat analysis revealed similar 5-year EFS estimates for the group that underwent autologous BMT (3674.7%) and for the group that received only intensive chemotherapy (3574.5%) (P ¼ 0.25). There was a high rate of treatment-related mortality in the autologous transplantation group. The study demonstrated superior results of allogeneic BMT for patients with histocompatible related donors (5-year EFS estimate 6375.4%) and of children with Down's syndrome (5-year EFS estimate, 6678.6%). The POG 9421 AML study evaluated high-dose Ara-C as part of the first induction course and the use of the multidrug resistance modulator cyclosporine. Preliminary results showed that patients receiving both highdose Ara-C for remission induction and the MDR modulator for consolidation had a superior outcome (5-year EFS estimate, 4278.2%) than did patients receiving other treatment; however, the difference was not statistically significant. These four studies demonstrate the importance of dose intensification of Ara-C in the treatment of childhood AML; cytogenetics as the single most prognostic factor and the unique curability of AML in children with Down's syndrome.

Incidence and predictors of treatment-related mortality in paediatric acute leukaemia in El Salvador

“…However, our report is the first to compare the relative contribution of TRM with treatment failure for children with ALL and AML in an LIC. In HICs, TRM accounts for more treatment failure in children with AML than ALL (Christensen et al, 2005;Ravindranath et al, 2005;Slats et al, 2005;Creutzig et al, 2006;Pui and Evans, 2006). Our finding suggests that in LICs, efforts to reduce TRM are as important for children with ALL as for those with AML.…”

“…In high-income countries (HICs), overall cure rates of approximately 80% have been achieved in acute lymphoblastic leukaemia (ALL) (Pui and Evans, 2006). Recent trials in children with acute myeloid leukaemia (AML) also have shown improved outcomes and have resulted in event-free survival (EFS) of approximately 50% (Stevens et al, 1998;Ravindranath et al, 2005;Creutzig et al, 2006). These advances have been attributed to more efficacious use of antileukaemic agents, intensification of treatment when appropriate, identification of prognostic factors for risk stratification, and improvements in supportive care (Ravindranath et al, 2005;Pui and Evans, 2006).…”

Improved treatment results for childhood acute myeloid leukemia in Taiwan

“…The 5-year EFS of 5474.4% achieved in studies TPOG-AML-97A, TPOG-APL-97, and TPOG-APL-2001 were at least comparable to the 31-54% attained in studies conducted in other developed countries during the same era, [25][26][27][28][29][30][31][32][33][34][35][36][37] and the treatment was well tolerated. However, like in the Dutch Childhood Oncology Group experience, a more effective, but less toxic, therapy and better supportive care guidelines for childhood AML are still needed.…”

The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia

“…Table 2 shows that patients with MLL-rearranged AML have an intermediate outcome, with a 5y-pEFS (probability of EFS at 5 years from diagnosis) ranging from 32 to 54% and a 5y-pOS (probability of OS at 5 years from diagnosis) ranging from 42 to 62%. 4,5,[69][70][71][72][73][74][75][76][77] Currently, hematopoietic stem cell transplantation is no longer advised in first remission. Recently, we identified the t(1;11)(q21;q23) subgroup as a new prognostic subgroup in pediatric AML.…”