Timed-sequential induction therapy improves postremission outcome in acute myeloid leukemia: a report from the Children's Cancer Group

Abstract

Timed sequencing of cycles of induction chemotherapy in acute myeloid leukemia (AML) has been proposed as a way to achieve maximal leukemic cell kill through recruitment and synchronization of residual neoplastic cells. Furthermore, whether intensive induction therapy should be continued in the presence of profound myelosuppression is an important question. The Children's Cancer Group (CCG) conducted a prospective randomized trial in which 589 patients with AML were randomized at diagnosis to one of two induction approaches involving a 4-day cycle of five active chemotherapeutic agents, with the second cycle administered either 10 days after the first cycle, despite low or dropping blood counts (intensive timing), or 14 days or later from the beginning of the first cycle, depending on bone marrow status (standard timing). All patients achieving remission received a total of four cycles of induction therapy. They were then allocated to allogeneic bone marrow transplantation (BMT) if a compatible family donor was present or randomized to aggressive nonmyeloablative therapy or to myeloablative therapy with purged autologous BMT rescue. The three postremission arms remain coded. Induction success and median days to complete induction were similar for the 295 patients randomized to the intensive timing arm (75%, 99 days) compared with the 294 patients randomized to the standard timing arm (70%, 105 days; P = .18 for remission). However, a marked improvement in outcome was demonstrated in patients randomized to the intensive timing arm, with an actuarial event-free survival at 3 years of 42% +/- 7% (95% confidence interval [CI]) versus 27% +/- 6% for patients on the standard timing arm (P = .0005). Disease-free survival results at 3 years from the end of induction were superior for patients receiving intensively timed induction therapy (N = 211), 55% +/- 9% versus 37% +/- 9% for standard timing patients (N = 195, P = .0002), with a median follow-up from achieving remission of 28 months. Superior results were documented for patients receiving intensive timing irrespective of the postremission therapy to which they were allocated. Intensively timed induction therapy for patients with AML markedly improves event-free survival, even for patients undergoing myeloablative therapy with BMT rescue. Without controlling for the type of induction therapy received, results of various BMT studies in AML comparing different preparative regimens will be difficult to interpret.

A population‐based study of childhood myelodysplastic syndrome in British Columbia, Canada

“…The hitherto dominant impression that childhood MDS constitutes <3% of the leukaemias may be explained partly by under-representation of MDS in treatment-based studies (Creutzig et al, 1987;Woods et al, 1996). Less than half the eligible MDS patients in our study were in fact entered into an open therapeutical study.…”

The value of allogeneic bone marrow transplant in patients with acute myeloid leukaemia at differing risk of relapse: results of the UK MRC AML 10 trial

“…Most younger patients (< 60 years) with acute myeloid leukaemia (AML) will enter complete remission with one of several chemotherapy regimens (Mayer et al, 1994;Zittoun et al, 1995;Woods et al, 1996;Hann et al, 1997). There is, however, no clear agreement on how best to prevent relapse when autologous or allogeneic stem cell transplant and intensive chemotherapy are available.…”

“…This was based on studies conducted in the 1980s which appeared to favour the transplant option (McGlave et al, 1988;Leung et al, 2000). This choice has become more complicated by the fact that, although the outcome of transplantation has gradually improved, the intensification of post-remission chemotherapy has improved survival considerably such that about 40% of patients will survive more than 5 years from diagnosis (Amadori et al, 1993;Woods et al, 1996;Hann et al, 1997;Cassileth et al, 1998).…”

High WT1 gene expression before haematopoietic stem cell transplant in children with acute myeloid leukaemia predicts poor event‐free survival

“…Second, treatment prior to transplant may also have been different in patients. While patients from our institution were mostly treated with timed-sequential induction therapy (Woods et al, 1996), multiple patients, who had been treated with a variety of pre-transplant chemotherapy regimens, were referred from outside institutions. As the intensity of the induction chemotherapy can affect the outcome post-HSCT (Woods et al, 2001), the fact that we cannot factor in the induction chemotherapy into our model is a shortcoming.…”