Intensive, myelosuppressive therapy is necessary to maximize outcomes for patients with acute myeloid leukemia (AML). A comparison was made of 3 aggressive postremission approaches for children and adolescents with AML in a randomized trial, CCG-2891. A total of 652 children and adolescents with AML who achieved remission on 2 induction regimens using identical drugs and doses (standard and intensive timing) were eligible for allocation to allogeneic bone marrow transplantation (BMT) based on matched related donor status (n ‫؍‬ 181) or randomization to autologous BMT (n ‫؍‬ 177) or to aggressive high-dose cytarabine-based chemotherapy (n ‫؍‬ 179).Only 115 patients (18%) refused to participate in the postremission phase of this study. Overall compliance with the 3 allocated regimens was 90%. At 8 years actuarial, 54% ؎ 4% (95% confidence interval) of all remission patients remain alive. Survival by assigned regimen ("intent to treat") is as follows: allogeneic BMT, 60% ؎ 9%; autologous BMT, 48% ؎ 8%; and chemotherapy, 53% ؎ 8%. Survival in the allogeneic BMT group is significantly superior to autologous BMT (P ‫؍‬ .002) and chemotherapy (P ‫؍‬ .05); differences between chemotherapy and autologous BMT are not significant (P ‫؍‬ .

These data indicate superior survival with CY/TBI conditioning, compared with Bu/CY conditioning, for HLA-identical sibling bone marrow transplants in children with ALL.

The association of ethnicity with the incidence of graft-versus-host disease (GVHD) and other clinical outcomes after transplantation is controversial. We compared the results of HLA-identical sibling bone marrow transplantations for leukemia, performed between 1990 and 1999, among different ethnic populations, including 562 Japanese, 829 white Americans, 71 African Americans, 195 Scandinavians, and 95 Irish. Results for adults and children were analyzed separately. Multivariate analyses of adult patients showed that white Americans, African Americans, and Irish cohorts were at significantly higher risk for acute GVHD than Japanese or Scandinavian cohorts (relative risk [RR] ‫؍‬ 1.77, P < .001; RR ‫؍‬ 1.84, P < .006; RR ‫؍‬ 2.22, P < .001, respectively). White Americans, African Americans, and Irish, but not Scandinavians, were at significantly higher risk for early (within 3 months of transplantation) transplant-related mortality (TRM) compared with Japanese (RR ‫؍‬ 2.99, P < .001; RR ‫؍‬ 5.88, P < .001; RR ‫؍‬ 2.66, P < .009, respectively). No differences in the risk for chronic GVHD, relapse, and overall survival were noted. In the pediatric cohort (limited to Japanese and white Americans), white Americans were at significantly higher risk for acute (RR ‫؍‬ 1.93; P ‫؍‬ .04) and chronic (RR ‫؍‬ 3.16; P ‫؍‬ .002) GVHD. No differences in other clinical outcomes were noted. Our findings suggest that ethnicity may influence the risk for GVHD, though overall survival rates after transplantation remain similar.

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.

Chronic myeloid leukemia (CML) is composed of 3% of pediatric leukemias, making evidence-based recommendations difficult. Imatinib has revolutionized the treatment for adult CML by eliminating allogeneic stem cell transplantation for almost all patients in chronic phase. Shown effective in pediatric CML, imatinib and successive tyrosine kinase inhibitors (TKI) have provided more therapeutic options. Because stem cell transplantation has been better tolerated in children and adolescents, the decision to treat by either TKI or transplantation is controversial. We present a recent case of a 12-month-old boy diagnosed with BCR-ABL ؉ CML to highlight the controversies in treatment recommendations. We review the pediatric stem cell transplantation outcomes as well as the pediatric experience with imatinib and other TKIs. Finally, we compare the side effects as well as costs associated with allogeneic stem cell transplantation versus TKI therapy. We recommend that frontline therapy for pediatric CML in chronic phase is TKI therapy without transplantation. Patients in accelerated or blast crisis or who fail to reach landmarks on TKIs either because of intolerance or resistance should pursue stem cell transplantation. Although we recommend adopting adult clinical experience to guide therapeutic decision making, the issues of infant CML, drug formulation, pharmacokinetics, and adolescent compliance merit clinical investigation.

Results suggest that aggressively timed induction therapy followed by marrow ablation and BMT rescue with either autologous or allogeneic grafts for children with newly diagnosed AML or MDS is both feasible and effective.

Steroid-refractory acute graft-versus-host disease (SR-aGVHD) following hematopoietic cell transplantation (HSCT) is associated with poor clinical outcomes. Currently, there are no safe and effective therapies approved for use in the pediatric population under the age of 12 years. Accordingly, there is an urgent need for new treatments that are safe, well tolerated, and effective in managing this debilitating and potentially fatal complication of HSCT. In early phase clinical trials, mesenchymal stromal cells (MSCs) have demonstrated efficacy in the treatment of acute GVHD (aGVHD) in pediatric patients. We now report the results of a phase 3, prospective, single-arm, multicenter study (NCT02336230) in 54 children with primary SR-aGVHD who were naive to other immunosuppressant therapies for aGVHD treated with MSC product (remestemcel-L) dosed at 2 £ 10 6 cells/kg twice weekly for 4 weeks. Remestemcel-L therapy significantly improved day 28 overall response rate (OR) compared with the prespecified control OR value of 45% (70.4% versus 45%, P = .0003). The statistically significant OR (70.4%) was sustained through day 100, including an increase in complete response from 29.6% at day 28 to 44.4% at day 100. Overall survival was 74.1% at day 100 and 68.5% at day 180. Overall response in all participants at day 28 was highly predictive of improved survival through 180 days, and survival was significantly greater in day 28 responders compared with nonresponders through day 100 (86.8% versus 47.1% for responders and nonresponders, respectively, P = .0001) and through day 180 (78.9% versus 43.8%, P = .003). Remestemcel-L was well tolerated with no identified infusion-related toxicities or other safety concerns. This study provides robust, prospective evidence of the safety, tolerability, and efficacy of remestemcel-L as first-line therapy after initial steroid failure in pediatric SR-aGVHD.

There has not been a reported series of children with therapy-induced myelodysplastic syndrome/acute myeloid leukemia (tMDS/tAML) who were treated systematically. This paper describes 24 children with tMDS/tAML who were assigned randomly to standard-or intensive-timing induction on protocol CCG 2891. Presenting features and outcomes of those children were compared with those of 960 patients with de novo MDS (62 patients) or AML (898 patients). Children with tMDS/ tAML were older at presentation (P ‫؍‬ .015), had lower white blood cell counts (P ‫؍‬ .01), and were more likely to have MDS (21% vs 7%) (P ‫؍‬ .02) and trisomy 8 (P ‫؍‬ .06). Fewer had hepatomegaly (P ‫؍‬ .02), splenomegaly (P ‫؍‬ .03), hepatosplenomegaly (P ‫؍‬ .02), or classic AML translocations [t(8;21), t(15;17), 16q22; P ‫؍‬ .02]. They had a poorer induction rate (50% vs 72%, P ‫؍‬ .016), overall survival (26% vs 47% at 3 years, P ‫؍‬ .007), and event-free survival (21% vs 39% at 3 years, P ‫.)320.؍‬ Disease-free survival after achieving remission was similar (45% vs 53%, P ‫؍‬ .868). Children with tMDS/ tAML who received intensive-timing induction had better outcomes than those who received standard-timing induction (overall survival 32% vs 0%, P ‫؍‬ .54). In this study, the latency period to development of tMDS/tAML was the same for presumed alkylator-induced as for topoisomerase-induced myeloid leukemia. The findings of this study confirm that most children with tMDS/tAML have disease resistant to current therapies. Standardtiming induction appears less effective for this population. (Blood. 2002;100: 427-434)