Autologous bone marrow transplantation for children with AML in first remission.

In Children's cancer group (CCG) 2891, newly diagnosed patients with AML were randomized between standard and intensive timing induction therapies. Patients in first remission who lacked an HLA matched family donor were randomized between an autologous bone marrow transplantation (ABMT) where marrow was purged with 4 hydroperoxycyclophosphamide and consolidation chemotherapy. One hundred and thirty seven patients received an ABMT. Myeloid and platelet engraftment occurred at a median of 44 and 42 days, respectively. Disease-free survival (DFS), relapse-free survival and overall survival at 8 years post induction were 47% (95% confidence interval (CI): 38-55), 50% (CI: 42-59) and 55% (CI: 46-63), respectively. Multivariate analysis of DFS showed WBC <50 000/microl and having received intensively timed induction therapy were associated with improved DFS. Recipients who received intensive timed induction therapy and whose WBC was less than 50 000/microl had a DFS at 8 years of 62% (CI: 49-73). Conversely, recipients who received intensive timed induction therapy patients whose WBC was > or =50 000/microl had a DFS of 33% (CI: 17-50), P=0.003. The results confirm previous studies that ABMT is effective post remission therapy for pediatric patients with AML in first remission.

The contribution of metal ions to the conformational stability of ribonuclease T1: crystal versus solution.

In the crystalline state, ribonuclease T1 binds calcium ions at different lattice-dependent positions. In solution, its conformational stability is also remarkably increased in the presence of divalent metal ions. Combining urea unfolding studies and X-ray crystallography, we compared the presence of several metal ions at specific sites in the protein to their contribution to the overall stabilizing effect in solution. We constructed thermodynamic cycles involving particular metal ions and specific carboxylate functions. The resulting coupling energies indicate that some (but not all) metal ions found at lattice contacts in crystal structures may indeed significantly contribute to stability enhancement in the presence of metal ions in solution.

A comparison of allogeneic bone marrow transplantation, autologous bone marrow transplantation, and aggressive chemotherapy in children with acute myeloid leukemia in remission.

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 =.21). No potential confounding factors affected results. Patients receiving intensive-timing induction therapy had superior long-term survival irrespective of postremission regimen received (allogeneic BMT, 70% +/- 9%; autologous BMT, 54% +/- 9%; chemotherapy, 57% +/- 10%). Allogeneic BMT remains the treatment of choice for children and adolescents with AML in remission, when a matched related donor is available. For all others, there is no advantage to autologous BMT; hence, aggressive nonablative chemotherapy should be used.

Trimeric domain-swapped barnase.

The structure of a trimeric domain-swapped form of barnase (EC 3.1. 27.3) was determined by x-ray crystallography at a resolution of 2.2 A from crystals of space group R32. Residues 1-36 of one molecule associate with residues 41-110 from another molecule related through threefold symmetry. The resulting cyclic trimer contains three protein folds that are very similar to those in monomeric barnase. Both swapped domains contain a nucleation site for folding. The formation of a domain-swapped trimer is consistent with the description of the folding process of monomeric barnase as the formation and subsequent association of two foldons.

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

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.

Intensively timed induction therapy followed by autologous or allogeneic bone marrow transplantation for children with acute myeloid leukemia or myelodysplastic syndrome: a Childrens Cancer Group pilot study.

PURPOSE: Childrens Cancer Group (CCG) protocol 2861 was designed to test the feasibility of aggressively timed induction therapy followed by autologous or allogeneic bone marrow transplantation (BMT) as the sole postremission therapy for newly diagnosed children with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). PATIENTS AND METHODS: Between April 1988 and October 1989, 142 patients were eligible for study. All patients entered received a timing-intensive five-drug induction of dexamethasone, cytarabine (Ara-C), thioguanine, etoposide, and daunorubicin (DCTER) over 4 days with a second cycle administered after 6 days of rest, irrespective of hematologic status at that time. Most patients subsequently received a second two-cycle induction course. Those who achieved remission were eligible for bone marrow ablative therapy with busulfan and cyclophosphamide, followed by 4-hydroperoxy-cyclophosphamide (4-HC)-purged autologous or allogeneic BMT rescue. RESULTS: One hundred eight (76%) patients achieved remission: 19 (13%) died of complications of the leukemia and/or chemotherapy, and 15 (11%) failed to achieve remission. Seventy-four patients subsequently underwent BMT with either autologous (n = 58) or allogeneic (n = 16) rescue. For patients who received autologous rescue with 4-HC-purged grafts, the actuarial disease-free survival (DFS) rate at 3 years from the day of transplant is 51%, compared with 55% for patients who received allogeneic grafts (P = .92). At 3 years, the overall actuarial survival rate for all 142 patients entered on this study is 45%, with an event-free survival (EFS) rate of 37%. Adverse prognostic factors for outcome included an elevated WBC count or the presence of CNS leukemia at the time of AML diagnosis. CONCLUSION: 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.