A B S T R A C T PurposeDespite improvements in treatment, approximately 20% of patients with acute lymphoblastic leukemia (ALL) experience relapse and do poorly. The Therapeutic Advances in Childhood Leukemia (TACL) Consortium was assembled to assess novel drugs for children with resistant leukemia. We hypothesize that novel agents and combinations that fail to improve baseline complete remission rates in comparable populations are unlikely to contribute to better outcomes and should be abandoned. We sought to define response rates and disease-free survival (DFS) rates in patients treated at TACL institutions, which could serve as a comparator for future studies. Patients and MethodsWe performed a retrospective cohort review of patients with relapsed and refractory ALL previously treated at TACL institutions between the years of 1995 and 2004. Data regarding initial and relapsed disease characteristics, disease response, and survival were collected and compared with those of published reports. ResultsComplete remission (CR) rates (mean Ϯ SE) were 83% Ϯ 4% for early first marrow relapse, 93% Ϯ 3% for late first marrow relapse, 44% Ϯ 5% for second marrow relapse, and 27% Ϯ 6% for third marrow relapse. Five-year DFS rates in CR2 and CR3 were 27% Ϯ 4% and 15% Ϯ 7% respectively. ConclusionWe generally confirm a 40% CR rate for second and subsequent relapse, but our remission rate for early first relapse seems better than that reported in the literature (83% v approximately 70%). Our data may allow useful modeling of an expected remission rate for any population of patients who experience relapse.
Purpose: Evaluate the clinical safety, toxicity, immune activation/modulation, and maximal tolerated dose of hu14.18-IL2 (EMD 273063) in pediatric patients with recurrent/refractory neuroblastoma and other GD2-positive solid tumors. Experimental Design:Twenty-seven pediatric patients with recurrent/refractory neuroblastoma and one with melanoma were treated with a humanized anti-GD2 monoclonal antibody linked to human interleukin 2 (IL-2). Cohorts of patients received hu14.18-IL2, administered i.v. over 4 hours for three consecutive days, at varying doses. Patients with stable disease, partial, or complete responses were eligible to receive up to three additional courses of therapy. Results: Most of the clinical toxicities were anticipated and similar to those reported with IL-2 and anti-GD2 monoclonal antibody therapy and to those noted in the initial phase I study of hu14.18-IL2 in adults with metastatic melanoma. The maximal tolerated dose was determined to be 12 mg/m 2 /d, with agent-related dose-limiting toxicities of hypotension, allergic reaction, blurred vision, neutropenia, thrombocytopenia, and leukopenia. Three patients developed doselimiting toxicity during course 1; seven patients in courses 2 to 4. Two patients required dopamine for hypotension.There were no treatment-related deaths, and all toxicity was reversible.Treatment with hu14.18-IL2 led to immune activation/modulation as evidenced by elevated serum levels of soluble IL-2 receptor a (sIL2Ra) and lymphocytosis. The median half-life of hu14.18-IL2 was 3.1 hours. There were no measurable complete or partial responses to hu14.18-IL2 in this study; however, three patients did show evidence of antitumor activity. Conclusion: Hu14.18-IL2 (EMD 273063) can be administered safely with reversible toxicities in pediatric patients at doses that induce immune activation. A phase II clinical trial of hu14.18-IL2, administered at a dose of 12 mg/m 2 /d  3 days repeated every 28 days, will be done in pediatric patients with recurrent/refractory neuroblastoma.
Untreated patients with Hurler syndrome (MPSIH) experience progressive neurologic deterioration and early death. Allogeneic bone marrow transplantation (BMT) ameliorates or halts this course. The Storage Disease Collaborative Study Group was formed to evaluate the effectiveness and toxicity of BMT. Effectiveness was defined as engrafted survival with continuing cognitive development. Fifty-four patients deficient in leukocyte α-l-iduronidase enzyme activity (median age, 1.8 years; range, 0.4 to 7.9) received high-dose chemotherapy with or without irradiation and BMT from HLA-genotypically identical sibling (GIS) or HLA-haploidentical related (HIR) donors between September 16, 1983 and July 14, 1995; all children were included in this report. Thirty-nine of 54 patients (72%) engrafted following the first BMT. The probability of grade II to IV acute graft-versus-host disease (GVHD) at 100 days was 32% for GIS and 55% for HIR patients. The probability of extensive chronic GVHD was 0% for GIS and 24% for HIR patients. The actuarial probability of survival at 5 years was 64% for all patients, 75% for GIS patients, 53% for HIR patients, and 53% for patients with donor marrow engraftment. The baseline Mental Developmental Index (MDI) was examined both for children less than and greater than 24 months of age at BMT. Children transplanted before 24 months had a mean baseline MDI of 78, while those transplanted after 24 months had a mean baseline MDI of 63 (P = .0002). Both baseline and post-BMT neuropsychologic data were available for 26 of 30 engrafted survivors. Of 14 patients transplanted before 24 months of age, nine demonstrated developmental trajectories that were normal or somewhat slower than normal. In contrast, of 12 patients transplanted after 24 months of age, only three showed developmental trajectories that were normal or somewhat slower than normal (P = .01). For children with a baseline MDI greater than 70, there was a significant correlation between the MDI at follow-up study and leukocyte α-l-iduronidase enzyme activity (P = .02). Children were more likely to maintain normal cognitive development if they were fully engrafted following BMT from a donor with homozygous normal leukocyte α-l-iduronidase enzyme activity. Children who developed acute GVHD of grade II or worse had significantly poorer cognitive outcomes (P < .009). No difference in the post-BMT MDI was observed between patients whose preparative therapies did (n = 10; radiation dose, 300 to 1,400 cGy) or did not (n = 16) include radiation. We conclude that MPSIH patients, particularly those less than 24 months of age with a baseline MDI greater than 70, can achieve a favorable long-term outcome with continuing cognitive development and prolonged survival after successful BMT from a related donor with homozygous normal enzyme activity.
This CR rate following a second therapeutic attempt and OS rate in patients with rAML is consistent with the literature. There are limited published data of CR rates for subsequent relapses. Our data can serve as a historical benchmark to compare outcomes of future therapeutic trials in rAML against traditional chemotherapy regimens.
Background Decisions about end-of-life care may be influenced by cultural and disease-specific features. We evaluated associations of demographic variables (race, ethnicity, language, religion, and diagnosis) with end-of-life characteristics (Phase I enrollment, do-not-resuscitate (DNR) orders, hospice utilization, location of death), and trends in palliative care services delivered to pediatric hematology, oncology, and stem cell transplant (SCT) patients. Procedure In this single-center retrospective cohort study, inclusion criteria were as follows: patients aged 0–35 who died between January 1, 2002 and March 1, 2014, and had been cared for in the pediatric hematology, oncology, and SCT divisions. The era of 2002–2014 was divided into quartiles to assess trends over time. Results Of the 445 included patients, 64% of patients had relapsed disease, 45% were enrolled in hospice, and 16% had received palliative care consultation. Patients with brain or solid tumors enrolled in hospice (P < 0.0001) and died at home more frequently than patients with leukemia/lymphoma (P < 0.0001). Patients who received Phase I therapy or identified as Christian/Catholic religion enrolled in hospice more frequently (P < 0.0001 and P = 0.03, respectively). When patient deaths were analyzed over quartiles, the frequency of DNR orders (P = 0.02) and palliative care consultation (P = 0.04) increased over time. Hospice enrollment, location of death, and Phase I trial enrollment did not change significantly. Conclusions Despite increases in palliative care consultation and DNR orders over time, utilization remains suboptimal. No increase in hospice enrollment or shift in death location was observed. These data will help target future initiatives to achieve earlier discussions of goals of care and improved palliative care for all patients.
BackgroundMany parents of children with advanced cancer pursue curative goals when cure is no longer possible. To the authors' knowledge, no pediatric studies to date have prospectively evaluated prognosis communication or influences on decision making in poor‐prognosis childhood cancer.MethodsThe authors conducted a prospective cohort study at 9 pediatric cancer centers that enrolled 95 parents of children with recurrent or refractory, high‐risk neuroblastoma (63% of those who were approached), a condition for which cure rarely is achieved. Parents were surveyed regarding the child's likelihood of cure; their primary goal of care; the child's symptoms, suffering, and quality of life; and regret concerning the last treatment decision. Medical records identified care and treatment decisions.ResultsOnly 26% of parents recognized that the chance of cure was <25%. When asked to choose a single most important goal of care, approximately 72% chose cure, 10% chose longer life, and 18% chose quality of life. Parents were more likely to prioritize quality of life when they recognized the child's poor prognosis (P = .002). Approximately 41% of parents expressed regret about the most recent treatment decision. Parents were more likely to experience regret if the child had received higher intensity medical care (odds ratio [OR], 3.14; 95% CI, 1.31‐7.51), experienced suffering with limited benefit from the most recent treatment (OR, 4.78; 95% CI, 1.16‐19.72), or experienced suffering from symptoms (OR, 2.91; 95% CI, 1.18‐7.16).ConclusionsParents of children with poor‐prognosis cancer frequently make decisions based on unrealistic expectations. New strategies for effective prognosis communication are needed.
Human CD83 (hCD83) is a 45 000 Mr cell-surface protein expressed predominantly by dendritic lineage cells. In this report, the genomic locus encoding mouse CD83 (Cd83) was isolated and the gene structure determined. The Cd83 gene spans approximately 19 kilobases (kb) and is composed of five exons, with two exons encoding a single extracellular immunoglobulin (Ig)-like domain. Mouse CD83 (mCD83) cDNAs were isolated by reverse transcriptase polymerase chain reaction of mouse RNA. Sequence determination revealed substantial conservation, with mCD83 and hCD83 sharing 63% amino acid identity. The transmembrane and cytoplasmic regions of CD83 were most highly conserved. Mouse CD83 mRNA of 2.4 kb was abundantly expressed in spleen and brain, but could also be detected in most tissues analyzed. These results suggest that in the mouse, as in humans, widely distributed dendritic cells may express mCD83. Chromosome localization revealed that the Cd83 gene is present on mouse chromosome 13 band A5, while the locus for the human gene (CD83) is located within a homologous region of human chromosome 6p23. Thus, the CD83 protein and gene appear to be well conserved during recent mammalian evolution. The isolation and characterization of the mCD83 cDNA and gene provides important information and tools that will facilitate the study of CD83 and dendritic cell function in a mouse model system.
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