Bruce Bostrom

Juvenile xanthogranuloma: Forms of systemic disease and their clinical implications

OBJECTIVE Juvenile xanthogranuloma (JXG) with systemic (extracutaneous) involvement is a rare histiocytic disorder in which significant morbidity and occasional deaths may occur. The objective of this study was to characterize the spectrum of anatomic involvement, associated clinical problems, and management considerations in children with systemic JXG. STUDY DESIGN Two current cases and literature reports of 34 children with various forms of systemic AG were analyzed with respect to age, clinical presentation, site(s) of involvement, therapy, and outcome. RESULTS The median age of the 36 patients was 0.3 years (range, birth to 12 years). Symptoms were usually referable to bulky or infiltrative disease. Twenty patients had disease in two or more sites. Cutaneous lesions were present in fewer than half the patients. The most frequent extracutaneous sites of disease were the subcutaneous soft tissue (12); central nervous system (8); liver/spleen (8); lung (6); eye/orbit, oropharynx, and muscle (4 each); with three or fewer instances of disease in each of several other sites. Most patients were treated with excision or had spontaneous regression (some with organ involvement). However, 12 patients received treatment that included radiation or systemic chemotherapy. Survivors, some with long-term disabilities, included young children who had received radiation therapy to the brain, eye, skin, or heart. Two patients died of disease. CONCLUSIONS Systemic AG may involve varying numbers and combinations of extracutaneous sites. The extent of disease should be determined in patients with AG who are suspected to have systemic involvement. In contrast to the cutaneous form, systemic AG may be associated with significant complications requiring aggressive medical care. When feasible, surgical excision of lesions may be curative. Optimal treatment for symptomatic, unresectable disease is currently undefined but should be selected to minimize toxic effects in these children who are typically younger than 1 year old at presentation.

Pleuropulmonary blastoma : a marker for familial disease

OBJECTIVE To catalog and evaluate patterns of disease in families of children with pleuropulmonary blastoma (PPB). METHODS Data have been collected since 1988 on 45 children with PPB and their families. All pathologic materials were centrally reviewed. Preliminary molecular genetic analyses were performed when possible. RESULTS In 12 of 45 patients, an association was found between PPB and other dysplasias, neoplasias, or malignancies in the patients with or in their young relatives. The diseases found to be associated with PPB include other cases of PPB, pulmonary cysts, cystic nephromas, sarcomas, medulloblastomas, thyroid dysplasias and neoplasias, malignant germ cell tumors, Hodgkin disease, leukemia, and Langerhans cell histiocytosis. Abnormalities of the p53 tumor suppressor gene, Wilms tumor suppressor gene (WT1), and the putative second genetic locus for Wilms tumor (WT2) were not found in preliminary investigations. CONCLUSIONS The occurrence of PPB appears to herald a constitutional and heritable predisposition to dysplastic or neoplastic disease in approximately 25% of cases. All patients with PPB and their families should be investigated carefully. Further research of this new family cancer syndrome may provide insight into the genetic basis of these diseases.

Prognostic Impact of Trisomies of Chromosomes 10, 17, and 5 Among Children With Acute Lymphoblastic Leukemia and High Hyperdiploidy (> 50 Chromosomes)

PURPOSE Children with acute lymphoblastic leukemia (ALL) and high hyperdiploidy (> 50 chromosomes) have improved outcome compared with other ALL patients. We sought to identify cytogenetic features that would predict differences in outcome within this low-risk subset of ALL patients. MATERIALS AND METHODS High-hyperdiploid ALL patients (N = 480) were enrolled between 1988 and 1995 on Childrens Cancer Group (CCG) trials. Karyotypes were determined by conventional banding. Treatment outcome was analyzed by life-table methods. RESULTS Patients with 54 to 58 chromosomes had better outcome than patients with 51 to 53 or 59 to 68 chromosomes (P = .0002). Patients with a trisomy of chromosome 10 (P<.0001), chromosome 17 (P = .0002), or chromosome 18 (P = .004) had significantly improved outcome compared with their counterparts who lacked the given trisomy. Patients with a trisomy of chromosome 5 had worse outcome than patients lacking this trisomy (P = .02). Patients with trisomies of both chromosomes 10 and 17 had better outcome than those with a trisomy of chromosome 10 (P = .09), a trisomy of chromosome 17 (P =.01), or neither trisomy (P<.0001). Multivariate analysis indicated that trisomy of chromosome 10 (P = .001) was the most significant prognostic factor for high-hyperdiploid patients, yet trisomy of chromosome 17 (P =.02) or chromosome 5 (P = .01) and modal chromosome number (P = .02) also had significant multivariate effects. CONCLUSION Trisomy of chromosomes 10 and 17 as well as modal chromosome number 54 to 58 identify subgroups of patients with high-hyperdiploid ALL who have a better outcome than high-hyperdiploid patients who lack these cytogenetic features. Trisomy of chromosome 5 confers poorer outcome among high-hyperdiploid patients.

Outcome of Patients Treated for Relapsed or Refractory Acute Lymphoblastic Leukemia: A Therapeutic Advances in Childhood Leukemia Consortium Study

PURPOSE Despite 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 METHODS We 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. RESULTS Complete remission (CR) rates (mean +/- SE) were 83% +/- 4% for early first marrow relapse, 93% +/- 3% for late first marrow relapse, 44% +/- 5% for second marrow relapse, and 27% +/- 6% for third marrow relapse. Five-year DFS rates in CR2 and CR3 were 27% +/- 4% and 15% +/- 7% respectively. CONCLUSION We 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.

Bortezomib with chemotherapy is highly active in advanced B-precursor acute lymphoblastic leukemia: Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Study

Therapy of relapsed pediatric acute lymphoblastic leukemia (ALL) is hampered by low remission rates and high toxicity, especially in second and subsequent relapses. Our phase 1 study, T2005-003, showed that the combination of bortezomib with vincristine, dexamethasone, pegylated asparaginase, and doxorubicin had acceptable toxicity. We report the phase 2 expansion of this combination in patients with relapsed ALL who failed 2-3 previous regimens. Twenty-two patients with relapsed ALL were treated with bortezomib combined with this regimen; their ages ranged from 1 to 22 years, and they had either B-precursor ALL (n = 20) or T-cell ALL (n = 2). Grade 3 peripheral neuropathy developed in 2 (9%) patients. After 3 patients died from bacterial infections, treatment with vancomycin, levofloxacin, and voriconazole prophylaxis resulted in no further infectious mortality in the last 6 patients. Fourteen patients achieved complete remission (CR), and 2 achieved CR without platelet recovery, for an overall 73% response rate, meeting predefined criteria allowing for early closure. B-precursor patients faired best, with 16 of 20 (80%) CR + CR without platelet recovery, whereas the 2 patients with T-cell ALL did not respond. Thus, this combination of bortezomib with chemotherapy is active in B-precursor ALL, and prophylactic antibiotics may be useful in reducing mortality. Bortezomib merits further evaluation in combination therapy in pediatric B-precursor ALL. This study is registered at http://www.clinicaltrials.gov as NCT00440726.

Bone Marrow Transplantation Versus Prolonged Intensive Chemotherapy for Children With Acute Lymphoblastic Leukemia and an Initial Bone Marrow Relapse Within 12 Months of the Completion of Primary Therapy: Children's Oncology Group Study CCG-1941

PURPOSE To compare conventional sibling bone marrow transplantation (CBMT), BMT with alternative donor (ABMT), and chemotherapy (CT) for children with acute lymphoblastic leukemia (ALL) and an early first marrow relapse. PATIENTS AND METHODS After informed consent, 214 patients with ALL and early marrow relapse began multiagent induction therapy. One hundred sixty-three patients with fewer than 25% marrow blasts and count recovery at the end of induction (second remission [CR2]) were allocated by donor availability. Fifty patients with sibling donors were allocated to CBMT. Seventy-two patients were randomly allocated between ABMT and CT while 41 patients refused allocation. RESULTS Overall, 3-year event free survival from entry is 19% +/- 3%. Thirty-two of 50 CBMT patients (64%) and 19 of 37 ABMT patients (51%) underwent transplantation in CR2 with 3-year disease-free survival of 42% +/- 7% and 29% +/- 7%. The 3-year DFS is 29% +/- 7%, 21% +/- 7%, and 27% +/- 8% for patients allocated to CBMT, ABMT, and CT, respectively. Contrary to protocol, 12 of 35 patients allocated to CT underwent BMT in CR2. Of these, five patients died after BMT and 5 patients relapsed. CONCLUSION More than one half of patients died, failed reinduction, or relapsed again before 3 months after CR2 (median time to BMT). Intent-to-treat pair-wise comparison of ABMT with CT, CT with CBMT, and CBMT with ABMT yields hazards of 1.2, 1.1, 0.8 with P values of .56, .80, and .36, respectively. Outcomes remain similar and poor for children with ALL and early marrow relapse. BMT is not a complete answer to the challenge of ALL and early marrow relapse.

Clinical features and treatment outcome of childhood T-lineage acute lymphoblastic leukemia according to the apparent maturational stage of T-lineage leukemic blasts: a Children's Cancer Group study.

PURPOSE Leukemic cells from T-lineage acute lymphoblastic leukemia (ALL) patients are thought to originate from T-lymphocyte precursors corresponding to discrete stages of T-cell ontogeny. Here we sought to determine the influence of leukemic cell apparent maturational stage on treatment outcomes in pediatric T-lineage ALL. PATIENTS AND METHODS From 1983 through 1993, 407 pediatric T-lineage ALL patients were enrolled onto two sequential series of risk-adjusted treatment protocols of the Childrens Cancer Group. In the current analysis, T-lineage ALL patients were immunophenotypically classified as follows: CD7+ CD2- CD5- pro-thymocyte leukemia (pro-TL), CD7+ (CD2 or CD5)+ CD3- immature TL, and CD7+ CD2+ CD5+ CD3+ mature TL. RESULTS Similar induction outcomes of 91.4%, 97.1%, and 98.3% were obtained by the pro-, immature, and mature TL groups, respectively. Four-year event-free survival (EFS) was lower for pro-TL patients (57.1%; SD = 8.4%,) compared with immature and mature TL patients (68.5%; SD = 3.5%; and 77.1%; SD = 4.0%, respectively) with an overall significance of .05 (log-rank test) or .04 (log-rank trend test). Relative hazards rates (RHR) were 2.11 and 1.22 for pro-TL and immature TL versus mature TL, respectively. Highly significant differences were found for overall survival (P = .005, log-rank test; P = .009, log-rank trend test). Multivariate analysis confirmed that the prognostic influence of ontogeny grouping was independent of that of other prognostic factors. CONCLUSION Leukemic cells of the pro-TL maturation stage identify a small subgroup of T-lineage ALL patients who have a significantly worse EFS outcome than patients whose cells are of a more mature stage of development.

Phase I study of bortezomib combined with chemotherapy in children with relapsed childhood acute lymphoblastic leukemia (ALL): a report from the therapeutic advances in childhood leukemia (TACL) consortium.

Outcomes remain poor for children after relapse of acute lymphoblastic leukemia (ALL), especially after early marrow relapse. Bortezomib is a proteasome inhibitor with in vitro synergy with corticosteroids and clinical activity in human lymphoid malignancies.

Escalating intravenous methotrexate improves event-free survival in children with standard-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group

Childrens Cancer Group-1991 selected 2 components from the Childrens Cancer Group studies shown to be effective in high-risk acute lymphoblastic leukemia and examined them in children with National Cancer Institute standard-risk acute B-precursor lymphoblastic leukemia. These were (1) vincristine and escalating IV methotrexate (MTX) without leucovorin rescue during the interim maintenance (IM) phases and (2) addition of a second delayed intensification (DI) phase. Eligible patients (n = 2078) were randomly assigned to regimens containing either oral (PO) MTX, PO mercaptopurine, dexamethasone, and vincristine or IV MTX during IM phases, and regimens with either single DI or double DI. Five-year event-free survival (EFS) and overall survival for patients on the PO MTX arms were 88.7% ± 1.4% and 96% ± 0.9% versus 92.6% ± 1.2% and 96.5% ± 0.8% for those on the IV MTX arms (P = .009, P = .66). Five-year EFS and overall survival for patients who received single DI were 90.9% ± 1.3% and 97.1% ± 0.8% versus 90.5% ± 1.3% and 95.4% ± 3.8% for those who received double DI (P = .71, P = .12). No advantage was found for a second DI; however, replacement of PO MTX, PO mercaptopurine, vincristine, and dexamethasone during IM with vincristine and escalating IV MTX improved EFS.

A Phase 1 Study of Combotox in Pediatric Patients With Refractory B-lineage Acute Lymphoblastic Leukemia

Background Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Combotox is a 1:1 mixture of RFB4-dgA and HD37-dgA which are immunotoxins that target the CD22 and CD19 antigens, respectively. Combotox has different toxicities and targets than chemotherapy and is, thus, a new candidate for the treatment of patients with relapsed ALL. Preclinical data have demonstrated which Combotox is effective in killing pre-B-ALL cell lines and cells from patients with pre-B ALL. Methods We designed and conducted a Phase 1 dose-escalation study using Combotox in children with refractory or relapsed B-lineage-ALL. Seventeen patients aged 1 to 16 years were enrolled in this multi-institution study. They were treated at 4-dose levels: 2 mg/m2, 4 mg/m2, 5 mg/m2, and 6 mg/m2. Results The maximum tolerated dose was 5 mg/m2 and graft versus host disease defined the maximum tolerated dose. Three patients experienced complete remission. Six additional patients experienced a decrease of >95% in their peripheral blood blast counts, and 1 patient experienced a decrease of 75%. Conclusions Combotox can be safely administered to children with refractory leukemia. It has clinically important anticancer activity as a single agent. The recommended dose for future studies is 5 mg/m2/dose.