Virginia Davenport

Ifosfamide, carboplatin, and etoposide (ICE) reinduction chemotherapy in a large cohort of children and adolescents with recurrent/refractory sarcoma: The Children's Cancer Group (CCG) experience

The prognosis for children with recurrent/refractory sarcomas is poor. We determined the overall response rate (ORR) and overall survival (OS) of children with recurrent/refractory sarcomas who were given ifosfamide, carboplatin, and etoposide (ICE) in three Childrens Cancer Group (CCG) phase I/II trials.

Childhood and adolescent non‐Hodgkin lymphoma: New insights in biology and critical challenges for the future

Pediatric non‐Hodgkin lymphoma (NHL) is a common and fascinating group of diseases with distinctive underlying genetic events that characterize the major histologic subtypes: diffuse large B‐cell lymphoma, Burkitt lymphoma, anaplastic large cell lymphoma and lymphoblastic lymphoma. With systematic improvements in therapy over recent decades, the vast majority of children with NHL of all subtypes are now cured. The similarities and differences between adult and childhood presentations of disease, and whether or not some subtypes of NHL and leukemia are the same or different disease entities, are interesting questions that will be addressed with advances in our understanding of the molecular and genetic bases of these diseases. As is the case with other pediatric malignancies, growing emphasis is now being placed on the development of less toxic, targeted therapeutic approaches, and this review highlights some of the biological discoveries that will potentially open these avenues. Pediatr Blood Cancer

Pediatric diffuse large B‐cell lymphoma demonstrates a high proliferation index, frequent c‐Myc protein expression, and a high incidence of germinal center subtype: Report of the French–American–British (FAB) international study group

Diffuse large B‐cell lymphoma (DLBCL) makes up 10–20% of pediatric non‐Hodgkin lymphoma, and these patients have a significantly better prognosis than adults with DLBCL. The difference in prognosis may be related to clinical, phenotypic, and/or biological differences between adult and pediatric DLBCL. In adult DLBCL, the germinal center (GC) phenotype is associated with a better prognosis than the activated B‐cell (ABC) phenotype. However, a high proliferative index and expression of Bcl2 and c‐Myc protein have all been associated with worse outcomes. While multiple studies have addressed the phenotype and expression patterns of adult DLBCL, relatively little is known about these biological variables in pediatric DLBCL. The goal of this study was to investigate the proliferative index, the relative frequencies of the GC and non‐GC subtypes, and the expression of Bcl2 and c‐Myc protein in a cohort of children with DLBCL treated in a uniform manner.

The role of interleukin-11 to prevent chemotherapy-induced thrombocytopenia in patients with solid tumors, lymphoma, acute myeloid leukemia and bone marrow failure syndromes

Thrombocytopenia occurs at various grades of severity in patients with malignancies undergoing myelosuppressive chemotherapy. In most instances, this is the major dose-limiting hematologic toxicity, especially in the treatment of potentially curable cancers. The standard preventive measure against chemotherapy-induced thrombocytopenia has been dose reduction and/or dose delay. This can often lead to poor outcomes, including reduced disease free periods and overall survival. With the availability of a platelet growth factor, recombinant human interleukin (IL)-11, an effective way to prevent chemotherapy-induced thrombocytopenia and accelerate platelet recovery, can now be provided to patients. The use of recombinant human IL-11 has also been extended to include patients with prolonged thrombocytopenia, such as those with bone marrow failure syndromes. With the use of recombinant human IL-11 in both malignant and non-malignant conditions, adverse reactions often seen with platelet transfusions, such as transfusion reactions, viral and bacterial infections and platelet refractoriness, can now be decreased or avoided.

Phase I/II dose escalation study of recombinant human interleukin-11 following ifosfamide, carboplatin and etoposide in children, adolescents and young adults with solid tumours or lymphoma: a clinical, haematological and biological study*

Thrombocytopenia remains the major dose‐limiting toxicity of myelosuppressive chemotherapy in children with solid tumours. Recombinant human interleukin‐11 (rhIL‐11) has been approved by the Food and Drug Administration as treatment for adults with solid tumours and lymphomas with severe chemotherapy‐induced thrombocytopenia. We conducted a phase I/II trial of rhIL‐11 following ifosfamide, carboplatin and etoposide (ICE) chemotherapy in children with solid tumours or lymphomas. Patients received ifosfamide 1800 mg/m2/d for 5 d, carboplatin 400 mg/m2/d for 2 d and etoposide 100 mg/m2/d for 5 d with rhIL‐11 subcutaneous (s.c.) at 25–125 μg/kg/d on days 6–33. Forty‐seven patients with median age 10·5 years (range, 0·7–26 years) were studied. Median days to absolute neutrophil count ≥0·5 × 109/l, platelet count ≥50 × 109/l and platelet transfusions were 23, 18, 18, 16·5 and 18·5, 21, 20, 18 and 3, 3, 4, and 2 d at doses 25, 50, 75 and 100 μg/kg respectively. There was a dose‐dependent increase in Cmax (7·6–25·5 ng/ml), AUC0−ρ (57–209 ng·h/ml) and T1/2 (4–8·2 h) respectively. There was a 4% incidence of anti‐IL‐11 antibody formation. Clinically important adverse events to rhIL‐11 were papilloedema and periosteal bone formation. In summary, rhIL‐11 was well tolerated at doses of ≤50 μg/kg (maximal tolerated dose) and associated with improved haematological recovery and reduced platelet transfusion requirements compared with historical controls receiving similar ICE chemotherapy without rhIL‐11.

A comparison of ex vivo expanded DCs derived from cord blood and mobilized adult peripheral blood plastic-adherent mononuclear cells: decreased alloreactivity of cord blood DCs *

BACKGROUND Cord blood (CB) has been used as an alternative source of transplantable allogeneic stem cells for a variety of malignant and non-malignant diseases. However, we have demonstrated delayed recovery of T- and B-cell function, and T-cell subsets post unrelated CB transplantation (UCBT), and deficiencies of CB mononuclear cells (MNC) in producing cytokines, including G-CSF, GM-CSF, M-CSF, IL-12, and IL-15. In this study we have investigated the ex vivo generation of DC from CB versus mobilized adult peripheral blood (APB) for later use as adoptive cellular immunotherapy. METHODS CB and APB-adherent MNC were cultured in serum-free media with GM-CSF IL-4, FLT-3 ligand, tumor growth factor-beta (TGF-beta), and tumor necrosis factor-alpha (TNF-alpha) for 7 days. Morphology, phenotype, immunohistochemistry, clonogenic activity, and alloreactivity in MLR were evaluated. RESULTS CB and APB monocyte-derived ex vivo expanded DC expressed similar DC markers CD83 (31.27+ 11.7% versus 34.0+ 5.2%, CB versus APB), CD1a (23.4+ 4.2% versus 27.6+ 6.3%), and CD80 (21.97+ 12.01% versus 27.7+ 5.95). Immunohistochemistry showed that cells with DC morphology expressed CDla but not CD14. Neither FLT-3 ligand nor TGF-fl enhanced DC expansion. Addition of 10% autologous plasma to CB cultures promoted greater cell survival and a 150% increase in CDla + /CD80+ cell recovery. CB DC were 62% as effective stimulators of adult allogeneic T-cels as APB DC (p < .05) in allogeneic MLR. DISCUSSION While phenotypically similar, CB and APB DC have differential potency in allogeneic MLR, which may account for the difference in GvHD and infection incidence and severity between UCBT and allogeneic stem cell transplantation, and may require a different approach for adoptive cellular immunotherapy. The mechanism(s) associated with these differences require further elucidation.

A Phase I Clinical, Pharmacologic, and Biologic Study of Thrombopoietin and Granulocyte Colony-Stimulating Factor in Children Receiving Ifosfamide, Carboplatin, and Etoposide Chemotherapy for Recurrent or Refractory Solid Tumors: A Children's Oncology Group Experience

Purpose: Ifosfamide, carboplatin, and etoposide (ICE) are associated with grade III/IV dose-limiting thrombocytopenia. The Childrens Oncology Group conducted a phase I dose escalation, pharmacokinetic, and biological study of recombinant human thrombopoietin (rhTPO) after ICE in children with recurrent/refractory solid tumors (CCG-09717) to assess the toxicity and maximum tolerated dose of rhTPO administered at 1.2, 2.4, or 3.6 μg/kg per dose. Experimental Design: Children received ifosfamide 1,800 mg/m2 on days 0 to 4, carboplatin 400 mg/m2 on days 0 to 1, and etoposide 100 mg/m2 on days 0 to 4. rhTPO was administered i.v. on days +4, +6, +8, +10, and +12 at 1.2, 2.4, or 3.6 μg/kg per dose. Results: rhTPO was well tolerated and maximum tolerated dose was not reached. Median time to platelet recovery ≥100,000/μL of rhTPO at 1.2, 2.4, and 3.6 μg/kg/d was 24 days (22-24d), 25 days (23-29d), and 22 days (16-37d), respectively. Patients required a median of 2 days of platelet transfusions (0-7 days). Mean (± SD) rhTPO maximum serum concentrations were 63.3 ± 9.7 and 89.3 ± 15.7 ng/mL and terminal half-lives were 47 ± 13 and 64 ± 42 hours after 2.4 and 3.6 μg/kg/d, respectively. There was a significant increase in colony-forming unit megakaryocyte upon WBC count recovery. Conclusions: rhTPO was well tolerated. Time to hematologic recovery and median number of platelet transfusions seem to be improved compared with historical controls receiving ICE + granulocyte colony-stimulating factor (CCG-0894).

Feasibility study of IL-11 and granulocyte colony-stimulating factor after myelosuppressive chemotherapy to mobilize peripheral blood stem cells from heavily pretreated patients.

Purpose Pediatric patients with solid tumors treated with prolonged dose-intensive chemoradiotherapy are poor mobilizers of peripheral blood stem cells (PBSC). We have conducted a pilot study to mobilize PBSC in eight pediatric patients with relapsed solid tumors using ifosfamide, carboplatin, and etoposide (ICE) followed-up by IL-11 plus granulocyte colony-stimulating factor (G-CSF). Patients and Methods Patients received ifosfamide 1.8 g/m 2 per day for 5 days, carboplatin 400 mg/m 2 per day for 2 days, and etoposide 100 mg/m 2 per day for 5 days. After completion of ICE chemotherapy, patients received daily subcutaneous injections of G-CSF (5 &mgr;g/kg per day) and IL-11 (50–100 &mgr;g/kg per day) until peripheral stem cell apheresis. Results The median age was 11 years. Diagnosis included three relapsed Hodgkin disease, three relapsed central nervous system tumors, one relapsed Wilms tumor, and one relapsed rhabdomyosarcoma. The median number of apheresis procedures required to obtain 5 × 10 6 CD34 + cells/kg was one. The mean ± standard error of mean (SEM) total CD34 + cells collected was 14.0 ± 2.7 × 10 6 /kg. The mean ± SEM total CD34 + /CD41 + cells collected was 4.6 ± 1.9 × 10 6 /kg. Seven of the eight patients have subsequently undergone myeloablative chemotherapy with autologous PBSC transplantation and have reconstituted hematopoiesis with a median time to neutrophil recovery of 10 days and platelet recovery of 15.5 days. Conclusions We conclude that the regimen of ICE/IL-11 plus G-CSF is successful in mobilizing large numbers of CD34 + PBSC cells with a limited number (one) of apheresis collections in patients that have previously been heavily pretreated with chemotherapy/radiotherapy.

Autologous bone marrow transplantation for childhood acute lymphoblastic leukemia: a novel combined approach consisting of ex vivo marrow purging, modulation of multi-drug resistance, induction of autograft vs leukemia effect, and post-transplant immuno- and chemotherapy (PTIC).

In an attempt to reduce the high relapse rate associated with ABMT, five children with high-risk first CR and 19 in second or subsequent CR lacking matched family allogeneic donors underwent ABMT with chemopurged bone marrow utilizing verapamil (VPL), vincristine, and VP-16. Patients were conditioned with TBI, VPL bolus and infusion with VP-16 and cyclophosphamide. The first cohort of patients (n = 4) received only cyclosporin A (CsA). The second cohort (n = 7) received CsA and alpha interferon (total = 11 with post-transplant immunotherapy alone.) The third cohort (n = 13) received CsA and six alternating cycles of αIFN and chemotherapy and six additional cycles of chemotherapy (vincristine, VP-16, Ara-C, prednisone) followed by G-CSF (post-transplant immune chemotherapy (PTIC)). The 2-year DFS is 42 ± 10% (90% confidence interval (CI) is 26.5–58.5%) and 2-year overall survival is 54 ± 10% (90% CI is 37.5–70.5%). Furthermore, patients receiving PTIC (n = 13) vsimmunotherapy alone (CsA ± αIFN) (n = 11) had a substantially better 2 year DFS and OS: 69 ± 13% vs 13 ± 12% and 85 ± 10% vs 25 ± 15% (P = 0.008 and P = 0.06, respectively). These results suggest that the use of ABMT with chemopurging, combined with PTIC is well tolerated and may be an alternative new approach in the treatment of a subset of children with high-risk first CR or ⩾ second CR ALL who lack closely matched family-related allogeneic donors. Bone Marrow Transplantation (2001) 27, 145–153.

Immunophenotypic identification of possible therapeutic targets in paediatric non-Hodgkin lymphomas: a children's oncology group report.

Immunophenotypic analysis can identify protein epitopes in non‐Hodgkin lymphomas (NHL) that may respond to targeted immunotherapies, such as anti‐CD20 and anti‐CD52. Recent studies suggest additional targets may provide therapeutic benefits in NHL. This study evaluated protein expression of CD25, CD52, CD74 and CD80 in paediatric NHL to determine possible targets for immune‐based therapeutic approaches. Patient samples were derived from paediatric NHL clinical trials sponsored by the Childrens Cancer Group (CCG, now the Childrens Oncology Group, COG) and included Burkitt lymphoma (BL), diffuse large B‐cell lymphoma (DLBCL), disseminated T‐ and B‐cell lymphoblastic lymphoma (T‐LBL and B‐LBL) and anaplastic large cell (ALCL). Immunophenotypic studies were performed on formalin‐fixed, paraffin‐embedded diagnostic tissues. CD25 was expressed in 8% of T‐LBL and 75% of ALCL cases, but not in BL, DLBCL, or B‐LBL. CD52 was expressed in 99% of cases of paediatric NHL of all subtypes. CD74 was expressed in 100% of B‐LBL, BL and DLBCL, but was absent in ALCL and T‐LBL. CD80 was expressed in 12% of B‐LBL, 6% of BL and 10% of DLBCL cases studied, but was not detected in T‐cell NHL. These expression patterns suggest that CD25, CD52 and CD74 may represent potential new therapeutic targets in paediatric NHL.