Robert J. Hayashi

Cyclophosphamide Plus Topotecan in Children With Recurrent or Refractory Solid Tumors: A Pediatric Oncology Group Phase II Study

PURPOSE To determine the response rate of the combination of cyclophosphamide and topotecan in pediatric patients with recurrent or refractory malignant solid tumors. PATIENTS AND METHODS A total of 91 pediatric patients, 83 of whom were fully assessable for response and toxicity, received cyclophosphamide (250 mg/m2/dose) followed by topotecan (0.75 mg/m2/dose), each given as a 30-minute infusion daily for 5 days. All patients received filgrastim (5 mcg/kg) daily until the absolute neutrophil count (ANC) was > or = 1,500 microL after the time of the expected ANC nadir. RESULTS A total of 307 treatment courses were given to the 83 fully assessable patients. Responses (complete response plus partial response) were seen in rhabdomyosarcoma (10 of 15 patients), Ewings sarcoma (six of 17 patients), and neuroblastoma (six of 13 patients). Partial responses were seen in two of 18 patients with osteosarcoma and in one patient with a Sertoli-Leydig cell tumor. Twenty-three patients had either minor responses (n = 6) or stable disease (n = 17); the median number of courses administered to patients with partial or complete response was six (range, two to 13 courses), and the median administered to those with stable disease was three (range, one to 11 courses). The toxicity of the combination was limited principally to the hematopoietic system. Of 307 courses, 163 (53%) were associated with grade 3 or 4 neutropenia, 84 (27%) with grade 3 or 4 anemia, and 136 (44%) with grade 3 or 4 thrombocytopenia. Despite the severe myelosuppression, only 34 (11%) of 307 courses were associated with grade 3 or 4 infection. Nonhematopoietic toxicity of grades > or = 3 was rare and consisted of nausea and vomiting (two courses), perirectal mucositis (one course), transaminase elevation (one course), and hematuria (two courses). CONCLUSION The combination of cyclophosphamide and topotecan is active in rhabdomyosarcoma, neuroblastoma, and Ewings sarcoma. Stabilization of disease was seen in osteosarcoma, although objective responses were rare in this disease. The therapy can be given with acceptable hematopoietic toxicity with the use of filgrastim support.

A novel reduced-intensity stem cell transplant regimen for nonmalignant disorders.

Summary:Bone marrow transplantation (BMT) benefits nonmalignant diseases but is limited by regimen-related toxicity, graft-versus-host disease (GVHD), donor availability, and graft rejection (GR). To overcome some of these barriers, we developed a new conditioning strategy for these patients. In total, 16 patients received Campath-1H (33/48 mg; days −21 to −19), fludarabine (150 mg/m2; days −8 to −4), melphalan (140/70 mg/m2; day −3), and transplant using related/unrelated stem cells. GVHD prophylaxis included cyclosporine/methylprednisolone for cord cells. Other recipients also received methotrexate. Risk factors for GR included multiple transfusions (6), low stem cell numbers (1), and immunologic/metabolic disorders (3). Donor engraftment was present in 14/16 recipients. Neutrophils (ANC>0.5 × 109/l) and platelets (>50 × 109/l) engrafted at a median of 13 and 24 days. Two patients died of Pseudomonas sepsis prior to engraftment, one of CMV disease, and another of intracranial hemorrhage. With median follow-up of 281 days (78–907), 12/16 are stable/improved, or cured. Acute GVHD was absent (n=10) or mild and transient (grade1–2 skin) (n=4). There was no chronic GVHD. Toxicities were predominantly early infections within 100 days, and correlated with lymphopenia (CD4+ T and B cells). Stable engraftment and low incidence of significant GVHD, irrespective of age or stem cell source, make this reduced-intensity regimen attractive for nonmalignant disorders.

Twenty years of follow-up among survivors of childhood and young adult acute myeloid leukemia: A report from the Childhood Cancer Survivor Study

Limited data exist on the comprehensive assessment of late medical and social effects experienced by survivors of childhood and young adult acute myeloid leukemia (AML).

Treatment of steroid-resistant acute graft-versus-host disease with anti-thymocyte globulin

Acute graft-versus-host disease (aGVHD) is a major cause of mortality after allogeneic stem cell transplantation. Although initial treatment with corticosteroids is effective in the majority of patients, 30–60% develop steroid resistance. Anti-thymocyte globulin (ATG) is commonly used as first-line therapy for steroid resistant (SR) aGVHD. However, data on its efficacy are limited. At two institutions we reviewed the results of treatment with ATG of 58 patients with SR aGVHD. Initial manifestations of aGVHD were treated with 2 mg/kg/day of methylprednisolone (MP). Equine ATG was administered as first-line therapy for SR aGVHD, a median of 9 days (range, 3 to 39) after initiation of MP. At the time of initiation of ATG, IBMTR severity indices B, C and D were observed in 6%, 40% and 54% of patients, respectively. Improvement was observed in 30% of patients treated with ATG. Skin disease was more likely to improve with ATG (79%), while progression of gut and liver aGVHD was observed in 40% and 66% of patients, respectively. Despite initial improvement, 52 patients (90%) died a median of 40 days after ATG therapy from progressive aGVHD and/or infection (74%), ARDS (15%), or relapse (11%). Only six patients (10%), three of whom had aGVHD limited to the skin at the time ATG was administered, are long-term survivors. We conclude that initial improvement of SR aGVHD occurs with ATG in a minority of patients, and very few patients become long-term survivors. Furthermore, this treatment is associated with a high rate of major complications. Bone Marrow Transplantation (2001) 27, 1059–1064.

Increasing Incidence of Chronic Graft-versus-Host Disease in Allogeneic Transplantation: A Report from the Center for International Blood and Marrow Transplant Research

Although transplant practices have changed over the last decades, no information is available on trends in incidence and outcome of chronic graft-versus-host disease (cGVHD) over time. This study used the central database of the Center for International Blood and Marrow Transplant Research (CIBMTR) to describe time trends for cGVHD incidence, nonrelapse mortality, and risk factors for cGVHD. The 12-year period was divided into 3 intervals, 1995 to 1999, 2000 to 2003, and 2004 to 2007, and included 26,563 patients with acute leukemia, chronic myeloid leukemia, and myelodysplastic syndrome. Multivariate analysis showed an increased incidence of cGVHD in more recent years (odds ratio = 1.19, P < .0001), and this trend was still seen when adjusting for donor type, graft type, or conditioning intensity. In patients with cGVHD, nonrelapse mortality has decreased over time, but at 5 years there were no significant differences among different time periods. Risk factors for cGVHD were in line with previous studies. This is the first comprehensive characterization of the trends in cGVHD incidence and underscores the mounting need for addressing this major late complication of transplantation in future research.

Safety and efficacy of allogeneic PBSC collection in normal pediatric donors: The Pediatric Blood and Marrow Transplant Consortium Experience (PBMTC) 1996–2003

Summary:The use of peripheral blood stem cells (PBSC) for allogeneic transplants in adults has greatly increased. This trend is reflected in pediatrics, where healthy children increasingly are donating PBSC or donor lymphocyte infusion (DLI) via apheresis for use by ill siblings. There is a potential concern that the risks of PBSC collection may differ for pediatric donors. However, no large studies have assessed safety issues in this population. To address this need, we reviewed 218 (213 PBSC, five DLI) collections in 201 normal pediatric donors (8 months to 17 years, median 11.8 years) at 22 institutions in the Pediatric Blood and Marrow Transplant Consortium. Donors received a median of 4 days of growth factor, and mean collection yield was 9.1 × 106 CD34+ cells/kg recipient weight. Younger age, days of apheresis, and male gender predicted increased yield of CD34+ cells/kg donor weight. Growth factor-induced pain was mild and reported in less than 15% of patients. Most donors <20 kg (23/25, 92%) required PRBC priming of the apheresis machine. This experience with over 200 collections demonstrates that PBSC collection is safe in normal pediatric donors and desired CD34 cell yields are easily achieved. Younger children utilize more medical resources and children <20 kg usually require a single blood product exposure.

Unrelated donor hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis

We report outcomes after unrelated donor hematopoietic cell transplantation (HCT) for 91 patients with hemophagocytic lymphohistiocytosis (HLH) transplanted in the US in 1989–2005. Fifty-one percent were <1 year at HCT and 29% had Lansky performance scores <90%. Most (80%) were conditioned with BU, CY, and etoposide (VP16) with or without anti-thymocyte globulin. Bone marrow was the predominant graft source. Neutrophil recovery was 91% at day-42. The probabilities of grades 2–4 acute GVHD at day-100 and chronic GVHD at 5 years were 41 and 23%, respectively. The overall mortality rate was higher in patients who did not receive BU/CY/VP16-conditioning regimen (RR 1.95, P=0.035). The 5-year probability of overall survival was 53% in patients who received BU/CY/VP16 compared to 24% in those who received other regimens. In the subset of patients with known disease-specific characteristics, only one of five patients with active disease at HCT is alive. For those in clinical remission at HCT (n=46), the 5-year probability of overall survival was 49%. Early mortality rates after HCT were high, 35% at day-100. These data demonstrate that a BU/CY/VP16-conditioning regimen provides cure in approximately 50% of patients and future studies should explore strategies to lower early mortality.

Low-Dose Chemotherapy and Rituximab for Posttransplant Lymphoproliferative Disease (PTLD): A Children's Oncology Group Report

Optimal therapy for posttransplant lymphoproliferative disease (PTLD) remains problematic. A phase II trial adding rituximab to a low‐dose cyclophosphamide and prednisone regimen was conducted for pediatric patients with Epstein–Barr virus (EBV) (+), CD20 (+) PTLD. Fifty‐five patients were enrolled. Toxicity was similar for cycles of therapy containing rituximab versus those without. The complete remission (CR) rate was 69% (95% confidence interval (CI); 57%–84%). Of 12 patients with radiographic evidence of persistent disease at the end of therapy, eight were in CR 28 weeks later without further PTLD therapy. There were 10 deaths, 3 due to infections while receiving therapy and 7 from PTLD. The 2‐year event‐free survival (alive with functioning original allograft and no PTLD) was 71% (95% CI: 57%–82%) and overall survival was 83% (95% CI: 69%–91%) with median follow‐up of 4.8 years. Due to small numbers, we were unable to determine significance of tumor histology, stage of disease, allograft type or early response to treatment on outcome. These data suggest rituximab combined with low‐dose chemotherapy is safe and effective in treating pediatric with EBV (+) PTLD following solid‐organ transplantation.

Hematopoietic Stem Cell Transplantation for Refractory or Recurrent Non-Hodgkin Lymphoma in Children and Adolescents

We examined the role of hematopoietic stem cell transplantation (HSCT) for patients aged< or =18 years with refractory or recurrent Burkitt (n=41), lymphoblastic (n=53), diffuse large B cell (DLBCL; n=52), and anaplastic large cell lymphoma (n=36), receiving autologous (n=90) or allogeneic (n=92; 43 matched sibling and 49 unrelated donor) HSCT in 1990-2005. Risk factors affecting event-free survival (EFS) were evaluated using stratified Cox regression. Characteristics of allogeneic and autologous HSCT recipients were similar. Allogeneic donor HSCT was more likely to use irradiation-containing conditioning regimens, bone marrow (BM) stem cells, be performed in more recent years, and for lymphoblastic lymphoma. EFS rates were lower for patients not in complete remission at HSCT, regardless of donor type. After adjusting for disease status, 5-year EFS were similar after allogeneic and autologous HSCT for DLBCL (50% vs 52%), Burkitt (31% vs 27%), and anaplastic large cell lymphoma (46% vs 35%). However, EFS was higher for lymphoblastic lymphoma, after allogeneic HSCT (40% vs 4%; P < .01). Predictors of EFS for progressive or recurrent disease after HSCT included disease status at HSCT and use of allogeneic donor for lymphoblastic lymphoma. These data were unable to demonstrate a difference in outcome by donor type for the other histological subtypes.

Posttransplant Lymphoproliferative Disease in Children: Correlation of Histology to Clinical Behavior

Purpose To determine whether the morphologic features of posttransplant lymphoproliferative disease (PTLD) correlated to a response to therapy. Patients and Methods We reviewed our experience with PTLD in the pediatric population. We identified 32 patients with a total of 36 episodes of PTLD. The diagnosis was confirmed by tissue examination and classified according to the degree of monomorphic features of the lesion. Thirty-four of 36 episodes were managed with immunosuppression reduction, and the patients were assessed for their response to this strategy. Chemotherapy was used to treat 10 of 15 patients who had progressive disease, and their subsequent course was also analyzed. Results Sixteen of 17 (94%) patients with polymorphic morphology responded to immunosuppression reduction compared with only 5 of 17 (29%) patients with monomorphic features (P < 0.001). All of the patients with progressive disease who did not receive additional therapy died. Standard chemotherapy regimens for lymphoma were administered to 10 patients with progressive disease, with a high response rate (90%), durable remissions, and acceptable toxicity. Conclusions We conclude that the morphologic characteristics of PTLD provide information to potentially help guide treatment strategies in the management of this disease. Standard chemotherapy regimens for malignant lymphoma appear to be a viable treatment option for patients with progressive disease, although further investigation is needed.