Allen Chauvenet

A risk-adapted, response-based approach using ABVE-PC for children and adolescents with intermediate- and high-risk Hodgkin lymphoma: the results of P9425

Current treatment strategies for Hodgkin lymphoma result in excellent survival but often confer significant long-term toxicity. We designed ABVE-PC (doxorubicin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide) to (1) enhance treatment efficacy by dose-dense drug delivery and (2) reduce risk of long-term sequelae by response-based reduction of cumulative chemotherapy. Efficient induction of early response by dose-dense drug delivery supported an early-response-adapted therapeutic paradigm. The 216 eligible patients were younger than 22 years with intermediate- or high-risk Hodgkin lymphoma. ABVE-PC was administered every 21 days. Rapid early responders (RERs) to 3 ABVE-PC cycles received 21 Gy radiation to involved regions; RER was documented in 63% of patients. Slow early responders received 2 additional ABVE-PC cycles before 21 Gy radiation. Five-year event-free-survival was 84%: 86% for the RER and 83% for the slow early responders (P = .85). Only 1% of patients had progressive disease. Five-year overall survival was 95%. With this regimen, cumulative doses of alkylators, anthracyclines, and epipodophyllotoxins are below thresholds usually associated with significant long-term toxicity. ABVE-PC is a dose-dense regimen that provides outstanding event-free survival/overall survival with short duration, early-response-adapted therapy.

Vincristine-induced neuropathy as the initial presentation of Charcot-Marie-Tooth disease in acute lymphoblastic leukemia: A Pediatric Oncology Group study

Purpose After profound peripheral neurotoxicity during induction chemotherapy for acute lymphoblastic leukemia (ALL) in the index patient with Charcot-Marie-Tooth hereditary neuropathy (CMT), study coordinators of the Pediatric Oncology Group (POG) front-line ALL protocols reviewed patient registrations to identify any other patients with possible CMT. The goal was to provide preliminary information about patients with undiagnosed CMT who develop ALL. Patients and Methods Five children with ALL who were enrolled in POG B-precursor or T-cell ALL protocols from 1994 to 1999 subsequently were determined to have CMT hereditary neuropathy. Their clinical presentations and treatment records were reviewed in detail. Records of all patients entered on POG 9201 (lesser-risk ALL) were reviewed to identify all cases of significant vincristine toxicity noted in the first 6 months of treatment. Results The five identified patients all had substantial peripheral neurotoxicity that required alteration in treatment and/or orthopedic/physical therapy evaluation and follow-up. The POG 9201 review identified 25 of 686 patients (3.6%) with significant peripheral neuropathy. Three of 25 were diagnosed with CMT; the others have had no testing reported. Conclusions A family history of CMT or other peripheral neuropathy should be sought at the time of diagnosis of ALL. Testing for CMT should be considered in any child with substantial vincristine-induced peripheral neurotoxicity. Treatment of such patients must be individualized. Testing of all patients with significant peripheral neuropathy would be necessary to determine the percentage of such neuropathy explained by underlying CMT.

Religiosity is Associated With the Use of Complementary Medical Therapies by Pediatric Oncology Patients

Purpose To determine the prevalence of complementary and alternative medicine (CAM) use in pediatric oncology patients, the types of CAM used, and the factors associated with the use of CAM. Patients and Methods A questionnaire regarding CAM use was administered to patients/families seen in the pediatric oncology clinic at Wake Forest University Baptist Medical Center over a 12-month period. Results Based on 195 completed questionnaires, 91 (47%) patients reported use of CAM since diagnosis. Among CAM users, the most commonly used CAM therapies were faith healing, megavitamins/minerals, massage, other dietary supplements, relaxation techniques, and herbal medicines/teas. Forty-one percent of CAM users had not discussed CAM use with their physician(s). In bivariate analysis, CAM use was not associated with age at the time of survey, time since diagnosis, sex, race, parental education, or family income. A trend was noted between CAM use and older age at diagnosis. Families who reported themselves to be “very” religious were more likely to use CAM than those that are “somewhat” or “not at all” religious. Conclusions Use of CAM is common among pediatric oncology patients and often is not discussed with the treating physician(s). Patients from very religious families are more likely to use CAM.

Intensive chemotherapy and low-dose radiotherapy for the treatment of advanced-stage Hodgkin's disease in pediatric patients: a Pediatric Oncology Group study.

Sixty-two patients with advanced-stage Hodgkins disease and a median age of 12 years (range, 3 to 22 years) were treated with four cycles of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) alternating with four cycles of doxorubicin, vinblastine, bleomycin, and dacarbazine (ABVD) followed by low-dose radiotherapy (RT). We determined the feasibility, immediate safety, and rapidity of response of patients to this regimen, as well as the relationship between prognostic factors and the rate of complete remission (CR), event-free survival (EFS), and overall survival. Therapy was well tolerated, and the major toxicity was hematopoietic. At the end of chemotherapy, 54 of 62 patients (87%) were in CR by clinical restaging, with a biopsy of residual disease where necessary. The actuarial 3-year EFS is 77% (SE, 11%), with a median follow-up of 35 months, and the survival is 91% (SE, 7%). With respect to EFS, female patients and those with stage II or III disease fared statistically better than males and patients with stage IV disease, respectively. Six patients have died: three of progressive Hodgkins disease, one of secondary acute myelocytic leukemia (AML), one of secondary non-Hodgkins lymphoma (NHL), and one of overwhelming bacterial sepsis. The Pediatric Oncology Group (POG) is currently engaged in a randomized study of these eight cycles of chemotherapy with and without RT to assess the role of RT in achieving comparable results.

POG 8625: A randomized trial comparing chemotherapy with chemoradiotherapy for children and adolescents with stages I, IIA, IIIA 1 Hodgkin disease: A report from the children's oncology group

To determine if 6 courses of chemotherapy alone could achieve the same or better outcome than 4 courses of chemotherapy followed by radiation therapy (chemoradiotherapy) in pediatric and adolescent patients with Hodgkin disease. Children ≤21 years old with biopsy-proven, pathologically staged I, IIA, or IIIA1 Hodgkin disease were randomly assigned 6 courses of alternating nitrogen mustard, oncovin, prednisone, and procarbazine/doxorubicin, bleomycin, vinblastine, and dacarbazine (treatment 1) or 4 courses of alternating nitrogen mustard, oncovin, prednisone, and procarbazine/doxorubicin, bleomycin, vinblastine, and dacarbazine +2550 cGy involved-field radiotherapy (treatment 2). The complete response rate was 89%, with a complete response and partial response rate of 99.4%. There was no statistically significant difference in event-free survival (EFS) or overall survival between arms. The EFS for those who achieved an early complete response was significantly higher than for those who did not. For pediatric patients with asymptomatic low-stage and intermediate-stage Hodgkin disease, chemotherapy and chemoradiotherapy both resulted in 3-year EFS of approximately 90% and statistically indistinguishable 8-year EFS and overall survival, without significant long-term toxicity. Early response to therapy was associated with higher EFS, a concept that has led to the Childrens Oncology Group paradigm of response-based risk-adapted therapy for pediatric Hodgkin disease.

Prospective Analysis of TEL Gene Rearrangements in Childhood Acute Lymphoblastic Leukemia: a Children's Oncology Group Study

PURPOSE To prospectively determine the prognostic significance of the TEL-AML1 fusion in children with acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS TEL gene status was determined for 926 patients with B-precursor ALL enrolled on the Pediatric Oncology Group ALinC 16 trials and patients were observed for a median time of 8 years. RESULTS Rearrangements of the TEL gene were detected in 244 patients (26%). The estimated 5-year event-free survival rate (+/- SE) for patients with TEL rearrangements was 86% +/- 2%, compared with 72% +/- 2% for those with germline TEL (P < .0001). TEL rearrangements were associated with a superior outcome among patients with standard-risk ALL, high-risk ALL, and rapid early responses to therapy. In a multivariate analysis that included risk group, sex, and day 15 marrow status, TEL status was an independent predictor of outcome (P = .0002). CONCLUSION We conclude that TEL gene status should be incorporated into risk classification schemes and suggest that patients who have standard-risk features, the TEL-AML1 fusion, and rapid early responses to therapy, should be treated with antimetabolite-based therapy designed to maintain their high cure rates and avoid late effects.

Surveillance Computed Tomography Imaging and Detection of Relapse in Intermediate- and Advanced-Stage Pediatric Hodgkin's Lymphoma: A Report From the Children's Oncology Group

PURPOSE Children with Hodgkins lymphoma (HL) routinely undergo surveillance computed tomography (CT) imaging for up to 5 years after therapy, resulting in cost and radiation exposure, without clear benefit. The objective of this study was to determine the contribution of surveillance CT, as compared with clinical findings, to detection of disease recurrence. PATIENTS AND METHODS Two hundred sixteen patients, age ≤ 21 years old, were treated on the multicenter Pediatric Oncology Group 9425 trial. Data for patients who experienced relapse were retrospectively reviewed to determine whether imaging or clinical events prompted suspicion of disease recurrence. Correlation was made to disease stage, time to recurrence, relapse site, and overall survival (OS). Results With a median follow-up time of 7.4 years, 25 (11.6%) of 216 patients had experienced a relapse, of whom 23 experienced local relapse. Median time to relapse was 7.6 months (range, 0.2 to 48.9 months). Nineteen relapses (76%) were detected based on symptoms, laboratory or physical examination findings, and two relapses (8%) were detected by imaging within the first year after therapy. Only four patients (16%) had their recurrence detected exclusively by surveillance imaging after the first year. Six deaths occurred, all in patients who experienced relapse within the first year after therapy. No patient with a recurrence after 1 year off treatment has died, regardless of how the recurrence was detected. CONCLUSION The majority of pediatric HL relapses occurred within the first year after therapy or were detected based on change in clinical status. Detecting late relapse, whether by imaging or clinical change, did not affect OS. These findings indicate that CT is overused for routine surveillance of patients with HL.

Response-Dependent and Reduced Treatment in Lower Risk Hodgkin Lymphoma in Children and Adolescents, Results of P9426: A Report from the Children’s Oncology Group

Hodgkin lymphoma is highly curable but associated with significant late effects. Reduction of total treatment would be anticipated to reduce late effects. This aim of this study was to demonstrate that a reduction in treatment was possible without compromising survival outcomes.

Recent Steroid Therapy Increases Severity of Varicella Infections in Children With Acute Lymphoblastic Leukemia

Objective. The varicella-zoster virus (VZV) continues to be a dangerous pathogen to immunocompromised children. Children with acute lymphoblastic leukemia (ALL) are treated with intermittent steroid therapy. This study was undertaken to examine the relationship between steroid therapy for ALL and severity of varicella infection. Methods. We performed a retrospective review of patients who were on Pediatric Oncology Group Protocol 9201 and had a history of varicella infection. Pediatric Oncology Group 9201 is a phase III study for the treatment of children with lesser risk ALL diagnosed between 1992 and 1999. Cases of varicella were coded 1 to 5 on the basis of severity: grade 1 caused minimal to no symptoms, grade 2 caused mild to moderate symptoms that did not require hospitalization, grade 3 caused symptoms severe enough to require hospitalization and intravenous acyclovir, grade 4 caused severe disease that had complications or that required intensive care, and grade 5 resulted in death. Results. Of 697 enrolled patients, 110 (15.8%) developed primary varicella; 59% of these were male. For analysis, disease grade was dichotomized into nonsevere (grades 1 and 2) and severe (grades 3, 4, and 5). Of the 110 patients, 56 had nonsevere disease; 54 had severe disease, including 2 deaths. Of the patients whose varicella was diagnosed within 3 weeks of receipt of prednisone, 70% had severe infection, whereas only 44% of those who had not received prednisone within 3 weeks had severe infection. The odds ratio for having a severe infection within 3 weeks of prednisone versus >3 weeks is 2.9 (95% confidence interval: 1.1–7.9). By multivariate analysis, older age at ALL diagnosis, years from ALL diagnosis to VZV diagnosis, and VZV diagnosis within the 4-week period of interest (during or within 3 weeks of prednisone therapy) all were independently associated with an increased risk for severe infection. Conclusions. This study represents the largest study to date of varicella in children with ALL and provides convincing evidence that prednisone therapy during the VZV incubation period significantly increases the risk for developing severe varicella infection. In addition, older age is associated with more severe infection. Despite the varicella vaccine and a dropping incidence of primary infections, VZV remains a dangerous pathogen for pediatric patients with ALL. With the possible exception of induction therapy, patients who are on ALL therapy and are exposed to varicella should have steroid therapy delayed until after the VZV incubation period. These findings may have implications for other diseases that are treated with corticosteroids.

Hematologic malignancies and Klinefelter syndrome: a chance association?

Klinefelter syndrome was first described in 1942 as an endocrine disorder characterized by gynecomastia, hypogonadism, small testes, and elevated levels of follicle-stimulating hormone. An extra X chromosome (i.e., 47,XXY) was subsequently demonstrated in these patients and an increased incidence of leukemia and lymphoma has been described. We report a retrospective study of a series of unselected patients with Klinefelter syndrome diagnosed by cytogenetic studies and the occurrence of hematologic malignancies. The literature is also reviewed.