Elaine Morgan

High Risk of Subsequent Neoplasms Continues With Extended Follow-Up of Childhood Hodgkin’s Disease: Report From the Late Effects Study Group

PURPOSE We present an update of a previously reported Late Effects Study Group cohort of 1,380 children with Hodgkins disease (HD) diagnosed between 1955 and 1986 in patients aged 16 years or younger. We describe the pattern and incidence of subsequent neoplasms (SNs) occurring with extended follow-up. PATIENTS AND METHODS Median age at diagnosis of HD was 11.7 years (range, 0.3 to 16.9 years) and at last follow-up was 27.8 years. Median length of follow-up was 17.0 years. RESULTS An additional 103 SNs were ascertained (total SNs = 212). The cohort was at an 18.5-fold increased risk of developing SNs compared with the general population (standardized incidence ratio [SIR], 18.5, 95% CI, 15.6 to 21.7). The cumulative incidence of any second malignancy was 10.6% at 20 years, increasing to 26.3% at 30 years; and of solid malignancies was 7.3% at 20 years, increasing to 23.5% at 30 years. Breast cancer was the most common solid malignancy (SIR, 56.7). Other commonly occurring solid malignancies included thyroid cancer (SIR, 36.4), bone tumors (SIR, 37.1), and colorectal (SIR, 36.4), lung (SIR, 27.3), and gastric cancers (SIR, 63.9). Risk factors for solid tumors included young age at HD and radiation-based therapy. Thirty-two patients developed third neoplasms, with the cumulative incidence approaching 21% at 10 years from diagnosis of second malignancy. CONCLUSION Additional follow-up of this large cohort of HD survivors documents an increasing occurrence of known radiation-associated solid tumors, (breast and thyroid cancers), as well as emergence of epithelial neoplasms common in adults, (colon and lung cancers) at a younger age than expected in the general population, necessitating ongoing surveillance of this high risk population.

Treatment of High-Risk Neuroblastoma With Triple-Tandem High-Dose Therapy and Stem-Cell Rescue: Results of the Chicago Pilot II Study

PURPOSE To investigate whether intensive induction therapy followed by triple-tandem cycles of high-dose therapy with peripheral-blood stem-cell rescue and local irradiation will improve event-free survival for patients with high-risk neuroblastoma. PATIENTS AND METHODS From August 1995 to January 2000, 25 consecutive newly diagnosed high-risk neuroblastoma patients and one child with recurrent MYCN-amplified disease were enrolled onto the Chicago Pilot II Protocol. After induction therapy and surgery, peripheral-blood stem cells were mobilized with three cycles of high-dose cyclophosphamide and granulocyte colony-stimulating factor. Patients then underwent triple-tandem cycles of high-dose therapy with peripheral-blood stem-cell rescue followed by radiation to the primary site. RESULTS Twenty-two of the 26 patients successfully completed induction therapy and were eligible for the triple-tandem consolidation high-dose therapy. Sufficient numbers of peripheral-blood stem cells were collected in all but one patient. Seventeen patients were able to complete all three cycles of high-dose therapy and peripheral-blood stem-cell rescue, two patients completed two cycles, and three patients completed one cycle. There was one toxic death, and one patient died from complications of treatment for graft failure. With a median follow-up of 38 months, the 3-year event-free survival and survival rates are 57% +/- 11% and 79% +/- 10%, respectively. CONCLUSION The results of this pilot study demonstrate that it is feasible to intensify consolidation with triple-tandem high-dose chemotherapy and peripheral-blood stem-cell rescue and local irradiation, and suggest that this treatment strategy may lead to improved survival for patients with high-risk neuroblastoma.

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.

Results of little or no treatment for lymphocyte-predominant Hodgkin disease in children and adolescents

Purpose The nodular lymphocyte-predominant form of Hodgkin disease (LPHD) is a distinct clinicopathologic entity with a favorable prognosis. To see if children and adolescents could be spared the adverse sequelae of treatment, the authors adopted a policy of little or no treatment of localized LPHD in 1989. Patients and Methods Presentation, pathology, and outcomes were reviewed for 15 consecutive children and adolescents with LPHD seen at a single institution since 1989. One patient was lost to follow-up and two patients were seen only once in consultation and treated elsewhere. These three cases were excluded, leaving twelve: nine males and three females, ranging in age at diagnosis from 2 to 17 years (median 11). Eleven of the 12 had stage I disease, and 1 had stage II. Six received no treatment following excisional biopsy, while five received a brief treatment with chemotherapy only. One was initially treated with involved field radiotherapy (IFRT) due to an initially imprecise histologic diagnosis of classic Hodgkin disease. Results All patients are alive, without evidence of disease, for periods ranging from 2 to 13+ years after diagnosis (median 6 years). One patient recurred locally with LPHD 6 years after initial brief chemotherapy and was then treated with IFRT, achieving a prolonged second remission. Conclusion Children and adolescents with localized LPHD have an excellent prognosis and may be safely approached either with a wait-and-see attitude of no initial therapy after initial adenectomy or with less aggressive treatments.

The spectrum of metabolic bone disease in lymphoblastic leukemia.

Eight patients with childhood acute lymphoblastic leukemia (ALL) and hypercalcemia, osteopenia, or vertebral compression fractures seen at our institution during the last 12 years were evaluated for biochemical evidence of bone disease. Five patients were hypercalcemic, three had abnormal phosphorous levels, and four had elevated alkaline phosphatase values. Parathyroid hormone (PTH) was measured by a polyvalent radioimmunoassay in five patients and these levels were abnormally high in three patients. Four of these five patients also had PTH measured by a midregion‐specific radioimmunoassay. One patient had a high PTH value. Two patients had low levels and one patient had a normal PTH level. Although these studies suggest diverse biochemical mechanisms may be contributing to the bone changes and hypercalcemia seen in childhood ALL, ectopic PTH production as well as ectopically produced fragments of PTH may have a role in mediating bone resorption and hypercalcemia. Cancer 59:346–350, 1987.

Treatment of poor-risk neuroblastoma patients with high-dose chemotherapy and autologous peripheral stem cell rescue

A single institutional pilot study was conducted in which 12 poor-risk neuroblastoma (NB) patients were uniformly treated with multi-agent induction chemotherapy followed by myeloablative consolidation chemotherapy and unpurged peripheral blood stem cell (PBSC) rescue. In addition to using standard criteria for evaluating response to induction chemotherapy, tumor cell contamination of the peripheral blood and/or bone marrow was analyzed in seven patients by immunocytology using a panel of five anti-NB monoclonal antibodies. Seven patients had morphologic evidence of bone marrow disease at the time of diagnosis, and two additional patients had tumor cells detected in bone marrow samples by immunocytology prior to the second cycle of chemotherapy. After three cycles of chemotherapy, two of the 12 patients continued to have evidence of bone marrow disease. Samples from 29 PBSC harvests collected from nine patients were also analyzed for the presence of contaminating tumor cells by immunocytology. In each case, the stem cells were found to be free of tumor. Eleven of the 12 patients underwent myeloablative therapy and PBSC rescue; five patients remain alive without disease progression, 28+ to 53+ months from diagnosis, and six patients have developed recurrent disease. We conclude that PBSCs can be successfully harvested from children with NB, and used for hematopoietic reconstitution following myeloablative chemotherapy. However, more effective therapy for poor-risk NB patients is still urgently needed.

Renal functional reserve in long-term survivors of unilateral Wilms tumor

We hypothesized that long-term survivors of unilateral Wilms tumor would have a decreased renal functional reserve secondary to the consequences of hyperfiltration in the nephrons of the remaining kidney. Therefore we evaluated the renal functional reserve in 12 long-term survivors of Wilms tumor after unilateral nephrectomy (mean +/- SE: 15 +/- 1.1 years; range 9 to 23 years). We measured the creatinine clearance before and after an acute, oral protein load to determine the renal functional reserve. Study subjects and control subjects were matched for age, gender, and body surface area. The basal creatinine clearances were similar (Wilms group 132 +/- 13 vs control group 142 +/- 11 ml/min/1.73 m2; p = not significant (NS]. There was no significant difference in the renal functional reserve between long-term survivors of Wilms tumor and matched control subjects (Wilms group 17 +/- 11 vs control group 25 +/- 11 ml/min/1.73 m2; p = NS). The change in creatinine clearance was not secondary to volume expansion because the fractional excretion of sodium was unchanged with protein loading (Wilms group before loading 0.92 +/- 0.12 vs after loading 0.99 +/- 0.13 (p = NS); control group before loading 0.91 +/- 0.12 vs after loading 1.0 +/- 0.14 (p = NS)). We conclude that up to 15 years after nephrectomy for unilateral Wilms tumor in childhood, there is no evidence of hyperfiltration injury.

Impact of chromosomal translocations on prognosis in childhood acute lymphoblastic leukemia.

The presence of a chromosomal translocation in the leukemic cells at diagnosis of acute lymphoblastic leukemia (ALL) in children is associated with a high risk for treatment failure. We have reexamined the relationship between translocations and prognosis in 146 children with ALL who received risk-based therapy such that high-risk patients were treated with intensive drug schedules. In univariate analysis, multiple factors were associated with a relatively poor event-free survival (EFS) including age less than 2 years or greater than 10 years (combined group), WBC count greater than 10 x 10(9)/L, French-American-British (FAB) morphologic classification L2, absence of common ALL antigen (CALLA, CD10) expression, absence of hyperdiploidy with a chromosome number of 50 to 60, and presence of the specific translocations t(4; 11)(q21;q23) or t(9;22)(q34;q11) (combined group). However, there was no disadvantage with respect to EFS in patients with translocations compared with those who lacked translocations (73% at 4 years in both groups). Furthermore, when patients with specific cytogenetic abnormalities for which the prognostic significance has been well established (hyperdiploid 50 to 60, t(4;11), and t(9;22] were removed from the analysis, the remaining group with other translocations had a better EFS than the remaining group lacking translocations, although this was not statistically significant (81% v 65% at 4 years, P = .24). In a multivariate analysis, a model including WBC count and FAB classification was the strongest predictor of EFS. The presence or absence of translocations was not an independent predictor of EFS and did not contribute to the ability of any model to predict EFS. In conclusion, when effective intensive therapy is used to treat childhood ALL with high-risk clinical features, categorization of patients on the basis of chromosomal translocations without attention to the specific abnormality is not useful as a prognostic factor.

Prior fungal infection is not a contraindication to bone marrow transplant in patients with acute leukemia

PURPOSE Our aim was to assess the feasibility of bone marrow transplantation (BMT) in patients with acute leukemia who have had prior documented invasive fungal infection within 5 months pretransplant treated aggressively with systemic amphoteric in B and, when applicable, surgical resection of the infected tissue. MATERIALS AND METHODS We reviewed the charts of patients with acute leukemia at our institution who underwent BMT between August 1992 and April 1994 after being treated for a severe fungal infection. We evaluated criteria for diagnosis of fungal infection, timing of infection in relation to BMT, and antifungal treatment modalities. We determined peritransplant complications, evidence for recurrence of fungal infection during BMT, morbidity related to antifungal drug therapy, and overall outcome in each patient. RESULTS Fungal infection developed in eight patients. Sites of involvement included lung, liver, spleen, and skin. All patients were treated with systemic amphotericin B. Some also underwent surgical resection of infected tissue following clinical control of infection. All patients underwent BMT. Seven of eight patients engrafted and survived BMT. One patient died of recurrent pulmonary mucormycosis. Three patients are alive and free of leukemia and fungal disease. Four patients died of noninfectious causes and had no evidence of fungal disease at the time of death. CONCLUSIONS Aggressive therapy of prior fungal infection followed by ongoing anti-fungal prophylaxis in acute leukemia patients may allow BMT without reactivation of the fungus. Reports of larger series of such patients as well as studies of the efficacy of chemoprophylaxis of fungal infections are needed.

Serum Neopterin Levels as a Diagnostic Marker of Hemophagocytic Lymphohistiocytosis Syndrome

ABSTRACT The objective of this study was to retrospectively evaluate the utility of serum neopterin as a diagnostic marker of hemophagocytic lymphohistiocytosis (HLH). The medical records of patients diagnosed with HLH (familial and secondary) between January 2000 and May 2009 were reviewed retrospectively, and clinical and laboratory information related to HLH criteria, in addition to neopterin levels, was recorded. A group of 50 patients with active juvenile dermatomyositis (JDM) (who routinely have neopterin levels assessed) served as controls for the assessment of the accuracy, sensitivity, and specificity of neopterin as a diagnostic test for HLH. The Pearson correlation was used to measure the association between serum neopterin levels and established HLH-related laboratory data. Serum neopterin levels were measured using a competitive enzyme immunoassay. During the time frame of the study, 3 patients with familial HLH and 18 patients with secondary HLH were identified as having had serum neopterin measured (all HLH patients were grouped together). The mean neopterin levels were 84.9 nmol/liter (standard deviation [SD], 83.4 nmol/liter) for patients with HLH and 21.5 nmol/liter (SD, 10.13 nmol/liter) for patients with JDM. A cutoff value of 38.9 nmol/liter was 70% sensitive and 95% specific for HLH. For HLH patients, neopterin levels correlated significantly with ferritin levels (r = 0.76, P = 0.0007). In comparison to the level in a control group of JDM patients, elevated serum neopterin was a sensitive and specific marker for HLH. Serum neopterin has value as a diagnostic marker of HLH, and prospective studies are under way to further evaluate its role as a marker for early diagnosis and management of patients.