Kathryn E. Dusenbery

Hematopoietic stem-cell transplantation in globoid-cell leukodystrophy.

BACKGROUND Globoid-cell leukodystrophy is caused by a deficiency of galactocerebrosidase, which results in progressive central nervous system deterioration. We investigated whether allogeneic hematopoietic stem-cell transplantation can provide a source of leukocyte galactocerebrosidase and thereby prevent the decline of central nervous system function in patients with the disease. METHODS Five children with globoid-cell leukodystrophy (one with the infantile type and four with late-onset disease) were treated with allogeneic hematopoietic stem-cell transplantation. Measurement of leukocyte galactocerebrosidase levels, neurologic examinations, neuropsychological tests, magnetic resonance imaging of the central nervous system, cerebrospinal fluid protein assays, and neurophysiologic measurements were performed before and after transplantation, with follow-up ranging from one to nine years. RESULTS Engraftment of donor-derived hematopoietic cells occurred in all patients and was followed by restoration of normal leukocyte galactocerebrosidase levels. In the four patients with late-onset disease, the central nervous system deterioration was reversed, and in the patient with the infantile form of the disease, signs and symptoms have not appeared. Magnetic resonance imaging showed a decrease in signal intensity in the three patients with late-onset disease who were assessed both before and after transplantation. Abnormalities in cerebrospinal fluid total protein levels were corrected in three patients with late-onset disease and substantially reduced in the patient with the infantile form. CONCLUSIONS Central nervous system manifestations of globoid-cell leukodystrophy can be reversed by allogeneic hematopoietic stem-cell transplantation.

Soft tissue sarcomas: Preoperative versus postoperative radiotherapy

External beam radiation may be given either before or after excision of a primary soft tissue sarcoma. This study was undertaken to determine whether or not the timing of radiotherapy was associated with any difference in either local control, survival, or incidence of complications. The files of 112 patients with a primary, nonmetastatic, extremity soft tissue sarcoma, treated with limb salvage surgery and irradiation were evaluated. Data regarding tumor stage, grade, site, surgical margin, dosage and timing of radiotherapy, treatment complications, disease relapse, and relapse‐free survival (RFS) were analyzed. Kaplan‐Meier lifetable analysis was used to determine survival estimates. There was no significant difference in the 5‐year RFS between patients receiving radiotherapy (RT) preoperatively versus postoperatively; 56 ± 15% and 67 ± 12% (P = 0.12, Mantel‐Cox), respectively. There was no significant difference in the overall survival between patients receiving RT preoperatively versus postoperatively; 75 ± 15% and 79 ± 11% (P = 0.94), respectively. Actuarial local control at 5 years for preoperative versus postoperative RT patients was not statistically different; 83 ± 12% versus 91 ± 8% (P = 0.41), respectively. Wound complications were more frequent in preoperative RT patients (31%) compared to postoperative RT patients (8%) (P = 0.0014, chi‐square). Preoperative irradiation was not associated with any benefit in terms of relapse‐free survival, overall survival or actuarial local control in this series. A higher incidence of major wound complications was found among patients treated with preoperative irradiation. We recommend that patients with a resectable extremity soft tissue sarcoma be treated with postoperative irradiation, reserving preoperative irradiation for those situations in which either the tumor is initially thought to be unresectable or the original tumor boundaries are obscured.

Extramedullary leukemia in children with newly diagnosed acute myeloid leukemia: A report from the Children's Cancer Group

Objectives To describe features of patients with acute myeloid leukemia presenting with extramedullary leukemic tumors (EML). Methods Among 1,832 patients entered on Childrens Cancer Groups chemotherapy trials with acute myeloid leukemia, 199 patients had EML, defined as any leukemic collection outside the bone marrow cavity. Three patient groups were denoted: group 1 (n = 109) with EML involving skin (with or without other sites of EML), group 2 (n = 90) with EML in sites other than skin, and group 3 (n = 1,633) without EML. Results The incidence of EML was 10.9%. Group 1 patients tended to be younger, had higher white blood cell counts, were more often CNS positive, had FAB M4 or M5 subtypes, and possessed more abnormalities of chromosome 11 than group 3 patients. Group 2 patients were younger, more often had the FAB M2 subtype, and had a higher incidence of t(8;21)(q22;q22) abnormality than group 3, but had similar white blood cell counts and incidence of CNS positivity at diagnosis. For group 1 the 5-year event-free survival was 26%, significantly worse than for group 3 at 29%. Event-free survival was better for group 2 patients (5-year estimate 46%), which remained a favorable prognostic factor by multivariate analysis. The authors retrospectively determined whether 118 (59%) of the EML patients received localized radiotherapy to the site of EML: 42 did and 76 did not. There were no differences in estimated event-free survival between patients who did and did not receive radiotherapy. Conclusions Non-skin (group 2) EML appeared to be an independent favorable prognostic factor. Localized radiotherapy to the site of EML at the end of induction chemotherapy did not improve outcome.

Unrelated donor bone marrow transplantation for children with acute leukemia.

PURPOSE To test the use of unrelated donor bone marrow transplantation (URD BMT) to cure children with high-risk acute leukemias. PATIENTS AND METHODS Between June 1985 and December 1994, 50 children with acute leukemia (15 acute myelogenous leukemia [AML], 35 acute lymphoblastic leukemia [ALL]; 22 greater than second complete remission [CR]) received BMT from a URD at the University of Minnesota. Ages ranged from 0.9 to 17.5 years (median, 8.8). Median follow-up is 2.1 years (range, 1 to 7.3). Thirty patients (60%) received bone marrow fully matched at HLA-A,B and DRB1; 20 (40%) received bone marrow with a major or minor mismatch at a single HLA-A or B locus. RESULTS The median time to neutrophil engraftment was day 24 (range, 14 to 42 days) in those receiving matched and day 25 (range, 15 to 32 days) in those receiving mismatched marrow (P = .35). The incidence of grades III to IV graft-versus-host disease (GVHD) was 23% (95% confidence interval [CI], 7% to 39%) in matched and 32% (95% CI, 8% to 52%) in HLA-mismatched patients (P = .57). The incidence of chronic GVHD was 50% (95% CI, 28% to 72%) in matched and 57% (95% CI, 23% to 91%) in mismatched patients (P = .80). Disease-free survival for patients with ALL is 37% (95% CI, 21% to 53%) at 1 year and 30% (95% CI, 15% to 46%) at 2 years; for patients with AML, 53% (95% CI, 28% to 78%) at 1 year and 33% (95% CI, 6% to 60%) at 2 years. CONCLUSION URD BMT is an effective treatment for children with poor-prognosis acute leukemia and should be considered for all high-risk patients. Early referral of patients is strongly recommended.

Haematopoietic cell transplantation in patients with Fanconi anaemia using alternate donors: results of a total body irradiation dose escalation trial

Allogeneic haematopoietic cell transplantation (HCT) is the only therapeutic modality capable of correcting the haematologic manifestations of Fanconi anaemia (FA). However, HCT from alternative donors has been associated with poor survival. Between June 1993 and July 1998, 29 FA patients (median age 12·1 years; range 3·7–48·5 years) were enrolled in a prospective phase I–II dose escalation study. All patients were treated with cyclophosphamide 40 mg/kg, total body irradiation (TBI) 450 cGy or 600 cGy and antithymocyte globulin (ATG), followed by HCT from an alternative donor. Graft‐versus‐host disease (GVHD) prophylaxis consisted of cyclosporin A for 6 months, short course methylprednisolone (2 mg/kg/day) between days +5 and +19 and marrow T‐cell depletion by counterflow elutriation. The probability of developing grade III–IV toxicity was 17% (95% CI 3–31%). For the 25 marrow recipients, the probability of neutrophil engraftment (ANC̊  0·5 × 109/l by day 45) was 63% (95% CI 42–82%). Probabilities of grade II–IV acute GVHD and chronic GVHD were 32% (95%CI 10–54%) and 0% respectively. With a median follow‐up of 18 months, the probability of survival for the entire cohort at 1 year was 34% (95% CI 17–51%). The presence of lymphocyte somatic mosaicism [i.e. the presence of diepoxybutane (DEB)‐insensitive cells] was associated with a significantly increased risk of graft failure. Disappointingly, the use of higher dose TBI and post‐transplant ATG did not improve engraftment. More effective peritransplant immunosuppression, especially in FA patients with somatic mosaicism, was required to overcome the barrier of graft rejection. New conditioning regimens adapted to each individuals alkylator sensitivity are needed to improve the outcome of alternative donor HCT for FA.

Preradiation Chemotherapy in Primary High-Risk Brainstem Tumors: Phase II Study CCG-9941 of the Children’s Cancer Group

PURPOSE This Childrens Cancer Group group-wide phase II trial evaluated the efficacy and toxicity of two chemotherapy arms administered before hyperfractionated external-beam radiotherapy (HFEBRT). PATIENTS AND METHODS Thirty-two patients with newly diagnosed brainstem gliomas were randomly assigned to regimen A and 31 to regimen B. Regimen A comprised three courses of carboplatin, etoposide, and vincristine; regimen B comprised cisplatin, etoposide, cyclophosphamide, and vincristine. Both arms included granulocyte colony-stimulating factor. Patients were evaluated by magnetic resonance imaging after induction chemotherapy and HFEBRT at a dose of 72 Gy. RESULTS Ten percent +/- 5% of regimen A patients objectively responded to chemotherapy. For combined induction and radiotherapy, 27% +/- 9% of patients improved. The neuroradiographic response rate for regimen B was 19% +/- 8% for chemotherapy and 23% +/- 9% after HFEBRT. Response rates were not statistically significant between regimens after induction or chemotherapy/HFEBRT. Event-free survival was 17% +/- 5% (estimate +/- SE) at 1 year and 6% +/- 3% at 2 years. Survival was significantly longer among patients who responded to chemotherapy (P <.05). Among patients who received regimen A induction, grades 3 and 4 leukopenia were observed in 50% to 65%, with one toxicity-related death. For regimen B, severe leukopenia occurred in 86% to 100%, with febrile neutropenia in 48% to 60% per course. CONCLUSION Neither chemotherapy regimen meaningfully improved response rate, event-free survival, or overall survival relative to previous series of patients with brainstem gliomas who received radiotherapy with or without chemotherapy.

Wolman disease successfully treated by bone marrow transplantation

Wolman disease is characterized by severe diarrhea and malnutrition leading to death during infancy. Lysosomal acid lipase deficiency is the cause of the symptoms and signs. It is inherited in an autosomal recessive manner. All Wolman disease patients have adrenal gland calcification. Previous therapeutic attempts have failed to provide remission. We report successful long-term bone marrow engraftment in a patient with Wolman disease resulting in continued normalization of peripheral leukocyte lysosomal acid lipase enzyme activity. Diarrhea is no longer present. Now, at 4 years of age, this patient is gaining developmental milestones. Cholesterol and triglyceride levels are normal. Liver function is normal. This is the first long-term continued remission reported for Wolman disease. Bone Marrow Transplantation (2000) 26, 567–570.

Mitoxantrone and cytarabine induction, high-dose cytarabine, and etoposide intensification for pediatric patients with relapsed or refractory acute myeloid leukemia: Children's Cancer Group Study 2951

PURPOSE To evaluate the response rate, survival, and toxicity of mitoxantrone and cytarabine induction, high-dose cytarabine and etoposide intensification, and further consolidation/maintenance therapies, including bone marrow transplantation, in children with relapsed, refractory, or secondary acute myeloid leukemia (AML). To evaluate response to 2-chlorodeoxyadenosine (2-CDA) and etoposide (VP-16) in patients who did not respond to mitoxantrone and cytarabine. PATIENTS AND METHODS Patients with relapsed/refractory AML (n = 101) and secondary AML (n = 13) were entered. RESULTS Mitoxantrone and cytarabine induction achieved a remission rate of 76% for relapsed/refractory patients and 77% for patients with secondary AML, with a 3% induction mortality rate. Cytarabine and etoposide intensification exceeded the acceptable toxic death rate of 10%. The response rate of 2-CDA/VP-16 was 8%. Two-year overall survival was estimated at 24% and was better than historical control data. Patients with secondary AML had similar outcomes to relapsed or refractory patients. Initial remission longer than 1 year was the most important prognostic factor for patients with primary AML (2-year survival rate, 75%), whereas for patients with primary AML, with less than 12 months of initial remission, survival was 13% and was similar to that of refractory patients (6%). CONCLUSION Mitoxantrone and cytarabine induction is effective with reasonable toxicity in patients with relapsed/refractory or secondary AML. The cytarabine and etoposide intensification regimen should be abandoned because of toxicity. Patients with relapsed AML with initial remissions longer than 1 year have a relatively good prognosis.

In vivo diode dosimetry for routine quality assurance in IMRT.

Due to the complexity of IMRT dosimetry, dose delivery evaluation is generally done using a treatment plan in which the optimized fluence distribution has been transferred to a test phantom for accessibility and simplicity of measurement. The actual patient doses may be reconstructed in vivo through the use of electronic portal imaging devices or films, but the assessment of absolute dose from these measurements is time-consuming and complicated. In our clinic we have instituted the use of routine diode dosimetry for IMRT patients following the same procedure used for standard radiation therapy patients in which each new treatment field is checked at the start of treatment. For standard cases the dose at dmax is calculated as part of the monitor unit calculation. For the IMRT cases, the dose contribution to the dmax depth for each field is taken from the treatment plan. We found that about 90% of the diode measurements agreed to within +/- 10% of the planned doses (45/51 fields) and 63% (32/51 fields) achieved +/- 5% agreement. By using this direct in vivo method to verify the clinical doses delivered, we have been able to make a uniform startup procedure for all patients while simplifying our IMRT QA process.

Outcome of second hematopoietic cell transplantation in Hurler syndrome

Hurler syndrome (HS) is an autosomal recessive, inherited metabolic storage disorder due to deficiency of lysosomal alpha-L-iduronidase (IDU) enzyme activity. Untreated patients develop progressive mental retardation and multisystem morbidity with a median life expectancy of 5 years. Allogeneic hematopoietic cell transplantation (HCT) can achieve stabilization and even improvement of intellect, with long-term survival. However, children with HS have an increased incidence of graft failure, usually with concomitant autologous marrow reconstitution. Between 1983 and 2000, 71 Hurler children underwent HCT at the University of Minnesota. Of these 71, 19 (27%) experienced graft failure. We report HCT outcomes in all 11 Hurler patients receiving a second HCT at the University of Minnesota. Median age at second HCT was 25 months (range, 16 to 45 months); median time from first HCT was 8 months (range, 4 to 18.5 months). The conditioning regimen consisted of cyclophosphamide/TBI/ATG (n = 8) or busulfan/cyclophosphamide/ATG (n = 3). The source of bone marrow was an unrelated donor in six, matched sibling in four, and mismatched related in one. Five of the 11 grafts were T cell depleted prior to infusion. Overall, 10 of 11 patients showed donor-derived engraftment, of whom three developed grade 3 to 4 acute GVHD. Five of 11 patients are surviving a median of 25 months (range, 2 months to 12 years) with an overall actuarial survival of 50% (95% CI, 27% to 93%) at 4 years. All five show sustained donor engraftment with normalization of IDU activity levels. Three of five evaluable patients demonstrated stabilization of neuropsychological function after second HCT. Currently, allogeneic donor-derived hematopoiesis provides the only chance for long-term survival and improved quality of life in Hurler patients. While graft failure in Hurler patients requires further investigation, a timely second HCT can be well-tolerated and beneficial.Bone Marrow Transplantation (2002) 29, 491–496. doi:10.1038/sj.bmt.1703395