Gregory A. Hale

Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial

BACKGROUND Current treatment for medulloblastoma, which includes postoperative radiotherapy and 1 year of chemotherapy, does not cure many children with high-risk disease. We aimed to investigate the effectiveness of risk-adapted radiotherapy followed by a shortened period of dose-intense chemotherapy in children with medulloblastoma. METHODS After resection, patients were classified as having average-risk medulloblastoma (< or = 1.5 cm2 residual tumour and no metastatic disease) or high-risk medulloblastoma (> 1.5 cm2 residual disease or metastatic disease localised to neuraxis) medulloblastoma. All patients received risk-adapted craniospinal radiotherapy (23.4 Gy for average-risk disease and 36.0-39.6 Gy for high-risk disease) followed by four cycles of cyclophosphamide-based, dose-intensive chemotherapy. Patients were assessed regularly for disease status and treatment side-effects. The primary endpoint was 5-year event-free survival; we also measured overall survival. This study is registered with ClinicalTrials.gov, number NCT00003211. FINDINGS Of 134 children with medulloblastoma who underwent treatment (86 average-risk, 48 high-risk), 119 (89%) completed the planned protocol. No treatment-related deaths occurred. 5-year overall survival was 85% (95% CI 75-94) in patients in the average-risk group and 70% (54-84) in those in the high-risk group (p=0.04); 5-year event-free survival was 83% (73-93) and 70% (55-85), respectively (p=0.046). For the 116 patients whose histology was reviewed centrally, histological subtype correlated with 5-year event-free survival (p=0.04): 84% (74-95) for classic histology, 77% (49-100) for desmoplastic tumours, and 57% (33-80) for large-cell anaplastic tumours. INTERPRETATION Risk-adapted radiotherapy followed by a shortened schedule of dose-intensive chemotherapy can be used to improve the outcome of patients with high-risk medulloblastoma.

Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients

T-cell immunotherapy that takes advantage of Epstein-Barr virus (EBV)-stimulated immunity has the potential to fill an important niche in targeted therapy for EBV-related cancers. To address questions of long-term efficacy, safety, and practicality, we studied 114 patients who had received infusions of EBV-specific cytotoxic T lymphocytes (CTLs) at 3 different centers to prevent or treat EBV(+) lymphoproliferative disease (LPD) arising after hematopoietic stem cell transplantation. Toxicity was minimal, consisting mainly of localized swelling at sites of responsive disease. None of the 101 patients who received CTL prophylaxis developed EBV(+) LPD, whereas 11 of 13 patients treated with CTLs for biopsy-proven or probable LPD achieved sustained complete remissions. The gene-marking component of this study enabled us to demonstrate the persistence of functional CTLs for up to 9 years. A preliminary analysis indicated that a patient-specific CTL line can be manufactured, tested, and infused for

Atypical Teratoid/Rhabdoid Tumors (ATRT): Improved Survival in Children 3 Years of Age and Older With Radiation Therapy and High-Dose Alkylator-Based Chemotherapy

6095, a cost that compares favorably with other modalities used in the treatment of LPD. We conclude that the CTL lines described here provide safe and effective prophylaxis or treatment for lymphoproliferative disease in transplantation recipients, and the manufacturing methodology is robust and can be transferred readily from one institution to another without loss of reproducibility.

Adenovirus infection after pediatric bone marrow transplantation.

PURPOSE To describe clinical features, therapeutic approaches, and prognostic factors in pediatric patients with atypical teratoid/rhabdoid tumors (ATRT) treated at St Jude Childrens Research Hospital (SJCRH). PATIENTS AND METHODS Primary tumor samples from patients diagnosed with ATRT at SJCRH between July 1984 and June 2003 were identified. Pathology review included histologic, immunohistochemical analysis, and fluorescence in situ hybridization for SMARCB1 (also known as hSNF5/INI1) deletion. Clinical records of patients with pathologic confirmation of ATRT were reviewed. RESULTS Thirty-seven patients were diagnosed with ATRT at SJCRH during the 19-year study interval. Six patients were excluded from this clinical review based on pathologic or clinical criteria. Of the remaining 31 patients, 22 were younger than 3 years. Posterior fossa primary lesions and metastatic disease at diagnosis were more common in younger patients with ATRT. All patients underwent surgical resection; 30 received subsequent chemotherapy. The majority of patients aged 3 years or older received postoperative craniospinal radiation. Two-year event-free (EFS) and overall survival (OS) of children aged 3 years or older (EFS, 78% + 14%; OS, 89% +/- 11%) were significantly better than those for younger patients (EFS, 11% +/- 6%; OS, 17% +/- 8%); EFS, P = .009 and OS, P = .0001. No other clinical characteristics were predictive of survival. Three of four patients 3 years or older with progressive disease were successfully rescued with ifosfamide, carboplatin, and etoposide therapy. CONCLUSION Children presenting with ATRT before the age of 3 years have a dismal prognosis. ATRT presenting in older patients can be cured using a combination of radiation and high-dose alkylating therapy. Older patients with relapsed ATRT can have salvage treatment using ICE chemotherapy.

Similar outcomes using myeloablative vs reduced-intensity allogeneic transplant preparative regimens for AML or MDS

Retrospective analysis of 206 patients undergoing 215 consecutive bone marrow transplants (BMT) at St Jude Children’s Research Hospital between November 1990 and December 1994 identified 6% (seven male, six female) with adenovirus infection. The affected patients had a median age of 7.9 years (range 3–24 years) at time of transplantation. Although transplants were performed for hematologic malignancies, solid tumors or non-malignant conditions, only patients with hematologic malignancies had adenoviral infections. Adenovirus was first detected at a median of 54 days (range −4 to +333) after BMT. Adenovirus developed in eight of 69 (11.6%) patients receiving grafts from matched unrelated or mismatched related donors, in four of 52 (7.7%) receiving grafts from HLA-matched siblings, and in one of 93 (1.1%) receiving autografts. The most common manifestation of adenovirus infection was hemorrhagic cystitis, followed by gastroenteritis, pneumonitis and liver failure. The incidence of adenovirus infection in pediatric BMT patients at our institution is similar to that reported in adult patients. Using univariate analysis, use of total body irradiation and type of bone marrow graft were significant risk factors for adenovirus infection. Only use of total body irradiation remained as a factor on multiple logistic regression analysis.

The graft-versus-leukemia effect using matched unrelated donors is not superior to HLA-identical siblings for hematopoietic stem cell transplantation.

Although reduced-intensity conditioning (RIC) and non-myeloablative (NMA)-conditioning regimens have been used for over a decade, their relative efficacy vs myeloablative (MA) approaches to allogeneic hematopoietic cell transplantation in patients with AML and myelodysplasia (MDS) is unknown. We compared disease status, donor, graft and recipient characteristics with outcomes of 3731 MA with 1448 RIC/NMA procedures performed at 217 centers between 1997 and 2004. The 5-year univariate probabilities and multivariate relative risk outcomes of relapse, TRM, disease-free survival (DFS) and OS are reported. Adjusted OS at 5 years was 34, 33 and 26% for MA, RIC and NMA transplants, respectively. NMA conditioning resulted in inferior DFS and OS, but there was no difference in DFS and OS between RIC and MA regimens. Late TRM negates early decreases in toxicity with RIC and NMA regimens. Our data suggest that higher regimen intensity may contribute to optimal survival in patients with AML/MDS, suggesting roles for both regimen intensity and graft vs leukemia in these diseases. Prospective studies comparing regimens are needed to confirm this finding and determine the optimal approach to patients who are eligible for either MA or RIC/NMA conditioning.

Allogeneic Transplants in Follicular Lymphoma: Higher Risk of Disease Progression after Reduced-Intensity Compared to Myeloablative Conditioning

Do some patients benefit from an unrelated donor (URD) transplant because of a stronger graft-versus-leukemia (GVL) effect? We analyzed 4099 patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myeloid leukemia (CML) undergoing a myeloablative allogeneic hematopoietic cell transplantation (HCT) from an URD (8/8 human leukocyte antigen [HLA]-matched, n=941) or HLA-identical sibling donor (n=3158) between 1995 and 2004 reported to the CIBMTR. In the Cox regression model, acute and chronic GVHD were added as time-dependent variables. In multivariate analysis, URD transplant recipients had a higher risk for transplantation-related mortality (TRM; relative risk [RR], 2.76; P< .001) and relapse (RR, 1.50; P< .002) in patients with AML, but not ALL or CML. Chronic GVHD was associated with a lower relapse risk in all diagnoses. Leukemia-free survival (LFS) was decreased in patients with AML without acute GVHD receiving a URD transplant (RR, 2.02; P< .001) but was comparable to those receiving HLA-identical sibling transplants in patients with ALL and CML. In patients without GVHD, multivariate analysis showed similar risk of relapse but decreased LFS for URD transplants for all 3 diagnoses. In conclusion, risk of relapse was the same (ALL, CML) or worse (AML) in URD transplant recipients compared with HLA-identical sibling transplant recipients, suggesting a similar GVL effect.

Cidofovir for the treatment of adenoviral infection in pediatric hematopoietic stem cell transplant patients

Reduced-intensity conditioning (RIC) regimens have been increasingly used for allogeneic hematopoietic stem cell transplantation (HSCT) in follicular lymphoma (FL). We compared traditional myeloablative conditioning regimens to RIC in FL. Outcomes of HLA-identical sibling HSCT for FL in 208 recipients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) between 1997 and 2002 were studied. Conditioning regimens were categorized as myeloablative (N = 120) or RIC (N = 88). Use of RIC regimens increased from <10% of transplants in 1997 to >80% in 2002 signaling a major shift in practice. Patients receiving RIC were older and had a longer interval from diagnosis to transplant. These differences did not correlate with outcomes. Median follow-up of survivors was 50 months (4-96 months) after myeloablative conditioning versus 35 months (4-82 months) after RIC (P < .001). At 3 years, overall survival (OS) for the myeloablative and RIC cohorts were 71 (63%-79%) and 62 (51%-72%; P = .15) and progression free survival (PFS), 67 (58%-75%) and 55 (44%-65%; P = .07), respectively. Lower Karnofsky performance score (KPS) and resistance to chemotherapy were associated with higher treatment-related mortality (TRM) and lower OS and PFS. On multivariate analysis, an increased risk of lymphoma progression after RIC was observed (relative risk = 2.97, P = .04). RIC has become the de facto standard in allogeneic HSCT for FL, and appears to result in similar long-term outcomes. Although disease-free survival (DPS) is similar compared to myeloablative conditioning, an increased risk of late disease progression after RIC is concerning.

T‐cell alloreactivity dominates natural killer cell alloreactivity in minimally T‐cell‐depleted HLA‐non‐identical paediatric bone marrow transplantation

Background. Adenovirus (ADV) infections are associated with significant morbidity and mortality after hematopoietic stem cell transplantation (HSCT). The virus is endemic in the general pediatric population and frequently causes severe disease in immunocompromised patients, especially children. We report our experience with cidofovir (CDV) for treatment of ADV infection in 57 HSCT patients, median age 8 years (range 0.5–26). Methods. Peripheral blood was prospectively screened weekly on all patients for ADV by quantitative real-time PCR for the first 100 days post-HSCT or longer if clinically indicated. Cultures for viral pathogens were performed from other involved sites. Upon detection of ADV by PCR, culture or tissue histopathology, CDV was given intravenously at 5 mg/kg weekly for 2 consecutive weeks, then every 2 weeks until 3 consecutive ADV-negative samples were documented from all previously invoved sites. Results. The clinical manifestations of ADV infection were: diarrhea (53%), fever (21%), hemorrhagic cystitis (12%), and pneumonitis (11%). Eight patients (14%) presented with disseminated disease. CDV treatment resulted in complete resolution of clinical symptoms in 56 (98%) patients in whom the virus became undetectable by all methods. One patient died due to ADV pneumonitis. No cases of dose-limiting nephrotoxicity were observed. Conclusions. Cidofovir appeared safe and effective for the treatment of ADV infection in this predominantly pediatric HSCT population. Vigilant surveillance and early treatment with CDV can prevent the poor outcomes associated with ADV disease. A larger prospective study is needed to further determine the role of CDV in the treatment of ADV after HSCT.

Significant Improvement in Survival After Allogeneic Hematopoietic Cell Transplantation During a Period of Significantly Increased Use, Older Recipient Age, and Use of Unrelated Donors

Summary. Natural killer (NK) cell alloreactivity resulting from killer immunoglobulin‐like receptor (KIR) ligand incompatibility improves outcomes in patients receiving extensively T‐cell‐depleted bone marrow (BM) grafts. Patients with KIR ligand incompatibility are at risk for donor T‐cell alloreactivity. We investigated the relative significance of NK‐cell and T‐cell alloreactivity in 105 paediatric patients who received a minimally T‐cell‐depleted human leucocyte antigen‐non‐identical BM transplantation. Donor NK‐cell incompatibility did not improve patient outcome [engraftment, graft‐versus‐host disease (GVHD), relapse or overall survival]. In contrast, donor T‐cell incompatibility was a risk factor for acute GVHD, chronic GVHD and death. Thus, T‐cell alloreactivity dominated that of NK cells in minimally T‐cell‐depleted grafts.