Cerebral X-linked adrenoleukodystrophy (X-ALD) is a disorder of very-long-chain fatty acid metabolism, adrenal insufficiency, and cerebral demyelination. Death occurs within 2 to 5 years of clinical onset without hematopoietic cell transplantation (HCT). One hundred twenty-six boys with X-ALD received HCT from 1982 to 1999. Survival, engraftment, and acute graft-versus-host disease were studied. Degree of disability associated with neurologic and neuropsychological function and cerebral demyelination were evaluated before and after HCT. Complete data were available and analyzed for 94 boys with cerebral X-ALD. The estimated 5-and 8-year survival was 56%. The leading cause of death was disease progression. Donor-derived engraftment occurred in 86% of patients. Demyelination involved parietal-occipital lobes in 90%, leading to visual and auditory processing deficits in many boys. Overall 5-year survival of 92% in patients with 0 or 1 neurologic deficits and magnetic resonance imaging (MRI) severity score less than 9 before HCT was superior to survival for all others (45%; P < .01). Baseline neurologic and neuropsychological function, degree of disability, and neuroradiologic status predicted outcomes following HCT. In this first comprehensive report of the international HCT experience for X-ALD, we conclude that boys with early-stage disease benefit from HCT, whereas boys with advanced disease may be candidates for experimental therapies. (Blood. 2004;104: 881-888)

Background Natural killer (NK) cells derived from patients with cancer exhibit diminished cytotoxicity compared with NK cells from healthy individuals. We evaluated the tumor response and in vivo expansion of allogeneic NK cells in recurrent ovarian and breast cancer. Methods Patients underwent a lymphodepleting preparative regimen: fludarabine 25 mg/m2 × 5 doses, cyclophosphamide 60 mg/kg × 2 doses, and, in seven patients, 200 cGy total body irradiation (TBI) to increase host immune suppression. An NK cell product, from a haplo-identical related donor, was incubated overnight in 1000 U/mL interleukin (IL)-2 prior to infusion. Subcutaneous IL-2 (10 MU) was given three times/week × 6 doses after NK cell infusion to promote expansion, defi ned as detection of ≥ 100 donor-derived NK cells/µL blood 14 days after infusion, based on molecular chimerism and flow cytometry. Results Twenty (14 ovarian, 6 breast) patients were enrolled. The median age was 52 (range 30–65) years. Mean NK cell dose was 2.16 × 107 cells/kg. Donor DNA was detected 7 days after NK cell infusion in 9/13 (69%) patients without TBI and 6/7 (85%) with TBI. T-regulatory cells (Treg) were elevated at day +14 compared with pre-chemotherapy (P = 0.03). Serum IL-15 levels increased after the preparative regimen (P = <0.001). Patients receiving TBI had delayed hematologic recovery (P = 0.014). One patient who was not evaluable had successful in vivo NK cell expansion. Conclusions Adoptive transfer of haplo-identical NK cells after lymphodepleting chemotherapy is associated with transient donor chimerism and may be limited by reconstituting recipient Treg cells. Strategies to augment in vivo NK cell persistence and expansion are needed.

Intensive, myelosuppressive therapy is necessary to maximize outcomes for patients with acute myeloid leukemia (AML). A comparison was made of 3 aggressive postremission approaches for children and adolescents with AML in a randomized trial, CCG-2891. A total of 652 children and adolescents with AML who achieved remission on 2 induction regimens using identical drugs and doses (standard and intensive timing) were eligible for allocation to allogeneic bone marrow transplantation (BMT) based on matched related donor status (n ‫؍‬ 181) or randomization to autologous BMT (n ‫؍‬ 177) or to aggressive high-dose cytarabine-based chemotherapy (n ‫؍‬ 179).Only 115 patients (18%) refused to participate in the postremission phase of this study. Overall compliance with the 3 allocated regimens was 90%. At 8 years actuarial, 54% ؎ 4% (95% confidence interval) of all remission patients remain alive. Survival by assigned regimen ("intent to treat") is as follows: allogeneic BMT, 60% ؎ 9%; autologous BMT, 48% ؎ 8%; and chemotherapy, 53% ؎ 8%. Survival in the allogeneic BMT group is significantly superior to autologous BMT (P ‫؍‬ .002) and chemotherapy (P ‫؍‬ .05); differences between chemotherapy and autologous BMT are not significant (P ‫؍‬ .

CCG-2961 incorporated 3 new agents, idarubicin, fludarabine and interleukin-2, into a phase 3 AML trial using intensivetiming remission induction/consolidation and related donor marrow transplantation or high-dose cytarabine intensification. Among 901 patients under age 21 years, 5-year survival was 52%, and event-free survival was 42%. Survival improved from 44% between 1996 and 1998 to 58% between 2000 and 2002 (P ‫؍‬ .005), and treatment-related mortality declined from 19% to 12% (P ‫؍‬ .025). Partial replacement of daunomycin with idarubicin in the 5-drug induction combination achieved a remission rate of 88%, similar to historical controls. Postremission survival was 56% in patients randomized to either 5-drug reinduction or fludarabine/ cytarabine/idarubicin. For patients with or without a related donor, respective 5-year disease-free survival was 61% and 50% (P ‫؍‬ .021); respective survival was 68% and 62% (P ‫؍‬ .425). Donor availability conferred no benefit on those with inv(16) or t(8;21) cytogenetics. After cytarabine intensification, patients randomized to interleukin-2 or none experienced similar outcomes. Factors predictive of inferior survival were age more than 16 years, non-white ethnicity, absence of related donor, obesity, white blood cell count more than 100 000 ؋ 10 9 /L, ؊7/7q؊, ؊5/5q؊, and/or complex karyo- IntroductionIn the past 2 decades, cooperative group trials in pediatric acute myeloid leukemia (AML) have increased overall 5-year survival (OS) from approximately 30% to more than 50%. [1][2][3][4][5][6] Intensification of dose, increased number of days of conventional induction chemotherapy, matched related donor bone marrow transplantation (MRD BMT) in first remission, and risk stratification of treatment have all contributed to this progress. Risk stratification typically classifies as favorable those patients with Down syndrome or with AML characterized by t(8;21), t(15;17), or inv(16) cytogenetic abnormalities and rapid early response to induction therapy. Unfavorable features include high white blood cell count, Ϫ7/7qϪ, Ϫ5/5qϪ, or complex cytogenetics, and slow or no early response. [7][8][9][10][11] The emerging consensus is that patients with favorable AML do not benefit from MRD BMT in first remission. 2,12 Since 1986, the Children's Cancer Group (CCG) explored a strategy to treat newly diagnosed AML using intensively timed 5-drug combination chemotherapy consisting of dexamethasone, cytarabine, thioguanine, etoposide, and rubidomycin (daunomycin) (DCTER) for remission induction followed by BMT for patients with matched related donors or intensively timed high-dose cytarabine/asparaginase (HidAC) after remission therapy for patients without related donors. [13][14][15] Intensive timing involves administration of the second cycle of 5 drugs on day 10 regardless of remission status or blood counts. In the previous phase 3 trial, CCG-2891, intensively timed DCTER achieved an event-free survival (EFS) of 41% and OS of 49% at 5 years.This manuscript describes the successor phase...

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Central nervous system manifestations of globoid-cell leukodystrophy can be reversed by allogeneic hematopoietic stem-cell transplantation.

We undertook an analysis of 2,150 recipients of bone marrow transplant (BMT) at the University of Minnesota to determine the incidence of post- BMT malignant neoplasms (MNs). Fifty-one patients developed 53 MNs, compared with 4.3 expected from general population rates (standardized incidence ratio [SIR], 11.6, 95% confidence interval [CI], 8.2–14.5). These included 22 occurrences of B-cell lymphoproliferative disorder (BLPD), 17 solid nonhematopoietic tumors, 10 myelodysplastic syndromes (MDS), 1 acute myelogenous leukemia (AML), 2 non-Hodgkin's lymphoma (NHL), and 1 Hodgkin's disease (HD). The estimated actuarial incidence of any post-BMT malignancy was 9.9% +/- 2.3% at 13 years posttransplant. The cumulative probability of BLPD plateaued at 1.6% +/- 0.3% by 4 years from transplant and factors independently associated with increased risk included in vitro T-cell depletion of marrow (relative risk (RR) = 11.9, P < .001), HLA mismatch (RR = 8.9, P < .001), use of antithymocyte globulin (ATG) for graft versus host disease (GVHD) prophylaxis (RR = 5.9, P < .001) or in the preparative regimen (RR = 3.1, P = .03) and primary immunodeficiency (RR = 2.5, P = .06). The cumulative probability of developing solid malignancy was 5.6% +/- 2.2% at 13 years from BMT. Malignant melanomas were the most common (SIR, 10.3, 95% CI 1.9 to 25.4). The actuarial incidence of MDS/AML plateaued at 2.1% +/- 0.8% at 9 years and was seen most often in older patients receiving autologous peripheral blood stem cells for HD or NHL. These data document that BMT recipients are at an increased risk of later malignancy, which may add significant morbidity and mortality to the transplant process. Methods for screening and identification of individuals at increased risk need to be addressed in future studies.

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.