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Biomedical subjects

Frederick R Appelbaum

Publications and source records attributed to Frederick R Appelbaum.

67 records · Page 4Linked to original sources
PubMed2002

Impact of trisomy 8 (+8) on clinical presentation, treatment response, and survival in acute myeloid leukemia: a Southwest Oncology Group study.

The prognostic impact of trisomy 8, alone or with other clonal aberrations, was evaluated in 849 patients with previously untreated acute myeloid leukemia (AML) who were registered to 5 Southwest Oncology Group trials. At presentation, 108 (12.7%) patients had +8 in their karyotypes, including 43 (5.1%) patients with +8 as the sole aberration; 307 (36.2%) were normal, and 434 (51.1%) had other cytogenetic abnormalities. Patients with +8 were slightly older (P =.033), had lower WBC (P =.011), and had lower percentages of peripheral blasts (P =.0004) than the patients without +8. Median survival time for all patients with +8 was 9.9 months (95% CI, 6.5-12.5), similar to that of "unfavorable" cytogenetics risk groups (8.3 months; 95% CI, 6.8-9.5.) Patients with +8 had significantly lower peripheral blasts (P =.0002), WBC (P <.0001) counts, and decreased overall survival (OS) than patients with normal cytogenetics (9.9 months vs 15.4 months; P =.006). However, survival of patients with +8 as the sole aberration did not differ significantly from those with normal cytogenetics (P =.36). Thus, the trisomy 8 group as a whole had poor survival, which was largely attributable to worsened outcomes among patients whose trisomy 8 was associated with other unfavorable cytogenetic abnormalities.

Acute Disease↗
PubMed2002

Therapy for chronic graft-versus-host disease: a randomized trial comparing cyclosporine plus prednisone versus prednisone alone.

Results of previous studies have suggested that transplantation-related mortality among patients with chronic graft-versus-host disease (GVHD) may be reduced by combined treatment with cyclosporine (CSP) and prednisone rather than by prednisone alone. In a randomized trial, we assessed the efficacy of cyclosporine plus prednisone versus prednisone alone as initial therapy for chronic GHVD among patients whose platelet counts were higher than 100,000/microL. Prednisone was administered initially at a dose of 1.0 mg/kg per day orally, followed by a prolonged taper, and cyclosporine was administered at 6 mg/kg orally twice daily every other day. The cumulative incidence of transplantation-related mortality at 5 years from enrollment was 17% (95% CI, 0.11-0.23) in the CSP plus prednisone arm and 13% (95% CI, 0.08-0.19) in the prednisone arm. The hazards of transplantation-related mortality, overall mortality, recurrent malignancy, secondary therapy, and discontinuation of all immunosuppressive therapy were not significantly different between the 2 arms, but survival without recurrent malignancy was lower in the 2-drug arm (P =.03). Avascular necrosis developed in 18 (13%) of the 142 patients in the CSP plus prednisone arm and in 32 (22%) of the 145 patients in the prednisone arm (P =.04). Treatment with CSP plus prednisone may reduce the risk for steroid-related toxicity, but results of the current study do not substantiate the hypothesis that the administration of CSP reduces transplantation-related mortality among patients with chronic GVHD.

Adolescent↗
PubMed2002

High-dose chemo-radioimmunotherapy with autologous stem cell support for relapsed mantle cell lymphoma.

Relapsed mantle cell lymphoma is a radiation-sensitive malignancy that is unlikely to be cured by treatment with conventional high-dose therapy and autologous stem cell transplantation. We tested the safety and efficacy of using a CD20-specific monoclonal antibody conjugated with (131)I to deliver high-dose radiation selectively to all lymphoma sites. Patients with relapsed or refractory mantle cell lymphoma received infusions of (131)I-labeled CD20-specific monoclonal antibody (Tositumomab). The antibody dose was 1.7 mg/kg body weight, and the amount of (131)I was calibrated to deliver 20 to 25 Gy to vital normal organs. This treatment was followed 10 days later by administration of high-dose etoposide (30-60 mg/kg), cyclophosphamide (60-100 mg/kg), and infusion of cryopreserved autologous stem cells. The 16 patients in this study had received a median of 3 prior treatments, and 7 had chemotherapy-resistant disease. The median dose of (131)I was 510 mCi (18.87 GBq). There were no therapy-related deaths. Among the 11 patients with conventionally measurable disease at the time of treatment, the respective complete and overall response rates were 91% and 100%. Fifteen patients remain alive, and 12 have had no progression of lymphoma at 6 to 57 months from transplantation and 16 to 97 months from diagnosis. Overall survival at 3 years from transplantation is estimated at 93%, and progression-free survival is estimated at 61%. High-dose treatment with (131)I-Tositumomab, etoposide, and cyclophosphamide results in a high remission rate and may provide long-term disease-free survival for patients with relapsed or refractory mantle cell lymphoma.

Adult↗
PubMed2002

A humanized non-FcR-binding anti-CD3 antibody, visilizumab, for treatment of steroid-refractory acute graft-versus-host disease.

Visilizumab is a humanized anti-CD3 monoclonal antibody characterized by a mutated IgG2 isotype, lack of binding to Fcgamma-receptors, and ability to induce apoptosis selectively in activated T cells. To test pharmacokinetics, safety, and immunosuppressive activity of visilizumab, 17 patients with glucocorticoid-refractory acute graft-versus-host disease (GVHD) were enrolled in a phase 1 study. Six patients were given 7 doses of visilizumab (0.25 or 1.0 mg/m(2)) on days 1, 3, 5, 7, 9, 11, and 13. Because multiple doses of 1 mg/m(2) caused delayed visilizumab accumulation and prolonged lymphopenia, the next 11 patients received a single dose of 3.0 mg/m(2) on day 1. GVHD improved in all patients; 15 were evaluable through day 42. Multiple dosing resulted in 1 of 6 complete responses (CRs) and 5 partial responses (PRs), but all 6 patients died at a median of 87 days after starting visilizumab therapy. Single dosing resulted in 6 of 9 CRs, 3 PRs, and 7 of 11 patients surviving after 260 to 490 days (median, 359 days; P =.03). There were no allergic reactions and 3 grade 1 acute infusional toxicities. Plasma Epstein-Barr virus (EBV) DNA titers more than 1000 copies/mL and posttransplant lymphoproliferative disease (PTLD) developed in 2 of the first 7 patients. Based on rising EBV DNA titers, 5 of the next 10 patients were given the B cell-specific monoclonal antibody, rituximab. EBV DNA became undetectable and no overt PTLD developed. Visilizumab is well tolerated and has activity in advanced GVHD. A phase 2 study incorporating preemptive therapy for PTLD is warranted to determine the efficacy of visilizumab in GVHD.

Acute Disease↗
PubMed2002

Factors associated with outcome after unrelated marrow transplantation for treatment of acute lymphoblastic leukemia in children.

Acute lymphoblastic leukemia (ALL) is the most common indication for transplantation of marrow from unrelated donors in children. We analyzed results of this procedure in children with ALL treated according to a standard protocol to determine risk factors for outcome. From January 1987 to 1999, 88 consecutively seen patients with ALL who were younger than 18 years received a marrow transplant from an HLA-matched (n = 56) or partly matched (n = 32) unrelated donor during first complete remission (CR1; n = 10), second remission (CR2; n = 34), third remission (CR3; n = 10), or relapse (n = 34). Patients received cyclophosphamide and fractionated total-body irradiation as conditioning treatment and were given methotrexate and cyclosporine for graft-versus-host disease (GVHD) prophylaxis. Three-year rates of leukemia-free survival (LFS) according to phase of disease were 70% for CR1, 46% for CR2, 20% for CR3, and 9% for relapse (P <.0001). Three-year cumulative relapse rates were 10%, 33%, 20%, and 50%, respectively, and 3-year cumulative rates of death not due to relapse were 20%, 22%, 60%, and 41%, respectively, for patients with CR1, CR2, CR3, and relapse. Grades III to IV acute GVHD occurred in 43% of patients given HLA-matched transplants and in 59% given partly matched transplants (P =.10); clinical extensive chronic GVHD occurred in 32% and 38%, respectively (P =.23). LFS rates were lower in patients with advanced disease (P <.0001), age 10 years or older (P =.002), or short duration of CR1 (P =.007). Thus, in addition to phase of disease, age and duration of CR1 were predictors of outcome after unrelated-donor transplantation for treatment of ALL in children. Outcome was particularly favorable in younger patients with early phases of the disease.

Adolescent↗
PubMed2002

Hematopoietic cell transplantation as a form of immunotherapy.

The association of graft-versus-host disease with diminished relapse rates following allogeneic hematopoietic cell transplantation, together with the dramatic responses sometimes seen following donor lymphocyte infusions, demonstrates the considerable power of the human immune system to eradicate hematological malignancies. The development of methods that reliably achieve complete engraftment of donor lymphohematopoiesis without subjecting patients to very-high-dose toxic chemoradiotherapy represents an important step in capitalizing on the allogeneic graft-versus-tumor effect. Nonmyeloablative hematopoietic cell transplantation can achieve complete chimerism in essentially all patients with HLA-matched siblings and the large majority of patients with matched unrelated donors. It can be carried out with relative safety, even in patients aged up to 70 years. Enduring complete responses have been seen in patients with virtually all varieties of hematological malignancies. Current studies are defining the role of this procedure in patient management. The greater challenge is to further capitalize on this approach by segregating the graft-versus-tumor effect from graft-versus-host disease.

Graft vs Host Disease↗
PubMed2002

PK11195, a peripheral benzodiazepine receptor ligand, chemosensitizes acute myeloid leukemia cells to relevant therapeutic agents by more than one mechanism.

Like Bcl-2, peripheral benzodiazepine receptors (pBzRs) reside in mitochondrial pores, are frequently over-expressed in tumor cells, and can protect cells from apoptotic cell death. We now show that the high-affinity, pBzR-specific ligand, PK11195, chemosensitizes AML cells to relevant chemotherapeutics, but is relatively non-toxic as a single agent, and does not chemosensitize normal myeloid cells. PK11195 can block p-glycoprotein efflux in AMLs, contributing to increased daunomycin toxicity in efflux-competent AMLs, but can also sensitize AMLs to cytarabine and DNR-sensitize efflux-incompetent AMLs, presumably via mitochondrial pore effects documented in other models. Therefore, PK11195 might contribute to improved clinical outcomes in AML.

Acute Disease↗
PubMed2002

Hematopoietic stem cell transplantation for advanced myelodysplastic syndrome after conditioning with busulfan and fractionated total body irradiation is associated with low relapse rate but considerable nonrelapse mortality.

The objectives of this study were to develop transplantation regimens for patients with advanced myelodysplastic syndrome (MDS) that would be associated with low transplantation-related mortality and improved relapse-free survival. Sixty patients with advanced MDS or acute myeloid leukemia evolving from MDS (sAML), 12 to 62 years old (median, 40 years), were conditioned with busulfan (7 mg/kg) and TBI (6 x 200 cGy) (BU/TBI) and received transplants from related (n = 20) or unrelated donors (n = 40). By French-American-British (FAB) criteria, 21 patients had refractory anemia with excess blasts (RAEB), 16 had RAEB in transformation (RAEB-T), 15 had sAML, and 8 had chronic myelomonocytic leukemia (CMML). By International Prognostic Scoring System (IPSS) criteria, 1 patient had low, 10 had intermediate-1, 13 had intermediate-2, and 31 had high-risk MDS (5 patients had proliferative CMML). All evaluable patients achieved sustained engraftment. The cumulative incidence (CI) of acute GVHD grades II to IV was 83% with unrelated donors and 85% with related donors. The CI of relapse was 25% at 3 years. The incidence of nonrelapse mortality (NRM) at 100 days was 38%. The Kaplan-Meier estimate of survival was 26% at 3 years. Major causes of death were relapse, organ failure, GVHD, and infection. In multivariate analysis, improved relapse-free survival was associated with good cytogenetic risk (P = .002) and shorter disease duration (P = .004). NRM was increased with longer disease duration (P = .0002), positive cytomegalovirus serology (P = .02), and male sex (P = .02). Relapse was associated with poor cytogenetic risk (P = .0004). Thus, BU/TBI conditioning as used in this trial was associated with relapse rates comparable to those observed with a previously used more intensive regimen combining BU/TBI with cyclophosphamide. However, despite the omission of cyclophosphamide, transplantation-related morbidity and mortality were considerable, particularly with transplants from unrelated donors. Future trials should explore the efficacy and tolerability of reduced-intensity conditioning regimens.

Adolescent↗
PubMed2002

Psoralen and ultraviolet A irradiation (PUVA) as therapy for steroid-resistant cutaneous acute graft-versus-host disease.

Psoralen plus ultraviolet A irradiation (PUVA) has immunomodulatory effects and is used to treat a variety of immune-mediated dermatologic diseases. We administered PUVA to 103 patients for treatment of steroid-resistant acute graft-versus-host disease (GVHD) of the skin. Twenty-nine patients had related donors (12 HLA-mismatched) and 74 had unrelated donors (23 HLA-mismatched). The median onset of GVHD was day 13 after transplantation, and the median onset of PUVA treatment was day 46. PUVA was administered as secondary therapy for 86 patients and tertiary therapy or greater for 17 patients. The median number of treatments was 16, and the mean cumulative exposure was 41 J/cm2. PUVA was generally well tolerated with 8 patients discontinuing therapy because of toxicity. At the start of PUVA treatment, 48 patients had rash affecting >50% of their body surface area (BSA), and 91 had rash involving >25% BSA. Of 65 patients who were evaluated after 6 weeks of PUVA treatment, 11 still had rash involving >50% BSA, 24 had rash involving >25% BSA, and 24 had no rash. The mean daily dose of prednisone at the start of PUVA therapy was 1.6 mg/kg compared to 0.7 mg/kg after 6 weeks of therapy. Fifty-nine patients (57%) did not require additional therapy for skin GVHD after starting PUVA. Ninety-two percent of patients developed chronic GVHD. Fifty-three patients (51%) remain alive at 129-1883 days after transplantation. These results suggest that PUVA can be an effective therapy for steroid-resistant acute GVHD of the skin.

Acute Disease↗
PubMed2002

Curative therapy of advanced essential thrombocythemia or polycythemia vera by hemopoietic stem cell transplantation.

Twenty-five patients with advanced essential thrombocythemia (ET; n = 13) or polycythemia vera (PV; n = 12) received hemopoietic stem cell transplants (HSCT) at the Fred Hutchinson Cancer Research Center. In most cases the indication to perform an HSCT was myelofibrosis with splenomegaly and peripheral blood cytopenias or the development of a myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Patients were 18-60 (median 43) years old with intervals from diagnosis to HSCT of 8-348 (median 168) months. All but five patients had been treated with cytotoxic agents, and nine patients were splenectomized before transplant. Conditioning was performed with chemotherapy only or chemotherapy plus total body irradiation regimens followed by the infusion of either marrow (n = 19) or peripheral blood stem cells (n = 6) from related (n = 16) or unrelated (n = 9) donors. All evaluable patients showed sustained neutrophil engraftment. Nine patients (seven with AML/MDS, two with myelofibrosis) died of transplant-related complications, and 16 are surviving, 14 of them in continuous unmaintained remission. With a median follow-up of 41 (range 5-116) months after transplant, survival at 3 years is 64%. These data provide evidence that HSCT can be a curative treatment for patients with advanced PV and ET.

Adolescent↗
PubMed2002

Acute lymphoblastic leukemia.

This is a comprehensive overview on the most recent developments in diagnosis and treatment of acute lymphoblastic leukemia (ALL). Dr. Dieter Hoelzer and colleagues give an overview of current chemotherapy approaches, prognostic factors, risk stratification, and new treatment options such as tyrosine kinase inhibitors and monoclonal antibodies. Furthermore the role of minimal residual disease (MRD) for individual treatment decisions in prospective clinical studies in adult ALL is reviewed. Drs. Ching-Hon Pui and Mary Relling discuss late treatment sequelae in childhood ALL. The relation between the risk of second cancer and treatment schedule, pharmacogenetics, and gene expression profile studies is described. Also pathogenesis, risk factors, and management of other complications such as endocrinopathy, bone demineralization, obesity, and avascular necrosis of bone is reviewed. Dr. Fred Appelbaum addresses long-term results, late sequelae and quality of life in ALL patients after stem cell transplantation. New options for reduction of relapse risk, e.g., by intensified conditioning regimens or donor lymphocyte infusions, for reduction of mortality and new approaches such as nonmyeloablative transplantation in ALL are discussed. Drs. Jacques van Dongen and Tomasz Szczepanski demonstrate the prognostic value of MRD detection via flow cytometry or PCR analysis in childhood ALL. They discuss the relation between MRD results and type of treatment protocol, timing of the follow-up samples, and the applied technique and underline the importance of standardization and quality control. They also review MRD-based risk group definition and clinical consequences.

Adult↗
PubMed2001

The current status of hematopoietic cell transplantation.

Hematopoietic cell transplantation is the preferred therapy for a substantial proportion of patients with life-threatening diseases of the lymphohematopoietic system. Recent advances in donor identification, disease eradication, and supportive care measures have broadened the application of transplantation and improved outcomes. This article provides a brief review of the major clinical principles of transplantation and results achieved to date.

Animals↗