PubMed Health⌕ Search

Biomedical subjects

Frederick R Appelbaum

Publications and source records attributed to Frederick R Appelbaum.

At least 37 records · Page 2Linked to original sources
PubMed2005

Allogeneic hematopoietic cell transplantation for infants with acute lymphoblastic leukemia.

The role of transplantation in infants with acute lymphoblastic leukemia (ALL) is not defined. We analyzed results of 40 infants diagnosed before age 12 months who received a hematopoietic cell transplant (HCT) between July 1982 and February 2003 in first complete remission (CR1; n = 17), CR2/3 (n = 7), or relapse (n = 16). Patients were conditioned with cyclophosphamide with total body irradiation (n = 39) or busulfan (n = 1). Donors were matched related (n = 8), mismatched related (n = 16), or unrelated (n = 16). Graft-versus-host disease (GVHD) prophylaxis was methotrexate or cyclosporine (n = 7) or methotrexate plus cyclosporine (n = 33). Thirty-nine patients engrafted, 20 developed acute GVHD, and 7 developed chronic GVHD. Sixteen patients relapsed and 7 died of other causes. Patients in CR1 had disease-free survival (DFS) of 76% compared with 45% for CR2/CR3 and 8% for relapse (P < .001). Of 33 patients with cytogenetic data, 26 (79%) had MLL gene rearrangement. Fourteen of these 26 were in CR1 and 11 survive in remission. Outcome was associated with phase of disease, but having the MLL gene was not a factor predictive of outcome. Late effects included growth and other hormone deficiencies. These data demonstrate that infants with ALL and MLL gene have excellent DFS when they received transplants in CR1, and consideration for transplantation in CR1 is warranted.

Cause of Death↗
PubMed2005

Randomized trial of allogeneic related bone marrow transplantation versus peripheral blood stem cell transplantation for chronic myeloid leukemia.

Seventy-two chronic myeloid leukemia patients were enrolled as part of a larger randomized trial at 3 centers between March 1996 and July 2001 to undergo either HLA-matched related allogeneic bone marrow (BM) or filgrastim (granulocyte colony-stimulating factor)-mobilized peripheral blood stem cell (PBSC) transplantation. Forty patients received BM, and 32 patients received PBSCs. There was no statistically significant difference in the incidence of acute or chronic graft-versus-host disease (GVHD), overall survival, disease-free survival, or non-relapse-related mortality between patients receiving BM or PBSC transplants. The cumulative incidence of grade II to IV acute GVHD was 49% in BM and 55% in PBSC recipients ( P = .48). The cumulative incidence of clinical extensive chronic GVHD was 50% in BM and 59% in PBSC recipients ( P = .46). Among 62 chronic phase chronic myeloid leukemia patients, there was no significant difference in overall survival (87% versus 81%; P = .59), disease-free survival (80% versus 81%; P = .61), or non-relapse-related mortality (13% versus 19%; P = .60) by cell source (BM versus PBSCs). Among chronic phase patients, however, there was a trend toward a higher cumulative incidence of relapse at 3 years in BM recipients (7% versus 0%; P = .10) and a higher cumulative incidence of chronic GVHD in PBSC recipients (59% versus 40%; P = .11). The trend toward a higher relapse incidence in BM recipients persisted with a longer follow-up.

Bone Marrow Transplantation↗
PubMed2005

Pretransplantation induction chemotherapy and posttransplantation relapse in patients with advanced myelodysplastic syndrome.

Hematopoietic cell transplantation is the only curative therapy for patients with myelodysplastic syndrome (MDS). However, treatment-related toxicity and, in patients with advanced MDS (refractory anemia with excess blasts [RAEB]; RAEB in transformation [RAEB-T]) or transformation to acute myeloid leukemia with multilineage dysplasia (tAML), posttransplantation relapse continue to be prevalent. Induction chemotherapy (IC) has been used in an attempt to decrease the risk of posttransplantation relapse, but the benefit for posttransplantation long-term survival is uncertain. We reviewed results in 125 patients with advanced MDS and tAML who received transplants from HLA-identical related or unrelated donors after preparation with myeloablative conditioning regimens. Thirty-three patients (3 with RAEB, 6 with RAEB-T, and 24 with tAML) received IC before transplantation, and 92 patients (62 with RAEB, 22 with RAEB-T, and 8 with tAML) did not. Seventy-six patients were conditioned with oral busulfan 16 mg/kg, which was adjusted to achieve steady-state plasma concentrations of 800 to 900 ng/mL, plus cyclophosphamide 2 x 60 mg/kg, and 49 patients received busulfan 7 mg/kg (without dose adjustment) and total body irradiation 6 x 200 cGy given over 3 days. There was no evidence of a benefit in posttransplantation outcome associated with prior IC, either for patients with RAEB/RAEB-T or those with tAML, with either conditioning regimen. There was a correlation of the severity of pretransplantation flow cytometric aberrancies on marrow cells and posttransplantation relapse. Further studies that randomize patients to IC versus no IC need to appropriately address the possible beneficial effect of IC.

Adolescent↗
PubMed2005

A phase I/II study of mycophenolate mofetil in combination with cyclosporine for prophylaxis of acute graft-versus-host disease after myeloablative conditioning and allogeneic hematopoietic cell transplantation.

Abstract In a phase I/II study, the combination of cyclosporine (CSP) and mycophenolate mofetil (MMF) was investigated as graft-versus-host disease (GVHD) prophylaxis after myeloablative conditioning and hematopoietic cell transplantation from an HLA-matched sibling donor. In phase I, 3 groups, each with 10 or 11 patients, received MMF (15 mg/kg) from day 0 to day 27 at decreasing dose intervals of every 12, 8, and 6 hours to determine a safe and effective total daily dose. At the 45 mg/kg/d dosage level, 4 of 11 patients developed only grade II GVHD, and a concentration at steady state of mycophenolic acid (the active moiety of MMF) consistent with a therapeutic range described for solid-organ transplantation was achieved. There was a suggestion of increased toxicity without improved efficacy at the 60 mg/kg/d dosage level. Accordingly, the 45 mg/kg/d dosage was therefore selected for phase II, and another 15 patients were added to this group from the phase I study (n=26). The concentrations at steady state for this dosage at days 0, 6, 13, 20, and 27 were 2.73, 3.02, 3.20, 2.62, and 2.64 microg/mL, respectively. No toxicities were attributed to MMF at this dose. The median time to engraftment after hematopoietic cell transplantation was 15 days (range, 10-20 days). The incidence of acute GVHD was 62%, which was comparable to a group of historical controls receiving CSP and methotrexate (MTX) for GVHD prophylaxis. Although a significant improvement in the prevention of GVHD was not suggested, compared with CSP and MTX, MMF in combination with CSP could be considered in cases in which MTX is contraindicated.

Adolescent↗
PubMed2005

Allogeneic hematopoietic cell transplantation for chronic myelomonocytic leukemia.

We evaluated the outcomes of allogeneic hematopoietic cell transplantation (HCT) in 43 patients with chronic myelomonocytic leukemia. Patients were classified according to the French-American-British and World Health Organization classifications, as well as the International Prognostic Scoring System and the M.D. Anderson prognostic score. Comorbidity scores were assessed by using an HCT-specific comorbidity index. Patients were aged 1 to 66 years (median, 48 years). Twenty-one patients received transplants from related donors (18 HLA-identical siblings and 3 HLA-nonidentical family members), and 22 received transplants from unrelated donors (18 HLA matched and 4 HLA nonidentical). Several busulfan or total body irradiation-based conditioning regimens were used. Sustained engraftment was achieved in 41 patients. Eighteen are alive at 1.9 to 14.1 years, for an estimated relapse-free survival of 41% at 4 years. Ten patients have relapsed, thus leading to a cumulative incidence of 23% at 4 years. Risk category by International Prognostic Scoring System, World Health Organization, M.D. Anderson prognostic score, or proliferative/dysplastic status had no statistically significant association with outcomes. However, patients with higher comorbidity scores had worse overall survival than patients with lower scores (P = .01). There was a trend for a higher relapse incidence among patients at higher risk by the M.D. Anderson prognostic score. The data suggest that patients with few or no comorbidities and those who undergo transplantation earlier in the disease course have the highest probability of successful outcome after allogeneic HCT.

Adolescent↗
PubMed2005

Increased AF1q gene expression in high-risk myelodysplastic syndrome.

The AF1q gene is expressed in normal haematopoietic progenitors, but less so in differentiated blood cells. In 47 patients with myelodysplastic syndrome (MDS), AF1q copy numbers were 0-6.8 x 10(6)/microg RNA compared with 1.5-2.4 x 10(5)/microg RNA in normal marrow. AF1q levels correlated with international prognostic scoring system (IPSS) scores (P = 0.004) and the risk of post-transplant relapse (P = 0.05). Among IPSS high-risk patients, survival correlated inversely with AF1q levels (P = 0.04). Thus, AF1q levels correlate with high-risk MDS and may provide a marker for risk stratification.

Adult↗
PubMed2004

Final adult height of patients who received hematopoietic cell transplantation in childhood.

Growth impairment and growth hormone (GH) deficiency are complications after total body irradiation (TBI) and hematopoietic cell transplantation (HCT). To determine the impact of GH therapy on growth, the final heights of 90 GH-deficient children who underwent fractionated TBI and HCT for malignancy were evaluated. Changes in height standard deviation (SD) from the diagnosis of GH deficiency to the achievement of final height were compared among 42 who did and 48 who did not receive GH therapy. At HCT, GH-treated patients were younger (P = .001), more likely to have undergone central nervous system irradiation (P = .007), and shorter (P = .005) than patients who did not receive GH therapy. After HCT, GH deficiency was diagnosed at 1.5 years (range, 0.8-9.5 years) for GH-treated and 1.2 years (range, 0.9-8.8 years) for nontreated patients. GH therapy was associated with significantly improved final height in children younger than 10 years at HCT (P = .0001), but GH therapy did not impact the growth of older children. Girls (P = .0001) and children diagnosed with acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), or myelodysplastic syndromes (MDS) (compared with acute lymphoblastic leukemia [ALL] or non-Hodgkin lymphoma [NHL]; P = .02) also showed more rapid growth than their counterparts. These data demonstrate that GH therapy improves the final height of young children after fractionated TBI.

Adolescent↗
PubMed2004

Duration of immunosuppressive treatment for chronic graft-versus-host disease.

Chronic graft-versus-host disease (GVHD) requires long-term immunosuppressive therapy after hematopoietic cell transplantation. We retrospectively analyzed a cohort of 751 patients with chronic GVHD to identify characteristics associated with the duration of immunosuppressive treatment. Among the 274 patients who discontinued immunosuppressive therapy after resolution of chronic GVHD before recurrent malignancy or death, the median duration of treatment was 23 months. Results of a multivariable model showed that treatment was prolonged in patients who received peripheral blood cells, in male patients with female donors, in those with graft-versus-host HLA mismatching, and in those with hyperbilirubinemia or multiple sites affected by chronic GHVD at the onset of the disease. Nonrelapse mortality was increased among patients with HLA mismatching or hyperbilirubinemia but not among those with other risk factors associated with prolonged treatment for chronic GVHD. Nonrelapse mortality was also increased in older patients and those with older donors, in patients with platelet counts less than 100 000/microL or progressive onset of chronic GVHD from acute GVHD, and in those receiving higher doses of prednisone immediately before the diagnosis of chronic GVHD. After the dose of prednisone was taken into account, progressive onset was not associated with an increased risk of nonrelapse mortality.

Adolescent↗
PubMed2004

Elevated expression of the AF1q gene, an MLL fusion partner, is an independent adverse prognostic factor in pediatric acute myeloid leukemia.

The AF1q gene, a mixed-lineage leukemia fusion partner, is highly expressed in hematopoietic progenitor cells but has low expression in differentiated cells. We determined the expression of the AF1q gene by reverse transcriptase-polymerase chain reaction in 64 pediatric acute myeloid leukemia (AML) patients treated on Children's Cancer Group clinical trial CCG-2891 and correlated its expression level to clinical characteristics and outcome. AF1q expression in patients varied from 0- to 154-fold compared with normal marrow, and increasing expression level was associated with worsening survival, with a hazard ratio of 1.02 per fold increase in AF1q expression (P = .032). We divided patients into tertile groups based on AF1q expression level. Patients with high AF1q expression (top tertile) had a higher predominance of French-American-British M1 compared to patients with lower 2 tertiles of AF1q expression (43% vs 9%, P = .003). High AF1q expression was associated with poor survival in univariate and multivariate models. Overall survival at 8 years for patients with the high AF1q expression was 19% versus 50% in patients with low AF1q expression, (P = .01). AF1q expression may correlate with clinical outcome in pediatric AML, although it is not clear if AF1q is simply a marker of a more primitive phenotype or contributes directly to leukemogenesis.

Acute Disease↗
PubMed2004

Cholesterol synthesis and import contribute to protective cholesterol increments in acute myeloid leukemia cells.

Cholesterol levels are abnormally increased in many acute myeloid leukemia (AML) samples exposed in vitro to chemotherapy. Blocking these acute cholesterol responses selectively sensitizes AML cells to therapeutics. Thus, defining the molecular mechanisms by which AML cells accomplish these protective cholesterol increments might elucidate novel therapeutic targets. We now report that the levels of mRNAs encoding the cholesterol synthesis-regulating enzyme, 3-hydroxy-3-methylglutaryl coenzyme A reductase, and the cholesterol-importing low-density lipoprotein (LDL) receptor were both increased by daunorubicin (DNR) or cytarabine (ARA-C) treatments in almost three fourths of cultured AML samples. However, less than one third of AML samples significantly increased LDL accumulation during drug treatments, suggesting that de novo synthesis is the primary mechanism by which most AML cells increase cholesterol levels during drug exposures. LDL increments were not correlated with cholesterol increments in ARA-C-treated AML samples. However, LDL and cholesterol increments did correlate in DNR-treated AML samples where they were measured, suggesting that a subset of AMLs may rely on increased LDL accumulation during treatment with particular drugs. Our data suggest that cholesterol synthesis inhibitors may improve the efficacy of standard antileukemia regimens, but that for maximum benefit, therapy may need to be tailored for individual patients with leukemia.

Biological Transport↗
PubMed2004

Addition of rituximab to fludarabine may prolong progression-free survival and overall survival in patients with previously untreated chronic lymphocytic leukemia: an updated retrospective comparative analysis of CALGB 9712 and CALGB 9011.

Fludarabine and rituximab combination therapies in chronic lymphocytic leukemia (CLL) have yielded promising early results, but no comparative efficacy data relative to standard fludarabine treatment regimens have been reported. To assess the effect of the addition of rituximab to fludarabine therapy, we retrospectively compared the treatment outcome of patients with similar clinical characteristics enrolled on 2 multicenter clinical trials performed by the Cancer and Leukemia Group B and the US Intergroup that used fludarabine and rituximab (CALGB 9712, n = 104) or fludarabine (CALGB 9011, n = 178). In multivariate analyses controlling for pretreatment characteristics, the patients receiving fludarabine and rituximab had a significantly better progression-free survival (PFS; P < .0001) and overall survival (OS; P = .0006) than patients receiving fludarabine therapy. Two-year PFS probabilities were 0.67 versus 0.45, and 2-year OS probabilities were 0.93 versus 0.81. Infectious toxicity was similar between the 2 treatment approaches. These comparative data are retrospective and could be confounded by differences in supportive care or dissimilar enrollment of genetic subsets on each trial. Confirmation of these findings will require a prospective randomized trial comparing fludarabine and rituximab to fludarabine.

Adult↗
PubMed2004

The peripheral benzodiazepine receptor ligand PK11195 overcomes different resistance mechanisms to sensitize AML cells to gemtuzumab ozogamicin.

The antibody-targeted therapeutic, gemtuzumab ozogamicin (GO, Mylotarg), is approved for treatment of relapsed acute myeloid leukemia (AML). We previously showed that AML blasts from GO refractory patients frequently express the drug transporters P-glycoprotein (Pgp) and/or multidrug resistance protein (MRP). We also previously reported that inhibition of drug transport by the Pgp modulator, cyclosporine A (CSA), can increase GO sensitivity in Pgp(+) AML cells and that the peripheral benzodiazepine receptor ligand, PK11195, sensitizes AML cells to standard chemotherapeutics both by inhibiting Pgp-mediated efflux and by promoting mitochondrial apoptosis. We now show that PK11195 also can overcome multiple resistance mechanisms to increase GO sensitivity in AML cells, including resistance associated with expression of drug transporters and/or antiapoptotic proteins. PK11195 substantially increases GO cytotoxicity in AML cells from many different cell lines and primary patient samples, often more effectively than CSA. We also show that PK11195 is nontoxic in NOD/SCID mice and can sensitize xenografted human AML cells to GO. Since PK11195 is well tolerated in humans as a single agent, its further study as a multifunctional chemosensitizer for anti-AML therapies, including GO-based therapies, is warranted.

Acute Disease↗
PubMed2004

Increasingly frequent diagnosis of acute gastrointestinal graft-versus-host disease after allogeneic hematopoietic cell transplantation.

The reported incidence of grades II to IV acute graft-versus-host disease (GVHD) after hematopoietic cell transplantation with HLA-identical sibling donors has increased considerably during the past 15 to 20 years at our center. The purpose of this study was to evaluate the potential reasons for this change. We reviewed organ stages and overall grades of GVHD for 2220 patients who received a first marrow or peripheral blood cell transplant from an HLA-identical sibling or an HLA-allele-matched unrelated donor with the use of a posttransplantation immunosuppressive regimen that included both methotrexate and cyclosporine between 1985 and 2001. The most striking change was an increased incidence of stage 1 gut involvement from 10% to 20% before 1992 to 50% to 60% since 1992, both with related and unrelated donors. This change increased the incidence of grade II GVHD with sibling donors, such that the overall incidence of grade II to IV GVHD is now 60% to 70%. Among patients with chronic myeloid leukemia in chronic phase, the increasingly frequent diagnosis of acute GVHD since 1992 has not been associated with decreased survival. A high diagnostic sensitivity and increased awareness that gut GVHD can occur without skin involvement account for the increased incidence of acute GVHD at our center.

Acute Disease↗
PubMed2004

Evaluation of a CD25-specific immunotoxin for prevention of graft-versus-host disease after unrelated marrow transplantation.

Donor T cells activated by recipient alloantigens cause graft-versus-host disease (GVHD) after hematopoietic cell transplantation. Activated T cells express CD25, among other components of the interleukin-2 receptor. We conducted a phase I/II study to determine whether administration of CD25-specific antibody conjugated to ricin toxin A could reduce the risk of grade III or IV GVHD after marrow transplantation from HLA-matched unrelated donors. All patients received methotrexate and cyclosporine after the transplantation. The immunotoxin was given to 36 patients for 4 consecutive days beginning approximately 36 hours after the marrow infusion was completed. Fourteen (40%) of the 35 patients who could be evaluated developed grade III or IV GVHD. In a contemporaneous population of 121 patients who received marrow from HLA-matched unrelated donors and were given methotrexate and cyclosporine without the immunotoxin, the incidence of grades III and IV GVHD was 24%. Cyclosporine blocked the induction of CD25 expression on alloactivated T cells in vitro but had no detectable effect on CD25 expression by T-regulatory cells. Taken together, these results are consistent with the hypothesis that cyclosporine protected alloactivated donor T cells from the effects of the immunotoxin, whereas the CD25+ T-regulatory cells remained susceptible, causing an unexpected exacerbation of acute GVHD.

Adult↗
PubMed2004

Immunobiologic therapies for myelodysplastic syndrome.

Recent progress in understanding the pathobiology of the myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) have led to the development of various immunologically oriented therapies for these diseases. The existence of elevated levels of tumor necrosis factor-alpha (TNF-alpha) in bone marrow during early stages of MDS, and the possibility that TNF- proportional, variant suppresses normal hematopoiesis led to studies of attempts to block the activity of TNF-alpha. An anti-TNF monoclonal antibody and an antibody comprised of the soluble extracellular ligand-binding portion of the TNF receptor have both been evaluated recently in several small pilot studies. The recognition that marrow suppression in MDS may, in part, be a T-cell mediated autoimmune process has stimulated various trials of antithymocyte globulin and other similar agents. Gemtuzumab ozogamicin, an antibody against CD33 conjugated to the cytotoxic agent calicheamicin, is approved for use in AML and is currently being investigated as a potential therapeutic agent in MDS. Clinical trials were conducted as either monotherapy or in combination with cytokines such as IL-11 and chemotherapeutic agents including idarubicin, fludarabine, and/or cytarabine. Other antibodies are being developed as immunoconjugates with radioisotopes as part of conditioning regimens prior to bone marrow transplantation for AML or MDS. These include (131)I-anti-CD45 antibody (BC8), (131)I anti-CD33 antibody (p67), (213)Bi-M195 antibody, and (188)Re-labeled anti-CD66 antibody. The clearest example of successful immunotherapy for MDS (and AML) is the use of the graft-versus-tumor effect associated with allogeneic hematopoietic cell transplantation. Recently, nonmyeloablative transplants have been explored with encouraging results. Vaccines using overexposed self-antigens such as WT1 and PR1 are other attempts to induce a T-cell mediated response against MDS.

Animals↗
PubMed2004

Hematologic responses of patients with MDS to antithymocyte globulin plus etanercept correlate with improved flow scores of marrow cells.

Myelodysplastic syndrome (MDS) comprises a spectrum of heterogeneous diseases. Most patients present with ineffective hematopoiesis. The pathophysiology involves immune-mediated effects, cytokine dysregulation, and apoptosis, among others. We treated 14 transfusion-requiring patients with MDS, 10 with refractory anemia (RA) and four with RA with excess blasts (RAEB) with a 4-day course of antithymocyte globulin (ATG) followed by intermittent etanercept for 4 months. Among 13 evaluable patients, five are red blood cell and platelet transfusion independent for intervals extending beyond 2 years, and two have normalized their peripheral blood parameters. One additional patient showed a transient rise of platelet and neutrophil counts, for an overall response rate of 46%. Responding patients showed striking improvements in marrow cell abnormalities as characterized by flow cytometry. These data show that a combination of ATG plus etanercept offers effective palliative therapy for unselected patients with MDS. Further trials incorporating these two agents are warranted.

Antilymphocyte Serum↗