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Biomedical subjects

David S Snyder

Publications and source records attributed to David S Snyder.

13 recordsLinked to original sources
PubMed2007

Prophylactic administration of imatinib after hematopoietic cell transplantation for high-risk Philadelphia chromosome-positive leukemia.

Relapse occurs frequently after allogeneic hematopoietic cell transplantation (HCT) for treatment of high-risk Philadelphia chromosome-positive (Ph+) leukemia. Administration of imatinib early after HCT might provide an effective approach for preventing recurrent Ph+ leukemia, but the feasibility of this approach has not been systematically tested. Twenty-two patients, 15 with Ph+ acute lymphoblastic leukemia and 7 with high-risk chronic myelogenous leukemia, were enrolled in a prospective study and given imatinib from the time of engraftment until 365 days after HCT. Before day 90, adults (n = 19) tolerated a median average daily imatinib dose of 400 mg/d (range, 200-500 mg/d), and children (n = 3) tolerated 265 mg/m2/d (range, 200-290 mg/m2/ d). The most common adverse events related to imatinib administration were grade 1-3 nausea, emesis, and serum transaminase elevations. We conclude that imatinib can be safely administered early after myeloablative allogeneic HCT at a dose intensity comparable to that used in primary therapy.

Adolescent↗
PubMed2006

The effects of imatinib mesylate treatment before allogeneic transplantation for chronic myeloid leukemia.

The impact of imatinib mesylate (IM) treatment for chronic myeloid leukemia (CML) on subsequent allogeneic transplantation is uncertain. To better understand this relationship, we retrospectively compared 145 patients with CML receiving IM for a minimum of 3 months before allogeneic hematopoietic cell transplantation (HCT) to 231 patients with CML who did not. IM treatment was associated with no increase in early hepatotoxicity or engraftment delay after HCT compared with the historical cohort. In addition, there was no statistically significant difference in the IM-treated cohort compared with the historical cohort with regard to overall survival, disease-free survival, relapse, and nonrelapse mortality. For chronic-phase (CP) patients, IM response prior to HCT was associated with post-HCT outcome. Patients who underwent transplantation in CP with a suboptimal response or a loss of response on IM had a statistically significant higher hazard of mortality when compared with CP patients who achieved a complete cytogenetic response (CCR) or major cytogenetic response (MCR) on IM (HR=5.31, 95% confidence interval [CI] 1.13-25.05, P=.03). These data indicate that pre-HCT IM is not associated with increased transplant-related morbidity (TRM) or poorer outcomes. However, patients with a suboptimal or loss of IM response before HCT do worse, suggesting a more aggressive disease course for these patients.

Adult↗
PubMed2006

Allogeneic hematopoietic cell transplantation following reduced intensity conditioning for treatment of myelofibrosis.

This report describes our experience with reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) using matched sibling and unrelated donors (MUDs) for treatment of myelofibrosis (MF). Nine patients with MF (median age, 54 years) were treated with RIC allogeneic HCT using MUDs for 7 of the 9 patients and sibling donors for 2 patients. By the Lille classification, 4 patients were characterized as having high risk, 4 as having intermediate risk, and 1 as having low risk. The RIC regimen consisted of fludarabine and a single dose of total body irradiation for the first patient and fludarabine/melphalan for the remaining 8 patients. Granulocyte colony-stimulating factor-primed peripheral blood stem cells (PBSCs) were used for all but 1 patient who received a total of 3 products because of graft failure, of which 2 were bone marrow cells and the third was PBSCs. Prophylaxis against graft-versus-host disease consisted of cyclosporin/mycophenolate with or without methotrexate. Seven patients were successfully engrafted with white blood cells, with an absolute neutrophil count > or =500 by a median of day +15 (range, 10-21 days). At the time of final fluorescence in situ hybridization and/or short tandem repeat analysis, 8 of 9 patients were chimeric, with 96%-100% donor cells and/or DNA. Five of the 9 patients were alive at the time of final contact, with a median follow-up of 32.2 months for the living patients. Overall survival probability at 1 year was 55.6% (95% confidence interval, 31.3%-77.4%). These results suggest that RIC MUD HCT using PBSCs can be an effective treatment for older patients with MF.

Aged↗
PubMed2006

Coexistence of inversion 16 and the Philadelphia chromosome in acute and chronic myeloid leukemias : report of six cases and review of literature.

We report 5 cases of chronic myelogenous leukemia (CML) and 1 case of acute myeloid leukemia (AML) with the dual presence of t(9;22) and inv(16). The 6 patients were 5 men and 1 woman with a median age of 42.5 years. All cases were BCR-ABL+ with p210 products detected in all CML cases and a p190 product detected in the AML case. An increase in bone marrow eosinophils was detected in 3 of 5 cases, and abnormal eosinophils were identified in these 3 cases. The CBFbeta-MYH11 fusion gene was confirmed in all 3 CML cases and the 1 AML case tested, and this correlated with the presence of abnormal eosinophils with coarse basophilic granules. Of 5 patients with CML, 4 had a rapid transformation to myeloid accelerated phase of blast crisis. The coexistence of t(9;22) and inv(16) in CML seems to correlate with more rapid transformation.

Adult↗
PubMed2005

Philadelphia chromosome-positive acute lymphoblastic leukemia secondary to chemoradiotherapy for Ewing sarcoma. Report of two cases and concise review of the literature.

Survivors of childhood solid tumors including Ewing sarcoma (ES) have an increased risk of secondary malignant neoplasms (SMNs) as a consequence of exposure to chemotherapy and/or radiation (see: Bhatia S, Sklar C. Nat Rev Cancer 2002;2:124-132). The most common hematologic SMNs are myelodysplasia (MDS) and acute myelogenous leukemia (AML). Acute lymphoblastic leukemia (ALL) is uncommon in this patient population, and Philadelphia chromosome positive (Ph+) ALL in particular, is rare. We report herein two cases of young adult patients who were both diagnosed with Ph+ ALL 19 years after successful treatment for ES with combined modality therapy. A review of the relevant literature follows the case reports.

Adult↗
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↗
PubMed2004

Detection of BCR-ABL kinase mutations in CD34+ cells from chronic myelogenous leukemia patients in complete cytogenetic remission on imatinib mesylate treatment.

The BCR-ABL kinase inhibitor imatinib mesylate induces complete cytogenetic response (CCR) in a high proportion of chronic myelogenous leukemia (CML) patients. However, patients in CCR usually demonstrate evidence of residual BCR-ABL-positive progenitors. The mechanisms underlying persistence of small numbers of malignant progenitors in imatinib-sensitive patients are unclear. BCR-ABL kinase domain mutations affecting drug binding can lead to secondary resistance to imatinib. We show here that kinase mutations could be detected in CD34+ cells isolated from CML patients in CCR on imatinib. Most mutations seen have not been reported in previous clinical studies. Interestingly, several of the involved amino acid positions have been implicated in an in vitro mutagenesis screen. These BCR-ABL mutations were associated with varying levels of imatinib resistance. Two of 5 patients in whom mutations were detected on initial evaluation have relapsed. In addition, 4 patients in whom mutations were not initially detected, but with rising BCR-ABL mRNA levels on quantitative polymerase chain reaction (Q-PCR) analysis, had mutations detected on follow-up evaluation. We conclude that BCR-ABL kinase mutations can be detected in CD34+ cells from CML patients in CCR on imatinib, may contribute to persistence of small populations of malignant progenitors, and could be a potential source of relapse.

Adult↗
PubMed2004

Late effects in survivors of chronic myeloid leukemia treated with hematopoietic cell transplantation: results from the Bone Marrow Transplant Survivor Study.

The purpose of this study was to analyze medical late effects among patients with chronic myeloid leukemia (CML) treated with hematopoietic cell transplantation (HCT). Subjects included 248 CML survivors who received an HC transplant (related donors [RDs], n = 150; unrelated donors [URDs], n = 70; or autologous, n = 28) and had survived at least 2 years, and a comparison group of 317 siblings. Subjects completed a 238-item survey on medical late effects. Compared with siblings, survivors were at a higher risk of developing ocular, oral health, endocrine, gastrointestinal, musculoskeletal, neurosensory, and neuromotor impairments. Multivariate analysis limited to RD and URD recipients found that chronic graft-versus-host disease (cGVHD) was associated with a higher risk of hypothyroidism, osteoporosis, cardiopulmonary, neurosensory, and neuromotor impairments. Overall health was reported as excellent, very good, or good in 78% of subjects, although those with cGVHD were more likely to report poor overall health. URD survivors were more likely to report a need for assistance with routine activities and that their current health prevented work or school attendance. This study demonstrates that HCT survivors, regardless of donor type, have a high prevalence of long-term health-related complications. However, adverse medical late effects with significant morbidity were uncommon. Chronic GVHD is the most important predictor of adverse medical late effects and poor overall health.

Adolescent↗
PubMed2004

Chronic myeloid leukemia with an e13a3 BCR-ABL fusion: benign course responsive to imatinib with an RT-PCR advisory.

A case of a patient with chronic myeloid leukemia whose cells expressed an e13a3 (b2a3) variant BCR-ABL p210 mRNA is presented. The variant splice was detected by a qualitative reverse transcriptase polymerase chain reaction using primers complementary to BCR exon 13 (b2) and ABL exon 3 (a3). The patient responded well to imatinib and achieved a complete cytogenetic response.

Adult↗
PubMed2003

Interleukin-2 after autologous stem-cell transplantation for adult patients with acute myeloid leukemia in first complete remission.

PURPOSE: To determine the disease-free survival (DFS) and toxicity of administering interleukin-2 (IL-2) immunotherapy early after autologous stem-cell transplantation (ASCT) to simulate a graft versus leukemia effect observed in allogeneic transplantation. PATIENTS AND METHODS: Fifty-six patients with acute myeloid leukemia in first remission received a single consolidation of high-dose cytarabine-idarubicin at a median of 1.1 month postremission with the intent to proceed to ASCT and IL-2 9 x 10(6) U/m(2)/24 h for 4 days, followed by 10 days of IL-2 1.6 x 10(6) U/m(2)/24 h on hematologic recovery. RESULTS: Eighty-four percent of patients received the intended ASCT, and 68% of patients received IL-2 treatment. With a median follow-up of 39.4 months (range, 1.2 to 76.3 months), the 2-year cumulative probability of DFS for all 56 patients is 68% (95% confidence interval [CI], 55% to 80%) and 74% (95% CI, 57% to 85%) for the 39 patients undergoing IL-2 treatment after ASCT. The 2-year cumulative probability of DFS for favorable, intermediate, and unfavorable cytogenetics is 88% (95% CI, 59% to 97%), 48% (95% CI, 26% to 67%), and 70% (95% CI, 23% to 93%), respectively. Toxicities from IL-2 were mainly thrombocytopenia, leukopenia, fever, and fluid retention. Two septic deaths occurred during neutropenia, which includes one during consolidation and one during transplant, for an overall 4% mortality rate. CONCLUSION: These results suggest that a moderate dose of IL-2 after high-dose cytarabine-idarubicin-mobilized ASCT is associated with a low regimen-related toxicity and may improve DFS. A phase III study of IL-2 is now warranted.

Adult↗
PubMed2003

Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment.

The BCR/ABL tyrosine kinase inhibitor imatinib mesylate (Gleevec, STI571; Novartis, Basel, Switzerland) has shown remarkable efficacy in the treatment of chronic myelogenous leukemia (CML), with a high proportion of patients achieving complete cytogenetic responses (CCRs). However, it is not clear whether remissions will be durable and whether imatinib mesylate can eliminate the malignant primitive progenitors in which the disease arises. We investigated whether residual BCR/ABL+ hematopoietic progenitors were present in patients who achieved CCRs with imatinib mesylate treatment. CD34+ progenitor cells were selected from bone marrow mononuclear cells (MNCs) and analyzed for the presence of the BCR/ABL fusion gene by fluorescence in situ hybridization (FISH). CD34+ cells were also plated in committed progenitor (colony-forming cell, or CFC) and primitive progenitor (long-term bone marrow culture-initiating cell, or LTCIC) cultures and resulting colonies analyzed for the presence of BCR/ABL+ cells by FISH. Using these assays, residual BCR/ABL+ progenitors were detected in all patients studied. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis demonstrated increased levels of BCR/ABL mRNA in CD34+ cells compared with total MNCs. Evaluation of samples collected at different time points demonstrated persistence of BCR/ABL+ progenitors despite continued treatment with imatinib mesylate. Our results indicate that inhibition of BCR/ABL tyrosine kinase activity by imatinib mesylate does not eliminate malignant primitive progenitors in CML patients. Patients in CCR with imatinib mesylate treatment need to be followed carefully to assess for risk of relapse.

Adult↗
PubMed2003

Specific killing of Ph+ chronic myeloid leukemia cells by a lentiviral vector-delivered anti-bcr/abl small hairpin RNA.

Chronic myeloid leukemia (CML) is characterized by a reciprocal chromosomal translocation between chromosomes 9 and 22 t(9;22)(q34;q11) that causes fusion of the bcr and abl genes. Transcription and splicing of the fusion gene generate two major splice variants of the bcr/abl transcript that encode an oncoprotein with tyrosine kinase activity. We have taken advantage of lentiviral vectormediated delivery of anti-bcr/abl short hairpin RNAs (shRNA) to downregulate the bcr/abl transcript in Philadelphia chromosome-positive (Ph+) K562 leukemia cells. This downregulation caused complete inhibition of proliferation of these cells and was accompanied by >90% inhibition of the bcr/abl transcript and p210 protein. These results demonstrate the feasibility of using a lentiviral vector to stably transduce therapeutic shRNAs into leukemia cells for the potential ex vivo purging of Ph+ cells in an autologous hematopoietic cell transplant setting. Furthermore, the robust expression of the shRNAs from our lentiviral vector suggests that this system could be generally useful for the expression of other shRNAs.

Base Sequence↗