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Armand Keating

Publications and source records attributed to Armand Keating.

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

Predictive value of karyotype on outcome of autotransplants for acute myeloid leukemia in second remission.

The impact of karyotype on the outcome of patients who undergo autotransplant for acute myeloid leukemia (AML) in second remission (CR2) has not been explored. We evaluated the outcomes of 40 patients who proceeded to autotransplant for AML in CR2 at 2 centers. The median age at autotransplant was 50 years (18-64 years) and the median duration of first remission was 15 months (0.8-51 months). High-dose therapy was melphalan 140-160 mg/m2 plus etoposide 60 mg/kg with or without total body irradiation (22), a busulfan-based regimen (17), and cyclophosphamide alone (1). Six patients (15%) died of treatment-related causes within the first 100 days. Event-free and overall survival at 3 years were both 38% (95% confidence interval 23-53%). At a median follow-up of 76 months (2?-?170) in surviving patients, 13 (32.5%) are alive and disease free. Graft purging did not significantly influence survival outcome (P=0.94), although platelet engraftment was significantly delayed (P=0.02). The relative risk of an event (relapse or death) for the karyotype risk groups was favorable 1.0; intermediate 4.2 (1.2-14.7); adverse 9.9 (1.5-63.9); unknown 2.3 (0.6-8.8) (P=0.028). We conclude that patients with AML in CR2 who undergo autotransplant can have durable remissions and those with a good risk karyotype are the most likely to obtain long-term disease-free survival.

Acute Disease↗
PubMed2004

Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML.

BACKGROUND: The progression of chronic myelogenous leukemia (CML) to blast crisis is supported by self-renewing leukemic stem cells. In normal mouse hematopoietic stem cells, the process of self-renewal involves the beta-catenin-signaling pathway. We investigated whether leukemic stem cells in CML also use the beta-catenin pathway for self-renewal. METHODS: We used fluorescence-activated cell sorting to isolate hematopoietic stem cells, common myeloid progenitors, granulocyte-macrophage progenitors, and megakaryocyte-erythroid progenitors from marrow during several phases of CML and from normal marrow. BCR-ABL, beta-catenin, and LEF-1 transcripts were compared by means of a quantitative reverse-transcriptase-polymerase-chain-reaction assay in normal and CML hematopoietic stem cells and granulocyte-macrophage progenitors. Confocal fluorescence microscopy and a lymphoid enhancer factor/T-cell factor reporter assay were used to detect nuclear beta-catenin in these cells. In vitro replating assays were used to identify self-renewing cells as candidate leukemic stem cells, and the dependence of self-renewal on beta-catenin activation was tested by lentiviral transduction of hematopoietic progenitors with axin, an inhibitor of the beta-catenin pathway. RESULTS: The granulocyte-macrophage progenitor pool from patients with CML in blast crisis and imatinib-resistant CML was expanded, expressed BCR-ABL, and had elevated levels of nuclear beta-catenin as compared with the levels in progenitors from normal marrow. Unlike normal granulocyte-macrophage progenitors, CML granulocyte-macrophage progenitors formed self-renewing, replatable myeloid colonies, and in vitro self-renewal capacity was reduced by enforced expression of axin. CONCLUSIONS: Activation of beta-catenin in CML granulocyte-macrophage progenitors appears to enhance the self-renewal activity and leukemic potential of these cells.

Adult↗
PubMed2004

A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome.

Bone marrow transplantation (BMT) can cure myelodysplastic syndrome (MDS), although transplantation carries significant risks of morbidity and mortality. Because the optimal timing of HLA-matched BMT for MDS is unknown, we constructed a Markov model to examine 3 transplantation strategies for newly diagnosed MDS: transplantation at diagnosis, transplantation at leukemic progression, and transplantation at an interval from diagnosis but prior to leukemic progression. Analyses using individual patient risk-assessment data from transplantation and nontransplantation registries were performed for all 4 International Prognostic Scoring System (IPSS) risk groups with adjustments for quality of life (QoL). For low and intermediate-1 IPSS groups, delayed transplantation maximized overall survival. Transplantation prior to leukemic transformation was associated with a greater number of life years than transplantation at the time of leukemic progression. In a cohort of patients under the age of 40 years, an even more marked survival advantage for delayed transplantation was noted. For intermediate-2 and high IPSS groups, transplantation at diagnosis maximized overall survival. No changes in the optimal transplantation strategies were noted when QoL adjustments were incorporated. For low- and intermediate-1-risk MDS, delayed BMT is associated with maximal life expectancy, whereas immediate transplantation for intermediate-2- and high-risk disease is associated with maximal life expectancy.

Adolescent↗
PubMed2004

Hematopoiesis in the elderly.

The effect of age on the hematopoietic system has always been an area of clinical interest. Alterations in lymphocyte immunophenotype and function with age have been clearly demonstrated as has a decrease in neutrophil function. However, controversy continues to surround the significance of unexplained anaemia in the elderly patient and the extent to which this could be a physiological occurrence. The weight of evidence from animal and human studies would suggest that anaemia is not a physiological occurrence but may have a multifactorial pathogenesis. Are older patients therefore, appropriate candidates for high dose therapy, including autologous stem cell transplantation? The loss of telomeric DNA from hematopoietic progenitor cells with aging implies that stem cell collections from an older patient may have compromised replicative capacity with a reduced response to hematopoietic growth factors. Recent studies, however, show that age is not an obstacle for the collection of a stem cell product, which is capable of restoring normal hematopoietic function. A study of autologous stem cell transplantation has shown comparable neutrophil and platelet recovery times between younger and older patients.

Aged↗
PubMed2003

Effect of radiation and cell implantation on wound healing in a rat model.

BACKGROUND AND OBJECTIVES: Having shown that intra-dermal injection of fibroblasts decreases the effect of radiation on healing of superficial wounds, we now test the effect of fibroblasts and syngeneic marrow stromal cells on irradiated deep and superficial wounds. METHODS: Wistar rats received bilateral buttock irradiation followed by partial excision of the gluteus muscle bilaterally. In Protocol 1, one irradiated wound was treated with 1.2 x 10(7) autologous cells injected intra-dermally. In Protocol 2, the experimental side was treated with a fibrin and autologous cell implant (1.2 x 10(7) cells). Twenty-one days later, wound mechanical characteristics were tested. In Protocol 3, the effect of pooled marrow stromal cells on healing of superficial irradiated wounds in Lewis rats was similarly tested. RESULTS: The fibrin-fibroblast implant (Protocol 2) had no effect on wound mechanics. Superficial injection of fibroblasts (Protocol 1) significantly improved wound breaking strength when compared to the control group (mean +/- SEM, breaking strength: treated 504.6 +/- 37.0 g vs. control 353.4 +/- 35.2 g, P = 0.005). The dermal injection of marrow stromal cells also resulted in marked increases in breaking strength (mean +/- SEM, breaking strength: treated 338.5 +/- 39.9 g vs. control 187.1 +/- 12.0 g, P < 0.01). In both Protocols 1 and 3, ultimate tensile strength and toughness were increased in the side receiving cell transplantation. CONCLUSIONS: Cell implantation holds promise for decreasing the effect of radiation on healing of irradiated wounds.

Animals↗
PubMed2003

Autologous stem cell transplant for relapsed and refractory peripheral T-cell lymphoma: variable outcome according to pathological subtype.

The purpose of this study was to evaluate the outcome of high-dose chemotherapy (HDCT) followed by autologous haematopoietic stem cell transplant (ASCT) for patients with relapsed T-cell non-Hodgkin's lymphoma. We reviewed 36 patients with peripheral T-cell lymphoma (PTL) who underwent ASCT between January 1987 and June 2001. Patients had chemosensitive disease, and received high-dose melphalan and etoposide with or without total body irradiation supported by unpurged autologous stem cells. Comparisons were made with 97 diffuse large B-cell lymphoma (DLBL) patients. PTL patients had a median age of 46 years (19-62 years). Twenty-nine had relapsed and seven had primary refractory disease. DLBL patients were statistically similar in baseline characteristics. Of patients with PTL, six (17%) died of treatment-related complications and 14 (39%) were in remission with a median follow-up of 42 months (range 6-116 months). Three-year overall survival and event-free survival (EFS) were 48% and 37%, respectively, for PTL, compared with 53% and 42% for DLBL (P = 0.41 and 0.29 respectively). There was no significant prognostic variable found by univariate analysis for the PTL cohort. Major PTL subtypes were analysed for outcomes. The 20 patients with PTL, not otherwise specified (PTL-NOS), had an inferior EFS compared with DLBL patients (23%, P = 0.028). In contrast, the nine patients with anaplastic large T/null cell lymphoma had a non-significant trend for improved EFS (67%, P = 0.41). While ASCT in patients with relapsed or primary refractory PTL results in long-term remission rates comparable to DLBL patients, those with PTL-NOS do significantly worse.

Adult↗
PubMed2003

Acute promyelocytic leukemia: a case-based review.

Retinoid therapy for acute promyelocytic leukemia (APL) is one of the major achievements of leukemia research in the last 15 years. Use of all trans retinoic acid (ATRA) has changed the prognosis of APL from a fatal leukemia to a highly curable disease. This case-based review examines the available clinical and scientific data to form evidence-based decisions in the management of APL. The main aim of this review is to highlight recent progress made in the management of APL and address the role of maintenance therapy, prognostic factors for relapse and treatment of relapsed disease.

Adult↗
PubMed2003

Advances in targeted therapy for chronic myeloid leukemia.

Despite the lack of long-term survival data, the impressive results obtained with imatinib mesylate (Gleevec) therapy and the lack of serious adverse events have significantly altered the management of patients with chronic myeloid leukemia. Nevertheless, a large proportion of patients with more advanced disease will develop resistance to imatinib mesylate monotherapy. To prevent the development of resistance, an understanding of the pathophysiology of chronic myeloid leukemia, including the signaling pathways that are activated by the BCR-ABL fusion protein, and the mechanisms of resistance to imatinib are required. This review summarizes the pathogenesis of chronic myeloid leukemia and the potential therapeutic impact of small molecule inhibitors that target pathways critical to the growth or survival of the leukemic cells in patients with chronic myeloid leukemia.

Animals↗
PubMed2002

Myelodysplastic syndrome and acute myeloid leukemia after autotransplantation for lymphoma: a multicenter case-control study.

Although numerous reports indicate that patients receiving autotransplants for lymphoma are at increased risk for myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), the separate contributions of pretransplantation- and transplantation-related therapy are not well characterized. We conducted a case-control study of 56 patients with MDS/AML and 168 matched controls within a cohort of 2 739 patients receiving autotransplants for Hodgkin disease or non-Hodgkin lymphoma at 12 institutions (1989-1995). Detailed abstraction of medical records was undertaken to determine all pre- and posttransplantation therapy, and transplantation-related procedures. In multivariate analyses, risks of MDS/AML significantly increased with the intensity of pretransplantation chemotherapy with mechlorethamine (relative risks [RRs] = 2.0 and 4.3 for cumulative doses < 50 mg/m2 and > or = 50 mg/m,2 respectively; trend over dose categories, P =.04) or chlorambucil (RRs = 3.8 and 8.4 for duration < 10 months or > or = 10 months, respectively; trend, P =.009), compared with cyclophosphamide-based therapy. Transplantation-conditioning regimens including total-body irradiation (TBI) at doses 12 Gy or less did not appear to elevate leukemia risk (RR = 1.3; P =.48) compared with non-TBI regimens; however, a statistically significant increased risk was found for TBI doses of 13.2 Gy (RR = 4.6; P =.03). Peripheral blood stem cells were associated with a nonsignificant increased risk of MDS/AML (RR = 1.8; P =.12) compared with bone marrow grafts. Our data show that type and intensity of pretransplantation chemotherapy with alkylating agents are important risk factors of MDS/AML following autotransplantation. Transplantation-related factors may also modulate this risk; however, the apparent contribution of high-dose TBI requires confirmation.

Acute Disease↗
PubMed2002

Bone marrow transplantation from HLA-identical siblings as treatment for myelodysplasia.

Allogeneic hematopoietic stem cell transplantation is the only curative therapy for myelodysplasia (MDS). To identify factors influencing transplantation outcome, we studied 452 recipients of HLA-identical sibling transplants for MDS from 1989 to 1997, reported to the International Bone Marrow Transplant Registry. Patients with treatment-related MDS or unclassified MDS were excluded. Median age was 38 years (range, 2-64 years). Sixty percent had refractory anemia with excess blasts (n = 136) or with excess blasts in transformation (n = 136). Conditioning regimens included total body irradiation in 199 (44%) cases. Marrow was T-cell depleted for 58 (13%) transplants. Cumulative incidences of neutrophil engraftment, grades II-IV acute graft-versus-host disease (GVHD), and chronic GVHD were 91% (95% confidence interval [CI], 88%-93%), 36% (95% CI, 31%-40%), and 39% (95% CI, 33%-44%), respectively. Three-year transplantation-related mortality (TRM), relapse, disease-free survival, and overall survival rates were 37% (95% CI, 32%-42%), 23% (95% CI, 19%-27%), 40% (95% CI, 36%-45%), and 42% (95% CI, 37%-47%), respectively. Multivariate analyses showed that young age and platelet counts higher than 100 x 10(9)/L at transplantation were associated with lower TRM and higher disease-free and overall survival rates. Relapse incidence was higher in patients with high percentages of blasts in the marrow at transplantation or presentation, with high International Prognostic Scoring System scores at diagnosis, and with T-cell-depleted transplants. These findings indicate that transplantation from an HLA-identical sibling offers the possibility of long-term, disease-free survival to patients with MDS. Best candidates are younger patients with a low percentage of blasts and preserved platelet counts.

Adolescent↗
PubMed2002

Donor stem cells home to marrow efficiently and contribute to short- and long-term hematopoiesis after low-cell-dose unconditioned bone marrow transplantation.

OBJECTIVE: To study the homing of donor stem cells, their contribution to short- and long-term hematopoiesis, and their functional capacity in an unconditioned marrow transplant model using a clinically relevant low marrow cell dose. MATERIALS AND METHODS: A sex-mismatch model was used in which 20 x 10(6) male Balb/cByJ cells were infused into unconditioned female Balb/cByJ mice. Male donor cells were detected in blood and marrow by fluorescence in situ hybridization. Serial transplantation into irradiated secondary recipients was used to assay donor stem cells. Donor hematopoiesis was stimulated after transplant by treating recipients with either stem cell factor (SCF) or sublethal irradiation. RESULTS: Donor-derived male cells were detected in recipient blood (1.2-3.0%) and marrow (2.4-5.4%) for up to 27 weeks, indicating a contribution to short-term hematopoiesis. Male repopulating units approached theoretically expected values, suggesting that transplantation was efficient. Donor stem cell levels after serial transplantation were similar to results observed in primary recipients. Donor stem cell levels 24 hours after infusion (1.3 +/- 0.2% SE) were similar to levels at later time points, indicating that homing was efficient. Stimulation by either SCF or sublethal irradiation after transplant did not alter donor marrow chimerism, suggesting that donor stem cells responded to the stress similarly to endogenous cells. CONCLUSION: We conclude that in a clinically relevant low-cell-dose unconditioned transplant model, stem cells home to the marrow efficiently, contribute to both short- and long-term hematopoiesis, and, once engrafted, respond to stress effectively. These findings provide a rationale for the use of genetically modified stem cells in clinical protocols that omit intensive conditioning.

Animals↗
PubMed2002

Comparison of outcome following allogeneic bone marrow transplantation with cyclophosphamide-total body irradiation versus busulphan-cyclophosphamide conditioning regimens for acute myelogenous leukaemia in first remission.

We evaluated transplant-related mortality (TRM), leukaemia relapse, leukaemia-free survival (LFS) and overall survival (OS) in patients receiving busulphan and cyclophosphamide (BuCy) or cyclophosphamide and total body irradiation (CyTBI) prior to allogeneic bone marrow transplantation (BMT) for acute myelogenous leukaemia (AML) in first remission. Outcomes of 381 human leucocyte antigen (HLA)-matched sibling transplants using BuCy were compared with 200 transplants using CyTBI performed between 1988 and 1996. The incidence of hepatic veno-occlusive disease was higher with BuCy (13%) than with CyTBI (6%) (P = 0.009). Risks of acute and chronic GVHD were similar. In multivariate analysis, relapse risk was higher in the BuCy group [relative risk (RR) = 1.72; 95% confidence interval (CI), 1.05-2.81; P = 0.031]. Eleven of 373 evaluable patients in the BuCy group had a central nervous system relapse in contrast to none of 194 evaluable patients in the CyTBI group (P = 0.016). There were no differences in TRM, LFS and OS. CyTBI conditioning may lower relapse risk but produces comparable TRM, LFS and OS to BuCy for HLA-matched sibling transplantation in first remission AML.

Adult↗
PubMed2002

Autologous versus allogeneic unrelated donor transplantation for acute lymphoblastic leukemia: comparative toxicity and outcomes.

For patients with high-risk or relapsed acute lymphoblastic leukemia (ALL) lacking a related histocompatible donor, autologous (Auto) and unrelated donor (URD) transplantation are available options. We compared outcomes and toxicities in 712 patients with ALL (517 URD, 195 Auto) in first complete remission (CR1) or second complete remission (CR2) who underwent transplantation. All patients were <50 years old, although URD patientswere younger (median age, 14 versus 18 years, P < .002). The proportion of patients in CR1 versus CR2 was similar (36% versus 38%, P = .57), but more URD recipients than Auto recipients had high-risk karyotypes (25% versus 13%, P = .003) and white blood cell (WBC) counts > or =50 x 10(9)/L (33% versus 14%, P < .001). Engraftment was similar in URD and Auto recipients. Ex vivo purging delayed but did not prevent engraftment after Auto transplantation. Transplantation-related mortality was higher after URD transplantation (42%+/-8%) than after Auto transplantation (20%+/-12%) in CR1 (P = .004) and also in CR2. Conversely, relapse was more frequent after Auto transplantation in CR1 (Auto, 49%+/-12% versus URD, 14%+/-5%) and CR2 (64%+/-8% versus 25%+/-5%) (P < .0001). These findings showed net similar outcomes for these 2 transplantation choices. Transplantation in CR1 yielded similar 3-year survival rates for URD (51%+/-7%) and Auto (44%+/-12%), as did transplantation in CR2 (40%+/-6% versus 32%+/-9%, respectively). Multivariate regression analysis identified significantly better disease-free survival after the first 6 months in matched URD versus Auto in younger patients, in those in CR2 with CR1 >1year, WBC <50 x 10(9)/L, performance status > or =90%, and in those who have undergone transplantation since 1995. These comparative data suggest that both matched URD and Auto transplantation can yield extended survival. Although URD transplantation offers substantially better protection against leukemic relapse, improvements in allotransplantation safety and refinements in patient selection are required to better aid treatment decision making for the best overall survival.

Adolescent↗
PubMed2002

Chronic myeloid leukemia: current therapies and the potential role of farnesyltransferase inhibitors.

The treatment of patients with chronic myeloid leukemia (CML) is evolving rapidly. With conventional chemotherapy the clinical course is characterized by a chronic phase (median duration, 4 to 5 years), followed by an accelerated phase with transition to a terminal blast crisis. Treatment with busulfan or hydroxyurea does not alter the natural history. Interferon alfa (IFN-alpha) prolongs life expectancy by approximately 20 months but is associated with significant toxicity. Evidence indicates that bone marrow transplantation from a related human leukocyte antigen (HLA)-identical donor can be curative in younger patients. However, transplantation is available to only a minority of patients and entails severe toxicity and transplant-related mortality. Dramatic advances in the understanding of the molecular pathophysiology of CML have led to a new era of targeted therapy. The specific tyrosine kinase inhibitor imatinib mesylate demonstrates a high level of efficacy in CML with acceptable toxicity. Farnesyltransferase inhibitors (FTIs) are another important class of targeted agents with the potential to act at multiple sites within dysregulated signal transduction networks. ZARNESTRA (formerly R115777, Ortho Biotech Oncology, Raritan, NJ), an oral FTI, has shown activity and is well tolerated in both chronic- and accelerated-phase patients. With their mechanistic specificity, the new modalities offer the promise of increased antileukemic activity and an improved therapeutic index.

Alkyl and Aryl Transferases↗
PubMed2002

Acute myeloid leukemia.

In this chapter, Drs. Keating and Willman review recent advances in our understanding of the pathophysiology of acute myeloid leukemia (AML) and allied conditions, including the advanced myelodysplastic syndromes (MDS), while Drs. Goldstone, Avivi, Giles, and Kantarjian focus on therapeutic data with an emphasis on current patient care and future research studies. In Section I, Dr. Armand Keating reviews the role of the hematopoietic microenvironment in the initiation and progression of leukemia. He also discusses recent data on the stromal, or nonhematopoietic, marrow mesenchymal cell population and its possible role in AML. In Section II, Drs. Anthony Goldstone and Irit Avivi review the current role of stem cell transplantation as therapy for AML and MDS. They focus on data generated on recent Medical Research Council studies and promising investigation approaches. In Section III, Dr. Cheryl Willman reviews the current role of molecular genetics and gene expression analysis as tools to assist in AML disease classification systems, modeling of gene expression profiles associated with response or resistance to various interventions, and identifying novel therapeutic targets. In Section IV, Drs. Hagop Kantarjian and Francis Giles review some promising agents and strategies under investigation in the therapy of AML and MDS with an emphasis on novel delivery systems for cytotoxic therapy and on targeted biologic agents.

Acute Disease↗
PubMed2001

The autologous blood and marrow transplant long-term follow-up clinic: a model of care for following and treating survivors of autotransplant.

The number of long-term survivors of autologous blood and marrow transplantation (ABMT) is increasing, but little is known about the models of care used to follow these patients. Such information would help in comparison of different methods of follow-up and allow other centers to create programs to follow their survivors. Here we describe a multidisciplinary long-term follow-up clinic for survivors of ABMT and report patient satisfaction with the clinic and economic analysis 1.5 years after its inception. In its first 1.5 years of operation, 83 new patients were seen in the clinic. Patients were evaluated a median of 4.0 years after ABMT (range 4.9 months to 12 years) and were a median of 48.5 years (range 22.5-69.0 years) old. Patients received their ABMT for non-Hodgkin's lymphoma ( n=26), Hodgkin's disease ( n=18), acute myeloid leukemia ( n=18), multiple myeloma ( n=15), breast cancer ( n=5), or desmoplastic round-cell tumor ( n=1). Patient satisfaction was assessed 1.5 years after the establishment of the long-term follow-up clinic by means of a self-report questionnaire. Seventy-five percent of patients returned the survey. Waiting times in the clinic were short, with 70% of patients seen within 30 minutes of arrival. Overall, patients were very satisfied with the new clinic model, with 85% patients reporting that the clinic met their expectations. An economic analysis indicated that the estimated annual cost of operating the clinic was approximately $53,000, which translates into $440 per patient visit, $962 per new patient or $172 per patient visit with the clinic operating at peak capacity. In conclusion, we present an inexpensive model of care for ABMT survivors that can be extended to adult survivors of malignancy not treated by ABMT.

Adult↗