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ABSTRACT: We evaluated the pharmacodynamic relationships between mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), and outcomes in 308 patients after nonmyeloablative hematopoietic cell transplant. Patients were conditioned with total body irradiation + fludarabine, received grafts from HLA-matched related (N=132) or unrelated (N=176) donors, and received post-grafting immunosuppression with MMF and a calcineurin inhibitor. Total and unbound MPA pharmacokinetics were determined to day 25; maximum a posteriori Bayesian estimators were used to estimate total MPA concentration at steady state (Css). Rejection occurred in nine patients, eight of whom had a total MPA Css less than 3 μg/mL. In patients receiving a related donor graft, MPA Css was not associated with clinical outcomes. In patients receiving an unrelated donor graft, low total MPA Css was associated with increased grades 3-4 acute graft versus host disease (aGVHD) and increased non-relapse mortality, but not with day 28 T-cell chimerism, disease relapse, cytomegalovirus reactivation, or overall survival. We conclude that higher initial oral MMF doses and subsequent targeting of total MPA Css to greater than 2.96 μg/mL could lower grades 3-4 aGVHD and non-relapse mortality in patients receiving an unrelated donor graft.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 05/2013; · 3.15 Impact Factor
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Merav Bar,
Brenda M Sandmaier,
Yoshihiro Inamoto,
Benedetto Bruno,
Parameswaran Hari,
Thomas Chauncey,
Paul Martin,
Rainer Storb,
David G Maloney, Barry Storer,
Mary E D Flowers
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ABSTRACT: The impact of donor lymphocyte infusion (DLI) initial cell dose on its outcome is known in patient with chronic myeloid leukemia, but limited in patients with other hematological malignancies. In this retrospective study, we evaluated the effect of initial DLI CD3+ cell dose on graft-versus-host disease (GVHD) and overall survival (OS) after DLI given for relapse of any hematological malignancies after allogeneic hematopoietic cell transplantation (HCT) with high or reduced intensity conditioning. The cohort included 225 patients. Initial DLI CD3+ cell dose/kg recipient body weight was ≤1x10(7) (n=84; Group A), >1.0 to <10 x10(7) (n=58; Group B), and ≥ 10x10(7) (n=66; Group C). Cumulative incidence rates of GVHD at 12 months after DLI were 21%, 45% and 55% for Groups A, B, and C, respectively. Multivariate analysis showed that initial DLI CD3+ cell ≥10x10(7) dose/kg is associated with an increased risk of GVHD after DLI (p=0.03). Moreover, initial DLI CD3+ cell dose of 10x10(7) or higher did not decrease the risk of relapse and did not improve OS. Thus, these results support the use of less than 10x10(7) CD3+ cell/kg as the initial cell dose of DLI for treatment of persistent or recurrent hematological malignancy after HCT.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 03/2013; · 3.15 Impact Factor
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ABSTRACT: We recently reported that clofarabine, high-dose cytarabine, and granulocyte colony-stimulating factor (GCLAC) produced a 46% complete remission rate in relapsed/refractory acute myeloid leukemia. GCLAC differs from FLAG by substitution of clofarabine for fludarabine, raising the question of the relative efficacy of these two regimens. We compared GCLAC given at the University of Washington Medical Center/Fred Hutchinson Cancer Research Center to fludarabine and cytarabine (FA) and FLAG given at MD Anderson Cancer Center. Independent multivariate analyses conducted at both institutions showed that after accounting for duration of first complete remission, salvage number, age, and cytogenetics, GCLAC was associated with a higher complete remission rate (odds ratio 9.57, p<0.0001) and longer survival (mortality hazard ratio 0.43, p=0.0002). Despite the retrospective nature of the analyses, GCLAC may be superior to FA/FLAG, particularly in patients with short duration of first complete remission or unfavorable cytogenetics. The study was registered as NCT00602225 on ClinicalTrials.gov.
Haematologica 07/2012; · 6.42 Impact Factor
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ABSTRACT: PurposeSixteen patients diagnosed with various hematologic malignancies participated in a phase II study evaluating the addition
of rabbit antithymocyte globulin (rATG, Thymoglobulin®) to the hematopoietic cell transplant (HCT) conditioning regimen of IV fludarabine monophosphate (fludarabine) and targeted
intravenous (IV) busulfan (fludarabine/Tbusulfan). Our goal was to evaluate pharmacologic biomarkers pertinent to both medications in these patients.
MethodsWe characterized the interpatient variability of pharmacologic biomarkers relevant to busulfan, specifically busulfan concentration
at steady state, and fludarabine, specifically F-ara-A area under the curve (AUC) and fludarabine triphosphate (F-ara-ATP)
intracellular accumulation and concentration in separate CD4+ and CD8+ T-lymphocyte populations.
ResultsAcute and chronic graft versus host disease (GvHD) occurred in 11 patients and one patient, respectively. Four patients died
before day +100 of non-relapse causes, which met the protocol stopping guidelines. The cumulative incidence of relapse was
25% at 3year post-HCT. Interpatient variability in the busulfan- and fludarabine-relevant pharmacologic biomarkers was 2.1-
to 2.5-fold. F-ara-A AUC and accumulated F-ara-ATP in CD8+ cells had the highest hazard ratio for non-relapse mortality and overall survival, respectively. However, neither achieved
statistical significance.
ConclusionsThe low rates of GvHD, particularly in its chronic form, were encouraging, and further biomarker studies are warranted to
optimize the fludarabine/Tbusulfan/rATG conditioning regimen.
KeywordsBusulfan–Fludarabine–Hematopoietic cell transplant–Biomarkers–Therapeutic drug monitoring–Pharmacokinetics
Cancer Chemotherapy and Pharmacology 04/2012; 69(1):263-272. · 2.83 Impact Factor
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Marco Mielcarek, Barry Storer,
Paul J Martin,
Stephen J Forman,
Robert S Negrin,
Mary E Flowers,
Yoshihiro Inamoto,
Thomas R Chauncey,
Rainer Storb,
Frederick R Appelbaum,
William I Bensinger
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ABSTRACT: Between 1996 and 1999, 172 patients (median age, 42 years) with hematologic malignancies were randomly assigned to receive either HLA-identical related bone marrow or G-CSF-mobilized peripheral blood mononuclear cells (G-PBMCs) after myeloablative conditioning. Early results showed that transplantation of G-PBMCs, compared with marrow, was associated with significantly superior 2-year disease-free survival (DFS) and overall survival. Ten-year follow-up showed a sustained DFS benefit associated with G-PBMCs (mortality or relapse hazard ratio, 0.64; 95% confidence interval, 0.4-1.0; P = .03), although the likelihood of overall survival was not significantly different between the 2 groups (mortality hazard ratio, 0.75; 95% confidence interval, 0.5-1.2; P = .20). The 10-year cumulative incidence of chronic GVHD and the duration of systemic immunosuppression were similar in the 2 groups. In summary, transplantation of HLA-identical related G-PBMCs, compared with marrow, was associated with superior short-term and long-term DFS, and there was no evidence that this benefit was outweighed by GVHD-related late mortality.
Blood 02/2012; 119(11):2675-8. · 9.90 Impact Factor
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ABSTRACT: Our objective was to describe the incidence of nonmalignant late complications and their association with health and functional status in a recent cohort of hematopoietic cell transplantation (HCT) survivors.
We determined the incidence of 14 nonmalignant late effects in adults who underwent transplantation from January 2004 through June 2009 at Fred Hutchinson Cancer Research Center who survived at least 1 year after HCT. Data were derived from review of medical records and annual self-reported questionnaires.
The 1,087 survivors in the study had a median age at HCT of 53 years (range, 21 to 78 years) and were followed for a median of 37 months (range, 12 to 77 months) after HCT. The prevalence of pre-existing conditions ranged from 0% to 9.8%. The cumulative incidence of any nonmalignant late effect at 5 years after HCT was 44.8% among autologous and 79% among allogeneic recipients; 2.5% of autologous and 25.5% of allogeneic recipients had three or more late effects. Survivors with three or more late effects had lower physical functioning and Karnofsky score, lower likelihood of full-time work or study, and a higher likelihood of having limitations in usual activities. Predictors of at least one late effect were age ≥ 50 years, female sex, and unrelated donor, but not the intensity of the conditioning regimen.
The burden of nonmalignant late effects after HCT is high, even with modern treatments and relatively short follow-up. These late effects are associated with poor health and functional status, underscoring the need for close follow-up of this group and additional research to address these complications.
Journal of Clinical Oncology 12/2011; 30(1):71-7. · 18.37 Impact Factor
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Joseph Pidala,
Georgia Vogelsang,
Paul Martin,
Xiaoyu Chai, Barry Storer,
Steven Pavletic,
Daniel J Weisdorf,
Madan Jagasia,
Corey Cutler,
Jeanne Palmer,
David Jacobsohn,
Sally Arai,
Stephanie J Lee
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ABSTRACT: The National Institutes of Health Consensus Conference proposed the term "overlap" graft-versus-host disease to describe the situation when both acute and chronic graft-versus-host disease are present.
We examined whether the overlap subtype of graft-versus-host disease was associated with a different prognosis, functional limitations, or patient-reported outcomes compared to "classic" chronic graft-versus-host disease without any acute features.
Prospective data were collected from 427 patients from nine centers. Patients were classified as having overlap (n=352) or classic chronic (n=75) graft-versus-host disease based on reported organ involvement. Overlap cases had a significantly shorter median time from transplantation to cohort enrollment (P=0.01), were more likely to be incident cases (P<0.001), and had a lower platelet count at onset of the graft-versus-host disease (P<0.001). Patients with overlap graft-versus-host disease had significantly greater functional impairment measured by a 2-minute walk test, higher symptom burden and lower Human Activity Profile scores. Quality of life was similar, except patients with overlap graft-versus-host disease had worse social functioning, assessed by the Short Form-36. Multivariable analysis utilizing time-varying covariates demonstrated that the overlap subtype of graft-versus-host disease was associated with worse overall survival (HR 2.1, 95% CI 1.1-4.7; P=0.03) and higher non-relapse mortality (HR 2.8, 95% CI 1.2-8.3; P=0.02) than classic chronic graft-versus-host disease.
These findings suggest that the presence of acute features in patients with chronic graft-versus-host disease is a marker of adverse prognosis, greater functional impairment, and higher symptom burden.
Haematologica 11/2011; 97(3):451-8. · 6.42 Impact Factor
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ABSTRACT: Cytogenetics and multicolor flow cytometry (MFC) are useful tools for monitoring outcome of treatment in acute myeloid leukemia (AML). However, no data are available regarding the meaning of results when the 2 tests do not agree.
The authors of this report analyzed 1464 pairs of concurrent cytogenetics and flow results from 424 patients, before and after hematopoietic cell transplantation, and compared the prognostic impact of discordant and concordant results.
Informative discordant results were observed in 22% of patients. Compared with patients who had double-negative test results, either positive result had a significant impact on overall survival and relapse-free survival. The hazard ratios with either positive cytogenetic results or positive MFC results pretransplantation were 3.1 (P = .009) and 2.5 (P = .0008), respectively, for reduced overall survival and 2.7 (P = .01) and 4.1 (P < .0001), respectively, for decreased recurrence-free survival. Similar findings were obtained post-transplantation. Molecular cytogenetics, ie, fluorescence in situ hybridization (FISH), added value to the evaluation of discordant cases.
The detection of residual AML by either cytogenetics or flow cytometry in patients who underwent hematopoietic cell transplantation predicted early relapse and shortened survival.
Cancer 09/2011; 118(9):2411-9. · 4.77 Impact Factor
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[show abstract]
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ABSTRACT: Sixteen patients diagnosed with various hematologic malignancies participated in a phase II study evaluating the addition of rabbit antithymocyte globulin (rATG, Thymoglobulin(®)) to the hematopoietic cell transplant (HCT) conditioning regimen of IV fludarabine monophosphate (fludarabine) and targeted intravenous (IV) busulfan (fludarabine/(T)busulfan). Our goal was to evaluate pharmacologic biomarkers pertinent to both medications in these patients.
We characterized the interpatient variability of pharmacologic biomarkers relevant to busulfan, specifically busulfan concentration at steady state, and fludarabine, specifically F-ara-A area under the curve (AUC) and fludarabine triphosphate (F-ara-ATP) intracellular accumulation and concentration in separate CD4(+) and CD8(+) T-lymphocyte populations.
Acute and chronic graft versus host disease (GvHD) occurred in 11 patients and one patient, respectively. Four patients died before day +100 of non-relapse causes, which met the protocol stopping guidelines. The cumulative incidence of relapse was 25% at 3 year post-HCT. Interpatient variability in the busulfan- and fludarabine-relevant pharmacologic biomarkers was 2.1- to 2.5-fold. F-ara-A AUC and accumulated F-ara-ATP in CD8(+) cells had the highest hazard ratio for non-relapse mortality and overall survival, respectively. However, neither achieved statistical significance.
The low rates of GvHD, particularly in its chronic form, were encouraging, and further biomarker studies are warranted to optimize the fludarabine/(T)busulfan/rATG conditioning regimen.
Cancer Chemotherapy and Pharmacology 09/2011; 69(1):263-72. · 2.83 Impact Factor
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ABSTRACT: Secondary cytopenias are serious complications following hematopoietic cell transplantation. Etiologies include myelotoxic agents, viral infections, and possibly transplant-related factors such as the intensity of the conditioning regimen and the source of stem cells.
We retrospectively analyzed data from 2162 hematopoietic cell transplant recipients to examine the effect of these factors on overall cytopenias occurring after 28 days in hematopoietic cell transplantation.
Advanced age of the patient, recipient cytomegalovirus seropositivity, unrelated donor status, human leukocyte antigen mismatch and lower doses of transplanted CD34(+) cells (≤ 6.4×10(6)/kg) significantly increased the risk of cytopenias after day 28. Non-myeloablative hematopoietic cell transplantation had protective effects on anemia and thrombocytopenia after day 28 (adjusted odds ratio 0.76, probability value of 0.05 and adjusted odds ratio 0.31, probability value of <0.0001, respectively) but not on overall or ganciclovir-related neutropenia. This lack of protection appeared to be due to the use of mycophenolate mofetil in the majority of recipients of non-myeloablative hematopoietic cell transplants. Peripheral blood stem cells did not confer protection from cytopenias when compared to bone marrow.
Elderly patients appear to be more prone to cumulative toxicities of post-transplant drug regimens, but non-myeloablative conditioning, optimized human leukocyte antigen matching, and higher doses of CD34(+) cell infusions may reduce the risk of cytopenia after day 28.
Haematologica 08/2011; 96(12):1838-45. · 6.42 Impact Factor
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ABSTRACT: To determine whether calcineurin inhibitor (CNI) blood concentrations within the first month after allogeneic hematopoietic cell transplantation (HCT) correlated with the incidence of graft-versus-host disease (GVHD) and other outcomes, we retrospectively analyzed data from 1181 patients with hematologic malignancies who had HCT from HLA-matched related (n = 634) or unrelated (n = 547) donors at a single institution between 2001 and 2009. After myeloablative HCT (n = 774), higher CNI concentrations were not associated with lower risks of acute or chronic GVHD (aGVHD, cGVHD). After nonmyeloablative HCT (n = 407), higher cyclosporine concentrations were associated with decreased risks of grade 2-4 and 3-4 aGVHD (hazard ratio [HR] per 100 ng/mL change in cyclosporine concentrations, 0.7; 95% confidence interval [CI], 0.6-0.82; and HR, 0.66, 95% CI, 0.49-0.9, respectively), nonrelapse mortality (HR, 0.6, 95% CI, 0.41-0.88), and overall mortality (HR, 0.83, 95% CI, 0.71-0.99). Cyclosporine concentrations were not associated with risks of cGVHD and recurrent malignancy after nonmyeloablative HCT. Among patients given tacrolimus after nonmyeloablative HCT, a similar trend of CNI-associated GVHD-protection was observed. Higher CNI concentrations were not associated with apparent renal toxicity. We conclude that higher cyclosporine concentrations relatively early after nonmyeloablative HCT confer protection against aGVHD that translates into reduced risks of nonrelapse and overall mortality.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 08/2011; 18(3):414-22. · 3.15 Impact Factor
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Pamela S Becker,
Hagop M Kantarjian,
Frederick R Appelbaum,
Stephen H Petersdorf, Barry Storer,
Sherry Pierce,
Jianqin Shan,
Paul C Hendrie,
John M Pagel,
Andrei R Shustov,
Derek L Stirewalt,
Stephan Faderl,
Elizabeth Harrington,
Elihu H Estey
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ABSTRACT: This phase I/II study was conducted to determine the maximum tolerated dose, toxicity, and efficacy of clofarabine in combination with high dose cytarabine and granulocyte colony-stimulating factor (G-CSF) priming (GCLAC), in the treatment of patients with relapsed or refractory acute myeloid leukaemia (AML). Dose escalation of clofarabine occurred without dose-limiting toxicity, so most patients were treated at the maximum dose, 25 mg/m(2) per day with cytarabine 2 g/m(2) per day, each for 5 d, and G-CSF 5 μg/kg, beginning the day before chemotherapy and continuing daily until neutrophil recovery. The complete remission (CR) rate among the 46 evaluable patients was 46% (95% confidence interval [CI] 31-61%) and the CR + CR but with a platelet count <100 × 10(9)/l rate was 61% (95% CI 45-75%). Multivariate analysis showed that responses to GCLAC were independent of age, cytogenetic risk category, and number of prior salvage regimens. GCLAC is highly active in relapsed and refractory AML and warrants prospective comparison to other regimens, as well as study in untreated patients.
British Journal of Haematology 08/2011; 155(2):182-9. · 4.94 Impact Factor
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Sally Arai,
Madan Jagasia, Barry Storer,
Xiaoyu Chai,
Joseph Pidala,
Corey Cutler,
Mukta Arora,
Daniel J Weisdorf,
Mary E D Flowers,
Paul J Martin,
Jeanne Palmer,
David Jacobsohn,
Steven Z Pavletic,
Georgia B Vogelsang,
Stephanie J Lee
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ABSTRACT: In 2005, the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic GVHD proposed a new scoring system for individual organs and an algorithm for calculating global severity (mild, moderate, severe). The Chronic GVHD Consortium was established to test these new criteria. This report includes the first 298 adult patients enrolled at 5 centers of the Consortium. Patients were assessed every 3-6 months using standardized forms recommended by the Consensus Conference. At the time of study enrollment, global chronic GVHD severity was mild in 10% (n = 32), moderate in 59% (n = 175), and severe in 31% (n = 91). Skin, lung, or eye scores determined the global severity score in the majority of cases, with the other 5 organs determining 16% of the global severity scores. Conventional risk factors predictive for onset of chronic GVHD and nonrelapse mortality in people with chronic GVHD were not associated with NIH global severity scores. Global severity scores at enrollment were associated with nonrelapse mortality (P < .0001) and survival (P < .0001); 2-year overall survival was 62% (severe), 86% (moderate), and 97% (mild). Patients with mild chronic GVHD have a good prognosis, while patients with severe chronic GVHD have a poor prognosis. This study was registered at www.clinicaltrials.gov as no. NCT00637689.
Blood 07/2011; 118(15):4242-9. · 9.90 Impact Factor
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ABSTRACT: Monosomal karyotype (MK), defined as ≥ 2 autosomal monosomies or a single monosomy in the presence of other structural abnormalities, was confirmed by several studies to convey an extremely poor prognosis in patients with acute myeloid leukemia (AML) with a 4-year overall survival after diagnosis of < 4%. A recent investigation by the Southwest Oncology Group found that the only MK(+) patients alive and disease free > 6 years from diagnosis received allogeneic hematopoietic cell transplantation (HCT). To expand this observation, we retrospectively analyzed 432 patients treated with HCT at the Fred Hutchinson Cancer Research Center, 14% of whom were MK(+). The 4-year overall survival of patients after HCT was 25% for MK(+) AML and 56% for MK(-) AML (adjusted hazard ratio = 2.29, P < .0001). Among the MK(+) patients, complex karyotype was associated with a significantly worse outcome than patients with noncomplex karyotype (adjusted hazard ratio = 2.70, P = .03). Thus, although the prognosis of MK(+) patients remains worse than that for MK(-) patients in the transplantation setting, HCT appears to improve the overall outcome of MK(+) patients, especially patients without a complex karyotype. However, the 28% of MK(+) patients > 60 years had only a 6% 4-year survival rate after HCT, stressing the need for new approaches in these patients.
Blood 06/2011; 118(6):1490-4. · 9.90 Impact Factor
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Luisa Giaccone, Barry Storer,
Francesca Patriarca,
Marcello Rotta,
Roberto Sorasio,
Bernardino Allione,
Fabrizio Carnevale-Schianca,
Moreno Festuccia,
Lucia Brunello,
Paola Omedè, [......],
Nicola Mordini,
Andrea Gallamini,
Renato Fanin,
Massimo Massaia,
Antonio Palumbo,
Giovannino Ciccone,
Rainer Storb,
Ted A Gooley,
Mario Boccadoro,
Benedetto Bruno
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ABSTRACT: Before the introduction of new drugs, we designed a trial where treatment of newly diagnosed myeloma patients was based on the presence or absence of HLA-identical siblings. First-line treatments included a cytoreductive autograft followed by a nonmyeloablative allograft or a second melphalan-based autograft. Here, we report long-term clinical outcomes and discuss them in the light of the recent remarkable advancements in the treatment of myeloma. After a median follow-up of 7 years, median overall survival (OS) was not reached (P = .001) and event-free survival (EFS) was 2.8 years (P = .005) for 80 patients with HLA-identical siblings and 4.25 and 2.4 years for 82 without, respectively. Median OS was not reached (P = .02) and EFS was 39 months (P = .02) in the 58 patients who received a nonmyeloablative allograft whereas OS was 5.3 years and EFS 33 months in the 46 who received 2 high-dose melphalan autografts. Among patients who reached complete remission in these 2 cohorts, 53% and 19% are in continuous complete remission. Among relapsed patients rescued with "new drugs," median OS from the start of salvage therapy was not reached and was 1.7 (P = .01) years, respectively. Allografting conferred a long-term survival and disease-free advantage over standard autografting in this comparative study.
Blood 06/2011; 117(24):6721-7. · 9.90 Impact Factor
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Abraham Guerrero,
Stanley R Riddell,
Jan Storek,
Terry Stevens-Ayers, Barry Storer,
John A Zaia,
Stephen Forman,
Robert S Negrin,
Thomas Chauncey,
William Bensinger,
Michael Boeckh
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ABSTRACT: Peripheral blood stem cell (PBSC) products contain more T cells and monocytes when compared with bone marrow (BM), leading to fewer bacterial and fungal infections. Cytomegelovirus (CMV) viral load and disease as well as CMV-specific immune reconstitution were compared in patients enrolled in a randomized trial comparing PSBC and BM transplantation. There was a higher rate of CMV infection and disease during the first 100 days after transplantation among PBSC recipients (any antigenemia/DNAemia: PBSC, 63% vs BM, 42%, P = .04; CMV disease: PBSC, 17% vs BM, 4%, P = .03). By 2 years, CMV disease rates were similar. The early increase in CMV events correlated temporarily with lower CMV-specific CD4(+) T helper and CD8(+) cytotoxic T lymphocyte function at 30 days after transplantation in PBSC recipients. By 3 months after transplantation and thereafter, CMV-specific immune responses were similar between BM and PBSC recipients. In conclusion, higher CMV infection and disease rates occurred in PBSC transplant recipients early after transplantation. These differences may be because of a transient delay in CMV-specific immune reconstitution following PBSC transplantation.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 05/2011; 18(1):66-75. · 3.15 Impact Factor
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ABSTRACT: We tested the hypothesis that changes in the phenotype of CD8(+) T cells from patients with chronic graft-versus-host disease (cGVHD) correlate with disease activity, and resolve or normalize in clinically tolerant patients successfully withdrawn from immunosuppression therapy (IST). No significant difference was found in the absolute CD8(+) T cell counts among cGVHD patients, tolerant patients, and healthy controls. However, compared with healthy normal controls, CD8(+) T cells from cGVHD patients had decreased expression of the IL-7 receptor and an increase in effector T cells, Ki-67, and perforin expression and apoptosis, suggesting that activation, differentiation, and proliferation of host-reactive CD8(+) effector T cells is a mechanism by which cGVHD is sustained and persists. The increase in effector T cells was most prominent in older patients and patients who were cytomegalovirus seropositive before transplantation. Use of IST was associated with a decreased number of CD45RA(-) CD8(+) effector T cells, a decreased expression of Ki-67, and an increased expression of CD95 (Fas). Together, these results demonstrate that CD8(+) T cells in patients with cGVHD are characterized by an increased level of activation and proliferation, and an expansion of effector cells that appear to be selectively sensitive to IST compared with other CD8(+) T cells. In GVHD-free tolerant patients, CD8(+) T cells showed an increased expression of granzyme and HLA-DR molecules compared with CD8(+) T cells from healthy controls, indicating that clinical tolerance in these patients can occur without full normalization of the CD8(+) T cell phenotype.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 03/2011; 17(8):1121-32. · 3.15 Impact Factor
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ABSTRACT: Combination therapy with azacitidine and etanercept was hypothesized to lead to improved responses in myelodysplastic syndrome (MDS) patients. Thirty-two patients with MDS/chronic myelomonocytic leukaemia were treated with azacitidine + etanercept; 30 completed at least three therapy cycles. At 3 months, nine patients had achieved complete response (CR), two had partial response, 10 had marrow CRs, seven had stable disease, two patients had haematological improvement without marrow response and two patients had disease progression. The overall response rate was 72%; median duration of response was not reached at 2 years. Marrow response rates and duration were improved with azacitidine + etanercept compared to azacitidine alone.
British Journal of Haematology 03/2010; 148(6):944-7. · 4.94 Impact Factor
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ABSTRACT: Immunosuppressive therapies have proven valuable in treating patients with myelodysplastic syndromes (MDS). We evaluated the combination of equine anti-thymocyte globulin (ATGAM) and the soluble tumour necrosis factor receptor, etanercept (Enbrel), in a phase II trial. Twenty-five patients with MDS [4-refractory anaemia (RA), 2-RA with ring sideroblasts, 15-refractory cytopenia with multilineage dysplasia (RCMD), 3-RCMD and ring sideroblasts, 1-RA with excess blasts type 1] in International Prognostic Staging System risk groups low (n = 11) or intermediate-1 (n = 14) were enrolled. All patients were platelet or red cell transfusion-dependent. Nineteen patients completed therapy with ATG at 40 mg/kg per day for four consecutive days, followed by etanercept, 25 mg subcutaneous twice a week for 2 weeks, every month for 4 months. Thirteen patients had haematological improvement (HI)-erythroid, 2 HI-neutrophil, and 6 HI-platelet. One patient with a co-existing diagnosis of multiple sclerosis and rheumatoid arthritis had a complete remission. The overall response by intent to treat analysis among the 25 patients was 56% (95% confidence interval 35-56%). Four patients did not complete their first course of therapy and one patient did not survive to the 8-week post-treatment assessment. Among patients who completed treatment and survived to the 8-week assessment, 70% had at least haematological responses lasting for at least 5 to more than 36 months. Thus, combination therapy with ATG and etanercept was active and safe in patients with MDS.
British Journal of Haematology 03/2010; 149(5):706-10. · 4.94 Impact Factor
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ABSTRACT: Warfarin is a widely prescribed drug that is difficult to use because of its narrow therapeutic window. Genetic polymorphisms associated with warfarin metabolism have been identified, but the clinical utility of genetic testing in warfarin dosing has not been established. External validation of published algorithms is critical to determine the best prediction for warfarin dosing in prospective trials. We used two independent datasets totaling 1095 patients to evaluate four published algorithms and a simple prediction algorithm developed in this study based on the CYP2C9*2, CYP2C9*3, and VKORC1 -1639 polymorphisms in 150 patients taking warfarin. Predicted warfarin doses were calculated and compared for accuracy with actual maintenance doses. All evaluated pharmacogenetics-based dosing algorithms performed similarly for both datasets. The proportion of variation explained (R(2)) was high (60% to 65%) in the small white-only Connecticut dataset but low (36% to 46%) in the large dataset on a diverse ethnic population from the International Warfarin Pharmacogenetics Consortium (IWPC). When comparing the percentage of patients whose predicted dosage are within 20% of actual, the IWPC algorithm performed the best overall (45.9%) for the two datasets combined while other algorithms performed nearly as well. Because no algorithm could be considered the best for all dosing ranges, it may be important to consider the nature of a local service population in choosing the most appropriate pharmacogenetics-based dosing algorithm.
The Journal of molecular diagnostics: JMD 03/2010; 12(3):283-91. · 3.48 Impact Factor
