Publications (22)152.97 Total impact
-
Article: Donor lymphocyte infusion for relapsed hematological malignancies after allogeneic hematopoietic cell transplantation: prognostic relevance of the initial CD3+ T cell dose.
[show abstract] [hide abstract]
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 -
Article: Cytomegalovirus viral load and virus-specific immune reconstitution after peripheral blood stem cell versus bone marrow transplantation.
[show abstract] [hide abstract]
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 -
Article: Non-myeloablative allogeneic haematopoietic cell transplantation for relapsed diffuse large B-cell lymphoma: a multicentre experience.
[show abstract] [hide abstract]
ABSTRACT: Patients with relapsed diffuse large B-cell lymphoma (DLBCL) who have failed or are ineligible for autologous haematopoietic cell transplantation (HCT) have a poor prognosis. We examined the outcomes of non-myeloablative allogeneic HCT in this setting. Thirty-one patients with DLBCL and one patient with Burkitt lymphoma received allogeneic HCT following 2 Gy total body irradiation with or without fludarabine. Median age was 52 years. Twenty-four patients (75%) had undergone prior autologous HCT. Disease status at HCT was complete response (14/32, 44%), partial response (9/32, 28%), or refractory (9/32, 28%). Cumulative incidences of acute graft-versus-host disease (GVHD) grades II-IV, grades III-IV, and chronic GVHD were 53%, 19%, and 47% respectively. With a median follow-up of 45 months, 3-year estimated overall (OS) and progression-free survival (PFS) was 45% and 35% respectively. Three-year cumulative incidences of relapse and non-relapse mortality were 41% and 25% respectively. In multivariate models, chemosensitive disease and receipt of >or=4 lines of treatment before HCT were associated with better OS. Patients with chemosensitive disease had 3-year OS and PFS of 56% and 43% respectively. Non-myeloablative allogeneic HCT can produce long-term disease-free survival in patients with chemosensitive relapsed DLBCL who have failed or are ineligible for autologous HCT.British Journal of Haematology 09/2008; 143(3):395-403. · 4.94 Impact Factor -
Article: Nonmyeloablative allogeneic hematopoietic cell transplantation in relapsed, refractory, and transformed indolent non-Hodgkin's lymphoma.
[show abstract] [hide abstract]
ABSTRACT: Few effective treatment options exist for chemotherapy-refractory indolent or transformed non-Hodgkin's lymphoma (NHL). We examined the outcome of nonmyeloablative allogeneic hematopoietic cell transplantation (HCT) in this setting. Sixty-two patients with indolent or transformed NHL were treated with allogeneic HCT from related (n = 34) or unrelated (n = 28) donors after conditioning with 2 Gy of total-body irradiation with or without fludarabine. Nine unrelated donors were mismatched for >/= one HLA antigen. Sixteen patients had histologic transformation before HCT. Twenty patients (32%) had progressive disease after previous high-dose therapy with autologous HCT. Median age was 54 years, and patients had received a median of six lines of treatment before HCT. Median follow-up time after HCT was 36.6 months. At 3 years, the estimated overall survival (OS) and progression-free survival (PFS) rates were 52% and 43%, respectively, for patients with indolent disease, and 18% and 21%, respectively, for patients with transformed disease. Patients with indolent disease and related donors (n = 26) had 3-year estimated OS and PFS rates of 67% and 54%, respectively. The incidences of grade 2 to 4 acute graft-versus-host disease (GVHD), grade 3 and 4 acute GVHD, and extensive chronic GVHD were 63%, 18%, and 47%, respectively. Among survivors, the median Karnofsky performance status at last follow-up was 85%. Nonmyeloablative allogeneic HCT can produce durable disease-free survival in patients with relapsed or refractory indolent NHL, even in this relatively elderly and heavily pretreated cohort. Outcomes were particularly good in patients with untransformed disease and related donors, whereas patients with transformed disease did poorly. Long-term survivors reported good overall functional status.Journal of Clinical Oncology 01/2008; 26(2):211-7. · 18.37 Impact Factor -
Article: Treatment for acute myelogenous leukemia by low-dose, total-body, irradiation-based conditioning and hematopoietic cell transplantation from related and unrelated donors.
[show abstract] [hide abstract]
ABSTRACT: The use of low-dose, irradiation-based preparative regimens have allowed the extension of allografting to older and medically infirm patients. The study reported here assessed outcomes for patients with acute myeloid leukemia (AML) in different stages of their disease, who were not considered candidates for conventional hematopoietic cell transplantation (HCT) because of age and/or other known risk factors and were given minimal conditioning followed by HCT from related or unrelated donors. The present study included 122 patients with AML, who were conditioned with 2 Gy total-body irradiation (TBI) on day 0 with or without preceding fludarabine (30 mg/m2/d from days -4 to -2), and given postgrafting cyclosporine at 6.25 mg/kg twice daily from day -3 and mycophenolate mofetil at 15 mg/kg twice daily from day 0. Durable engraftment was observed in 95% of the patients. Cumulative incidences of acute graft-versus-host disease grades 2 to 4 at 6 months were 35% after related and 42% after unrelated HCT, respectively. With a median follow-up of 44 months (range, 26 to 79 months), 51 patients were alive, of whom 48 were in complete remission (CR). Cumulative nonrelapse mortalities were 10% and 22%, and cumulative mortalities from disease progression were 47% and 33% at 2 years for related and unrelated recipients, respectively. Overall, 2-year survival was 48%, and disease-free survival was 44%. Patients receiving transplantation in CR1 had 2-year overall survivals of 44% after related and 63% after unrelated HCT, respectively. We conclude that HCT from related and unrelated donors after low-dose TBI is a promising treatment for elderly patients with AML.Journal of Clinical Oncology 02/2006; 24(3):444-53. · 18.37 Impact Factor -
Article: Nonmyeloablative Hematopoietic Cell Transplantation
[show abstract] [hide abstract]
ABSTRACT: Conventional allografting produces considerable regimen-related toxicities that generally limit this treatment to patients younger than 55 years and in otherwise good medical condition. T cell-mediated graft-versus-tumor (GVT) effects are known to play an important role in the elimination of malignant disease after allotransplants. A minimally myelosuppressive regimen that relies on immunosuppression for allogeneic engraftment was developed to reduce toxicities while optimizing GVT effects. Pre-transplant total-body irradiation (200 cGy) followed by post-transplant immunosuppression with cyclosporine (CSP) and mycophenolate mofetil (MMF) permitted human leukocyte antigen (HLA)-matched sibling donor hematopoietic cell engraftment in 82% of patients (n= 55) without prior high-dose therapy. The addition of fludarabine (90 mg/m2) facilitated engraftment in all 28 subsequent patients. Overall, fatal progression of underlying disease occurred in 20% of patients after transplant. Non-relapse mortality occurred in 11% of patients. Toxicities were low. Grade 2–4 acute graft-versus-host disease (GVHD) associated with primary engraftment developed in 47% of patients, and was readily controlled in all but two patients. Donor lymphocyte infusions (DLI) were not very effective at converting a low degree of mixed donor/host chimerism to full donor chimerism; however, the addition of fludarabine reduced the need for DLI. With a median follow-up of 244 days, 68% of patients were alive, with 42% of patients in complete remission, including molecular remissions. Remissions occurred gradually over periods of weeks to a year. If long-term efficacy is demonstrated, such a strategy would expand treatment options for patients who would otherwise be excluded from conventional allografting.Annals of the New York Academy of Sciences 01/2006; 938(1):328 - 339. · 3.15 Impact Factor -
Article: Randomized trial of allogeneic related bone marrow transplantation versus peripheral blood stem cell transplantation for chronic myeloid leukemia.
[show abstract] [hide abstract]
ABSTRACT: 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.Biology of Blood and Marrow Transplantation 03/2005; 11(2):85-92. · 3.87 Impact Factor -
Article: Allogeneic hematopoietic cell transplantation after fludarabine and 2 Gy total body irradiation for relapsed and refractory mantle cell lymphoma.
[show abstract] [hide abstract]
ABSTRACT: We carried out HLA-matched related (n = 16) and unrelated (n = 17) hematopoietic cell transplantation (HCT) in 33 patients with relapsed and refractory mantle cell lymphoma after nonmyeloablative conditioning with fludarabine and 2 Gy total body irradiation. Postgrafting immunosuppression consisted of cyclosporine and mycophenolate mofetil. Fourteen patients had failed high-dose autologous HCT. Of the 33 patients studied, 31 had stable engraftment, whereas 2 patients experienced nonfatal graft rejections. The incidences of acute grades II, III, and IV, and chronic graft-versus-host disease (GVHD) were 27%, 17%, 13%, and 64%, respectively. The overall response rate in the 20 patients with measurable disease at the time of HCT was 85% (n = 17; 75% complete remissions [CR] and 10% partial remissions [PR]), whereas 3 patients had progressive disease. Only one of the 17 patients who responded and none of the 13 who received transplants in CR had disease relapse with a median follow-up of 24.6 months. Relapse and nonrelapse mortalities were 9% and 24%, respectively, at 2 years. The Kaplan-Meier probabilities of overall and disease-free survivals at 2 years were 65% and 60%, respectively. Allogeneic HCT after nonmyeloablative conditioning is a promising salvage strategy for patients with relapsed and refractory mantle cell lymphoma. The high response and low relapse rates with this approach suggest that mantle cell lymphoma is susceptible to graft-versus-tumor responses.Blood 01/2005; 104(12):3535-42. · 9.90 Impact Factor -
Article: Targeted busulfan and cyclophosphamide as compared to busulfan and TBI as preparative regimens for transplantation in patients with advanced MDS or transformation to AML.
[show abstract] [hide abstract]
ABSTRACT: Hematopoietic cell transplantation is the only curative therapy for patients with myelodysplasia (MDS). However, treatment-related toxicity and, in patients with advanced MDS (RAEB, RAEB-T) and those who have transformed to AML (tAML), post-transplant relapse continues to be problematic. We reviewed results in 128 patients with advanced MDS and tAML transplanted from HLA-identical related or unrelated donors after preparation with myeloablative conditioning regimens. Seventy-eight patients were conditioned with busulfan (Bu), prescribed dose 16 mg/kg, adjusted to achieve plasma concentrations of 800-900 ng/ml, plus cyclophosphamide (Cy), 2 x 60 mg/kg [tBuCy], and 50 patients were conditioned with Bu 7 mg/kg (without dose adjustment) and total body irradiation (TBI) 6 x 200 cGy given over 3 days [BuTBI]. There was no statistically significant difference in regards to overall survival, relapse-free survival (RFS), or non-relapse mortality (NRM) between the 2 regimens regardless of donor status. However, there was a trend towards higher rates of relapse (HR 1.33, P=0.38) and lower rates of NRM (HR 0.61, P=0.09) in patients conditioned with tBuCy. The increased rate of relapse seen with tBuCy was significant when restricted to only those patients with a diagnosis of RAEB (HR 4.50, P=0.02). Patients given BuTBI had a higher incidence of GvHD; however, the incidence of GvHD regardless of grade did not differ significantly between patients who relapsed and those who did not. Thus, in patients with advanced MDS/tAML, the use of a less toxic conditioning regimen resulted in a non-significant overall gain in RFS largely due to lower rates of NRM. New concepts of conditioning regimens are needed which reduce toxicity without increasing the risk of relapse.Leukemia and Lymphoma 01/2005; 45(12):2409-17. · 2.58 Impact Factor -
Article: Adoptive immunotherapy with donor lymphocyte infusions after allogeneic hematopoietic cell transplantation following nonmyeloablative conditioning.
[show abstract] [hide abstract]
ABSTRACT: This study retrospectively analyzed data from 446 patients given hematopoietic cell transplants from HLA-matched related or unrelated donors after conditioning with 2 Gy total body irradiation with or without fludarabine and postgrafting immunosuppression with mycophenolate mofetil and cyclosporine following grafting. Fifty-three of 446 patients received donor lymphocyte infusion (DLI) with a median CD3 dose of 1 x 10(7) cells/kg. Their diagnoses included myelodysplastic syndrome (n = 10), acute leukemia (n = 10), chronic leukemia (n = 11), multiple myeloma (n = 9), lymphoma (n = 9), and solid tumors (n = 4). Patients received DLI for persistent disease (n = 8), disease relapse (n = 17), progressive disease (n = 12), low donor chimerism with disease (n = 11), or low chimerism with disease remission (n = 5). Seventeen of the 53 patients (32%) are alive with a median follow-up of 30 months; 5 are in complete remission (CR), 2 are in partial remission (PR), and 10 have stable or progressive disease. Nine of 53 patients (17%) developed grades II to IV acute graft-versus-host disease. Of 48 patients receiving DLI for treatment of disease, 7 achieved CR and 5 PR, with an overall response rate of 25%. Six of 16 patients who received DLI for chimerism had increases in donor chimerism leading to sustained engraftment, whereas 10 eventually rejected their grafts. In conclusion, DLI is a potential treatment strategy, with acceptable toxicity, for patients with persistent, relapsed, or progressive disease after nonmyeloablative hematopoietic cell transplantation.Blood 03/2004; 103(3):790-5. · 9.90 Impact Factor -
Article: Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma.
[show abstract] [hide abstract]
ABSTRACT: The full potential of a graft-versus-myeloma effect after allogeneic hematopoietic cell transplantation (HCT) for patients with multiple myeloma (MM) has not been realized because of excessive early transplantation-related mortality (TRM) with conventional HCT. Autologous HCTs have been characterized by almost universal disease recurrences. The current trial combined autologous HCT with subsequent nonmyeloablative allogeneic HCT to maintain the benefits of both approaches with acceptable toxicity. Fifty-four patients, 52 years of age (median; range, 29-71 years), with previously treated stage II or III MM (52% refractory or relapsed disease) were given melphalan 200 mg/m2 and autologous HC transplants. Regimen-related toxicities after autologous HCT were moderate with a median of 6 days of neutropenia, 7 days of hospitalization, and 1 death from infection. Forty to 229 days later (median, 62 days), 52 patients received a single fraction dose of 2 Gy total body irradiation and HC transplants from HLA-identical siblings with postgrafting immunosuppression with mycophenolate mofetil (MMF) and cyclosporine (CSP). Patients experienced medians of 0 days of hospitalization, neutropenia, and thrombocytopenia. Sustained engraftment was uniform. With a median follow-up of 552 days after allografting, overall survival is 78%. One patient (2%) died before day 100 from disease progression. Thirty-eight percent of patients developed acute graft-versus-host disease (GVHD; grade II in all but 4 cases) and 46% chronic GVHD requiring therapy. Tumor responses occurred slowly. Thus far, 57% of patients have achieved complete remissions and 26% have achieved partial remissions for an overall response of 83%. Despite being evaluated in elderly patients with MM, this 2-step approach has reduced the acute toxicities of allogeneic HCT while achieving potent antitumor activities.Blood 12/2003; 102(9):3447-54. · 9.90 Impact Factor -
Article: HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative conditioning for patients with hematologic malignancies.
[show abstract] [hide abstract]
ABSTRACT: A hematopoietic cell transplantation (HCT) approach was developed for elderly or ill patients with hematologic malignancies that employed nonmyeloablative conditioning to avoid common regimen-related toxicities and relied on graft-versus-tumor effects for control of malignancy. Eighty-nine patients, median age 53 years, were given fludarabine (90 mg/m2) and 2 Gy total body irradiation. Marrow (n = 18) or granulocyte colony-stimulating factor (G-CSF)-stimulated peripheral blood mononuclear cells (G-PBMCs; n = 71) were transplanted from unrelated donors matched for human leukocyte antigen A (HLA-A), -B, -C antigens and -DRB1 and -DQB1 alleles. Postgrafting immunosuppression included mycophenolate mofetil and cyclosporine. Donor T-cell chimerism was higher for G-PBMCs compared with marrow recipients. Durable engraftment was observed in 85% of G-PBMCs and 56% of marrow recipients. Cumulative probabilities of grade II, III, and IV acute graft-versus-host disease (GVHD) were 42%, 8%, and 2%, respectively. Nonrelapse mortality at day 100 and at 1 year was 11% and 16%, respectively. One-year overall survivals and progression-free survivals were 52% and 38%, respectively. G-PBMC recipients had improved survival (57% vs 33%) and progression-free survival (44% vs 17%) compared with marrow recipients. HLA-matched unrelated donor HCT after nonmyeloablative conditioning is feasible in patients ineligible for conventional HCT. G-PBMCs conferred higher donor T-cell chimerism, greater durable engraftment, and better progression-free and overall survivals compared with marrow.Blood 10/2003; 102(6):2021-30. · 9.90 Impact Factor -
Article: HLA-matched related hematopoietic cell transplantation for chronic-phase CML using a targeted busulfan and cyclophosphamide preparative regimen.
[show abstract] [hide abstract]
ABSTRACT: Allogeneic blood or marrow transplantation (BMT) is a curative therapy for chronic myeloid leukemia (CML). We have previously reported that the pharmacologic targeting of busulfan combined with cyclophosphamide (TBU/CY) can minimize regimen-related toxicity while preserving antileukemic effects. We report here on 131 consecutive chronic-phase CML patients treated with allogeneic related BMT using a TBU/CY preparative regimen, where the busulfan dose was targeted to achieve a steady-state plasma concentration of at least 900 ng/mL. The median age of the patients was 43 years (range, 14-66 years). Estimates of the probabilities of nonrelapse mortality, relapse, survival, and disease-free survival 3 years after transplantation were 14%, 8%, 86%, and 78%, respectively. Age had no statistically significant effect on survival. Although approximately 60% of the patients developed clinically extensive chronic graft-versus-host disease, the median Karnofsky score at last contact date among survivors was 95%. Of surviving patients, 11% were molecularly positive for the bcr-abl mRNA at last contact, with a median level of bcr-abl transcripts of 4.6 copies/microg RNA. These data suggest that TBU/CY is a very effective preparative regimen for CML in chronic phase, associated with an expected survival at 3 years of approximately 85%, with most patients being in molecular remission.Blood 08/2003; 102(1):31-5. · 9.90 Impact Factor -
Article: Predictive factors for outcome of allogeneic hematopoietic cell transplantation for adult acute lymphoblastic leukemia.
[show abstract] [hide abstract]
ABSTRACT: Between January 1990 and December 1997, 182 adults with acute lymphoblastic leukemia (ALL) received allogeneic hematopoietic cell transplants according to Fred Hutchinson Cancer Research Center protocols. Patients eligible for transplantation included those in first remission, especially those at high risk of relapse (n = 41), and any patient in second or later remissions (n = 46) or in relapse (n = 95). The median patient age was 29.4 years (range, 18.0-57.6 years), and the median duration of disease was 13.3 months (range, 2.4-221.9 months). Fifty-six patients had Philadelphia chromosome-positive ALL. Most patients (n = 169) received a conditioning regimen of cyclophosphamide 120 mg/kg plus 12.0 to 15.75 Gy of total body irradiation and a combination of cyclosporine and methotrexate as graft-versus-host disease (GVHD) prophylaxis. One hundred twenty-one patients received stem cells from HLA-identical donors (88 related donors and 33 unrelated donors), and 61 received stem cells from HLA-mismatched donors (26 related donors and 35 unrelated donors). Actuarial disease-free survival at 5 years was 21% for all patients, 43% for patients in first remission, 24% for patients in second or later remissions, and 9% for patients in relapse. Univariate and multivariate Cox regression analyses were performed to identify factors associated with survival, relapse, nonrelapse mortality, and disease-free survival. Factors significantly associated (P <.01) with improved survival and disease-free survival included younger age and being in first remission. Lower disease-free survival was associated with receiving cyclosporine alone as GVHD prophylaxis (P <.01). Risk of relapse correlated only with disease status at transplantation: patients who underwent transplantation in relapse had a 9-fold increased risk compared with patients who underwent transplantation in first remission. Acute or chronic GVHD had no significant effect on relapse. Increased nonrelapse mortality was associated with HLA-mismatched donors, a positive cytomegalovirus serology before transplantation, and GVHD prophylaxis with only cyclosporine. Patients with Philadelphia chromosome-positive ALL had survival and relapse rates similar to patients with normal cytogenetics.Biology of Blood and Marrow Transplantation 07/2003; 9(7):472-81. · 3.87 Impact Factor -
Article: Low-dose total body irradiation (TBI) and fludarabine followed by hematopoietic cell transplantation (HCT) from HLA-matched or mismatched unrelated donors and postgrafting immunosuppression with cyclosporine and mycophenolate mofetil (MMF) can induce durable complete chimerism and sustained remissions in patients with hematological diseases.
[show abstract] [hide abstract]
ABSTRACT: Toxicities of high-dose conditioning regimens have limited the use of conventional unrelated donor hematopoietic cell transplantation (HCT) to younger, medically fit patients. Based on preclinical studies, an HCT approach has been developed for elderly or medically infirm patients with HLA-matched or mismatched unrelated donors. In this study, 52 patients with hematological diseases were included. Most (88%) had preceding unsuccessful conventional HCT or refractory/advanced disease. Patients were treated with fludarabine 30 mg/m(2)/d from days -4 to -2, 2 Gy total body irradiation on day 0, cyclosporine at 6.25 mg/kg twice daily from day -3, and mycophenolate mofetil at 15 mg/kg twice daily from day 0. Durable donor chimerism was attained in 88% of the patients. By day 28, a median of 100% of CD56(+) cells were of donor origin. Granulocyte and T-cell donor chimerism increased to medians of 100% on day 56 and day 180 (range, 55%-100%), respectively. Acute GVHD, grade II, was seen in 42% (CI, 29%-56%); grade III in 8% (CI, 0%-15%); and grade IV in 13% (CI, 4%-23%) of patients; it was fatal in 9%. The 100-day transplantation-related mortality was 11%. Complete remissions, including molecular remissions, were seen in 45% of patients with measurable disease before transplantation. Mortality from disease progression was 27% at one year. With a median follow-up of 19 months, 18 of the 52 patients (35%) were alive and 25% were in remission. HCT from HLA-matched or mismatched unrelated donors can be performed with a reduced intensity conditioning regimen in patients ineligible for conventional HCT.Blood 03/2003; 101(4):1620-9. · 9.90 Impact Factor -
Article: Engraftment of early erythroid progenitors is not delayed after non-myeloablative major ABO-incompatible haematopoietic stem cell transplantation.
[show abstract] [hide abstract]
ABSTRACT: We hypothesized that patients undergoing major ABO-incompatible non-myeloablative haematopoietic stem cell transplantation (nm-HSCT) might experience prolonged haemolysis after transplant due to the delayed disappearance of host plasma cells producing anti-donor isohaemagglutinins (HAs). To address this question, we analysed data from 107 consecutive patients transplanted with allogeneic peripheral blood stem cells from human leucocyte antigen-matched (related, n = 84; unrelated, n = 23) donors after non-myeloablative conditioning (200 cGy total body irradiation +/- fludarabine). In total, 23 out of the 107 patients received major or major/minor ABO-incompatible transplants. Red blood cell (RBC) transfusion requirements during the first 120 d post transplant were higher in major ABO-mismatched than in ABO-matched recipients (0.12 vs 0.03 median units RBC concentrate/d, P = 0.04). Two patients developed transient pure red cell aplasia, which had resolved spontaneously by 9 months after transplant. Major ABO incompatibility did not influence rates of engraftment. Patients with sustained engraftment experienced gradual declines of anti-donor HAs, and the estimated median time to reaching IgM and IgG titres of < 1:1 was at least 133 d in evaluable patients, approximately twice longer than reported after myeloablative conditioning. There was a strong correlation between degrees of donor chimaerism in erythroid burst-forming units, granulocyte macrophage colony-forming units and granulocytes, indicating that donor erythroid engraftment, defined by early erythroid progenitors, was as prompt as myeloid engraftment. In conclusion, our data suggest that major ABO-incompatibility is not a barrier to successful non-myeloablative HSCT.British Journal of Haematology 12/2002; 119(3):740-50. · 4.94 Impact Factor -
Article: Curative therapy of advanced essential thrombocythemia or polycythemia vera by hemopoietic stem cell transplantation.
[show abstract] [hide abstract]
ABSTRACT: Twenty-five patients with advanced essential thrombocythemia (ET; n = 13) or polycythemia vera (PV; n = 12) received hemopoietic stem cell transplants (HSCT) at the Fred Hutchinson Cancer Research Center. In most cases the indication to perform an HSCT was myelofibrosis with splenomegaly and peripheral blood cytopenias or the development of a myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Patients were 18-60 (median 43) years old with intervals from diagnosis to HSCT of 8-348 (median 168) months. All but five patients had been treated with cytotoxic agents, and nine patients were splenectomized before transplant. Conditioning was performed with chemotherapy only or chemotherapy plus total body irradiation regimens followed by the infusion of either marrow (n = 19) or peripheral blood stem cells (n = 6) from related (n = 16) or unrelated (n = 9) donors. All evaluable patients showed sustained neutrophil engraftment. Nine patients (seven with AML/MDS, two with myelofibrosis) died of transplant-related complications, and 16 are surviving, 14 of them in continuous unmaintained remission. With a median follow-up of 41 (range 5-116) months after transplant, survival at 3 years is 64%. These data provide evidence that HSCT can be a curative treatment for patients with advanced PV and ET.Leukemia and Lymphoma 08/2002; 43(7):1409-14. · 2.58 Impact Factor -
Article: Incidence and outcome of cytomegalovirus infections following nonmyeloablative compared with myeloablative allogeneic stem cell transplantation, a matched control study.
[show abstract] [hide abstract]
ABSTRACT: Nonmyeloablative allogeneic hematopoietic stem cell transplantation (HSCT) is increasingly being explored as therapy in patients who are not eligible for conventional myeloablative HSCT. Whether these transplants are associated with reduced risk of transplantation-related infections is unknown. We analyzed the incidence of posttransplantation cytomegalovirus (CMV) infections in 56 consecutive mycophenolate mofetil (MMF) patients with hematologic malignancies who underwent nonmyeloablative HSCT (TBI, 2Gy, day 0; MMF/cyclosporine after transplantation). In addition, 18 of 56 patients received 30 mg/m(2)/d fludarabine on days -4 to -2. Most donors were HLA matched and related (93%). Each case patient was matched to 2 controls who were treated by conventional HSCT during the same time period (January 1997 through April 2000). Matching criteria included CMV risk group, HSC source, donor type, age, and underlying diseases. No CMV disease occurred in the low (donor and recipient serologically negative) and intermediate (donor serologically positive and recipient negative) CMV risk groups during the first 100 days. Among cases at high risk for CMV (seropositive recipients), trends to less CMV antigenemia (P =.11), viremia (P =.16), and disease (P =.08) compared with controls were observed; all severe manifestations combined (CMV viremia and disease) were significantly reduced among cases (P =.01). However, by day 365, the overall incidence of CMV disease became similar in both groups. The onset of CMV disease was significantly delayed among case patients compared with controls (median, 130 days versus 52 days; P =.02). It was concluded that CMV disease was significantly delayed in nonmyeloablative cases, but that the overall 1-year incidence was similar to myeloablative HSCT patients. Therefore, nonmyeloablative HSCT patients should receive CMV surveillance beyond day 100 and pre-emptive ganciclovir treatment similar to that of myeloablative HSCT patients.Blood 04/2002; 99(6):1978-85. · 9.90 Impact Factor -
Article: Nonmyeloablative hematopoietic cell transplantation: status quo and future perspectives.
[show abstract] [hide abstract]
ABSTRACT: In nonmyeloablative allogeneic hematopoietic stem cell transplantation (HSCT), high-dose cytotoxic therapy as the conceptual basis for treating hematopoietic malignancies has been replaced by graft-versus-tumor effects. The use of potent pre- and postgrafting immunosuppression derived from preclinical studies has allowed omission of myeloablative cytotoxic therapy without compromising hematopoietic donor cell engraftment. This results in a marked reduction in transplant-related toxicities that makes older or medically infirm patients candidates for this treatment option. This patient group is more representative of the population with cancer and would have been ineligible for conventional HSCT. Initial results in patients with a variety of hematologic malignancies have been encouraging with documented sustained cytogenetic and molecular remissions in a substantial number of sometimes heavily pretreated and previously refractory patients. Even though patients with hematologic malignancies will likely require conversion to full donor hematopoiesis for long-term disease control, a state of mixed hematopoietic chimerism might suffice to "cure" the disease phenotypes in various nonmalignant diseases. Strategies aimed at optimizing peritransplant immunosuppression may eventually eliminate the need for pretransplant total body irradiation, which is relevant for minimizing late toxicities. Enhancing graft-versus-tumor effects by virtue of postgrafting vaccination of recipients against tumor-specific antigens may help to use this transplant approach more effectively in the treatment of solid tumors.Journal of Clinical Immunology 04/2002; 22(2):70-4. · 3.08 Impact Factor -
Article: Hematopoietic stem cell transplantation for advanced myelodysplastic syndrome after conditioning with busulfan and fractionated total body irradiation is associated with low relapse rate but considerable nonrelapse mortality.
[show abstract] [hide abstract]
ABSTRACT: The objectives of this study were to develop transplantation regimens for patients with advanced myelodysplastic syndrome (MDS) that would be associated with low transplantation-related mortality and improved relapse-free survival. Sixty patients with advanced MDS or acute myeloid leukemia evolving from MDS (sAML), 12 to 62 years old (median, 40 years), were conditioned with busulfan (7 mg/kg) and TBI (6 x 200 cGy) (BU/TBI) and received transplants from related (n = 20) or unrelated donors (n = 40). By French-American-British (FAB) criteria, 21 patients had refractory anemia with excess blasts (RAEB), 16 had RAEB in transformation (RAEB-T), 15 had sAML, and 8 had chronic myelomonocytic leukemia (CMML). By International Prognostic Scoring System (IPSS) criteria, 1 patient had low, 10 had intermediate-1, 13 had intermediate-2, and 31 had high-risk MDS (5 patients had proliferative CMML). All evaluable patients achieved sustained engraftment. The cumulative incidence (CI) of acute GVHD grades II to IV was 83% with unrelated donors and 85% with related donors. The CI of relapse was 25% at 3 years. The incidence of nonrelapse mortality (NRM) at 100 days was 38%. The Kaplan-Meier estimate of survival was 26% at 3 years. Major causes of death were relapse, organ failure, GVHD, and infection. In multivariate analysis, improved relapse-free survival was associated with good cytogenetic risk (P = .002) and shorter disease duration (P = .004). NRM was increased with longer disease duration (P = .0002), positive cytomegalovirus serology (P = .02), and male sex (P = .02). Relapse was associated with poor cytogenetic risk (P = .0004). Thus, BU/TBI conditioning as used in this trial was associated with relapse rates comparable to those observed with a previously used more intensive regimen combining BU/TBI with cyclophosphamide. However, despite the omission of cyclophosphamide, transplantation-related morbidity and mortality were considerable, particularly with transplants from unrelated donors. Future trials should explore the efficacy and tolerability of reduced-intensity conditioning regimens.Biology of Blood and Marrow Transplantation 02/2002; 8(3):161-9. · 3.87 Impact Factor
Top co-authors
Top Journals
Institutions
-
2003–2008
-
Fred Hutchinson Cancer Research Center
- Division of Clinical Research
Seattle, WA, USA
-
-
2006
-
University of Washington Seattle
- Department of Medicine
Seattle, WA, USA -
University of Leipzig
Leipzig, Saxony, Germany
-
