Long-Term Outcomes of Myeloablative Conditioning and Matched-Related Donor Hematopoietic Cell Transplantation for Patients with High-Risk and Advanced-Stage Hematolymphoid Malignancies

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4383-4383
Author(s):  
Jonathan E. Benjamin ◽  
Ginna G. Laport ◽  
Laura J. Johnston ◽  
Sally Arai ◽  
Wen-Kai Weng ◽  
...  
Keyword(s):  
High Risk ◽  
Graft Versus Host Disease ◽  
Hematopoietic Cell Transplantation ◽  
Conditioning Regimen ◽  
Free Survival ◽  
Host Disease ◽  
Graft Versus Host ◽  
Related Donor

Abstract Patients with high-risk hematolymphoid malignancies who relapse or who do not achieve a complete remission to induction chemotherapy generally do not achieve long-term survival when treated with the best available non-transplant therapies. The benefit of allogeneic hematopoietic cell transplantation has been well described for patients in first complete remission, but less so for patients with advanced disease. We report the long-term follow-up of 131 patients with leukemia or lymphoma who received an HLA-matched related donor transplant following myeloablative conditioning with fractionated total body irradiation (1320cGy), etoposide (60mg/kg), and cyclophosphamide (60mg/kg). Eligibility for transplantation under this protocol included induction failure or high-risk disease that was beyond first remission. All patients were treated at a single institution. Diagnosis at the time of transplantation included ALL (n=57), AML (n=38), NHL (n=20), CML (n=10), MDS (4), JMML (n=2). Of the 95 patients with acute leukemia, 62 (65%) were not in remission at the commencement of the conditioning regimen. The median age at transplantation was 29 years (range 2–55). Seventy-four (56%) patients received unmanipulated bone marrow and the remainder received filgrastim-mobilized peripheral blood. Median follow-up of surviving patients was 8 years (range 0.3–17). The estimated five-year overall survival and event-free survival were 34% (95% confidence interval: 22–42%) and 32% (95% confidence interval: 24–39%), respectively. Leading causes of death included relapse (n=43), infection (n=11), acute graft-versus-host disease (n=8), respiratory failure (n=5) and hepatic veno-occlusive disease (n=4). Grade II–IV acute graft-versus-host disease occurred in 26% of patients. The cumulative incidence of extensive chronic graft-versus-host disease among those patients who survived beyond day 100 was 32%. These results indicate that patients with high-risk or advanced disease can experience long-term disease-free survival following an aggressive conditioning regimen that combines radiotherapy, etoposide, and cyclophosphamide. Relapse remains the most significant cause of mortality, and future efforts should focus on augmenting the graft-versus-malignancy effect.

Cyclosporine (CSP) or CSP plus methylprednisolone for graft-versus-host-disease prophylaxis in patients with high-risk lymphohemopoietic malignancies: long-term follow-up of a randomized trial

Blood ◽  
2000 ◽  
Vol 96 (3) ◽  
pp. 1194-1196 ◽  
Author(s):  
H. Joachim Deeg ◽  
Mary E. D. Flowers ◽  
Wendy Leisenring ◽  
Frederick R. Appelbaum ◽  
Paul J. Martin ◽  
...  
Keyword(s):  
High Risk ◽  
Randomized Trial ◽  
Graft Versus Host Disease ◽  
Host Disease ◽  
Graft Versus Host ◽  
Long Term Follow Up

Adult Recipients of Matched Related Donor Blood Cell Transplants (BCT) Given Pretransplant Low-Dose Antithymocyte Globulin (ATG) Have Less Chronic Graft-Versus-Host Disease (cGVHD) and Transplant-Related Mortality (TRM): A Matched Pair Analysis.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2250-2250
Author(s):  
James A. Russell ◽  
A. Robert Turner ◽  
Loree Larratt ◽  
Ahsan M. Chaudhry ◽  
Oluyeme Jeje ◽  
...  
Keyword(s):  
Blood Cell ◽  
Graft Versus Host Disease ◽  
Antithymocyte Globulin ◽  
Progression Free Survival ◽  
Not Given ◽  
Free Survival ◽  
Host Disease ◽  
Graft Versus Host ◽  
Related Donor ◽  
Related Mortality

Abstract Because pretransplant antithymocyte globulin (ATG) seems to reduce graft-versus-host disease (GVHD) and transplant-related mortality (TRM) after unrelated donor bone marrow transplant (BMT) we have investigated this agent in matched related donor (MRD) blood cell transplant (BCT). Of 82 adults receiving myeloablative conditioning and first MRD BCT between 01/99 and 05/02, 54 were matched for disease and stage with 54 patients (pts) not given ATG between 12/94 and 11/98. Median age was 42 (range 18 – 63) for ATG pts and 41 (range 22 – 54) for controls. Included in each group were 22 standard-risk pts (16 AML CR1, 6 ALL CR1), and 14 with high-risk acute leukemia of whom 12 had active AML (7 arising from MDS, 3 induction failures, 1 refractory, 1 relapse), and 2 ALL (1 refractory, 1 relapse). An additional 18 pts included 2 AML CR2, 1 ALL CR2, 2 CML AP/CP2, 2 MM, 8 relapsed/refractory NHL (2 mantle cell, 4 low, 1 intermediate, 1 high-grade) and 3 relapsed/refractory CLL. More control pts had conditioning incorporating TBI (32 vs 11, p<0.0001). All pts were given cyclosporine A and “short course” methotrexate with folinic acid. The study group received Thymoglobulin (Genzyme) (ATG) 4.5 mg/kg in divided doses over 3 consecutive days pretransplant finishing D0. ATG recipients were followed for 22 to 62 months (median 46) and control patients for 65–112 months (median 84). The actuarial incidence of acute GVHD grades II – IV was 25±6% in ATG recipients compared with 37±7% in the controls (p = ns). The figures for grade III – IV disease were 13±5% and 20±7% respectively (p = ns). Incidence of cGVHD at two years was 40±7% with ATG vs 97±3% without ATG (p < 0.0001), figures for extensive disease were 32±7% and 94±3% respectively (p < 0.0001). Sites of involvement by cGVHD were similar apart from gastrointestinal disease which was relatively more frequent in those ATG recipients who developed cGVHD (26% vs 5%, p = 0.03). Non-relapse mortality with and without ATG respectively was 4±3% vs 17±5% at 100 days and 9±4% vs 32±7% at 2 years (p = 0.004). Deaths were GVHD related in 3 ATG treated patients vs 13 controls (p=0.01). In the control group 2 year TRM was 26±8% in 32 TBI recipients compared with 42±11% in 22 patients not given TBI (p = ns). Relapse rate at 2 years was 36±7% for ATG recipients and 23±7% in controls (p = 0.06). Six of 21 relapsing patients in the ATG group survive having achieved another remission (4) or disease stabilization (2) after more treatment. One of 12 control patients who relapsed is currently alive in remission after a second BCT. Survival at 2 years was 70±6% in the patients given ATG vs. 54±7% in the controls (p=0.08) and progression-free survival was 57±7% vs 52±7% respectively. This study indicates that MRD BCT recipients given pretransplant ATG experience less cGVHD, less overall TRM and lower mortality related to both acute and chronic GVHD. These findings are not due to more control pts receiving TBI. Despite a trend to more relapse progression-free survival is unaffected, there is a trend to improved survival and presumably quality of life is generally better in ATG recipients because fewer of them have cGVHD.

Malignant Neoplasms in Long-Term Survivors of Bone Marrow Transplantation – Follow up

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 453-453 ◽  
Author(s):  
Bernhard Heilmeier ◽  
Nadine Stowasser ◽  
Gerard Socie ◽  
Maria Teresa van Lint ◽  
Andre Tichelli ◽  
...  
Keyword(s):  
Risk Factors ◽  
Graft Versus Host Disease ◽  
Cumulative Incidence ◽  
Marrow Transplantation ◽  
Malignant Neoplasms ◽  
Host Disease ◽  
Graft Versus Host ◽  
Long Term Survivors

Abstract Patients who receive allogeneic hematopoietic stem cell transplants have an increased risk for new malignancies because of several risk factors, including conditioning with radiation and chemotherapy, immune modulation, and malignant primary disease. The frequency of and risk factors for malignant neoplasm in long-term survivors should be assessed. A former analysis of the EBMT observing the 1036 patients of this study with a median observation time of 10.7 years showed older patient age and immunosuppressive treatment of chronic graft-versus-host disease as main risk factors for secondary malignancies. We have tried to determine the cumulative incidence and define potential risk factors for new malignancies in long-term survivors after marrow transplantation in a retrospective multi center follow-up study. This study of the Late Effects Working Party was performed with 45 transplantation centers cooperating in the European Cooperative Group for Blood and Marrow Transplantation. 1036 consecutive patients who underwent transplantation for leukemia, lymphoma, inborn diseases of the hematopoietic and immune systems, or severe aplastic anemia. Patients were transplanted before December 1985 and had survived more than 5 years. Reports on malignant neoplasms were evaluated, and the cumulative incidence was compared to that in the matched general population. Patient age and sex, primary disease and disease stage at transplantation, histocompatibility of the donor, conditioning regimen, type of prophylaxis of graft-versus-host disease, development of acute and chronic graft-versus-host disease, and treatment of chronic graft-versus-host disease were evaluated as variables. Univariate analysis was performed using the log rank test for the time until malignancy occurred; significant risk factors were studied in multivariate analysis (Cox regression). Median follow-up since transplantation was 17.9 years (range, 5 to 32.3 years). Malignant neoplasms were seen in 114 patients; the cumulative incidence was 4.0% at 10 years, 8.5% at 15 years, 14.0% at 20 years and 21.0% at 25 years. The rate of new malignant disease was 6-fold higher than that in an age-matched control population (P &lt;0.001). The most frequent malignant diseases were neoplasms of the skin (23 patients), breast (16 patients), thyroid gland (13 patients), oral cavity (12 patients), uterus including cervix (7 patients), and glial tissue (3 patients). Median ages of patients and their donors at the time of transplantation were 21 years for both groups (range 0.5 – 52 years). Follow up data were avaible in 636 patients, 100 patients were deceased at the time of prior analysis, 300 patients were lost to follow up. Compared with the analysis of the same cohort of patients 10 years ago, the most striking increase in secondary malignancies was seen in breast cancer (4-fold), thyroid cancer (3-fold) and neoplasms of the skin and oral cavity (2-fold). In multivariate analysis patient age above 30 years (hazard ratio 1.8, 95% CI 1.2 – 2.6; p=0.006), radiotherapy for conditioning (hr 2.3, CI 1.2 – 4.3; p=0.01) and immunosuppression (hr 1.5, CI 1.0 – 2.2; p=0.05) (in particular cyclosporine or methotrexate) were risk factors for new malignancies after hematopoietic stem cell transplantation. In conclusion longer followup shows the continuous increase of the cumulative incidence of secondary neoplasms in long-term survivors. With longer follow-up a shift in the risk factors occurs: Until 10–15 years after allogeneic transplantation immunosuppression is the major risk factor for new malignancies, whereas more than 15 years after transplantation radiotherapy becomes the dominant risk factor.

Genomic instability after allogeneic hematopoietic cell transplantation is frequent in oral mucosa, particularly in patients with a history of chronic graft-versus-host disease, and rare in nasal mucosa

Blood ◽  
2010 ◽  
Vol 116 (10) ◽  
pp. 1803-1806 ◽  
Author(s):  
Faisal M. Khan ◽  
Sarah Sy ◽  
Polly Louie ◽  
Alejandra Ugarte-Torres ◽  
Noureddine Berka ◽  
...  
Keyword(s):  
Genomic Instability ◽  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Host Disease ◽  
Graft Versus Host ◽  
Allogeneic Hct ◽  
History Of

Abstract Genomic instability (GI) of cells may lead to their malignant transformation. Carcinoma after hematopoietic cell transplantation (HCT) frequently involves some (eg, oral) but not other (eg, nasal) epithelia. We examined GI in oral and nasal mucosal specimens from 105 subjects, including short-term (7-98 days, n = 32) and long-term (4-22 yrs, n = 25) allogeneic HCT survivors. Controls included autologous HCT survivors (n = 11), patients treated with chemotherapy without HCT (n = 9) and healthy controls (n = 27). GI was detected in 60% oral versus only 4% nasal specimens in long-term allogeneic HCT survivors (P < .001). None of the controls showed GI. In oral specimens, GI was significantly associated with history of oral chronic graft-versus-host disease (cGVHD). We conclude that GI after HCT is frequent in some (oral) but rare in other (nasal) epithelia. This may explain why some epithelia (especially those involved with cGVHD) are prone to develop cancer.

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