[Economic costs of autologous hematopoietic progenitor cell transplantation].
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Costs and Cost Analysis↗
Biomedical subjects
E Carreras
Publications and source records attributed to E Carreras.
European results of matched unrelated donor bone marrow transplantation for chronic myeloid leukemia. Impact of HLA class II matching. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation.
We have retrospectively analyzed the impact of prognostic factors on the outcome of serologically HLA-matched unrelated donor (UD) BMT for CML. For this purpose, we have studied a cohort of 366 patients transplanted in Europe between January 1985 and December 1994. The median age of the 211 males and 155 females was 34 years; 238 patients were transplanted in first chronic phase and 116 in advanced phases. The median interval from diagnosis to BMT was 827 days. GVHD prophylaxis consisted of CsA and MTX in 202 patients or of ex vivo or in vivo T cell depletion (TCD) in 129. Recently, DNA-based methods of HLA-class II typing have been used to improve donor selection. We obtained complete data on 300 donor/recipient (D/R) pairs. Among them, we have identified three groups of patients, according to specific HLA-DRB1 D/R compatibility. Two hundred and ten patients received marrow from donors identical for HLA-DRB1 (group 1). Thirty-one patients received BMT from a donor who was HLA-DRB1 mismatched (group 2) and 59 from a donor in whom specific HLA-DRB1 typing was not performed (group 3). The overall survival was 37 +/- 3% at 2 years and leukemia-free survival (LFS) was 31 +/- 3%. In univariate analysis, five variables had a favorable effect on LFS: transplant in first chronic phase (P = 0.0001), time interval from diagnosis to BMT shorter than the median (P = 0.01), prophylaxis of GVHD without TCD (P + 0.001), acute GVHD < grade III (P = 0.0009) and HLA-DRB1 D/R matching (P = 0.0001). Transplant-related mortality (TRM) was 49 +/- 4% in group 1, 79 +/- 8% in group 2 and 80 +/- 6% in group 3 (P = 0.0001). Multivariate analysis confirmed that HLA-DRB1 matching was the most significant factor influencing survival (P = 0.04), LFS (P = 0.013) and TRM (P = 0.0049). From these results, we have defined a 'good risk' group, ie patients transplanted in first chronic phase, from an HLA-DRB1 matched donor, without TCD as prophylaxis against GVHD. The 2 year LFS, TRM and relapse incidence for this group were 51 +/- 5%, 47 +/- 5% and 2 +/- 2%, respectively. This suggests that the long-term outcome of patients with favorable prognostic features can approach that of patients transplanted from geno-identical siblings. In contrast, the TRM for patients transplanted for advanced disease from non HLA-DRB1-identical donors was 94%. Such a high TRM clearly indicates that UD BMT is not justifiable for these individuals.
Adolescent↗
Long-term results after allogeneic bone marrow transplantation for chronic myelogenous leukemia in chronic phase: a report from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation.
The purpose of this study was to determine the long-term results of allogeneic bone marrow transplantation for chronic myeloid leukemia. A retrospective analysis was carried out of the outcome of 373 consecutive transplants performed at 38 European institutions between 1980 and 1988 and reported to the registry of the European Group for Blood and Marrow Transplantation. All transplants were carried out for first chronic phase of chronic myelogenous leukemia using unmanipulated marow cells from HLA-identical sibling donors. The probability of survival and leukemia-free survival at 8 years were 54% (95% CI: 49-59) and 47% (95% CI: 41-52) respectively. The probabilities of developing acute GVHD (II-IV) at 100 days and chronic GVHD at 4 years after transplant were 47% (95% CI: 41-53) and 52% (95% CI: 46-58) respectively. The probabilities of transplant-related mortality and leukemic relapse 8 years after BMT were 41% (95% CI: 36-48) and 19% (95% CI: 14-25), respectively. Transplant within 12 months of diagnosis was associated with reduced transplant-related mortality (34 vs 45%, P = 0.013) and resulted in improved leukemia-free survival (52 vs 44%, P = 0.03). The probability of relapse was significantly reduced in patients who developed chronic GVHD (RR = 0.33, P = 0.004). The probability of relapse occurring more than 2 years after transplant was increased more than five-fold in patients transplanted from a male donor (RR = 5.5, P = 0.006). Sixty-seven patients in hematologic remission were studied for residual disease by two-step RT/PCR for BCR-ABL mRNA and 61 (91%) tested negative. We conclude that bone marrow transplantation can induce long-term survival in approximately one-half of CML patients; the majority of survivors have no evidence of residual leukemia cells when studied by molecular techniques. The probability of late relapse is increased with use of a male donor.
Adolescent↗
Successful autografting in chronic myelogenous leukaemia using Philadelphia negative blood progenitor cells mobilized with rHuG-CSF alone in a patient responding to alpha-interferon.
Several non-randomized studies suggest a possible survival advantage for chronic myelogenous leukaemia (CML) patients treated with an autologous stem-cell transplantation. Due to the possible contribution of residual leukaemic cells present in the inoculum in post-transplant relapse, several methods are being evaluated to eliminate neoplastic cells or to select 'normal' (Ph1 negative) progenitor cells for autografting. Recently, several studies have shown that Ph1 negative blood progenitor cells can be mobilized by rHuG-CSF alone in patients who have a cytogenetic response to alpha-interferon (IFN). We describe the first case, as far as we are aware, of a CML patient responding to IFN autografted by using blood progenitor cells collected by rHuG-CSF alone.
Adolescent↗
[Mobilization of Ph-negative hematopoietic stem cells using rhG-CSF in patients with chronic myeloid leukemia treated with interferon-alfa. Experience of the Clinic Hospital of Barcelona].
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Adolescent↗
[Allogeneic transplant of peripheral blood hematopoietic progenitors. Preliminary experience].
Myeloablative treatment followed by allogeneic transplantation of peripheral blood hemopoietic progenitors (alloPBT) was administered to five leukemia patients with a high risk of relapse. The donors subcutaneously received 10 micrograms/kg/day of G-CSF for five days. The tolerance to this medication was good with only complaints of moderate bone pain. Two of the peripheral blood donors had previously been bone marrow donors and both expressed their preference for the new method. The product of peripheral blood leukapheresis contained from one to four-fold more hemopoietic progenitors and approximately ten-fold more T-lymphocytes than the bone marrow received from normal donors. Prophylaxis of the graft versus host disease (GVHD) consisted of cyclosporine A (CsA) in one case and CsA and methotrexate (MTX) in four cases. The bone marrow implantation was verified with a neutrophil count of up to more than 0.5 x 10(9)/l between days 12 to 21 after transplant and a platelet count higher than 20 x 10(9)/l from days 11 to 41 after transplant. Acute GVHD was clinical grade O (two cases), II (one case) and grade III (two cases). In conclusion, alloPBT may be more safely and comfortably performed to the donor. This method may provide rapid recovery of neutrophils and platelets in patients without an apparent increase in the risk of developing graft versus host disease.
Adolescent↗
Study of hematopoietic chimerism following allogeneic peripheral blood stem cell transplantation using PCR amplification of short tandem repeats.
Allogeneic peripheral blood progenitor cell transplantation (PBPCT) is increasingly being used to treat hematologic malignancies. However, the capacity of PBPC to maintain long-term hematopoiesis remains controversial. To add further information to this issue we studied the chimeric status in 12 patients receiving G-CSF-mobilized PBPC from HLA-identical sibling donors. All patients were conditioned with cyclophosphamide and total body irradiation. In six cases the apheresis product was partially T-cell depleted by counterflow centrifugation (n = 2) or the immunoadsorption biotin-avidin method (n = 4). The follow-up was longer than 6 months in five patients, with a maximum of 420 days. Molecular analysis of the engraftment was done using PCR amplification of short tandem repeats. Apparent complete donor chimerism was detected in all patients between 28 and 420 days after engraftment. This study indicates that full short-term engraftment is achieved in patients receiving allogeneic G-CSF-mobilized PBPC from healthy donors and suggests that this might also be true for long-term engraftment.
Adult↗
Effects of G-CSF administration and peripheral blood progenitor cell collection in 20 healthy donors.
The effects of both daily G-CSF administration and subsequent peripheral blood progenitor cell collection (PBPCC) by apheresis on 20 healthy adult donors were studied. All received daily G-CSF (filgrastim) 10 micrograms/kg for 5-7 days by subcutaneous injection. G-CSF administration was well tolerated, except for moderate bone pain and headache. Peak values of CD34+ cells were observed on days 5 (n = 12) or 6 (n = 8). In all donors a significant increase in CD3+, CD4+, CD8+, CD19+, and NK cells was observed on day 5 in relation to the baseline values. CD4/CD8 lymphocyte ratio was unmodified by G-CSF. None of the donors required a central venous line for PBPCC. Immediately after PBPCC, a platelet count below 100 x 10(9)/1 was observed in nine of 18 cases, although in all donors platelet counts were over 100 x 10(9)/1 7 days later. A lymphocytopenia on day 7 following PBPCC was observed, although there was a tendency to achieve baseline values 30-90 days after the procedure. Mean numbers ( +/- SD) of collected cells x 10(6)/kg after a median of two (1-4) apheresis sessions and a median of 20 1 (10-40) processed were: CD34+ 5.5 ( +/- 2.3), CD3+ 326 ( +/- 105), CD4+ 207 ( +/- 64), CD8+ 164 ( +/- 60), CD19+ 88 ( +/- 32), and NK cells 32 ( +/- 14). We conclude that G-CSF administration to healthy donors is a well-tolerated procedure which is associated with (a) obtaining a high number of hematopoietic progenitor cells, and (b) a significant increase in T, B, and NK cells in donors' blood. In addition, PBPCC by apheresis results in a moderate, rapidly reversible, and clinically irrelevant thrombocytopenia and a moderate lymphocytopenia, which tends to resolve within 3 months following the procedure.
Adolescent↗
Undetected viral infection in diffuse alveolar damage associated with bone marrow transplantation.
To investigate the presence of nondiagnosed viral lung infections in patients who developed acute respiratory failure and diffuse pulmonary infiltrates after bone marrow transplantation (BMT), we studied necropsy-obtained lung specimens with features of diffuse alveolar damage (DAD) where no other specific histological diagnosis could be established, by using in situ hybridization and immunohistochemistry. Lung tissue samples obtained at necropsy from 19 patients (12 males and 7 females; 31 +/- 11 yrs mean +/- SD age) who died 56 +/- 36 days after BMT (12 allogeneic and 7 autologous), were studied retrospectively using specific deoxyribonucleic acid (DNA) probes to detect cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein-Barr virus (EBV), and adenovirus genomes. Tissue samples were additionally processed with antibodies to CMV and HSV antigens. Cells infected by CMV were detected by in situ hybridization in five cases, and by immunohistochemistry in four cases. Combining the results of both procedures, a previously undiagnosed CMV infection was found in six patients. All of them had received an allogeneic BMT and had developed graft-versus-host disease (GVHD). No evidence of cells infected by HSV, EBV, or adenovirus was found in any case. No viral infection was detected either in recipients of autologous marrow or in recipients of allogeneic BMT without GVHD. These results indicate that pulmonary cytomegalovirus infection not detected by conventional histological examinations may be present in patients with diffuse alveolar damage associated with bone marrow transplantation, especially in recipients of allogeneic marrow who develop graft-versus-host disease. Furthermore, the use of in situ hybridization and/or immunohistochemistry on pulmonary histology might improve the diagnosis of viral lung infections in patients receiving bone marrow transplantation.
Adolescent↗
Feasibility and results of bone marrow transplantation after remission induction and intensification chemotherapy in de novo acute myeloid leukemia. Catalan Group for Bone Marrow Transplantation.
PURPOSE: To evaluate prospectively the feasibility and results of bone marrow transplantation (BMT) after induction and intensification chemotherapy (CT) in patients with de novo acute myeloid leukemia (AML). PATIENTS AND METHODS: A total of 159 patients less than 51 years of age were treated. Induction CT consisted of daunorubicin 60 mg/m2 for 3 days, cytarabine (ARA-C) 100mg/m2 for 7 days, and etoposide 100 mg/m2 for 3 days. The first intensification therapy included mitoxantrone 10 mg/m2 for 3 days and ARA-C 1.2 g/m2 every 12 hours for 4 days. Amsacrine (100 or 150 mg/m2 for 3 days) and ARA-C (1.2 g/m2 every 12 hours for 2 or 4 days) were given as the second intensification therapy. Depending on the availability of a human leukocyte antigen (HLA)-identical sibling, the intention of treatment after CT was allogeneic BMT (allo-BMT) or autologous BMT (ABMT). RESULTS: Complete remission (CR) was obtained in 120 patients (75%) and partial remission (PR) in 11 (7%), while 15 patients (10%) were refractory and 13 (8%) died during induction. There was a trend for better leukemia-free survival (LFS) at 4 years for patients assigned to the ABMT group (50% +/- 6%) compared with the allo-BMT group (31% +/- 7%) (P = .08). This difference in LFS reached statistical significance when considering only transplanted patients (63% +/- 3% at 4 years after ABMT and 38% +/- 11% after allo-BMT, P = .02). The favorable results in patients who received ABMT (no toxic deaths and 37% +/- 7% probability of relapse at 4 years) contrast with the poor outcome of allografted patients (11 patients with transplant-related mortality). CONCLUSION: Our study reflects the difficulties in the completion of a therapeutic strategy that include BMT and suggests that intensification before BMT may be useful in the setting of ABMT, but this approach was associated with a high mortality rate in allo-BMT patients.
Acute Disease↗
Neurologic complications of autologous and allogeneic bone marrow transplantation in patients with leukemia: a comparative study.
We retrospectively evaluated the neurologic complications in 425 patients who underwent bone marrow transplant (BMT) (310 allogeneic, 115 autologous) for leukemia. Forty-six patients (11%) developed 47 central and three peripheral neurologic complications. The most common complications were cerebral hemorrhage (3.8%), metabolic encephalopathy (3%), and CNS infections (2%). All CNS infections occurred with allogeneic BMT. Eleven of 16 hemorrhages were subdural hematomas (69%), which were more frequent in autologous (8%) than in allogeneic (0.6%) BMT (p < 0.0001), and in patients with acute myelogenous leukemia (AML) (5%) than in the remaining leukemia patients (0.8%) (p = 0.013). Eight of 11 subdural hematomas occurred in AML patients receiving autologous BMT. When we compared patient-, disease-, and transplant-related characteristics of these patients with those without subdural hematoma, only platelet refractoriness correlated with an increased risk of subdural hematoma. The actuarial probability of developing subdural hematoma was 44% in patients with platelet-refractory disease and only 2.5% in the other patients (p < 0.0001). Ten patients with subdural hematoma did not have surgery and eight had significant clinical improvement associated with reduction or resolution of the hematoma, confirmed by CT scan in six patients. The subdural hematoma was the cause of death in only one patient. This study shows that the frequency of the different neurologic complications varies among types of BMT. Patients undergoing autologous BMT for AML with platelet refractoriness have an increased risk of subdural hematoma that may be treated with conservative measures.
Adolescent↗
Allogenic transplants with peripheral blood progenitor cells: a report of six cases.
Six patients with high-risk leukaemia received a myeloablative regimen followed by allogeneic peripheral blood progenitor cells transplantation (PBPCT) from an HLA-identical sibling donor. Donors received 10-12 mu g/kg/day of G-CSF subcutaneously for 5 days. G-CSF was well tolerated except for moderate bone pain. Peripheral blood leukapheresis product contained 1-4 times more CD34+ cells and approximately a log more of T lymphocytes than marrow grafts from normal donors. In the two first cases the leukapheresis product was partially depleted of T-lymphocytes using counterflow centrifugation. No growth-factors were administered post-transplant. GVHD prophylaxis consisted of cyclosporin A (CyA) in one case, and CyA and methotrexate in five cases. All patients engrafted with a neutrophil count reaching more than 0.5 x 10(9)/L by day 12 to 21 post-transplant and a platelet count above 20 x 10(9)/L by day 6 to 41 post-transplant. Acute GVHD was clinical grade 0 (n = 2), I (n = 1), II (n = I), grade III (n = I) and grade IV (n = 1). One case presents an extensive chronic cutaneous GVHD and is currently being treated with methylprednisolone. In conclusion, allogeneic transplants using PBPC can be performed safely. This may result in a rapid neutrophil and platelet engraftment, without an apparent increased risk of GVHD.
Acute Disease↗
Risk factors for hepatic veno-occlusive disease following HLA-identical sibling bone marrow transplants for leukemia.
The objective was to analyze risk factors for veno-occlusive disease of the liver (VOD) after allogeneic bone marrow transplantation. A cohort of 1717 recipients of HLA-identical sibling transplants for leukemia between 1988 and 1990, in 200 transplant teams worldwide, was studied. Patients were scored as having VOD if liver tissue showed typical histologic features or if they had all three of the following: (1) jaundice; (2) hepatomegaly and right upper quadrant abdominal pain; and (3) ascites and/or unexplained weight gain. Patients surviving more than 7 days post-transplant without histologic or any of these clinical features of VOD were classified as not having VOD. Patient-, disease- and transplant-related characteristics of 95 patients with VOD were compared to those of 1514 without VOD. Variables correlated with an increased risk of VOD were: pretransplant conditioning with busulfan and cyclophosphamide compared to total body radiation (relative risk (RR) 2.8; P < 0.0001), pretransplant fungal infection (RR 4.1; P = 0.011), pretransplant Karnofsky performance score < 90% (RR 1.9; P = 0.012), prior liver disease (RR 1.9; P = 0.05) and age > 20 years (RR 1.8; P = 0.05). In patients receiving radiation for conditioning, intravenous immune globulin decreased VOD risk (RR 0.26; P = 0.003). This analysis identifies risk factors for VOD. The data suggest several strategies for modifying transplant regimens to reduce VOD risk and which patients might be suitable subjects for trials of strategies of VOD prevention.
Acute Disease↗
Physical and psychosocial functioning of 117 survivors of bone marrow transplantation.
All surviving patients receiving a BMT at our center since 1976 were surveyed. Among 163 eligible patients, 145 were contacted and 117 (81%) responded. Their median follow-up was 55 months (range 6-154). The research instruments consisted of a demographic questionnaire, a current medical status form, a quality of life questionnaire (Nottingham Health Profile), and a screening instrument for psychiatric morbidity (the 28-item version of the General Health Questionnaire). Current functioning varied considerably across patients. They reported a high use of medical services (37%) and varied ongoing medical problems within the last 6 months. Most of them (93%) received Karnofsky ratings of 80 or above. Eight percent had current chronic GVHD. Comparing our patients' quality of life with a British reference population, most important differences were found for physical mobility, work, and sex life. Psychiatric morbidity in BMT survivors was higher than in a Spanish general population. Multivariate analyses revealed that a higher systemic symptomatology score, a lower educational level, an older age at BMT, a shorter time post-BMT, a female gender, and impotence were significant predictors of an impaired overall quality of life. Similarly, a higher systemic symptomatology score, a shorter time post-BMT, a higher number of major infections, and a lower educational level were predictive factors of a higher psychosocial distress. No differences in quality of life or psychosocial status between allogeneic and autologous transplants were found. Quality of life and psychosocial distress improved with the passage of time, specially within the first 3 years.
Adolescent↗
Allogeneic peripheral blood progenitor cell transplantation: analysis of short-term engraftment and acute GVHD incidence in 33 cases. allo-PBPCT Spanish Group.
The results of 33 allogeneic peripheral blood progenitor cells transplants (allo-PBPCT) in adult patients with hematologic malignancies were analyzed in a retrospective and multicenter study. In 21 of 33 cases (63%) the disease was refractory or in advanced stage and eight of the 33 cases (24%) were second transplants after relapse. Donors were treated with a median of 10 (4-16) micrograms/kg/day of rhG-CSF subcutaneously for 5-7 days. Three required a central venous line for harvesting. Peripheral blood leukapheresis product contained a median of 5.9 (1.8-13) 10(6)/kg CD34+ cells and a median of 309.5 (153-690) 10(6)/kg CD3+ cells. After a myeloablative regimen, all patients received PBPC from HLA-identical donors as the sole source of progenitor cells. Cyclosporin A (CsA) alone (n = 2), CsA and steroids (n = 9), and CsA and methotrexate (MTX) (n = 22) were used for GVHD prophylaxis. Growth factors post-transplant were given to 11 patients (33%). The median follow-up of the patients was 3 months. Actuarial median day for hemopoietic recovery was: neutrophils to >0.5 (>1) x 10(9)/l, day 14 (15); platelets to >20 (>50) x 10(9)/l, day 14 (21). The quantity of CD34+ cells infused did not significantly affect the engraftment kinetics, from a starting cutoff of 2.5 x 10(6)/kg. The speed of neutrophil recovery seemed to be influenced strongly by using rhG-CSF post-transplant and marginally by the type of GVHD prophylaxis. Actuarial probability for grade II-IV acute GVHD of the whole group was 37% (95% Cl, 20-54%).
Actuarial Analysis↗
Transvenous liver biopsies in marrow transplant recipients.
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Biopsy↗
Acute graft-versus-host disease: grade and outcome in patients with chronic myelogenous leukemia. Working Party Chronic Leukemia of the European Group for Blood and Marrow Transplantation.
Acute graft-versus-host disease (aGVHD) has been classified according to the Seattle criteria as grades 0, I, II, III, and IV for 20 years. The predictive value of such detailed grading is a matter of debate; publications usually report GVHD as present or absent or as absent, moderate, or severe. The Working Party Chronic Leukemia of the European Group for Bone Marrow Transplantation analyzed data of 1,294 patients transplanted from an allogeneic donor for chronic myelogenous leukemia (CML) in first chronic phase and tested the predictive value of aGVHD grading for the following end-points: day 100 mortality (D100M), transplant-related mortality (TRM), relapse incidence (RI), leukemia-free survival (LFS), and survival (SURV). aGVHD was absent in 462 patients (35.7%), grade I occurred in 335 (25.8%), grade II in 264 (20.5%), grade III in 110 (8.5%), and grade IV in 123 patients (9.5%). A total of 297 patients (23%) died within 100 days, 495 patients (38%) died of any TRM, and 100 patients (8%) died of relapse. D100M according to grades 0, I, II, III, and IV was 17%, 13%, 19%, 38%, and 70%, respectively, with significant difference between 0-II versus III-IV. TRM was 28%, 27%, 43%, 68%, and 92%, respectively, with a distinct separation between 0-I versus II-IV. RI showed a continuous decrease of 37%, 30%, 23%, 18%, and 8%, respectively, with increasing aGVHD. LFS was 45%, 51%, 44%, 26%, and 7%, respectively, and was best for patients with grade I aGVHD. This finding was also reflected in a better overall survival (60%, 64%, 53%, 30%, and 8%, respectively). The better LFS for grade I aGVHD patients compared with patients with grade 0 or II aGVHD was confirmed (P = .05) in a multivariate analysis. These data document the value of the present 5-point grading of aGVHD, ie, different outcome is observed depending on endpoint analyzed. Restricting information about aGVHD to presence or absence is not warranted.
Acute Disease↗
Whether methotrexate administration in graft-versus-host disease prophylaxis significantly delays the engraftment in allogeneic peripheral blood progenitor cell transplantation.
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Acute Disease↗